Professional Documents
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Stephen G. Waxman
Bridget Marie Flaherty Professor of Neurology
Neurobiology, and Pharmacology;
Director, Center for Neuroscience &
Regeneration/Neurorehabilitation Research
Yale University School of Medicine
New Haven, Connecticut
USA
Donald G. Stein
Asa G. Candler Professor
Department of Emergency Medicine
Emory University
Atlanta, Georgia
USA
Dick F. Swaab
Professor of Neurobiology
Medical Faculty, University of Amsterdam;
Leader Research team Neuropsychiatric Disorders
Netherlands Institute for Neuroscience
Amsterdam
The Netherlands
Howard L. Fields
Professor of Neurology
Endowed Chair in Pharmacology of Addiction
Director, Wheeler Center for the Neurobiology of Addiction
University of California
San Francisco, California
USA
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ISBN: 978-0-444-63327-9
ISSN: 0079-6123
v
vi Contributors
Seth A. Hays
The University of Texas at Dallas, School of Behavioral Brain Sciences, and
The University of Texas at Dallas, Texas Biomedical Device Center, Richardson,
TX, USA
Takao K. Hensch
FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical
School, Boston, and Center for Brain Science, Department of Molecular & Cellular
Biology, Harvard University, Cambridge, MA, USA
Nori Jacoby
Interdisciplinary Center for Neural Computation, The Hebrew University,
Jerusalem, and Music Department, Bar Ilan University, Ramat Gan, Israel
Michael P. Kilgard
The University of Texas at Dallas, School of Behavioral Brain Sciences, and
The University of Texas at Dallas, Texas Biomedical Device Center, Richardson,
TX, USA
Robert T. Knight
Department of Neurological Surgery, University of California—San Francisco, San
Francisco; Helen Wills Neuroscience Institute, and Department of Psychology,
University of California Berkeley, Berkeley, CA, USA
Iris-Tatjana Kolassa
Clinical & Biological Psychology, University of Ulm, Ulm, Germany
Bryan Kolb
Canadian Centre for Behavioural Neuroscience, University of Lethbridge,
Lethbridge, AB, Canada
Nina Kraus
Auditory Neuroscience Laboratory, Northwestern University; Communication
Sciences; Institute for Neuroscience; Neurobiology and Physiology, and
Otolaryngology, Evanston, IL, USA
Olivia Küster
Clinical & Biological Psychology, University of Ulm, Ulm, Germany
Hyunkyu Lee
Brain Plasticity Institute at Posit Science Corporation, San Francisco, CA, USA
Michael M. Merzenich
Brain Plasticity Institute at Posit Science Corporation, San Francisco, CA, USA
Jyoti Mishra
Departments of Neurology, Physiology and Psychiatry, University of California,
San Francisco, CA, USA
Arif Muhammad
Canadian Centre for Behavioural Neuroscience, University of Lethbridge,
Lethbridge, AB, Canada
Contributors vii
Richelle Mychasiuk
Canadian Centre for Behavioural Neuroscience, University of Lethbridge,
Lethbridge, AB, Canada
Ikue Nagakura
Picower Institute for Learning and Memory, Department of Brain and Cognitive
Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
Mor Nahum
Brain Plasticity Institute at Posit Science Corporation, San Francisco, and
Department of Optometry, University of California, Berkeley, CA, USA
Lindsay Oberman
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA, USA
Devon Oosting
Yale Center for Translational Developmental Neuroscience, Yale Child Study
Center, New Haven, CT, USA
Alvaro Pascual-Leone
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA, USA
Brian N. Pasley
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley,
CA, USA
Kevin A. Pelphrey
Yale Center for Translational Developmental Neuroscience, Yale Child Study
Center, New Haven, CT, USA
Robert L. Rennaker
The University of Texas at Dallas, School of Behavioral Brain Sciences;
The University of Texas at Dallas, Texas Biomedical Device Center, and The
University of Texas at Dallas, Erik Jonsson School of Engineering and Computer
Science, Richardson, TX, USA
Winfried Schlee
Clinical & Biological Psychology, University of Ulm, Ulm, Germany
Hiroki Sugihara
Picower Institute for Learning and Memory, Department of Brain and Cognitive
Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
Mriganka Sur
Picower Institute for Learning and Memory, Department of Brain and Cognitive
Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
Anne E. Takesian
FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical
School, Boston, MA, USA
viii Contributors
Paula Tallal
Rutgers, The State University of New Jersey, Center for Molecular and Behavioral
Neuroscience, Newark, NJ, USA
Edward Taub
Department of Psychology, University of Alabama at Birmingham, Birmingham,
AL, USA
Adam Tierney
Auditory Neuroscience Laboratory, Northwestern University, and Communication
Sciences, Evanston, IL, USA
Gitendra Uswatte
Department of Psychology, and Department of Physical Therapy, University of
Alabama at Birmingham, Birmingham, AL, USA
Thomas M. Van Vleet
Brain Plasticity Institute at Posit Science Corporation, San Francisco, and
Department of Veteran Affairs, Martinez, CA, USA
Pamela E. Ventola
Yale Center for Translational Developmental Neuroscience, Yale Child Study
Center, New Haven, CT, USA
Sophia Vinogradov
San Francisco Department of Veterans Affairs Medical Center, and Department of
Psychiatry, University of California, San Francisco, CA, USA
David A. Ziegler
Departments of Neurology, Physiology and Psychiatry, University of California,
San Francisco, CA, USA
Introduction
The science of neuroplasticity has resulted in a new level of understanding of the
neurological origins of human ability (Merzenich, 2013). From this science, the
“rules” governing learning and behavioral control have been further defined, in in-
creasingly complete and elaborate detail, in terms of the neurological processes that
underlie them. That scientific elucidation has led to the development of a new class
of therapeutic tools that exploit neuroplasticity to achieve strengthening or corrective
neurological changes in the brains of many classes of neurologically impaired indi-
viduals. A description of this science, the therapeutic strategies that stem from it, and
the initial application of this science to treat psychiatric and neurological clinical in-
dications is the subject of this volume.
It should be noted that the development and medical application of neuroplasticity-
based therapeutics is a result of a sea change in how we view development of the
physical brain and the personal evolution of our operational abilities across our life
spans. In the late nineteenth and early twentieth centuries, most neurologically focused
scientists viewed the brain as “plastic,” that is, physically modified by our experiences
in ways that accounted for the acquisition and improvement of skills and abilities
underlying our remarkable behavioral evolution across our passage through life (see
Boring, 1929; Hebb, 1949; James, 1890; Merzenich, 2013). Primarily in the middle
decades of the last century, a “locationist” perspective emerged, then predominated.
By that view, remodeling of brain connections was limited to an early “sensitive”
or “critical period”; by the end of that developmental epoch in childhood, neuronal
connections were believed to be “hardwired,” with all brain neurons and supporting
elements achieving their mature status. Postnatal changes in the physical brain were
commonly viewed as a continuation of embryological maturation (e.g., see Hubel
and Wiesel, 2005; Hensch, Chapter 1). In sum, most neuroscientists in this era believed
that the brain rapidly completed its development postnatally and from that point for-
ward was a hardwired, aplastic machine.
This perspective arose in part because studies of brain connectivity employed rel-
atively crude strategies for tracking destination-to-destination connectivity. The ma-
jor trunk lines connecting different brain areas were shown to be modifiable in a
limited perinatal epoch, but at older ages the rerouting of major connectional path-
ways was no longer achievable. Although we now know that large-scale, station-to-
station connectional strengthening and local network changes are occurring on a
large scale, throughout life, they could not have been recorded using the crude
methods used. Studies conducted in the most heavily studied models of developmen-
tal plasticity, the emergent “ocular-dominance columns” and “orientation columns”
of the primary visual cortex (V1; Brodmann area 17), and the “barrel field” repre-
senting the facial vibrissae in the primary somatosensory cortex (S1) of rodents, also
contributed greatly to the locationist model. In normal animals, competitive pro-
cesses in an early postnatal developmental period that had a defined beginning and
ending in early prenatal life resulted in a balanced, banded division of the primary
xxi
xxii Introduction
visual cortex’s layer-4 zones separately dominated by the two eyes (and, in later
studies, segregating and topographically ordering neurons preferring different visual
stimulus orientations) (see Hubel and Wiesel, 1977, 2005) and in the elegant vibrissa-
by-vibrissa representation of sensory facial whiskers in S1 (Woolsey and Wann,
1976). As a result of closing one eye or removing vibrissae through this narrow widow
of time in early development, the open eye or remaining vibrissae competitively (plas-
tically) captured an expanded cortical territory. This territorial competition between
active versus nonactive anatomical inputs for the domination of neurons in layer 4 in
V1 or S1 was shown to be strictly limited to a several-day-to several-week-long “crit-
ical” or “sensitive” period. While some simple manipulations could shorten or
lengthen this epoch of dramatic physical and functional remodeling, it was argued that
no significant changes on that scale could be recorded in animals of an older age. How-
ever, later studies have shown that the “anatomical maturation” of ocular-dominance
and orientation columns in V1 and of “barrels” in S1 is special to these cortical zones-
and that even with their hardening, large-scale local connectional remodeling can and
does occur as a result of neurobehavioral engagement on a large scale, even in these
least-plastic cortical areas, throughout adult life. The marked plasticity of the critical
period, and the transition to “adult” plasticity, is still a very important aspect of any
deep understanding of brain plasticity. Here, that important aspect of the development
of our neurobehavioral abilities is reviewed by two major, current contributors to it,
Drs. Hensch and Kolb (Chapters 1 and 2, respectively).
Collectively, these (and many other) studies led to the predominant conclusion, in
the neuroscience mainstream and in neurological and pediatric medicine, that the
brain was aplastic from early childhood onward. Brain connectivity and local brain
circuits and the constituent neurons within them “matured” in early life to achieve an
“adult” status that was inalterable, to the end of life. By this view, once “maturation”
was fully realized, the only aspect of change in play was age-related deterioration.
NEUROPLASTICITY
In parallel with studies that so strongly entrenched a doctrine of strict “locationism,”
other experiments conducted principally by physiological psychologists across this
same era supported the view that the brain was continuously plastic. These parallel
investigations recorded physical (primarily neuroanatomical) and neuronal response
changes in adult animals resulting from exposure of animals to “enriched environ-
ments,” or from training them using Pavlovian (classical) conditioning (Pavlov,
1927). In the former case, studies beginning with seminal experiments conducted
in the University of California laboratory of Mark Rosenzweig repeatedly showed
that the cortical mantle thickened as a result of environmental enrichment
(Diamond et al., 1964; Rosenzweig et al., 1962). Those thickness and volume
changes, recorded in both subcortical and cortical areas, were primarily accounted
for by dendritic, axonal arbor, and synapse elaboration that manifested large-scale
connectional remodeling of local networks.
Introduction xxiii
Chapters 7 (Tallal), 8 (Tierney and Kraus), and 10 (Ventola et al.) provide clear ex-
amples in their studies of neuroplasticity-based training designed to overcome devel-
opmental impairment and increase resilience to forestall the emergence of serious
psychiatric problems in child populations. Drs. Uswatte and Taub (Chapter 15), Pas-
ley and Knight (Chapter 17), and Van Vleet and DeGutis (Chapter 13) provide dif-
ferent compelling models showing how substantial recovery from brain injury and
stroke can result from neuroplasticity-based training. Other chapters in this volume
document plastic changes contributing to neurobehavioral strengthening and recov-
ery in adult patients with tinnitus (Hays et al., Chapter 11), schizophrenia (Biagianti
and Vinogradov, Chapter 12), in children with autism (Sur et al., Chapter 9; Ventola
et al., Chapter 10), and in aging populations (Fissler et al., Chapter 16; Mishra et al.,
Chapter 14; Nahum et al., Chapter 6). Chapters 11 (Hays et al.), Chapter 13 (Van
Vleet and DeGutis), and 4 (Oberman and Pascual-Leone) all describe important
strategies by which plasticity can be amplified by manipulating the modulatory con-
trol machinery governing learning-induced changes, either via training or by clini-
cally practical electrical stimulation of specific brain inputs or cortical areas.
Taken together, these different classes of investigation culminating in the prac-
tical demonstration of the therapeutic value of brain plasticity-based training have
established a sharp revision of our perspective about the brain. We now know that
it is continuously physically and functionally plastic; that this plasticity can be ap-
plied at any stage in life to drive positive strengthening and corrective change; and
that this science is now rapidly generating a new class of therapeutic treatments that
shall transform neurological and psychiatric medicine.
We hope that this collective report illustrates both the dramatic progress and now-
undeniable clinical possibilities of this exciting new subdiscipline of applied
neuroscience.
Michael M. Merzenich
Mor Nahum
Thomas M. Van Vleet
References
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complexity and training on brain chemistry and anatomy: a replication and extension. J.
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Thompson, R.F., 2005. In search of memory traces. Annu. Rev. Psychol. 56, 1–13.
de Villers-Sidani, E., Alzghoul, L., Zhou, X., Simpson, K.L., Lin, R.C., Merzenich, M.M.,
2010. Recovery of functional and structural age-related changes in the rat primary auditory
cortex with operant training. Proc. Natl. Acad. Sci. U. S. A. 107 (31), 13900–13905. http://
dx.doi.org/10.1073/pnas.1007885107.
de Villers-Sidani, E., Merzenich, M.M., 2011. Lifelong plasticity in the rat auditory cortex:
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Weinberger, N.M., Diamond, D.M., 1987. Physiological plasticity in auditory cortex: rapid
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CHAPTER
Balancing Plasticity/Stability
Across Brain Development
*
Anne E. Takesian*, Takao K. Hensch*,{,1
1
FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School,
Boston, MA, USA
{
Center for Brain Science, Department of Molecular & Cellular Biology, Harvard University,
Cambridge, MA, USA
1
Corresponding author: Tel.: 617-384-5882; Fax: 617-495-4038,
e-mail address: hensch@mcb.harvard.edu
Abstract
The potency of the environment to shape brain function changes dramatically across the lifespan.
Neural circuits exhibit profound plasticity during early life and are later stabilized. A focus on the
cellular and molecular bases of these developmental trajectories has begun to unravel mechanisms,
which control the onset and closure of such critical periods. Two important concepts have emerged
from the study of critical periods in the visual cortex: (1) excitatory–inhibitory circuit balance is a
trigger; and (2) molecular “brakes” limit adult plasticity. The onset of the critical period is deter-
mined by the maturation of specific GABA circuits. Targeting these circuits using pharmacological
or genetic approaches can trigger premature onset or induce a delay. These manipulations are so
powerful that animals of identical chronological age may be at the peak, before, or past their plastic
window. Thus, critical period timing per se is plastic. Conversely, one of the outcomes of normal
development is to stabilize the neural networks initially sculpted by experience. Rather than being
passively lost, the brain’s intrinsic potential for plasticity is actively dampened. This is demonstrated
by the late expression of brake-like factors, which reversibly limit excessive circuit rewiring beyond
a critical period. Interestingly, many of these plasticity regulators are found in the extracellular mi-
lieu. Understanding why so many regulators exist, how they interact and, ultimately, how to lift them
in noninvasive ways may hold the key to novel therapies and lifelong learning.
Keywords
critical period, GABA, parvalbumin, perineuronal net, lynx1, myelin, epigenetics
1 INTRODUCTION
Neural circuits are shaped by experience—the potency of which changes dynami-
cally across the lifespan. A focus on the cellular and molecular bases of these changes
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00001-1
© 2013 Elsevier B.V. All rights reserved.
3
4 CHAPTER 1 Mechanisms of Critical Period Plasticity
has begun to unravel mechanisms, which control the onset and closure of such “crit-
ical periods” for plasticity. This work in animal models offers new insight for tapping
into the brain’s potential to rewire both in the clinic and classroom. Two important
concepts have emerged (Fig. 1A):
FIGURE 1
Mechanisms controlling onset and closure of critical periods. (A) Precocious plasticity is
prevented during the precritical period by early factors, such as polysialic acid (PSA) on
neural cell adhesion molecule (NCAM), limiting PV circuit function. Critical period onset is
triggered once factors such as Otx2, BDNF, and NARP promote PV cell maturation, leading
to an optimal ratio of excitatory and inhibitory circuit activity. This triggers a sequence of
molecular events, including second messenger molecules (CaMKII, ERK), miR-132,
CREB, protein synthesis, protease (tPA) release, and homeostatic factors (TNFa), which
ultimately induce structural changes (spine pruning, regrowth, axonal rewiring). The critical
period then closes as molecular brakes gradually emerge to dampen plasticity, including
PNNs (CSPGs), Nogo receptor (NgR)—PirB signaling, Lynx1 and epigenetic changes
(HDAC).
Continued
1 Introduction 5
FIGURE 1—Cont’d
(B) Critical period triggers and brakes act at various sites within cortical microcircuits on
excitatory pyramidal cells (green), PV inhibitory cells (blue), and non-PV inhibitory cells
(gray). Many factors controlling plasticity are found within the extracellular matrix surrounding
PV cells.
It is increasingly clear that the cortex does not adhere to a simplified model of shift-
ing between plastic and nonplastic states. Instead, transitions in and out of critical
periods might reflect shifts in plasticity sites or mechanisms (Wang et al., 2012)
due to evolving molecular factors or changes in cortical activity patterns
(Toyoizumi et al., 2013). Here, we review recent findings primarily in the visual cor-
tex and discuss how these principles may apply more broadly.
6 CHAPTER 1 Mechanisms of Critical Period Plasticity
this principle has been extended to the cerebellum, where elimination of excessive
climbing fiber inputs onto Purkinje cells during an early critical period is regulated
by GABA levels (Nakayama et al., 2012).
Downstream of the E–I trigger, lies a sequence of structural changes which ulti-
mately execute circuit rewiring and its consolidation (Hensch, 2005). Regulated re-
lease of proteases such as tissue-type plasminogen activator (tPA) cleaves the
physical connections between pre- and postsynaptic partners to induce dendritic
spine motility (Mataga et al., 2004; Oray et al., 2004). This requires 2 days of mon-
ocular deprivation once GABA function is mature, and persists for about 1 week.
During this time, spines are lost and then gradually recover as tPA levels return
to baseline (Mataga et al., 2002, 2004).
Finally, the classical shrinkage of deprived eye axons and later sprouting of open
eye axons from the visual thalamus (LGN) is observed, requiring new protein syn-
thesis (Antonini and Stryker, 1993; Antonini et al., 1999; Taha and Stryker, 2002;
Trachtenberg and Stryker, 2001). Several factors have further been identified to cou-
ple E–I circuit balance to the physical rewiring process, such as protein kinases
(CaMKII, PKA, ERK; Di Cristo et al., 2001; Fischer et al., 2004; Taha et al.,
2002; Yang et al., 2005) and homeostatic regulators which ultimately strengthen
open eye connections (TNFa; Kaneko et al., 2008a).
Recently, an experience-dependent MicroRNA (miRNA), miR-132, has been
identified in mouse V1 that is important for ocular dominance plasticity. miRNAs
are small non-coding RNAs that regulate post-transcriptional gene expression.
Visual experience induces histone mark modifications at CRE loci close to the
miR-132 coding sequence (Tognini et al., 2011). Such modifications may underlie
the developmental upregulation of miR-132 that occurs after eye opening and per-
sists throughout the critical period. Manipulating miR-132 in vivo, by either increas-
ing levels with a double-stranded mimic (Tognini et al., 2011) or decreasing them
with a competitive inhibitor (sponge)-expressing lentivirus that sequesters endoge-
nous miR-132 (Mellios et al., 2011), completely blocks ocular dominance plasticity
during the critical period. miR-132 elevates the percentage of mushroom/stubby
spines, suggesting that it may play a role in the structural modifications that occur
during critical periods.
Notably, neither the release of tPA, pruning of spines, nor the rewiring of thala-
mocortical afferents occurs readily in adulthood. Rather than a simple loss of plas-
ticity machinery, recent evidence detailed below reveals that further rewiring is
actively gated in the mature brain. This notion of molecular “brakes” on plasticity
is already evident during the critical period. Spine maturation is normally slowed
down by cell adhesion molecules like Icam-5 (aka telencephalin; Matsuno et al.,
2006). Genetic deletion of Icam-5 accelerates tonotopic map changes in primary au-
ditory cortex (A1), effectively shortening the duration of the critical period (Barkat
et al., 2011). Windows of plasticity, therefore, arise between the maturation of an
optimal E–I balance controlling the machinery of synaptic pruning and a later set
of emerging brake-like factors, which persistently offset them (Fig. 1A).
8 CHAPTER 1 Mechanisms of Critical Period Plasticity
(Wen and Barth, 2011). Effects of deprivation within intracortical circuits have also
been shown to be age dependent in V1 by examining excitatory connections between
L4 pyramidal cells using paired recordings. Whereas deprivation during the precrit-
ical period increases the strength of these connections, the same manipulation during
the critical period leaves these synapses unaltered (Maffei et al., 2004, 2006). Such
age-dependent changes within these V1 intracortical networks may be due to devel-
opmentally-gated plasticity mechanisms. During the precritical period, LTD is read-
ily induced; however, upon critical period opening, LTD induction fails and is
replaced by LTP. This developmental switch in the sign of plasticity is prevented
by visual deprivation, suggesting that the recruitment of critical period plasticity
mechanisms is triggered by experience (Wang et al., 2012). In contrast, intracortical
excitatory plasticity within auditory cortex shows similar plasticity expression and
mechanisms throughout life (Blundon and Zakharenko, 2013).
In addition to synaptic changes, critical period plasticity may involve alterations
in intrinsic cell excitability. High-frequency firing in cortical pyramidal cells leads to
a long-lasting increase in evoked firing rates. This increased excitability depends
upon the recruitment of a signaling cascade involving PKA and calcium
(Cudmore and Turrigiano, 2004) that reduces a persistent potassium current
(IK-TEA; Nataraj et al., 2010). It has recently been suggested that such intrinsic plas-
ticity may play a role in critical periods. Cells acquire this form of plasticity at a post-
natal age that coincides with the critical period onset. However, monocular
deprivation during the critical period reduces cell excitability and increases IK-TEA
in monocular V1 (where competition from the other eye is not possible), presumably
by preventing this form of plasticity (Nataraj et al., 2010). Notably, monocular and
binocular visual cortices show distinct temporal profiles of intrinsic plasticity
expression and differential effects of deprivation (Nataraj and Turrigiano, 2011).
Immediate electrophysiological changes are followed by structural changes in
excitatory synapses and axonal projections. Across brain regions, spines are more
dynamic during early life than in adults (Alvarez and Sabatini, 2007). For example,
pruning of spines along pyramidal cell dendrites occurs in binocular V1 following
monocular deprivation during the critical period, but fails to be seen in adulthood
(Mataga et al., 2004; Oray et al., 2004). Parallel changes in thalamic axons are in-
duced by monocular deprivation, causing shrinkage of arbors arising from the closed
eye and expansion of arbors serving the open eye (Antonini and Stryker, 1993, 1996).
Structural changes may also occur in A1 during critical periods. The tonotopic crit-
ical period is associated with a rapid maturation of stubby spines (Barkat et al., 2011),
which are direct targets of thalamocortical axons (Richardson et al., 2009).
principal cells, less attention was directed toward plasticity of inhibition. However, a
barrage of recent studies has made it clear that both GABAergic synapses and
glutamatergic synapses onto inhibitory neurons exhibit robust activity-dependent
plasticity (Kullmann et al., 2012).
Across brain regions, developing inhibitory cells are susceptible to early life sen-
sory experience (Feldman, 2009; Hensch, 2005; Le Magueresse and Monyer, 2013;
Sanes and Kotak, 2011; Takesian et al., 2009). Partial or total loss of activity in sen-
sory cortex generally leads to downregulation of GABAergic transmission. Blocking
activity with tetrodotoxin leads to a decline in miniature inhibitory current ampli-
tudes in visual cortical cultures (Kilman et al., 2002). This is consistent with the ef-
fects of sensory deprivation: dark rearing from birth (Morales et al., 2002), whisker
trimming during a critical period (Jiao et al., 2006), and early hearing loss (Kotak
et al., 2008; Takesian et al., 2010) all reduce the amplitude of inhibitory currents
recorded in cortical excitatory cells.
Such inhibitory plasticity may be developmentally regulated. Deprivation before
or after the critical period does not cause the same readjustments in inhibitory func-
tion (Maffei et al., 2010; Morales et al., 2002; Takesian et al., 2012; Yazaki-
Sugiyama et al., 2009). Experience-dependent changes of inhibitory function are
consistent with anatomical alterations in the number of inhibitory synapses. For ex-
ample, in A1, developmental hearing loss leads to a significant reduction in the num-
ber of inhibitory terminals identified by GAD immunoreactivity (Sarro et al., 2008).
In somatosensory cortex, neonatal whisker trimming reduces inhibitory synapses by
52% (Sadaka et al., 2003). Early visual deprivation leads to a decline in the inhibitory
innervation of cortical pyramidal cell somata (Chattopadhyaya et al., 2004; Kreczko
et al., 2009). Thus, sensory experience has an impact on the establishment of cortical
inhibitory projections across brain regions.
Cortical inhibitory synapses are formed by a diverse group of GABAergic inter-
neurons (Markram et al., 2004) that respond differentially to early sensory experi-
ence. Early monocular deprivation induces a robust decrease in the strength of
inhibitory connections between fast-spiking, parvalbumin (PV)-expressing cells
and pyramidal cells; however, inhibitory connections formed by regular-spiking
nonpyramidal interneurons exhibit an opposite increase in strength (Maffei et al.,
2004). Similarly, dark rearing reduces the response evoked by laser photo-uncaging
of GABA onto somatic but not axonal receptors (Katagiri et al., 2007).
Early auditory deprivation also induces cell type-specific adjustments of cortical
inhibitory pathways. The PV cell pathway exhibits both a reduction of fast excitatory
drive onto PV neurons and a reduction of inhibitory drive from PV to pyramidal neu-
rons; whereas, the low-threshold spiking inhibitory pathway does not (Takesian
et al., 2010, 2013). The divergent effects of sensory experience on inhibitory cell
subtypes suggest that these cells may play diverse roles in critical period plasticity
(see Section 4).
Single-cell recordings in vivo reveal that PV cells in V1 undergo bidirectional
plasticity in response to monocular deprivation: an early paradoxical shift toward
the closed eye inputs after 3 days of deprivation and then a later shift toward the open
4 Critical Period Triggers and Brakes 11
eye inputs (Yazaki-Sugiyama et al., 2009). This change in bias can be explained by
applying STDP rules and offers a novel mechanism for the suppression of deprived
eye responses during the early phase of ocular dominance plasticity. Recently, even
faster dynamics have confirmed decreased PV cell firing rates already 1 day after
deprivation when excitatory cells remain unaffected (Kuhlman et al., 2013). The
degree to which PV cells are suppressed within hours after closing one eye of kittens
predicts the degree to which neighboring excitatory cells will undergo ocular
dominance plasticity (Aton et al., 2013).
A similar reduction of thalamocortical drive onto PV cells occurs in the somato-
sensory (Chittajallu and Isaac, 2010) and auditory cortices (Takesian et al., 2013)
following sensory deprivation, yielding decreased feed-forward inhibition onto ex-
citatory cells (Chittajallu and Isaac, 2010). Notably, a rapid reduction of inhibition in
response to nucleus basalis (NB)-tone pairing in mature A1 may be necessary for
adult receptive field plasticity (Froemke et al., 2007). In adult V1, recent evidence
suggests a structural loss of inhibitory synapses onto pyramidal neurons is an effec-
tive component of experience-induced plasticity with limited need for rearranging
the excitatory circuitry (Chen et al., 2011; van Versendaal et al., 2012). These studies
highlight the importance of understanding the transient sensory-evoked changes in
inhibition, which may be a fundamental mechanism of cortical plasticity.
and mediates Otx2 binding to PNNs. Infusing an RK peptide to block this specific
recognition significantly decreases Otx2 content of PV cells (Beurdeley et al., 2012).
Strikingly, this blockade of Otx2 transfer within cortex (Beurdeley et al., 2012) or
knockdown of Otx2 synthesis from the choroid plexus (Spatazza et al., 2013) reac-
tivates ocular dominance plasticity in mature V1, enabling recovery from amblyopia.
The CSPG sulfation patterns determine the condensation of CSPGs into tight
PNNs. Developmental increases in the carbon 4-/6-sulfation ratio of CSPGs occur
in parallel with critical period closure. This shift occurs in the somatosensory cortex
before the visual cortex, consistent with the staggered windows of plasticity between
these regions. Transgenic mice engineered to retain a low 4S/6S ratio exhibit deficits
in normal PNN formation and disrupted Otx2 transfer into PV cells (Miyata et al.,
2012). These mice, as well as those lacking the link protein that forms the PNN back-
bone (Carulli et al., 2010), then show extended plasticity into adulthood.
Together, these studies suggest that PNNs play a persistent role in controlling
plasticity by capturing Otx2 within PV cells. Otx2 regulation of plasticity can be
explained by a two-threshold model: the critical period is triggered as Otx2 is first
captured by PV cells, but then closes as maturing PNNs condense and permit even
higher levels of Otx2 to accumulate. Otx2 protein is present in PV cells across var-
ious brain regions outside of the visual cortex, including prefrontal, auditory, and
somatosensory cortices, as well as the basolateral amygdala and hippocampus, sug-
gesting that this factor may be a global regulator of PV cell maturation and associated
critical period plasticity (Spatazza et al., 2013).
4.4 Narp
In addition to Otx2, PNNs might also facilitate the accumulation of other molecules
that modulate PV cell function. For example, the build-up of neuronal activity-
regulated pentraxin (NARP) at excitatory synapses onto PV cells depends upon
the presence of PNNs. Narp is an activity-dependent protein that is secreted from
presynaptic excitatory neurons and regulates GluR4-containing AMPA receptor
levels in hippocampal PV cells. Genetic deletion of Narp prevents homeostatic upre-
gulation of excitatory input onto these PV cells during increased network activity
(Chang et al., 2010). In V1, Narp KO mice show reduced excitatory drive onto
PV cells, resulting in widespread hyperexcitability that is reminiscent of the imma-
ture cortex. Strikingly, these mice fail to express ocular dominance plasticity
throughout life, suggesting that Narp-dependent enhancement of excitatory drive
onto PV cells plays an important role in opening critical periods (Gu et al., 2013).
B complex (PirB; Atwal et al., 2008). Adult mice lacking NgR or its ligands (Nogo-
A/B) exhibit ocular dominance plasticity well beyond the critical period (McGee et al.,
2005), as do mice lacking functional PirB, revealed by a greater cortical induction
of the activity-regulated immediate-early-gene Arc upon open eye stimulation
(Syken et al., 2006).
NgR deletion also reopens a critical period for acoustic preference in mice. Ex-
posing WT juvenile mice to music reverses their innate preference to dwell in a silent
shelter. However, WT mice exposed as adults continue to show a preference for si-
lence, suggesting that acoustic preference is shaped during an early critical period.
However, mice lacking the gene for NgR maintain an open-ended critical period,
continuing to show shifts in acoustic preference into adulthood. This shift in prefer-
ence is associated with elevated activation of the medial prefrontal cortex, as
assessed by cFos expression (Yang et al., 2012). Therefore, NgRs may limit plastic-
ity within diverse circuits beyond primary sensory regions.
Limiting structural changes may be one mode of NgR action. Two photon in vivo
imaging in somatosensory cortex reveals increased dendritic spine turnover in adult
mice lacking NgR1, similar to levels observed in juvenile mice (Akbik et al., 2013).
These mutants also exhibit more robust extinction of freezing following fear condi-
tioning (Akbik et al., 2013), a behavior that is associated with spine turnover (Lai
et al., 2012). Interestingly, NgR is also expressed in PNN-ensheathed (presumably
PV) cells in mouse V1 (Ye and Miao, 2013) and has been found to act as a receptor
for CSPGs (Dickendesher et al, 2012). Dark rearing from birth prevents the dramatic
developmental increase in NgR within PNN-bearing cells. Thus, a potential cross-
talk between myelin factors and PNNs might stabilize synapses in adulthood,
restricting spine turnover on pyramidal cells as well as input onto aspiny PV cells.
Proper development of myelin depends upon the early environment. Social experi-
ence may regulate myelination in the prefrontal cortex during a developmental critical
period. Mouse pups socially isolated for 2 weeks after weaning showed deficits in PFC-
dependent behaviors, such as sociability and working memory. These deficits were ac-
companied by alterations in oligodendrocyte morphology and a reduced expression of
myelin genes, like MAG and myelin basic protein (Makinodan et al., 2012). A specific
ErbB3 signaling pathway is essential for this experience-dependent maturation of
oligodendrocytes and behavior (Makinodan et al., 2012). Notably, these changes occur
in a juvenile critical period overlapping that of acoustic preference behaviors in PFC
(Yang et al., 2012) and are not reversed by subsequent exposure to a social environment.
Thus, changes in myelin signaling may impact a range of critical periods, shaping di-
verse neural processes from basic sensory perception to higher order cognition.
may favor temporally coherent inputs for STDP, enhancing synaptic competition
(Hensch, 2005; Kuhlman et al., 2010).
A role for GABA in synaptic competition is elegantly demonstrated in a recent
study using two-color uncaging of glutamate and GABA onto rat hippocampal CA1
pyramidal cells. GABA uncaging induces spine shrinkage and elimination when
paired with a STDP protocol, which depends upon a signaling cascade involving
NMDA receptors, calcineurin, and actin depolymerizing factor (Hayama et al.,
2013). To examine heterosynaptic competition along a dendrite, neighboring spines
were stimulated: one spine with an LTP protocol to induce enlargement and a neigh-
boring spine with an LTD protocol to induce shrinkage. Remarkably, GABA induces
widespread spine shrinkage across the dendrite to neighboring spines, except for the
spine stimulated with the LTP protocol (Hayama et al., 2013). In this manner, GABA
promotes the competitive selection of individual spines along a dendrite, a process
that is elevated during critical periods of development (Hensch, 2005).
A second possible mechanism is that PV circuits may initiate a cascade of mo-
lecular events that create a permissive extracellular milieu for structural changes. For
example, altered inhibition may trigger a transient increase in proteolytic activity by
the tPA enzyme that degrades the extracellular matrix. tPA elevation during monoc-
ular deprivation underlies the spine pruning that is essential for ocular dominance
plasticity (Mataga et al., 2002, 2004; Oray et al., 2004). This deprivation-induced
increase in tPA, along with spine pruning, fails to occur in mature mice or those lack-
ing GAD65 (Mataga et al., 2002, 2004).
A third mechanism may involve the coordination of synchronized network activ-
ity. PV cells form networks that are interconnected by both chemical and electrical
synapses (Galarreta and Hestrin, 2002). Such networks show synchronous activity
and play an important role in generating gamma (30–100 Hz) rhythms in the cortex
and hippocampus (Cardin et al., 2009; Fuchs et al., 2007; Le Magueresse and Monyer,
2013; Sohal et al., 2009). During early postnatal life, emergence of the mature elec-
trophysiological properties of PV cells may lead to more coherent network activity of
higher gamma band frequencies (Doischer et al., 2008). It is currently unknown
whether such coordinated activity contributes to critical period plasticity.
A fourth theory is that inhibitory maturation enables the transition from precrit-
ical period to critical period plasticity by reducing spontaneous activity. This hypoth-
esis takes note of the fact that many forms of activity-dependent plasticity are equally
robust before and during the critical period. Therefore, critical period onset may not
reflect the engagement of new plasticity mechanisms, but rather when there is a shift
in the predominant learning cues from internally driven spontaneous activity to ex-
ternally driven sensory-evoked activity (Toyoizumi et al., 2013). Recordings from
awake-behaving mice confirm that critical period onset is accompanied by a reduc-
tion in the spontaneous-to-visual activity ratio. Therefore, shifts in spontaneous-to-
evoked ratios may be timed to match distinct critical periods across cortical regions,
representing a global mechanism governing developmental plasticity.
Finally, it is possible that inhibitory circuit plasticity itself underlies the changes
in cortical response properties that occur during critical periods (Aton et al., 2013;
18 CHAPTER 1 Mechanisms of Critical Period Plasticity
Gandhi et al., 2008; Kameyama et al, 2010; Kuhlman et al., 2013; Ma et al., 2013;
Yazaki-Sugiyama et al., 2009). By understanding how experience-dependent alter-
ations of the PV circuit influence cortical plasticity, we will gain insight into the con-
ditions that make the circuits of the brain most labile to experience.
6 IMPLICATIONS
6.1 Mental Disorders
The realization that critical period timing is itself plastic offers insight into neurode-
velopmental disorders. Targeting these molecular triggers and brakes may offer ther-
apeutic strategies to reinstate plasticity when it is inappropriately timed or fails to
close properly. In the postmortem schizophrenic brain, deficient myelination,
reduced perisomatic GABA synapses, and excessive spine pruning are commonly
observed (Insel, 2010). Moreover, PNNs are compromised in the amygdala and pre-
frontal cortex (Mauney et al., 2013; Pantazopoulos et al., 2010). These are hallmarks
of a brain whose plasticity brakes have not come on fully, suggesting that the failure
to stabilize circuits at least during the prodromal stage may contribute to psychoses.
Mapping the developmental trajectory of critical period plasticity may become an
important diagnostic and potential therapeutic tool.
Likewise, E–I imbalance, in particular of PV circuits, has been noted across au-
tism spectrum disorders (Gogolla et al., 2009b; Rubenstein and Merzenich, 2003),
suggesting a mis-timing of critical period onset. Due to the hierarchical nature of
critical periods, even a small jitter in the earliest plastic windows may have a cas-
cading effect on later stages to yield complex cognitive phenotypes. Mouse models
of autism are starting to confirm such timing errors, which encouragingly can be
reversed by rebalancing circuit function. For example, in the Mecp2-deficient mouse
model of Rett syndrome, PV circuits are paradoxically hyper-mature preceding a
regression of cortical function. In the visual cortex, this can be reversed by dark rear-
ing the animals or further genetic disruption of NMDA receptor 2A subunits (Durand
et al., 2012). PV cells are preferentially sensitive to NMDA receptor function, and
low-dose ketamine treatment restores neural activity across brain regions in the
Mecp2 KO mouse (Kron et al., 2012). Other mouse models of autism, such as Fragile
X (Harlow et al., 2010), may instead show an opposite, delayed onset of plasticity
due to impoverished PV cell networks (Gogolla et al., 2009b). This would require
an appropriately timed enhancement of GABA function for rescue.
Strikingly, this effect declines with later onset of deprivation, while early life rewiring
conversely interferes with later recovery of function if sensory input is restored (Lee
et al., 2001). Inhibitory transmission and plasticity mechanisms are typically kept in a
refractory state of development by exposure to darkness (Huang et al., 2010; Kang
et al., 2013) or rejuvenated by environmental enrichment (Sale et al., 2007; Scali
et al., 2012), suggesting an explanation for these effects in humans.
An elegant animal model exhibiting cross-modal development in response to al-
tered early sensory input is the barn owl (Keuroghlian and Knudsen, 2007). Multi-
modal integration of auditory and visual maps is essential for proper localization and
targeted flight toward an object or prey. The microsecond inter-aural time differ-
ences (ITD) of arriving sounds emitted from a source are superimposed onto the
visual receptive fields in the optic tectum. When misaligned during development,
such as with prism goggles, an aggressive period of rewiring ensues over the follow-
ing weeks to retune ITD preferences to match the displaced visual scene of individual
neurons. This prolonged process is ultimately consolidated by the physical growth of
axons in the direction of the newly acquired tuning.
Notably, there is a further targeted growth of novel inhibitory connections as well
to silence the unused representation in the tectum (Zheng and Knudsen, 1999). In this
manner, the barn owl remains free of confusion while retaining the capacity for mul-
tiple maps to coexist. Indeed, when confronted with an environment that was previ-
ously experienced during the critical period, adult barn owls exhibit rapid and broad
shifts of ITD maps even if they are incapable of acquiring new ones. Similar ability to
shift ocular dominance is observed in adult mice that previously experienced it ear-
lier in life (Hofer et al., 2006). Inhibitory connections in V1 are also strengthened by
monocular deprivation during the critical period (Maffei et al., 2006; Skangiel-
Kramska and Kossut, 1984).
Such dramatic anatomical changes are not observed in adult barn owls
(Linkenhoker et al., 2005). However, the clever use of incremental training procedures
does enable cumulative shifts in ITD tuning even in adult owls (Linkenhoker and
Knudsen, 2002). Moreover, raising them in an enriched environment, such as active
hunting rather than cage rearing (Brainard and Knudsen, 1998), extends the duration
of the critical period. Thus, as in mouse V1, critical period plasticity per se is plastic
and can be tapped noninvasively by engaging environments where perception for ac-
tion is needed. Such strategies have recently been employed in video-game training
approaches to rescue amblyopia in adult humans (Bavelier et al., 2010).
observations reveal the remarkable plasticity that is present throughout life in higher
associational brain areas and support the hierarchical nature of critical periods. In-
terestingly, PV circuit maturation follows this gradient along the visual pathway in
primates (Condé et al., 1996).
The adult brain does not process all inputs equally, but learns through experience
that certain events are more likely to occur than others. This Bayesian view further
attests to the importance of establishing early, firm foundations in order to generate
higher cognitive function. A gradient of developmental hard wiring ensures that sta-
ble primary inputs are passed on to generate more flexible associations in higher as-
sociational areas. For example, the expansion of multimodal receptive fields to
encompass tool use in adult monkey parietal cortex is accompanied by significant
anatomical growth of new axons as the animals gradually learn their use over several
weeks (Iriki, 2006; Quallo et al., 2009). Interestingly, such evolutionarily advanced
associational cortices are the least invested in CSPGs and are known to myelinate last
(Braak and Braak, 1996; Brückner et al, 1999). Thus, the cellular and molecular con-
straints that are present at earlier stages seem to be loosened or absent. Unfortunately,
this lifelong plasticity may not be without consequence, as these regions are prefer-
entially vulnerable to neurodegeneration with age (Mesulam, 1999). Critical period
closure may then also be considered neuroprotective.
7 FUTURE DIRECTIONS
Neural circuits are molded early in life to best represent the sensory input arriving at
that time, and then eventually become hard-wired. The use of a molecular/genetic
approach has revealed that specific GABA circuits orchestrate the functional and
structural rewiring of neural networks during “critical periods” of cortical plasticity,
which become limited in adulthood by the further expression of “brake-like” factors.
Ongoing work focuses on (1) confirming to what extent these mechanisms generalize
across brain regions, and (2) translating basic animal research into therapeutic strat-
egies for devastating neurological disorders in humans.
Given the limited environments in which most animals live, critical periods may
have evolved as an effective survival strategy for their relatively short lifespan. Crit-
ical period duration is in fact correlated with average life expectancy (e.g., in V1;
Berardi et al., 2000). However, in the past century, humans have enjoyed a rapid in-
crease in longevity and the ability to drastically change their surroundings on short
timescales. Perhaps our species is now acutely feeling the limitations of critical pe-
riod biology—not only as linguistic awkwardness when immersed in a foreign land,
but more seriously manifest as neuropsychiatric disorders of developmental origin.
In order to leverage these recent insights for lifelong learning, several conse-
quences should be explored further:
(1) Individual variability in critical period timing. Appreciating the powerful role of
E–I circuit balance (in particular, one class of GABA neuron) and its sensitivity
References 23
Acknowledgments
Supported by the Canadian Institute for Advanced Research (A. E. T., T. K. H.) and the Nancy
Lurie Marks Family Foundation (A. E. T.).
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CHAPTER
Abstract
The developing normal brain shows a remarkable capacity for plastic change in response to a
wide range of experiences including sensory and motor experience, psychoactive drugs,
parent–child relationships, peer relationships, stress, gonadal hormones, intestinal flora, diet,
and injury. The effects of injury vary with the precise age-at-injury, with the general result
being that injury during cell migration and neuronal maturation has a poor functional outcome,
whereas similar injury during synaptogenesis has a far better outcome. A variety of factors
influence functional outcome including the nature of the behavior in question and the age
at behavioral assessment as well as pre- and postinjury experiences. Here, we review the
phases of brain development, how factors influence brain, and behavioral development in both
the normal and perturbed brain, and propose mechanisms that may underlie these effects.
Keywords
brain development, prefrontal cortex, recovery of function, types of plasticity
1 INTRODUCTION
The development of the brain and behavior is guided not only by a basic genetic blue-
print but also by a wide range of experiences that shape the emerging brain. Brains
exposed to different environmental events such as sensory stimuli, stress, injury,
diet, drugs, and social relationships show a unique developmental trajectory. The
explosion of epigenetic studies in the past few years has also demonstrated that pre-
natal, and even preconceptual, experiences modify the organization of neural
networks. The goal of this review is to consider the manner in which the developing
brain can be modified by a range of prenatal and postnatal factors that can influence
how the brain responds to other experiences later in life. Our focus will be on the
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00005-9
© 2013 Elsevier B.V. All rights reserved.
35
36 CHAPTER 2 Brain Plasticity in the Developing Brain
neocortex of the rat because the majority of our knowledge regarding the modulation
of brain development is based on studies of neocortical development. We begin with
a brief review of the stages of brain development followed by a consideration of how
factors influence brain development and behavior.
Dorsomedial
neocor tex
2 days
D eo
n
or co
so r t
lat ex
er
3 days
al
Ventricular
LA
zone TE
Head
RA
LC
Ventrolateral
neocor tex
OR
TIC
Striatum
AL
STR
EAM
4 days
Reservoir
Pirifo
5 days
rm
co
Basal ?
r te
telencephalon
x
FIGURE 1
A summary figure showing cell migration in the anterior and middle parts of the developing
neocortex. Neurons generated in the ventricular zone (striped layer) migrate radially to
the dorsal cortical plate in 2 days, migrate laterally to the lateral cortical plate in 3 days and
to the ventrolateral cortical plate in 4 days. Some cells generated in the ventricular zone
migrate in the lateral cortical stream for up to 4 days and accumulate in the reservoir.
Some migrate into the pyriform cortex, whereas others migrate to as yet unidentified areas in
the basal telencephalon.
From Bayer and Altman (1991), with permission.
organization, have been implicated in disorders such as epilepsy, autism, and schizo-
phrenia among others (e.g., Mochida and Walsh, 2004). Furthermore, prenatal expo-
sure to drugs, such as diazepam (a GABA agonist), can alter migration patterns
(Cuzon et al., 2006).
Once the cells reach their appropriate locations, there is a rapid differentiation
into cell types and growth of dendrites and axons, a process that peaks at 7–10 days
postnatal (P). Synapse production begins once neurons mature with a rapid increase
beginning around P10. Micheva and Ceaulieu (1996) counted the number of GABA
and non-GABA cells and found that the cell volume peaks at about P30 in
38 CHAPTER 2 Brain Plasticity in the Developing Brain
somatosensory cortex. There was no further change in synapse number at P60, which
was the oldest age that the authors examined. It is well documented that in primates
there is an overproduction and later elimination of synapses (e.g., Huttenlocher,
1984; Petanjek et al., 2011), which in humans continues well into the third decade
of life. However, the possible overproduction and pruning of synapses is not well
studied in the rat. Although Micheva and Beaulieu did not see any change up to
P60 in somatosensory cortex, it is likely that at least some regions are shedding syn-
apses after P60. Van Eden et al. (1990) showed a decline in cortical thickness in pre-
frontal cortex from P60 to P90 and Vinish et al. (2013) showed a decrease in spine
density over a similar time period in medial prefrontal cortex (mPFC). These results
imply that a more systematic analysis of synaptic formation beyond weaning is re-
quired in the rat. The need for neuronal and synaptic pruning is likely related to the
uncertainty in the number of neurons that will reach their appropriate destinations
and the appropriateness of the connections that they form.
Three features of brain development are especially important in the current con-
text. First, the cells lining the subventricular zone include stem cells that remain ac-
tive throughout life. These stem cells can produce neural or glial progenitor cells that
are able to migrate into the cerebral white or gray matter in adulthood. The role of
these cells is poorly understood as they appear to remain quiescent for extended pe-
riods but can be activated to produce neurons or glia, especially after injury
(e.g., Kolb et al., 2007). Second, cells in the dentate gyrus of the hippocampus
are generated there throughout life, although this production declines with aging.
These cells appear to play a role in functions such as memory (e.g., Spanswick
and Sutherland, 2010). Third, dendrites and spines show remarkable plasticity in re-
sponse to experience and can form synapses within hours and possibly even minutes
after some experiences (e.g., Greenough and Chang, 1989). We discuss this in the
following section.
E18 Cortex develops with odd structure Kolb, Cioe, and Muirhead (1998)
Functional recovery
P1–6 Small brain, dendritic atrophy Kolb and Gibb (1993)
Poor functional outcome
P7–12 Dendrite and spine hypertrophy Kolb and Gibb (1993)
Cortical regrowth Kolb et al. (1998a,b)
Functional recovery
P25–35 Small brain Kolb and Whishaw (1981)
Partial recovery Nemati and Kolb (2012)
Dendritic hypertrophy
P55 No recovery Nemati and Kolb (2012)
Interestingly, complex housing can promote the development of the visual system
even in the absence of visual stimulation in animals housed in the dark (Bartoletti
et al., 2004). In fact, the latter study showed that the nonvisual effects of complex
housing could reverse the effects of raising animals in the dark. Although the mech-
anism of this effect is not known, one possibility is that pups raised in complex en-
vironments receive more maternal care (Sale et al., 2004), which is known to be a
strong factor in changing brain development (see below).
There are few studies of other cortical regions but one particular study showed
enhanced auditory functioning in rats raised in complex environments (Cai et al.,
2009). Early complex housing also alters the development of the parietal cortex.
Kolb et al. (2003a) placed weanling rats in complex environments and compared
the cortical changes to animals placed in the same environments as adults. Whereas
adult rats showed increased dendritic length and spine density after 90 days, juvenile
rats showed a similar increase in dendritic length but a decrease in spine density.
That is, the young animals showed a qualitatively different change in the distribution
of synapses on pyramidal neurons compared to the older animals. This result was
surprising, so the researchers wondered what earlier experience might do. In a
follow-up experiment, pregnant dams were placed in complex environments for
8 h a day beginning a week prior to their pregnancy and then throughout the 3-week
gestation. The brains of their offspring were examined in adulthood and showed a
decrease in dendritic length and an increase in spine density in parietal cortex
76
* * * *
74
Percent global methylation
72
Maternal enrichment
Paternal enrichment
70
Control
68
66
Hippocampus Frontal cortex
FIGURE 2
Average global DNA methylation levels in the hippocampus and frontal cortex of offspring
of males who were housed in complex environments for 28 days prior to mating with a
control female and females who were housed in complex environments for 7 days prior to
conception and for the duration of the pregnancy.
After Mychasiuk et al. (2012).
42 CHAPTER 2 Brain Plasticity in the Developing Brain
(Gibb, 2004). Thus, complex housing has qualitatively different effects at different
developmental ages. In a parallel study, Pena et al. (2009) found enduring effects of
complex housing from weaning until adulthood on pituitary–adrenal function, social
behavior, and cognitive behavior in adulthood.
Early complex housing has also been shown to attenuate the effects of exposure to
both methylphenidate and amphetamine later in life. Alvers et al. (2012) found a re-
duction in the self-administration of low, but not high, doses of methylphenidate,
whereas Li, Robinson, and Kolb (unpublished observations) found that lifetime com-
plex housing reduced amphetamine-induced behavioral sensitization as well as the
dendritic changes in mPFC and nucleus accumbens.
Finally, Mychasiuk et al. (2012b) placed male rats in complex environments for
28 days before mating the males with control females and compared the epigenetic
effects to maternal housing as in the earlier Gibb (2004) study (Fig. 2). The offspring
of the complex-environment housed males showed a significant decrease in gene
methylation, reflecting the increased expression of about 1000 genes. More surpris-
ing, however, was that the levels of gene expression changes were remarkably sim-
ilar to those observed in the offspring of females who were housed in similar
complex environments while pregnant.
In sum, complex housing during development has profound and enduring effects
on brain development and function. A key question relates to exactly what it is about
the complex housing experience that is altering brain development.
10
* * * *
9
Spines / 10 mm
Tactile
7 stimulation
Control
5
AID Amygdala Cg3-basilar Cg3-apical
FIGURE 3
The effects of neonatal tactile stimulation on spine density in mPFC (Cg3), OFC (AID), and
amygdala. Similar results were shown for dendritic length and branching.
After Richards et al. (2012).
4 Factors Influencing Brain Development in the Normal Brain 43
4.6 Stress
Although it has long been known that stress alters the brain and behavior of adults, it
is only recently that the role of perinatal stress has been appreciated. For example,
prenatal stress is now known to be a risk factor in the development of schizophrenia
attention-deficit hyperactivity disorder (ADHD), depression, and drug addiction
(Anda et al., 2006; van den Bergh and Marcoen, 2004). Studies with laboratory an-
imals have also shown that perinatal stress produces a wide range of behavioral ab-
normalities, including an elevated and prolonged stress response, impaired learning
4 Factors Influencing Brain Development in the Normal Brain 45
1. Dendritic branching
44 control c
a a
PS 21
41 MS
Branch order
Branch order
38 a,c 20
a,c
35
19
32
29 18
2. Excitatory synapses
a,c
# of synapses (x000)
# of synapses (x000)
2.6 a,c 1.6
a,c a b
2.3
1.5
2.0
1.7 1.4
3. Spine density
b,c
13
# of spines per 10 µm
12 a b
b,c
11
10 a,c
9 a
8
NAc AID Cg3B Cg3A
FIGURE 4
Mean ( SEM) total number of branch bifurcations (dendritic branching), number of
excitatory synapses, and spine density in Nucleus accumbens (NAc), OFC (AID), and mPFC
(Cg3Basilar field; Cg3Apical field). The mean branch order and number of synapses are in the
same scale shown on the right vertical axis for NAc, AID, and Cg3B but are in a different scale
for the Cg3A, which is on the left vertical axis. The letters “a” and “b” represent the
comparisons of the effects prenatal stress (PS) and maternal separation (MS), respectively,
compared to controls. The letter “c” represents comparisons between PS and MS
(ps <0.05 or better).
After Muhammad et al. (2012).
46 CHAPTER 2 Brain Plasticity in the Developing Brain
and memory, altered social and play behavior, increased anxiety, deficits in atten-
tion, and increased preference for alcohol (Weinstock, 2008).
Stress has long been known to alter the prefrontal cortex of adults (e.g., Liston
et al., 2006), but it has become apparent that the changes in the developing prefrontal
cortex are very different. For example, adult stress leads to a decrease in spine den-
sity in mPFC, but an increase in orbital cortex (Liston et al., 2006). In contrast,
Murmu et al. (2006) found that prenatal stress in degus from E16 to E21 produced
a decrease in both spine density and dendritic length in both mPFC and OFC in adult-
hood. Using a somewhat different paradigm, our laboratory exposed rats to gesta-
tional stress at E12–16 and found an increase in spine density in both mPFC and
OFC when the brains were examined at weaning or in adulthood (Muhammad
et al., 2012; Mychasiuk et al., 2012). We also compared the effects of prenatal stress
and postnatal maternal separation and found very different effects of the two
stressors (see Fig. 4). Thus, the effects of perinatal stress vary with the nature of
the stress, the precise embryonic age of the stress, and the age at which the brain
is examined.
One explanation for the difference between the Murmu results and our results
may be related to differences in epigenetic changes related to intensity of the stress.
Mychasiuk et al. (2012) found that mild gestational stress increased global methyl-
ation in prefrontal cortex (using a combined sample of mPFC and OFC), whereas
greater stress had the opposite effect. A whole-genome microarray showed that over
700 genes in the prefrontal cortex and hippocampus were differentially expressed
following prenatal stress, with most genes being downregulated.
The effects of gestational stress can be surprisingly subtle. Mychasiuk et al.
(2011a,b,c,d) housed pregnant females together for the duration of their pregnancies.
One rat received stress at E12–16 while the other (the bystander) did not. The off-
spring of both dams showed significant changes in methylation, gene expression, and
dendritic organization but the patterns of gene expression and dendritic changes were
qualitatively different (Mychasiuk et al., 2011a,b,c,d). It appears that both dams were
stressed but in different ways, which led to differential effects on the offspring brains.
One obvious question is to ask how prenatal stress affects the brain response to other
postnatal developmental experiences such as complex housing, tactile stimulation,
play, and so on.
in males than females, whereas the opposite is found in OFC (e.g., Kolb and Stewart,
1991). Furthermore, there are sex differences in the effects of many perinatal expe-
riences including gestational stress, complex housing, and injury (e.g., Kolb and
Stewart, 1995; Mychasiuk et al., 2011a,b,c,d).
4.9 Diet
There is an extensive literature on the effects of caloric- and/or protein-restricted
diets on brain and behavioral development (e.g., Lewis, 1990) but little research
on brain plasticity and restricted diets per se. Similarly, little is known about the
effects of enhanced diets on brain development. It is reasonable to predict that
brain development might be facilitated by vitamin and/or mineral supplements.
Dietary choline supplementation during the perinatal period leads to enhanced
spatial memory in various spatial navigation tasks (e.g., Meck and Williams,
2003; Tees and Mohammadi, 1999) and increases the levels of nerve growth fac-
tor in hippocampus and neocortex (e.g., Sandstrom et al., 2002). Halliwell and
Kolb (2003) did similar studies and found increased dendritic length in pyramidal
cells across the cerebral cortex and CA1 of the hippocampus with choline
supplementation.
Halliwell (2011) also studied the effects of a vitamin/mineral supplement to the
food of lactating rats. The same dietary supplement was reported to improve mood
and aggression in adults and adolescents with various disorders (Leung et al., 2011)
and reduced social withdrawal and anger in children with autism (Mehl-Madrona
et al., 2010). Analysis of the adult offspring of lactating rats fed the same supplement
found an increase in dendritic length in pyramidal neurons in mPFC and parietal
48 CHAPTER 2 Brain Plasticity in the Developing Brain
cortex but not in OFC. Furthermore, the same diet facilitated recovery from perinatal
mPFC lesions in rats.
There were, however, a series of studies by Sam Hicks in the 1950s in which ionizing
radiation was used to alter brain development, which in some cases led to surpris-
ingly good outcomes in spite of abnormal brains, provided there was no hydroceph-
alus (e.g., Hicks and D’Amato, 1961).
In sum, functional outcome is good if injury is during the latter part of neurogen-
esis (E18) but poor if it is during migration and the beginning of synaptogenesis. It is
better again after migration is done and synaptogenesis is burgeoning. We must note
that although we have focused on mPFC lesions, a similar pattern is seen after OFC,
motor cortex, posterior cingulate cortex, posterior parietal cortex, visual cortex, and
auditory cortex lesions (see review by Kolb et al., 2010). As might be expected, how-
ever, recovery is not equivalent across all regions, with posterior injury allowing less
recovery than anterior lesions.
Results from studies of cats and monkeys present a similar pattern, although the
dates vary because of differences in gestational rate. Villablanca and his colleagues
conducted an extensive series of studies on the behavior of cats with frontal or pre-
frontal injuries (e.g., Villablanca et al., 1993). Cats are an interesting comparison to
the rat and monkey because they are embryologically older than rats at birth with a
gestation period of about 65 days, but they are much younger at birth than monkeys.
Overall, Villablanca has found that although cats with prefrontal lesions shortly after
FIGURE 5
Photographs of brains of animals given midline frontal cortrex lersions on postnatal day 10
and then sacrificed on postoperative days 1, 3, 8, or 23. The lesion cavity is evident at day 1 but
by day 23 is only visible as a scar. By day 90 (not shown) the scar is no longer visible.
After Kolb et al. (1998a,b).
50 CHAPTER 2 Brain Plasticity in the Developing Brain
birth show good recovery relative to animals with lesions later in life, cats with pre-
natal lesions have severe behavioral impairments. Thus, the newborn cats appear
similar to P10 rats, whereas the prenatal cats are similar to P1–6 rats.
Monkeys are different again. They are born much older than rats, cats, or even
humans. Although Kennard reported better outcomes with infant lesions, as did
Harlow et al. (1964), the bulk of the later evidence largely by Goldman and col-
leagues did not report this (see reviews by Goldman, 1974; Goldman et al.,
1983). In contrast, however, prenatal lesions in monkeys allow substantial recovery
(Goldman and Galkin, 1978). The prenatal lesions are more similar in embryological
time to newborn cats and P10 rats. We can predict that if Goldman and Galkin had
made their prenatal lesions even earlier, the outcome would be similar to the prenatal
lesions in cats and lesions in newborn rats.
But what are the anatomical correlates of this recovery? Studies of unilateral mo-
tor cortex lesions (e.g., Hicks and D’Amato, 1975) found anomalous projections
from the intact hemisphere to the spinal cord, leading to the presumption that these
projections supported the functional recovery. They likely did. Similarly, there are
anomalous projections in the cat visual system that are associated with functional
recovery (Payne and Lomber, 2001) as well as extensive anomalous connections af-
ter neonatal hemidecortication in both rats and cats that are correlated with recovery.
But anomalous projections are also associated with poor outcomes. For example,
whereas rats with P1 mPFC lesions have significant abnormal connections, P10 an-
imals do not (Kolb et al., 1994a) but it is the P10 animals that show recovery, not the
rats with the rewired brain. There are several other types of anatomical changes that
support recovery in P10 rats. For example, there is widespread dendritic hypertrophy
of cortical pyramidal neurons as well as increased spine density. Furthermore,
there is evidence that for at least some types of P10 lesions, namely mPFC and pos-
terior cingulate, there is spontaneous neurogenesis that fills the lesion cavity (Fig. 5)
(Kolb et al., 1998a,b). The neurons that reform the frontal region establish connec-
tions with subcortical regions such as the striatum and have electrical activity that is
nearly normal (Driscoll et al., 2007). In the process of studying the apparent regen-
eration of the lost cortex, we discovered serendipitously that injections of the mitotic
marker, bromodeoxyuridine (BrdU), on E12–14 disrupt the postnatal activity of stem
cells (Kolb et al., 1999) and completely block the postinjury neurogenesis (Kolb
et al., 1998a,b, 2012). Not surprisingly there is no functional recovery if there is
no neurogenesis.
Finally, one other mechanism appears to be the survival of neurons in the thal-
amus that should have degenerated after the injuries. Normally, if cortical regions are
damaged, the thalamocortical projection cells die. This is true after neonatal visual
cortex lesions but not after prefrontal lesions. Cells in the dorsal medial thalamus,
which projects to prefrontal cortex, survive and form connections with remaining
frontal regions in both monkeys and rats (Goldman and Galkin, 1978) and rats
(Kolb and Nonneman, 1978), although this likely depends on the age at injury.
Van Eden et al. (1998) used unbiased stereology to count neurons after P6 mPFC
5 Brain Development After Early Brain Injury 51
lesions and found no difference from adults with similar lesions. This study should be
repeated with P10 lesions.
But age at assessment can work in reverse as well. When rats were given mPFC
lesions on P1 or P10 and then behaviorally tested at P22–25, both groups were
severely impaired relative to controls (Kolb and Gibb, 1993). However, when the
rats were tested at P52–55, the P10 rats were no longer impaired whereas the P1 rats
were. The recovery of the P10 rats was correlated with hypertrophy of cortical
pyramidal neurons that was not present in the brains of P25 animals. Thus, not only
can animals grow into deficits but out of them too.
Ipsilateral forelimb
80
Neonate
70
Adult
60
*
50
Hit percent
40
30
20
10
80
Contralateral forelimb
70
60
50
Hit percent
40
30
20
*
10
*
*
0
Control Small Med Large Hemi
FIGURE 6
Performance on a skilled reaching task by rats with adult or P5 unilateral lesions of
varying sizes (small, medium, and large) of the motor cortex or the entire neocortex
(hemidecorticate). Reaching was affected bilaterally, although more severely in the
contralateral forepaw and increased with lesion size. Rats with neonatal lesions showed
significantly better reaching with the contralateral paw than the adults.
After Whishaw and Kolb (1988).
6 Unilateral Versus Bilateral Injury 53
Table 4 Summary of the effects treatments on recovery from early brain injury
Treatment Outcome Basic reference
Behavioral therapy
Complex housing Improved behavior Kolb and Elliott (1987)
Tactile stimulation Improved behavior Kolb and Gibb (2010)
Chemical therapy
FGF-2 (P3 mPFC) Improved behavior Comeau et al. (2007a,b)
FGF-2 (P10 Motor) Nearly normal behavior Monfils et al. (2006)
Manipulation of gonadal Impaired recovery Kolb and Stewart (1995)
hormones
Prenatal experiences
FGF-2 Improved behavior Comeau et al. (2007a,b)
Tactile stimulation Improved behavior Gibb (2004)
Diazepam Improved behavior Kolb et al. (2008)
Fluoxetine Blocked recovery kolb et al. (2008)
Excessive exercise Reduced recovery Gibb (2004)
Gestational stress Blocked recovery Halliwell (2011)
54 CHAPTER 2 Brain Plasticity in the Developing Brain
FIGURE 7
Sagittal brain sections illustrating normal motor cortex (A), a P10 motor cortex lesion
(B), and a P10 motor cortex lesion and FGF-2 treatment (C). Compared to control cortex,
the FGF-2 stimulated regrowth does not illustrate a laminar distribution. Scale bars in
(A), (B), and (C) are 550 mm. Scale bars in (D) and (E) are 250 mm.
After Monfils et al. (2008).
performed in our laboratory, we gave FGF-2 and placed animals in complex housing
at weaning (Hastings, 2003). This combination made the animals worse, possibly
because the combined treatments raised FGF-2 to a toxic level.
8 SUMMARY
We have shown that the developing normal and injured brain shows a remarkable ca-
pacity for plastic change, both for better and worse. A key remaining question is how
this happens. Although we have not discussed it here one consistent observation in both
the normal and injured brain is a sex difference in experience-dependent plasticity. It is
not simply that one sex is more plastic but rather that there is a sexual dimorphism in
both the functional and anatomical effects of experiences. One clear example is the
effect of prenatal stress on gene expression (Mychasiuk et al., 2011b). Although there
are large changes in gene expression in the prefrontal cortex of each sex, there are few
overlapping gene expression changes. But both sexes show a marked alteration in den-
dritic organization, suggesting that there are multiple mechanisms underlying the ob-
served plastic changes. This is clearly grist for future studies.
Acknowledgments
This research was supported by NSERC of Canada grants to B. K. and R. G.
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CHAPTER
Cortical Plasticity,
Excitatory–Inhibitory
Balance, and Sensory
Perception
3
Ioana Carcea*,{,{, Robert C. Froemke*,{,{,1
*
Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and
Medicine at the Skirball Institute for Biomolecular Medicine, Department of Physiology and
Neuroscience, New York University School of Medicine, New York, NY, USA
{
Department of Otolaryngology, New York University School of Medicine, New York, NY, USA
{
Center for Neural Science, New York University, New York, NY, USA
1
Corresponding author: Tel.: þ1-212-263-4082; Fax: þ1-212-263-7760,
e-mail address: robert.froemke@med.nyu.edu
Abstract
Experience shapes the central nervous system throughout life. Structural and functional plas-
ticity confers a remarkable ability on the brain, allowing neural circuits to adequately adapt to
dynamic environments. This process can require selective adjustment of many excitatory and
inhibitory synapses in an organized manner, in such a way as to enhance representations of
behaviorally important sensory stimuli while preserving overall network excitability. The
rules and mechanisms that orchestrated these changes across different synapses and through-
out neuronal ensembles are beginning to be understood. Here, we review the evidence con-
necting synaptic plasticity to functional plasticity and perceptual learning, focusing on the
roles of various neuromodulatory systems in enabling plasticity of adult neural circuits. How-
ever, the challenge remains to appropriately leverage these systems and forms of plasticity to
persistently improve perceptual abilities and behavioral performance.
Keywords
neuromodulation, sensory cortex, synaptic plasticity, excitatory–inhibitory balance,
perception
1 INTRODUCTION
Phylogenetic evolution ensures that sensory perception matches the type of environ-
ment experienced by an organism, largely by applying genetically encoded filters at
the level of sensory organs (e.g., audible and visible spectra) (Darwin, 1859). In ad-
dition, throughout ontogenetic development, organisms refine and optimize their sen-
sory acuity by experience-dependent mechanisms. In mammals, these mechanisms can
be rapid and long-lasting, are more pronounced during development, and rely primar-
ily on structural and functional plasticity of neocortical circuits (de Villers-Sidani and
Merzenich, 2011; de Villers-Sidani et al., 2007; Hensch, 2005).
Unlike the developing neocortex and the adult association areas, primary sensory
and motor cortices become resistant to activity-induced synaptic modifications after
maturation (Hensch, 2005). This might explain the maintenance of stable perceptual
and motor representations throughout life, a requirement for easily and successfully
navigating familiar environments. However, demanding or novel behavioral tasks
can release sensory cortices from an implastic state in order to allow adaptive mod-
ifications to internal representations (Bao et al., 2004; Dahmen and King, 2007;
Elbert et al., 2002; Flor et al., 1995; Pantev et al., 2001; Polley et al., 2006; Sterr
et al., 1998). A growing number of studies have indicated that information about be-
havioral state is conveyed to the sensory cortex by a diverse array of neuromodula-
tors (Lee and Dan, 2012). Different neuromodulators have been shown to initiate and
control plasticity in the adult brain by coordinating modifications at selected sets of
neuronal synapses. The precise set of changes that occur to synaptic transmission and
network function depends on which neuromodulatory system or systems are acti-
vated and on the extent to which intracellular Ca2þ signaling and NMDA receptor
activation are engaged by different stimulus patterns.
Understanding the synaptic mechanisms by which experience shapes functional
sensory circuits during development and adulthood is crucial for designing therapeu-
tic interventions to correct inherited and acquired defects in sensory perception.
Here, we will summarize recent research describing circuit mechanisms by which
the adult neocortex encodes salient and relevant properties of the environment,
how neuromodulators control these mechanisms, and how they contribute to percep-
tual learning. We will emphasize remaining questions that concern the contribution
of different neuromodulators to cortical plasticity and the distinctions between adult
and developmental plasticity. Although we will focus on the auditory cortex and
acoustic behavioral tasks, references to other sensory cortical areas will be made.
receptive fields when the complement of excitatory and inhibitory synaptic inputs
matures, making them differentially sensitive to one or more attributes of the envi-
ronment (Dorrn et al., 2010; Hensch and Stryker, 2004; Hensch et al., 1998; Sun
et al., 2010). In vivo intracellular electrophysiological recordings during the presen-
tation of well-defined stimulus sets can estimate the relative contribution of excit-
atory and inhibitory inputs to the synaptic receptive field of a neuron (Fig. 1A).
Excitatory inputs are isolated by clamping the membrane potential of the patched
cortical neuron at 70 mV, the reversal potential for chloride, whereas inhibitory
inputs are measured by clamping the cell at the reversal potential for sodium
(0 mV). The ratio of excitatory to inhibitory currents is then calculated for each
stimulus presented.
During development, activity in sensory circuits gradually increases the correla-
tion of cortical excitatory and inhibitory receptive fields with respect to the stimulus
set. For example, in the developing auditory cortex, evoked excitation and inhibition
are unbalanced at the time hearing begins (around postnatal day 10 in rodents) but
A B
1.5
Normalized current
1.5
1.0
Spikes/tone
1.0
0.5
EPSCs 0.5
IPSCs
0.0 0.0
0.5 1 2 4 8 16 32 0.5 1 2 4 8 16 32
Frequency (kHz) Frequency (kHz)
32
16
2
1 mm
1 KHz
FIGURE 1
Information encoding in the primary auditory cortex. (A) Excitatory and inhibitory synaptic
tuning curves of an example neuron; triangle indicates the best frequency of this neuron
(reproduced from Froemke et al., 2007). (B) Example spiking tuning profile (reproduced from
Froemke et al., 2013). (C) Tonotopic map in the primary auditory cortex based on
characteristic frequency (reproduced from Kenet et al., 2007).
68 CHAPTER 3 Cortical Plasticity, Excitatory–Inhibitory Balance
FIGURE 2
Multidimensionality of behavioral states. Multiple neuromodulatory systems contribute in
various combinations to creating different behavioral states. To allow visualization, only three
dimensions and three behavioral states are shown here.
basal forebrain cells. Basal forebrain neurons also receive dopaminergic and seroto-
ninergic inputs (Eggermann et al., 2001; Sara and Bouret, 2012).
Neuromodulators act on distributed neural circuits to generate and store specific
patterns of activity within neuronal ensembles important for behavioral performance.
Blocking the activity of these neuromodulators systemically or specifically in their
sensory cortex terminal fields can prevent associative and perceptual learning
(Fletcher and Wilson, 2002; Kroon and Carobrez, 2009; Letzkus et al., 2011). Recent
in vitro data on the dynamics of adult sensory cortex plasticity uncovered both shared
and specific modes of action for different neuromodulators (Kruglikov and Rudy,
2008). Can different neuromodulator combinations orchestrate adaptive synaptic plas-
ticity in sensory cortices? In answering this question further, it is important to (1) study
the effects of different neuromodulatory systems separately and at different naturalistic
activation frequencies and intensities and (2) uncover the combinatorial actions of these
neuromodulators in ratios that would be relevant for behavioral states (Fig. 2). An ex-
ample of cooperative effects of two neuromodulators was described in the visual cortex,
where integrity of both noradrenergic and cholinergic fibers is required for proper de-
velopment of the ocular dominance columns (Bear and Singer, 1986). In this example,
the two neuromodulators have a compensatory type of interaction, but in other structures
or under different conditions, they might act synergistically or additively.
Next, we will discuss recent in vivo data on the role of the basal forebrain and
other neuromodulatory systems in inducing synaptic plasticity of sensory cortices.
hippocampus, horizontal limb of the diagonal band projecting to the olfactory bulb
and the piriform cortex, and nucleus basalis magnocellularis and substantia innomi-
nata complex projecting uniformly to the neocortex (Gritti et al., 2003, 2006; Manns
et al., 2001; Mesulam, 2004; Zaborszky, 2002; Zaborszky et al., 1999, 2005).
Nucleus basalis neurons have elevated spiking and bursting activity during wakeful-
ness and REM sleep and can also discharge in response to behaviorally relevant,
novel, or recent sensory stimuli (Cape and Jones, 2000; Duque et al., 2007; Kanai
and Szerb, 1965; Manns et al., 2000a,b; Szymusiak et al., 2000). Nucleus basalis neu-
rons can be electrically stimulated to induce acetylcholine release in their terminal
fields, which leads to desynchronization of cortical electrical activity and enhanced
cortical responsiveness to sensory stimuli (Metherate and Ashe, 1991, 1993). Pairing
of nucleus basalis stimulation with the presentation of a sensory stimulus results in
long-lasting cortical plasticity (Bakin and Weinberger, 1996; Froemke et al., 2007;
Kilgard and Merzenich, 1998b) (Fig. 3A–C). However, electrical stimulation is not
specific and can simultaneously activate other neuronal populations in the nucleus
basalis. Recently, specific stimulation of cholinergic neurons has been achieved
using optogenetics in mice and rats expressing channelrhodopsin-2 in neurons pos-
itive for choline acetyltransferase, an enzyme necessary for the biosynthesis of ace-
tylcholine (Kalmbach et al., 2012; Witten et al., 2010). Future studies using this
approach are necessary to parse out the contribution of identified cell types in the
basal forebrain to cortical activation, cortical plasticity, and behavior.
Acetylcholine release in the cortex can induce activation of pyramidal neurons
(Detari, 2000; Detari et al., 1999; Dringenberg and Vanderwolf, 1997; Linster and
Hasselmo, 2001). In the auditory cortex, two disinhibitory network mechanisms have
been described in vivo. One of them depends on activation of muscarinic receptors in
mid- and deep cortical layers, which results in a rapid depression of stimulus-evoked
inhibitory inputs on pyramidal neurons (Froemke et al., 2007; Metherate and Ashe,
1993). Most likely, this effect depends on decreased release of GABA from fast-
spiking interneurons that express presynaptic muscarinic M2 receptors (Kruglikov
and Rudy, 2008). In the adult rat primary auditory cortex, repeatedly pairing nucleus
basalis activation with the presentation of a pure tone of defined frequency and in-
tensity leads to a decrease in the inhibition evoked by the paired stimulus and there-
fore to a spectrally restricted increase in the excitatory–inhibitory ratio. At the same
time, activation of muscarinic receptors may extend the integration window for ex-
citatory inputs as is the case in the somatosensory cortex (Kruglikov and Rudy,
2008).Together, these muscarinic actions seem to permit Hebbian plasticity of excit-
atory inputs at the paired stimulus and a gradual retuning of the synaptic and spiking
receptive fields (Bakin and Weinberger, 1996; Froemke et al., 2007) (Fig. 3D and E).
At the population level, these modifications induce an overrepresentation of the
paired stimulus in the tonotopic map (Kilgard and Merzenich, 1998b).
The other mechanism by which cholinergic inputs trigger disinhibition in the au-
ditory cortex has been characterized in upper cortical layers by Letzkus et al. (2011).
Activation of nicotinic receptors on layer 1 inhibitory neurons leads to their robust
spiking, which results in the inhibition of their postsynaptic partners—layer 2–3
72 CHAPTER 3 Cortical Plasticity, Excitatory–Inhibitory Balance
A B
Prepairing NB pairing Postpairing
Tone (5–15 min) (2–5 min) (15+ min)
Rec Stim
Tone
A1
NB stimulation
250 ms, 100 Hz
EPSC
(-70 mV) 50 pA
25 ms
NB IPSC
(-20 mV)
C D E
NB pairing 200 NB pairing (atropine)
-90
0 50
50
0.5 1 2 4 8 16 32 -20 0 20 40 60 -20 0 20 40 60
Frequency (kHz)
Time (s) Time (s)
FIGURE 3
Synaptic modifications induced by nucleus basalis pairing. (A) Sagittal drawing through the
rodent brain shows the position of the stimulating electrode in the nucleus basalis (NB) and
the recording pipette in the primary auditory cortex (A1). The extensive cortical projections of
cholinergic neurons are shown. (B) The pairing procedure: pure tones of various frequencies
are played prepairing in a pseudorandomized order, and then one frequency is paired with
nucleus basalis stimulation and then the full set of tones is again played postpairing.
Representative excitatory and inhibitory synaptic currents evoked by the paired tone were
recorded pre- and postpairing in the same cell. (C) Retuning of the excitatory synaptic curve:
the response to the paired stimulus increases and the response to the original best stimulus
decreases. (D) Fast decrease in inhibition and slower increase in excitation evoked by the
paired stimulus during pairing. (E) Blocking muscarinic receptors in the auditory cortex
prevents the effects of pairing. Artwork in (A) by Jana Pivkova.
(Reproduced from Froemke et al. (2007) and Froemke et al. (2013)).
responses in the lateral geniculate nucleus and the visual cortex following nucleus
basalis stimulation.
In the somatosensory cortex, an additional interesting mechanism by which cho-
linergic innervation could induce plasticity has been reported by Takata, Mishima,
and colleagues. In an elegant study, they showed that acetylcholine released during
nucleus basalis stimulation activates muscarinic receptors on astrocytes, which in-
duces calcium waves in these cells and the subsequent release of D-serine. In turn,
D-serine binds neuronal NMDA receptors and, when this coincides with stimulus-
evoked activity, a long-lasting potentiation at the paired stimulus ensues (Takata
et al., 2011). Importantly, a similar role for astrocytes in cholinergic-mediated cor-
tical plasticity was later described in the visual cortex, indicating that this may be a
general mechanism to modify cortical synapses (Chen et al., 2012).
In the piriform cortex, acetylcholine released by neurons in the horizontal limb of
the diagonal band can also have immediate and long-lasting effects. Specifically,
acetylcholine depolarizes both pyramidal and inhibitory neurons, increasing their
spontaneous and stimulus-evoked spiking (Barkai and Hasselmo, 1994; Tseng and
Haberly, 1989a,b). Stimulation of basal forebrain projections initially suppresses in-
puts from association fibers but subsequently enhances these inputs, a phenomenon
thought to contribute to odor discrimination (Hasselmo and Barkai, 1995; Linster
and Hasselmo, 2001; Wilson, 2001). In the piriform cortex, an additional level of
regulation has been reported, where acetylcholine decreases both the adaptation
of pyramidal cell spiking to current injections and the afterhyperpolarization, thus
permitting Hebbian plasticity (Barkai and Hasselmo, 1994; Constanti and Sim,
1987; Saar et al., 2001).
Due to its possible role in the progression of Alzheimer’s disease, the basal fore-
brain generated a large interest in the scientific community and therefore provides a
model for exploring how neuromodulation and brain state affect processing and plas-
ticity in cortical circuits. We will next summarize some of the recent insights into
other neuromodulatory systems.
the anxiolytic effects of oxytocin (Knobloch et al., 2012; Viviani et al., 2011). It is
important to determine if similar actions underlie the tuning of responses to pup calls
in maternal auditory cortex.
structures like the striatum, the amygdala, and the prefrontal cortex are integrated in
the circuit remain to be determined.
Could sensory cortical plasticity contribute to this proposed progressive engage-
ment of downstream elements in the network? One possibility is that the convergent
synchronized activity of a larger pool of sensory cortical cells on a downstream post-
synaptic neuron will push the membrane potential of this neuron above the spike
threshold, thus generating a postsynaptic spike. Therefore, either classical long-term
potentiation or spike timing-dependent potentiation of synapses in structures post-
synaptically connected to sensory cortices becomes possible. As the cortical map re-
covers normal representation in time, synapses of neurons that continue to respond to
the paired stimulus maintain strong conductances with the postsynaptic cell, whereas
synapses of neurons that recover their original best stimulus will be depressed (e.g.,
through spike timing-dependent depression) (Fig. 4).
Two nonexclusive mechanisms are proposed here to answer the second
question—how do adult sensory circuits recover their original tuning following plas-
ticity? As discussed earlier, nucleus basalis pairing modifies corticocortical inputs
but spares the thalamocortical ones (Froemke et al., 2007). It is possible that these
FIGURE 4
Proposed model for how plasticity in the auditory cortex contributes to constructing memory
traces in downstream structures. Prepairing or prelearning, connections between presynaptic
neurons in the auditory cortex and postsynaptic downstream “effector” cells are weak (small
hexagons). Postpairing, the synchronous discharge of auditory neurons induced spiking of
the “effector” cell (purple color) and potentiation of synapses (large hexagons). Later on, after
auditory neurons recover their original tuning, most of the synapses are depressed but some
are still strong and capable to drive firing of the postsynaptic neuron.
5 Improving Perception by Manipulating Neuromodulation 79
spared inputs will slowly drive the network back to its original state. Alternatively or
concomitantly, synchronized spontaneous activity in cortical neurons can recalibrate
the network. In the auditory and visual cortices, neurons selectively responding to the
same stimulus feature have a higher probability to synchronize their spontaneous
activity or have a higher connectivity probability (Bao et al., 2003; Ko et al.,
2011). In their remarkable study, Ko, Hofer, and colleagues imaged calcium spikes
in the mouse visual cortex to identify neuronal ensembles responding to different
orientations and directions of the visual stimulus. They then prepared acute slices
from the imaged brains, recovered the recorded neurons, and used intracellular re-
cordings to measure the connectivity probability between pairs of cells. Neurons
had significantly higher probability of being connected to other neurons with similar
orientation and direction selectivity than to neurons with distinct selectivities. If
these properties are unaffected by nucleus basalis pairing, they can possibly drive
the sensory network back to its basal state.
Although we did not address here the role of neuromodulators during develop-
ment, this is an important issue for timing corrective or enhancing manipulations
of neuromodulatory centers. The majority of neuromodulators and neuromodulatory
receptors are abundantly expressed during development, including in primordial sen-
sory systems, when they can play important roles in cell fate determination, cell mi-
gration, axon growth and guidance, dendrite growth, and synapse formation
(Erzurumlu and Gaspar, 2012). Neuromodulation is also required for normal circuit
assembly and plasticity in developmental sensory cortices. For example, excess se-
rotonin resulting from knockout of the serotonin transporter in the mouse alters the
normal development of thalamocortical fibers in the somatosensory cortex and thus
prevents the formation of barrel fields (Persico et al., 2001). In the visual cortex, nor-
adrenergic and cholinergic fibers are required for normal ocular dominance plasticity
following developmental monocular deprivation (Bear and Singer, 1986).
In an elegant study, Lee and colleagues showed that similar level of control could
be achieved in the perceptual domain (Lee and Dan, 2012). They showed that driving
the activity of parvalbumin interneurons optogenetically sharpened the tuning of
orientation-selective cortical neurons in the visual cortex. At the behavioral level,
this approach improved stimulus discrimination as determined by significant in-
creases in the discriminability index. However, it is unclear whether these improve-
ments in behavior endure over time. Based on the electrophysiological data
presented here, we believe that control over the neuromodulatory systems can gen-
erate robust and long-lasting improvement in behavioral performance. Next, we will
describe supporting evidence that temporally discrete manipulations of the cholin-
ergic system can improve different dimensions of auditory perception.
The functions of the auditory system are to detect, identify, and localize stimuli
that might be behaviorally relevant. These capacities are acquired during develop-
ment as a result of synaptic maturation in the sensory circuit and can be improved
by training in adulthood (Sanes and Woolley, 2011). Lesions of cortical cholinergic
fibers can result in decreased detection, identification, and localization of stimuli and
impaired learning, storage, and flexible retrieval of sensory associations (Berger-
Sweeney et al., 2000; Butt et al., 2002; Cabrera et al., 2006; Leach et al., 2013;
Vale-Martinez et al., 2002).
Sensory detection refers to the capacity to perceive the presence of a signal. As a
general rule, detection degrades with age due to alterations at the level of sensory
organs. In human auditory perception, the cumulative effect of age on hearing is
called presbycusis. It becomes manifest around age 18, when detection of high-
frequency sounds (>16 kHz) becomes greatly reduced. In time, most frequencies,
including those in the speech range (300–3400 Hz), will be perceived only at high
intensities (Liu and Yan, 2007). Pathological conditions unrelated to normal aging
can negatively impact the detection ability of sensory systems. When developed dur-
ing childhood, such pathological conditions can interfere with the normal maturation
of neuronal circuits and thus can have long-lasting effects on sensory perception. It is
therefore important to design interventions for correcting and enhancing auditory
perception.
In our studies of rodent auditory perception, we trained rats to make a nose poke
in response to a particular tone frequency (target tone, 4 kHz) and to withhold from
nose poking in response to other frequencies (Fig. 5A). During training, the target
tone was played at high amplitude, 70 dB SPL. After the animal learned the associ-
ation, we varied the amplitude of the tones from soft (20 dB SPL) to loud (80 dB
SPL). Unsurprisingly, the hit rate increased with the amplitude of the target tone,
such that low-amplitude sounds were hardly perceptible under normal conditions.
When we paired the presentation of the target tone at low amplitudes (30–40 dB
SPL) with the stimulation of the basal forebrain for 5 min, the hit rate postpairing
increased for the paired amplitude, indicating increased detection (Fig. 5B). This im-
provement was not observed when muscarinic and NMDA receptors in the auditory
cortex were blocked during the pairing procedure. Thus, engaging the cholinergic
system can lead to improved auditory detection in adults. Importantly, this occurs
5 Improving Perception by Manipulating Neuromodulation 81
B NB + saline C Narrowband
100 100
Hits
Responses (%)
Responses (%)
50 Before 50
False
alarms After
0 0
20 40 60 80 2.8 3.4 4.0 4.8 5.7
Intensity (dB SPL) Frequency (kHz) at 70 dB SPL
FIGURE 5
Nucleus basalis pairing can improve behavioral performance on perceptual tasks. (A) The
go–no go operant conditioning task: rats learn to nose poke in response to 4 kHz tones and to
withhold from poking after other frequencies. (B) Before pairing (black lines), rats do not
detect low-intensity targets, but after pairing (red lines) a 4 kHz tone played at 30 dB SPL with
nucleus basalis pairing, detection at the paired intensity increases significantly. (C) Pairing of
the target tone with nucleus basalis stimulation improves recognition of the target tone from
foil tones that are at a small perceptual distance from each other (same color code as in b).
Reproduced from Froemke et al. (2013).
even when the pairing is done outside of the behavioral context or in anesthetized
rats, indicating that plasticity in the auditory system alone is sufficient to improve
detection and that modifications at sensory–motor circuits are not required for
achieving this (Froemke et al., 2013; Reed et al., 2011).
Perceptual identification or recognition can refer to two related concepts. First, it
refers to ability of a sensory system to identify a stimulus as a specific sensory object or
as part of such object. Secondly, it refers to the ability to discriminate or separate a
stimulus from background noise or from other coincidental stimuli. In the adult rat
primary auditory cortex, we and others found that changing synaptic weights by pair-
ing the presentation of the target tone with basal forebrain stimulation led to retuning
of spiking receptive fields and therefore to increased representation of the target stim-
ulus to the disadvantage of foil stimuli (Detari et al., 1999; Froemke et al., 2013). At the
behavioral level, the pairing resulted in improved recognition of the target tone from
82 CHAPTER 3 Cortical Plasticity, Excitatory–Inhibitory Balance
foil tones even when these were at short perceptual distance from each other (one-sixth
of an octave) and therefore hard to discriminate under normal conditions (Fig. 5C).
In the future, optogenetic and pharmacogenetic control of cholinergic and other
neuromodulatory fibers will offer a more specific control of cortical circuits and will
likely result in enduring enhancement of perception.
6 CONCLUSIONS
We summarized here recent data showing that experience, via the activation of neu-
romodulatory systems, can modify cortical neural circuits to improve perception. We
stress the following points:
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CHAPTER
Changes in Plasticity
Across the Lifespan: Cause
of Disease and Target
for Intervention
4
Lindsay Oberman, Alvaro Pascual-Leone1
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, USA
1
Corresponding author: Tel.: þ617-667-0203; Fax: þ617-975-5322
e-mail address: apleone@bidmc.harvard.edu
Abstract
We conceptualize brain plasticity as an intrinsic property of the nervous system enabling rapid
adaptation in response to changes in an organism’s internal and external environment. In pre-
natal and early postnatal development, plasticity allows for the formation of organized nervous
system circuitry and the establishment of functional networks. As the individual is exposed to
various sensory stimuli in the environment, brain plasticity allows for functional and structural
adaptation and underlies learning and memory. We argue that the mechanisms of plasticity
change over the lifespan with different slopes of change in different individuals. These
changes play a key role in the clinical phenotype of neurodevelopmental disorders like autism
and schizophrenia and neurodegenerative disorders such as Alzheimer’s disease. Altered plas-
ticity not only can trigger maladaptive cascades and can be the cause of deficits and disability
but also offers opportunities for novel therapeutic interventions. In this chapter, we discuss the
importance of brain plasticity across the lifespan and how neuroplasticity-based therapies offer
promise for disorders with otherwise limited effective treatment.
Keywords
plasticity, aging, lifespan, transcranial magnetic stimulation, autism spectrum disorders,
schizophrenia, Alzheimer’s disease
1 INTRODUCTION
Brain plasticity is an intrinsic property of the nervous system that allows an individ-
ual to adapt to a rapidly changing environment through strengthening, weakening,
pruning, or adding of synaptic connections and by promoting neurogenesis
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00016-3
© 2013 Elsevier B.V. All rights reserved.
91
92 CHAPTER 4 Changes in Plasticity Across the Lifespan
relatively spared in normal aging (Raz et al., 2004; Salat et al., 2004). Furthermore,
DTI can reveal structural changes in white matter structure (myelination) and con-
nectivity. For example, DTI has demonstrated that white matter connections, largely
in frontostriatal areas, have reduced myelination as age increases (Salat et al., 2005).
Functional MRI can reveal changes in activation of brain circuits across the age
span. One example of this is a reduction in prefrontal hemispheric asymmetry in
elderly individuals, referred to as the HAROLD (hemispheric asymmetry reduction
in older adults) model (Cabeza et al., 2002). According to the HAROLD model, the
older brain displays less localizable and more bilateral activation during certain cog-
nitive tasks. A second pattern is a shift in evoked neural activity from posterior to
anterior cortex, a model referred to by Davis et al. as PASA (posterior–anterior shift
in aging) (Davis et al., 2008). The PASA model posits that the aging brain is more
likely to recruit prefrontal, rather than occipitotemporal, cortex in the service of task
execution. In addition to life-span changes in task-related brain activation patterns,
resting-state fMRI is revealing age-related differences in the functional connectivity
across large-scale brain networks. One such large-scale brain functional network, the
default mode network (DMN), has been shown to undergo notable modifications
with advancing age in health and disease (Buckner et al., 2008). Older individuals
reportedly exhibit significantly lower DMN activity in the posterior cingulate and
a tendency toward lower activity in all other DMN regions as compared to younger
subjects (Koch et al., 2010). Functional connectivity within the DMN also seems to
be reduced in older adults (Grady et al., 2010). During performance of a working
memory task, the pattern of deactivation of the DMN also seems to be affected
by aging, with older individuals showing not only decreased connectivity but also
decreased ability to suppress low-frequency oscillations of the DMN (Sambataro
et al., 2010). Age-specific changes in activation and connectivity are also seen in
the task-positive network (TPN), though the functional significance of this remains
uncertain (Grady et al., 2010; Sambataro et al., 2010). During memory encoding and
recognition, age-related changes appear to occur mainly in the long-range connec-
tions with widespread reductions associated with aging in the frontotemporal and
temporoparietal regions and a few age-related increases in the posterior parietal re-
gions (Wang et al., 2010). During developmental years, children and young adults
appear to have similar patterns of functionally connected regions but with differences
in the size of functionally connected regions and in the strength of functional con-
nectivity between brain regions (Jolles et al., 2011).
Though useful for understanding the consequences of plasticity at the circuit
level, brain imaging does not directly probe plasticity but rather reveals its conse-
quences. Direct measures of circuit-level plasticity in humans in vivo can be obtained
using novel transcranial magnetic stimulation (TMS) paradigms (Huang et al., 2005;
Huerta and Volpe, 2009; Thickbroom, 2007; Ziemann, 2004). TMS is a noninvasive
way to induce, measure, and modify local and network plasticity, and a number of
experimental TMS measures of brain plasticity have been introduced. Single-pulse
TMS combined with EMG, EEG, fMRI, or other brain imaging methods can be
used to quantify cortical reactivity before and following a given intervention
94 CHAPTER 4 Changes in Plasticity Across the Lifespan
(Pascual-Leone et al., 2011). TMS can provide a controlled and quantifiable input
that can be matched across individuals of different ages. Comparison of TMS mea-
sures of cortical reactivity before and after an intervention may thus provide an index
of brain plasticity in response to said intervention. When the intervention itself in-
volves TMS (as in paired associative stimulation (PAS) or repetitive (r)TMS proto-
cols), it is possible to assess the efficacy of the mechanisms of plasticity in a defined
cortical brain region in humans in vivo. PAS builds on the Hebbian principle of spike
timing-dependent synaptic plasticity (Classen et al., 2004). In its most common form,
PAS involves repeated pairing of median nerve electric stimulation with timed TMS
over the contralateral primary motor cortex. In this form, PAS has been shown to
modulate the excitability of the motor system in either the positive (with an ISI of
25 ms) or negative (with an ISI of 10 ms) direction (Classen et al., 2004). Repetitive
TMS (rTMS) consists in the application of a train of TMS pulses of the same inten-
sity to a single brain area at a given frequency that can range from 1 to 20 or more
stimuli per second (Pascual-Leone et al., 1994). Such a train of rTMS can induce a
modulation of cortical excitability beyond the duration of the train itself. Depending
on the stimulation parameters, particularly frequency and pattern of stimulation, cor-
tical reactivity is potentiated or depressed (Pascual-Leone et al., 1994). In general, a
continuous train of lower frequencies of rTMS, in the1 Hz range, leads to a transient
suppression of excitability in the targeted cortical area, while bursts of high-
frequency stimulation ( 5 Hz) lead to a temporary increase in cortical reactivity
(Kobayashi and Pascual-Leone, 2003). Patterned bursting protocols have also been
developed that mimic paradigms used to assess synaptic plasticity in animal models
(Huang et al., 2005, 2008). Specifically, theta burst stimulation (TBS) involves ap-
plication of three bursts of 50 Hz rTMS repeated every 200 ms either continuously
for a total of 40 s or intermittently (every 8 s) for about 3 min. When applied to the
motor cortex, continuous (cTBS) and intermittent TBS (iTBS) were shown to result
in depression and potentiation of cortical reactivity as indexed through suppression
and facilitation of motor-evoked potentials (MEPs), respectively (Huang et al.,
2005). Results of animal and human studies are consistent with the notion that the
modulatory effects of TMS protocols on cortical reactivity reflect plasticity mech-
anisms (for review, see Cardenas-Morales et al., 2011).
pioneering work from Barnes (Barnes, 1979; Rosenzweig and Barnes, 2003) in the
late 1970s, have demonstrated an age-associated decline in synaptic plasticity in spe-
cific brain regions that correlates with neurocognitive impairments. In aged rodents,
thresholds for induction of the hippocampal LTP and LTD appear to increase and
decrease, respectively (Rosenzweig and Barnes, 2003). Once induced, LTP decays
faster in older rats, and this appears to be associated with a greater degree of forget-
fulness (Barnes and McNaughton, 1980; Kelly et al., 2006). Moreover, deficits in the
balance between LTP and LTD result in impaired learning and memory (Bliss, 2003;
Larson et al., 1986; Roman et al., 1987).
Direct evidence of this age-related decline in plasticity has also been shown in
humans through studies using TMS measures of plasticity. For example, in a
cross-sectional study of 36 healthy volunteers throughout the adult age span ranging
from 19 to 81 years, Freitas et al. (2011) found the duration and magnitude of corti-
cospinal excitability modulation by rTMS was inversely and significantly correlated
with age (Fig. 1). These data provide direct experimental evidence that, in humans,
LTD-like plasticity becomes increasingly less efficient with advancing age. Such de-
creasing plasticity in the motor cortex with advancing age may be associated with the
decrement of hand motor function (e.g., longer reaction time) observed during nor-
mal aging in both men and women (e.g., Carmeli et al., 2003) and to the age-related
deficits in motor learning (e.g., Brown et al., 2009). Such age-related changes in
plasticity are also linked to an individual’s cognitive ability and age-related
cognitive decline may be associated to them. An individual’s risk of age-related cog-
nitive decline (and ultimately the manifestation of symptoms of dementia) might
FIGURE 1
Schematic representation of the influence of aging on plasticity and cognitive ability.
3 Disease as a Manifestation of Aberrant Plasticity 97
then depend on the individual’s starting point and slopes of change in plasticity ef-
ficiency over the lifespan. Indeed, as will be further discussed later, studies in pa-
tients with early Alzheimer’s disease, the most common dementing illness, reveal
an abnormally suppressed efficacy of plasticity mechanisms (Freitas et al., 2011;
Koch et al., 2012).
FIGURE 2
(A) Schematic representation of how factors such as expression of certain genes, diseases,
brain injury, or behavior can impact the slope of change in plasticity across the lifespan. (B)
Schematic representation of how degree of plasticity and cognitive ability at any given time in
the lifespan is a consequence of both a given individual’s starting point and slopes of change.
and ultimately the cerebral cortex. This may represent a mechanism by which motor
and cognitive behaviors may be affected in ASD (Blatt and Fatemi, 2011). Other
genes coding for molecules such as neuroligins 3 and 4 that are implicated in synap-
togenesis (Jamain et al., 2003), SH3 and multiple ankyrin repeat domains 3
(SHANK3) that encodes a protein involved in dendritic development (Durand
et al., 2007) and c3orf58, sodium/hydrogen exchanger isoform 9 (NHE), and
protocadherin-10 (PCDH10) thought to be critically involved in synaptic develop-
ment and plasticity (Durand et al., 2007; Jamain et al., 2003; Morrow et al.,
2008) have all been identified as candidate genes that confer increased risk of
ASD (Cook, 2001; Lamb et al., 2000; Persico and Bourgeron, 2006).
In addition, single gene disorders associated with autism implicate proteins that
play important roles in synaptic plasticity. Among these are mutations in FMRP
(fragile X mental retardation protein), thought to contribute to the neurological def-
icits of fragile X syndrome by enhancing synaptic potentiation and favoring exag-
gerated LTD-like plasticity. Other examples include mutations in TSC1 and
TSC2 that cause tuberous sclerosis, in NF1 that cause neurofibromatosis, and in
phosphatase and tensin homolog (PTEN) that cause PTEN macrocephaly (Dolen
and Bear, 2009). Although the contributions of these genes and proteins to synaptic
plasticity are incompletely described, animal models of these human single gene syn-
dromic causes of autism predictably demonstrate aberrant synaptic plasticity. These
genetic findings have inspired others to propose that autism should be thought of as a
“synaptopathy” (Dolen and Bear, 2009) whereby proteins that are involved in syn-
aptic development and plasticity are affected.
Animal ASD models reveal abnormal plasticity mechanisms (reviewed in
Tordjman et al., 2007). For example, a recent study exploring the parvalbumin
(PV)-positive basket cell (a key player for critical period plasticity) in two animal
models of autism (valproic acid (VPA) and neuroligin 3 knockout models) found
a reduction or complete lack of PV cells in the parietal and occipital cortices
(Gogolla et al., 2009), suggesting a possible molecular mechanism underlying a pro-
posed hyperpotentiated state. When the microcircuits of these animals were inves-
tigated, their reactivity to stimulation, as measured by the number of spikes and
the number of postsynaptic potentials following stimulation, was nearly twice that
of wild-type animals (Rinaldi et al., 2008b). This hyperreactivity has been found
in multiple regions including the somatosensory cortex (Rinaldi et al., 2008b), pre-
frontal cortex (Rinaldi et al., 2008a), and amygdala (Markram et al., 2008), thus in-
dicating a widespread enhancement in reactivity of the cortical and subcortical
neurons. Synaptic responses have also been recorded in pyramidal neurons following
a Hebbian pairing stimulation protocol in these animals, and though the presynaptic
response was normal, the postsynaptic cell had a more than twofold increase in re-
sponse, indicating a state of hyperpotentiation (Rinaldi et al., 2007). Similarly, ab-
normal synaptic plasticity, specifically exaggerated LTD, has also been shown in
mouse models of genetic disorders associated with autism, namely, the FMR1-null
mouse (fragile X syndrome) and MECP2-null mouse (Rett syndrome) (Dani et al.,
2005; Huber et al., 2002).
100 CHAPTER 4 Changes in Plasticity Across the Lifespan
3.2 Schizophrenia
Schizophrenia is another neurodevelopmental disorder where researchers are begin-
ning to implicate neuroplasticity mechanisms in its pathophysiology. Several lines of
evidence suggest that the neurotransmitter mechanisms mediating plasticity in the
cortex are altered in schizophrenia. For example, both NMDA and GABA
receptor-mediated neurotransmission have been implicated in the pathophysiology
of schizophrenia. Blockade of NMDA receptor-mediated neurotransmission is asso-
ciated with worsening of psychosis in patients with schizophrenia (Krystal et al.,
2002) and produces behaviors in healthy subjects that are similar to the positive
and negative symptoms experienced by patients with schizophrenia (Krystal
et al., 1994). Moreover, neuroanatomical (Benes and Berretta, 2001) and neurophys-
iological evidence (Daskalakis et al., 2002; Fitzgerald et al., 2002; Freedman et al.,
2000) suggests that both a decrease and a disruption of cortical GABAergic inhib-
itory neurotransmission are associated with the pathophysiological findings of
schizophrenia. In addition, genetic and postmortem studies have implicated abnor-
malities in dysbindin, neuregulin, and reelin, proteins involved in synaptic plasticity,
as possible contributors to pathological findings in schizophrenia (Fatemi et al.,
2000; Stefansson et al., 2003; Straub et al., 2002; Weeber et al., 2002).
Behaviorally, patients with schizophrenia demonstrate an inability to learn com-
plex motor skills. For example, studies suggest that patients with schizophrenia show
impaired motor learning as indexed through the rotary pursuit task and a lack of in-
crease in blood oxygen level-dependent premotor activity following one week of
training as compared to healthy subjects (Kodama et al., 2001; Schwartz et al.,
1996). A recent TMS study confirms these findings showing that following motor
training, both medicated and unmedicated patients with schizophrenia demonstrated
significantly reduced motor reorganization as indexed by TMS-induced motor-
evoked potentials compared with healthy subjects (Daskalakis et al., 2008).
102 CHAPTER 4 Changes in Plasticity Across the Lifespan
Several other TMS studies have been conducted that also support plasticity
abnormalities in schizophrenia. Fitzgerald et al. (2004) showed reduced plastic brain
responses in medicated and unmedicated patients with schizophrenia. Specifically,
LTD-like suppression of cortical excitability was reduced in patients in response to a
single 15 min train of 1 Hz rTMS applied to the motor cortex, compared with a
healthy control group. Frantseva et al. (2008) conducted a study using PAS and dem-
onstrated that schizophrenia patients, compared with healthy subjects, showed def-
icits in MEP facilitation, indicating disrupted LTP-like plasticity, which appeared to
be associated with impaired motor skill learning. Finally, McClintock et al. (2011)
reported the findings of an rTMS study in a group of six first-episode patients with
schizophrenia who had 42% reduced duration of rTMS-induced aftereffects com-
pared with age- and gender-matched healthy control subjects, suggesting that corti-
comotor plasticity mechanisms are already abnormally reduced in early stages of
schizophrenia.
underlying these disorders and in doing so prevent the behavioral symptoms from
developing (Cramer et al., 2011).
The potential of rTMS to induce a long-lasting modulation of cortical excitabil-
ity and plasticity offers the possibility of its use for therapeutic purposes in neuro-
logical and psychological conditions thought to be a result of altered excitability or
plasticity of specific neural circuits. Studies examining behavioral performance
prior to and following rTMS have shown rTMS-induced changes in sensory
(Kosslyn et al., 1999), cognitive (Hilgetag et al., 2001; Mottaghy et al., 2002),
and affective processing (see Lee et al., 2012 for a review). Low-frequency rTMS
protocols and a specific type of theta burst stimulation (continuous, cTBS) gener-
ally induce lasting suppression of the excitability, while high-frequency rTMS and
a different type of theta burst stimulation (intermittent, iTBS) generally induce
lasting facilitation (Maeda et al., 2000). However, it should be noted that these
effects are state-dependent and there is significant intersubject and intrasubject
variability (Silvanto and Pascual-Leone, 2008). Thus, in order to induce the desired
effect, one must consider (1) the brain region, as even a small shift in the targeted
region may greatly affect the behavioral impact; (2) the current state of the
stimulated cortex as state-dependent changes have been observed; and (3) the
exact stimulation protocol being applied as opposite effects can be induced by even
slight modifications of the parameters. rTMS-based treatments are already being
proposed and tested in the aforementioned disorders.
its small sample size and lack of sham control condition. Following this initial study,
the same group conducted several follow-up studies with slightly larger samples. In
the first of these follow-up studies, the group replicated their previous finding of nor-
malized ERPs and a reduction in repetitive–ritualistic behaviors following the same
protocol (Sokhadze et al., 2010) in 13 individuals with ASD. In the second follow-up
study, the same investigators applied bilateral low-frequency TMS (1 Hz) once a
week for 12 weeks, with the first six treatments to the left DLPFC and the next
six to the right DLPFC in 16 patients with ASD. EEG and behavioral evaluations
pre- and post-rTMS revealed normalization of induced gamma activity and a reduc-
tion in both repetitive behaviors and irritability (Baruth et al., 2010). Using this same
protocol, this group explored error monitoring pre- and post-rTMS and found im-
provements in both ERP indices and behavioral measures of error monitoring follow-
ing 1 Hz stimulation once a week first to left then to right DLPFC in 20 individuals
with ASD (Sokhadze et al., 2012). Lastly, using a similar design, the same group also
recently published a paper describing improvements in ERP indices of visual proces-
sing, accuracy on a selective attention task, and behavioral measures of repetitive
behavior and irritability of 25 individuals with ASD following the 12-week protocol
described in the preceding text (Casanova et al., 2012). Again, these studies provide
promising preliminary data for the use of low-frequency rTMS to DLPFC for the
alleviation of aberrant behavior and physiological indices in ASD but are limited
by small sample size and unblinded designs. It is also unclear in the paradigms where
both left and right hemisphere were stimulated whether the effect was driven by one
or the other hemisphere or whether the effect was a result of the combination of both.
Finally, the behavioral improvements appear to be limited to repetitive behaviors,
irritability, and specific measures of attention.
We have also published reports showing improved performance on a behavioral
task in patients with ASD following a TMS protocol. Fecteau et al. (2011) conducted
a study where they applied a single session of low-frequency (1 Hz) rTMS to left and
right pars triangularis and pars opercularis (the two regions that comprise Broca’s
area) in 10 individuals with ASD and 10 matched neurotypical control participants
in a double-blind, pseudorandomized, sham-controlled study. Compared to the sham
condition, all 10 individuals with ASD showed reduced latency to name objects on
the Boston Naming Test following stimulation to the left pars triangularis (BA 45)
while 9/10 showed an increased latency following stimulation to the adjacent left
pars opercularis (BA44). The findings suggest that in individuals with ASD, left
BA45 exerts an abnormally excessive amount of inhibition on left BA44, thus inhi-
biting left BA45 results in a suppression of the excessive inhibitory control and a
behavioral improvement. However, this interpretation has yet to be empirically
tested. Findings from this study though short-lived, given the single-session design,
suggest that rTMS to BA45 may lead to improvements in language processing in
ASD and warrant further studies aimed at long-term improvements in this domain
(Fecteau et al., 2011). This study also demonstrated the importance of strict anatom-
ical targeting as the opposite result was found when the target region was in the
adjacent BA44 region.
106 CHAPTER 4 Changes in Plasticity Across the Lifespan
4.2 Schizophrenia
Studies using TMS and rTMS in schizophrenia have been more extensively reviewed
in Freitas et al. (2009). Initial rTMS studies focused on the clinical efficacy of rTMS
on the positive and negative symptoms of the disease, but overall, the results were
4 The Use of TMS as a Novel Treatment Strategy 107
inconsistent and effect sizes rather small. For positive symptoms (specifically audi-
tory hallucinations), the goal was to inhibit the left temporoparietal cortex via 1 Hz
rTMS, based on the rationale that increased temporal activity correlates with positive
symptoms (for a review, see Freitas et al., 2009). In regard to negative symptoms,
numerous studies attempted to increase the activity in the left prefrontal region
via high-frequency rTMS as this might regulate the dopamine release and ameliorate
the negative symptoms.
Among numerous studies that targeted the negative symptoms, only five random-
ized controlled trials assessed the cognitive effects (Fitzgerald et al., 2008; Mittrach
et al., 2010; Mogg et al., 2007; Novak et al., 2006; Schneider et al., 2008). Mogg et al.
applied 10 consecutive daily sessions of 10 Hz rTMS to the left DLPFC and reported
a significant improvement in verbal learning in a series of patients with prominent
negative symptoms. In addition, two intraindividual crossover studies applied 10 ses-
sions of 20 Hz rTMS to the left DLPFC (Huber et al., 2003; Rollnik et al., 2000), and
though initially failed to detect a significant effect of rTMS on cognition (Rollnik
et al., 2000), when analyzed stratifying for gender, an improvement of visuomotor
tracking was observed in females (Huber et al., 2003).
Further studies seem warranted, specifically considering the encouraging find-
ings of open, proof-of-principle trials. For example, Cohen et al. (1999) stimulated
the PFC bilaterally with 20 Hz using a double-cone coil, a special coil considered to
stimulate deeper brain regions compared to standard figure-of-eight coil. Following
10 sessions of rTMS, the authors reported an improvement in visual memory. In a
recent study, Levkovitz et al. (2011) performed bilateral deeper stimulation of the
prefrontal cortex (L > R) using an H-coil and reported improvement in executive
functions, spatial working memory, attention, and rapid visual information proces-
sing. It seems that indeed the use of special TMS coils that enable direct stimulation
of deeper brain structures may be important in this setting. Studies using more con-
ventional TMS coils with limited depth penetrance have yielded less encouraging
results. For example, Sachdev et al. applied 20 sessions of 20 Hz rTMS to the left
DLPFC and found no improvement in cognitive functions (Sachdev et al., 2005).
Another promising approach in schizophrenia appears to be the targeting of
nodes of identified neural networks. Specifically, targeting cerebellar vermis to have
an impact of distributed bihemispheric neural networks is an intriguing notion
(Demirtas-Tatlidede et al., 2011). Schutter et al. (2003) reported early promising re-
sults targeting the cerebellar vermis. In a carefully designed open-safety study, we
embraced this novel approach and targeted the cerebellar vermis using an intermit-
tent TBS paradigm (Demirtas-Tatlidede et al., 2010). Following 10 sessions of stim-
ulation in 5 days (twice per day with a minimum gap of 4 h), we observed an
improvement in working memory and visual learning domains while no significant
decline was found. The direction of improvement in 70% of the neuropsychological
variables suggests a trend toward improvement in cognition. A double-blind, sham-
controlled phase II study is currently underway.
Another important consideration in this setting is the possibility of employ-
ing stimulation paradigms tuned to specific brain oscillations and targeting
108 CHAPTER 4 Changes in Plasticity Across the Lifespan
bihemispheric structures. The combination of TMS with EEG and specifically EEG-
gated TMS protocols enables such approaches (Shafi et al., 2012). For example,
rTMS can lower the excessive gamma oscillatory activity found in patients with
schizophrenia when applied at appropriate stimulation frequency bilaterally over
the DLPFC (Barr et al., 2011). This was associated with significant improvements
in working memory.
cholinesterase inhibitor therapy (stable dose for 2 months). Seven patients were
randomized to TMS-CR while eight were double sham controls. They followed ex-
actly the same protocol as our pilot study and found a mean improvement on the
ADAS-cog of 3.8 points in the active TMS-CR group, as compared with a mean im-
provement of 0.5 in the control group (p ¼ 0.04, mean difference in ADAS-cog be-
tween groups at endpoint of 4.3 points). There was also a significant improvement in
the average CGIC score in the real versus sham groups (p < 0.05): the CGIC is a 7-
point “global change” rating in which 4 ¼ no change and 3, 2, and 1 or 5, 6, and 7 is
“minimal,” “moderate,” and “marked” improvement or worsening, respectively. The
real TMS-CR group showed an average change rating of 3.6 and the sham group an
average change rating of 4.3, representing slight average improvement and worsen-
ing, respectively. The difference between means, in this case 0.7, is what represents
the degree of difference between treatments in global change. This mean difference
compares favorably to the one encountered in trials of marketed treatments, which
has been in the 0.3–0.4 range. There were no reported side effects of treatment. A
double-blind, multiple site European study is under way to confirm these promising
findings.
We have recently completed an investigator-initiated randomized, double-blind
clinical trial in 12 patients with mild–moderate AD (MMSE 18–26). Patients were
randomized to active (n ¼ 6) or sham (n ¼ 6) intervention. Patients underwent 6
weeks of daily 1 h sessions of active or sham TMS-CR as adjunct to their stable phar-
macological therapy (five sessions per week, Monday to Friday, total of 30 sessions).
A short train of repetitive TMS was applied to a given brain region immediately be-
fore cognitive training tailored to engage the targeted brain circuit. Six different
brain regions engaged in major cognitive functions affected by AD were targeted,
as identified using the patient’s own brain MRI scan. The cognitive tasks were de-
veloped to fit these regions and engaged the modulated brain circuits. The primary
outcome measure was to assess improvement relative to sham on the ADAS-cog
score at the end of the 6 weeks of intervention and at a 3-month follow-up. The active
treatment group improved by 2.9 points relative to baseline, whereas the sham treat-
ment group worsened by 2.7 points (p < 0.01). Therefore, a primary analysis for the
difference between groups at endpoint, controlling for baseline (effectively a covari-
ance analysis or a test of difference scores), revealed a mean difference in ADAS-cog
between groups at endpoint of 5.6 points, markedly greater than the reported effect of
pharmacological or nonpharmacological interventions. It is further compelling that
relative to baseline, all patients in the active TMS-CR group showed an improvement
(either immediately after the intervention or within 1 month), while none of the
patients in the sham group showed improvement.
The few trials conducted to date reveal positive effects and provide initial evi-
dence on the potential of noninvasive brain stimulation for cognitive enhancement
in AD. However, these studies have not been replicated and the evidence remains
preliminary. While the initial target in patients with mild cognitive impairment
and mild AD should be to halt the progression of the disease, cognitive enhancement
strategies in moderate to severe AD should target multiple cognitive domains in
110 CHAPTER 4 Changes in Plasticity Across the Lifespan
5 CONCLUSION
The brain changes across the lifespan. First, growing evidence demonstrates that the
brain undergoes a complex array of neuroanatomical and neurophysiological modifi-
cations from birth till death, so that concepts such as “development” and “senescence”
have become increasingly arbitrary in their definition. Instead, the lifespan and the ag-
ing process itself might be best viewed as a “lifelong developmental process,” which is
thought to constitute the underpinnings of shifts in cognition and behavior throughout
each individual’s life. Second, along with changes in brain structure and function, the
mechanisms by which structure and function can be modified (the mechanisms of
brain plasticity themselves) appear to also change over the lifespan. This developmen-
tal process is very well controlled by the processes described in the preceding text in-
cluding LTP, LTD, and homeostatic and metaplastic control of these processes. Over
the course of development, the brain goes through critical periods where a specific re-
gion of cortex has heightened or exclusive capacity for plasticity.
This chapter highlights the importance of brain plasticity throughout the lifespan
for optimal brain health. In health, local cortical and network plasticity might keep a
fine-tuned balance, which optimizes functionality (Pascual-Leone et al., 2011). Such a
“lifelong dynamic, plastically changing brain” poses several challenges, including the
definition of a functionally “normal” brain at a given point in time in a given individ-
ual. A functionally “normal” brain is a changing brain, a brain whose capacity and
mechanisms of change are shifting appropriately from one time point in life to another.
We have also highlighted how pathology of brain plasticity may underlie a num-
ber of neuropsychological disorders across the lifespan. ASD and schizophrenia may
represent two sides of the same coin with the symptoms of ASD potentially stem-
ming from uncontrolled excitatory plasticity and an overall potentiated cortex and
symptoms of schizophrenia stemming from a lack of excitatory plasticity. At the
other end of the lifespan, in late adulthood, maintaining the capacity for plastic
change may be critical for avoiding age-related cognitive decline with dementia
and AD representing an inability for plastic change.
If, as we propose, these diseases and disorders stem from aberrant plasticity
mechanisms, then modulating such systems using TMS may represent a novel alter-
native to drug treatments. Pilot studies suggest promise for the treatment of ASD,
schizophrenia, and AD using specific rTMS protocols. As of now, these treatments
should be considered highly experimental and in need for further replication in
properly powered and controlled trials. However, they offer valuable proof-of-
principle support for the concept of harnessing and guiding brain plasticity for
neurotherapeutics.
References 111
Acknowledgments
Dr. Pascual-Leone serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neu-
roscience, Neuroelectrics, and NeoSync and is listed as an inventor on several issued and pend-
ing patents on the real-time integration of transcranial magnetic stimulation (TMS) with
electroencephalography (EEG) and magnetic resonance imaging (MRI). Work on this study
was supported by a grant from the National Institutes of Health—Harvard Clinical and Trans-
lational Science Center/Harvard Catalyst (UL1 RR025758), and the Sidney Baer Foundation.
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CHAPTER
Abstract
Individuals substantially improve with training, indicating that a large degree of plasticity
is retained across ages. In the past 20 years, many studies explored the ability to boost
cognitive skills (reasoning, linguistic abilities, working memory, and attention) by training
with other tasks that exploit limited cognitive resources. Indeed, individuals with long-term
training on challenging skills (musicians and action video gamers) show impressive behav-
ior on related tasks (linguistic and visual attention, respectively). However, a critical eval-
uation of training studies that last weeks to months shows typically mild effects, mainly
with respect to control groups that either did not practice or practiced with less challenging,
rewarding, or exciting conditions. These findings suggest that future training studies should
evaluate these factors carefully and assess whether they mainly impact the testing sessions
or actual longer-term skills, and whether their impact can be further strengthened. The lack
of a comprehensive theory of learning that integrates cognitive, motivational, and alertness
aspects poses a bottleneck to improving current training procedures.
Keywords
perceptual learning, working memory, musical education, cognitive training, generalization,
action video games, positive affect
The potential promise in adult training is exciting. Yet, in spite of impressive evi-
dence for behavioral improvement and for neural plasticity, our understanding of
the underlying mechanisms and of the relations between training procedures and
their outcomes is extremely limited. Particularly challenging is the extent of transfer
from trained to untrained tasks and contexts. Most theories of perceptual learning
(e.g., Dosher and Lu, 2007; Seitz and Watanabe, 2005) address specific experimental
contexts and hence do not have comprehensive predictions regarding tasks or pro-
cedures that are expected to increase generalization. An exception is Reverse hier-
archy theory (RHT; though see also a recent version of a theory by Dosher et al.,
2013) that addresses the relations between training procedures and their expected
outcomes (Ahissar and Hochstein, 2004; Ahissar et al., 2009; Hochstein and
Ahissar, 2002). However, RHT’s predictions are also quite limited, since it assumes
a comprehensive understanding of the nature of hierarchical representations of stim-
uli, which we still largely lack (Ahissar, 2001). Additionally, it does not integrate
motivational, alertness, and related factors, whose impact is probably substantial
and perhaps also interacts with the training procedure.
Understanding these general factors, which relate to the state of the participant
while performing the task, is important for the formation of a systematic conceptu-
alization of the anticipated gains. These factors include time of day (May and Hasher,
1998), general emotional state (Isen, 2008), motivation and alertness (Boot et al.,
2013; Duckworth et al., 2011; Langer et al., 2010), training duration (Censor
et al., 2006), limits on response duration (Green et al., 2010), and intervals between
training sessions and sleep (Censor et al., 2006; Karni et al., 1994; Korman et al.,
2007; Stickgold, 2005; Stickgold et al., 2000). The effect of these parameters may
be larger than that of the systematically studied parameters, as we shall show in this
chapter.
Given our limited theoretical understanding of the comprehensive learning
experience, the aim of this chapter is to define operative guidelines for evaluating
the success of past and future training studies, with respect to their goals. Based
on our review, we propose further directions for future studies. An important
distinction, which was typically ignored in previous studies, is the difference be-
tween clinical and theoretical goals. Typically, the design of a given study cannot
optimize both. For example, if a procedure improves the performance of a popu-
lation on a poorly performed range of tasks, it may be a successful rehabilitation
procedure even if the mechanisms are not understood, and their control was very
crude. However, well-controlled studies that yield a very small improvement com-
pared with careful controls may have a theoretical impact but perhaps no
immediate application. The two goals are closely related in longer-term develop-
ment, where improving training procedures would gain immensely if their
underlying mechanisms would be understood. Defining priorities when designing
the studies would facilitate our understanding and hence our long-term ability to
improve training protocols.
1 What is a Good Control? 123
memory task with completely novel stimuli, and by administering novel working
memory tasks. If there is improvement in the untrained task (i.e., scores are similar
to those attained on the trained one), the sources of this transfer would indeed be hard
to tap. Yet, most learning is quite specific to the combination of trained task and stim-
uli (e.g., Ahissar and Hochstein, 1993). Thus, the transfer to novel stimuli, with
which participants were not previously tested but whose relative difficulty is
expected to be similar to that of trained ones, is likely to be informative. See for ex-
ample, a recent use of control tasks within the experimental paradigm in Anguera
et al. (2013), which would provide a systematic characterization of the learning pro-
cess. Very few training studies (e.g., Klingberg et al., 2002, 2005; Olesen et al., 2003;
Schmiedek et al., 2010) used this within-group control for showing that transfer at least
encompassed very different stimuli or even very closely related tasks. Even when such a
test battery was used, it mainly served as a collection from which significantly improved
tasks could be pulled out rather than as a systematic characterization of the pattern of
specificity and generalization that the training induced.
In the typical case, particularly when participants’ performance in other tasks is not
systematically characterized and there are no suitable test–retest norms, a control test–
retest group should be added, in order to verify that the training process contributed to the
post-training improvement. If there is indeed a significant difference between the trained
and untrained groups, it means that some training-related improvement occurred, but we
cannot tell what this improvement should be attributed to, as the differences between
groups’ procedures encompass many aspects. Still, if the gains of the trained group
are large and much larger than those of a “no-contact” control, it means that this proce-
dure is useful for applied purposes, even though the intergroup difference may be due to a
very general aspect of practice (e.g., “positive psychology”; see Yang et al., 2013; for a
review, see Isen, 2008). An important aspect, which is difficult to determine, is whether
the potentially general effects underlying group differences reflect a difference in learn-
ing or merely a difference in performance during the testing session itself (for a critical
discussion of these issues, see Boot et al., 2011; Duckworth et al., 2011; Shipstead et al.,
2012). Since the dissociation between short- and long-term effects of general factors is
difficult to determine, one should perhaps equate within-testing factors of “positive psy-
chology” for the two groups. In general, the main limit of having a no-contact control is
that we cannot tell how to improve the training procedure. However, if the intergroup
effects are large, namely, the protocol as a whole was effective, a useful continuation
could be to determine the mechanisms that underlie the intergroup difference. For
example, it would be useful to know whether this improvement could have been obtained
without any training at all, for example, by encouraging the tested participants. Indeed,
a recent meta-analysis found that studies with greater incentive yield significantly
(0.6 standard deviations) larger scores in intelligence tests, previously considered
to robustly reflect individual cognitive abilities (Duckworth et al., 2011).
2011; Shavelson et al., 2008; Thorell et al., 2009; Van der Molen et al., 2010; Zhao et al.,
2011; for a review see Shipstead et al., 2012). But what should an active control group
train with? In the case of working memory training, a common solution is an active con-
trol group that is trained with an easy, fixed-stimuli task, whereas the test group is trained
with an adaptive, challenging working memory task. However, when post-training per-
formance differs between the trained groups (e.g., Jaeggi et al., 2008; Klingberg et al.,
2002, 2005), it is not clear what such improvement should be attributed to. Does it stem
from training a working memory task? Would one get similar gains if paid for successful
performance instead of training? Would one get similar gains in any challenging task?
Perhaps the participants trained with a nonadaptive procedure perform worse because
they are bored and have lost interest. In this type of control, the potentially crucial role
of motivation, excitement, and challenges that differ between the two training protocols
is overlooked when inter group differences in the outcomes are specifically attributed
to training with a working memory task. Again, one should note that here too, group
differences in the testing session may be related to the different levels of anticipation
(how well do we expect to perform) of the two tested groups. Such differences may
affect performance, even in perceptual tasks. For example, by affecting the “mind
setting” of tested individuals, so that they expect to perform better, participants actually
perform better, even in visual acuity tasks, considered a robust measure of the visual sys-
tem (Langer et al., 2010).
the pre-training correlation between the trained and untrained tasks, these individuals
will tend to have lower pre-training scores also in the untrained task. If following
training, performance is similar for the selected (higher training gain) and unselected
(lower training gain) individuals then the calculated gain of the selected individuals
will be larger due to this selection bias even when there is no transfer. Such a bias can
account for the transfer, that is, correlation in gains, reported in Jaeggi et al. (2011).
Jaeggi et al. (2011) trained two groups of third graders, one (N=32) on general
knowledge and vocabulary (“active control”) and the other (N=32) on a spatial work-
ing memory task. This initial study had null results. Namely, the two groups did not
differ in their general intelligence scores, either before or after training, suggesting
no transfer. However, rather than acknowledging null results, Jaeggi et al. (2011)
divided the group trained on the working memory task into two subgroups (median
split), with high and low gains in working memory, respectively. They found that the
subgroup that had larger working memory gains also had larger intelligence gains.
The main basis for the “transfer” claim is that individuals who had larger gains in the
trained task had larger “gains” in the transfer tasks (e.g., standard tasks for measuring
intelligence). Yet the group of individuals who had larger gains in the trained task did
not have higher post-training scores in the untrained intelligence tasks. In this study,
the reported correlation could be fully accounted for quantitatively without assuming
any transfer of learning, that is, solely on the basis of biased statistics (see for details
Jacoby and Ahissar, submitted).
The same concept of correlation in gains as supporting evidence for transfer is
used in many other training studies. For example, Chein and Morrison (2010)
claimed “a strong and statistically significant relationship between enhancement
of trained participants’ spatial complex working memory span and their improve-
ment in reading comprehension [r=.49, p<0.005].” Similarly, in an attempt to sup-
port a transfer effect between working memory and fluid intelligence in children with
ADHD, Klingberg et al. (2002) claimed that “the association between the reasoning
task and the working memory tasks is further substantiated by the significant corre-
lation between improvement on the visuo-spatial working memory task and im-
provement on Raven’s progressive matrices” (p. 789). Schmiedek et al. (2010)
reported a significant correlation between latent trained factors of episodic memory
and untrained ones and used it as supportive evidence for transfer effect. Banai and
Ahissar (2009) observed a marginally significant correlation between improvement
in a perceptual task (two-tone discrimination) and working memory (Spearman rho
0.59, p¼0.07) and interpreted it as “support (for) the suggestion that the improve-
ment in working memory scores is specifically related to the 2-tone discrimination
training.” Green and Bavelier (2003) used the correlation between improvements in
game scores and improvements in attentional skills as support for a transfer claim.
Most recently, Anguera et al. (2013) trained elderly individuals with a dual-task con-
dition of an action video game and used the correlation between improvement in this
trained condition (“multitasking”) and working memory gains to support the claim of
transfer from training multitasking in action video games to enhanced working mem-
ory capacity (see Anguera et al., 2013 figure 3d on page 99).
128 CHAPTER 5 A Critical Evaluation
they do. Moreover, changes in brain responses are often interpreted as reflecting
“real” changes compared with behavior-only experiments, even when behavioral
modifications are the real goal of the study.
Many studies assessing the neural correlates of behavioral improvement only
show that known brain correlates of performance indeed change when performance
changes. For example, several studies (e.g., Anguera et al., 2013; François et al.,
2012; Moreno et al., 2009) showed that when behavior improves following training,
ERP components, known to correlate with performance and measured while partic-
ipants perform the task, are increased. A recent example is Anguera et al. (2013) who
trained older adults with a lab-version dual-task condition of an action video game.
They showed that age-related EEG activity (midline–frontal theta power and frontal–
posterior theta coherence) was increased after training. However, the EEG was mea-
sured on a task that is almost identical to the trained task. They did not show this
enhanced EEG activity on a different multitasking activity. For the purpose of reha-
bilitation, the important aspect is the ability to improve age-related neural mecha-
nisms in general. However, in the Anguera et al. study, the other condition that
was used for measuring multitasking—a novel dual-task paradigm—was not signif-
icantly improved in the group trained with the dual-task compared with controls
trained with one task at a time.
Another example that demonstrates this issue is the study by François et al.
(2012), who characterized the effects of music training in children that practiced mu-
sic for 2 years starting from the age of 8 years old. They showed significant changes
in performance in speech segmentation compared with a control group that practiced
painting. Following training, they also showed increased activation of frontal elec-
trodes at 450–550 ms post-stimulus onset, when performing this task. In their previ-
ous work, Francois and Schön (2011) associated this component with N400-like
component, known to be correlated with linguistic skills (Elger et al., 1997). Thus,
the observation that improved behavior is coupled with an increase in the expected
ERP component is reassuring, but does not point to any specific underlying mecha-
nism. Such observations would be more revealing regarding underlying mechanisms
if there were several known ways to attain better performance, accompanied by
different brain correlates, or if the same known brain correlate were shown to
increase in untrained conditions.
A different type of overinterpretation of imaging and ERP studies stems from
their greater susceptibility to posterior statistics and hence to spurious significant
effects, because they typically involve many more measures (voxel clusters, voxel
combinations, ERP electrodes, or electrode combinations) compared with behavioral
studies. An extreme example of this case is a recent study by Neville et al. (2013),
who administered a family-based training program designed to improve “brain sys-
tems for selective attention” in preschool children of lower socioeconomic status. A
main claim for the success of the program to boost cognitive measures compared
with an active control group was the group-specific change in ERP indices used
for assessing selective attention. Neville et al. used a selective auditory attention
130 CHAPTER 5 A Critical Evaluation
paradigm and measured ERP with 29 electrodes. This myriad of electrodes allows for
many post hoc selections for analysis. In this study, the choice of electrodes for an-
alyses made the difference. Neville’s group used this ERP index in a series of pre-
vious studies. In all these studies (Coch et al., 2005; Sanders et al., 2006; Stevens
et al., 2008, 2009, 2013), they showed that the anterior and medial electrodes convey
this component, and therefore, they discarded posterior electrodes. But in Neville
et al. (2013), the experimental group showed no modifications in anterior electrodes.
Based on previous analyses, this means a null ERP result. However, these partici-
pants showed changes in posterior electrodes, and Neville et al. conducted an ante-
rior–posterior ANOVA analysis, in which the experimental group “showed a
significant increase in this response (time, P <0.05) that was largest at posterior
recording sites.”
the range of social conditioning and positive priming (see Boot et al., 2011). Jaeggi
et al. (2008) trained 70 young students: 35 completed a working memory training
program of 8–19 days and the other participants composed a no-contact control
group. The trained group improved their intelligence scores (Cohen’s d ¼ 0.65)
more than the control group (Cohen’s d ¼ 0.25). Lilienthal (2013) studied 52 stu-
dents who either trained with an adaptive n-back working memory task or trained
with a nonadaptive task or were only tested with a similar inter-test interval. They
found that participants in the adaptive training group also showed improvement on
a span task, which measures the capacity of the focus of attention. The effect sizes
computed from their reported data was 0.17, 0.06, and 0.86 for the no-contact,
nonadaptive, and adaptive groups, respectively. Other studies that conducted
similar training procedures (e.g., Boot et al., 2008; Owen et al., 2010; Redick
et al., 2013) did not find any transfer and naturally found only a small or very small
effect size (0–0.5).
Other studies trained participants on action video games and measured their
subsequent performance on a range of tasks, often measuring the efficiency of
spatial attention. This training was motivated by the observation that avid players
of action video games, who have thousands of hours of experience, show substantial
advantages compared with nonplayers in a range of tasks of visual attention, parti-
cularly those that require fast responses to briefly presented stimuli (Achtman et al.,
2008; Castel et al., 2005; Chisholm et al., 2010; Dye et al., 2009a,b; Green and
Bavelier, 2006a,b, 2007, 2008; Hubert-Wallander et al., 2011; Hubert-Wallander
et al., 2011; Li et al., 2009, 2010, 2011; Mishra et al., 2011). For example, Green
and Bavelier (2006b) trained individuals who do not play action video games on
either an action video game or on a control game (Tetris). They showed that training
facilitates the processing of multiple objects in a multiple-object-tracking task.
The effect sizes (calculated from their figures) were high—d ¼ 1.01 and d ¼ 1.39—
compared with the control d ¼ 0.25 and d ¼ 0.01 for tracking four and six objects,
respectively. Li et al. (2010) trained nonaction video players intensively (50 h over
9 weeks) and found reduced lateral masking with intervals of 60 and 90 ms, with effect
sizes (calculated from their figures) of d ¼ 0.77 and d ¼ 0.80, respectively. There
was almost no effect in the control group, who trained on a nonaction video game
(The Sims 2). The same group (Li et al., 2009) also trained nongamers with action
video games and showed that contrast sensitivity, which is routinely assessed in clin-
ical evaluations of vision, had improved (d ¼ 1.08 for frequency of 6 cycles/deg)
compared with a much smaller improvement (d ¼ 0.17) in a control group that trained
with a nonaction video game (The Sims 2). A recent study (Anguera et al., 2013)
trained elderly individuals on a dual-task condition of a video game (NeuroRacer
game). The effect sizes of delayed-recognition working memory task and test of
variables of attention was 0.98 and 0.89, respectively, compared to the no-contact
group. An additional group trained in a very similar task but did not have a multitasking
component. The effect size compared with this group was medium (0.67 and 0.46 to
the two earlier-mentioned tasks, respectively). However, this effect was obtained for
132 CHAPTER 5 A Critical Evaluation
two tasks of a larger testing battery. One of the additional tasks was another dual-task
paradigm for which no significant improvement was found in the main group com-
pared with the other groups.
Though these effect sizes are not small, they would probably not be statistically
resilient to corrections for the total number of tasks assessed. Moreover, other groups
who trained participants on similar action video games did not obtain transfer to
other cognitive tasks (e.g., Boot et al., 2008; Lee et al., 2012). These differences
might stem from the use of slightly different experimental (e.g., the duration and
color of the masking stimulus in the functional field of view task) and recruitment
strategies. This suggests that here too, even though control groups also trained with
challenging games, the effects depend on additional components, whose nature
should be further studied. In another study, Boot et al. (2013) measured the expec-
tations of subjects (N ¼ 200) who watched videos of either an action video game or a
control game (Tetris or The Sims). They were then asked if they think that training
for many hours with the video games presented would improve their performance on
a list of other cognitive tasks that were also presented with detailed explanations and
videos. Their results show surprisingly high agreement between subjects’ expecta-
tion and the extent of transfer reported in the literature (Green and Bavelier,
2012). These results suggest that indirect effects, such as subject’s expectation,
may be crucial for the replication of training effects.
A somewhat similar case is that of musical education. Most people who study
music do so for pleasure rather than as a means for attaining other skills, just as
is the case for avid players of action video games. Yet, expert musicians were
reported to have enhanced verbal and phonological skills (Anvari et al., 2002;
Besson et al., 2007; Butzlaff, 2000; Forgeard et al., 2008; François et al., 2012;
Moreno et al., 2009) and higher intelligence (Lynn et al., 1989; Schellenberg,
2004, 2006). Although these may reflect a selection bias for people playing music,
an exciting hypothesis is that their musical education contributed to their linguistic
skills (Kraus and Chandrasekaran, 2010) or intelligence (Schellenberg, 2006).
The causal relations between training and enhanced performance were studied in
several longitudinal studies (Costa-Giomi, 1999; Flohr, 1981; Forgeard et al., 2008;
François et al., 2012; Hurwitz et al., 1975; Hyde et al., 2009; Moreno et al., 2009;
Morrongiello and Roes, 1990; Schellenberg, 2004; Thompson et al., 2004). Most
training studies reported significant improvements after medium (few months) to
long (about 2 years) trainings. For example, Schellenberg (2004) reported a small
to medium effect of increased IQ, which was significantly more prominent in
6-year-old children taking music lessons (for children that received keyboard and
voice music lessons, the effect sizes were 0.69 and 0.70, respectively), compared
with control groups that studied drama (d ¼ 0.37) or did not participate in any special
training program (d ¼ 0.40). François et al. (2012) studied the effect of music training
in children that practiced music starting at the age 8 years old. They showed signif-
icant improvement in speech segmentation in children practicing music, compared
with a control group that practiced painting; the effect size of the improvement in the
music group compared with the painting was around 1 both for 1 and 2 years of
5 Conclusions and Future Directions 133
training. However, Rickard et al. (2012) reported results with two large studies
(N ¼ 127 and N ¼ 100 children) with school-based music instruction that did not
show a cognitive enhancement. In a correlation study that we conducted (Banai
and Ahissar, 2013) among third-grade children, we found that auditory thresholds
were more correlated with verbal memory among children that were not musically
trained. Among children with about 1 year of musical education, only auditory
thresholds were better than those expected when intelligence was statistically con-
trolled for, whereas higher verbal memory scores could be accounted for by higher
general intelligence scores. Thompson et al. (2004) showed that music keyboard les-
sons do not enhance performance in identifying emotional content of semantically
neutral speech more than control (drama lessons) even after a year of training. These
mixed results leave the question of the impact of musical education (1–2 years) on
linguistic skills largely open. The effect sizes on tasks that are not closely related to
those directly trained are small. For example, in a meta-analysis of over 30 music
intervention studies by Standley (2008), the average effect size on reading skills
was small (d ¼ 0.32).
In a recent study (Hai, Granot, and Ahissar, submitted), we asked whether adult
musicians (24 years old), who had prolonged and intensive musical training, may
still have language and reading difficulties. We found that there are indeed poor
readers among musicians. Their performance in auditory, sensory, and sensorimotor
(tapping) tasks was as good as that of their musician peers and superior to that of their
nonmusician peers. But their working memory abilities were impaired compared with
their musician peers. Overall, dyslexia seems milder among musicians. Still, these
findings indicate that musical education was not sufficient for enhancing their working
memory skills to an extent that they would no longer pose a bottleneck to reading.
In summary, the evidences from working memory, action video games, and mu-
sic training are quite similar. Relatively short periods of targeted training do not pro-
vide a substantial widespread cognitive enhancement. The magnitude of these effects
is typically in the range of positive priming and enhanced motivation, implying that
the sources underlying the transfer effects should be further studied.
Bavelier, 2003, 2008, 2012). This pattern suggests that perhaps, the more important
aspect for generalization resides in participants’ and perhaps experimenters’ emo-
tional state (such as motivation, arousal, and reward) rather than in the specific
choice of cognitive tasks in these studies. An interesting question is whether these
emotional effects interact with cognitive states. In order to examine these intricate
questions systematically, we must add to the relevant test dimensions the emotional
and social aspects (including accurate measures of engagement and challenge) and
systematically evaluate their contribution.
Another important yet unresolved question is that of the target population. Reha-
bilitation is typically oriented toward individuals with specific impairments, compared
with the general population. But we still do not know whether individuals with specific
deficits are more or less likely to gain from training and whether similar training pro-
cedures are likely to be useful to different populations. Here too, we lack a theoretical
account for addressing this question. On the one hand, the dynamic range that may be
relevant for individuals with specific difficulties is perhaps larger. In the general pop-
ulation, it is often the case that individuals who start with poorer performance improve
more than others (e.g., see Duckworth et al., 2011). On the other hand, individuals who
did not gain sufficiently with “ecological” training conditions are perhaps more resil-
ient to practice, as suggested by the phenomenon of dyslexic musicians (Hai, Granot,
and Ahissar, submitted). For example, Oganian and Ahissar (2012) compared auditory
and reading skills of adequate readers and dyslexics with and without musical educa-
tion. They found that among adequate readers, auditory and reading skills were higher
in individuals with musical training. However, among dyslexics, auditory and reading
skills did not differ between individuals with and without formal musical education.
Taken together, the limited success of training studies in attaining generalization
would perhaps be improved when a broader range of factors will be systematically
considered and when the outcome of these studies will be integrated into a compre-
hensive theory that will guide the design of future procedures.
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CHAPTER
Principles of Neuroplasticity-
Based Rehabilitation
*
Mor Nahum*,{, Hyunkyu Lee*, Michael M. Merzenich*,1
6
Brain Plasticity Institute at Posit Science Corporation, San Francisco, CA, USA
{
Department of Optometry, University of California, Berkeley, CA, USA
1
Corresponding author: Phone/Fax: þ415-394-3105
e-mail address: mike.merzenich@positscience.com
Abstract
The purpose of this review is to summarize how our perspective about the neuroscience of
brain plasticity, informed by perceptual, experimental, and cognitive psychology, has led to
the designs of a new class of therapeutic tools developed to drive functionally distorted
and damaged brains in corrective directions. How does neuroplasticity science inform us about
optimal therapeutic program designs? How do we apply that science, using modern technol-
ogy, to drive neurological changes that address both the neurobehavioral distortions and the
resulting behavioral deficits that are expressed in specific neurological and psychiatric disor-
ders? By what strategies can we achieve the strongest and most complete rehabilitative cor-
rections? These are questions that we have extensively explored in our efforts to establish new
medical applications of neuroplasticity-based therapeutics. Here, we summarize the state of
this rapidly emerging area of translational neuroscience, beginning with an explanation of
the scientific premises and strategies, then describing their implementation in therapeutic soft-
ware to address two human illnesses: the treatment of social cognition deficits in chronic
schizophrenia and in autism; and the amelioration of age-related functional decline using strat-
egies designed to delay the onset of—and potentially prevent—Alzheimer’s Disease and re-
lated causes of dementia in aging.
Keywords
brain plasticity, social cognition, Alzheimer’s Disease prevention, cognitive training,
therapeutic programs, BrainHQ
1 INTRODUCTION
We begin the chapter with a description of our approach to creating brain
plasticity-based therapeutic tools to treat neurological and psychiatric impairment
attributable to “disease” and brain injury by outlining the principles derived from
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00009-6
© 2013 Elsevier B.V. All rights reserved.
141
142 CHAPTER 6 Principles of Neuroplasticity-Based Rehabilitation
abilities. If an individual has an evident failure in memory, for example, the therapist
most often engages the patient to practice remembering, or to develop compensatory
strategies to help them work around their memory loss. By contrast, from a more
neurological perspective, we focus on improving the many deficits across the
various system levels that contribute to the degradation of the neurological represen-
tation of information that the patient is struggling to record. Going back to the mem-
ory failure example, the focus of neuroplasticity-informed training would be on the
clarity, in neurological terms, with which they represent that information, the sup-
pression of distractors that disrupt remembering, the baseline levels of attention that
support all epochs of remembering (among others), all aimed at improving the dif-
ferent operations of the relevant brain network before reexercising explicit memory
abilities themselves.
Response coordination
Number/unit volume
Old trained
Old trained
Old trained
Young
Young
Young
Young
Trained
Old
Old
Old
Old
Trans-cortical distance
Old trained
Old trained
Old trained
Old trained
Young
Young
Young
Young
Young
Old
Old
Old
Old
Old
FIGURE 1
Ten of the more than 40 specific measures of neocortical structure, chemistry, and function
shown to differ in the aged versus the young Norway rat brain (A–J). As with these
examples, all indices manifested a degraded physical and functional status of the cerebral
cortex in the aged versus the young adult animal; and all indices were substantially or
completely reversed in aged rats by training them (a) to respond to variant stimuli against
a repeated background of standard stimuli, with a staircase adaptation of variant-to-standard
disparities, or (b) to respond to a target presented in a background of “distractors,” with the
disparities between distractors and targets again adapted in a staircase progression. Note that
many of these same measures (all that were measured) were seen to very rapidly change
to the aged-rat status in healthy normal young adult rats by applying strategies that increased
cortical process noise (uncorrelated neuronal “chatter”) over a 3-week-long young adult
epoch (Zhou et al., 2011).
Illustration adapted from de Villers-Sidani et al. (2010); and Mishra et al. (in review).
closely match one another. It is also manifested by the fact that accelerated changes
leading to “premature aging,” carried forward far enough, similarly result in the
reopening of the “critical period” (Zhou et al., 2011; and see Chapter 1).
Because chronic neurological or psychiatric illness and brain injury invariably
leads to “negative plasticity” attributable to an increase in background “chatter”
(noise that is not correlated with the behavior in play), the fundamental reversal
of these functional characteristics of the neurological machinery of the brain is a tar-
get of every training program that we have developed, on the path to renormalizing
neurological processing and the physical brains of individuals with various clinical
indications.
in psychotic and autistic patients and (b) achieving functional rejuvenation and
resilience training in aging. For other examples of therapeutic programs that are
based on this approach, see Chapters 7, 12, and 13.
performance benchmark (i.e., threshold) in each brain training cycle. That bench-
mark has two values for the trainee. First, it documents the trainee’s abilities at
that task, compared to those of all others who have completed the same task for
the first time. That performance data can be related specifically to the average
ability of others in their (or in other) demographic(s) - for example, to an indi-
vidual of the same gender and age in the normal distribution, or to the distribution
of all other patients also in treatment for the same clinical indication. Second,
these benchmark “scores” provide a standard that the patient is challenged to
improve upon, through repetitive tries. Their goal is to ratchet up training
achievements cycle by cycle in training - documenting, with each try, the growth
of their abilities again referenced to those neurological capabilities in the grand
trainee population.
Finally, we continuously document training gains for the patient as a part of
training task implementation, and across the course of training, in ways designed
to contribute to trainee motivation. For addressing clinical indications using
tools that are prescribed and monitored in use by rehabilitation professionals,
patient compliance and outcomes data can be provided to those clinicians via
an established social network link. This professional monitoring is designed
to help promote patient compliance, inform the clinician about trainee progress,
provide them with insights into how their other treatments might contribute to
more-complete positive recoveries, and provide a continuous line of commu-
nication between patients and the professionals responsible for their treatment
and care.
domains, normally acquired early in life, enable the social behaviors that underlie our
function as part of a society.
However, in schizophrenia, in addition to the various positive and negative symp-
toms associated with the illness, as well as persistent cognitive deficits (see Green,
2006), patients exhibit deficits in all five domains of SC (e.g., Addington and
Addington, 1998; Brune et al., 2007; Edwards et al., 2002; Frith and Corcoran,
1996; Harrington et al., 2005; Mandal et al., 1998; Williams et al., 2003; see recent
reviews in Billeke and Aboitiz, 2013; Kohler et al., 2010; Hellewell and Whittaker,
1998). These deficits are considered core in schizophrenia, as they persist throughout
the course of the illness (Green et al., 2012), are expressed very early in the course of
the illness (Edwards et al., 2001; Green et al., 2012; Pinkham et al., 2007), and are
even recorded in prodromal patients (Pinkham et al., 2007) and in unaffected rela-
tives of schizophrenia patients. Moreover, SC deficits are closely linked to functional
ability in schizophrenia (Pinkham et al., 2003; Penn et al., 2008) and affect daily liv-
ing factors including occupational status, community functioning, independent liv-
ing skills, relapse rate, and quality of life (Addington et al., 2006; Bell et al., 2009;
Couture et al., 2006; Fett et al., 2010; Horan et al., 2012; Sergi et al., 2007; Vauth
et al., 2004). In addition, SC deficits have been found to mediate the relationship
between neurocognition and functional outcomes in schizophrenia (Couture et al.,
2006), as well as predict conversion to psychosis in young individuals at risk for psy-
chosis (Vauth et al., 2004). In fact, the degree of SC impairment is a stronger pre-
dictor of the level of everyday functional ability than are cognitive abilities or the
severity of positive symptoms (Horan et al., 2012).
These behavioral deficits have been recently shown to be rooted in anatomical
and functional abnormalities within the complex brain network known as “the social
brain” (Adolphs, 1999, 2009; Botvinick et al., 2005; Lamm et al., 2007; Wicker et al.,
2003). Significant anatomical and functional abnormalities have been localized to
the superior temporal sulcus (STS; Straube et al., 2013), anterior insula (Sheng
et al., 2013), amygdala (Gur et al., 2002; Schneider et al., 1998), medial prefrontal
cortex (mPFC; Russell et al., 2000), and to the cingulate cortex (Pinkham et al.,
2008a,b), all are known to be critically involved in perception and processing of
social information.
Collectively, these behavioral and neurological abnormalities make SC an
important target for neuroplasticity-based intervention in schizophrenia. As the
goal of any effective treatment is to improve life outcomes for patients, the direct
link between SC and functional outcome in schizophrenia makes renormalization
of SC function a clear target. The fact that SC deficits are resistant to pharmaco-
logical treatments including second-generation antipsychotic medications (Green,
2007) or to cognitive training per se (see Sacks et al., 2013 and Chapter 12 for sum-
mary of cognitive training in schizophrenia) further stresses the importance of
targeted SC training for schizophrenia. Indeed, several studies have recently shown
some promising effects of social skills and SC training in chronic patients (see
recent reviews in Bartholomeusz and Allott, 2012; Choi et al., 2009; Kurtz and
Richardson, 2012).
5 Part 4: Examples of Practical Therapeutic Tools 157
FIGURE 2
The SocialVille social cognition training program. (A) Upon entering the training (through
a Web browser), the user is prompted with the SocialVille “city” map, which shows the
open locations that should be visited today (1). Upon entering a location on the map, an
introductory screen is shown, explaining the task (2). Then, the exercise starts, comprised
of several (20–70) trials (3); feedback is given following every trial. A “Results” screen is
also accessible, showing the points earned from each location, and the bonus awards and
friends earned (4). (B) An example of the SocialVille “name that feeling” exercise (café
location on the map). On every trial, an image of a person showing emotion is presented on the
screen for a short period of time. The picture is followed by a mask for 500 ms, which is
then followed by a response array with emotion names. The user should select the correct
emotion by clicking on it. A feedback is given after every trial. The presentation time of
the target is adaptively set based on the user’s responses. A block of this task contains
70 trials, which allow calculating the threshold for about 75% correct in the task. The number
of response options in the array, and the number of emotions vary throughout training.
game friends upon completion of game milestones. These meta-game awards and
progress can be reviewed in a separate “Results” screen.
Embedded assessments are included for each of the SocialVille exercises, which
allow measuring progress on this particular exercise in the course of training. Assess-
ments are completed by the user at the beginning, half-way through, and at the end of
training for each exercise, to allow tracking user progress in the course of training.
Data from each training exercise is transferred to a secure clinician Web portal,
which allows the treating clinician to track progress and compliance, derive perfor-
mance thresholds, and enroll new users to training.
We have thus far successfully completed a feasibility study of SocialVille use in
17 early schizophrenia patients (Nahum et al., submitted). We further initially
5 Part 4: Examples of Practical Therapeutic Tools 159
tested the program in several other clinical populations that show similar SC deficits.
These include children and adolescents with autistic spectrum disorders or Asper-
ger’s Syndrome, and healthy older adults. The program is now being localized to
be applicable to these populations.
aging in numerous human studies (Hahn et al., 2013; Heister et al., 2011; Kenny et al.,
2012; Lo et al., 2011; Weiner et al., 2013). Blood flow and glucose metabolism studies
have repeatedly documented progressive, negative changes in this meso- and neocor-
tical machinery in parallel with losses in cognitive and action-control abilities in nor-
mal aging. Importantly, the degree of this “functional disconnection” resulting in
default system inactivity is strongly, directly correlated with the emergence of patho-
logical markers of AD.
In our own studies, we have shown that “noise” (neuronal “chatter”) grows pro-
gressively in the brain as we age (see de Villers-Sidani et al., 2010; Mishra et al., in
review; Zhou et al., 2011). That growing noise results in natural plastic changes in the
way that the brain represents, by its neural activities, the details of what you see or
hear or feel or smell. Because those striking changes in brain speed, accuracy, and
reliability ultimately degrade the quality of information “fed forward” in our fore-
brain systems to the default-network level of our brain’s operation, these “highest
levels” of brain systems are the first to be functionally disconnected in age-related
decline (see de Villers-Sidani and Merzenich, 2011; Merzenich, 2013, for review).
The emergence of AD pathology adds to this progressive, highest level deactivation
because the pathology amplifies an individual’s “brain noise” and weakens feedback
to lower brain system levels, including the modulatory machinery that enables plas-
ticity itself.
What underlies the poisonous production and release of amyloid and amyloid-
body formation in the first place? What engenders the destructive proliferation of
microtubules in nerve cells? We know that they are both contributed to by com-
promised immune processes. The altered blood perfusion attributable to changes
in neuronal activity is an almost-certain contributor to connectional diselabora-
tion, accumulated cellular debris, and immunological compromise. A recovery
of more normal perfusion resulting from more normal levels of default system
engagement could be expected to result in immune system strengthening. More-
over, the increased brain activity expressed through a functional recovery of the
default system should result in its parallel metabolic recovery. We also know that
there is a substantial downregulation of brain-produced noradrenaline in most
aged individuals (Mufson et al., 2002; Zarow et al., 2003; and see Heneka
et al., 2006), and that the physical (metabolic, neuronal population, noradrenaline
production, transporters) status of its primary brain source, the mid-brain locus
coeruleus, is directly correlated with cognitive performance abilities and with
risks of AD onset in elder populations. Noradrenaline is a key regulator of the
subpopulation of microglial cells that scavenge infectious agents and debris in
brain tissues. Damage to the neurons supplying it results in a rapid increase in
amyloid production and release (Heneka et al., 2006; Jardanhazi-Kurtz et al.,
2009). Increasing circulating levels of noradrenaline in older brains results in a
faster clearance of cellular debris following focal lesions and increases the scav-
enging of soluble amyloid itself (Heneka et al., 2010). A key design goal in cre-
ation of our therapeutic treatment strategy is to reinvigorate this machinery in the
older brain.
5 Part 4: Examples of Practical Therapeutic Tools 161
(connectivity) of the default network, where AD pathology rises with particular ini-
tial virulence. In this course, trainees initially complete extensive survey information
documenting their neurological status, and self-assess their quality of life. They
then complete 12 program-delivered assessments that are specifically designed
to evaluate default-network functionality before - and at periodic benchmarks
after - training. We also collect daily information about lifestyle and other probable
contributors to their improving brain health. Those queries also provide self-reports
of trainees about their neurological and physical status that are very important for
documenting far-transfer training impacts, and for documenting how other changes
in lifestyle contribute to recovered brain health. After approximately 50-training-hour
epochs, self-reports related to brain and physical health and quality of life and the
12 special automated assessment measures are repeated, to determine the improve-
ments in neurobehavioral status and the resilience values of this training course.
In its present form, TAP delivers more than a hundred hours of brain training
designed to be used in 30-min daily training sessions completed over a period of
40–50 weeks. Our goal is to extend training in program participants out into the
future, potential to the end of their lives.
with the highest levels of operation in SC, these explicit behaviors normally di-
rectly engage frontal, posterior parietal, anterior and posterior cingulate, medial
ventral and hippocampal zones that undergo disconnection as a preamble to AD
onset. (5) Broad far-transfer effects are recorded - for example, to everyday quality
of life (Ball et al., 2007; Smith et al., 2008), to sustained confident independence
(Edwards et al., 2009; Wolinsky et al., 2010a), to resilience impacts against the on-
set of depression (Wolinsky et al., 2009), to measures documenting improved brain
health (Wolinsky et al., 2006, 2010b), and to sustained (Edwards et al., 2009) and
safer automobile driving (Ball et al., 2010) - among other indices (Wolinsky et al.,
2006, 2007, 2009, 2010a,b; Ball et al., 2010; Edwards et al., 2009). (6) Positive
improvements have been shown to endure for many months to years following
training completion (e.g., Wolinsky et al., 2006, 2009, 2013; Zelinski et al., 2011).
Does this form of training delay AD onset? Does it block, and can it reverse neu-
ropathology progressions? Answering that question is the current goal of a large con-
trolled Internet-delivered trial, led by Dr. Hyunkyu Lee that is now underway. A
growing body of evidence provides increasingly compelling evidence that this is,
indeed, the case. By training thousands of individuals at risk for AD onset at BrainHQ,
we should be able to answer this question, with finality, in the immediate future.
6 CONCLUSIONS
Neuroplasticity-based training strategies are emerging as a new class of therapeutic
tools providing a new level of organic treatment of neurological and psychiatric ill-
ness. Because they can broadly address neurological impairments and disease-driven
neurological distortions, they hold promise of driving more complete and more en-
during changes in the brains of patients with many brain-related clinical indications.
Training programs constructed on these bases are relatively inexpensive to produce
and validate, and can be delivered to patients in need of help at low cost via the In-
ternet. Confirmation of use, compliance, and training benefits are routinely recorded,
with the supervising clinician “in the loop,” as an integral part of program use. Pa-
tient use and outcomes are measured by assessments embedded directly in these pro-
grams. We strongly believe these new therapeutic tools shall be a large part of the
picture of improved medical treatments of developmental and acquired-adult neuro-
logical and psychiatric impairments and disease over the coming decade.
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CHAPTER
Abstract
In 1996, I cofounded Scientific Learning Corporation (SLC) with Drs Michael Merzenich,
William Jenkins, and Steve Miller. I coined the term “Cogniceutical” to describe the new type
of company we envisioned. SLC was the first company cofounded by academic scientists with
the mission of building neurocognitive interventions. Fast ForWord® is the registered trade
name of the platform SLC built to translate basic neuroplasticity-based training research into
clinical and educational products. Fast ForWord® was the first cognitive neurotherapeutic in-
tervention, the first to be individually adaptive in real time, the first “brain fitness” program
that collected data over the Internet, and the first to use computer gaming technologies to
change brains and enhance human potential. We included lofty goals in our first business plan
for SLC. These included: using neuroplasticity-based training to improve language, literacy,
and other academic skills; helping seniors maintain and recover function; helping people learn
English as a second language; helping patient populations with neurological or mental disor-
ders. SLC’s first focus became improving language and literacy. Mike, Bill, Steve, and I began
this journey together in 1994 with a laboratory-based research study that included seven chil-
dren. To date, over two million children in 46 countries have used Fast ForWord® products. On
any given school day, approximately 60,000 children log in to train on 1 of 10 Fast ForWord
Language, Literacy, or Reading programs. We did not know at the time that we were creating
what became a “disruptive innovation.” This chapter chronicles this transformational journey.
Keywords
neurocognitive training, video games, language, literacy, reading, language-learning impair-
ments, neuroplasticity-based training, dyslexia, autism, Fast ForWord®:, Scientific Learning
Corporation
1 INTRODUCTION
Fast ForWord® grew out of over 25 years of basic and clinical research in two dis-
tinct scientific disciplines. One utilized behavioral, electrophysiological, and neuro-
imaging methods to study individual differences in language development and the
etiology of developmental language-based learning disabilities (including specific
language impairment (SLI), autism, and dyslexia). The other utilized neurophysio-
logical methods in animals to study neuroplasticity, that is, changes at the cellular
level driven by behavioral training techniques. This chapter reviews (1) how these
two lines of research were integrated to form the scientific basis of Fast ForWord®
(and subsequently its sister product Posit Science Corporation’s Brain Fitness
Program®), and (2) the steps taken to translate and instantiate our integrated labo-
ratory research into clinical and classroom interventions that could be scaled up for
distribution around the world, while remaining efficient and effective.
When we began our collaboration in 1993, the now rapidly growing fields of “cog-
nitive neurotherapeutics” and “neuroeducation” did not exist. The concept of using
neuroplasticity-based training to improve “brain fitness” in humans did not exist.
Few clinics or schools had computers and fewer still had Internet access. The methods
we developed which subsequently were the basis of over 50 patents were the first to use
video gaming technologies with the explicit goal of improving human performance.
Over the past 17 years since inception, Scientific Learning Corporation (SLC) has de-
veloped a large series of perceptual, cognitive, language, literacy, and early math train-
ing exercises, “disguised” as interactive, individually adaptive, computer games,
trademarked Fast ForWord®. SLC products, now delivered over the Internet, include
a wide variety of individually adaptive assessment and intervention exercises that pro-
vide real-time feedback and rewards as well as ongoing, electronic data analysis and
detailed reporting to the end user. A sister company, Posit Science Corporation,
cofounded by Dr Michael Merzenich, delivers similar products to aging adults and
adult patient populations. Posit’s first product, The Brain Fitness Program®, adapted
several of the original Fast ForWord® auditory processing, verbal memory, and lan-
guage comprehension exercises, including the use of acoustically modified speech.
risk for a cascade of negative life outcomes (Hart and Risley, 1995). Despite the crit-
ical role aural language plays in academic success, with over 80% of classroom in-
struction presented aurally, it is remarkable that there is little if any formal school
curriculum focused explicitly on receptive (comprehension) and expressive (spoken)
language development. Rather, early education focuses on teaching written language
(reading, writing, spelling). During the preschool years the focus is on “reading read-
iness.” Once formal education begins, if a child begins to struggle, intervention is
focused on reading. Put simply, schools are in the business of teaching a child to learn
to read, not to talk or listen. However, if our ultimate goal is to improve literacy out-
comes, what is needed is a better scientific understanding of how the brain learns to
process and produce language, how language forms the foundation upon which lit-
eracy skills depend, and how to effectively transfer this scientific knowledge to
clinics and classrooms in the form of effective and efficient intervention tools.
The Fast ForWord® series of training programs (there are currently 10 products, in-
cluding Fast ForWord® Language, Literacy, and Reading Levels 1–5) was devel-
oped to address this need.
The most basic unit of any language is the phoneme, the smallest unit of sound
that can change the meaning of a word. For most languages, in order to learn how to
read and become a proficient reader, the child must become aware that words can be
segmented into smaller units of sound (phonemes) and it is these sounds that the let-
ters represent. This is referred to as phonological awareness. Phonemes are the basic
building blocks for both spoken and written language. Not surprisingly, phonological
skills have been shown to correlate both prospectively as well as concurrently with
both aural and written language ability throughout life (Tallal, 2004). To improve
literacy outcomes, we need to understand the language to literacy continuum, and
how at a fundamental level phonemes of a language come to be organized or “repre-
sented” in the brain. As phonemes are, themselves, comprised of smaller, dynami-
cally changing, acoustic spectrotemporal features, the role that complex auditory
processing plays in the development of phonological systems has been a major topic
of research, and one that was fundamental to the design of the series of Fast For-
Word® Language and Literacy products.
As is the case in all other sensory modalities, the acoustic information within the
complex waveform of speech can be broken down into distinct physical features (fre-
quency, duration, amplitude), each of which is represented in fine grained detail in
the auditory system (Kraus et al., 1995, 1996). According to Hebb (1949), when a
complex signal occurs, all of the neurons that are activated by this complex set of
features, per unit time, fire together. The likelihood that a particular pattern will
come to be represented increases with each additional exposure of a firing pattern
ensemble. It has been increasingly documented that phonological systems are devel-
oped through exposure to the native language(s) (Kuhl et al., 1997). Each language
has its own set of phonemes that must be learned from experiencing repeating acous-
tic patterns within the ongoing speech waveform. As infants are exposed to a con-
tinuous speech stream from the environment, they must parse the incoming acoustic
signal into consistent, replicable chunks of time that occur in statistically predictable
178 CHAPTER 7 Fast ForWord: A Transformational Journey
sequences (Saffran, et al., 1996). It is hypothesized that when sensory inputs enter the
nervous system differentially in time, the neuronal representation develops as dis-
tinct and separable. However, when information enters the nervous system either si-
multaneously or within a critical window of time (tens of milliseconds) that is too
rapid to separate, the information is “bound” together and thus is neurally coded
as a unit (Wang et al., 1995). It is in this way that the many different physical features
of a complex stimulus, such as speech, are combined (bind together) to form a unified
phonological percepts (Tallal, 2004). For speech, statistically consistent acoustic
patterns occur frequently and consistently within the ongoing acoustic waveform
in chunks of various durations. Chunking within the tens of milliseconds (ms)
time window will allow for the fine grain analysis needed to represent the acoustic
differences between individual phonemes such as /b/ and /d/. Chunking over longer
periods of time (hundreds of milliseconds) will result in firing patterns consistent
with syllable length representations (Hickok and Poeppel, 2007). It is these chunks
of acoustic information, which form the building blocks for language, that can be
infinitely combined to form both spoken and written words. Furthermore, based
on optimal control theory (Todorov, 2006), it is hypothesized that similar unsuper-
vised statistical learning processes are at play for learning how words are combined
to form sentences that are consistent with the specific grammatical rules that govern
how each language is constructed.
While most children develop language without the need for explicit training, a
growing number of children are entering formal education without sufficient lan-
guage skills to support proficient written language and literacy development. Chil-
dren who fall within the lower end of the continuum of individual differences in
language development are diagnosed as having “language-based learning disabil-
ities.” In addition to linguistic studies that focus on describing the differential pattern
of language development in these populations of children (Leonard, 1998), research
has focused on delineating basic domain-general sensory, motor, and cognitive def-
icits that consistently co-occur with language impairments (Tallal et al., 1993). In
1973, I reported for the first time that children with developmental language impair-
ments were significantly impaired in both discriminating and sequencing two brief
(75 ms) complex tones differing in fundamental frequency when they were separated
by an inter-stimulus-interval (ISI) of 150 ms or less, but performed as well as age-
matched controls with longer duration ISIs (Tallal and Piercy, 1973). In a series of
follow-on papers, we showed that this deficit in “rapid auditory processing” (RAP)
extended to verbal stimuli that incorporated similarly brief, rapidly successive acous-
tic cues that are critical for speech identification and discrimination (Tallal and
Piercy, 1974, 1975). For example, the major cue for stop-consonants is the rapidly
changing frequency spectrum of the second and third formant transitions that is not
only transitional but also of short duration (approximately 40 ms). We hypothesized,
and subsequently demonstrated, that rather than being impaired in all aspects of
speech perception, children with developmental language impairments are selec-
tively impaired only in identifying and discriminating between those speech sounds
that depended on the processing of brief, rapidly successive acoustic cues. To further
3 Integrating Neuroplasticity-Based Training Research 179
specify the nature of this deficit, we used computer speech synthesis to control the
exact duration of acoustic cues within speech syllables (intrasyllabically). Specifi-
cally, we extended the duration of the formant transition within the syllables /ba/
and /da/ from 43 to 95 ms. The results of this study showed, for the first time, that
not only were children with SLI selectively impaired in discriminating the brief du-
ration of the discriminable components within speech syllables but that their percep-
tion could be virtually normalized by extending in time these brief duration acoustic
cues. Subsequent studies in our own and many other labs in the ensuing 20 years
showed that there is a highly significant correlation between a language impaired
child’s RAP performance (as measured by the ISI needed between two brief nonver-
bal tones) and (1) their speech perception and production abilities, (2) their language
comprehension abilities, and (3) their phonological awareness abilities as measured
by their nonword reading abilities (Stark and Tallal, 1988; Tallal, 2004). In subse-
quent prospective longitudinal studies beginning in infancy, we showed that the sin-
gle best predictor of verbal IQ in toddlers (36 months old) was their RAP threshold
(as measured by the ISI needed between two brief nonverbal tones) established when
they were infants (Benasich and Tallal, 2002). Importantly, infants’ RAP thresholds
did not predict subsequent nonverbal IQ, demonstrating the specificity of the rela-
tionship between RAP and language development. Remarkably, out of a large battery
of perceptual and cognitive tests, RAP thresholds established at 6 months of age
proved to be the single most powerful variable that, when combined with gender,
predicted 94% correctly those children who would score in the “impaired” range
on the Stanford Binet Verbal IQ test by age 3 years.
FIGURE 1
Screenshots from two Fast ForWord® Language V1 games are shown. (A) One of the speech
processing exercises (phonic match) that was designed in the format of a “concentration game.”
5 Designing Neuroplasticity-Based Training Games 183
FIGURE 1—Cont’d In this game, a series of squares with the same picture on them are laid out
on the computer screen in a visual grid. When each square is clicked, a syllable is presented
acoustically. The goal of this game is to find two syllables that match. When clicked
sequentially these two squares disappear. Bonus points, as indicated by the point counter
bottom right of the screen, are given when the screen is cleared with the fewest number of
clicks. To indicate this, the “progress creature” on the left begins at the top of the screen and
moves toward the chair with each successive click. The task begins at an easy level, with only
four squares and two pairs of syllables that were acoustically easy to discriminate. As each
player progresses, the number of squares in the grid increases (this screenshot shows nine
squares) while the acoustic difference between syllables decreases. (B) The game Language
Comprehension Builder adapted from Curtiss and Yamada Comprehensive Evaluation of
Language (CYCLE®, 2013) to train each role of English grammar. To initiate a trial, a
participant clicks on the hand on the ear button to indicate that they are ready to listen.
A command is presented acoustically, in this example, “Point to, the cup is broken.” One
correct picture and two or three foils were carefully designed to assure that comprehension of
a specific grammatical rule, not just vocabulary, is required to answer each command
correctly. Correct responses are rewarded by a “ding” sound and winning of a sticker along
the bottom and a point is added to the point counter. Incorrect responses are indicated by a
“clunk” sound, the command is repeated, and the correct picture is highlighted. After each
row of 10 stickers at the bottom is completed, additional reward in the form of bonus points
and an equivalent number of “ding” sounds are given. To assure that memorization of
commands does not occur, the same set of picture is also used for the command, “The cup is
not broken.” From Scientific Learning Corporation.
184 CHAPTER 7 Fast ForWord: A Transformational Journey
the context of listening comprehension. Yet another exercise (shown in Fig. 1B) was
designed to train English grammatical rules. The commands used in this game were
licensed from the Curtiss and Yamada Comprehensive Evaluation of Language
(CYCLE #). We adapted this comprehension assessment that was based on years
of laboratory research on the progression of normal and delayed language development
(Curtiss and Yamada, 2013) into a training exercise designed to train the rules of En-
glish grammar. These speech discrimination and language exercises were developed to
be individually adaptive; the goal being to find for each child a level of cognitive and
linguistic functioning that could be responded to at a high rate of accuracy (approxi-
mately 80% correct). As the exercise progressed, the goal was to move toward more
rapid and less amplified, natural speech following correct linguistic responses or back
to easier (more acoustically modified speech) following incorrect responses.
In addition to the speech discrimination and language comprehension exercises,
one game was designed to increase the speed of auditory processing. This computer
game used adaptive training with the goal of driving more efficient (shorter) tempor-
ospectral integration thresholds for rapidly successive acoustic sweep tones
(computer-generated tones that sweep from either high frequency to low frequency,
or low to high). To increase generalization across the entire frequency range of
speech, three different frequency ranges were selected that covered the frequency
range of human speech. As a child progressed in this game, the sweep tone stimuli
were individually adapted to decrease in the duration of the tones, the ISI between
tones, and the slope of the sweeps, based on each child’s trial-by-trial performance.
The overarching goal of these combined verbal and nonverbal training exercises was
to drive, through adaptive training, each child into the normal processing rate of tens
of milliseconds (the range important for phoneme perception) while simultaneously
increasing each child’s ability to process more complex linguistic structures.
received the exact same language training, but with natural speech. As such, this
study allowed a direct evaluation of whether or not there was added value of provid-
ing speech language training with the acoustically modified speech. Furthermore, the
Experimental group played the computer game designed to improve RAP skills,
while the Control group played a visual computer game for an equivalent period
of time that did not require rapid processing and was not temporally adaptive.
The camp ran for 6 weeks. In weeks 1 and 6, all subjects received a battery of stan-
dardized tests (pre- and post-training measures, respectively). They then received
training 5 days a week for 4 weeks. Training sessions were intermixed with breaks
for snacks, outdoor games, and art activities. Both groups participated together in the
same “computer camp” and received the same amount of training, reinforcement,
homework (listening to an audio storybook either with or without acoustically mod-
ified speech), and rewards for performance. This allowed a direct control for other
potential variables that could have an effect on performance such as test–retest ef-
fects, Matthew effects, regression to the mean, etc.
The results of these experiments were published in two back-to-back papers in
Science in 1996. The language results are reported in Tallal et al. (1996). Tradition-
ally, few children with language-learning impairments receive more than one or two
short (30–60 min) sessions of individual or group speech therapy per week and little
progress is expected to occur within only 4 weeks of clinical intervention. In contrast,
results from this study demonstrated that the rigor, scope, and consistency of the
training (100 min, 5 days per week for 4 weeks) resulted in highly significant im-
provements in speech discrimination, language processing, and grammatical under-
standing for both groups of children. This result has important clinical implications
for the intensity of speech therapy that needs to be provided for children with
language-based learning disabilities. However, in addition to showing the benefit
of more intensive language intervention, this controlled laboratory study also dem-
onstrated the added benefit of providing language instruction using acoustically
modified speech. Results showed that the Experimental group who received language
intervention training with acoustically modified speech demonstrated significantly
better outcomes in speech discrimination, language processing, and grammatical un-
derstanding than the Control group who received the same language intervention, but
with natural (unmodified) speech.
An accompanying paper published in the same issue of Science reported the re-
sults of the nonverbal rapid auditory sequencing training that the Experimental group
received for 20 min a day, 5 days a week for 4 weeks (Merzenich et al., 1996). This
study showed for the first time that basic auditory thresholds are highly modifiable in
human children by behavioral training. Importantly, this study also showed that the
measured improvement in a child’s auditory temporal threshold for correctly seg-
menting and sequencing successive nonverbal auditory sweep tones was signifi-
cantly correlated with post-training outcomes in real-time language processing
(r ¼ 0.81, p < 0.05). That is, the amount of improvement a child made in nonverbal
auditory processing speed was highly correlated with the amount of improvement
that child made in language comprehension.
186 CHAPTER 7 Fast ForWord: A Transformational Journey
in clinics and classrooms with fully computerized exercises, under the supervision of
clinicians and teachers (rather than trained researchers). In addition, in order to as-
sure consistency in program delivery, data collection and analysis, and quality con-
trol across multiple sites and long distances, the computerized adaptive training
programs were created in the form of a CD-Rom. Our next hurdle was to figure
out how to monitor the implementation of the program remotely, and interact with
the professionals delivering it to children at many different sites simultaneously
across days, weeks, and months. In this first version of what became Fast ForWord®
Language, trial-by-trial responses for each of the seven exercises in the program
were recorded on the hard drive of the computer each child used to play the games.
These responses were sent daily, protected by individual client ID numbers, over
the Internet to SLC where they are analyzed, tabulated, and immediately returned
electronically to the professional supervising the training. We recruited licensed
speech language pathologists (SLPs) who were interested in collaborating with us
to provide this novel intervention in their clinic or classroom to children who met
the criteria as LLI. We developed a 2-day, hands-on training workshop for SLPs that
covered the study design, subject selection inclusionary and exclusionary criteria,
how to set up the training on their own computer, how to upload and download
the data they were going to collect over the Internet, how to help children who might
be struggling to progress in the various exercises, and how to keep children moti-
vated throughout the daily exercises that were to be delivered for 100 min a day,
5 days a week for 4–8 weeks. What we had not anticipated, and what turned out to be
the most difficult early barrier to translating Fast ForWord® Language to real-world
settings, was that few SLPs in 1996 had a computer in their clinic or classroom, and
virtually none had an Internet connection! Thus, for many of our collaborating
schools and clinics, Fast ForWord® was their first experience using computer/
Internet technology.
Clinicians who volunteered to participate in this field trial were encouraged to
select a battery of standardized central auditory processing, speech, and language
tests that they used most commonly in their own clinical practice to assess children
with LLI. Children who were receiving speech therapy and scored at least one or
more standard deviations below the mean in the area of central auditory processing,
speech discrimination, and/or language comprehension were eligible for inclusion.
Case history records indicated that children who met these study criteria had one or
more of the following diagnostic classifications: SLI, attention deficit disorder, per-
vasive developmental disability, autism, central auditory processing disorder
(CAPD), dyslexia, or learning disability.
The first field trial included over 500 children aged 4–14 identified by 60 profes-
sionals at 35 clinical or educational sites. At each site, these independent speech lan-
guage professionals collected all of the pre- and poststandardized test data as well as
administered the Fast ForWord® Language training program to students who met the
study criteria. The goals of this first field trial were to determine (1) whether or not the
results obtained in the laboratory could be replicated by clinicians who most often treat
children with language-based learning problems; (2) whether the result would
188 CHAPTER 7 Fast ForWord: A Transformational Journey
generalize to a broader population of children with a variety of speech, oral, and writ-
ten language and/or CAPDs; and (3) whether efficacy would generalize to the wide
variety of standardized tests that are most commonly used clinically. This first field
trial was not designed to be a controlled study, but rather a “proof of concept” for scal-
ing up this novel approach for clinical and education settings while still maintaining
efficacy in terms of improved language functions. This is important because if the
training failed to improve language outcomes in the hands of clinicians in the field,
this would have indicated that the basic methods we were planning to use to scale
up our research were not effective in field settings. However, if the results did replicate
those found in the controlled laboratory studies, we could proceed to further scale up in
the field, as a randomized control trial had already demonstrated that the method was
effective in the laboratory. A summary of results from this first field trial are presented
in Miller et al. (1999), comparing pre-Fast ForWord training standardized test scores to
post-test standard scores. On average, the 35 sites reported convincing evidence that
clinicians can be trained to provide Fast ForWord® Language in their clinics and class-
rooms according to the prescribed protocol. Specifically, 90% of the children experi-
enced significant gains in one or more tested areas. Most children made significant
gains in multiple areas, including central auditory processing, phonemic awareness,
listening, speaking, attention, language fundamentals, grammar, and ability to follow
directions. On average, children advanced 1–2 years, based on standardized tests, fol-
lowing 4–8 weeks of Fast ForWord® Language participation. Significant improve-
ment was obtained in areas targeted by Fast ForWord® Language training. In
addition, results showed that efficacy generalized beyond areas directly trained to in-
clude improved expressive (spoken) language abilities as well as some early reading
(phonological awareness) abilities, despite the fact that no letters were included in any
of the Fast ForWord® Language exercises. Importantly, this finding demonstrated that
these methods not only improved skills that were directly trained but also generalized
to related skills that were not directly trained.
There was considerable variability across children as to the degree and pattern of
improvements they made across domains, as would be expected, based on the variety
of symptomatology and clinical classifications of this large heterogeneous group of
children with language-learning problems. Figure 2 shows that significant efficacy
was obtained for a much broader group of children than had been included in the
initial laboratory studies. Further analysis showed that differences in the degree of
efficacy were not based on the child’s clinical diagnostic classification, age, gender,
or degree of impairment. That is, this intervention method was shown to improve
language skills in both male and female children between the ages of 4 and 14 years
with a variety of clinical diagnoses and across a broad range of language functioning.
These results are significant not only in magnitude of improvement but specifically
in light of the very brief period of time (weeks rather than years) over which the in-
tervention (training) was provided. Thus, this first multisite, field trial, which was
conducted entirely by professional licensed SLPs in their own clinics or classrooms,
showed that the results that we initially found in our controlled laboratory studies
were broadly replicable in clinics and classrooms.
7 Scaling up: The “Neurotherapeutic Revolution” Fast 189
FIGURE 2
Comprehensive language quotients (Test of Language Development and Comprehensive
Evaluation of Language Function) for all children pre- and post-Fast ForWord® training.
Scores are shown for all children with language impairment (LI) combined, as well as for LI
children diagnosed clinically as having pervasive developmental disorder (PDD), or with
comorbid attention deficit disorder (ADD), or central auditory processing disorder (CAPD).
Although the degree of language deficit differed at pretest among these groups of children
(with children diagnosed as PDD having the most severe language disorder and CAPD having
the least severe), there were no significant differences in the magnitude of improvement
across groups achieved with training. All groups were 1 or more SD below the mean at pretest
and showed significant improvement (p < 0.0001) from pre- to posttraining. Although the
PDD group improved significantly following training, they still remained more than 1 SD below
the mean following training, based on these test batteries. The children with LIs comorbid for
ADD or CAPD entered the study with pretest scores more than 1 SD below the mean, while
their average test scores approached the normal median posttraining.
Adapted from Tallal et al. (1998).
trial included over 400 kindergarten through 3rd grades who were selected by their
teachers as “at-risk” for academic failure. Once students were selected by their
teachers as being “at risk,” they were randomly assigned to either receive Fast
ForWord® Language training or to receive the traditional educational services
being provided in their school for “at-risk” students. Students in the Comparison
group were matched by age and gender to the Experimental group. All participants
also received a battery of standardized tests both at the beginning and end of
the study.
One of the most striking findings from this field trial of school children se-
lected by their classroom teacher as being “academically at risk” was the finding
that, based on standardized test scores obtained prior to training, low receptive
language comprehension test scores proved to be these children’s most common
problem. Recall that these teachers were not instructed or encouraged to select
children for this trial based on language impairment, but rather based on their in-
tuition that a child was “at risk for academic failure.” As part of this study, we
asked teachers to complete a checklist indicating why they thought the child was
“at risk.” Most frequently checked were reading problems, attention deficits, im-
maturity, and behavioral problems. Least frequently checked were language com-
prehension deficits. This suggests that classroom teachers are not aware that it
may be weak receptive language skills that they are actually recognizing in “ac-
ademically at risk” students. Rather, once a child begins to fail in formal educa-
tion, it is assumed they are having difficulty learning to read and any special
services they receive generally focus on improving reading and other literacy
skills. This is compatible with results from an epidemiological study showing that
only 29% of children meeting the criteria for SLI in kindergarten had ever been
previously identified as language impaired (Tomblin, et al., 1997).
The results of this field study showed that before training, over half of the sub-
jects identified by their teachers as “academically at risk” scored one or more
standard deviations below the mean in oral language comprehension. As pre-
sented in Fig. 3, after Fast ForWord® Language, post-training results showed that
the oral language comprehension performance of these “academically at risk”
children significantly improved, shifting substantially to within the normal distri-
bution. These data confirmed the earlier findings from our laboratory-based con-
trol trial (Tallal et al., 1996). Consistent with the laboratory results, average gains
in this school-based randomized trial were 1–2 years on standardized measures of
language comprehension or phoneme awareness following 4–6 weeks of Fast
ForWord® Language participation. Furthermore, improvements were signifi-
cantly greater in children receiving Fast ForWord® Language, as compared to
the control group receiving standard intervention strategies (see Miller et al.,
1999; Tallal et al., 1998 for details).
Much of the data from these large-scale field trials have been published in
book chapters rather than peer-reviewed journals (Merzenich et al., 1998,1999;
Miller et al., 1999; Tallal et al., 1999). When we attempted to submit these data
for publication in peer-reviewed academic journals, we encounter a surprising
FIGURE 3
Pre- and post-Fast ForWord® Language v1 training frequency histograms for “at-risk”
students using z-scores of language comprehension performance (TACL-R) for the speech
and language training group (N-288). The bold lines superimpose a bell curve on the
histogram to represent the standard normal distribution of scores on this test. The change
from pre training (top) to posttraining (bottom) indicates a large positive shift in the
distribution of performance following 4–8 weeks of training. Prior to training, the language
comprehension performance for both groups was well-below average, approximately at
the 12.5 percentile for the normal distribution (−1.14 z-scores), a finding consistent with the
“at-risk” status assigned by their classroom teachers. At posttesting, control group
performance (not shown) had improved (21st percentile or −0.8 z-scores), but was still well-
below age-expected performance levels and lower than the performance of the training group
(38th percentile or −0.3 z-scores). The number of subjects performing at or above the median
in age-corrected language comprehension performance improved for the trained subjects
from 11.4% to 39.0% as compared to 12.0% to 16.2% for the control group (w2 ¼ 22.06,
p < 0.0001) for posttesting difference between experimental and control subjects. Scientific
Learning Corporation MAPS for Learning: Product Report 3 (1)1:13. http://www.scilearn.
com/alldocs/rsrch/sbr/30052ffwlanguageprodrpt.pdf.
192 CHAPTER 7 Fast ForWord: A Transformational Journey
setback to our translational efforts as scientists. Our papers were rejected, in some
cases even from being considered for peer-review because they now pertained to a
commercial product that we were helping to develop. When we raised the issue as
to how research data being translated out of the lab into clinics and classrooms
were supposed to be disseminated throughout the translational process, we were
told by one journal editor that this kind of data generally was published in product
manuals and on company websites, not in scientific journals.
used parents rather than the trained professionals to deliver the program to their
own impaired child at home. It is also important to emphasize that regardless of
when the study was actually published, all of the data included in this meta-
analysis were collected prior to 2005 using two very early, and now discontin-
ued, versions of Fast ForWord® Language v1.
Of the five studies included in the Strong et al. (2011) meta-analysis, the Gillam
et al. (2008) NIH-funded trial had by far the best implementation. The results from
this study demonstrated that students who used the Fast ForWord® Language prod-
ucts for 50 h achieved statistically significant improvements in language and reading
skills—improvements comparable to an active control group receiving 50 h of
one-on-one therapy with a licensed SLP. In this trial, 74% of the language impaired
children who received Fast ForWord® Language had follow-up scores that were
significantly higher than their pretest scores 6 months after treatment ended. In
addition, those children who received the computer-based interventions significantly
outperformed the active control groups in early reading skills, specifically phonolog-
ical awareness. It is confounding, considering these positive data on the efficacy of
Fast ForWord® Language reported in this NIH-funded trial, which is clearly the best
of the five studies included in this meta-analysis, that Strong et al. (2011) published
the following conclusion: “There is no evidence from the analysis carried out
that Fast ForWord is effective as a treatment for children’s oral language or reading
difficulties.” This statement is blatantly incorrect and in direct conflict with the
actual data.
In the years since these early studies were conducted, SLC has significantly al-
tered and improved the Fast ForWord® software, created improved protocols, and
provided better training and support to schools and clinics. In addition, nine new
products including a series of six products explicitly designed for reading interven-
tion have been released. It is important to emphasize that none of the data included in
this meta-analysis was derived from any of the currently used Fast ForWord® prod-
ucts. We encourage scientists and educators to consider the entire corpus of more
than 200 studies on Fast ForWord® products that are available or summarized on
the Scientific Learning website (http://www.scientificlearning.com/results). These
studies demonstrate the efficacy that has been achieved using more current versions
of Fast ForWord® Language (v2 and Literacy) and the Reading series (Readiness
and Levels 1–5), as well as the benefits that accrue when these products are imple-
mented with fidelity by experienced Fast ForWord® professionals in the educational
and clinical settings for which they were designed.
received Fast ForWord® Language training in their school under the supervision of an
experienced Fast ForWord® provider. Functional MRI was performed on 20 children
with dyslexia (8–12 years old), while they performed a phonological processing task in
the scanner, both before and after remediation with Fast ForWord® Language. Results
showed significantly improved oral language and reading performance after training.
After training, the children with dyslexia also showed increased metabolic activity in
the left temporoparietal cortex and left inferior frontal gyrus, brain regions associated
with phonological processing, bringing brain activation in these regions closer to that
seen in typical readers. Increased activity was also observed in right-hemisphere
frontal and temporal regions and in the anterior cingulate gyrus. Finally, a significant
correlation was found between the magnitude of increased activation in left tempor-
oparietal cortex and improvement in oral language ability.
In Gaab et al. (2007), whole brain fMRI was performed on 22 children with devel-
opmental dyslexia and 23 typical-reading children. In this study, nonspeech analogue
stimuli that differed in the duration of onset and offset were used as stimuli. As had
been found in adults, fMRI results with these nonspeech stimuli demonstrated that
the typical-reading children showed activation for rapid (20 ms) compared to slow
(200 ms) transitions in left prefrontal cortex. Children with developmental dyslexia
failed to show any differential metabolic response in these regions to rapid versus slow
transitions. Remarkably, after only 8 weeks of training with Fast ForWord® Language,
the children with developmental dyslexia not only showed significant improvements in
language and reading skills but also exhibited substantially “normalized” activation for
rapid relative to slow transitions in left prefrontal cortex. Gaab et al. (2007) concluded
that the presence of a disruption in the neural response to rapid versus slow acoustic
transitions in children with developmental dyslexia prior to remediation, coupled with
significant improvement in language and reading scores and increased brain activation
after remediation, gives further support to the inclusion of training aimed at increasing
RAP in interventions for reading disabilities.
A study done in Helen Neville’s lab examined whether 6 weeks of high-intensity
(100 min/day 5 days per week) training with Fast ForWord® Language would influ-
ence neural mechanisms of selective auditory attention previously shown to be de-
ficient in children with SLI (Stevens et al., 2008). Twenty children, 8 diagnosed with
SLI and 12 with typically developing language received training in the lab. An ad-
ditional 13 children with typically developing language received no specialized
training (NoTx control group) but were tested and retested after a comparable time
period to control for maturational and test–retest effects. Before and after training,
children completed standardized language assessments and an event-related brain
potential measure of selective auditory attention. Relative to the NoTx control group,
both the dyslexic and typical children who received training showed significant in-
creases in standardized measures of receptive language as well as larger increases in
the effects of attention on neural processing. The enhanced effect of attention on neu-
ral processing represented a large effect size (Cohen’s d ¼ 0.8) and was specific to
changes in signal enhancement of attended stimuli. These findings indicate that the
7 Scaling up: The “Neurotherapeutic Revolution” Fast 195
The Fast ForWord® Reading series currently includes the following six products;
each product includes five to seven exercises “disguised” as computer games:
Fast ForWord® Reading Readiness builds prereading skills, with a focus on letter
recognition and naming, phonological awareness, and letter-sound associations.
Fast ForWord® Reading Level 1 builds critical early reading skills, with an
emphasis on phonemic awareness, early decoding skills, vocabulary knowledge
and skills, and motivation for reading.
Fast ForWord® Reading Level 2 consolidates early reading skills, with a focus on
applying phonics and decoding strategies, improving word recognition, and
understanding the rules for reading comprehension.
Fast ForWord® Reading Level 3 builds on the Fast ForWord® Reading Level 2
product by concentrating on reading knowledge and fluency, with a focus on
phonology and spelling, morphological properties and complexity, syntactic
complexity, vocabulary and comprehension.
Fast ForWord® Reading Level 4 builds reading skills in school by applying
knowledge of word origins, word forms, sentence structures, and punctuation
rules to improve comprehension.
Fast ForWord® Reading Level 5 is appropriate for students in upper elementary,
middle, and high school. It concentrates on enhancing advanced reading
comprehension skills and expanding vocabulary skills.
Details pertaining to the science behind the development of each exercise within the
Fast ForWord® Reading series, school-based research studies evaluating their effi-
cacy, and descriptions and screen shots of each exercise can be found at: http://www.
scilearn.com/products/fast-forword-reading-series/.
used a repeated measures design that was based on tracking literacy scores on
statewide standardized achievement tests over a number of years before and sub-
sequently after the school introduced Fast ForWord® products. The goal of this
design was to determine if the slope of the trajectory of students’ scores was sig-
nificantly increased after Fast ForWord® use. Figure 4 shows the highly signif-
icant results one district achieved using this design, both in literacy and math.
Although it is very difficult to do in a regular school setting, some school-based
studies conducted randomized control trials (RTC). Two were conducted by
teachers in their own schools for their doctoral research (Rogowsky, 2010;
Slattery, 2003). Both of these studies found significantly greater literacy improve-
ments in the students who had been randomly assigned to receive Fast ForWord®
training as compared to the students in the control groups who participated in an-
other school program. For example, for her thesis research, Rogowsky (2010)
conducted an RTC of Fast ForWord® Literacy and Fast ForWord® Reading Level
2 products with middle school students. As a middle school writing instructor, she
was particularly interested in whether these products would lead to improvements
in Standardized Edited American English (SEAE) writing skills, as measured by a
standardized writing assessment. After 6 weeks of training, her results showed
that the children who had received Fast ForWord® training improved in authentic
writing skills significantly more than those that had been randomly assigned to
the active control groups. Rogowsky et al. (2013) followed up this middle school
study with a college population. Twenty-five college students (12 native English
language; 13 English Second Language), who demonstrated poor writing skills,
received daily training during the spring semester (11 weeks) with Fast For-
Word® Literacy and upper levels of Fast ForWord® Reading (Levels 3–5). A
comparison groups of students (N ¼ 28) attending the same university did not re-
ceive training. All students took the Gates MacGinitie Reading Test (GMRT) and
the Oral and Written Language Scales (OWLS) at the beginning (Time 1) and end
(Time 2) of the spring college semester. Results from this study showed that the
training group made a statistically greater improvement from Time 1 to Time 2 in
both their reading skills and their writing skills than the comparison group. As can
be seen in Fig. 5, the group who received training began with statistically lower
writing skills before training, but exceeded the writing skills of the comparison
group after training (Rogowsky et al., 2013).
Studies on the effectiveness of educational interventions are inherently
difficult, in part because of the many skill sets required to conduct these studies
in real-world clinics and school settings. Before introducing a new method,
curriculum, or product, schools have to answer a practical question: does the
new approach lead to better outcomes for their students than whatever interven-
tion strategies they currently have in place? In translating research from the lab-
oratory to classrooms, we have found that most schools’ administrators and
curriculum directors are only willing to make important decisions for their school
after they have conducted their own, internal, independent study. As a result, hun-
dreds of independent school-based studies, some of them RTC, of one or more
FIGURE 4
District-wide longitudinal trends of 4th-grade Louisiana Education Assessment Program (LEAP)
achievement levels of the St. Mary Parish district in 2003 (3 years before Fast ForWord®
implementation began in 2006) and extending through 2011, as compared to Louisiana state-
wide LEAP scores. In the 2006–2007 school year, the St. Mary Parish Public School System
started school-wide use of the Fast ForWord® Language and Reading products at eight
elementary schools that were in Academic Assistance (a designation for schools that fail to
improve sufficiently). During the 2008–2009 school year, the remaining elementary schools
began using the Fast ForWord® products as well. Top: Percentage of students at or above Basic
Level on initial LEAP English Language Arts (ELA). Bottom: Percentage of students at or above
Basic Level on initial LEAP Math. Solid line: St. Mary’s Parish School district, dashed line: state-
wide average from 2006 to 2011, 4th grade English Language Arts proficiency levels rose from
55% to 81%; Math proficiency levels rose from 59% to 80%. Learning: Research Reports 16(2):
1–9. http://www.scilearn.com/alldocs/rsrch/sbr/30530stmaryparishedurpt.pdf.
200 CHAPTER 7 Fast ForWord: A Transformational Journey
FIGURE 5
College students’ Written Expression Scale standard scores of the Oral and Written
Language Scales (OWLS) for struggling and average writers. Mean values for the struggling
writers (N ¼ 25) who participated in the training group (filled squares) and N ¼ 28
comparison participants (open circles) are shown at Time 1 compared to Time 2, 11
weeks later. Vertical bars indicate standard errors of mean. While the comparison group
outperformed the training group students on the OWLS Writing Expression Scale at Time
1, the trained group’s considerable spurt in writing following Fast ForWord® Language v2
and Reading (Levels 3–5) intervention led to a reversed performance pattern at Time 2,
with higher standard writing scores achieved by the trained students. From Rogowsky
et al. (2013).
students), breaking out results further into Proximal and Distal effect sizes. The two RCT
studies (Miller et al., 1999; Slattery, 2003) showed large proximal effect sizes (7.45 and
1.46, respectively), while the Slattery study also showed a Large Distal effect size (1.05).
For full report, see http://www.rti4success.org/instructionTools.
Nevada Senate Bill 185 (SB 185) funded districts to purchase and implement in-
novative and remedial educational programs, materials, and strategies specific to their
academic needs. The Nevada Department of Education commissioned the Colorado-
based Leadership and Learning Center (LLC) to conduct an in-depth evaluation of the
programs that were purchased with SB 185 grants. Their 2010 Interim Report includes
a review of the performance of Fast ForWord® products, which were used at three
schools. The Leadership and Learning Center used multivariate analysis to determine
the impact of programs on student achievement: “Emphasis was placed on measuring
student growth toward academic proficiency and mastery using state and local
assessments. . .. The analyses were completed as a result of extensive site visits, phone
interviews, and an examination of two-year sets of school cohort achievement data for
Criterion- Referenced Tests (CRT) for grades three through eight and High School
Proficiency Exams (HSPE) for grades nine through twelve.” The advantage of this re-
port is that it compares many of the currently available commercial products. This re-
port concludes that Fast ForWord® products increased student reading achievement
scores by an average of 22.2 percentage points. Fast ForWord® was found to have
the largest average impact of all programs reviewed in the report and it qualified Fast
ForWord® to be classified as a “High-Gain Program.”
The What Works Clearing House (WWC) was created by the NSF Institute for Ed-
ucation Sciences (IES) to review and give ratings to products and programs aimed at
teaching and improving academic skills. According to their website the WWC has de-
veloped and standardized a stringent rating scale both for the quality of a research study
as well as the effectiveness of a product or program. WWC selects specific topics of
most concern to educators, strictly defines the scope for each topic area, and specifies
the grade range that each review will include. Fast ForWord® products have been
reviewed and received positive rating in three areas: Early Reading K-3rd grade, Ad-
olescent Literacy 3rd–10th grade, and English Language Development K-6th grade.
WWC: Early Reading Effectiveness Rating K-3rd Grade. The WWC identified
nine studies of Fast ForWord® that both fell within the scope of the Beginning Read-
ing topic area and met WWC evidence standards. Seven studies met standards with-
out reservations and two studies meet WWC evidence standards with reservations.
Together, these studies included 1390 students from several areas of the United
States and Western Australia. Results show that WWC considers the extent of evi-
dence for Fast ForWord® on the reading skills of beginning readers to be medium to
large for two outcome domains—alphabetics and comprehension—and small for one
outcome domain—reading fluency.
WWC: Adolescent Literacy Effectiveness Rating Grades 3-10. The WWC identi-
fied two studies of Fast ForWord® that fell within the scope of the Adolescent Literacy
review protocol that met evidence standards, and six studies that met WWC evidence
10 Cognitive Neurotherapeutics: The Challenges of Translation 203
standards with reservations. The eight studies included approximately 2000 students,
ranging in age from 5 to 17 years, who attended elementary, middle, and high schools
in Indiana, Maryland, North Carolina, Ohio, Pennsylvania, Virginia, an urban district
in the northeastern United States, and Australia. Based on these eight studies, the
WWC considered the extent of evidence for Fast ForWord® on adolescent learners
to be small for the alphabetics and reading fluency domains and medium to large
for the comprehension and general literacy achievement domains.
WWC: English Language Development Grades K-6. The WWC identified one study
of Fast ForWord® Language that met evidence standards and a second study that met
standards with reservations. The two studies included a total of 250 K—6th grade En-
glish Language Learners (ELL) from 16 school districts. The studies examined English
language development and reading achievement. For some unspecified reason, for this
topic area phonological and phoneme awareness, which are the most important early
reading skills for elementary ELL and those that Fast ForWord® Language has been
shown to most significantly improve, were considered to be outside the scope of this
review and were not included in measures of reading achievement. Given that none
of the Fast ForWord® Reading products were evaluated, improvement in higher levels
of reading would not be expected. On the other hand, Fast ForWord® Language re-
ceived a positive rating for improvement of English language development, raising
the English language scores of ELL students by an average of þ31 percentile points.
This was one of the highest ratings given by WWC for English Language Development
for ELL K-6 students.
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CHAPTER
Abstract
The beneficial effects of musical training are not limited to enhancement of musical skills, but
extend to language skills. Here, we review evidence that musical training can enhance reading
ability. First, we discuss five subskills underlying reading acquisition—phonological aware-
ness, speech-in-noise perception, rhythm perception, auditory working memory, and the abil-
ity to learn sound patterns—and show that each is linked to music experience. We link these
five subskills through a unifying biological framework, positing that they share a reliance on
auditory neural synchrony. After laying this theoretical groundwork for why musical training
might be expected to enhance reading skills, we review the results of longitudinal studies pro-
viding evidence for a role for musical training in enhancing language abilities. Taken as a
whole, these findings suggest that musical training can provide an effective developmental
educational strategy for all children, including those with language learning impairments.
Keywords
music, reading, phonological, speech, brain, rhythm
Decades of research have established that musical training has profound effects on the
development of the brain. Lifelong musicians show reliable differences in brain structure
when compared to nonmusicians, including white matter organization within the corpus
callosum (Lee et al., 2003; Schmithorst and Wilke, 2002; Steele et al., 2013) and the ar-
cuate fasciculus (Bengtsson et al., 2005) and thicker gray matter in motor and auditory
cortices (Bangert and Schlaug, 2006; Bermudez et al., 2009; Elmer et al., 2013; Gaser and
Schlaug, 2003a,b; Hyde et al., 2009; Keenan et al., 2001; Schlaug, 2001; Schlaug et al.,
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00008-4
© 2013 Elsevier B.V. All rights reserved.
209
210 CHAPTER 8 Music Training and Reading
1995, 2005; Schneider et al., 2002, 2005; Sluming et al., 2002). Musical training’s ability
to alter the structure of the brain is an impressive demonstration that neural development
is shaped by a complex interaction between genes and environment and can be, therefore,
dramatically changed by experience throughout life.
That musical training shapes the brain is not in question. However, the limits of
the influence of musical training are still being established. Are the benefits of mu-
sical experience limited to musical abilities, or do they extend to language abilities as
well? Here, we review evidence that musical training can enhance language skills
underlying reading ability. One of the ingredients necessary for transfer of learning
from musical experience to language skills is overlap between the processes under-
lying the perception and production of language and music (Patel, 2010, 2011, 2013).
The first section of this review, therefore, is structured around abilities and neural
functions that have been shown to be vital for reading: phonological awareness,
speech-in-noise perception, rhythm perception, auditory working memory, and
sound pattern learning. All of these processes have also been shown to be enhanced
by musical training. These links between musical and linguistic abilities, and evi-
dence for an overlapping biological basis for performance in the two domains, dem-
onstrate the close relationship between these two systems. Moreover, these findings
suggest that musical training might provide an effective developmental educational
strategy for all children, including those with language learning impairments. After
laying this theoretical groundwork for why musical training might be expected to
enhance reading skills, we review the results of longitudinal experimental studies
providing evidence for a role for musical training in enhancing language abilities.
1 PHONOLOGICAL AWARENESS
Many language skills, from reading to speech perception and production, rely upon
phonological awareness, the explicit knowledge of the components of speech and
how they can be combined (Ramus, 2003; Ramus et al., 2003; Rvachew and
Grawburg, 2006; Siegel, 2006). Phonological awareness, in turn, relies upon the abil-
ity to categorize speech sounds (Berent et al., 2012; Boets et al., 2008, 2011; King
et al., 2002; Kraus et al., 1996; Reed, 1989; Richardson et al., 2003; Serniclaes et al.,
2004; Sharma et al., 2006; Tsao et al., 2004; Vandermosten et al., 2011), which are
distinguished by small differences in timing and frequency content. The syllable
[da], for example, can be distinguished from [ta] by as little as 10 ms voice onset
time. The auditory system’s hallmark ability to represent timing and frequency with
high degrees of precision is, therefore, vital to language acquisition and use, and chil-
dren who display deficits in auditory temporal and frequency resolution also exhibit
problems with language skills. For example, children with language learning impair-
ments have difficulty detecting a sound when it is followed immediately by a noise
burst, a phenomenon known as backward masking (Gibson et al., 2006; Griffiths
et al., 2003; Marler et al., 2001, 2002; McArthur and Hogben, 2001; Montgomery
et al., 2005; Tierney and Kraus, 2013a; Wright et al., 1997). These children do
not perform poorly when the noise is presented simultaneously with the tone
1 Phonological Awareness 211
(Montgomery et al., 2005), suggesting that the problem does not stem from a global
auditory deficit but that language skills are specifically tied to the precision of tem-
poral encoding in the auditory system. Further evidence for a link between reading
ability and auditory temporal encoding comes from research showing that reading
skill is linked to the ability to tap consistently to a beat and the ability to discriminate
rhythmic patterns (reviewed below).
Not only is precise temporal encoding necessary for speech discrimination, but
precise frequency representation is crucial as well, as many speech sounds can be
differentiated on the basis of frequency content or changing frequency contours. Ac-
cordingly, the ability to detect sinusoidal changes in frequency is also linked to read-
ing skills and phonological awareness (Boets et al., 2008, 2011; Gibson et al., 2006;
Talcott et al., 2000; Wright and Conlon, 2009). Further evidence for a link between
frequency and pitch perception and reading skill comes from studies of the ability to
discriminate pitch patterns. For example, normal-reading subjects perform better
than learning-disabled readers on tests of tonal pattern discrimination (Atterbury,
1983, 1985). Other researchers (Barwick et al., 1989) found that reading ability cor-
related with tonal memory and chord discrimination in a group of 9-year-olds. Lamb
and Gregory (1993) found that pitch discrimination was significantly related to read-
ing ability in 5-year-olds. Anvari et al. (2002) found that melody and chord discrim-
ination correlated with phonemic awareness and reading. Forgeard et al. (2008)
found that children with dyslexia showed deficits on melody discrimination.
Speech sounds are brief in natural speech. As a result, detecting and discriminat-
ing speech sounds not only requires precise representations of time and frequency
information; the listener must also be able to make rapid auditory judgments, which
may therefore be particularly important for the development of phonological aware-
ness. Certain perceptual judgments are only difficult for children with language
learning problems if they must be completed rapidly, in a brief amount of time
(Tallal and Gaab, 2006); these skills include detection of the order of stimuli
(Breier et al., 2003; Griffiths et al., 2003; Rey et al., 2002; Tallal, 1980; Tallal
and Piercy, 1973a,b), detection of tone pairs (Choudhury et al., 2007), and speech
sound discrimination (Tallal, 2004; Tallal and Piercy, 1974, 1975). Moreover, rapid
auditory processing ability in infants and toddlers can predict the acquisition of lan-
guage skills later in life (Benasich and Tallal, 2002). Consistent with this relationship
between reading and temporal processing, there is also, as discussed in detail below,
a strong relationship between reading and the perception of rhythm.
Reading ability, therefore, relates to temporal and frequency resolution, rapid au-
ditory processing, and phonological awareness. These four skills may in turn rely
upon a common neural foundation—neural synchrony in the auditory system—which
may be crucial for the acquisition of reading. Supporting this Neural Synchrony
Hypothesis, the electrophysiological responses to sound of children with language
impairments differ from those of normally developing peers in a number of ways,
all indicative of reduced neural synchrony on time scales ranging from microseconds
to seconds. For example, both rapid subcortical and cortical neural responses to sound
are delayed in language-impaired children (Banai et al., 2005, 2009; Basu et al., 2010;
212 CHAPTER 8 Music Training and Reading
Benasich et al., 2006; Billiet and Bellis, 2011; Hayes et al., 2003; Hornickel et al.,
2009, 2011; King et al., 2002; Rocha-Muniz et al., 2012; Song et al., 2008).
Language-impaired children also tend to have subcortical responses to speech sounds
with diminished representations of the higher frequencies (300 Hz and above) critical
for speech sound discrimination (Banai et al., 2009; Hornickel et al., 2011, 2012;
Rocha-Muniz et al., 2012; Wible et al., 2004), indicating decreased phase-locking that
may underlie diminished behavioral frequency tracking. Language-impaired chil-
dren’s diminished neural synchrony may hinder their ability to discriminate speech
sounds, as children with poor phonological awareness have subcortical responses that
distinguish to a lesser degree between different speech sounds (Hornickel et al., 2009,
2011). Reading ability is also linked to trial-by-trial consistency in the subcortical re-
sponse to sound (Hornickel and Kraus, 2013). Similarly, trial-by-trial response consis-
tency in the cortex is diminished in rats with allelic variations in a gene associated with
dyslexia (Centanni et al., 2013).
Many of these same indices of auditory neural synchrony are enhanced by musical
training. For example, musicians have faster neural responses (on the scale of tenths of
milliseconds) to both musical and speech sounds (Musacchia et al., 2007, 2008;
Parbery-Clark et al., 2009b, 2012a,b,c; Strait et al., 2009, 2012, 2013a,b). Musicians
also show enhanced encoding of the same frequencies of speech stimuli (above
300 Hz) which are less robustly represented in language-impaired children. Further-
more, just like the neural responses of good readers, the neural responses of musicians
better encode the differences between speech sounds. See Fig. 1 for an illustration of
how neural differentiation of speech sounds is impaired in participants with poor pho-
nological awareness and enhanced in musicians. The trial-by-trial consistency of the
neural response to sound has also been linked to the ability to move to a beat
(Tierney and Kraus, 2013b) and is enhanced in older musicians compared to nonmu-
sicians (Parbery-Clark et al., 2012b). See Fig. 2 for an illustration of how trial-by-trial
response consistency relates systematically to reading ability (Hornickel and Kraus,
2013) and is enhanced in musicians (Skoe and Kraus, 2013). Cortical responses have
been shown to be enhanced in musicians as well (Schneider et al., 2002, 2005; Shahin
et al., 2003, 2004; Tervaniemi et al., 2006, 2009).
FIGURE 2
Trial-by-trial neural response consistency varies systematically with reading ability (left panel)
(modified from Hornickel and Kraus, 2013) and is enhanced in musicians (right panel)
(modified from Skoe and Kraus, 2013). Musicians were trained on a wide variety of
instruments beginning by age 12. These data span a wide variety of ages, combined across
several studies, and thus the number of years of training varied depending on the age of the
population studied. Response consistency is measured by dividing all the neural responses to
a sound collected in a given subject into two halves, averaging these trials to form two different
waveforms, and then correlating the two waveforms.
214 CHAPTER 8 Music Training and Reading
correlations between the stimulus and the response, delayed responses, and smaller
amplitudes (Anderson et al., 2010; Cunningham et al., 2001; Warrier et al., 2004;
Wible et al., 2005).
Musical training, on the other hand, increases the auditory system’s resilience to
noise and other sources of signal degradation, decreasing the effects of background
noise and reverberation on response amplitude, timing, and encoding of speech har-
monics (Bidelman and Krishnan, 2010; Parbery-Clark et al., 2009b, 2012a; Strait
et al., 2012, 2013b; Tierney et al., 2013 reviewed in Strait and Kraus, 2013). Musicians
also are better able to perceive speech degraded by noise or reverberation across the
life span, from infancy through old age (Bidelman and Krishnan, 2010; Parbery-Clark
et al., 2009a, 2011a, 2012a; Zendel and Alain, 2012, 2013; Tierney et al., 2013;
reviewed in Kraus et al., 2012). See Fig. 3 for a demonstration of the musician advan-
tage for speech-in-noise perception, the excessive noise-induced delay in reading im-
paired children (Anderson et al., 2010), and the smaller noise-induced delay in the
musician neural response to sound (Strait et al., 2012). See Table 1 for an overview
of the neural “signatures” to speech syllables linked to both reading ability and musical
experience (Kraus and Nicol, in press).
3 RHYTHM
Correctly perceiving the structure of music requires the perception and maintenance
in memory of patterns in time extending over several seconds. Rhythmic structure in
music does not consist solely of durational patterns, however; notes are also given
different levels of prominence based on how they align with a metrical framework
that operates on multiple levels (Palmer and Krumhansl, 1990). The presence of met-
ric structure helps guide beat perception: When tapping to the beat of rhythmic pat-
terns, participants tend to tap close to beats that fall at the beginning of a measure
rather than in the middle (Patel et al., 2005). Similarly, when perceiving speech,
the listener can take advantage of durational regularities such as the slowing that
tends to occur as speakers approach the ends of sentences (Fant et al., 1991; Klatt
and Cooper, 1975; Vaissière, 1991; Venditti and van Santen, 1998) and the some-
what predictable occurrence of syllables with different degrees of stress, one corre-
late of which is duration (Lieberman, 1960). These temporal regularities can be
useful cues for speech segmentation (Cutler and Butterfield, 1992; Nakatani and
Schaffer, 1978; Smith et al., 1989), which is necessary for the development of pho-
nological awareness. Supporting the role of speech rhythm in the development of
phonological awareness and reading ability, good readers show a greater sensitivity
to speech rhythm as measured by tasks such as distinguishing between compound
nouns and noun phrases (i.e., “lighthouse” vs. “light house”) and matching a low-
pass-filtered spoken phrase with one of two nonfiltered phrases (Gutiérrez-Palma
and Palma Reyes, 2007; Holliman et al., 2010; Whalley and Hansen, 2006;
Wood, 2006; Wood and Terrell, 1998).
3 Rhythm 215
School-age
Speech-in-noise perception
-5 -5
70 children Young adults Older adults
60
*** -4 ** -4
50 **
-3 -3
40
30 -2 -2
20
-1 -1
10
0 0 0
Musicians Nonmusicians Musicians Nonmusicians Musicians Nonmusicians
Neural timing (ms)
Tracking rhythmic patterns is, therefore, vital for both music and speech percep-
tion, which in turn is important for the acquisition of reading skills. Moreover, it has
been suggested that the same neural mechanism is responsible for tracking rhythm in
music and speech. An influential theory of musical rhythm perception, Dynamic
Attending Theory, proposes a set of neural oscillators that phase-lock and resonate
to the temporal structure of music, resulting in an attentional focus that waxes and
wanes, following the rhythmic structure of a piece or song (Large, 2000, 2008;
Large and Jones, 1999; McAuley and Jones, 2003; Velasco and Large, 2011). As
evidence in support of this theory, listeners are faster at performing a variety of per-
ceptual tasks if stimuli are presented aligned with an expected beat (Barnes and
Jones, 2000; Bolger et al., 2013; Escoffier et al., 2010; Grube and Griffiths, 2009;
Table 1 Musicians and good readers show enhancements in similar neural measures in response to speech syllables, suggesting
overlapping biological bases for musical expertise and reading ability
F0 syllable Speech formant Onset Syllable Response Response disruption by
representation representation timing harmonics consistency background noise
In particular, reading acquisition may rely on neural synchrony, which musical training enhances.
3 Rhythm 217
Jones et al., 2002; Ladinig et al., 2009; Miller et al., 2013). Stimuli aligned with
stronger metrical positions also give rise to larger electrophysiological potentials
(Abecasis et al., 2005, 2009; Brochard et al., 2003; Geiser et al., 2009, 2010;
Ladinig et al., 2009; Pablos Martin et al., 2007; Potter et al., 2009; Schaefer
et al., 2011; Vlek et al., 2011; Winkler et al., 2009) and greater oscillatory activity
in the beta and gamma range (Iversen et al., 2009; Snyder and Large, 2005). More-
over, neural oscillations have been recorded which reproduce the perceived rhythmic
structure of abstract rhythmic patterns (Nozaradan et al., 2011, 2012).
A similar neural mechanism has been proposed for the tracking of the rise and fall
of speech amplitude over time (Goswami, 2011; Poeppel et al., 2008): phase-locking
of slow neural oscillations in the delta and theta range (2–7 Hz). This Temporal Sam-
pling Hypothesis proposes that delta/theta oscillatory phase-locking selectively
“samples” the low-frequency information in the amplitude envelope, which is crucial
for the segmentation of speech and discrimination of speech sounds (Drullman,
1994). Supporting this hypothesis, electrophysiologic recordings from auditory cor-
tex can reflect the speech envelope (Abrams et al., 2008; Aiken and Picton, 2008;
Doelling et al., 2013), and the phase of slow oscillations in neural responses can
be used to discriminate spoken sentences (Luo and Poeppel, 2007). That this enve-
lope tracking is important for the development of language skills rather than a mere
epiphenomenon is demonstrated by the fact that while good readers show right-
lateralized envelope tracking, poor readers show envelope tracking that is distributed
symmetrically across the two hemispheres (Abrams et al., 2009). Similarly, while
normally developing subjects show right-lateralized phase-locking to low-frequency
(2 Hz) amplitude modulation, subjects with dyslexia show symmetrically distributed
phase-locking (Hämäläinen et al., 2012).
If the Dynamic Attending Theory and the Temporal Sampling Hypothesis are
both correct, rhythm in music and the envelope of speech may be tracked biologi-
cally via the same mechanism—phase-locking of low-frequency neural oscillators
to slow rises and falls of amplitude, a mechanism that (like the fine temporal and
frequency representation discussed in the first section of this chapter) relies upon ro-
bust neural synchrony. Thus, strengthening this mechanism through training in one
domain could lead to benefits for the other. This shared mechanism could explain
why reading ability and phonological awareness relate to a variety of rhythm-
tracking abilities, including discrimination of stimuli based on amplitude rise times
(Goswami et al., 2002, 2011; Hämäläinen et al., 2005; Leong et al., 2011; Muneaux
et al., 2004; Surányi et al., 2008; Thomson and Goswami, 2008; Thomson et al.,
2006) and temporal patterns (Anvari et al., 2002; Atterbury, 1983, 1985; Douglas
and Willatts, 1994; Forgeard et al., 2008; Huss et al., 2011; McGivern et al.,
1991; Overy, 2000, 2003; Strait et al., 2011), reproduction of rhythmic patterns
(Atterbury, 1983, 1985; Creak, 1936; Dellatolas et al., 2009; Peynircioglu et al.,
2002; Rautenberg, 2013), tempo reproduction (Moritz et al., 2012), and tapping to
the beat of music (David et al., 2007). Children with language learning impairment
have been shown to tap more variably to a beat (Corriveau and Goswami, 2009;
Thomson and Goswami, 2008; Thomson et al., 2006; Wolff, 2002), and this
218 CHAPTER 8 Music Training and Reading
60 60
40 40
30 30
20 20
10 10
80 90 100 110 80 90 100 110 120
Nonword reading Word reading
Rhythm
Neural response
Reading
consistency
FIGURE 4
The ability to tap to a beat is linked to reading ability and is strengthened with musical training
(Slater et al., 2013). (Top) Good readers (according to score on the Woodcock-Johnson III
standardized tests Word Attack and Letter-Word ID) tap less variably to the beat of a
metronome (replotted with permission from Tierney and Kraus, 2013a). Word reading,
r ¼ 0.38, p ¼ 0.0036; nonword reading, r ¼ 0.35, p ¼ 0.0067. (Bottom) The relationship
between reading and rhythm may in part be driven by a shared reliance on precise auditory
encoding, as both reading and beat synchronization ability relate to the consistency of the
neural response to sound.
School-age
children
130
110
100
90
80
Good Poor
readers readers
School-age
Young adults children Older adults
Auditory working memory
130 130
130
FIGURE 5
Auditory working memory is linked to both reading ability and musical training. (Top) School-
age good readers (divided into halves based on performance on the Test of Silent Word
Reading Fluency) perform better (standardized scores) than poor readers on the Woodcock-
Johnson III test of auditory working memory (unpublished data). (Bottom) Musical
experience is linked to an enhancement of auditory working memory across the lifespan.
Modified from Kraus et al. (2012).
Musicians, on the other hand, show an enhanced ability to lock onto regularities
in sound. Francois and Schön (2011) demonstrated that musicians were better able to
learn both musical and linguistic regularities in a sung language: the degree to which
stimuli followed an underlying musical or linguistic rule modulated electrophysio-
logical responses to a greater extent in musicians compared to nonmusicians. In a
follow-up longitudinal study, François et al. (2013) studied 8-year-old children
for 2 years as they were trained in either music or painting. At pretest, after 1 year,
and after 2 years of training, the painting group was unable to learn the transitional
probabilities between stimuli. The music group performed at chance at pretest, but
performed above chance after 1 year and again after 2 years of training, demonstrat-
ing an enhanced ability to extract the rules underlying word segmentation. Further-
more, whether or not stimuli followed the learned rule modulated
electrophysiological responses to a greater extent in the music group after 2 years
of training. Similarly, Skoe et al. (2013) found that subjects with musical training
were better able to detect the transitional probabilities within tone sequences and
6 Summary and Limitations of Cross-Sectional Studies 221
the number of years of training correlated with the extent to which the presence of
statistical patterns in tone sequences affected the subcortical response to sound.
Another, simpler way to examine the neural tracking of stimulus regularities is to
present a speech sound in one of two contexts: either within a stream consisting of
only that same sound or among a set of other sounds. In good readers, the sound pre-
sented in the consistent, predictable context elicits a larger electrophysiological re-
sponse compared to the unpredictable condition. In poor readers, however, the
response is more similar in the two conditions (Chandrasekaran et al., 2009; Strait
et al., 2011), suggesting that reading is tied to the ability to track patterns in sound.
This predictability enhancement is also tied to musical aptitude (Strait et al., 2011)
and is larger in musicians than in nonmusicians (Parbery-Clark et al., 2011b). Mu-
sical training may, therefore, exercise mechanisms for the detection of patterns in
sound that are also critical for reading acquisition.
training and reading comprehension performance, even after controlling for age, so-
cioeconomic status, IQ, and number of hours that children spent reading per week.
Length of music training has also been reported to correlate with speech-in-noise
perception (Parbery-Clark et al., 2009a) and auditory working memory (Strait
et al., 2012; reviewed in Skoe and Kraus, 2013). Nevertheless, it remains possible
that participants with certain personality characteristics are more likely, a priori,
to continue with musical training rather than stopping after a few years (Corrigall
et al., 2013). Longitudinal experimental studies, therefore, provide the most ironclad
evidence for a causative relationship between musical experience and reading
ability. In the past few decades, there have been numerous attempts to design lon-
gitudinal experiments to investigate the question of how undergoing musical training
affects linguistic ability, including the acquisition of reading and precursor skills
such as phonological awareness. In this section, we review the literature on musical
training and reading. See Table 2 for a summary of the experimental design and
results of these studies.
the neural encoding of sound—that is, using the same measure irrespective of age or
species—would enable cross-study comparison, allowing researchers to determine
how musical training affects different populations or how the effects of different
kinds of musical training vary. We have pioneered the use of a neural, scalp-
electrode recorded measure with several unique attributes, the complex auditory
brainstem response (cABR). This electrophysiological response closely mirrors
the acoustic characteristics of the evoking stimulus (Skoe and Kraus, 2010), and
can be modified by experience (Kraus and Chandrasekaran, 2010). Moreover, while
the cABR shows a high degree of test–retest reliability (Hornickel et al., 2012;
Krishnan et al., 2012), there are large individual differences in aspects of the cABR
between participants which have been linked to a variety of communication skills,
including speech-in-noise perception and reading (Anderson et al., 2010). Under-
standing the source of these individual differences and how they underlie differences
in communication skills is an important direction for future neuroeducational work.
This neural response represents a snapshot into a neural hub of hearing—depicting a
cohesive sensory-cognitive-reward system. More widespread adoption of this mea-
sure would, therefore, both enable researchers to study the effects of music on the
biological basis of speech perception and language skills and facilitate the synthesis
of music training research into an integrated whole. To facilitate the cABR’s adoption
as a widely used measure across studies future work should focus on the improvement
of the efficiency and ease-of-use of the collection of this biological metric.
traditional nonmusical classes. The music group showed greater gains in phoneme
segmentation ability and oral skills. Costa-Giomi (2004) randomly assigned children
to either a training group who received private, one-on-one piano instruction
designed by individual piano teachers for 3 years or a control group that received
no instruction and found no effects on academic achievement in either language
or math. Register et al. (2007) compared second-grade students engaged in a music
curriculum designed by the experimenters to students receiving no musical training
and found that the music group experienced greater gains pre- to posttest in word
knowledge. However, given that the music curriculum included instruction in read-
ing strategies it is difficult to know whether the increased reading skill was driven by
the musical aspects of the training. In a pilot study, Forgeard et al. (2008) found that
six children given musical training improved more than children who received no
training on word reading. (The exact nature of the musical training—in particular,
whether it was classroom training or a program designed by the experimenter—is
difficult to determine from the manuscript.)
Early work on musical training and reading skill using random assignment, there-
fore, did not provide strong evidence for the effectiveness of musical training; the
studies cited above all either reported null results, used extremely small numbers
of subjects, or presented musical training which included linguistic training. How-
ever, more recent work has used larger subject populations and reported much more
promising results. Moreno et al. (2009), for example, gave children computer-based
training designed by the experimenter to enhance either painting skills or musical
skills. Only the children in the music group showed improvement in a reading task
after training. Herrera et al. (2010) examined the development of phonological abil-
ities in children in a control group, a group receiving phonological training, and a
group receiving phonological training featuring additional musical elements. The
training programs were designed by the authors. At posttest, the musical training
group outperformed the other two groups on phonological awareness. Degé and
Schwarzer (2011) compared the effects of a music program and a phonological skills
program (both created by the authors) in preschoolers and found that the two training
groups led to similar gains in phonological awareness. Taub and Lazarus (2013) gave
children either training in synchronizing movements to a metronome or no training
and found at posttest that the experimental group’s reading scores were higher than
the control groups’ scores. Bhide et al. (2013) gave a group of 6–7-year-old children
either a computer-assisted reading intervention or rhythm training designed by the
experimenters including both musical and linguistic elements; both groups improved
in reading ability by similar amounts. However, given that the rhythm training con-
tained both musical and linguistic elements, it is difficult to determine whether the
gains shown by the children in the rhythm group could be elicited by the musical
elements alone. Cogo-Moreira et al. (2013), in a large-scale clinical study, found that
musical training designed by the experimenters (compared to no training) led to in-
creases in reading ability and phonological awareness in young poor readers when
compliance was taken into account. Rautenberg (2013) found that music classes
designed by the experimenter led to an improvement in word reading compared
228 CHAPTER 8 Music Training and Reading
to either visual arts classes or no classes. Finally, a longitudinal study from our re-
search group is currently examining the development of reading skills over time in
two groups of children, one of whom was assigned musical training as part of the
Harmony Project, a nonprofit organization which for years has provided musical
training to underserved children in gang-reduction zones of Los Angeles. All partic-
ipants requested to participate in the Project; these participants were pseudo-
randomly assigned to two groups. In the first year of the study, one group received
musical training while a matched control group did not. The control group began
music classes the following year. Preliminary results suggest that musical training
led to increases in reading ability, speech in noise, and rhythm skills (Slater et al.,
2013).
10 WHY MUSIC?
In summary, there is a theoretical basis for a link between musical training and read-
ing ability, as the neural and cognitive resources necessary for reading acquisition
and those resources drawn upon in the course of learning to play music overlap.
Moreover, extensive empirical evidence collected over several decades indicates that
musical training can enhance reading ability. Noteworthy is that some of the same
aspects of neural encoding of speech that are deficient in individuals with commu-
nication difficulties such as dyslexia, reflecting decreased neural synchrony, are
strengthened in musicians compared to their nonmusician peers, suggesting overlap-
ping biological bases for musical expertise and reading ability (Kraus and
Chandrasekaran, 2010; Strait and Kraus, 2011). These results may indicate that mu-
sical training can lead to increased neural synchrony throughout the auditory system,
suggesting that music could be an effective way to boost reading skills in children.
Nevertheless, the question remains: why not simply train reading itself? Would that
not be a more direct, and potentially more effective, way of enhancing reading abil-
ity? Certainly, we do not mean to suggest that musical training should supplant read-
ing training. Instead, we would argue for the inclusion of musical training as a part of
a balanced school curriculum, including reading, foreign language instruction, math-
ematics, science, athletics, etc. Difficulties with reading can stem from a variety of
sources. Some children are likely to draw the greatest benefit from musical training,
while other children may respond better to other forms of instruction.
One of the reasons musical training can be such a powerful educational tool is that
music is inherently rewarding, emotion-inducing, and attention-grabbing (Menon
and Levitin, 2005; Patel, 2011, 2013). Neural plasticity can be enhanced by attention
(Fritz et al., 2013) and motivation (David et al., 2012; Rutkowski and Weinberger,
2005), and neural plasticity can enhance perceptual learning (Reed et al., 2011). The
rewarding nature of music listening and music performance (Salimpoor et al., 2013)
makes it ideal for getting children interested in school and giving them the auditory,
motor, and cognitive skills they need to learn to read and succeed, both in school and
later in life. In fact, active training in early life can lead to benefits in task
References 229
performance in adulthood (Sarro and Sanes, 2011), but passive exposure to stimuli in
juveniles does not have long-term benefits (Engineer et al., 2004; Sarro and Sanes,
2011). As music is one of the most active, absorbing ways that children can interact
with sound, even a few years of music instruction early in life can have profound
effects on the functioning of the nervous system years later (Skoe and Kraus, 2012;
White-Schwoch et al., 2013). And of course, even if a given child receives no
extramusical benefit from his or her instruction, at worst they will have gained an
aesthetic appreciation with the potential to last a lifetime.
Acknowledgments
This research is supported by NSF BCS-1057556 and BCS-0921275, NIH R01-HD069414,
and the Knowles Hearing Center. We would also like to thank Samira Anderson, Travis
White-Schwoch, Jessica Slater, and Elaine Thompson for comments on a previous version
of this Chapter.
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CHAPTER
Mechanisms of Plasticity in
the Developing and Adult
Visual Cortex
Mriganka Sur1, Ikue Nagakura, Naiyan Chen, Hiroki Sugihara
9
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences,
Massachusetts Institute of Technology, Cambridge, MA, USA
1
Corresponding author: Tel.: þ1-617-253-8784; Fax: þ1-617-253-9829
e-mail address: msur@mit.edu
Abstract
The visual cortex provides powerful evidence for experience-dependent plasticity during de-
velopment, and for stimulus and reinforcement-dependent plasticity in adulthood. The synap-
tic and circuit mechanisms underlying such plasticity are being progressively understood.
Increasing evidence supports the hypothesis that plasticity in both the developing and adult
visual cortex is initiated by a transient reduction of inhibitory drive, and implemented by per-
sistent changes at excitatory synapses. Developmental plasticity may be induced by alterations
in the balance of activity from the two eyes and is implemented by a cascade of signals that
lead to feedforward and feedback changes at synapses. Adult plasticity is imposed on mature
synapses and requires additional neurotransmitter-dependent mechanisms that alter inhibition
and subsequently response gain.
Keywords
circuits, sensory cortex, ocular dominance plasticity, reinforcement learning, inhibition,
excitatory synapses, glutamate receptors, parvalbumin neurons
The visual system is a powerful model system for analyzing how sensory experience
and electrical activity regulate the development of synapses and neuronal circuits in a
processing pathway. In particular, the primary visual cortex, or V1, has been a prov-
ing ground for revealing both the phenomena and mechanisms of developmental
plasticity in the mammalian cerebral cortex. The visual cortex exhibits profound
plasticity during development: for example, an alteration in visual drive induced
by even a brief eyelid closure of one eye, which induces unbalanced inputs from
the two eyes, results in weakening of V1 neuron responses to the deprived (closed)
eye while strengthening the responses to the nondeprived (open) eye (Gordon and
Stryker, 1996; Hubel and Wiesel, 1970). The mechanisms underlying developmental
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00002-3
© 2013 Elsevier B.V. All rights reserved.
243
244 CHAPTER 9 Mechanisms of Plasticity
plasticity in the visual cortex have been the subject of intense study (Espinosa and
Stryker, 2012; Nagakura et al., 2013).
The visual cortex also exhibits prominent plasticity in adulthood, as revealed by
systematic changes in neuronal responses due to prolonged visual stimulation
(Dragoi et al., 2000) or by pairing visual stimuli with neuromodulatory inputs
(Chen et al., 2012). While it is generally accepted that adult V1 is less susceptible
to passive experience-driven changes and therefore exhibits less plasticity than dur-
ing the critical period, considerable plasticity can be induced in V1 and other sensory
cortex by reinforcement-dependent associative learning; however, the mechanisms
of adult plasticity are less understood. In this review, we suggest that both develop-
mental and adult plasticity share common features related to initiating and maintain-
ing changes in neuronal responses. Specific mechanisms by which response
plasticity is maintained may differ in the developing and adult cortex, as would spe-
cific mechanisms by which plasticity is initiated, but the conceptual similarities point
to important principles underlying experience and stimulation-dependent plasticity
of neuronal responses and representations in cortical circuits.
are known to be required for plasticity in the visual cortex layer 6, but it appears not
in the layer 2/3 nor 5 (Daw et al., 1999; Rao and Daw, 2004).
The signaling initiated by glutamate and its receptors is conveyed inside a neuron
into a cascade of downstream signaling. The cAMP-dependent protein kinase (pro-
tein kinase A or PKA) regulates glutamate receptor-mediated synaptic plasticity by
phosphorylating GluA1 and regulating glutamate receptor complexes (Heynen et al.,
2003; Kameyama et al., 1998). Moreover, PKA translocates into the nucleus for
downstream cAMP response element (CRE)-mediated gene expression together with
extracellular signal-regulated kinase 1,2 (ERK) (Cancedda et al., 2003). Both PKA
and ERK are required for ODP (Beaver et al., 2001; Di Cristo et al., 2001), likely
through CRE-mediated gene expression (Fig. 1).
Gene expression analysis in the primary visual cortex during the critical period
and following visual deprivation provides a comprehensive view of cortical changes
during normal development and experience-dependent plasticity. The critical period
in mice is accompanied by a distinct transcriptional profile that includes genes
Ca2+
Presynaptic excit neuron NMDAR/AMPAR
GABAR
ACh
Presynaptic inhib neuron
mGluR
Pyramidal neuron
Glutamatergic synapse
Ca2+
Gene transcription
G
A
B
A
er
gi
c
sy
Initiating/activating plasticity
na
ps
e
FIGURE 1
Schematic of a cortical pyramidal neuron with an excitatory synapse (top left) and inhibitory
synapse (bottom right). Symbols are explained in the key (top right). Increasing evidence
supports the hypothesis that plasticity in the developing and adult cortex is initiated by a
transient reduction of inhibitory drive, and implemented by persistent changes at excitatory
synapses. See text for details.
246 CHAPTER 9 Mechanisms of Plasticity
(Dragoi et al., 2000, 2001, 2002). Perceptually, the “tilt aftereffect” demonstrates
that viewing a tilted contour even briefly causes the perceived orientation of a sub-
sequently viewed contour to be tilted away from the adapting contour (Gibson, 1937;
Paradiso et al., 1989; Wenderoth and Johnstone, 1988). These forms of visual plas-
ticity induced by passive exposure are often of short duration, and persistent training-
induced plasticity in the adult brain often requires prolonged practice coupled with
reinforcement.
Adult plasticity on long time scales induced by reinforced associative learning
importantly involves neuromodulatory systems including ACh, norepinephrine, se-
rotonin, dopamine, and histamine. These neuromodulators can alter cellular excit-
ability and induce plasticity through presynaptic and/or postsynaptic mechanisms
(Gu, 2002). Among the neuromodulators, the role of ACh in the sensory cortex, in-
cluding the visual cortex, is best understood. The cortex receives its main source of
ACh from cholinergic axons that originates in the nucleus basalis of the basal fore-
brain (Metherate et al., 1992). When cholinergic activation of the adult cortex is
paired with both intracellular depolarization of neurons (Woody et al., 1978) and ap-
plication of glutamate (Lin and Phillis, 1991; Metherate et al., 1987), prolonged fa-
cilitation of neuronal responses is observed. Pairing cholinergic and sensory
stimulation in the adult cortex can induce both neuronal and representational plas-
ticity in the adult somatosensory cortex (Donoghue and Carroll, 1987; Howard
and Simons, 1994; Lamour et al., 1988; Metherate et al., 1987; Rasmusson and
Dykes, 1988; Tremblay et al., 1990a,b), auditory cortex (Bakin and Weinberger,
1996; Dimyan and Weinberger, 1999; Edeline et al., 1994; Kilgard and
Merzenich, 1998a,b; Kilgard et al., 2001), and visual cortex (Chen et al., 2012).
ACh-induced changes can occur at both single cell and cortical map levels. The for-
mer involves neuronal plasticity characterized by potentiation of glutamatergic syn-
apses at pyramidal neurons, while the latter involves representational plasticity as
characterized by reorganization of sensory maps that represent and encode specific
parameters of sensory stimuli (Bakin and Weinberger, 1996; Bao et al., 2003;
Froemke et al., 2007; Kilgard and Merzenich, 1998a; Puckett et al., 2007).
The mechanisms underlying ACh-induced plasticity include direct and indirect
pathways, and appear to involve mechanisms for both initiating and implementing
plasticity. Activation of M1 muscarinic receptors by ACh can directly potentiate re-
sponses in pyramidal neurons through inhibition of postsynaptic SK channels
(Buchanan et al., 2011; Giessel and Sabatini, 2010). ACh leads to prolonged but
prominent calcium responses in astrocytes in vitro (Perea and Araque, 2005), and
in vivo (Navarrete et al., 2012; Takata et al., 2011), making astrocytes a potential
mediator of nucleus basalis-mediated plasticity of cortical responses. Indeed, stim-
ulation of the nucleus basalis directly and strongly activates calcium responses in V1
astrocytes via muscarinic receptors, and mice with conditional knockout of
astrocyte-specific IP3R2 receptors do not have ACh-induced calcium elevation
and fail to show neuronal plasticity induced by paired visual and nucleus basalis
stimulation (Chen et al., 2012). Astrocytes can induce release of gliotransmitters
or regulate extracellular glutamate (Schummers et al., 2008) and potassium
3 Common Principles of Developmental and Adult Plasticity 249
(Seigneur et al., 2006); these mechanisms can lead to increased levels of extracellular
glutamate (Fellin et al., 2004) or D-serine (Henneberger et al., 2010) that can activate
neuronal NMDARs to implement plasticity at excitatory synapses (Fig. 1).
ACh stimulation also elicits rapid responses in inhibitory neurons (Alitto and
Dan, 2012; Kawaguchi, 1997; McCormick and Prince, 1986), including excitatory
responses from subsets of inhibitory neurons and inhibitory responses from other
subsets (Arroyo et al., 2012). An important correlate of basalis-induced plasticity
in the auditory cortex is a transient reduction of inhibition to pyramidal neurons
(Froemke et al., 2007), and reinforcement learning in the adult auditory cortex is ac-
companied by a reduction of PV neuron firing by cholinergic inputs (Letzkus et al.,
2011). Since PV neurons provide divisive inhibition and regulate the response
gain of their target neurons (Wilson et al., 2012), a reduction in PV neuron firing
provides a powerful way to enhance the influence of inputs to pyramidal neurons.
Thus, the rapid reduction of PV-mediated inhibition to pyramidal neurons, together
with sensory drive, may be a necessary condition for initiating plasticity in the adult
sensory cortex.
Acknowledgments
Supported by grants from the NIH and the Simons Foundation (M. S.), and a fellowship from
A*STAR, Singapore (N. C.).
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CHAPTER
Brain Mechanisms of
Plasticity in Response to
Treatments for Core
Deficits in Autism
10
Pamela E. Ventola1, Devon Oosting, Laura C. Anderson, Kevin A. Pelphrey
Yale Center for Translational Developmental Neuroscience, Yale Child Study Center,
New Haven, CT, USA
1
Corresponding author: Tel.: þ203-785-5657, e-mail address: pamela.ventola@yale.edu
Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by social
communication impairments and repetitive behaviors. Although the prevalence of ASD is es-
timated at 1 in 88, understanding of the neural mechanisms underlying the disorder is still
emerging. Regions including the amygdala, superior temporal sulcus, orbitofrontal cortex,
fusiform gyrus, medial prefrontal cortex, and insula have been implicated in social processing.
Neuroimaging studies have demonstrated both anatomical and functional differences in these
areas of the brain in individuals with ASD when compared to controls; however, research on
the neural basis for response to treatment in ASD is limited. Results of the three studies that
have examined the neural mechanisms underlying treatment response are promising; follow-
ing treatment, the brains of individuals with ASD seem to “normalize,” responding more sim-
ilarly to those of typically developing individuals. The research in this area is in its early stages,
and thus a focused effort examining the neural basis of treatment response in ASD is crucial.
Keywords
autism, ASD, treatment, social brain, social cognition, neuroimaging, treatment response
1 INTRODUCTION
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized
by deficits in social communication and the presence of repetitive behaviors and re-
stricted interests. Social and communicative deficits include impaired peer relation-
ships, a paucity of nonverbal communication, difficulty engaging in reciprocal social
interactions/conversations, and an impairment in theory of mind (ToM: the ability to
ascribe emotional and mental states to other people) (American Psychiatric
Association, 2000). Restricted and repetitive behaviors and interests range from
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00007-2
© 2013 Elsevier B.V. All rights reserved.
255
256 CHAPTER 10 Neural Basis of Treatment Response in ASD
preoccupations with ordering or categorizing (i.e., reciting numbers and letters in se-
quence or grouping objects based on physical properties), to the self-stimulatory
mouthing of objects, to an intense interest in a particular topic (e.g., a certain tele-
vision show or parts of the human body) (American Psychiatric Association, 2000).
As a spectrum disorder, ASD is heterogeneous in its presentation and impacts indi-
vidual competencies in the domains described above in different ways. Some lower-
functioning children are unable to communicate and present with a more severe
symptom profile, whereas those with high-functioning ASD are typically verbally flu-
ent but have difficulty understanding the nuances of social interactions (Geschwind
and Levitt, 2007). According to the Centers for Disease Control (CDC) 2008 estimate,
ASD affects 1 in every 88 children in the United States and is disproportionately repre-
sented in males, occurring at a rate nearly five times that of females (Centers for
Disease Control [CDC], 2012). The National Center for Health Statistics’ recent study
on parent-reported ASD identified a prevalence rate of 1 in 50 children (Blumberg
et al., 2013). These prevalence estimates support the relevance and necessity of a better
understanding of the etiological mechanisms underlying this disorder.
While behavioral symptoms typically become a concern for parents around
2 years of age, the average age at which a child receives a professional diagnosis
ranges from 4 to 6 years old depending on symptom severity (CDC, 2012). This delay
in diagnosis eclipses a crucial time span in which intervention services have been
shown to be particularly effective at ameliorating ASD symptoms (Dawson,
2008; Princiotta and Goldstein, 2013). During early childhood, the brain is especially
able to adapt and change in response to new experiences (Dawson, 2008). This plas-
ticity makes this period an important target for the implementation of interventions
whose methods have been shown to mediate the abnormalities in brain structure and
function commonly seen in individuals with ASD (Dawson, 2008). In this chapter,
we will outline the current findings on the atypical development of the social brain in
ASD, the different types of treatment options for individuals with ASD, and then
finally summarize the current, yet early stage research on neural plasticity in
response to empirically validated interventions in this population.
(e.g., Butter et al., 1968; Damasio et al., 1990; Dicks et al., 1969; Eslinger and
Damasio, 1985; Kling and Steklis, 1976). Studies investigating brain responsivity
at the level of single neurons have identified particular neurons in the monkey tem-
poral cortex that process facial expressions (Hasselmo et al., 1989; Perrett et al.,
1984) and the gaze of other animals (Perrett et al., 1984), two important components
of social cognition.
These findings from lesion and single-cell studies led Brothers (1990) to propose
a model for a “social brain” network composed of regions of the primate brain that
are critically involved in social processing. This model of the social brain included
the following regions: amygdala, superior temporal sulcus (STS), orbitofrontal
cortex, and fusiform gyrus (FG). In the decades since, many neuroimaging studies
have confirmed the importance of these brain regions in social cognition and have
added other regions to the list such as medial prefrontal cortex (mPFC) and insula,
among others (Allison et al., 2000; Amodio and Frith, 2006; Decety and Grezes,
1999; Lamm and Singer, 2010).
One of the regions of the social brain that continues to be implicated in various
aspects of social and emotional processing in typical development is the amygdala, a
subcortical structure in the anterior medial temporal lobe. Amygdala lesions lead to
impaired fixation to the eyes, emphasizing the role of the amygdala in attention
modulation and the evaluation of emotional expressions (Adolphs and Spezio,
2006; Gamer and Buchel, 2009; Kennedy and Adolphs, 2010; Whalen, 2007).
Although the amygdala has often been studied in the context of fear processing,
evidence suggests that the amygdala plays a broader role in the detection of a variety
of salient stimuli including biological motion (Davis and Whalen, 2001; Morris et al.,
1998; Pelphrey et al., 2003a,b) and codes for the motivational significance of
environmental stimuli (Nishijo et al., 1988).
The STS is another brain region that has been continually implicated in a variety
of social tasks. Single-cell studies in monkeys have shown that the STS is critical
for following the gaze of others (Campbell et al., 1990; Perrett et al., 1990,
1992). Similarly, in humans, the STS is involved in perceiving the movement of con-
specifics including whole-body motion (see Allison et al., 2000 and Decety and
Grezes, 1999 for reviews) as well as eye movements (Pelphrey et al., 2003a,b,
2004a,b; Puce et al., 1998; Wicker et al., 1998). The ability to perceive the motion
of other humans and to predict their future behaviors may be a precursor to ToM
abilities (Pelphrey and Carter, 2008).
The orbitofrontal cortex, including ventral medial prefrontal cortex (vmPFC), has
also been associated with social processes. The first evidence that this brain region
plays an important role in social cognition came in 1848, when Phineas Gage en-
dured a frontal lobe lesion after being impaled by a tamping rod and soon afterwards
became uncaring and socially inappropriate (Damasio et al., 1994). Since then, other
studies investigating the effects of frontal lobe lesions have concluded that patients
with vmPFC damage maintain normal intellectual abilities but they lack the ability to
plan and organize, they behave in socially inappropriate ways, and they have little
concern for others (Ackerly and Benton, 1948; Brickner, 1932), suggesting that
258 CHAPTER 10 Neural Basis of Treatment Response in ASD
et al., 2013) have even evidenced differential neural patterns in infants at risk for
developing ASD (by virtue of having an older sibling with the disorder), suggesting
that social brain abnormalities in those with a family history of ASD may serve as an
early-emerging endophenotype of the disorder. Although it is unclear whether social
brain dysfunction in ASD is a cause or a consequence of the disorder, prospective,
longitudinal studies including high-risk infants are beginning to disambiguate cause
and effect by elucidating the development of the social brain in both typical and atyp-
ical development (e.g., Elsabbagh et al., 2012; Lloyd-Fox et al., 2013).
3 TREATMENT OVERVIEW
Since autism was first identified in the early 1940s (Kanner, 1943), multiple theories on
its origins have been examined. Twin studies and DNA analysis of individuals with ASD
have provided strong support for the contribution of genetics to the development of the
disorder, though reliable genetic markers of ASD have yet to be established (Meek et al.,
2013). Environmental exposure to toxic substances, abnormal immune responses, and
adverse prenatal experiences, especially those during critical periods such as the first
trimester and parturition, have also been implicated (Gregory et al., 2013; Landrigan,
2010; Rossignol and Frye, 2012). Furthermore, some purport that deficits in specific
cognitive processes, such as executive functioning and ToM, that are often present in
individuals with ASD may stem from neurological abnormalities in connectivity and
structure and may underlie some of the social impairment and restricted behaviors
characteristic of the disorder (Frith, 1997, 2012; Minshew and Williams, 2007).
Though in the past decades, there have been a plethora of theories about the
origins of ASD and specific brain regions have been consistently implicated, we have
yet to pinpoint the primary underlying neurobiological causes of the disorder. There-
fore, many current interventions target the secondary behavioral symptoms of ASD.
Using behavior modification techniques, these treatments aim to reduce or redirect
socially inappropriate behaviors and restricted interests while also teaching social
strategies, language, and daily living skills (Koegel and Koegel, 2012; Lovaas
et al., 1973). In addition, psychopharmacological treatments that seek both to alle-
viate often comorbid aberrant behavioral issues (e.g., hyperactivity, aggression, self-
injurious behavior) as well as to ameliorate core ASD symptoms are emergent
(Hollander et al., 2007; Tsai, 1999). In what follows, the predominant treatments
in each category are discussed.
and consequences of behaviors and then modify these parameters using tools, such as
reinforcement or environmental restructuring, in order to encourage the child to learn
the desired behavior or response (Vismara et al., 2010). ABA can be implemented in
the home or at school, and programs are often intensive, with children receiving 20 or
more hours per week of direct therapy (Harris and Delmolino, 2002). Early work by
Lovaas et al. (1973) showed that children who were treated intensively with ABA
(40 þ hours per week) made significant cognitive gains compared to controls, with
nearly half of the sample achieving intellectual functioning typical of their chrono-
logical age (Lovaas et al., 1973). Subsequent studies demonstrated intellectual func-
tioning improvement after intensive therapy as well, though the magnitude of
improvement and study conditions varied (Harris and Delmolino, 2002; Smith
et al., 2000). Findings regarding the effect of ABA on adaptive behavior (i.e., daily
living skills) are mixed (Peters-Scheffer et al., 2011).
in its naturalistic approach to skill acquisition, utilizing ABA strategies to teach spe-
cific behavioral lessons during developmentally appropriate time periods (Dawson
et al., 2010). ESDM can be administered in either group or individualized settings
and heavily emphasizes positive reciprocal relationships and parental involvement,
in addition to direct contact with therapists. A randomized controlled trial of ESDM
implemented with toddlers with ASD reported significant gains in cognitive ability,
receptive and expressive language, and adaptive behavior after completion of a
2-year program executed primarily by parents with therapist guidance (Dawson
et al., 2010; Rogers et al., 2012). Other studies and reviews have supported the trial
described above, showing improvements in intellectual functioning, language, adap-
tive behavior, and ASD symptomology (Princiotta and Goldstein, 2013; Vismara
et al., 2010; Warren et al., 2011).
(McCracken et al., 2002). Other studies support these results, reporting decreased
hyperactivity and conduct problems in both children and adults with ASD as well
as a decrease in internalizing symptoms in adults (Malone et al., 2002; McDougle
et al., 1998; Pandina et al., 2007; Shea et al., 2004). These results may be of particular
importance because the aggressive and self-injurious behaviors shown to decline
upon treatment with Risperidone are often some of the most concerning for parents
and caregivers (McCracken et al., 2002).
Table 1 Case-study results: Social communication and adaptive skills following PRT
treatment
Pre (t1) Post (t2)
ADOS Algorithm Total Score (Autism Total Score cut-off ¼ 9; Higher score indicates higher
level of impairment)
Child 1 (age 5:5 at start of treatment) 12 6
Child 2 (age 5:1 at start of treatment) 14 16
Pragmatics Profile Subtest Score (Typical range > 120)
Child 1 86 132
Child 2 49 74
Vineland age equivalent (months) Child 1 Child 2
Pre (t1) Post (t2) Pre (t1) Post (t2)
Receptive 78 90 26 59
Expressive 66 53 38 67
Written 73 82 68 84
Personal 90 78 38 42
Domestic 66 91 18 35
Community 74 71 47 56
Interpersonal relationships 54 31 46 46
Play and leisure time 70 78 46 67
Coping skills 27 55 29 47
in social communication skills. Furthermore, when comparing the fMRI results pre-
and posttreatment, the children showed increased activation in portions of State and
Trait regions after treatment, meaning, after treatment, the children showed in-
creased activation in areas of the brain responsible for processing social information.
This is exemplified in Fig. 1, which illustrates the differential response between
pre- and posttreatment. The colored areas of the figure reflect brain regions with
increased activation following treatment.
Thus, PRT resulted in increased activation in regions recruited by typically de-
veloping children during social perception. Specifically, one child demonstrated
greater activation in three regions after treatment; two distinct regions of the
State-defined left FG and a portion of the Trait-defined left dorsolateral prefrontal
cortex (dlPFC). The other child demonstrated greater activation in four regions after
treatment; a portion of the State-defined right pSTS, State-defined left vlPFC,
State-defined right FG, and State/Trait-defined left FG. Therefore, the results suggest
that the social brain is not irretrievably “broken” in children with ASD; instead, it is
simply not being effectively recruited in the processing of biological motion. Impor-
tantly, although these results are promising, they are very preliminary, and additional
work with a larger sample is needed to make firm conclusions.
Another recent study (Dawson et al., 2012) investigating the plasticity of the so-
cial brain in response to intervention in ASD examined the ESDM (Rogers and
264 CHAPTER 10 Neural Basis of Treatment Response in ASD
FIGURE 1
Case-Study fMRI results following PRT treatment. Results of t2–t1 beta maps
(Biological > Scrambled) (beta difference >0.5, k ¼ 4) limited to state, trait, and
compensatory regions as defined by Kaiser and colleagues (2010). The colored areas reflect
brain regions with increased activation following treatment (differences between pre- and
posttreatment). After treatment, Child 1 demonstrated greater activation in a portion of the
state-defined right posterior superior temporal sulcus (pSTS), state-defined left ventrolateral
prefrontal cortex (vlPFC), state-defined right fusiform gyrus (FG), and state/trait-defined left
FG. Child 2 demonstrated increased activation to biological motion in trait-defined left
dorsolateral prefrontal cortex (dlPFC) and two distinct regions of the state-defined left FG.
predict that the most successful therapeutic use of oxytocin will be by administering
the compound prior to evidence-based behavioral treatments that provide opportu-
nities for feedback and learning in supportive social contexts.
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272 CHAPTER 10 Neural Basis of Treatment Response in ASD
Abstract
Pathological neural activity in a variety of neurological disorders could be treated by directing
plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal func-
tion. Brief bursts of acetylcholine and norepinephrine can enhance the neural plasticity asso-
ciated with coincident events. Vagus nerve stimulation (VNS) represents a safe and effective
means to trigger the release of these neuromodulators with a high degree of temporal control.
VNS-event pairing can generate highly specific and long-lasting plasticity in sensory and mo-
tor cortex. Based on the capacity to drive specific changes in neural circuitry, VNS paired with
experience has been successful in effectively ameliorating animal models of chronic tinnitus,
stroke, and posttraumatic stress disorder. Targeted plasticity therapy utilizing VNS is currently
being translated to humans to treat chronic tinnitus and improve motor recovery after stroke.
This chapter will discuss the current progress of VNS paired with experience to drive specific
plasticity to treat these neurological disorders and will evaluate additional future applications
of targeted plasticity therapy.
Keywords
vagus nerve stimulation (VNS), cortical plasticity, recovery, neuromodulators, acetylcholine,
norepinephrine, targeted plasticity
neuromodulatory release (Eckenstein et al., 1988; Levitt and Moore, 1978); there-
fore, the effects acetylcholine and norepinephrine are restricted by the coincident
network activity in the local circuitry. Temporal specificity is a product of the rel-
ative timing of neuromodulatory release and coincident neuronal activity. The tem-
poral requirements for synaptic plasticity are well described, and small changes in
timing of neuronal firing can have major impacts on spike-timing-dependent plastic-
ity (STDP) (Dan and Poo, 2004). Neuromodulators influence the temporal rules that
define STDP (Pawlak et al., 2010). The presence of acetylcholine or norepinephrine
dictates the polarity of synaptic plasticity, and the ratio of these neuromodulators
determines the temporal requirements for STDP (Seol et al., 2007). Studies using
lesions and pharmacological antagonism have demonstrated that these neuromodu-
latory systems interact to facilitate plasticity and learning (Bear and Singer, 1986;
Decker and Gallagher, 1987; Decker et al., 1990). As these neuromodulatory
systems cooperate during processes that drive plasticity and learning, concurrent
control of both acetylcholine and norepinephrine release would be useful to direct
plasticity.
plasticity due to saturation and poor temporal control. It would be valuable for a tar-
geted plasticity therapy to remain constant over time, thus permitting repeated expo-
sures until the desired benefits are achieved.
Several manipulations that fit some or all of these criteria may be successful at
specifically targeting plasticity to treat neurological disease. Deep brain stimulation,
transcranial magnetic stimulation, optogenetic stimulation, or intensive repeated
training could potentially trigger sufficient neuromodulatory release during experi-
ence to induce therapeutic plasticity. In this chapter, we will focus on one particular
technique to drive targeted plasticity. This method uses stimulation of the vagus
nerve paired with behavioral experience to drive specific forms of neural plasticity.
Vagus nerve stimulation (VNS) engages multiple neuromodulatory systems and can
be precisely temporally controlled. Additionally, VNS is a safe and approved method
currently being used in over 60,000 patients for management of intractable epilepsy
and depression (Ben-Menachem, 2002; Englot et al., 2011; Sackeim et al., 2001).
Recent studies have demonstrated that VNS paired with sensory, motor, or cognitive
training can drive specific forms of cortical plasticity that result in behaviorally rel-
evant changes. As a result, VNS applied as a targeted plasticity therapy offers the
potential to treat sensory, motor, and cognitive dysfunction.
(Berthoud and Neuhuber, 2000; Foley and DuBois, 1937; George et al., 2000; Leslie
et al., 1982). These fibers synapse bilaterally on neurons within the nucleus tractus
solitarius, which then project to the noradrenergic locus coeruleus and the choliner-
gic basal forebrain (Berntson et al., 1998; George et al., 2000; Henry, 2002; Semba
et al., 1988; Van Bockstaele et al., 1999). Electrical stimulation of the vagus nerve
drives neuronal activity within these regions and consequently induces release of
neuromodulators throughout the cortex (Detari et al., 1983; Dorr and Debonnel,
2006; Follesa et al., 2007; Groves et al., 2005; Roosevelt et al., 2006). A reduction
in either noradrenergic or cholinergic transmission reduces the effects of VNS in the
central nervous system (Krahl et al., 1998; Nichols et al., 2011), suggesting that VNS
is exerting its effects through both the locus coeruleus and basal forebrain.
FIGURE 1
Model of targeted plasticity therapy driving specific changes in neural circuits and not in other
areas. (A) (i) Presentation of an 8 kHz tone drives circuit activity in the auditory cortex (green).
(ii) Temporally precise release of neuromodulators (blue), such as that induced by VNS,
paired with this activity drives plasticity. (iii) After targeted plasticity, the map reorganization
results in an increase in representation of the paired tone (Engineer et al., 2011). Previously
subthreshold inputs (yellow) drive activity (green) after pairing with VNS. (B) (i) Activity within
neurons of the motor cortex results in movement of the shoulder. (ii) Diffuse release of
neuromodulators paired with movement drives plasticity in the motor cortex. (iii) After
targeted plasticity, the number of circuits representing the shoulder movement is increased
(Porter et al., 2011). The large rectangles represent topographical organization of the auditory
and motor cortices, and the activity of neurons is represented within each individual box.
Green denotes suprathreshold action potential firing, yellow denotes subthreshold
depolarization, and gray denotes no response.
(Porter et al., 2011). To this end, rats were trained to perform one of two skilled
motor tasks. The first task was designed to primarily engage the shoulder and re-
quired the rat to rapidly press a lever located outside the cage twice within 500 ms.
The second task was designed to primarily engage the forepaw and required the rat
to reach through a small slot in the floor of the cage and spin a wheel 145 within
2 s. After reaching proficiency on one of the tasks, rats underwent an additional 5
days of training with or without stimulation of the vagus nerve delivered on the
successful trials. Intracortical microstimulation mapping was then used to derive
the area of motor cortex controlling specific movements. Rats that received re-
peated VNS paired with training on the lever press task demonstrated a major in-
crease in areal representation of the shoulder, but no increase in forepaw compared
to rats that did not receive VNS. Similarly, rats that receive VNS paired with train-
ing on the wheel spin task exhibited a significant increase in the area of motor cor-
tex representing the forepaw with no expansion of the shoulder. Therefore, VNS
facilitated robust expansion of the motor cortex representation of the specific move-
ment that was paired with stimulation. Both tasks were designed such that reward
pellets were delivered on successful trials and were typically consumed 1–2 s after
the delivery of VNS. Despite the relatively close timing of pellet consumption and
mastication with VNS, no increase was observed in the jaw representation, suggest-
ing VNS must be precisely timed with an event to drive specific plasticity. These
findings closely parallel the results observed in the auditory cortex and demonstrate
that VNS paired with events can induce robust plasticity specific to the event with
which stimulation is paired.
correlates of tinnitus, including map distortion and elevated synchrony. This study
provides evidence that VNS paired with tones can reverse pathological plasticity
and ameliorate chronic tinnitus. A clinical trial utilizing this implementation of
VNS paired with tones was conducted to treat chronic tinnitus in patients and dem-
onstrated promising results (Arns and De Ridder, 2011; Microtransponder, 2010).
4.2 Stroke
Stroke is a common cause of disability, affecting 795,000 people in the United States
each year, with as many as 85% of cases leading to impairments in upper limb func-
tion (Dobkin, 2004; Roger et al., 2012). A stroke typically causes a unilateral disrup-
tion of blood flow to the brain, and because of the anatomy of the neurovasculature,
the motor cortex is susceptible to cell death. The death of neurons in the motor cortex
interferes with the circuitry responsible for controlling muscle groups, leading to a
loss of coordinated motor function. The most common poststroke intervention, phys-
ical rehabilitation, leads to some functional gains, but in the majority of cases, the
improvement is incomplete, leaving patients with chronic disability (Dobkin,
2004, 2005; Lai et al., 2002).
Notable reorganization of motor maps occurs after stroke, in both the surviving
peri-infarct region and the undamaged contralateral motor cortex (Calautti and
Baron, 2003; Nudo and Friel, 1999). Plasticity in these areas is believed to be the sub-
strate for functional recovery (Hallett, 2001). As detailed earlier, a study from Porter
and colleagues demonstrated that VNS paired with physical training can enhance
plasticity within the motor cortex (Porter et al., 2011). Therefore, VNS paired with
physical training after a stroke may enhance reorganization within spared circuitry
of the motor cortex and improve function outcomes (Fig. 2B). Khodaparast and col-
leagues tested this hypothesis in two studies using a rat model of ischemic stroke
(Khodaparast et al., submitted). In the first study, rats were trained on the bradykinesia
assessment task, a skilled forelimb task that provides unbiased, quantitative measure-
ments of multiple parameters of forelimb movement speed (Hays et al., 2013). All rats
became highly proficient at the task. After induction of ischemic damage in the motor
cortex contralateral to the trained limb, performance dropped significantly. Rats were
then assigned to receive rehabilitative training with or without the delivery of VNS.
VNS paired with rehabilitative training fully restored task performance by the second
week of treatment and significantly improved performance compared to rehabilitative
training without VNS. VNS paired with rehabilitative training also improved fore-
limb movement speed compared to rehabilitative training alone. These findings dem-
onstrate that VNS paired with physical rehabilitation can improve recovery of
forelimb speed after stroke compared to rehabilitative training without VNS.
A second study by the same group extended these findings to recovery of fore-
limb strength after stroke (Khodaparast et al., 2013). Rats were trained to proficiency
on the isometric force task, an automated method to quantify forelimb strength (Hays
et al., 2012). After induction of ischemic lesion, performance on the task and fore-
limb strength were significantly reduced. VNS paired with rehabilitative training
resulted in significantly better performance and stronger maximal pull force over
5 Mechanisms of Targeted Plasticity Directed by VNS 287
the course of therapy compared to rehabilitative training without VNS. These ben-
efits persisted after the cessation of VNS, suggesting a long-term improvement.
Highlighting the benefits of VNS, 100% of subjects that received VNS paired with
rehabilitative training demonstrated a full recovery of forelimb strength, while only
22% of subjects that received rehabilitative training without VNS demonstrated a full
recovery. In both studies, no difference in lesion size was observed, suggesting that
VNS is not conferring a neuroprotective effect but rather improving recovery by en-
hancing plasticity. These findings provide initial evidence that VNS paired with re-
habilitative training can restore clinically relevant parameters of forelimb function
after a stroke. Based on these findings, a clinical trial applying VNS paired with
physical rehabilitation in stroke patients is ongoing (Microtransponder, 2012).
Naritoku et al., 1995; Nichols et al., 2011; Roosevelt et al., 2006). There is a high
degree of similarity in the auditory plasticity evoked by VNS paired with tones
(Engineer et al., 2011; Shetake et al., 2011) compared with direct stimulation of
the nucleus basalis paired with tones (Kilgard and Merzenich, 1998a,b), indicating
that these pathways may share a common mechanism. Several studies demonstrate
that disruption of neuromodulatory transmission occludes the effects of VNS. Nor-
epinephrine is necessary, as lesions of the locus coeruleus prevent the antiepileptic
effects of VNS (Krahl et al., 1998). Cholinergic antagonists abrogate the electrophys-
iological effects of VNS in the auditory cortex, implicating acetylcholine in the ef-
fects of VNS in the central nervous system (Nichols et al., 2011). These findings
suggest that both the cholinergic and noradrenergic systems contribute to the ability
of VNS to specifically direct plasticity.
VNS promotes several downstream changes in molecular signaling cascades that
are known to underlie plasticity. VNS drives expression of brain-derived neuro-
trophic factor (BDNF), an important regulator of plasticity (Follesa et al., 2007).
BDNF engages a variety of downstream effectors, including activation of cAMP re-
sponse element-binding protein, that drive synaptic plasticity (Ernfors and
Bramham, 2003; Mattson et al., 2004). Activity-regulated cytoskeletal protein
(Arc) is regulated by BDNF and is strongly associated with plasticity (Bramham
and Messaoudi, 2005; Bramham et al., 2008). Other downstream pathways affected
by BDNF, such as Nogo receptor signaling, are known to contribute to recovery after
motor cortex damage, suggesting a possible mechanism for VNS-dependent en-
hancement of recovery after stroke (Fang et al., 2010; Takei, 2009; Tsai et al.,
2011). Consistent with increased BDNF expression, VNS increases phosphorylation
of multiple sites in the BDNF receptor, TrkB (Furmaga et al., 2012). A compound
that inhibits Trk autophosphorylation prevents the VNS-dependent increases in TrkB
phosphorylation, indicating that VNS is driving activation of TrkB through the ca-
nonical mechanism. These phosphorylated sites on TrkB are associated with broad
downstream effects, such as activation of mitogen-associated protein kinase,
phosphatidylinositol-3 kinase, and phospholipase C-g, which are linked to plasticity
(Gottschalk et al., 1999; Thomas and Huganir, 2004). Additionally, VNS induces
expression of interleukin-1b (Hosoi et al., 2000), which is associated with plasticity
and memory (Avital et al., 2003). VNS also increases expression of the trophic factor
basic fibroblast growth factor (Follesa et al., 2007), which is believed to promote
recovery after motor cortex lesion (Rowntree and Kolb, 1997). VNS may even
directly alter the expression of NMDAR and GABAAR expression levels, thereby
influencing neuronal excitability (Zhang and Zhang, 2002). The extensive activation
of signaling cascades demonstrates that VNS engages many molecular mechanisms
that are known to enhance plasticity and memory.
The molecular changes induced by VNS translate into changes in neuronal and
network properties. Low-intensity stimulation of the vagus nerve results in the acti-
vation of a slow hyperpolarizing current in the cortical neurons, suggesting that in-
trinsic neuronal properties may be modified by VNS (Zagon and Kemeny, 2000).
Synaptic properties are also altered by VNS, as stimulation causes long-lasting
6 Targeted Plasticity Requires Less VNS than Approved Protocols 289
on stimulation cycle (Handforth et al., 1998; Sackeim et al., 2001). The antiepileptic
effects of VNS are mediated by the locus coeruleus (Krahl et al., 1998), so a sustained
increase in the level of norepinephrine may drive EEG desynchronization and seizure
suppression. Consistent with this, lower amounts of current are less effective at pre-
venting seizures (Handforth et al., 1998). The requirement of sustained neuromodu-
lator levels for seizure suppression is further supported by the finding that treatment of
epilepsy with VNS becomes more effective over time (Heck et al., 2002). Alterna-
tively, for the plasticity-enhancing effects of paired VNS, a discrete, phasic release
of neurotransmitter release is required to drive specific plasticity. Only events occur-
ring coincident with VNS are reinforced while surrounding events are not (Engineer
et al., 2011; Porter et al., 2011). Temporally precise release of acetylcholine and nor-
epinephrine triggered by VNS coincident with an event may serve to “label” its im-
portance and reinforce this event in comparison with other unlabelled events. Because
of the temporal requirements, a continuous delivery of VNS would not be expected to
be effective in driving specific plasticity. The benefits of targeted plasticity using
VNS persist for weeks or months after discontinuation of stimulation because targeted
plasticity therapy drives long-lasting changes in neural circuits (Arns and De Ridder,
2011; Engineer et al., 2011; Khodaparast et al., 2013). In summary, the effectiveness
of VNS is likely dependent on the temporal requirements for changes in neuromodu-
latory levels; therefore, sustained increases are efficacious for epilepsy and depres-
sion, and discrete, phasic increases are required for the enhancement of plasticity.
7 FUTURE APPLICATIONS
The low levels of current delivered for VNS-directed plasticity suggest that targeted
plasticity therapy using VNS can be safely implemented into patients. The proof-of-
concept experiments discussed in the preceding text demonstrate the efficacy of tar-
geted plasticity therapy and suggest that it holds promise for treating tinnitus, stroke,
and PTSD. In principle, the ability to specifically manipulate plasticity represents
considerable potential for treating a variety of neurological disorders.
Pain disorders can be extremely debilitating and have massive economic, social,
and personal consequences. Pain is typically treated with drugs that carry a signif-
icant risk of tolerance and dependency (Martell et al., 2007; Schnoll and Weaver,
2003), highlighting the significant clinical need for a safe, effective therapy. Tar-
geted plasticity therapy may be effective in treating disorders related to sensory dys-
function, such as chronic pain, in the same manner as tinnitus. As chronic pain is
thought to be related to an increased somatosensory cortical representation
(Birbaumer et al., 1997; Flor, 2003; Flor et al., 1995, 1997), sensory input of non-
painful areas paired with VNS may be effective in renormalizing the cortical repre-
sentations and thereby reducing the percept of pain. A similar implementation may
be effective for phantom limb pain.
The proof-of-concept evidence demonstrating the effectiveness of VNS paired
with rehabilitative training to improve motor function after ischemic stroke opens
8 Concluding Remarks 291
the possibility that targeted plasticity therapy may drive plastic changes that are ben-
eficial in other disorders of motor function (Khodaparast et al., 2013; submitted).
Hemorrhagic stroke is a devastating subtype that has a mechanistically distinct path-
ophysiology compared to ischemic stroke and typically affects subcortical structures
and white matter. It is not clear whether VNS will be effective after white matter
damage, but VNS paired with rehabilitative training may be amenable for restoring
function by driving plasticity in spared circuitry. Neuronal death from the initial im-
pact of a traumatic brain injury or the resulting sequelae can impair motor function
and may benefit from targeted plasticity therapy. Despite significantly different un-
derlying pathologies, VNS paired with rehabilitation could be tested in models of
spinal cord injury and Parkinson’s disease. Significant development is still required,
but targeted plasticity therapy could potentially promote plasticity within intact
motor circuitry to confer therapeutic benefits.
The memory-enhancing effects of VNS paired with training indicate that targeted
plasticity therapy could potentially be applied to treat a range of cognitive disorders.
Based on the VNS-dependent enhancement of cued fear extinction in rats (Peña
et al., 2012), it has been suggested that VNS may improve exposure therapy. Exposure
therapy is beneficial for some patients experiencing generalized anxiety disorder and
PTSD. The therapy aims to reduce the response to fear-inducing stimuli through habit-
uation (Frueh et al., 1995). As VNS sped the reversal of a fearful memory in rats, similar
principles may allow VNS to enhance the effects of exposure therapy in patients. Paired
with the appropriate exposure, VNS may bolster the effects of the therapy and provide a
more robust, rapid reversal of the fear response. Maladaptive plasticity is associated
with a variety of other cognitive disorders, including anxiety, bipolar disorder, schizo-
phrenia, depression, drug addiction, and attention-deficit hyperactivity disorder
(Brunoni et al., 2008; Lozano, 2011). The complex cognitive aspects of these disorders
have left them undermanaged, emphasizing the need for effective, flexible treatments
that can address the underlying pathophysiology. VNS, if paired with the appropriate
behavioral exposure, may be able to improve these disorders.
8 CONCLUDING REMARKS
The remarkable capacity for experience-dependent plasticity in the sensory, motor,
and cognitive systems is a testament to its importance. In many neurological disor-
ders, insufficient and maladaptive plasticity can hinder recovery. The ability to har-
ness and specifically direct plasticity may reduce the suffering caused by these
disorders. Targeted plasticity therapies, including VNS paired with relevant events,
may represent such an intervention. While proof-of-concept studies have provided
encouraging results, continuing studies should be directed at defining the optimal
parameters to maximize benefit, delineating the factors that affect outcomes, and
identifying other disorders that may respond to targeted plasticity therapy.
VNS is one of many potential tools that can drive specific plasticity and subse-
quently treat neurological disorders. Mirroring aspects of the development of
292 CHAPTER 11 Targeting Plasticity with Vagus Nerve Stimulation
FIGURE 3
Vaccination and targeted plasticity therapy are based on similar principles. (A) Injection of an
antigen alone causes a generally weak immunologic response. Injection of an adjuvant alone
causes a nonspecific inflammatory response. Many different compounds can act as
adjuvants, including aluminum salts, virosomes, or saponins (Cox and Coulter, 1997).
Concurrent presentation of the antigen and adjuvant results in a significantly enhanced
immunologic response beyond that evoked by either element alone, resulting in specific and
long-lasting immunity. (B) Targeted plasticity therapy is based on similar principles of
synergism. Experience alone drives activity within circuitry but does not result in plasticity.
Neuromodulators alone have generalized neuronal effects, but do not drive lasting changes. A
variety of factors can cause release of neuromodulators, including attention, pain, or VNS.
When bursts of neuromodulators correspond with experience, specific and long-lasting
plasticity results.
vaccines, VNS acts as an adjuvant, while experience mimics the antigen (Fig. 3).
Together, these elements synergistically provoke a significant biological response
that surpasses the typical physiological response to the antigen alone. As such,
VNS paired with experience enhances the brain’s response to experience and, when
targeted appropriately in a disease state, can promote recovery or reversal of neuro-
logical disease. The development of other tools that can act as an adjuvant to rein-
force the response to experience could also be applied as targeted plasticity therapies.
Considering the transformative potential of targeted plasticity therapies, efforts
should be focused on the development and translation of VNS and other methods
for targeting plasticity to treat neurological disease and improve human health.
Acknowledgments
We would like to thank Dr. Andrew Sloan, Navid Khodaparast, and Daniel Hulsey for insight-
ful comments and discussion about the chapter. This work was supported by grants from the
Michael J. Fox Foundation, the US National Institute for Deafness and Other Communicative
Disorders, Texas Biomedical Device Center, and Vulintus.
Conflict of interest: M. P. K. is a consultant for and has a financial interest in MicroTran-
sponder, Inc.
References 293
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CHAPTER
Computerized Cognitive
Training Targeting Brain
Plasticity in Schizophrenia
*
12
Bruno Biagianti*,{, Sophia Vinogradov*,{,1
San Francisco Department of Veterans Affairs Medical Center, San Francisco, CA, USA
{
Department of Psychiatry, University of California, San Francisco, CA, USA
1
Corresponding author: Tel.: (415) 750-2073; Fax: (415) 750-6996
e-mail address: Sophia.vinogradov@ucsf.edu
Abstract
Two important paradigm shifts have occurred recently in the field of schizophrenia research.
First, we now understand schizophrenia to be a neurodevelopmental disorder, one that is char-
acterized by aberrant patterns of activation and connectivity in cortical and subcortical neural
networks that are present before illness onset and that worsen as an individual progresses into
later stages of the disease. Second, we now understand that these abnormalities are not immu-
table and fixed, but instead can respond to interventions targeting brain plasticity, particularly
when delivered in the prodromal and early phases of schizophrenia.
In this chapter, we will first describe some of the neurocognitive impairments that charac-
terize schizophrenia, highlighting the developmental course of the illness. We will then briefly
review salient features of currently available computerized cognitive training programs that
target these impairments. Next, we will present an overview of current research findings re-
garding neurobiological effects of computerized cognitive training in schizophrenia and how
these results shed light on the critical neuroplasticity mechanisms that support successful train-
ing. Finally, we will present recommendations for future research to optimize computerized
cognitive training programs, with an aim to promoting functional recovery.
Keywords
schizophrenia, neurocognition, neurodevelopmental, cognitive training, neural system
impairments
FIGURE 1
Neurodevelopmental model of schizophrenia, highlighting the pre-emptive period and
intervention targets discussed in this review (adapted and modified by permission of Tyrone
Cannon, PhD). DA, dopamine; HPA, hypothalamic-pituitary-adrenal.
functioning, which are not typically evident until adolescence or very early adult-
hood, when brain maturation is nearing completion (Andreasen, 2010; Hoffman
and McGlashan, 1997). At that point, usually as a response to environmental
stressors, the individual (who may until then have had no observable symptoms
or only mild nonspecific symptoms), experiences “psychosis,” or a break with real-
ity—often initially in mild or attenuated form, which if left untreated then progress
into a full-blown psychotic episode. Schizophrenia must thus be understood as a neu-
rodevelopmental neurocognitive disorder characterized by decreased efficiency and
abnormal connectivity in cortical and subcortical neural networks—rendering young
individuals particularly vulnerable to the deleterious effects of stress.
working memory, verbal learning and memory, executive functioning, global cog-
nition, and IQ are observed prior to the first psychotic episode (Becker et al.,
2010; Brewer et al., 2005; Eastvold et al., 2007; Jahshan et al., 2010; Keefe et al.,
2006; Kim et al., 2011a,b; Lencz et al., 2006; Niendam et al., 2006; Seidman
et al., 2006; Simon et al., 2007). From high risk status to first psychotic episode, in-
dividuals show continued cognitive impairment (Becker et al., 2010; Hawkins et al.,
2008), or further cognitive decline (Jahshan et al., 2010; Keefe et al., 2006; Simon
et al., 2007; Wood et al., 2007). A recent longitudinal study in a population-
representative sample indicated that a decline in processing speed was particularly
characteristic, occurring gradually from childhood to beyond the early teen years
(Meier et al., 2013). Cognitive deficits are not surprisingly associated with poorer
functional outcome (Green, 1996; Green et al., 2000): in young individuals who have
just experienced their first episode of psychosis, verbal memory, speed of processing,
and attention have been shown to predict psychosocial and vocational functioning 7
years later (Milev et al., 2005).
Interestingly, in both recent onset and chronic schizophrenia, cognitive functioning
and symptom severity are for the most part independent of one another: cognitive def-
icits are present in the absence of florid symptoms, and while antipsychotic medications
are effective in ameliorating some of the clinical symptoms, they have little effect on
cognitive impairment or long-term outcome (Goldberg et al., 2007; Keefe et al., 2007).
Given the relative independence of cognitive dysfunction and symptoms, as well as the
deleterious effects of cognitive impairment on social and occupational outcomes and
quality of life, it is clear that cognitive enhancement is a critical treatment goal in
schizophrenia. Moreover, cognitive enhancement is likely to be a key means for inter-
vening preemptively to ameliorate the course of illness, or perhaps even to inoculate the
at-risk individual against the onset of a first psychotic episode.
Previously, there was a great deal of skepticism about the possibility of adaptive
plasticity and neural system improvement in serious neuropsychiatric disorders such
as schizophrenia. This was due in part to the fact that these illnesses are characterized
by long-standing and fairly serious impairments in behavior and in multiple distrib-
uted limbic, prefrontal and frontostriatal neural circuits. Further, recent findings by
Balu and Coyle (2011) indicate that many schizophrenia-risk genes are involved in
regulating neuroplasticity, perhaps contributing to abnormal patterns of synapse for-
mation and cortical connectivity. It is thus possible that there are some inherent lim-
itations in the “brain plasticity” mechanisms of certain individuals with
schizophrenia.
Despite this skepticism, emerging data over the past 5 years suggest that it is pos-
sible to develop intensive computerized cognitive training methods that successfully
harness the brain-learning machinery in schizophrenia to generate widespread adap-
tive behavioral and neural responses (Dale et al., 2010; Eack et al., 2009, 2010a;
Fisher et al., 2009; Subramaniam et al., 2012). These adaptive improvements include
better cognition and functioning as well as increases in gray matter volume and plas-
tic changes in cortical activation patterns (e.g., Adcock et al., 2009; Eack et al.,
2010b; Subramaniam et al., 2012). Positive results in younger individuals are partic-
ularly promising (Eack et al., 2010a; Fisher et al., 2013).
CogPack, Marker Information on rationale and approach not • 64 programs for testing and training, each with several
Software available variants for visuomotor, comprehension, reaction, vigilance,
memory, language, intellectual, and professional skills
• Exercises can be edited and expanded
• Difficulty level and the sequence of exercises can be modified
CogRehab, Originally developed for traumatic brain injury. • Hierarchical approach: training of fundamental cognitive
Psychological Based on the rationale that diffuse traumatic functions followed by more complex functions
Software Services lesions rarely have just one behavioral effect, • 8 modules target 4 domains: simple attention and executive
and the degree to which a single behavior skills, visuospatial skills, memory, and problem solving
will be normal (or pathological) may depend • 2 modules of increasing complexity within each domain
on its interactions with other functional systems • Exercises follow a standard sequence and progression of
(Chen et al., 1997) difficulty. Subjects graduate to new tasks after reaching a
prescribed performance level
Brain Fitness Originally developed for children with learning • Exercises are grounded in basic principles of learning-
Program Auditory disabilities but has been subsequently heavily induced neuroplasticity
Module, Posit modified and adapted for adults, with an emphasis • Intensive—many thousands of learning trials are performed
Science Inc. on both individuals with schizophrenia and the for each specific exercise
cognitive decline associated with aging. Applied to • Neuroadaptive—the dimensions of each exercise (e.g.,
patients with schizophrenia based on the known speed, working memory load) are parametrically and
impairments in auditory processing and frontally continuously modified on a trial-by-trial basis for each
mediated verbal memory operations individual user during the course of each exercise in order to
maintain performance at 80% accuracy
• Attentionally engaging—each trial is gated by a “ready” signal
from the user to indicate and require directed attention
• Rewarding—correct responses are continuously rewarded by
amusing auditory and visual stimuli in order to drive high
levels of training compliance and to engage reward and
novelty detection systems for successful learning
306 CHAPTER 12 Computerized Cognitive Training
schizophrenia (N ¼ 21) completed fifteen, 45 min daily sessions over 3 weeks and
showed significant gains on immediate and delayed verbal memory as well as proces-
sing speed relative to 21 inpatients on a waitlist. Wölwer et al. (2005) used CogPack
tasks of attention, memory, and executive functioning, in combination with desk work
and training of compensatory strategies (verbalization and self-instruction) among in-
patients and outpatients (N ¼ 24) and also found gains on measures of verbal learning
and memory compared to a “treatment as usual” group (N ¼ 25).
McGurk et al. (2005, 2007b) tested the effects of 3 months of a combination of
CogPack exercises (attention, psychomotor speed, learning and memory, and exec-
utive functions), therapist-guided compensatory strategies (“Thinking Skills for
Work”), and supported employment among 23 schizophrenia outpatients versus
participation in supported employment only (N ¼ 21). Similar to Sartory et al.
(2005) and Wölwer et al. (2005), subjects who completed the cognitive training
showed gains on measures of verbal learning and processing speed. Importantly,
over a 2–3-year period post-treatment, subjects who received cognitive training
were more likely to work, held more jobs, worked more weeks and total hours,
and earned more wages compared to subjects receiving supported employment
alone. In a second study, the authors combined the training with vocational
rehabilitation (N ¼ 18) and found similar cognitive effects and better work outcomes
over a 2-year follow-up period relative to vocational rehabilitation alone (N ¼ 16)
(McGurk et al., 2009).
Lindenmayer et al. (2008) provided 45 inpatients with 24 h of CogPack exercises
(attention and concentration, psychomotor speed, learning and memory, and execu-
tive functions) in conjunction with a work program in a psychiatric center. Relative
to a computer games (CG) control group (N ¼ 40), subjects who completed the
cognitive training showed gains on measures of verbal learning, processing speed,
and global cognition. Further, over a 12-month follow-up, subjects who completed
cognitive training worked more total weeks relative to subjects in the control group.
CogPack showed positive effects on both cognition and quality of life in 50
outpatients in a rehabilitation program who completed 36 h of exercises in verbal
memory, verbal fluency, psychomotor speed and coordination, executive function-
ing, working memory, attention, culture, language, and simple calculation skills
(Cavallaro et al., 2009). Relative to subjects who completed computer-assisted
non-domain-specific activities (N ¼ 36), subjects who completed CogPack showed
gains on measures of attention, reasoning and problem solving, and the Quality of
Life Scale, as well as durability of gains at 6- and 12-month follow-up (Poletti
et al., 2010).
CogPack appears to have consistent positive effects on verbal learning and mem-
ory and processing speed in schizophrenia (Table 2), and substantially improves vo-
cational outcomes when combined with supported employment or vocational
training programs (Table 3). Sample sizes studied have been relatively small, how-
ever, and control groups have varied widely. Additional research is required to de-
termine the specificity of CogPack’s effects and to replicate the findings of improved
quality of life.
3 Computerized Cognitive Training in Schizophrenia: Behavioral Results 307
Continued
308 CHAPTER 12 Computerized Cognitive Training
Continued
310 CHAPTER 12 Computerized Cognitive Training
Cognitive enhancement therapy (CET) (Hogarty and Flesher, 1999, 2004, 2006)
is a small-group approach for the treatment of social cognitive and neurocognitive
deficits in schizophrenia. Subjects work in pairs and complete approximately 75 h
of computerized cognitive training exercises, which also included attention exercises
from the Orientation Remediation Module (Ben-Yishay et al., 1987), and CogRehab
exercises of memory and problem solving. Four to six months cognitive training,
subjects begin 1.5 h per week of social cognitive group therapy, with treatment de-
livered over a 2-year period. Hogarty et al. (2004) tested the effects of CET (N ¼ 67)
relative to Enriched Supportive Therapy (EST, N ¼ 54) in outpatients with schizo-
phrenia. At 12 months of treatment, the CET group showed significant gains in speed
3 Computerized Cognitive Training in Schizophrenia: Behavioral Results 311
compared to the computer skills training group. In this study, both groups received
equivalent computer time and equivalent staff interaction. Interestingly, both groups
showed improvements in processing speed, working memory, episodic memory
(verbal and visual), and executive functioning, indicating that nonspecific engage-
ment and stimulation has a salutary effect on neurocognition.
In summary, in studies where CogRehab training exercises of attention and
working memory have been used in sufficient doses, gains in working memory
have been consistently reported (Table 2). Further, the addition of CogRehab
has provided significant benefits on work outcomes in studies that added cognitive
training to work therapy or vocational programs (Table 3). Again, sample sizes
have been small, control groups have varied widely, and the specificity of the ef-
fects is not yet clear.
50 h of the training over a 10-week period and were compared to an active CG con-
trol condition (N ¼ 26) designed to control for the effects of computer exposure, con-
tact with research personnel, and monetary payments. Relative to the control group,
using a per protocol analysis, the auditory training showed positive effects on mea-
sures of verbal working memory, verbal learning and memory, and global cognition.
Effect sizes in verbal learning and memory, and in global cognition, were large
(Cohen’s d 0.86–0.89). At a 6-month no-contact follow-up, improved cognition
was significantly associated with improved functional outcome.
Popov et al. (2011) tested the effects of BFP compared to CogPack among inpa-
tients in Germany. Patients in the BFP condition (N ¼ 20) completed 20 one-hour
sessions over 4 weeks, while patients in the CogPack condition (N ¼ 19) followed
the standard protocol recommended by the developers of 60–90 min sessions, three
times per week, for 4 weeks. Both subject groups showed improvement in verbal
learning and verbal memory; however, the BFP group showed significantly greater
gains in verbal working memory and verbal learning. Patients who completed BFP
also showed normalization of auditory sensory gating deficits not seen in the Cog-
Pack group (described in the next section).
In a multisite feasibility study (Keefe et al., 2013), 25 outpatients were random-
ized to BFP plus weekly support groups, or to a CG control condition plus weekly
healthy lifestyles groups (N ¼ 22). Subjects completed 3–5 one-hour sessions per
week for 40 sessions or 12 weeks, whichever came first. After 20 sessions, in an in-
tent-to-treat-analysis, the BFP group showed significant gains in verbal learning
(d ¼ 0.69), auditory frequency discrimination (d ¼ 0.84), and global cognition
(d ¼ 0.28) relative to the control group. However, at the endpoint of the study, the
effects on verbal learning and global cognition did not reach significance. The au-
thors suggest this is likely due to the study completion deadline—that 9 out of the
25 auditory training subjects did not complete the entire 40 sessions within the
12-week period, which may have reduced the efficacy of the training.
A single-arm, open-label, multisite, trial of 40 training sessions, using a repeated
baseline assessment design, found no overall gain in a cognition summary score in
stable outpatients, but did find that participants with greater improvement in auditory
processing speed (evidence of target engagement in auditory system) showed larger
gains in cognition (Murthy et al., 2012). Finally, a pilot study of 10 weeks of an
unspecified number of hours of auditory training combined with visual training ex-
ercises found no significant effects on cognitive or event-related potential measures
compared to a TV watching control group or a treatment-as-usual group; however,
methodological issues make interpretation/comparison difficult (e.g., interleaving
training across visual and auditory domains, unequal baseline cognitive performance
in subject groups, combining of raw scores across tests into a summary score; Rass
et al., 2012).
Once again, sample sizes have been small and study methods have varied, though
three of the five studies have used an active control group that permitted maintenance
of a double-blind. These early data suggest some specificity of BFP for verbal pro-
cesses and global cognition.
314 CHAPTER 12 Computerized Cognitive Training
this finding is limited by the fact that the relationship between serum BDNF and
brain processes is unknown.
Dysfunction of glutamatergic neurotransmission mediated by the N-methyl-D-as-
partate (NMDA) receptors and D-serine (an endogenous receptor agonist) may also
be involved in the pathophysiology of schizophrenia (reviewed in Labrie et al.,
2012). Since animal studies indicate that learning and memory can affect the levels
of D-serine (Vargas-Lopes et al., 2011), we predicted that training-induced cognitive
gains would be associated with changes in serum D-serine levels. At baseline, we
found reduced serum D-serine in schizophrenia subjects compared to healthy control
subjects, consistent with previous findings in both serum and cerebrospinal fluid
(Bendikov et al., 2007; Hashimoto et al., 2003; Panizzutti et al., 2013). We also found
a significant positive correlation between cognitive improvement, and increases in
serum D-serine, in subjects who underwent 50 h of the BFP exercises, but not in
subjects who were in the CG control condition. These results raise the possibility that
D-serine and/or the NMDA receptor is involved in the neurophysiological changes
induced by BFP cognitive training in schizophrenia.
During this trial, we also determined the anticholinergic activity of medications
taken by participants, as measured via serum radioimmunoassay. We found that im-
provements in global cognition after training were negatively correlated with serum
anticholinergic burden; in fact, serum anticholinergic activity accounted for 20% of
the variance in the change in global cognition independent of the effects of IQ, age, or
symptom severity (Vinogradov et al., 2009b). These findings have implications
for the design and evaluation of neuroplasticity-based cognitive treatments for
schizophrenia in situations where participants are administered medications with an-
ticholinergic burden.
Finally, it is possible that common variants in genes known to influence cognition
affect an individual’s response to cognitive training. One small study investigated the
association between the COMT Val158Met polymorphism and neuropsychological
improvement after 36 h of Cogpack exercises in 27 patients with schizophrenia
(Bosia et al., 2007). Patients with the COMT Met allele made greater gains in cog-
nitive flexibility than patients without the Met allele. In contrast, another study failed
to observe a significant association between the COMT Val158Met polymorphism
and cognitive improvement following therapist-led pencil-and-paper cognitive re-
mediation therapy (Greenwood et al., 2011). In a recent small study, we genotyped
48 schizophrenia outpatients who had participated in our cognitive training studies
using BFP. We analyzed the association between the training-induced improvement
in global cognition, and DNA variants in three genes known to show a relationship
with cognitive performance—DISC1, COMT, and BDNF. Changes in global cogni-
tion after training were nominally associated with single nucleotide polymorphisms
in the COMT and DISC1 genes. The strongest association was with COMT
rs165599, a SNP previously associated with neurocognition in healthy subjects
(Panizzutti et al., 2013). It is probable that a wide number of gene variants that affect
aspects of cognition or learning potential will play a significant role in determining
the magnitude of patients’ response to cognitive training interventions.
316 CHAPTER 12 Computerized Cognitive Training
In another MEG study, Miller and collaborators used measures of auditory sen-
sory gating, a finding related to early auditory processing abnormalities in schizo-
phrenia, to explore the effects of BFP auditory training and CogPack training
(Popov et al., 2011). Four weeks (approximately 20 h) of BFP normalized sensory
gating in patients with schizophrenia, while this effect was not evident in subjects
who completed CogPack. These results indicate that exercises that specifically target
perceptual discrimination ability in the auditory system—as opposed to providing
more generalized cognitive training—may normalize early auditory gating impair-
ments in schizophrenia.
Weiss et al. (2011) also investigated the effects of this form of cognitive training
on early perceptual operations. Two MEG recordings were acquired during perfor-
mance of an FM sweep discrimination task used to improve the acuity of auditory
processing, before and after 2.5 h of task practice. Practice increased power and mu-
tual information, an index of communication between brain regions, in temporal-
parietal regions. Participants showed improved accuracy after practice, and these
improvements correlated with the increase in power and mutual information.
Overall, the emerging MEG data suggest that carefully designed computerized
training of auditory processes can increase the fidelity, precision, and signal-to-noise
ratio of early auditory representations in the brain, with important downstream be-
havioral effects.
FIGURE 2
Whole brain fMRI analysis during reality-monitoring task performance reveals signal increase
within: (A) the medial prefrontal cortex (mPFC) in 15 Healthy Comparison Subjects (HC),
(B) the posterior cingulate cortex, rather than the mPFC, in patients with schizophrenia
(SZ) prior to computerized cognitive training, and (C) the mPFC in only the group of
schizophrenia patients who completed 80 h of Active Training (SZ-AT) but not those who
completed the Computer Games control condition (SZ-CG). From Subramaniam et al. (2012).
changes in patients after TAR exercises correlated with their behavioral improve-
ment in emotion identification.
More recently, in a double-blind randomized controlled trial, our group investi-
gated the behavioral and neural effects of intensive computerized cognitive and so-
cial cognitive training in schizophrenia on a facial emotion recognition task (Hooker
et al., 2013). Twenty-two schizophrenia participants were randomly assigned to ei-
ther 50 h of auditory-based cognitive training plus SCT which consisted of exercises
from the Microexpressions and Subtle Expressions Training Tool (METT/SETT,
Eckman, 2003) and MindReading (Baron-Cohen et al., 2003) or to 50 h of a placebo
CG condition. We found a group by session interaction which was driven by the SCT
subjects who showed greater neural increases in two emotion-processing regions—
including the superior temporal cortex and somatosensory-related cortex—as com-
pared to the CG subjects. Furthermore, neural increases in these regions were
correlated with behavioral improvement on an independent emotion perception mea-
sure (MSCEIT: Perceiving Emotions). Together, these findings suggest that com-
bined cognitive and social cognitive training increased neural activation of the
320 CHAPTER 12 Computerized Cognitive Training
systems that supported better emotion recognition. Because facial emotion recogni-
tion has been shown to predict functional outcome even after accounting for the con-
tribution of general cognition (Hooker and Park, 2002; Poole et al., 2000), these
findings indicate that a combination of computerized basic cognitive and social cog-
nitive training interventions has the highest likelihood of improving quality of life for
people with schizophrenia.
Overall, it appears unequivocally that the higher-order behavioral and neural im-
pairments in schizophrenia are not fixed and that, even during complex operations
such as verbal working memory, reality monitoring, and social cognition, they
can demonstrate significant plasticity in response to well-designed cognitive training
interventions.
5 FUTURE DIRECTIONS
There is now a consensus in the field that cognitive training offers a number of
significant advantages as we seek to develop meaningful approaches to not only
treat, but to pre-empt schizophrenia. Over 10 years ago, Bentall and Morrison
(2002) noted that, as compared to pharmacological treatments, behavioral interven-
tions for schizophrenia have fewer deleterious side effects, are less stigmatizing,
and target the presenting nonspecific symptoms through a normalizing approach.
In addition, they are generally more tolerable and acceptable than medications
References 321
(Morrison et al., 2004). We posit that, in at least some forms, they are also more
scalable, and can be delivered via web-based technology to remote or under-
resourced clinical sites. More importantly, if we are able to achieve the goal of en-
gendering adaptive plastic changes in impaired neural systems, then such methods
can halt or reverse the pathological neural system changes that characterize
schizophrenia.
While the emerging data are promising, much important work remains to be
done. A strong and rigorous approach to methodological issues such as sample size
and sample characteristics, assessment criteria, clinical staging, and optimal trial
design and data analytic approaches must be implemented in order to build a con-
vincing evidence base. With the current rapid advances in the development of
cognitive-enhancing medications, we must also be prepared to explore the most ad-
vantageous ways in which these agents can—and probably should—be combined
with behavioral treatments in order to optimize patients’ outcomes (Keefe et al.,
2011). Indeed, some agents may be of no value when given alone, but may substan-
tially facilitate the effects of cognitive training in schizophrenia.
Medications are not the only possible approaches to enhance the brain’s response
to behavioral interventions. Exercise is a potent, safe, and highly valuable “neuro-
trophic agent” that should become a significant part of the treatment armamentarium
for schizophrenia (see Pajonk et al., 2010). Neuromodulatory techniques such as di-
rect current stimulation are known inducers of cortical plasticity (Celnik et al., 2009;
Khedr et al., 2010). All of these areas are under active investigation at present in
combination with cognitive training.
Finally, advances in information technology and in interactive and entertainment
software indicate that web-based treatment delivery methods can be developed that
will generate the same interest, engagement, perceived value, and social acceptabil-
ity as web-based games. Indeed, novel collaborative efforts are already underway to
develop socially-networked browser-based cognitive therapy for schizophrenia as
well as highly engaging game-like cognitive training tools for early psychosis pa-
tients. We are only a few steps away from the development of web-deliverable brain
plasticity-based treatments for impaired neural systems that can be delivered on a
scale never before imagined for any other behavioral intervention. We are at a con-
ceptual threshold that could not have been imagined even a decade ago, facing the
real possibility that we may be able to move beyond pre-emption in schizophrenia, to
inoculation against its cognitive and psychosocial ravages.
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CHAPTER
Abstract
In addition to deficits in spatial attention, individuals with persistent spatial neglect almost uni-
versally exhibit nonspatially lateralized deficits in sustained and selective attention, and working
memory. However, nonspatially lateralized deficits in neglect have received considerably less
attention in the literature than deficits in spatial attention. This is in spite of the fact that non-
spatially lateralized deficits better predict the chronicity and functional disability associated with
neglect than spatially lateralized deficits. Furthermore, only a few treatment studies have spe-
cifically targeted nonspatially lateralized deficits as a means to improve spatial neglect. In this
chapter, we will briefly review several models of spatial attention bias in neglect before focusing
on nonspatial deficits and the mechanisms of nonspatial–spatial interactions and implications for
treatment. Treatment approaches that more completely address nonspatial deficits and better ac-
count for their interactions with spatial attention will likely produce better outcomes.
Keywords
spatial neglect, hemineglect, neglect, spatial attention, sustained attention, rehabilitation
1 INTRODUCTION
Approximately one-third of all individuals suffering unilateral brain injury exhibit a
complex, debilitating array of neurological deficits known as the neglect syndrome
(Halligan et al., 2003; Heilman et al., 1987, 1993; Mesulam, 1990). This collection of
spatial and nonspatially lateralized attention deficits vary greatly in presentation and
severity (Appelros et al., 2002; Buxbaum et al., 2004; Pedersen et al., 1997), and
endure more often following right hemisphere damage (Ringman et al., 2004;
Stone et al., 1993). The most apparent problem is failure, or dramatic slowing, of
response to stimulation presented to the side of space opposite the lesion (Azouvi
et al., 2003; Driver and Vuilleumier, 2001; Heilman et al., 1985; Hornak, 1992;
Ishiai et al., 2006; Mattingley et al., 1998). Although less obvious, deficits that
are not spatially lateralized (Danckert and Ferber, 2006; Husain et al., 1997;
Robertson et al., 1997a; Van Vleet and Robertson, 2006) are also fundamental to
persistent neglect. In fact, the severity of nonspatial deficits is a stronger predictor
of the chronicity of spatial neglect in the post-acute phase of recovery than the spatial
deficits themselves (Duncan et al., 1999; Hjaltason et al., 1996; Husain et al., 1997;
Peers et al., 2006; Robertson et al., 1997a).
In this chapter, we will briefly review several models of spatial attention bias in
neglect before focusing on nonspatial deficits and the mechanisms of nonspatial/spa-
tial interactions and implications for treatment. We contend that treatment ap-
proaches that more completely address nonspatial deficits and account for
nonspatial/spatial interactions will produce better outcomes and may eventually lead
to effective, practical treatments for this debilitating disorder that currently has no
widely accepted standard of care.
(e.g., disengaging from rightward stimuli to attend to leftward stimuli) several years
post-insult (Johnston and Diller, 1986; List et al., 2008; Posner et al., 1984). Over the
last 40 years, several theories have been proposed to account for these goal-directed
spatial attention deficits in neglect, many of which are not mutually exclusive. While
a review of these theories is beyond the scope of this chapter, we briefly describe
several popular theories below.
3.1.2 Right Hemisphere Pays Attention to Both Sides of Space, Left Pays
Attention to the Right Side of Space
Another traditional and popular theory of neglect postulates that the right hemisphere
controls goal-directed attention to both sides of space, while the left hemisphere only
controls attention to the right side of space (Mesulam, 1981). According to this the-
ory, damage to the right hemisphere is associated with more severe spatial attention
impairments (as the left cannot compensate), whereas after left hemisphere damage
the right hemisphere is able to successfully compensate (i.e., attend to both sides of
space). There has not been a wealth of neuroimaging support for this theory; in fact,
studies in healthy controls generally show that brain regions involved in goal-
directed spatial attention (e.g., intraparietal sulcus, IPS) are sensitive to the opposing
side of space in an equal and opposite fashion (Silver et al., 2005; Snyder and
330 CHAPTER 13 Nonspatial Side of Spatial Neglect and Related Approaches
Chatterjee, 2004). However, a recent report has shown that with increasing visual
short-term memory load, an asymmetry does in fact emerge: left IPS regions show
load effects for the right side of space whereas right IPS regions show load effects for
both sides of space (Swisher et al., 2007). This suggests that asymmetries in attention
may only be pronounced during demanding tasks (e.g., searching for items in a clut-
tered array) and further suggests a crucial link between spatial attention and the cog-
nitive load of a task, which we will expand upon below.
Russell et al., 2004). Further, recent studies suggest that children with ADHD exhibit
lateralized attention deficits similar to neglect (though typically smaller in magni-
tude) and that this is ameliorated by ADHD-targeted medications that boost the abil-
ity to sustain attention (Bellgrove et al., 2013).
Though several treatment approaches have been developed over the last 30-years
(for a review, see Luauté, 2006), these approaches have collectively shown limited
success. Furthermore, the majority of treatment studies have judged treatment suc-
cess as the amelioration of spatial deficits only, largely ignoring nonspatial deficits.
Because nonspatial deficits are a fundamental aspect of chronic neglect and may
underlie (and perpetuate) spatial deficits, we argue and provide evidence that
addressing these deficits first or in concert with spatial deficits may produce better
treatment outcomes. Below we review several neglect spatial and nonspatial treat-
ments and suggest ways that these treatments can be developed and intelligently
combined to produce better outcomes in patients suffering from neglect.
and phasic alertness. As mentioned previously, Tonic alertness refers to the ongoing
state of intrinsic readiness that fluctuates on the order of minutes to hours, and is
intimately involved with sustaining attention and also provides the cognitive tone
necessary for performing more complicated functions such as working memory
and executive control (Harvey et al., 1995; Matthias et al., 2010). In contrast, phasic
alertness is the rapid modulation in alertness due to any briefly engaging event, and is
vital for operations such as orienting and selective attention (Matthias et al., 2010).
To improve tonic alertness, computerized interventions for neglect have required
patients to maintain attentional engagement over prolonged time periods. For exam-
ple, an intervention referred to as AIXTENT (Sturm et al., 2006; Thimm et al., 2006)
challenges individuals with neglect to continuously drive a virtual car while
responding to cues to slow down (e.g., virtual traffic lights). Studies of AIXTENT
in individuals with neglect have shown benefit. In one study, six out of seven
neglect patients improved on at least one spatial neglect test (e.g., line bisection,
cancellation tasks, visual search tasks, drawing tasks); improvements persisted
for 4 weeks after training was terminated in two patients. Further, for those patients
showing behavioral improvement, neuroimaging revealed partial restoration of
the right hemisphere functional network known to subserve intrinsic alertness in
healthy individuals, especially in the right dorsolateral or medial frontal cortex.
Individuals that did not improve showed an increase of activation only in the left
hemisphere, suggesting that training did not fully re-engage the damaged hemisphere
in some patients.
In contrast to attempts to enhance tonic alertness, experimental interventions
aimed at improving the efficiency of phasic alertness in neglect have utilized extrin-
sic, unexpected alerting events (e.g., unexpected tone) (Robertson et al., 1998). How-
ever, due to the short-acting effect of extrinsic alerting and the close relationship
between phasic and tonic alertness, recent studies have examined phasic alertness
in the context of tonic alertness, and thus utilize paradigms that require continual
monitoring of successive stimuli for behaviorally relevant events (e.g., phasic spike
in alertness to infrequent and unexpected appearance of a target stimulus) (DeGutis
and Van Vleet, 2010a; Sturm et al., 2006; Thimm et al., 2006; Van Vleet and
DeGutis, 2013). This top-down approach to phasic alertness may engage similar
but distinct mechanisms (Singh-Curry and Husain, 2009) from bottom-up ap-
proaches. Electrophysiological studies have shown that bottom-up approaches
may have a frontal source (Comerchero and Polich, 1999), whereas top-down ap-
proaches may have a more posterior, parietal source (Herrmann and Knight, 2001).
A recent series of treatment studies from our lab using a computer-based task that
targets both tonic and phasic alertness (tonic and phasic alertness training, TAPAT)
has shown promising results (DeGutis and Van Vleet, 2010a; Van Vleet and
DeGutis, 2013). TAPAT was designed to challenge patients to better intrinsically
sustain attention via prolonged training epochs (3 12-min blocks per session).
TAPAT training involves performing visual and auditory continuous performance
tasks with key elements to foster sustained attention. First, the tasks employed jit-
tered interstimulus intervals, shown to improve response control in other clinical
340 CHAPTER 13 Nonspatial Side of Spatial Neglect and Related Approaches
populations, such as ADHD (Bouret and Sara, 2005; Wodka et al., 2009). The train-
ing also included numerous rich, novel and colorful stimuli (particularly in the visual
TAPAT) to further engage attention (Schultz et al., 1997). Further, participants were
required to respond via button press to frequent and centrally presented images or
tones while trying to inhibit their response to an infrequent and randomly presented
target stimulus (a unique target image or target tone was committed to memory prior
to each 12-min training epoch), similar to other go-no-go paradigms (Comerchero
and Polich, 1999; Robertson et al., 1997a,b). The unexpected presentation of the
target image (or tone), which informed participants to inhibit the execution of the
pre-potent motor response, was particularly salient (i.e., producing a strong phasic
modulation in alertness) (Aston-Jones and Cohen, 2005). Finally, all stimuli in
TAPAT were presented at central fixation, which ensured that patients with visual
field deficits could also benefit.
Following only limited training (5 h over 9 days), patients with neglect improved
their intrinsic alertness as reflected in improvements in accuracy on go and/or no-go
trials in all but 2 of 20 patients. Further, improvements in target accuracy (i.e., in-
hibitory control/phasic alertness) across TAPAT training was significantly corre-
lated with improvements on sensitive measures of spatial attention following only
limited training (5 h over 9 days) (DeGutis and Van Vleet, 2010a; Van Vleet and
DeGutis, 2013). Specifically, individuals with neglect that trained on TAPAT versus
a spatial search training task (utilizing the same stimuli used in TAPAT) showed
group-level performance improvements on a sensitive conjunction search task
(List et al., 2008); post-training, the time required to locate targets on the left versus
the right side of the search array was not different. Benefits in spatial attention (i.e.,
absence of spatial bias) were also evident on an alternate, novel conjunction search
array and an adaptive landmark task in patients that completed TAPAT training ver-
sus spatial search training. These effects are notable as it clearly demonstrates that
patients with neglect are capable of re-regulating intrinsic alertness, thereby normal-
izing spatial attention. Figure 1 shows performance from a representative patient on
the conjunction search task, delivered at the end of each TAPAT training session and
daily for several weeks post-training in this case. The distribution shows a clear evo-
lution of the treatment effect over several sessions and its impact following 2 weeks
without additional training.
Finally, as mentioned, all training was conducted at central fixation; thus, the re-
sults show a clear transfer of training-related benefit (i.e., greater intrinsic alertness)
to untrained tasks of spatial attention. In addition, TAPAT training versus control
resulted in normative performance (i.e., performance was not different from an
age-matched healthy control group) on a nonspatially lateralized, visual working
memory updating task (attentional blink) (Husain et al., 1997; Pattyn et al., 2008;
Van Vleet and Robertson, 2006). Outcomes on all measures examined were most
improved in those patients with worse neglect at baseline.
Taken together, these results support models of neglect that advance the critical
role of alertness and sustained attention to affect not only spatial attention, but also
other nonspatial functions such as selective attention/attention to transient events.
7 Future Directions 341
FIGURE 1
Daily performance on a sensitive conjunction search task (List et al., 2008) for a
representative patient with neglect following right parietal damage (DW). Figures show
performance pre, during and post TAPAT training. Differences in threshold presentation
times (TPT) for right targets–left targets are shown. A score of zero represents symmetrical
target detection, positive values represent a rightward bias and negative values leftward bias.
The results from behavioral treatment studies that target nonspatial deficits clearly
show the influence of plasticity, as these nonspatial mechanisms are shown to be re-
mediable rather than permanently damaged (even in very chronic patients; Van Vleet
and DeGutis, 2013).
7 FUTURE DIRECTIONS
As the other chapters in this volume detail, many studies now show that the proces-
sing machinery of the brain is plastic, remodeled throughout life by learning and
experience, enabling the strengthening of skills or abilities or the acquisition of
new skills, at any age. These studies show that continual engagement in goal-directed
and rewarded behaviors is advantageous to sustaining efficient brain operations, en-
gaging targeted brain structures and causing the release of specific neurotransmitters
that enable, amplify, and shape plasticity in the adult brain. This rich body of liter-
ature offers numerous insights that can be applied to the proper development of treat-
ment methods to more efficiently drive the extensive, requisite, and generalized
changes required for significantly improving neurological syndromes such as neglect
(see Chapter 9).
As discussed throughout this chapter, recent advances in knowledge regarding
the influence of nonspatially lateralized deficits on spatial attention in neglect
require future rehabilitation efforts to consider novel approaches that directly address
these functions. The successes of such simple nonspatial treatments such as TAPAT
are promising, but represent only the beginning of this exciting area of rehabilitation
342 CHAPTER 13 Nonspatial Side of Spatial Neglect and Related Approaches
research. For example, a number of studies have shown that task complexity and spa-
tial working memory load contribute to the magnitude of spatial deficits in neglect.
Thus, intervention strategies that target spatial working memory capacity for exam-
ple, shown effective in other clinical populations (Klingberg et al., 2005), may be
beneficial for patients suffering from neglect (see Striemer et al., 2013 for expanded
discussion). Additionally, first person action video game training has shown to sig-
nificantly enhance selective attention and detection of transient events in healthy in-
dividuals. By modifying these games for patients suffering from neglect (e.g.,
slowing down the action and making adjustments for contralesional hypokinesia),
it may be possible to boost arousal and potentially improve nonspatial and spatial
symptoms. In addition, future research on the nature of spatial–nonspatial attention
interactions will enable the development of more effective and targeted treatments
for neglect.
Finally, two additional considerations for future development of treatments for ne-
glect. First, treatments that more comprehensively and completely engage nonspatial
mechanisms may prove more useful or longer lasting if combined with spatial thera-
pies (e.g., prism adaptation to also improve directional hypokinesia). Combined ther-
apies may also prove synergistic. As discussed, a number of recent studies have shown
benefits in spatial attention following TMS of the intact hemisphere. Combined com-
puterized training targeting nonspatially lateralized deficits (e.g., sustained attention)
may bolster these TMS effects, driving behaviorally specific alterations in the under-
lying neural mechanisms. Alternatively, computer-based training paired with transcra-
nial direct current stimulation that excites peri-lesional right-sided regions and
dampens homologous regions in the left hemisphere may produce more pronounced
and longer-lasting improvements in neglect symptoms.
Second, future rehabilitation efforts should also consider the “real-world” impli-
cations of treatment. For example, “statistical learning” deficits, (Shaqiri et al., 2013)
or poor ability to implicitly ascertain properties of a particular environment (i.e., ap-
preciate elements that occur more often than others), can affect decision making ca-
pacity in neglect. The statistical learning model suggests that neglect is a breakdown
in the accurate construction of mental models of the environment, in which future
predictions or decisions are based. This multilevel conceptualization of neglect takes
into account a number of nonspatially lateralized deficits (e.g., temporal mispercep-
tions, spatial working memory deficits) that contribute to functional disability. Con-
sideration of the cumulative effects of nonspatially lateralized dysfunctions in
neglect can inspire the development of more comprehensive rehabilitation interven-
tions designed to improve functional abilities. For example, treatments that target
deficits in temporal perception and spatial working memory may also improve
patient’s future predictions about the location of relevant events. Ultimately, im-
provements in functional ability or transfer of training-related benefits to untrained
real-word functions, is the most important aim of neglect rehabilitation. A multi-
modal, cognitive neuropsychological approach, which capitalizes on known proper-
ties of neuroplasticity is the best method to achieve this goal.
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CHAPTER
A Cognitive Framework
for Understanding
and Improving Interference
Resolution in the Brain
14
Jyoti Mishra1, Joaquin A. Anguera, David A. Ziegler, Adam Gazzaley1
Departments of Neurology, Physiology and Psychiatry, University of California, San Francisco,
CA, USA
1
Corresponding authors: Tel.: þ1-415-502-7322; Fax: þ1-415-502-7538,
e-mail address: jyoti@gazzaleylab.ucsf.edu; adam.gazzaley@ucsf.edu
Abstract
All of us are familiar with the negative impact of interference on achieving our task goals. We
are referring to interference by information, which either impinges on our senses from an ex-
ternal environmental source or is internally generated by our thoughts. Informed by more than
a decade of research on the cognitive and neural processing of interference, we have developed
a framework for understanding how interference impacts our neural systems and especially
how it is regulated and suppressed during efficient on-task performance. Importantly, exter-
nally and internally generated interferences have distinct neural signatures, and further, dis-
tinct neural processing emerges depending on whether individuals must ignore and
suppress the interference, as for distractions, or engage with them in a secondary task, as dur-
ing multitasking. Here, we elaborate on this cognitive framework and how it changes through-
out the human lifespan, focusing mostly on research evidence from younger adults and
comparing these findings to data from older adults, children, and cognitively impaired popu-
lations. With insights gleaned from our growing understanding, we then describe three novel
translational efforts in our lab directed at improving distinct aspects of interference resolution
using cognitive training. Critically, these training approaches were specifically developed to
target improved interference resolution based on neuroplasticity principles and have shown
much success in randomized controlled first version evaluations in healthy aging. Our results
show not only on-task training improvements but also robust generalization of benefit to other
cognitive control abilities. This research showcases how an in-depth understanding of neural
mechanisms can then inform the development of effective deficit-targeted interventions,
which can in turn benefit both healthy and cognitively impaired populations.
Keywords
interference, distraction, multitasking, attention, cognitive control, cognitive training, neuro-
plasticity, aging
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00013-8
© 2013 Elsevier B.V. All rights reserved.
351
352 CHAPTER 14 Cognitive Framework for Interference Resolution
1 INTRODUCTION
In our modern-day environment, we are immersed in digital media and related mo-
bile technologies that constantly barrage us with an overload of sensory information.
More than ever before, there are constant cognitive demands on our neural systems to
selectively attend to sensory inputs that are relevant to immediate goals and critically
to ignore or minimize the priority of other interfering sources of information. Those
individuals who can successfully identify and prioritize relevant information over
interference are able to achieve planned goals and function efficiently in demanding
cognitive settings. Understanding cognitive functions that allow us to integrate
with our complex world in a goal-directed way is the domain of top-down cognitive
control research (Bar, 2003; Corbetta and Shulman, 2002; Frith, 2001).
More than a decade of research in the Gazzaley laboratory has revealed that the
two sides of top-down control, enhancement of goal-relevant inputs versus suppres-
sion of interference, are both equally important and notably are distinct in their un-
derlying neural mechanisms (Clapp et al., 2010, 2011; Gazzaley et al., 2005a, 2008;
Zanto et al., 2010). This emerging research recently inspired a new framework for the
characterization of interference (Fig. 1, Clapp and Gazzaley, 2012). Per this frame-
work, interference can be generated from either external or internal information
sources. External interference occurs from environmental sensory stimuli and can
be further classified into “distractions” and “interruptions.” Distractions are to-be-
ignored sensory information, like the background chatter when working at a café.
Interruptions are external stimuli that need to be attended but are of secondary
priority in our top-down goal sets. Interaction with interruptions while attending
to primary goal-relevant stimuli qualifies as multitasking, such as may occur when
conversing with a copassenger while driving a car. Indeed, research described in the
following sections has shown that distractions and interruptions have distinct neural
processing. Importantly, this framework has helped clarify prior research in the field
that had generated confusing results when both types of external interference were
interchangeably employed in cognitive paradigms.
Similar to external interference, internal interference can also be classified either
as irrelevant internal distractions termed “intrusions,” as may occur during mind-
wandering or daydreaming, or as internal interruptions (i.e., “diversions”) that
FIGURE 1
The conceptual framework for classification of different types of interference.
Adapted from Clapp and Gazzaley (2012).
2 External Interference Resolution Across the Lifespan 353
engage cognitive systems while another primary goal-relevant task is being per-
formed. Planning today’s dinner while reading this chapter is an example of an in-
ternal diversion, which like external interruptions involves attempts at multitasking.
Note that an understanding of the neural mechanisms that subserve internal interfer-
ence processing is still a nascent field. While many new studies suggest that internal
interference engages a known default mode network (DMN) in the brain (i.e., spe-
cific brain regions that are more active during non-task-oriented behaviors;
Andrews-Hanna, 2012; Buckner et al., 2008), the exact neural signatures that distin-
guish internal intrusions versus diversions require sophisticated methodologies such
as predictive pattern classification algorithms and are yet to be fully determined.
The following sections serve as an introduction to the basis of the impact of dif-
ferent kinds of interference on human performance. Note that either external or in-
ternal interference can occur while one is engaged in either an external or internal
goal-relevant primary task. For example, the primary task could be an immediate
discrimination task in which individuals must accurately and rapidly respond to rel-
evant stimuli that occur sequentially or simultaneously intermixed with irrelevant
inputs, such as taking possession of the ball in a soccer game and making a speedy
sensorimotor decision that leads to a goal score in the face of interference from the
opponent team. Or the primary task could be a working memory (WM) task that re-
quires maintenance and manipulation of information in mind for short time periods,
such as remembering a phone number until the end of a conversation. Alternatively,
the primary task could even stretch over longer time scales, drawing on long-term
memory (LTM), where stimulus information is maintained over several minutes
to hours, while other tasks occur in the interim. Here, we review evidence for inter-
ference during each of these multi-time scale cognitive operations: discrimination,
WM, and LTM. Note that the research reviewed here is from the standpoint of
behavioral and underlying neural performance, that is, neural mechanisms that en-
able the observed behavioral outcomes. Considering young healthy 20–30-year-old
adults as a reference point, we review evidence for modified interference resolution
abilities in older age and in children. The second portion of the chapter focuses on
novel cognitive training strategies that we have developed as guided by our under-
standing of interference processing in the brain and the first set of evidence of the
effectiveness of these novel approaches.
recognition of these items. Visual distractors during the recall phase significantly re-
duced LTM accuracy. Neurally, diminished recollection was associated with the dis-
ruption of functional connectivity in a network involving the left IFG, hippocampus,
and VAC. The authors concluded that bottom-up influences from visual distractions
interfere with the top-down selection of episodic details mediated by a capacity-
limited frontal control region, resulting in impaired recollection. Subsequently,
Wais and Gazzaley (2011) showed a similar impact of auditory distractions on LTM.
Overall, these studies characterize the impact of external interference on cognition
in young adults. To put this research in context of everyday function, there is growing
concern that the constant presence of media in our daily lives is distracting and dimin-
ishing task productivity. Indeed, a recent study investigated cognition in young adults
as a factor of their media-multitasking index (MMI; Ophir et al., 2009). The MMI
probed how often individuals engaged with more than one form of media simulta-
neously including print media, television, online videos, music, nonmusical audio,
video games, phone calls, instant and text messaging, email, web-surfing, and other
computer-based applications. Individuals with high MMIs were significantly more sus-
ceptible to interference from irrelevant stimuli in cognitive tasks and could not filter out
interference in memory, relative to those with low MMIs. Note that while these findings
show that high media multitasking is associated with poor interference resolution as
also recently shown by Sanbonmatsu et al. (2013), this evidence is not causal.
In contrast to media multitasking, engagement with a single form of media for ex-
tended periods of time and its impact on cognitive control abilities have been exten-
sively studied for action video games (AVGs). Young adults who are AVG experts
(i.e., engage in AVGs for >5 h per week) have been consistently shown to have su-
perior attention capacities (Dye et al., 2009; Green and Bavelier, 2003). Interestingly,
the neural basis of this superior performance was shown to be enhanced suppression of
distracting sensory information compared to neural activity in nongamers (Mishra
et al., 2011). Of course, from these findings alone, one must not infer that in order
to develop superior interference suppression capacities, one must play AVGs. This
is especially the case as commercial AVGs have much violent content that has raised
popular concern about the negative impact on social affect. Such concern, however, is
not completely based on research. In fact, increasing video-game play over the last few
years has been associated with declining crime rates, speculated to be due to availabil-
ity of a safe alternate avenue to vent real-life frustration in action game play
(Puzzanchera et al., 2011). While it was serendipitous that commercial AVGs were
found to benefit attention, they are likely unsuitable as therapeutics because game dy-
namics are developed to maximally immerse the user, but are not targeted to specif-
ically influence or improve neural function. Targeted therapeutics that can selectively
address neural, cognitive, and behavioral deficits are an urgent need; we discuss our
first interventions that address interference suppression in the second half of this chap-
ter. The next subsection describes alterations in interference processing in healthy
aging, which has been a focus area in the Gazzaley laboratory. We then review a
few related studies in this field in healthy child populations and briefly describe the
status of interference suppression in diverse neuropsychiatric populations.
356 CHAPTER 14 Cognitive Framework for Interference Resolution
2.3 Children
Managing sources of external interference during childhood is an emerging societal
concern, especially given the tremendous influx of diverse media technologies in
modern times that can present pernicious sources of goal-irrelevant interference
(Bavelier et al., 2010; Healy, 1998; Jordan, 2004; Schmidt and Vandewater,
2008). Some research even suggests associations between diagnoses of attention-
deficit hyperactivity disorder (ADHD) and media use, although this evidence is
far from certain (Acevedo-Polakovich et al., 2006; Chan and Rabinowitz, 2006;
Milich and Lorch, 1994). The American Academy of Pediatrics recommends limit-
ing media exposure in children to 2 h per day or less based on findings that elevated
media use is associated with poor physical, cognitive, and social development and
academic underperformance in children (Johnson et al., 2007; Junco, 2011; Junco
and Cotten, 2011, 2012; Ozmert et al., 2002). From a neurodevelopmental stand-
point, the cortex does not attain full capacity to manage interference until late ado-
lescence/young adulthood (Giedd, 2012; Hagen and Hale, 1974; Harnishfeger and
Bjorklund, 1994; Leon-Carrion et al., 2004; Spronk and Jonkman, 2012), which
makes neural systems all the more prone to the negative impacts of heightened ex-
posure to interference. Indeed, a recent study showed that teenagers intentionally en-
gage with sources of interference, such as texting and Facebook, even in an observed
study environment, which ultimately was associated with poor outcomes on their
academic learning (Rosen et al., 2013).
The interference framework that was recently proposed in adults (Clapp et al.,
2010) still remains to be neurophysiologically investigated in children. In a first
replication of the WM paradigm introduced by Gazzaley et al. (2005a),
Wendelken et al. (2011) showed enhanced fMRI-based BOLD activations for
task-relevant stimuli in stimulus-selective visual cortex and in dorsolateral pre-
frontal cortex (DLPFC). The strength of these activations increased with age from
8 to 14 years, as did improvements in WM accuracy. In contrast to the young and
older adult studies, however, this study did not show modulations in irrelevant-
stimulus processing, suggesting this critical cognitive operation may be underde-
veloped in children. This is not too surprising as top-down control regions, such as
the DLPFC, demonstrate particularly delayed maturation in terms of cortical thick-
ness (Gogtay et al., 2004). Further myelination processes, white matter tract devel-
opment, and increases in tract coherence progressively advance throughout middle
childhood and young adulthood (Barnea-Goraly et al., 2005; Giedd, 2004). Putting
these significant developmental structural changes in perspective, much future
work is needed to understand interference processing and suppression abilities
in developing brains. Finally, we note that future research on neural interference
suppression during development is even more imperative from the standpoint of
crucial deficits in this ability in various young special needs populations such as
ADHD (Minear and Shah, 2006) and autism (Adams and Jarrold, 2012; Allen
and Courchesne, 2001; Marco et al., 2011). An understanding of the underlying
neural correlates and processing deficits in these neural systems would become im-
portant targets for future therapeutic remediation.
358 CHAPTER 14 Cognitive Framework for Interference Resolution
Smallwood et al., 2004); it does not affect performance on easy, mundane tasks, but
negatively impacts tasks that involve cognitive control such as WM (Teasdale et al.,
1995). Further, the frequency of internal distractions correlates negatively with WM
capacity (Kane et al., 2007; Mason et al., 2007; McVay and Kane, 2009). Finally, in-
dividuals with ADHD report more internal distractions under a variety of conditions
(Shaw and Giambra, 1993).
Neuroimaging research has begun to demonstrate some of the neural correlates of
internal distractions, with correlations between mind-wandering and activity in the
DMN network as a primary focus. DMN activity is increased during episodes of
mind-wandering (Andrews-Hanna et al., 2010; Christoff et al., 2009; Preminger
et al., 2011) and the general predilection of participants to mind-wander correlates
with increased DMN activity during cognitive tasks (Christoff et al., 2009; Mason
et al., 2007). A recent study further showed that DMN activity was high during ep-
isodes of mind-wandering when the participants were unaware of the internal distrac-
tion but dropped off once the mind-wandering event entered awareness, at which
time activity in frontal cognitive control circuits increased (Christoff et al., 2009).
A subsequent study of functional connectivity showed positive correlations between
DMN activity and cognitive control regions, but a negative correlation with primary
sensory and motor areas (Christoff, 2012). This pattern suggests a decoupling of sen-
sory and cognitive control cortices during internal distractions—a finding that is also
supported by converging encephalography (EEG) evidence showing attenuated sen-
sory ERPs during episodes of mind-wandering (Kam et al., 2011).
As internal interference is detrimental to on-task performance, it is an imperative
target for regulation and suppression. In fact, failure to adequately regulate the im-
pact of internal interference can lead to significant impairments in cognition, social
conduct, and affect regulation (Beauregard et al., 2001; Dolcos and McCarthy, 2006;
Killingsworth and Gilbert, 2010). Pathological failure to regulate this interference
likely plays an important role in a range of mental illnesses (Broyd et al., 2009;
Buckner et al., 2008), including ADHD (both inattentive and hyperactive behaviors,
Fassbender et al., 2009), posttraumatic stress disorder (intrusive recollections trig-
gered by external cues, Pitman et al., 2012; Yehuda and LeDoux, 2007), major de-
pressive disorder (ruminations and impairments in cognition and attention),
traumatic brain injury (executive function deficits), obsessive compulsive disorder
(uncontrollable anxieties/obsessions and compulsive behaviors), and substance de-
pendence disorders (uncontrollable cravings and contextual triggers for relapse;
Sayette et al., 2010). Because of this vulnerability to disease or trauma, there is much
future research needed to understand the capacity and plasticity of internal interfer-
ence regulation systems, especially for developing targeted interventions that reme-
diate deficits in these regulation processes.
documented that healthy older adults show decreased WM capacity and deficits in
executive control (Braver and Barch, 2002; Gazzaley and D’Esposito, 2007;
Salthouse, 1994; Ziegler et al., 2010) and in external distractor suppression
(Gazzaley, 2013). Thus, if mind-wandering is inversely related to executive function,
we might predict an increased susceptibility of older adults to internal distractions.
Surprisingly, several studies have shown that older adults report significantly fewer
internal distractions on a variety of tasks (Giambra, 1989; Jackson and Balota, 2012;
McVay et al., 2013). One interpretation of these findings is that older adults have
insufficient resources to maintain both task-relevant and task-irrelevant thoughts;
this notion is consistent with the view that mind-wandering results from failures
of cognitive control.
3.3 Children
Very few studies have explored the frequency and nature of internal interference in
children. A major hurdle to studying this phenomenon is the potential lack of meta-
cognitive insight in children about the target of their attentional focus, although
children do appear to have some intuition about the concept of mind-wandering
as early as 5½ years of age (Flavell and Flavell, 2004). Early studies that used
the Imaginal Processes Inventory to assess mind-wandering and daydreaming
found that high school students reported more daydreaming (i.e., intentional diver-
sions as per our framework) but less uncontrolled mind-wandering, when com-
pared to older college students (Taylor et al., 1978). Further, emergence of
“constructive daydreaming” and a more positive attitude toward daydreaming oc-
curs between the ages of 5 and 10 (Gold and Henderson, 1990; Henderson and
Gold, 1983). More recent studies have sought to assess internal interference by ex-
amining relative activity within the DMN during development (Immordino-Yang
et al., 2012). In children between 8 and 14 years of age, DMN activity decreased as
task demands increased; further, children with ADHD failed to show this deacti-
vation (Fassbender et al., 2009). Children with ADHD showed significantly greater
levels of behavioral variability, and this variability was inversely correlated with
the degree of DMN deactivation. Converging evidence comes from a study that
found that children with ADHD had reduced resting state functional connectivity
between DMN regions (Fair et al., 2010). These studies demonstrate the critical
importance of the DMN for the regulation of internal interference and again point
to a potential neural target for the remediation of deficient interference control in
clinical populations such as ADHD.
Having described the recently developed cognitive framework for interference
resolution and the impact of interference across the lifespan, we now transition to
reviewing novel intervention strategies in this domain. We recently developed these
interventions in an attempt to remediate deficits in interference resolution in a tar-
geted manner.
4 Neuroplasticity-Targeted Interventions for Interference Resolution 361
has not been directly targeted in past efforts. Notably, there is a need for training that
is specifically targeted to the interference regulation deficit given that nonspecific
brain training programs show little or no transfer of benefit to these critical cognitive
functions, especially in the setting of daily life cognitive tasks (Owen et al., 2010;
Zelinski, 2009).
signal-to-noise contrasts in post- versus pretraining ERPs. This early frontal theta
localized to known cognitive control sites that have been shown to be involved in
interference regulation in the region of the IFJ (Brass et al., 2005; Zanto et al.,
2011). Finally, a close link between the frontal and sensory regions was revealed
by theta phase coherence modulations between frontal and temporal (auditory sen-
sory) regions at peak activity electrode sites. This phase coherence was exclusively
diminished for distractors posttraining and selectively in trained older humans. This
reduced frontosensory phase coherence for trained distractors was interpreted as re-
duced distractor encoding in a functional network that represents task-relevant tar-
gets. These coherence effects are in line with recent research from the lab showing
that sensory cortices encoding task-relevant versus distracting information preferen-
tially connect with different cognitive control networks, the frontoparietal network
and the DMN, respectively (Chadick and Gazzaley, 2011).
Overall, the neural data demonstrated converging and multiple scales of neural
plasticity exhibited in both rats and humans as a result of adaptive distractor training.
The investigation in anesthetized rats provided insight into pure bottom-up sensory
plasticity in the absence of top-down cognitive control influences. This can be rarely
achieved in humans. The neural findings in humans complemented the results in rat
data, showing evidence for improved sensory distractor suppression posttraining.
Human neurophysiology further highlighted that distractor suppression is a dynamic
network process, such that top-down frontal regulation is intimately modulated along
with the observed sensory changes. Finally, in this study, we evaluated transfer of
benefit of the tone-based distractor training in humans on standard measures of cog-
nitive control, which assayed WM span, delayed WM recognition accuracy in the
presence of interference and sustained attention. WM span was exclusively benefit-
ted in the training group at an effect size of 0.94; it was notable that these gains were
observed for sequence span of letter and number stimuli despite the fact that the train-
ing used elementary tone stimuli. While the other two cognitive tests did not show
group-level improvements, individual-level benefits were observed such that indi-
viduals who improved most in adaptive distractor training also showed the most
gains in sustained attention and in WM recognition in the presence of interference,
thus offering some evidence of improved interference regulation with training. Over-
all, this training study showed how adaptive training can be used to selectively tune
deficient neural circuits by focusing the adaptive task challenge on the deficient neu-
robehavioral process, here distractor suppression. This critical insight paves the way
for the effective development of future cognitive training and neurotherapeutic
approaches that are selectively targeted to specific neural dysfunctions.
FIGURE 2
“NeuroRacer” experimental conditions shown as screenshot captures from the training task.
Adapted from Anguera et al. (2013).
366 CHAPTER 14 Cognitive Framework for Interference Resolution
Pre–post TOVA RT
2.70
2.35 Older adults Younger adults
Power (dB)
2.00
1.65 45
1.30
0.95
Older adult post-training
0.60
0.25 22.5
–0.10
–0.45
–0.80
–1.15 0
–1.50
–22.5
–1 0 1 2 3 4 5
Post–pre mfTheta power (dB)
Multitask Single task No-contact
training training contact
FIGURE 3
Midline frontal theta activity modulation in “NeuroRacer,” adapted from Anguera et al.
(2013). (A) Theta power 1-month after training improved significantly only for the multitask
training group; and increased power was observed for younger versus older adults. (B)
Correlation in the multitask training group between the change in midline frontal theta power
and behavioral improvement on the TOVA (a test of sustained attention). {p < 0.05 within
group improvement from pre to post, *p < 0.05 between groups.
50%
5 CONCLUSIONS
In this chapter, we describe our recently developed framework for interference in
cognitive processing. Much research from our lab laid the groundwork for the devel-
opment of the interference framework, which divides cognitive interference as either
externally or internally generated. Each of these divisions can then be further sub-
divided into two levels based on the extent of required top-down engagement with
the external/internal interference. External and internal distractions imply irrelevant
information that must be ignored, while external and internal interruptions set up
multitasking scenarios where the individual must engage in two simultaneous tasks.
Notably, this multilevel classification has helped resolve much debate in the litera-
ture regarding interference processing, as research from our lab has shown that dis-
tractions versus interruptions have distinct underlying neural mechanisms and neural
network dynamics. Critically, we have further elucidated that older adults exhibit
aberrant neural dynamics of both types of interference processing relative to young
adults, which impacts their performance on a variety of cognitive tasks. We are now
in the process of characterizing interference processing in the developing child brain,
which notably has much real-world relevance in our media and technology-heavy,
interference-laden modern environments.
370 CHAPTER 14 Cognitive Framework for Interference Resolution
Finally, we describe three novel cognitive training approaches that we recently de-
veloped to selectively target and improve processing of external distractions, external
interruptions/multitasking, and internal distractions. The need for distinct training ap-
proaches for each of these forms of interference follows logically from neuroscientific
evidence for distinct underlying neural networks subserving these interference pro-
cesses. We principally demonstrate that neuroplasticity-based training strategies,
which provide continuous performance feedback and adaptively modify interference
challenge during training, are highly successful in the remediation of interference res-
olution abilities. Thus, we envisage that our approaches can be potentially applied to
benefit clinical populations that have significant deficits in interference resolution and
thus inform the future of targeted neurotherapeutic interventions.
Acknowledgments
This work was supported by the National Institutes of Health grants 5R01AG030395 (AG),
5RO1AG0403333 (AG), 5R21AG041071 (AG), and 5R24TW007988-05 subaward
VUMC38412 (JM); the UCSF Institutional Research and Career Development Award
(JAA); the Robert Wood Johnson Foundation; and the Posit Science Corporation.
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CHAPTER
Constraint-Induced
Movement Therapy: A
Method for Harnessing
Neuroplasticity to Treat
15
Motor Disorders
Gitendra Uswatte*,{, Edward Taub*,1
*
Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
{
Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA
1
Corresponding author: Tel.: þ1 205 934-2471; Fax: þ205 975-6140
e-mail address: etaub@uab.edu
Abstract
Constraint-Induced Movement therapy or CI therapy is an approach to physical rehabilitation
elaborated from basic neuroscience and behavioral research with primates. The application of
the CI therapy protocol to humans began with the upper extremity after stroke and was then
modified and extended to cerebral palsy in young children, traumatic brain injury, and multiple
sclerosis. A form of CI therapy was developed for the lower extremities and has been used
effectively after stroke, spinal cord injury, fractured hip, multiple sclerosis, and cerebral palsy.
Adaptations of the CI therapy paradigm have also been developed for aphasia, focal hand dys-
tonia in musicians, and phantom limb pain. Human and animal studies using a variety of
methods provide evidence that CI therapy produces marked neuroplastic changes in the struc-
ture and function of the CNS. Moreover, these changes appear to be important for the inter-
vention’s therapeutic effect.
Keywords
Constraint-Induced Movement therapy, rehabilitation, hemiparesis, aphasia, stroke, cerebral
palsy, multiple sclerosis, traumatic brain injury, spinal cord injury
Taub et al., 1994). The actions shaped included (a) pointing at visual targets (Taub
et al., 1975a) and (b) thumb-forefinger prehension in juveniles deafferented on day of
birth (Taub et al., 1973) and prenatally by intra-uterine surgery (Taub et al., 1975b)
who had not exhibited any prehension previously. In both cases, shaping produced an
almost complete reversal of the prior motor disability, which progressed from total
absence of the target behavior to good (although not normal) performance.
During the course of this century, several other investigators have found that a
behavioral technique could be employed in animals to substantially improve a motor
deficit resulting from neurological damage (Chambers et al., 1972; Lashley, 1924;
Ogden and Franz, 1917; Tower, 1940). However, none of these observations was em-
bedded in a formal theoretical context that permitted prediction nor was the gener-
ality of the mechanisms recognized. Consequently, these findings remained a set of
disconnected observations that received little attention.
tasks on the Wolf Motor Function Test (WMFT), a laboratory test involving simple
upper-extremity movements and performance of some tasks. There was no report of
whether the improvements transferred to the life situation. Though the effect size was
small (d0 ¼ 0.2), it was reliable. The results appeared promising, especially since
training had not been used and there was some question of compliance by some
patients with the instruction to wear the sling for most of waking hours during the
intervention period. This type of intervention involving only use of a restraint device
is termed Forced Use therapy; it is not CI therapy since it consists of only one of
the four primary components of CI therapy.
MAL, motor activity log; AS and HW scales, amount and how well scales of the MAL; MCP,
metacarpophalangeal joints; IP, interphalangeal joints; PIP, proximal interphalangeal joints; DIP, distal
interphalangeal joints; LF-MAL, lower functioning motor activity log.
Each movement must be repeated three times in 1 min. Grade 6 patients would fall below the minimum
Grade 5 criteria.
a
Informally assessed when picking up and dropping a tennis ball.
b
Informally assessed when picking up and dropping a washcloth.
c
Initiation is defined for the purposes of criteria as minimal movement (i.e., below the level that can be
measured reliably by goniometer).
Motor Activity Log (MAL) (Taub et al., 1993), which is a structured scripted inter-
view tracking arm use in a number of important activities of daily living (ADL) with
an established reliability and validity (Uswatte et al., 2005, 2006; van der Lee et al.,
2004). On the MAL, the treatment group showed a large increase in real-world arm
use over the 2-week period and no decrease in retention of the treatment gain in real-
world use when tested 2 years after treatment. In other experiments, we have found a
20% decrement in retention over a 2-year posttreatment period in patients with a sim-
ilar (mild/moderate) deficit as the patients in this experiment. The control subjects
exhibited no change or a decline in real-world arm use over the 2-week treatment
period. The treatment group also demonstrated a significant increase in motor ability
384 CHAPTER 15 CI Therapy
as measured by both laboratory motor tests (WMFT, AMAT) over the treatment pe-
riod, whereas the control subjects showed no change or a decline in arm motor ability.
These results have since been confirmed in an experiment using shaping (Taub et al.,
1994) of more-affected arm movements instead of task practice and less-affected arm
constraint (Taub et al., 2006a). This experiment also had a larger sample (N ¼ 41) and a
more credible control procedure than in the first study. The shaping procedure involved
requiring that improvements in performance be made in small steps (successive approx-
imations), providing explicit feedback and verbal reinforcement for small improve-
ments in task performance, and selecting tasks that were tailored to address the
motor deficits of the individual patient (Taub et al., 1994, 1996). Modeling, prompting,
and cuing of task performance were also used. The control group was designed to con-
trol for the duration and intensity of the therapist–patient interaction and the duration
and intensity of the therapeutic activities. The control procedure was a general fitness
program in which subjects performed strength, balance, and stamina training exercises,
engaged in games that stimulated cognitive activity, and practiced relaxation skills for
10 days. Both experimental and control subjects were at least 1-year poststroke
(mean ¼ 4.5 years) and exceeded the minimum motor criterion used in the first exper-
iment prior to entry into the study. In addition, all subjects exhibited a substantial lack of
spontaneous use of their more-affected arm in their daily life, as defined by a score of
less than 2.5 on the MAL (less than half as much use of the more impaired arm compared
to before the stroke in the life situation). The motor deficit and amount of arm use of
subjects in the two groups prior to treatment was not significantly different. As in the
first experiment, the treatment group demonstrated a significant increase in motor abil-
ity on the WMFT and a large increase in real-world arm use over the course of the in-
tervention, whereas the control subjects did not. Control subjects’ answers to an
expectancy and self-efficacy questionnaire about their expectations for rehabilitation
prior to the control intervention and their reported increase in quality of life after the
intervention, as measured by the SF-36 (Ware and Sherbourne, 1992), suggested that
they found the control intervention to be credible.
4 COMPONENTS OF CI THERAPY
The upper-extremity CI therapy protocol, as practiced in the UAB laboratory, con-
sists of four basic components (Taub, 2004; Taub et al., 2006a,b): (1) intensive train-
ing of the more-affected arm for multiple days; (2) training with a behavioral
technique termed shaping; (3) the TP, a set of behavioral techniques designed to fa-
cilitate transfer of therapeutic gains from the treatment setting to daily life; and (4)
discouraging compensatory use of the less-affected arm for a target of 90% of waking
hours for the entire treatment period by using a restraining device, originally a sling
and more recently a heavily padded protective safety mitt; the amount of time the
device is worn is recorded by a timer inserted in the device.
Shaping is a training method in which a motor or behavioral objective is
approached in small steps by “successive approximations” (i.e., a task is gradually
4 Components of CI Therapy 385
made more difficult with respect to a participant’s motor capabilities). Its principles
were explicitly formulated by Skinner (1938, 1968) and they have been applied to the
rehabilitation of movement in this laboratory (Taub et al., 1993, 1994). For rehabil-
itation, shaping involves (a) providing immediate and very frequent feedback con-
cerning improvements in the quality of movement, (b) selecting tasks that are
tailored to address the motor deficits of individual participants, (c) modeling,
prompting, and cuing of task performance, and (d) systematically increasing the dif-
ficulty level of the task performed in small steps when improvement is present for a
period of time. The CI therapy shaping protocol is described in greater detail than
here in Taub et al. (1994, 2013b) and Morris et al. (2006).
The TP consists of a set of techniques in common use in the behavior analysis
field for the treatment of a variety of conditions for such problems as medication
adherence, adherence to an at-home exercise regimen for low back pain, drug addic-
tion treatment, addiction relapse prevention, and alteration of autism spectrum be-
haviors; but they have not been used systematically in rehabilitation. The TP
techniques used here are: behavioral contracts, daily home diary, daily administra-
tion of the MAL to track amount and quality of use of the more-affected arm in 30
important ADL, problem solving to overcome perceived barriers to more-affected
arm use in ADL performance, written assignment during treatment of practice at
home both of tasks carried out in the laboratory and use of the more-affected arm
in specified ADL, posttreatment home skill practice assignments, weekly telephone
calls for the first month after laboratory treatment in which the MAL is given and
problem solving carried out. These techniques are described in detail in Taub
et al. (2013b).
A 2 2 factorial experimental components analysis of CI therapy was carried out
to assess the relative contribution made by the TP and shaping to the magnitude of the
treatment effect (Taub et al., 2013b). The two factors were TP (presence, absence)
and Type of Training (shaping, repetitive practice). Each of the four groups in the
study received the same amount of treatment: 3.5 h per day for 10 weekdays. Partic-
ipants (N ¼ 40) were outpatients 1-year poststroke with mild/moderate hemiparesis
(Grade 2). Presence of the TP, regardless of the type of training received, resulted in
pre- to posttreatment gains in use of the more-affected arm in daily life, as measured
by the MAL, that were 2.4 times as large as the gains in its absence (p < 0.01). Pres-
ence of the TP, regardless of Type of Training, also enhanced gains in more-affected
arm motor capacity, as measured by the WMFT in the laboratory. Although type of
training did not influence everyday use of the more-affected arm, groups that re-
ceived shaping had larger gains than groups that received repetitive practice in
more-affected arm motor capacity.
The TP, thus, would appear to be a method for enhancing spontaneous use of a
more-affected arm in everyday life. In most rehabilitation regimens, the participant is
required to carry out exercises guided by a therapist primarily during treatment ses-
sions. The TP makes the patient a more active participant in their own improvement,
not only during the treatment sessions but also at home. The TP provides a systematic
means of specifying explicitly what the participant is expected to do when outside the
386 CHAPTER 15 CI Therapy
treatment setting, monitoring what in fact is done, and providing a structure within
which to solve apparent barriers to carrying out treatment goals. Thus, the TP permits
participants to be immersed in a therapeutic environment for a meaningful portion of
their day. Therapy is not confined to the limited period that the current system per-
mits (Taub and Uswatte, 2013).
omitted by vote (six vs. one) of the site principal investigators over the recommen-
dation of one of the authors (E. T.). Moreover, the TP procedures as a whole were not
emphasized in the EXCITE trial because the components analysis study described
previously had not been done (Taub and Uswatte, 2013).
7 OTHER CONDITIONS
The CI therapy protocols, that is, upper- and lower-extremity interventions, for adults
with stroke have been applied with similar success to the upper extremity in traumatic
brain injury (Shaw et al., 2003) and to the upper and lower extremity in multiple scle-
rosis (Mark et al., 2008, 2013). Results as good as or better than with adults after stroke
have also been obtained for the upper extremity in children with cerebral palsy and
other pediatric motor disorders of neurological origin across the full range of childhood
years, that is, from 1 year through the teens (Taub et al., 2004, 2007, 2011). Since the
initial study from our laboratory (Taub et al., 2004), over 25 studies of pediatric upper-
extremity CI therapy have been published; two reviews of this literature conclude that
the intervention is efficacious (Brady and Garcia, 2009; Huang et al., 2009). For young
children, the adult upper-extremity protocol is modified to render the intervention suit-
able for this age range, for example, the shaping activities are embedded within games.
CI therapy principles have also been used to devise successful interventions for focal
hand dystonia in musicians (Candia et al., 1999, 2002), phantom limb pain after
amputation (Weiss et al., 1999), and aphasia after stroke.
8 Mechanisms Responsible for CI Therapy Treatment Effect 389
enabled very extensive and purposive use of a deafferented limb from which all myo-
tatic reflex activated had been abolished. This demonstration and later control exper-
iments showed that the Sherringtonian reflexological explanation of the primate
unilateral deafferentation experiments in this formulation could not be correct. What
then could account for the absence of purposive movement after unilateral forelimb
deafferentation? The need to address that salient question led to the formulation of
the concept of LNU.
Several converging lines of evidence suggested that nonuse of a single deaffer-
ented forelimb is a learning phenomenon involving a conditioned suppression of
movement termed LNU. The restraint and training techniques appear to be effective
because they overcome LNU. We offer the following explanation for further empir-
ical test and hypothesis formation, though several central predications stemming
from this formulation have been experimentally verified (Taub, 1977, 1980).
Substantial neurological injury usually leads to a depression in motor and/or per-
ceptual function that is considerably worse than the level of function that will be
attained after spontaneous recovery has taken place. The processes responsible for
the initial depression of function and the later gradual recovery that occurs at the
level of both the spinal cord and the brain is, at present, incompletely understood.
Whatever the mechanism, however, recovery processes come into operation follow-
ing deafferentation so that after a period of time movements can once again, at least
potentially, be expressed. In monkeys, the initial period of depressed function lasts
from 2 to 6 months following forelimb deafferentation (Taub, 1977, 1980).
Thus, immediately after surgical deafferentation of a forelimb, monkeys cannot
use that extremity; recovery from the initial depression of function requires consid-
erable time. Animals with one deafferented forelimb are unsuccessful in attempts to
use that extremity during this period. Efforts to use the deafferented limb often lead
to painful and otherwise aversive consequences, such as incoordination and falling,
loss of food objects, and in general, failure of any activity attempted with the deaf-
ferented limb. Many learning experiments have demonstrated that punishment has
the effect of suppressing the behavior associated with it (Azrin and Holz, 1966;
Catania, 1998; Estes, 1944). The monkeys, meanwhile, get along quite well in the
laboratory environment on three limbs and are therefore positively reinforced for this
pattern of behavior which, as a result, is strengthened. Thus, the response tendency to
not use the affected limb persists and, consequently, monkeys never learn that the
limb has become potentially useful several months after surgery.
When the movements of the intact limb are restricted several months after uni-
lateral deafferentation, the situation is changed dramatically. Animals either use the
deafferented limb, or cannot with any degree of efficiency feed themselves, loco-
mote, or carry out large portions of their daily activities. This new constraint on be-
havior increases the drive to use the deafferented limb, thereby inducing monkeys to
use it and overcoming the LNU. However, current ongoing environmental contin-
gencies, such as the relative inefficiency of the affected upper extremity compared
with the unaffected arm, continue to strengthen use of the affected extremity. How-
ever, if a movement-restriction device is placed on the intact forelimb and left on for
8 Mechanisms Responsible for CI Therapy Treatment Effect 391
several days or longer, use of the deafferented limb acquires strength and then when
the device is removed can compete successfully with the strongly overlearned non-
use of that limb.
The conditioned response and shaping conditions described above, just like the
restriction of the intact limb, place major constraints on the animals’ behavior. In
conditioned response situations, if the monkeys do not perform the required response
with the deafferented limb, they are either punished or do not receive food pellets or
liquid when hungry or thirsty, respectively. Similarly, during shaping, reward is con-
tingent on making an improved movement with the deafferented limb. The monkeys
cannot get by using just the intact forelimb as they can in the colony environment.
These new sets of conditions, just as the movement-restriction device, constrain the
animals to use their deafferented limb to avoid punishment or obtain reward and
thereby induce the animals to use their deafferented limb and overcome the LNU.
The studies just described employed functional brain imaging and brain mapping
techniques to demonstrate that CI therapy could alter the function of specific brain
regions. The question remained whether CI therapy could measurably alter brain
structure in humans. Starting at the beginning of the first decade of this century it
was shown that experienced taxi drivers have significantly expanded hippocampi
(Maguire et al., 2000), jugglers acquire significantly increased temporal lobe density
(Draganski et al., 2004), and thalamic density significantly declines after limb am-
putation (Draganski et al., 2006). Moreover, in an animal model of stroke, CI therapy
combined with exercise reduced tissue loss associated with stroke (DeBow et al.,
2003). Accordingly, structural imaging studies became a logical initial step toward
understanding whether there are anatomical changes following the administration of
CI therapy and whether these are correlated with clinical improvements.
Longitudinal voxel-based morphometry (pre- vs. posttreatment) was performed
on subjects enrolled in our study of the contribution made by the TP to CI therapy
outcome (Gauthier et al., 2008). It was found that structural brain changes paralleled
changes in amount of use of the impaired extremity for ADL. Groups receiving the
TP showed profuse increases in gray matter tissue in sensorimotor cortices both con-
tralateral and ipsilateral to the more-affected arm, as well as in bilateral hippocampi.
The aforementioned sensorimotor clusters were bilaterally symmetrical and encom-
passed the hand/arm regions of primary sensory and motor cortices as well as the
supplementary motor area and portions of Brodmann’s area 6 (Fig. 1, right side).
It was of importance that increases in gray matter were correlated with increases
on the MAL for the sensorimotor clusters on both sides of the brain and the prede-
fined hippocampus region of interest (r’s > 0.45, p’s < 0.05). Thus, this change in the
brain’s morphology is directly related to administration of the TP which in turn sub-
stantially increases the amount of real-world use of the affected arm. In contrast, the
groups that did not receive the TP showed relatively small improvements in real-
world arm use and failed to demonstrate gray matter increases. In addition, the in-
crease in gray matter from pre-to posttreatment differed significantly between
groups. The fact that the anatomical change is directly related to the TP both lends
increased credibility to the importance of the TP.
In another study (Sterling et al., 2013), children with hemiparetic cerebral palsy
also showed increases in gray matter in the bilateral sensorimotor cortices (Fig. 1, left
side). These changes showed a strong correlation with improvements in spontaneous
real-world arm use as recorded on the pediatric version of the MAL. More focal in-
creases occur in children. This finding is consistent with previous research, which
has shown that, compared to children, adults show significantly more widespread
cortical activation when a manual task is performed including not only bilateral sen-
sorimotor cortices as in children but parietal and supplementary motor areas as well
(Mall et al., 2005).
It is not possible to make a causal attribution regarding the observed cortical
structural changes and improvement in motor function. The gray matter increase
could be either a cause or an effect of increased motor ability and behavioral change,
or it could simply be an independent accompaniment. However, the trend observed
394 CHAPTER 15 CI Therapy
FIGURE 1
Cortical surface-rendered image of gray matter change after CI therapy in (A) children with
hemiparetic cerebral palsy and (B) adults with chronic stroke for comparison. Gray matter
increases displayed on a standard brain. Surface rendering was performed with a depth of
20 mm. Color bar values indicate t statistics ranging from 2.0 to 6.7. For the black and white
version of the figure, cross-hatched areas indicate t statistics in the same range.
This figure is reproduced with permission from: Taub, E., & Uswatte, G. (2013). Constraint-Induced Movement
therapy: a family of neurorehabilitation treatments that harnesses the plasticity of the central nervous system.
Neurologie & Rehabilitation, 19, 161–175.
for a correlation between increases in gray matter volume and magnitude of motor
improvement raises the possibility of a causal relationship. Future research with ei-
ther animals or humans in which CI therapy is administered and cortical structural
change is suppressed may resolve this issue (Taub and Uswatte, 2013).
In both studies increases were also observed in the gray matter of the hippocampus,
which may have included the adjacent subventricular zone. The hippocampus is known
to be involved in learning and memory and these two processes are associated with the
improved limb use that occurs with CI therapy. Evidence also indicates that stem cells
are located at this site in the adult mammalian brain (Eriksson et al., 1998; Yamashima
et al., 2004) and simulated stroke in animals can increase the quantity of these cells
(Yamashima et al., 2004). One might speculate that the increases in gray matter observed
in the hippocampal region and sensory and motor areas of the brain are mediated in part
by increased production of neuronal or glial stem cells that might participate in the
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CHAPTER
Novelty Interventions to
Enhance Broad Cognitive
Abilities and Prevent
Dementia: Synergistic
16
Approaches for the
Facilitation of Positive
Plastic Change
Patrick Fissler1, Olivia Küster, Winfried Schlee, Iris-Tatjana Kolassa
Clinical & Biological Psychology, University of Ulm, Ulm, Germany
1
Corresponding author: Tel.: þ49-7531-5026588; Fax: þ49-7531-5026599,
e-mail address: patrick.fissler@uni-ulm.de
Abstract
Process-based cognitive trainings (PCTs) and novelty interventions are two traditional ap-
proaches aiming to prevent cognitive decline and dementia. However, both have their limita-
tions. PCTs improve performance only in cognitive tests similar to the training tasks with
inconsistent transfer effects on dissimilar tests. We argue that this learning specificity is
due to a low training task variability. Novelty interventions are characterized by a high task
variability but do not target specific processing demands affected in aging and dementia. To
overcome the limitations of both approaches, we developed a process-based novelty interven-
tion using a card and board game-based training approach. Here, we use highly variable tasks,
which overlap in targeted processing demands (“overlapping variability” framework). An-
other nontraditional training approach combines cognitively with physically challenging tasks
to induce multimechanistic effects, which might even interact positively. Initial results of both
synergistic approaches indicate their potential to enhance broad cognitive abilities and prevent
dementia.
Keywords
challenging mental activity, novelty intervention, process-based cognitive training, process-
based novelty intervention, physically demanding novelty intervention, learning specificity,
variability of practice, executive control, dementia
1 INTRODUCTION
As the world population ages, costs of dementia are expected to double within the
next 40 years (Hurd et al., 2013). Effective interventions to prevent dementia are ur-
gently sought after. Currently, no preventive or curative pharmacological therapy for
dementia exists (Daviglus et al., 2011; Plassman et al., 2010); however, a vast and
steadily growing literature suggests cognitive health benefits from engaging in
mentally challenging activities (see, e.g., Verghese et al., 2003; Wang et al.,
2013) and physical activities (see, e.g., Smith et al., 2010; Sofi et al., 2011;
Weuve et al., 2004). Here, we review interventional studies on mentally challenging
activities, excluding studies on pure physical activities such as aerobic (Kramer et al.,
1999; Smith et al., 2010) and resistance exercise (Nagamatsu et al., 2012). We con-
clude that currently used cognitive interventions, namely, novelty interventions and
process-based cognitive trainings (PCTs), did not tap specific processes or showed
only inconsistent transfer effects on cognitive tests dissimilar to the training tasks,
respectively. Addressing these limitations, the rationale for a synergistic process-
based novelty intervention is presented, followed by initial results that indicate
improvement in executive control. Finally, the rationale and cognitive effects of
physically demanding novelty interventions are depicted.
group discussion (Mortimer et al., 2012) showed beneficial effects on cognitive out-
comes. On the contrary, there are also a few studies failing to find any effect from
action and strategy video gaming (Boot et al., 2008, 2013). In contrast to the studies
mentioned earlier, Cheng et al. (2013) investigated the potential to improve cogni-
tion in people with dementia rather than in healthy individuals. Participants in the
intervention group played the Chinese tile-based game mahjong for 1 h, 3 days a
week for 3 months, while the active control group was engaged in simple handicraft
for the same duration. Six months after treatment completion, the mahjong group
differed by 4.5 points (95% confidence interval: 2.0–6.9; d ¼ 0.48) on the Mini-
Mental State Examination from the active control group. To our knowledge, no
experimental study investigated the effects of a pure novelty intervention on
incidence of dementia. Thus, conclusions as to whether these cognitive benefits
translate to a delay of dementia onset cannot be drawn. Taken together, novelty in-
terventions showed promising and rather consistent effects on cognitive outcomes,
indicating enhancement of cognitive ability. Nevertheless, the tasks used in novelty
interventions did not tackle specific processes affected in aging and dementia, such
as executive control processes (see Fig. 1). PCT addresses this issue.
FIGURE 1
Traditional cognitive intervention approaches. Novelty interventions or PCTs depict the most
promising traditional cognitive interventions. Novelty interventions are challenging through
difficult novel tasks, include a high variability of tasks, but target only unspecific cognitive
processes, thus leading to broad transfer but only small improvements in unspecific abilities.
PCT is challenging primarily through task difficulty adaptation to participants’ performance,
targets specific processes, but traditionally implements only a small variability of training
tasks, thus leading to large effects on trained tasks but only very limited transfer on the
cognitive ability level. Limitations of traditional approaches are depicted in italic and bold
letters.
2.3 Conclusion
Overall, observational (e.g., Fritsch et al., 2005) and experimental studies (e.g.,
Klusmann et al., 2010) have shown beneficial effects of exposure to novelty on cog-
nitive functions with only a few exceptions (e.g., Boot et al., 2013). In contrast to
3 Rationale and Evidence for Synergistic Approaches 409
PCT, the training tasks applied in novelty interventions have no obvious similarity to
cognitive outcome tests, allowing a straightforward interpretation of results. How-
ever, to our knowledge, no study investigated the effect of novelty interventions
on the incidence of dementia. Furthermore, novelty interventions provided rather
unspecific processing demands, thus not tackling specific processes, which are par-
ticularly prone to deterioration in aging and dementia (see Fig. 1). It seems reason-
able that interventions targeting these specific processes might be more effective.
PCT aims to address this issue by targeting perceptual (e.g., Mahncke et al.,
2006a) and higher-order cognitive abilities such as working memory (e.g.,
Buschkuehl et al., 2008) or task switching (e.g., Karbach and Kray, 2009). Regarding
the efficacy of PCTs, we conclude that several methodological issues leave room for
different interpretations of observed effects (see also Shipstead et al., 2012). There
is abundant evidence that PCTs improve task-specific skills, but most decisively, it
seems that the potential for improvement exists even on the level of broad cognitive
abilities (e.g., Jaeggi et al., 2010; Wolinsky et al., 2013). However, this potential
seems to be exploited only to a very limited degree with current training programs,
especially in older adults (see Fig. 1, Schmiedek et al., 2010, and Dahlin et al.,
2008a). Therefore, new synergistic training approaches are needed, which
enable both the targeting of specific processes shown to deteriorate in aging and
dementia and a generalization to the level of broad cognitive abilities rather than
task-specific skills.
FIGURE 2
Process-based novelty interventions. In contrast to previous process-based approaches, the
new approach targets a specific process, for example, executive control, by using a high
variability of training tasks with overlapping processing demands (“overlapping variability”
framework). It thus enables broad transfer on specific cognitive abilities. Strengths of this
synergistic approach are depicted in bold letters.
plastic changes can be induced in broad cognitive abilities by variable practice re-
gimes, which overlap in the targeted processing demands while excluding overlap
in demands on lower-order processes. That means that the targeted processing level
on which the different tasks overlap is the one where plastic changes take place but
only if all lower-order processes are varied. The framework that we outline in the
following section can be applied to a wide range of processes including perceptual
and motor processes.
What is the differential neuronal underpinning between these specific and gen-
eralizing effects?
higher rather than lower processing networks but also to induce task-invariant
higher-order processing capabilities. These processing networks could then be uti-
lized also by subsequent novel tasks. On the behavioral level, this seems to be
reflected by transfer effects on tasks never encountered before. On the other hand,
constant or repeated practice on the same task appears to redistribute the involved
processes from higher- to lower-order networks (e.g., Kantak et al., 2010), thus en-
abling fast learning and highly efficient processing of these tasks but without transfer
to dissimilar ones (Schmidt and Bjork, 1992). What can be deduced from these stud-
ies to the training of executive control?
As mentioned earlier, we conclude that the training of a variety of tasks rather
than the constant practice of a single task yielded better transfer to subsequent
untrained tasks. This seems to be accompanied by higher-order processing networks
able to efficiently process demands of a wide variety of tasks. With regard to exec-
utive control, we propose that training of variable tasks tapping overlapping execu-
tive control processes enhances a shared frontoparietal control network, thus leading
to an improvement even in dissimilar tasks, which tap these task-invariant processing
capabilities (see Duncan, 2010, proposing the existence of such a common fronto-
parietal processing network). On the other hand, repeated practice on a single or a
limited amount of executive control tasks will induce initial plastic changes in
higher-order processes followed by a shift to plastic changes in increasingly
lower-order processing levels. This may be reflected by fast improvements on the
training task but with only very limited transfer to dissimilar tasks.
task-switching training with and without task variability. However, Karbach and Kray
(2009) did not induce variability by novel task-switching paradigms but by novel di-
mensions between which participants had to switch. That is, the constant task-
switching group had to switch only between the dimensions “transportation” and
“number,” while the variable training group also needed to switch between several
additional dimensions such as “plant” and “color” or “animal” and “direction.”
The variable training group outperformed the nonvariable conditions in the near-
transfer outcome. In this outcome test, exactly the same task as during the training
sessions was administered but with novel, untrained switching dimensions. There
was no differential group effect between the variable and constant task-switching con-
ditions in far-transfer measures of intelligence, working memory, or interference. We
assume that variability of task paradigms rather than of stimulus dimensions is deci-
sive for far transfer. A rule of thumb may be that the variation level must be equal to
the transfer level. For example, varying speakers in an identification task may induce
transfer on new speakers in this identification task. Varying stimuli dimensions in a
task paradigm may induce transfer on new stimuli dimensions in this paradigm. That
means that a variation in task paradigms within a specific ability is needed to induce a
“farer” transfer on a new paradigm within this specific ability.
A study by Dahlin et al. (2008a) supports this idea: their 5-week training inter-
vention (45 min, three sessions/week) consisted of a single running span paradigm
with five different kinds of stimuli and a keep-track task. A numerical n-back task
and a Stroop task were assessed as a near- and far-transfer measure, respectively.
fMRI served to investigate neuroplastic changes mediating transfer effects. Despite
the fact that the Stroop and the training task activated a shared frontoparietal network
at the baseline assessment, no transfer effect was found. Only the similar near-
transfer n-back task improved as a function of training group. Strikingly, this
near-transfer effect was only evident in young adults, while no improvement was
found in older adults. As a number running span task was part of the training, the
training and the near-transfer task were identical regarding the kind of stimuli used
and differed slightly only by the response format (recalling the last four numbers as
soon as the presentation list ended vs. indicating whether each presented item
matched an item that appeared three items back). The similarity of training and
near-transfer task and the absence of transfer effects to the far-transfer Stroop task
suggest that plastic brain changes occurred at a lower-order level only. Indeed, pre–
post changes in the fMRI revealed a pattern of activation redistribution from higher-
to lower-order brain areas during the training task: while the activation in striatal,
temporal, and occipital areas increased, frontal and parietal activation decreased.
The striatal activation also increased during the near-transfer n-back task and was
interpreted as the mediating area for the transfer effect. Those results allow different
interpretations, but clearly, the higher-order frontoparietal network did not mediate
the near-transfer effects.
Taken together, the variation of stimulus dimensions improved performance on
the near-transfer but not the far-transfer outcome measures, indicating some gener-
alization effect, however only on that level where variation took place. This inter-
pretation is in line with the shift from higher- to lower-order processing in a
3 Rationale and Evidence for Synergistic Approaches 415
training task after 5 weeks of a repeated practice protocol (see Buschkuehl et al.,
2012, for a comprehensive review of training-induced neuronal effects).
In conclusion, repeated practice of a single task leads to a shift from higher-order
to lower-order processing (see Ahissar and Hochstein, 2004, concluding the same in
the perceptual domain), whereas generalization seems to be promoted by high task
variability (see Schmidt and Bjork, 1992, concluding the same for motor and verbal
learning). On that background, it seems surprising that pervious training programs
aiming to improve working memory, shifting, or inhibition applied only a very lim-
ited amount of tasks, which shared most task characteristics. We suggest that enhanc-
ing variability of training tasks (not only of stimuli material but also of task
paradigms) while targeting specific executive control processes enhances generali-
zation on the cognitive ability level (see Fig. 2).
and challenges, to extend and exercise one’s capacities, to explore, and to learn [. . .].
From the time of birth, children, in their healthiest states, are active, inquisitive, cu-
rious, and playful.” From an evolutionary perspective, there should be an uncondi-
tional predisposition to strive for factors that increase fitness. Moreover, Ryan and
Deci (2000) not only stressed the natural tendency of humans to strive for challenge
and variability but also proposed its value for cognitive development and psycho-
logical well-being.
Therefore, novelty interventions seem to fit well to nourish intrinsic motivation
by providing an environment which comprises the basic ingredients to elicit feelings
of interest and curiosity. In which way is intrinsic motivation functional for interven-
tions? First, intrinsic motivation determines the environment people choose (guiding
function), allowing long-term adherence to interventions. Second, the motivation-
associated psychological states such as interest and curiosity have been shown to
go hand in hand with the activation of the neuromodulatory control system—a cen-
tral regulatory system for the facilitation of plastic brain changes (plasticity facili-
tation function; see, e.g., Bao et al., 2001, for the role of dopamine). For
example, it has been shown that curiosity is associated with activation of caudate
regions, which are innervated by dopaminergic neurons and part of the neuromodu-
latory control system. Curiosity during learning was associated with improved recall
one to two weeks later, indicating its plasticity facilitating effect (Kang et al., 2009).
applied. That means every game was played not more than three times and 2 h in
total. Overall, participants completed 30 training hours within 15 sessions.
Outcome measures were selected on the basis of the methodological prerequisites
for the assessment of broad abilities rather than task-specific skills (see Section 2.2).
Aiming to assess multiple measures of executive control dissimilar to the training
tasks, three computerized tests assessing inhibition (flanker task, Stahl et al.,
2013), switching (Stahl et al., 2013), and updating (Oberauer et al., 2000) were ap-
plied. Additionally, two complex executive control tests, namely, the Standard Pro-
gressive Matrices (Raven et al., 1990) and the Culture Fair Test 20-R (Weiß, 2006),
were used. The primary outcome operationalizing executive control was calculated
by averaging the standardized single-test scores. Despite the small sample size, linear
mixed effect modeling revealed a marginally significant Group Session interaction
effect, F(1,15) ¼ 4.39, p ¼ 0.054, net effect size, 0.53 SD (see Fig. 3), indicating per-
formance improvement in the intervention group compared to the passive control
group. While the gaming group improved performance in executive control
(0.46 SD, p ¼ 0.04), performance in the passive control group did not change
(0.06 SD; p ¼ 0.70). The use of a passive rather than an active control group limits
the interpretation of effects. Nevertheless, a marginally significant improvement of
the gaming group, in contrast to the control group, in a broad measure of executive
control composed of tests dissimilar to the training tasks was revealed. The result
indicates improvement in executive control, that is, a broad cognitive ability, over-
coming often observed learning specificity.
Control group
0.5 *
0.0
−0.5
Pretest Posttest
FIGURE 3
Intervention effect. Change of executive control (standardized) from pre- to posttraining as a
function of intervention group in a pilot study of a process-based novelty intervention using
card and board games. While the waiting-list control group (dark triangles) remained stable,
the intervention group (white squares) significantly improved, resulting in a marginally
significant group time interaction. Arrows represent standard errors. Statistically significant
effects are marked by asterisks: * p < 0.05.
418 CHAPTER 16 Novelty Interventions for Brain Health
FIGURE 4
Guided plasticity facilitation framework.
catecholamine levels supporting their effect-mediating role. In line with this result,
Roig et al. (2012) found that an acute bout of 20 min intense cycling immediately be-
fore and after a motor task, compared with a period of rest, improved retention of a
learned motor skill 24 h and 7 days after practice. Interestingly, the effect of an acute
bout of exercise after the motor task, in contrast to before practice, had even larger
effect on retention 7 days after motor practice. Taken together, the timing of physical
activity in relation to cognitive activity seems to be crucial in the “guided plasticity
facilitation” framework (see Fig. 4).
3.2.3 Evidence
There is a growing evidence from observational studies indicating that engaging in a
number of different types of activities ranging from cognitive to physical and social
activities is able to reduce cognitive decline (Chan et al., 2005; Lee et al., 2009;
Wang et al., 2013) or dementia incidence (Karp et al., 2006; Paillard-Borg et al.,
2009; Verghese et al., 2003; Wang et al., 2002). Interestingly, beneficial effects
of leisure activity types on cognition follow a dose–response relationship (Wang
et al., 2013). For example, cognition declined over a 2-year period in participants
engaged in low levels in all three activity types, while cognition was stable in par-
ticipants who engaged in high levels in one activity type, and engagement in multiple
activities even predicted cognitive improvement. In this, the different types of activ-
ities had differential effects on several cognitive domains. This result supports the
rationale that multidomain interventions induce multimechanistic effects; thus, they
may be best suited to address a multicausal disease. Karp et al. (2006) demonstrated
that even dementia risk could be reduced by engaging in physical, social, or cognitive
leisure activities and that the strongest effect was present in individuals who engaged
in more than one type of activity. A dose–response pattern of the number of different
activity types—including physical, cognitive, and social activity—for dementia risk
was also found in a study by Paillard-Borg et al. (2009): high engagement in no or
only one type of activity served as the reference group. High engagement in two
types of activities reduced the risk by 34%, and high engagement in all three types
of activities reduced the risk even by 49%. The combination of multiple lifestyle ac-
tivities is decisive for prevention of cognitive decline and dementia and should be
further investigated (see also Lee et al., 2009). One leisure activity that is a good
model for an integrative physical, cognitive, social, and emotional approach is danc-
ing. In an observational study, Kattenstroth et al. (2010) demonstrated that long-time
amateur dancers outperformed age-, education-, and gender-matched controls in re-
action times, motor behavior, and cognitive performance, exhibiting the potential of
this challenging, multicomponent activity.
However, as mentioned earlier, observational studies cannot exclude other inter-
pretations of effects. So what does experimental evidence tell us about the effective-
ness of a combined physical and cognitive approach?
Several interventional studies investigated the effect of combined physical and
cognitive interventions on cognition (Barnes et al., 2013; Fabre et al., 2002;
Legault et al., 2011; Oswald et al., 2006; Shatil, 2013). Apart from the first two studies,
3 Rationale and Evidence for Synergistic Approaches 421
which showed better effects of the combined approach (Fabre et al., 2002; Oswald
et al., 2006), the more recent studies could not show additional or synergistic effects
of the combination of both interventions (Barnes et al., 2013; Legault et al., 2011;
Shatil, 2013). Those studies investigated the effect of combined interventions, but each
component was separated in time from each other. As depicted in the rationale for the
guided plasticity facilitation framework, simultaneous cognitive and physical activi-
ties might be crucial for interaction effects, explaining the negative findings.
Physically demanding novelty interventions provide simultaneous cognitive and
physical activity (see Fig. 5). Indeed, there are several interventional studies which
found beneficial effects on cognition for such a multimodal approach. For example,
consistent and large improvements in cognitive outcomes were found in older adults
allocated to a dancing intervention (Kattenstroth, Kalisch, Holt, Tegenthoff, and
Dinse, 2013), mind–body exercises like Tai Chi (Mortimer et al., 2012), theater play
(Noice and Noice, 2009; Noice et al., 2004), or “exergaming” (Anderson-Hanley
et al., 2012; Maillot et al., 2012), that is, physical exercise carried out in a mentally
stimulating and motivating virtual reality environment. Mixed results, showing im-
provements in some cognitive tests but not others, were found by Pieramico et al.
(2012) for a 1-year multimodal training program consisting of various activities
and by Coubard et al. (2011) for a dancing intervention.
After a 6-month dancing intervention, elderly adults significantly improved in
cognitive outcomes, such as attention and memory functions, compared to partici-
pants of an inactive control group (Kattenstroth, Kalisch, Holt, Tegenthoff, and
Dinse, 2013). Noice et al. (2004) compared the outcome of a 7-session theater course
for healthy older adults not only to the one of an inactive control group but also to an
active visual arts control group. The mentally and physically challenging theater
course resulted in an enhancement in problem solving compared to both control
groups and an improvement in episodic memory when compared to the inactive
FIGURE 5
Physically demanding novelty interventions. Dancing, Tai Chi, cybercycling, and theater arts
depict examples of this combined physical–cognitive approach. In contrast to traditional
novelty interventions, they include physical demands in addition to highly variable, novel tasks
and thus enhance the transfer to unspecific cognitive based abilities.
422 CHAPTER 16 Novelty Interventions for Brain Health
control group. Similar effects were found for the same intervention with older adults
in retirement homes (Noice and Noice, 2009). Compared to physical training only,
greater improvements were yielded by cybercycling, that is, cycling within a men-
tally challenging virtual reality environment (Anderson-Hanley et al., 2012), and by
Tai Chi (Mortimer et al., 2012).
Finally, there is even initial experimental evidence that long-term Tai Chi train-
ing decreases the incidence of dementia, evaluated with the Clinical Dementia Rat-
ing (Lam et al., 2011, 2012). However, this study had some limitations with respect
to dropout rates, operationalization of dementia incidence, and baseline differences
between groups. Therefore, caution is necessary in the interpretation of results.
To sum up, the evidence for physically demanding novelty interventions such as
dancing, Tai Chi, theater play, or exergaming is promising. To elucidate whether the
combination of activities is decisive, further research is needed comparing physically
demanding novelty interventions with pure physical and novelty interventions. Also,
more research investigating the potential for dementia prevention must follow.
4 CONCLUSIONS
Observational and experimental studies suggest that novelty interventions are effec-
tive behavioral means to delay cognitive decline (e.g., Eskes et al., 2010; Klusmann
et al., 2010) and the onset of dementia (e.g., Fritsch et al., 2005). However, this ap-
proach is rather unspecific, that is, it does not tackle specific processes shown to de-
teriorate in aging and dementia (see Fig. 1). PCT addresses this problem and has
shown transfer effects on untrained cognitive tests. Crucially, however, consistent ef-
fects were only shown for cognitive tests sharing superficial training task character-
istics, suggesting learning specificity with only limited transfer to broad cognitive
abilities (see Fig. 1, e.g., Redick et al., 2013; Barnes et al., 2013). Based on a growing
literature on biological and behavioral effects of variable practice, in contrast to con-
stant practice, we propose in line with Green and Bavelier (2012) that low task var-
iability of currently available PCTs is partly responsible for limited transfer (compare
Figs. 1 and 2). A process-based novelty intervention, using variable card and board
games in a socially meaningful context, addressed this issue and showed initial evi-
dence for an enhancement in the broad cognitive ability of executive control (see
Fig. 3). Furthermore, rather small transfer effects of novelty interventions might be
enhanced by engaging in novel challenging mental activities which also comprise
physical demands such as dancing or Tai Chi (see Fig. 5). A mechanism of action
of this multimodal approach may be guided plasticity facilitation (see Fig. 4).
With respect to current evidence, we suggest four principles that behavioral
interventions for the prevention of dementia should implement:
• Challenge: The training tasks should induce a mismatch of supply and demand
(see Lövdén et al., 2010).
• “Overlapping variability”: The training tasks should have a high task variability
but a low variability in targeted processes. In other words, tasks should overlap in
4 Conclusions 423
Novelty interventions are specifically powerful with regard to these four principles
as they induce a mismatch of supply and demand, go along with high variability, and
provoke interest and curiosity, that is, nourish intrinsic motivation (see Fig. 1). For
even more beneficial effects, this approach may be implemented in a process-based
or a physically demanding approach (see Figs. 2 and 5).
According to a recent National Institute of Health consensus and state-of-the-
science statement prepared by independent panels of public representatives and
health professionals, no intervention can be recommended to delay dementia, as
“the evidence is inadequate to conclude that any are effective” (Daviglus et al.,
2010, p. 12). We propose that no single type of activity such as cognitive or physical
activity should be considered as a prevention technique. The focus should rather lie
on a style of activity engagement, a composition of activities, or underlying effective
factors such as novelty, variability, process overlap, and challenge. This is crucial as
activities interact to produce their beneficial effects, which is clearly demonstrated
by variable and constant practice protocols. Therefore, we propose that recommen-
dations for single-activity types are inherently flawed. We come to an alternate con-
clusion for dementia prevention in recommending a lifestyle composed of both
physical demands and novel challenging mental activities integrated in a socially
meaningful context. This conclusion is based on the earlier-mentioned findings of
novelty interventions and on the ratio of their potential costs and benefits: (1) poten-
tial emotional and financial benefits through dementia prevention are high on both a
personal and a societal level, and (2) costs for engagement in such activities are with
exceptions rather low.
For future interventional studies, we suggest that they should assess the most im-
portant outcome of interventions, which is the incidence of dementia. To accomplish
this aim with clinically meaningful results, we are convinced that long-term interven-
tion with high adherence is key (see Unverzagt et al., 2012). Therefore, interventions
should be personally meaningful to participants (see, e.g., Carlson et al., 2008;
Lautenschlager and Cox, 2013) while nourishing intrinsic motivation. Thus, in the
coming years, structured programs for the prevention of dementia might be exper-
imentally validated allowing for widespread public recommendations and imple-
mentation in the health-care system (see Dehnel, 2013).
424 CHAPTER 16 Novelty Interventions for Brain Health
Acknowledgments
We thank Lisa Dommes for her ideas and her engagement in the development of the game-
based novelty intervention; Julia Günzer, Manuela Rappel, and Sarah Köhler for their contri-
bution in the organization and execution of the earlier-mentioned game-based pilot study;
Andreas Fritz, Johannes Moog, Alexandra König, Friedrich Meixner, Ferdinand Pittino,
and Tanja Dolpp for administering the training sessions; Dana Fischer, Julia Berger, and Susan
Leutloff for their contributions in data collection and data analysis; Lisa Gabriel, Isabell
Ehrmann, Anna Gässler, Christa Selig, and Julia Fischerkeller for selecting the outcome tests
and administering the test sessions; and Florian Schmitz for providing expert advice regarding
the assessment of executive control and for providing the computerized inhibition and swit-
ching tasks. We also thank Steven Jaeger for proofreading and Laura Loy for her ideas and
helpful comments on the chapter.
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CHAPTER
Abstract
Aphasia is an acquired language disorder with a diverse set of symptoms that can affect vir-
tually any linguistic modality across both the comprehension and production of spoken lan-
guage. Partial recovery of language function after injury is common but typically
incomplete. Rehabilitation strategies focus on behavioral training to induce plasticity in un-
derlying neural circuits to maximize linguistic recovery. Understanding the different neural
circuits underlying diverse language functions is a key to developing more effective treatment
strategies. This chapter discusses a systems identification analytic approach to the study of
linguistic neural representation. The focus of this framework is a quantitative, model-based
characterization of speech and language neural representations that can be used to decode,
or predict, speech representations from measured brain activity. Recent results of this approach
are discussed in the context of applications to understanding the neural basis of aphasia symp-
toms and the potential to optimize plasticity during the rehabilitation process.
Keywords
aphasia, speech, language, neural encoding, decoding
1 INTRODUCTION
Aphasia is a language disorder resulting from brain damage, often to frontotemporal
cortex, that causes behavioral deficits in the production or comprehension of speech.
Aphasic symptoms affect a diversity of language components, including auditory,
phonological, or lexical function. This diversity represents a challenge for
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00018-7
© 2013 Elsevier B.V. All rights reserved.
435
436 CHAPTER 17 Decoding Speech for Understanding and Treating Aphasia
development of effective treatments that must target specific brain circuits underly-
ing the heterogeneity of language abilities.
Treatment of aphasia relies on behavioral interventions that encourage structural
and/or functional brain plasticity for recovery of language ability. The rehabilitation
process may be aided by maximizing neural plasticity in language areas to recover
damaged circuits. Defining the basic neural mechanisms supporting specific lan-
guage functions is an important building block for clinical insights that can help
to identify injured cortical systems and to improve targeted treatments.
a clinical perspective, patients who have bilateral language representation will have
more rapid recovery from aphasia.
In sum, these observations indicate that the location of brain damage largely de-
termines the type of aphasic symptoms that arise. This is consistent with the view of
the brain’s language system as a modular network, with specific language functions
organized into functionally distinct neural circuits (Friederici, 2011; Hickok and
Poeppel, 2007; Rauschecker and Scott, 2009). However, the complexity and inter-
dependence of language functions, and that of aphasic symptoms, also suggests a
more distributed system where language abilities are supported by multiple, intercon-
nected brain regions (Friederici, 2011; Hickok and Poeppel, 2007; Rauschecker and
Scott, 2009).
To begin to understand the link between brain injury and the variety of aphasic
symptoms, and how function can be recovered through rehabilitation and reorgani-
zation of the underlying circuits, experimental and analytic tools from systems neu-
roscience can be brought to bear. This chapter focuses on a systems identification
approach that, by use of neural encoding and decoding models, characterizes how
neural activity relates to heterogeneous aspects of speech. The advantage of this ap-
proach is it offers a quantitative, model-based description of the speech features
encoded by specific neural circuits, providing insights into the dependence of apha-
sic symptoms on the location of injury and potential treatment avenues.
Logothetis, 2008; Hickok and Poeppel, 2007; Sahin et al., 2009; Tankus et al., 2013).
At the lowest level, these areas may code the activation of individual muscles within
the vocal tract (Lofqvist, 1999) that control the complex sequence of movements dur-
ing articulation. At a higher level, speech motor control may involve coding of entire
“gestures” or coordinated muscle synergies (Graziano and Aflalo, 2007; Lofqvist,
1999). Higher-level linguistic functions such as lexical, grammatical, and phonolog-
ical information may also be coded in Broca’s area (Sahin et al., 2009).
Within this broad framework, the neural representation of language remains
a difficult experimental question that has resisted precise delineation for over
150 years. Animal models have been widely explored in nonhuman mammals and
avians in the context of lower-level auditory and motor processing (Aertsen and
Johannesma, 1981; De Boer, 1967; deCharms et al., 1998; Depireux et al., 2001;
Georgopoulos et al., 1982; Theunissen et al., 2001; Todorov, 2004). However,
extending these findings to higher-level speech processing in humans has been
impeded because fine-scale, invasive recording opportunities are limited. In general,
this experimental barrier, and the intricacy of human language ability, has made it
difficult to develop effective neural models of language that approach the detail
and predictive accuracy achieved by existing animal models. Speech is unique to
humans, and there are significant specializations that have evolved for speech pro-
cessing in the human brain that cannot be readily studied in animal models.
intracranial human recordings that seeks to bridge the gap between detailed animal
models of low-level auditory-motor processing and relatively unexplored models of
intermediate- and higher-level speech processing in humans.
FIGURE 1
(A) Example of single-trial ECoG responses in superior temporal gyrus (STG) to four spoken
words. Top panel, spectrogram of four spoken words presented to the subject. Bottom panel,
amplitude envelope of the speech stimuli (green), high-gamma ECoG neural responses at
four different electrodes (gray), and predicted response from the spectrogram model (black).
The ECoG responses are taken from five representative electrodes in STG (shown in yellow
in C). (B) Spectrogram model, represented as h(f,t), where h is the weight matrix as
a function of frequency f and time t. This representation is equivalent to the standard linear
spectrotemporal receptive field (STRF). Positive weights (red) indicate stimulus components
correlated with increased high-gamma activity, negative weights (blue) indicate components
correlated with decreased activity, and nonsignificant weights (green) indicate no
relationship. STRFs for each site in the electrode grid are shown (white curve marks the
sylvian fissure). Anatomical distribution of these sites is shown in (C). Yellow circles indicate
electrodes that are shown in (A).
3 A Neural Systems Approach to Language 441
FIGURE 2
(A) Fitted spectrogram models for 2 STG sites. Right panels; pure-tone frequency
tuning (black curves) matches frequency tuning derived from fitted frequency models
(red curves). Pure tones (375–6000 Hz, logarithmically spaced) were presented for
100 ms at 80 dB. Pure-tone tuning curves were calculated as the amplitudes of the
evoked high-gamma response across tone frequencies. Model-derived tuning curves
were calculated by first setting all inhibitory weights to zero and then summing across the
time dimension (David et al., 2007). At these two sites, frequency tuning is either high-pass
(top) or low-pass (bottom). (Reproduced from Pasley et al., 2012.) (b) Distribution of
sites with significant modulation model predictive accuracy in the temporal, parietal, and
frontal cortex.
responses to predict or decode the stimulus features under study. For example, in
brain–machine interface applications, decoding models have been used to predict
the position of a computer cursor by learning the mapping from a population of
motor neurons to the direction and velocity of the cursor on the screen (Carmena,
2013). Quantifying which stimulus or behavioral features are successfully
decoded or reconstructed from population activity reveals which aspects of the
stimulus are encoded by the neuronal population as a whole.
Neural encoding and decoding models are central to sensory neurophysiology
(Wu et al., 2006) and brain–machine interface (Carmena, 2013). Recent work has
also demonstrated how this approach can be usefully applied to study different as-
pects of speech or language in the human cortex (Brumberg et al., 2010; Tankus
et al., 2013). Multiple levels of speech representation have been successfully
decoded using intracranial neural signals. These include auditory representations
(Guenther et al., 2009; Pasley et al., 2012), consonants and vowels (Pei et al.,
2011a,b; Tankus et al., 2012), and words (Kellis et al., 2010). Later, we will review
a number of these results as applied to three different levels of speech representation:
auditory, phonetic, and articulatory processing.
442 CHAPTER 17 Decoding Speech for Understanding and Treating Aphasia
FIGURE 3
Top panel, spectrogram model. The neural response across time r(t) is modeled as a linear
function h(f,t) of the spectrogram representation of sound S(f,t) where t is time, f is
acoustic frequency, r is high-gamma neural activity, h is the weight matrix (STRF), and S is the
acoustic spectrogram. For a single frequency channel, the instantaneous output may be high
or low and does not directly indicate the modulation rate of the envelope. Bottom panel,
modulation model. The neural response r(t) is modeled as a linear function h(s,r,f,t) of the
modulation representation M(s,r,f,t), where s is spectral modulation (scale) and r is temporal
modulation (rate). The modulation encoding model explicitly estimates the modulation rate
by taking on a constant value for a constant rate (Adelson and Bergen, 1985; Chi et al., 2005).
FIGURE 4
(A) Example stimulus and response predictions from a representative electrode in the STG.
High-gamma field potential responses (gray curve, bottom panel) evoked as the subject
passively listened to a validation set of English sentences (spectrogram, top panel) not used in
model fitting. Neural response predictions are shown for spectrogram (blue) and modulation
models (red). The modulation model provides the highest prediction accuracy (r ¼ 0.44).
(B) Example of fitted encoding models and response prediction procedure at an individual
electrode site (same as in A). Top right panel; spectrogram model. Convolution of the STRF
with the stimulus spectrogram generates a neural response prediction (bottom left panel, blue
curve). Prediction accuracy is assessed by the correlation coefficient between the actual
(bottom left panel, gray curve) and predicted responses. Bottom right panel; an example
modulation energy model in the rate domain (for visualization, the parameters have been
marginalized over frequency and scale axes). The energy model is convolved with the
modulation energy stimulus representation (middle left panel) to generate a predicted neural
response (bottom left panel, red curve). The energy and envelope models capture different
aspects of the stimulus–response relationship and generate different response predictions.
(C) Prediction accuracy of envelope versus modulation energy model across all predictive
sites (n ¼ 199). The modulation energy model has higher prediction accuracy (p < 0.005,
paired t-test).
FIGURE 5
(A) Top, the spectrogram of four English words presented aurally to the subject. Middle, the
energy-based reconstruction of the same speech segment, which is linearly decoded from a
set of responsive electrodes. Bottom, the envelope-based reconstruction, linearly decoded
from the same set of electrodes. (B) The contours delineate the regions of 80% spectral power
in the original spectrogram (black), energy-based reconstruction (top, red), and envelope-
based reconstruction (bottom, blue). (C) Mean reconstruction accuracy (correlation
coefficient) for the joint spectrotemporal modulation space across all subjects (N ¼ 15).
Energy-based decoding accuracy is significantly higher compared to envelope-based
decoding for temporal rates >2 Hz and spectral scales > 2 cyc/oct (p < 0.05, paired t-tests).
Envelope decoding accuracy is maintained (r 0.3, p < 0.05) for lower rates (<4 Hz rate,
<4 cyc/oct scale), suggesting the possibility of a dual energy and envelope coding scheme
for slower temporal modulations. Shaded gray regions indicate SEM (Pasley et al., 2012).
FIGURE 6
The word and phonetic transcription of a sentence is shown. The vowel [ux] (TIMIT phonetic
alphabet) occurs twice during the sentence. The spectrogram for the two instances differs
as shown. The spectrogram encoding model assumes neural responses are sensitive to
acoustic variation across phone instances. A phonetic model assumes neural responses are
invariant to acoustic variability across phone instances.
3 A Neural Systems Approach to Language 447
environmental conditions, the human auditory system solves the problem of acoustic
variability with remarkable efficiency. How does the human brain build invariant
categorical representations of highly variable acoustic signals in order to extract
meaning? How does brain injury alter this process and lead to language impairments
observed in aphasia?
To investigate phonetic neural representation, we examined the pattern of neural
responses to continuous streams of natural speech, which contain characteristic se-
quences of consonant–vowel (CV) patterns (Greenberg, 2006). In an auditory stream
of speech, words and syllables function as discrete units, yet the sound itself is con-
tinuous. Speech comprehension depends on segmentation cues that allow listeners to
segment continuous speech sounds into meaningful phonetic units, for instance CV
syllables. What do the auditory encoding models described in the previous section
reveal about the neural basis of this segmentation process? To address this question,
we investigated the relationship between patterns of stimulus tuning in the encoding
models and the average cortical response to consonants and vowels embedded in
phonetically transcribed English sentences (Garofolo et al., 1993). First, we found
a number of electrode sites that showed a robust high-gamma response to vowels
compared to consonants (Fig. 7). The distinct spectrotemporal properties of conso-
nants and vowels (Mesgarani and Shamma, 2011; Mesgarani et al., 2008) suggested a
possible basis for this response selectivity. In particular, consonants are transient
sounds with rapid onset/offset, activating high temporal rates (>8 Hz). In contrast,
vowels are characterized by a fast onset of harmonic structure (activating high rates)
that persists at relative steady state for the duration of the vowel, activating interme-
diate rates (2–8 Hz) (Mesgarani and Shamma, 2011; Mesgarani et al., 2008). Nota-
bly, modulation tuning observed across the full electrode ensemble was well
matched to these intermediate rates (2–8 Hz, Fig. 7). This suggests that modulation
tuning might explain the observed sensitivity to consonants versus vowels. To further
examine if neural tuning patterns can account quantitatively for sensitivity to vowels
versus consonants, we used the estimated models to filter a large set of natural speech
stimuli and assessed the average predicted CV response selectivity (David et al.,
2006). For each site, we compared the measured CV response selectivity to that pre-
dicted by the fitted models. The measured high-gamma CV response difference is
strongly correlated with that predicted by estimated modulation models (Fig. 7,
r ¼ 0.77, p < 107). Selectivity for vowellike sounds can therefore be explained in
part by the modulation tuning measured at specific cortical sites. This finding sug-
gests an interesting possibility that vowel-sensitive sites in higher-order auditory cor-
tex may participate in the process of syllable segmentation by detecting the presence
of vowellike structures, which, in many languages, comprise the syllable nucleus
(Greenberg, 2006).
Recent work has also demonstrated that categorical information about CV sylla-
bles can be decoded directly from STG (Chang et al., 2010). Using a classic psycho-
physical paradigm (Liberman et al., 1967), Chang and Rieger et al. (Chang et al.,
2010) measured ECoG activity in the STG during auditory presentation of three
CV syllables, /ba/, /da/, and /ga/. In this paradigm, a series of stimuli are synthesized
448 CHAPTER 17 Decoding Speech for Understanding and Treating Aphasia
FIGURE 7
Vowel-sensitive cortical sites and multisyllable responsivity. (A) The average high-gamma
response difference (vowels, V, minus consonants, C) across all single syllable sites (n ¼ 5).
Gray curves denote SEM over C/V occurrences. (B) The fitted energy models are used to filter
a large set of English sentences and the average predicted response difference for
consonants versus vowels is compared to the measured high-gamma response difference
between the two classes. Across electrodes, the measured high-gamma CV response
difference is highly correlated with that predicted from the energy model (r ¼ 0.77, p < 107).
(C) The average high-gamma response difference (VCV–CCV) across all multisyllable sites
(n ¼ 8). Time from phoneme onset is time-locked to the final vowel in the CCV or VCV
sequence. (D) Left panel; example modulation model in the rate domain at a vowel-sensitive
site. Right panel; average high-gamma response to consonants (C, blue curve) and vowels
(V, red curve) embedded in English sentences. The high-gamma time series was first
normalized by converting to z-scores. Gray curves denote SEM over CV occurrences.
that vary continuously in the starting frequency of the F2 transition (second vocal
tract resonance) such that the listener’s perception varies across three initial conso-
nants from /ba/, to /da/, to /ga/. Although the actual acoustic parameter, the starting
F2 frequency, varies continuously, the perception of the listener is discrete, corre-
sponding to one of the three discrete CV categories. Using this dissociation between
perception and physical stimulus, Chang and Rieger (Chang et al., 2010) identified
neural signals that encoded the categorical perception, as opposed to the continuous
acoustic parameter. A classification algorithm was used to decode CV category from
ECoG signals recorded across STG. The results revealed a distributed representation
3 A Neural Systems Approach to Language 449
FIGURE 8
Distribution of categorical responses to syllable perception in STG (Chang et al., 2010).
Color indicates STG sites that discriminate specific pairs of syllables. Red: discriminates ba
versus da; green: da versus ga; blue: ba versus ga. Mixed colors: electrode discriminates
more than one pair. Phoneme decoding depends on distributed, interwoven networks
with little overlap.
of STG sites that allowed the classifier to accurately decode the subject’s categorical
percept as opposed to the continuous physical stimulus (Fig. 8). The findings reveal
that the use of encoding and decoding models, as described in these examples, can
help identify important stimulus features coded by the neural system and the distri-
bution of cortical sites that support the given function or behavior.
For speech production, one possible encoding model is based on the pattern of
muscle activation in a set of speech articulators across time. In this example, we fo-
cus on the major articulators that have robust cortical representations in the motor
homunculus, including the lips, tongue, and larynx. The basic premise of this
articulator-based representation is the observation that different phonemes have dis-
tinct temporal patterns of coordinated articulator movement (Lofqvist, 1999). The
specific temporal sequence for a given utterance is commonly referred to as a “ges-
tural score” (Browman and Goldstein, 1989). Across time, individual articulators be-
come active and inactive in a coordinated fashion to produce specific phonetic
signals. Articulatory phonology makes the key assumption that phonological con-
trast in speech can be defined in terms of different gestural scores. This assumption
is supported by articulatory measurements where, to a large extent, there is a one-to-
one mapping from the physical configuration of the vocal tract’s articulators to the
phoneme (Deng and O’Shaughnessy, 2003). An articulatory-based encoding model
takes advantage of this direct correspondence. Specifically, the model uses one input
feature for each individual articulator, with a simple on/off coding for whether or not
the articulator is active at each time point. This model assumes that motor neural
activity is a linear function of temporal patterns of muscle activation in a set of ar-
ticulators. In a sense, the neural activity serves as a first-order proxy for the under-
lying gestural score, which can then be used to decode individual phonemes.
To determine average gestural scores for individual phonemes, we used the
MOCHA-TIMIT speech corpus (Wrench and Hardcastle, 2000), which includes si-
multaneous acoustic and articulatory measurements obtained from electromagnetic
articulography (Fig. 9). The time-stamped phonetic transcription can be used to de-
rive linear estimates of the various articulator activities during the articulation of
each phone. Figure 9 shows the articulatory impulse response of three different
phones. As expected, the bilabial consonants /b/ and /p/ have similar responses fo-
cused on the upper and lower lips. In contrast, the dental consonant /l/, which is ar-
ticulated with a flat tongue against the alveolar ridge and upper teeth, exhibits a
strong response in the tongue foci.
We next investigated the relationship between motor cortex ECoG activity and
the average gestural scores of speech articulators during phoneme production.
Figure 9 shows, for a single patient, the cortical motor representation of three major
articulators, the lips, tongue, and larynx. These sites are determined by electrical cor-
tical stimulation mapping in which stimulation is applied to evoke movements in or-
der to map out the motor cortex for presurgical evaluation. Figure 9 shows that
individual articulator dynamics are represented in motor cortex ECoG activity as pa-
tients read aloud visually displayed monosyllables, such as /ba/, /pa/, and /la/. Time
zero indicates the acoustic onset of the spoken syllable as determined from the audio
recording. For /ba/ and /pa/, high-gamma activity in the lip electrode (blue curve)
increases prior to acoustic onset, while tongue activity (red curve) is flat. This is qual-
itatively consistent with the gestural score for bilabial consonants. Similarly, for /la/,
activity in the tongue electrode (red) increases prior to acoustic onset, while lip ac-
tivity remains relatively flat. Interestingly, activity in the larynx electrode (green
3 A Neural Systems Approach to Language 451
FIGURE 9
Articulatory-based encoding model. (A) Upper panel, a hypothesized mapping of articulators
to motor cortex. Muscles corresponding to various articulators in the vocal tract likely have
anatomical representations in the motor homunculus. A “gestural score” (Browman and
Goldstein, 1989) describes the temporal sequence of articulator activity during an utterance.
The physical movement illustrated by the gestural score might then be “readout” via neural
activity in the motor cortex. (B) Anatomical sites of three articulators in the motor map for a
representative patient. Sites are determined both by electrical stimulation mapping
performed during presurgical evaluation and by the presence of ECoG activity during
movement of individual articulators. (C) Left panel, high-gamma ECoG activity during the
articulation of three CV monosyllables. Right panel, linear estimates of the articulator
movement response (e.g., “gestural score”) for the same three consonants. The linear
articulator response was derived from electromagnetic articulography measurements
provided by the MOCHA speech corpus. Neural and articulator responses are qualitatively
similar, indicating that motor map neural activity can be used to distinguish individual
phonemes on the basis of articulatory patterns.
452 CHAPTER 17 Decoding Speech for Understanding and Treating Aphasia
curve) is robust and remains elevated for the duration of all three syllables. This is
likely due to the abduction and adduction of the laryngeal muscles during preparation
and maintenance of voicing onset (Hajime, 1999).
To directly evaluate this simple encoding model, the muscle activity of individual
articulators would need to be measured simultaneously with ECoG neural signals, a
difficult experimental setup. Nevertheless, the qualitative comparison offered here
illustrates the general usefulness of an encoding model approach to the neural basis
of speech production. In principle, the predictive power of this first-order articulator
model could be compared directly to alternative encoding models that propose
higher-level movement representations incorporating second- and higher-order in-
teractions between articulators. For example, recent evidence from sensorimotor cor-
tex suggests the existence of a phonetically organized gesture representation during
speech articulation (Bouchard et al., 2013).
4 APPLICATIONS TO APHASIA
A systems identification approach to investigate different representation levels in the
language system provides a principled experimental framework for study of under-
lying neural mechanisms. Encoding and decoding models can be used to identify
speech features or language rules that are represented by distributed neural activity
in language-related cortex. Prediction accuracy of alternative models can be com-
pared to test hypotheses about which representations best explain measured neural
activity.
A better understanding of the neural mechanisms underlying different language
functions will help identify injured neural circuits in aphasic patients and potentially
suggest targeted strategies to induce neural plasticity during rehabilitation. For ex-
ample, recent work (Robson et al., 2013) identified impairments in basic spectrotem-
poral modulation processing of auditory stimuli in Wernicke’s aphasia patients with
lesions to parietal and superior temporal areas. Notably, these same areas, STG and
parietal cortex, have well-defined patterns of modulation tuning, as described earlier
(Fig. 4) and in Pasley et al. (2012). It is possible that disruption to this modulation
tuning underlies the observed auditory impairments. In this case, aphasic symptoms
appear to have a close relationship with the underlying speech representation in the
lesioned cortical areas.
While this example offers a possible functional explanation for specific aphasic
symptoms, a more powerful application of the systems identification approach would
be to directly measure changes in neural representation induced by rehabilitation. For
example, neural encoding models could be estimated continuously during the reha-
bilitation process to characterize changes in modulation tuning induced by treatment
procedures. Lack of change in the underlying neural tuning would indicate an inef-
fective treatment. On the other hand, observed increases to modulation sensitivity
could be used to optimize and guide training-induced plasticity. With accurate
encoding models for each level of cortical speech representation, the same approach
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Index
Note: Page numbers followed by f indicate figures and t indicate tables.
457
458 Index
O R
Ocular dominance plasticity (ODP), 244–246, 247, Rapid auditory processing (RAP), 178–179
249–250 Rehabilitation, 381–382
Orbital prefrontal cortex (OFC), 42f, 43 CNS neuroplasticity to, 395
Oxytocinergic system, 76–77 of paretic arm, 381–382
Oxytocin therapy, 261 shaping procedure, 384–385
Reverse hierarchy theory (RHT), 122, 143
P Risperidone therapy, 261–262
Robust neural synchrony, 217–218
Parvalbumin (PV), 247, 249–250
Phonetic encoding, auditory cortex
consonant–vowel (CV) patterns, 447 S
CV response selectivity, 447–449 SC. See Social cognition (SC)
speech sounds variability, 446–447 Schizophrenia, 101–102
vowel-sensitive cortical sites and multisyllable computerized cognitive training methods, 304
responsivity, 447, 448f brain fitness program, 312–313
word and phonetic transcription, 446–447, 446f CogPack (Marker Software), 304–307
Phonological awareness CogRehab (Psychological Software Services),
backward masking, 210–211 308–312
frequency representation, 211 comparative effects, 314
neural differentiation of, 212, 213f functional magnetic resonance imaging (fMRI)
neural synchrony hypothesis, 211–212 (see Functional magnetic resonance imaging
perceptual judgments, 211 (fMRI))
trial-by-trial neural response, 212, 213f magnetoencephalography (MEG), 316–317
Pivotal response treatment (PRT), 260 psychophysical findings, 316
Prenatal stress (PS), 45f, 46 serum biomarker and genetic findings, 314–315
Prenatal therapy, 56 voxel-based morphometry, 320
Presbycusis, 80 dementia praecox, 303
Primary auditory cortex genes involved, 304
excitatory and inhibitory synaptic tuning curves, neurocognitive impairments in, 302–303
67f neurodevelopmental model of, 301–302, 302f
spiking tuning profile, 67f, 68 Sensory cortex, adult plasticity. See Adult plasticity
tonotopic map, 67f, 68–69 Signal Transducers and Activators of Transcription
Process-based cognitive trainings (STAT1) family, 246–247
neurofunctional and neurostructural outcomes Single-task training (STT), 365–366
measurement, 406–407 Social cognition (SC)
physically demanding novelty interventions anatomical and functional abnormalities, 156
evidence, 420–422 behavioral and neurological abnormalities, 156
guided plasticity facilitation, 418–420 definition, 155–156
tackling multiple mechanisms, 418 in schizophrenia, 156, 157
for synergistic approaches Socialville delivery strategies, 157–159
implementation in, 416–417 Somatosensory cortex, 68, 74, 79
intrinsic motivation, 415–416 Spatial attention
learning specificity, 411 hemispheric asymmetry, 337
neural underpinning of, 412–413 in neglect
overcoming learning specificity, 410–413 allocentric, 328
overlapping variability framework, 415 feature integration, 330–331
464 Index
U 247–248
glutamatergic synapses, 245f, 250
University of Alabama at Birmingham (UAB),
M1 muscarinic receptors, 248–249
382–384
orientation tuning curves, 247–248
reinforcement learning, 249
V Voxel-based morphometry, 320
Vagus nerve stimulation (VNS)
antiepileptic effects, 289–290
cellular-and circuit-level changes, 289 W
chronic tinnitus, 284–286 What Works Clearinghouse (WWC)
cognitive dysfunction, 287 adolescent literacy effectiveness rating grades,
mechanisms of 202–203
brain-derived neurotrophic factor (BDNF), 288 English language development K-6, 203
cholinergic antagonists, 287–288 Wolf Motor Function Test (WMFT),
neural plasticity 381–384, 385
memory and neuromodulatory release, Working memory (WM), 353, 362, 364
280–281 children, 357
neurological dysfunction, 276 internal distractions, 358–359
neuromodulatory control of, 276–279 older adults, 356
stimulation, auditory cortex reorganization, 281 young adults, 354
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