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Resting-state brain networks: Literature review and clinical applications

Article  in  Neurological Sciences · June 2011


DOI: 10.1007/s10072-011-0636-y · Source: PubMed

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Neurol Sci (2011) 32:773–785
DOI 10.1007/s10072-011-0636-y

REVIEW ARTICLE

Resting-state brain networks: literature review and clinical


applications
Cristina Rosazza • Ludovico Minati

Received: 21 January 2011 / Accepted: 13 May 2011 / Published online: 11 June 2011
Ó Springer-Verlag 2011

Abstract This review focuses on resting-state functional Introduction


connectivity, a functional MRI technique which allows the
study of spontaneous brain activity generated under resting In the past 20 years, functional magnetic resonance (fMRI)
conditions. This approach is useful to explore the brain’s has gained widespread acceptance as a powerful tool for
functional organization and to examine if it is altered in mapping brain function. fMRI is typically used to study
neurological or psychiatric diseases. Resting-state func- small changes in the blood oxygen level-dependent
tional connectivity has revealed a number of networks (BOLD) signal which are induced by performance of a task
which are consistently found in healthy subjects and rep- or by administration of a stimulus. In the past decades,
resent specific patterns of synchronous activity. In this research efforts concentrated on identifying regions spe-
review, we examine the behavioral, physiological and cialized in given cognitive tasks, but more recently the
neurological evidences relevant to this coherent brain interest has shifted toward a wider prospective aiming at
activity and, in particular, to each network. The investi- understanding how brain multiple regions interact with one
gation of functional connectivity appears promising from a another and how this leads to behavioral phenomena. The
clinical perspective, considering the amount of evidence recent advances in functional neuroimaging have provided
regarding the importance of spontaneous activity and that new tools to study the brain, according to this view, that is,
resting-state paradigms are inherently simple to implement. as a network of interacting regions. Functional connectivity
We also discuss some examples of existing clinical appli- represents a novel approach of fMRI which enables to
cations, such as in Alzheimer’s disease, and emerging investigate the neural activity of regions that are func-
possibilities such as in pre-operative mapping and disorders tionally connected even when they are anatomically dis-
of consciousness. tant. Functional connectivity can be defined as the
synchrony of neural activity among regions. Areas of the
Keywords Functional connectivity  Resting state  brain which exhibit signal fluctuations correlated in time
Spontaneous brain activity  Coherence  Cognitive are assumed to be functionally connected. These BOLD
correlates  Clinical applications signal fluctuations occur at low frequencies (\0.1 Hz) and
have been observed throughout the brain.
Functional connectivity can be studied during the per-
formance of active tasks, such as finger tapping or visual
stimulation, as well as during resting state, a condition in
which the participant is not performing any active task and
is simply instructed to remain still, with eyes closed or
open while fixating a cross. In fact, it is well known that
C. Rosazza (&)  L. Minati under resting conditions the brain is engaged in spontane-
Scientific Department,
ous activity which is not attributable to specific inputs or to
Fondazione IRCCS Istituto Neurologico
‘‘Carlo Besta’’, via Celoria, 11, 20133 Milan, Italy the generation of specific output, but is intrinsically origi-
e-mail: cristina.rosazza@istituto-besta.it nated. The brain under normal physiological conditions is

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never idle, but always remains neuro-electrically and ICA uses a mathematical algorithm to decompose a set of
metabolically active. signals into independent components also known as source
The concept of functional synchrony is not new. His- signals. In particular, on the basis of the measured signals,
torically, the study of functional connectivity developed in ICA can reveal the hidden sources which have generated
the 80s, in the context of electroencephalography (EEG) them, under the assumptions that sources are statistically
[45]. The importance of functional connectivity arises from independent. When applied to fMRI, ICA is able to extract
the observation of long-range EEG coherencies across from the BOLD time series a number of independent
cortical regions and between the hemispheres, e.g., [74]. components which are spatial maps associated with the
The coherencies that are observed throughout the whole time courses of the signal sources [79]. Each component
cortex appear to originate from a relatively small number can be interpreted as a network of similar BOLD activity.
of interacting regions and processes [64]. Clearly, EEG and This may correspond to an actual neural functional network
fMRI are very different in that, the temporal resolution of or in some cases to common physiological activity or
EEG is considerably higher and comparable to the time- neuroimaging artefacts. The studies using ICA have shown
scale of neural events, whereas that of fMRI is limited to a high level of consistency in the reported components
the order of several seconds by the hemodynamic response suggesting that ICA is a powerful technique that can be
lag. As a consequence, using fMRI it is only possible to applied to the study of multiple connectivity patterns [19,
characterize coherent activity in very low-frequency bands, 37, 107]. However, a possible disadvantage of this tech-
i.e., \0.1 Hz, which are not directly associated with the nique is that the components are not always easy to
EEG activity in this frequency range. However, it appears interpret.
that a correspondence does exist at a more abstract level— ROI-based analysis and ICA represent two very differ-
these low-frequency BOLD signal fluctuations track ent approaches of data analysis: the former is a hypothesis-
spontaneous changes in the main EEG rhythms. Indeed, driven method, which relies on the a priori definition of
this correspondence is expected, since the BOLD and EEG ROIs and which generates results that are limited to the
signals share a common neurophysiological correlate, the given ROIs. In contrast, ICA is an exploratory, hypothesis-
local field potentials (LFP). In particular, it is hypothesized free method, which is designed to examine the general
that the observed BOLD signal fluctuations are due to low- patterns of functional connectivity across brain regions and
frequency LFPs and low-frequency modulations of high- which generates results not at inter-regional level such the
frequency LFPs [88]. The observed correspondence ROI-based analysis, but at network level. Even though
between EEG and fMRI phenomena can be typified by a ROI-based analysis and ICA are very different in terms of
simple example. The default mode network (DMN), a methodology, the studies comparing the two techniques
widespread circuit described below, displays an activity have provided similar results [8, 75, 77, 94, 96, 108] and
pattern that inversely correlates with arousal and effort. the functional networks that the two methods generate are
The EEG displays a similar phenomenon consisting of quite overlapping [5–7, 21, 26, 27, 29, 80, 99, 106, 107].
decrease in occipital alpha rhythm; however, the exact This is expected, as they represent the same underlying
relationship between EEG- and fMRI-based connectivity connectivity, reflecting the synchrony of neural activity
needs to be explored further, as the empirical evidence is over spatially distinct regions. However, one needs to bear
still scant, e.g., [78] and a very limited literature is avail- in mind the potential differences between the two tech-
able in terms of theoretical models. niques related to the effect of physiological activity, sys-
Multiple analysis techniques are used to look at the temic changes and potential scanner drifts which can
datasets. The most commonly employed ones are the induce diffusely coherent signal fluctuations. While ICA
region-of-interest (ROI) based analysis and the indepen- attempts to segregate specific components on the basis of
dent component analysis (ICA). The first is based on the their statistical features, ROI-based analysis is non-selec-
extraction of the time-course of the BOLD signal from a tive and may therefore be more sensitive to signal con-
pre-defined ROI and subsequent identification of the tamination by generators of non-neural origin. In practice,
regions showing a significant correlation with the ROI. this discrepancy is attenuated by the fact that the time
This time-course correlation analysis produces functional courses are typically pre-processed by means of baseline
connectivity maps showing which areas are connected with removal, removal of movement-related variance and band-
the given ROI and to what extent. This method represents pass filtering.
the most straightforward way to study the functional con- The first report of resting-state fMRI is by Biswal et al.
nectivity, as the results are relatively clear and simple to [6]. The authors demonstrated that under resting conditions
interpret [42, 48]. ICA, by contrast, is a statistical tech- the BOLD signal fluctuations, measured in the left senso-
nique that does not involve any a priori assumption and rimotor cortex, were correlated with fluctuations in the
allows the exploration of multiple whole-brain networks. contralateral sensorimotor cortex, in the right

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Fig. 1 Independent component analysis (ICA) spatial maps, gener- sensorimotor component, 3 executive control component, 4 mesial
ated from the analysis of 40 healthy subjects, shown on a cortical visual component, 5 and 6 lateralized fronto-parietal components, 7
rendering and standard brain views [94]. This figure shows the most auditory component, 8 temporo-parietal component
frequently reported resting-state components, including 1 DMN, 2

supplementary motor area and in right premotor areas, a set Nowadays the most studied network is the DMN, a
of regions constituting the well-known sensorimotor system of areas involving the precuneus/posterior cingu-
network. late, the lateral parietal area and the mesial prefrontal

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cortex [48, 89]. It has been demonstrated that this network connectivity [30]. However, even if functional connectivity
is more intensely engaged under resting conditions and reflects structural connectivity, the two connectivity mea-
relatively de-activated whenever the participant is involved sures are not completely coupled: for instance, functional
in active tasks: for this reason, it has been called the default connectivity is observed between regions which lack direct
mode network [98]. anatomical projections, for instance between the right and
An important question is what these spontaneous fluc- left amygdala [93], which indicates that functional corre-
tuations represent. The issue is still unanswered, as the lations are mediated by indirect structural connections.
meaning and function of this low-frequency signal are Moreover, as it will be discussed below, functional con-
unclear. A reasonable hypothesis is that these fluctuations nectivity can be modulated by a cognitive task, despite
reflect spontaneous cognitive processes. In the absence of a structural connectivity remains unchanged [2].
task or a stimulus attracting our attention, we naturally tend
to think on the recent past, to imagine future events or
simply to wander with our thoughts. However, even though Description of resting-state components
unconstrained cognitive processes are likely to contribute
to spontaneous fluctuations, they are unlikely to be the sole Using both ROI-based analysis and ICA, functional con-
source. In fact, the spontaneous activity is observed across nectivity studies have reported a number of networks that
various behavioral states including different resting con- result to be strongly functionally connected during rest [5,
ditions [108] and task performance, [53] and, as examined 7, 21, 29, 94, 99, 106, 108]. As shown in Fig. 1, the key
below, persists in different consciousness states including networks, also referred as components, which are more
sleep [60], anesthesia [50] and in disorders of conscious- frequently reported include: the DMN, the sensorimotor
ness [109]. Further, it has been observed in monkeys [110] component, the executive control component, up to three
as well as in rats [61]. Spontaneous fluctuations are also visual components, two lateralized fronto-parietal compo-
found across virtually all brain regions, including sensori- nents, the auditory component and the temporo-parietal
motor areas which are typically not involved in associative component. As already reported, these resting-state net-
processing. Finally, strongly coherent spontaneous activity works consist of anatomically separated, but functionally
among regions is believed to reflect which areas typically connected regions displaying a high level of correlated
interact with one other. The regions which tend to be BOLD signal activity. These networks result to be quite
engaged simultaneously throughout daily tasks generally consistent across studies, despite differences in the data
maintain synchronous spontaneous activity even in resting acquisition and analysis techniques. Importantly, most of
conditions. Indeed, the temporal coherence of some com- these resting-state components represent known functional
ponents has been shown to be modulated by performing an networks, that is, regions that are known to share and
active task immediately prior to resting-state study: this support cognitive functions [26]. For instance, the pattern
evidence suggests that the recent experience as well as of resting-state functional connectivity displayed by the
consolidated abilities can leave ‘a memory trace’ and that, executive control component has been associated with the
more generally, spontaneous fluctuations may be involved performance on a corresponding executive functioning task
in memory consolidation [2, 56, 102]. Overall, these data [96]. Discovering the functional correlate of a component
point to a more complex interpretation, that is, the pattern is particularly valuable as it shows a direct link between
of correlated activity is likely to reflect a combination of resting-state functional connectivity patterns and behavior.
conscious activity and internal neural dynamics, which are
essential for the emergence of behavioral functions and are Default mode network
also present in the absence of a behavioral correlate [14].
Another important issue regards what supports this This signal component is identifiable in: (1) precuneus/
spontaneous BOLD activity. These spatially distinct brain posterior cingulate, (2) lateral parietal cortex, (3) mesial
regions are maintained functionally connected by a struc- prefrontal cortex.
ture of anatomical connections that enables ongoing com- The DMN is the component that has by far received the
munication among areas. These anatomical connections most attention throughout the clinical and research com-
consist of white matter tracts that both directly (with munity [15, 48, 89, 91]. This set of regions is typically
monosynaptic connections) and indirectly (with multisy- observed to be more intensely activated during the rest and
naptic connections) interconnect brain regions [51]. Com- relatively de-activated during the demanding tasks requir-
bining functional connectivity with diffusion tensor ing focused attention such as working memory tasks and
imaging (DTI), an MRI technique that allows the study of visuo-spatial tasks [25, 48]. Activation of the DMN regions
white matter fiber bundles, a number of studies has sug- tend to correlate negatively with the areas that increase
gested a direct association between functional and structural activity during such demanding tasks [43].

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Several studies have demonstrated that precuneus/pos- consolidation of episodic memory [49]. In support of this
terior cingulate shows a strong correlation in its activation view, in the studies on AD the DMN has been found to
pattern with the other members of the DMN (the mesial be affected by reduced functional connectivity and atro-
prefrontal cortex and the lateral parietal area) and these phy [15, 49], as described later with respect to the clinical
three regions together form the core of the DMN [15, 44]. applications of functional connectivity. Also in mild
The precuneus/posterior cingulate node seems to be par- cognitive impairment (MCI), patients showed decreased
ticularly important, because it appears to be directly related network-level connectivity in the DMN compared to
with the other nodes of the network and putatively acts as a controls [100].
mediator of intrinsic connectivity across these regions. This A recent study by Hasson et al. [56] has demonstrated
is likely because it is one of the most intensively inter- that the connectivity pattern throughout the DMN varies in
connected regions in the whole brain [22, 52]. This inter- response to a cognitive task performed immediately prior
pretation is in fact coherent with the recent view that the to the data acquisition. The intensity of functional con-
precuneus is essential for introspective processes as well as nectivity throughout this network was significantly corre-
for awareness [15]. lated with the level of performance in the task. This
The DMN has been associated to unconstrained cogni- relevant finding demonstrates that not only the demands of
tive processes, given that it is generally observed more a current task determine the synchronized activity observed
active during passive cognitive states than during active in a given region, but also the characteristics of the task
tasks. Its activity has been associated to introspective performed just before the data acquisition modulate this
mental processes, to the tendency of human minds to coherent activity.
wander, to our ability to rethink about the recent past and to Spontaneous correlations have also been observed
imagine future events [15]. Other studies suggest that the throughout the DMN across various states of altered
DMN is also active when focused attention is directed consciousness, including sleep [59, 60] and anesthesia
away from external stimuli and generally relaxed. For [13, 50]. Indeed, coherent BOLD signal fluctuations were
example, the studies of transient lapses of attention induced found to persist within the DMN during reduced levels of
by demanding cognitive tasks have demonstrated that when consciousness like light sleep, as shown by the EEG
participants are slower in responding due to distraction or recordings [59, 60]. Interestingly, during deep sleep, the
when they make mistakes, the activity of DMN is increased coherence of spontaneous activity within DMN generally
principally in the precuneus [70, 112]. persisted, but a significant reduction in the connectivity
However, the DMN has been found to be engaged also between the medial prefrontal cortex and parietal regions
during the performance of active tasks. For example, was observed. The reduction of correlation between
Hampson et al. [53] have demonstrated that two regions of frontal and parietal areas of the DMN might reflect the
the DMN, the precuneus and the mesial frontal gyrus, were changes in consciousness induced by deep sleep. Finally,
functionally connected during the rest as well as during an spontaneous BOLD correlations have also been found in
active-working memory task. Importantly, the working anaesthetized monkeys, in regions corresponding to the
memory performance was positively correlated with the DMN [110]. The resemblance between the human and
intensity of functional connectivity observed throughout monkey DMN correlation maps is striking and suggests
the DMN. This suggests that the DMN may facilitate or that some components of the network may be conserved
monitor performance of active tasks, rather simply de- across species. Furthermore, this suggests that the DMN
activate during active tasks. Further studies have supported is not only associated to conscious mental activity, but
this view showing that the DMN connectivity is related to also reflects intrinsic properties of the brain to some
working memory, being modulated by different working extent.
memory loads [36] and also correlated to individual task Overall, we can conceptualize that coherent activity
performance [38] in normal subjects. In general, a signifi- throughout the DMN: (1) emerges principally under resting
cant correlation between functional connections and conditions, but is also present during the performance of
behavior suggests that the study of resting-state functional active tasks; (2) has been observed across different states of
connectivity might be a powerful tool for investigating consciousness and also in non human primates; (3) is
individual differences and their related anatomy. This has influenced by the characteristics of the task performed just
also clinical implications: if resting-state connectivity before the data acquisition. As mentioned before, the exact
among regions of the DMN is a marker of a given cognitive nature of these temporally coherent fluctuations remains to
ability, the strength of this connection may be of diagnostic be clarified. It appears likely that all the hypotheses listed
value for different clinical conditions and diseases. above are, to some extent, valid, but it remains to clarify to
According to some investigations, the DMN comprises what extent each of these distinct aspects is influential in
also the hippocampi and it is involved in the determining the dynamics of the system.

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Sensorimotor component fluctuations have dynamic components that are experience-


dependent and which may have a role in memory consol-
This component involves (1) precentral gyrus, (2) post- idation. This is conceptually in line with findings for the
central gyrus (3) supplementary motor area. DMN reported by Hasson et al. [56] and results obtained
This network is characterized by the engagement of for the lateralized fronto-parietal component reported by
regions that anatomically correspond to motor as well as Albert et al. [2] that will be described below.
sensory areas. However, the correspondence between this
network and sensorimotor functions is not only based on Executive control component
anatomy, but also on the functional evidences. Indeed, it
has been observed that the activity of the sensorimotor This signal component is identifiable in: (1) medial frontal
cortex in resting state shows a degree of hemispheric lat- gyrus, (2) superior frontal gyrus, (3) anterior cingulate
eralization which correlates with the lateralization of cortex.
activity in the same regions that emerges during an active These regions, which in some cases also include lateral
finger tapping task [33]. This demonstrates that the sen- parietal areas, are generally involved in tasks relying on
sorimotor network is associated with functionally relevant executive functions, such as control processes and working
neural activity, that is, the spontaneous fluctuations memory. As before, it has been investigated whether this
observed in this network are likely to reflect the neural network was specifically linked to a specific cognitive
activity which subserves active motor tasks. An important function. The study by Seeley et al. [96] has shown that
question is why spontaneous and task-evoked activity intrinsic connectivity throughout this network is correlated
patterns are so similar. One possibility is that regions that with the performance on the trail-making test, a neuro-
tend to be activated together during active tasks show psychological exam tapping executive functioning. The
correlations in their spontaneous activity, like a memory of results demonstrate a link between individual differences in
previous coordinated processing [40]. intrinsic connectivity and the variability observed in the
fundamental features of cognitive functioning.
Visual components
Lateralized fronto-parietal components
Throughout literature up to three distinct components have
been reported: Throughout the literature, one commonly finds two
strongly lateralized components, one predominantly in the
Component 1 is characterized by the activity in mesial
right hemisphere and the other in the left hemisphere
visual areas, namely striate cortex and extra-striate
usually with a specular pattern. This involves: (1) the
regions typically mesial, such as lingual gyrus,
inferior frontal gyrus, (2) the medial frontal gyrus, (3) the
Component 2 is associated with lateral visual areas such
precuneus, (4) the inferior parietal (5) the angular gyrus.
as the occipital pole and occipito-temporal regions,
Although most of these resting-state components tend to
Component 3 is associated with activity in the striate
represent known functional networks, that is, regions that
cortex and in polar visual areas.
are known to share a cognitive function, the role of this
The different number of visual components observed network remains less clear, also because prefrontal and
across studies may, in part, be related to the effects that the parietal regions are closely coupled in a wide range of
choice of decomposition parameters and the intensity of cognitive processes. The fronto-parietal component has
physiological and other artefactual signal components have been associated to different functions, i.e., memory [29],
on ICA decomposition. For example, it has been shown language [99], attention [32, 43] and visual [34] processes.
that increasing model order leads to branching of some A resting-state functional connectivity study which inves-
components, such as the visual network [1]. Specific tigated language and reading networks found a map of
techniques are available that enable one to assess the sta- correlations to Broca’s area which included the medial
bility of ICA decomposition, such as ICASSO [57]. frontal gyrus and, more weakly, the angular gyrus [54].
The visual component number 2 has been investigated in Although the activation pattern included a large portion of
a recent resting-state fMRI study [102]. This study has occipito-temporal cortex and did not overlap entirely with
demonstrated that resting-state BOLD fluctuations were the lateralized fronto-parietal component described here,
modulated by a visual task performed prior to the data their findings are relevant as they show a connectivity-
acquisition. Even the sole exposure to visual stimuli can behavior relationship. In particular, the strength of func-
modulate the subsequent functional connectivity, specifi- tional connectivity between Broca’s area and angular gyrus
cally in the regions that are relevant to the visual tasks. during both reading and rest was significantly correlated
This evidence supports the view that resting-state BOLD with reading ability.

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A recent investigation has shown that resting-state which has been found to be important for language com-
activity in the fronto-parietal network was specifically prehension [35], displayed a resting-state functional con-
affected by prior sensorimotor learning [2]. The authors nectivity pattern which overlapped considerably with that
measured resting-state spontaneous fluctuations before and of the temporo-parietal component [105]. Overall, these
after the execution of a sensorimotor task and showed that results support the view that patterns of resting-state
the network was modulated by motor learning. Here, the functional connectivity reflect an intrinsic functional
temporal coherency was enhanced after learning, reflecting organization underlying cognitive processes and in this
increased functional connectivity. These results are rele- case language processes.
vant as they suggest that a recently acquired motor ability
can leave a ‘memory trace’ that is measurable as a func-
tional connectivity change in the rest condition after Why study resting-state functional connectivity
learning. As before, this finding is consistent with the view for clinical applications?
that synchronous BOLD fluctuations are modulated by the
recent experience and may be involved in memory Overall relevance
consolidation.
The study of functional connectivity in resting state is
Auditory component important for two distinct reasons. The first is a theoretical
one: spontaneous activity is the most metabolic demanding
This component involves: (1) superior temporal gyrus, (2) component of neural activity, which consumes more than
Heschl’s gyrus, (3) Insula, (4) postcentral gyrus. 80% of the brain’s energy [90]. This baseline neuronal
Cordes et al. [26] used resting-state functional connec- activity supports neural signaling processes subserving the
tivity to compare the resulting maps with those obtained integration of information originating from internal as well
using a text-listening task. Task-based fMRI showed an as external phenomena. It has been estimated that the
extensive region of the superior temporal gyrus which additional energy consumption associated with the task-
overlapped well with the regions identified with resting- evoked activity is surprisingly small, often less than 5%
state fMRI. However, the correspondence was only ana- [88] and that, in general, cognitive functions consume a
tomical, as it was not demonstrated any link between the relatively small fraction of the brain’s energy budget [90].
neural activity of the resting-state network and the lan- Therefore, when one aims to have a comprehensive eval-
guage task. uation of brain function, the analysis of spontaneous
The map of this component overlaps nicely with the activity is at least as important as stimulus-evoked activity.
pattern of resting-state functional connectivity observed by The second reason is practical: resting-state studies do
Koyama et al. [65]. That pattern was associated to reading- not rely on active participation by the patients, therefore,
related areas and involved the superior temporal gyrus, area they may be the sole form of functional imaging suitable
known to be implicated in speech perception. However, the with uncooperative populations, where an adequate level of
map of this component is different from the pattern performance may be difficult to attain. Patient immobility
observed by Turken and Dronkers [105] for the posterior is essential also for resting-state study, since movement-
superior temporal sulcus, given that it apparently did not related artefacts and signal components can significantly
include the Heschl’s gyrus, the insula and the postcentral impair the detection of spontaneous activity components.
gyrus. However, resting-state fMRI can be performed also in
patients who need to be sedated to attain an acceptable
Temporo-parietal component level of immobility [50, 63]. Moreover, resting-state fMRI
is free from the potentially confounding effects of differ-
This component involves: (1) inferior frontal gyrus, (2) ences in the level of task performance.
medial temporal gyrus, (3) superior temporal gyrus, (4) While functional connectivity has been initially used as
angular gyrus. a research tool to investigate the functional architecture of
This component is characterized by the engagement of the brain in healthy volunteers, a host of potential clinical
regions typically associated to language processing. The applications rapidly emerged shortly after the first publi-
connectivity map of this network was consistent with the cations. A number of research groups has now applied
resting-state functional connectivity study of regions resting-state functional connectivity to study various neu-
involved in reading, which identified the posterior middle rological and psychiatry disorders (for clinical reviews, see
temporal gyrus and the inferior frontal gyrus as important [41, 97, 116]. In clinical settings, this technique has been
loci of functional interaction among five different reading found to be particularly useful to detect differences
networks [65]. Indeed, the posterior middle temporal gyrus, between patients and controls and, more importantly, to

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correlate the resting-state differences to clinical variables. absent in noncarriers, even if it was an increase rather than
Highly consistent findings have been obtained for some a decrease of functional connectivity [39]. The results
diseases like AD (see below), multiple sclerosis [12, 76, suggest that the ApoE e4 allele modulates brain function,
92] and amyotrophic lateral sclerosis [83, 103], while for in particular throughout the memory system, decades
other disorders like schizophrenia (see below) results are before the onset of any clinical symptoms and its influence
more discordant. A detailed analysis of resting-state can be detected even in young, asymptomatic adults by
abnormalities for each clinical disease is beyond the scope measuring resting-state functional connectivity [81].
of this work. However, in this section, we present some Another hypothesis considers the role of some brain
examples of the clinical applicability of this technique, regions with an extremely high number of connections,
including the most commonly studied clinical applications such as posterior cingulate, which act as relay hub for
such as AD, and some emerging applications, such as information processing. In these areas, it is hypothesized
presurgical mapping and disorders of consciousness. that the accumulation of AD pathology may be accelerated
due to their elevated metabolic rate [16–18].
Alzheimer’s disease
Schizophrenia
One of the first clinical applications of resting-state fMRI
has been in the context of AD. Early identification of the Another field where resting-state functional connectivity
people at risk of AD has become a priority [81]. One of the has been applied is schizophrenia [20]. This is a severe
first studies which used functional connectivity in this psychiatric disorder characterized by altered perception of
clinical context was by Li et al. [71]. The authors exam- reality and associated with structural brain abnormalities
ined AD and MCI patients, hypothesizing that the accu- [28]. Patients suffer from disturbances of thought, hallu-
mulation of brain pathology could affect the spontaneous cinations, loss of emotion, as well as cognitive deficits
fluctuations of neural activity resulting in reduced syn- including language, memory and executive functions [66].
chrony across regions. In fact, using an ROI-based Most of the work on schizophrenia focused on the DMN:
approach, AD patients were reported to have impaired since one of the main symptoms is the disturbance of
functional connectivity in both hippocampi, compared to thought, the association between schizophrenia and DMN
control subjects. For MCI patients, the reduction was sig- appears straightforward, as the network is involved in
nificantly less severe than for AD patients, but it was internal thinking and mental simulation. It is conceivable to
pathological compared to controls. Importantly, this hypothesize that patients have difficulties in the control of
reduction in functional connectivity was correlated with the DMN: although this issue is still poorly understood,
the loss of cognitive ability, thus suggesting that this there seems to be a dynamic competition between the
technique might be of great potential clinical value. Sub- DMN and brain systems supporting focused attention [43].
sequently, by means of ICA, Greicius et al. [49] studied The complex symptoms observed in schizophrenia could
hippocampal connectivity in relation to other brain regions arise from a disruption of the interactions between the
within the DMN. AD patients were found to have a dis- DMN and other competing systems, resulting in an over-
rupted DMN, in particular, the deficit of functional con- active DMN [15]. This hypothesis would be in line with the
nectivity was evident in the posterior cingulate and in the observation that for these patients imagination and reality
hippocampi. This finding could explain the hypometabo- do not always have clear boundaries. In support of this
lism that is normally found in posterior cingulate in PET view, a number of studies have reported a general increase
studies of AD [82]. Even in MCI patients at risk of con- of connectivity within the DMN in schizophrenia [55, 114,
verting to AD, the DMN connectivity has been found to be 117]. The work by Garrity et al. [46] demonstrated
significantly reduced compared to healthy participants increased DMN activity for patients with schizophrenia
[100]. In particular, functional connectivity between the compared to controls and importantly, showed that subre-
hippocampi and the posterior cingulate was present in gions of the network, including medial frontal gyrus and
controls but not in patients, likely reflecting the conse- precuneus, correlated with severity of positive symptoms.
quence of early degeneration. In contrast, MCI patients Another study which used ICA demonstrated in these
demonstrated no change in other networks extracted with patients an increased connectivity for a number of com-
ICA. Investigations that built on the original work by Li ponents, including the DMN [62].
et al. [71] further demonstrated that important functional However, other groups found that the disease was
connections within the DMN are disrupted in AD [3, 100, mainly associated with a decrease in connectivity, in
101, 111]. Interestingly, young and healthy subjects car- particular, between precuneus and cerebellum [9] in the
rying the apolipoprotein E e4 allele, a genetic risk factor thalamocortical connectivity [113], and in the amygdalo-
for AD, exhibited a modulation of the DMN that was frontal connectivity [58]. Overall, the resting-state

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functional connectivity results in schizophrenia are not Disorders of consciousness


consistent across studies, likely because distinct and
contrasting physiological processes could exist at different Another emerging application of resting-state functional
scales [116]. Furthermore, other factors might limit the connectivity is in the context of the disorders of con-
reproducibility of results: the existence of dissimilar dis- sciousness. These include: coma, defined as a state of un-
ease subtypes, various effects of medications and the use arousable unresponsiveness; vegetative state, characterized
of very different methods to study schizophrenia [72]. For by loss of awareness of self and environment despite clear
these reasons, at least for now existing results should be signs of wakefulness (e.g., preserved sleep–wake cycles);
taken cautiously, as they neither allow to identify nor minimally conscious state, where patients show limited,
distinguish the clinical diagnostic patterns observed in but clear evidence of awareness; locked-in syndrome,
schizophrenia. where wakefulness and awareness are largely preserved but
patients are unable to generate speech, and purposeful limb
Presurgical planning and facial movements [47, 68, 87]. A critical problem with
these patients is that the clinical diagnosis is based on the
Resting-state functional connectivity has also been behavior exhibited by the patient and can be inaccurate in
applied in the context of presurgical planning. While the up to 40% of cases [4, 95]. In the last decade, functional
importance of traditional task-based fMRI for pre-oper- imaging techniques have been used to explore whether
ative mapping is well established, the potential relevance some types of cognitive processing were still available in
of resting-state analysis has emerged only recently. Up to patients suffering from disorders of consciousness and for a
date, a few studies have explored the feasibility of the few cases it was shown that the technique detected residual
approach in this area. Liu et al. [73] studied six patient cognitive abilities and signs of conscious awareness in
candidates to brain surgery with tumors or epileptic foci patients in vegetative state [69, 84, 86]. Indeed, functional
near the motor cortex, and compared the resting-state imaging, including task-based fMRI and resting-state
functional connectivity maps with the task-elicited acti- functional connectivity, has been used with the purpose of
vations of the motor cortex. Functional connectivity was obtaining diagnostically and prognostically relevant infor-
measured with ROI-based analysis, selecting hand and mation, complementing clinical evaluation and neuro-
tongue motor areas as ROIs. The results obtained with physiological studies as well as structural MRI [10, 24, 67,
the two methods were highly comparable at level of 68, 87]. Due to the etiological heterogeneity of these
single subjects and showed that resting-state functional patients, the involvement of visual, motor and sensory
connectivity is able to localize hand and tongue regions pathways can be very variable: as a consequence, the study
of the motor cortex precisely. One of the six patients was of brain activity under resting state appears as a solution of
further studied with direct cortical stimulation: functional minimum complexity to assess the integrity of intrinsic
connectivity activation maps displayed hand and tongue brain function in these patients. To date, the literature
regions overlapping with the localization of the elec- remains limited. Cauda et al. [23] considered resting-state
trodes that disrupted hand and tongue movements. functional connectivity in three vegetative state patients
Another investigation by Zhang et al. [115] studied four and, using ICA, showed that the DMN was present but with
patients with tumors infiltrating sensory and motor cor- reduced intensity. In one patient, other functional networks
tices, and compared resting-state functional connectivity such as the visual and the motor components were reported
to task-based fMRI and cortical stimulation mapping to be intact, but no illustration was provided. An interesting
(CSM). As before, resting-state functional connectivity preliminary finding is that patients seemed to show more
was able to localize sensorimotor areas in accordance left lateralized activation on resting-state component maps,
with CSM for each individual patient. In some cases, compared to controls. This may be related to the view that
resting-state functional connectivity proved to be even self-awareness processes are critically dependent on the
more reliable than task-based fMRI, as for one patient integrity of the right hemisphere [31]. The study by Boly
task-evoked fMRI failed for unknown reasons, and for et al. [11] has also demonstrated the presence of the DMN
another patient it displayed an artefactual activation, in a vegetative state patient, albeit with a significant
absent with functional connectivity fMRI. However, reduced connectivity compared to controls. Distant
further studies with larger patient populations are needed regions, as for instance the prefrontal cortex or the inferior
to confirm these results. Indeed, these studies combining frontal gyrus, were found to correlate, as well as anticor-
fMRI with CSM investigated presurgical motor function relate, with the precuneus. However, thalamo-cortical
mapping only, and they did not consider if resting-state connections were absent. By contrast, in a brain dead
fMRI can be likewise useful for language and memory patient neither thalamo-cortical connections nor long-range
mapping. cortico-cortical functional connectivity were observed

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782 Neurol Sci (2011) 32:773–785

across regions. The absence of thalamo-cortical connec- to address the relevance of other components beyond the
tivity in the vegetative state patient suggests that the DMN, and to develop means of representing the interactions
integrity of a thalamo-cortical network might be essential among distinct functional networks.
for the emergence of consciousness [85, 104]. Van-
haudenhuyse et al. [109] conducted a relevant resting-state Acknowledgments We thank Dr. Maria Grazia Bruzzone and Dr.
Davide Sattin for useful advice on the clinical applications and gen-
functional connectivity study, including patients in coma eral revisions to the manuscript.
and vegetative state as well as minimally conscious and
locked-in syndrome patients. Using ICA, the authors Conflict of interest All authors declare that they do not have any
demonstrated that it was possible to identify the DMN, real or perceived conflicts of interest pertaining to the present study.
even though its intensity was reduced with respect to
controls, a finding consistent with the previous investiga-
tions. Importantly, the authors demonstrated that the
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