European Neuropsychopharmacology (2015) 25, 733748

www.elsevier.com/locate/euroneuro

Connectomics: A new paradigm for

understanding brain disease
Alex Fornitoa,n, Edward T. Bullmorea,b,c,d

a
Monash Clinical and Imaging Neuroscience, School of Psychology and Psychiatry &
Monash Biomedical Imaging, Monash University, 770 Blackburn Rd, Clayton 3168, Victoria, Australia
b
Brain Mapping Unit, Department of Psychiatry, and Behavioural and Clinical Neuroscience Institute,
University of Cambridge, Cambridge, UK
c
GlaxoSmithKline, ImmunoPsychiatry, Alternative Discovery & Development, Stevenage, UK
d
Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, UK

Received 8 August 2013; received in revised form 20 January 2014; accepted 12 February 2014

KEYWORDS Abstract
Graph analysis; In recent years, pathophysiological models of brain disorders have shifted from an emphasis on
Complex network; understanding pathology in specic brain regions to characterizing disturbances of intercon-
Psychosis; nected neural systems. This shift has paralleled rapid advances in connectomics, a eld
Dementia; concerned with comprehensively mapping the neural elements and inter-connections that
fMRI;
constitute the brain. Magnetic resonance imaging (MRI) has played a central role in these
DTI
efforts, as it allows relatively cost-effective in vivo assessment of the macro-scale architecture
of brain network connectivity. In this paper, we provide a brief introduction to some of the basic
concepts in the eld and review how recent developments in imaging connectomics are yielding
new insights into brain disease, with a particular focus on Alzheimers disease and schizo-
phrenia. Specically, we consider how research into circuit-level, connectome-wide and
topological changes is stimulating the development of new aetiopathological theories and
biomarkers with potential for clinical translation. The ndings highlight the advantage of
conceptualizing brain disease as a result of disturbances in an interconnected complex system,
rather than discrete pathology in isolated sub-sets of brain regions.
& 2014 Elsevier B.V. and ECNP. All rights reserved.

The brain is vulnerable to a plethora of diseases that vary in
terms of clinical expression, severity, causes and outcome.
Pathophysiological models of these diseases have largely
been cast in terms of two fundamental principles of brain
n
Corresponding author. Tel.: +61 3 9902 9796.
E-mail address: alex.fornito@monash.edu (A. Fornito).
organization: functional segregation and integration (Tononi
et al., 1996). Functional segregation refers to the speciali-
zation of discrete brain regions or systems in performing
specic mental operations. Evidence for segregation can be
found across multiple spatial scales in the brain, ranging
from the highly selective ring properties of individual
neurons through to the large-scale, functionally specialized

http://dx.doi.org/10.1016/j.euroneuro.2014.02.011
0924-977X & 2014 Elsevier B.V. and ECNP. All rights reserved.
734 A. Fornito, E.T. Bullmore

and spatially distributed neuronal ensembles underlying
higher-order cognitive, emotional and sensorimotor pro-
cesses. Functional integration is achieved via precise dyna-
mical coordination of these segregated elements and is
contingent on intact axonal and synaptic connectivity.
Early clinical observations that focal brain lesions often
led to highly specic cognitive and behavioral decits
exemplied by famous cases such as Brocas Leborgne
(Broca, 1861)offered empirical support for the idea,
promulgated in Galls phrenology, that discrete mental
functions could be ascribed to spatially localized and
functionally specialized neural elements. This idea laid
the foundation for a major emphasis on segregationist
accounts of the brain in much subsequent research (Fodor,
1983). Accordingly, pathophysiological models of many brain
disorders highlighted the prominence of specic brain
regions, such as the striatum in Huntingtons disease (Ross
and Tabrizi, 2011; Tabrizi et al., 2009), striatonigral neurons
in Parkinsons disease (Samii et al., 2004), the medial
temporal lobe in Alzheimers disease (Blennow et al.,
2006; Braak and Braak, 1991) and the prefrontal cortex in
schizophrenia (Lewis et al., 2005; Weinberger et al., 2001).
This regional emphasis may also be construed, in part, as a
reection of technological limitations since the clinical,
histopathological and electrophysiological techniques then
available only allowed inferences on a limited number of
brain regions at any one time. Conceptually, however, the
importance of understanding the role of brain connectivity
in neuropathology has been recognized for over a century
(Geschwind, 1965; Jackson, 1889; Wernicke, 1906).
The past few decades have witnessed rapid advances in
our capacity to map the detailed connectivity architecture
of the brain and thus better understand functional integra-
tion across multiple spatio-temporal scales. Central to this
endeavor is the generation of a comprehensive map of the
full set of elements and inter-connections comprising the
brainthe so-called connectome (Sporns et al., 2005).
Connectomic maps can be generated in different species
and at varying resolutions, from the neuronal level (White
et al., 1986) through to the macro-scale connections linking
large-scale neuronal populations (Ktter et al., 2001;
Hagmann et al., 2007; Modha and Singh, 2010; Shanahan
et al., 2013). Accordingly, various strategies have been used
to generate connectomic maps for species as diverse as the
nematode worm Caenorhabditis Elegans (White et al., 1986)
(the only organism to have its connectome mapped at the
level of each and every synapse), fruit y Drosophila
Melanogaster (Chiang et al., 2011), mouse (Bota et al.,
2012), pigeon (Shanahan et al., 2013), cat (Young et al.,
1994), macaque (Modha and Singh, 2010; Stephan et al.,
2001) and human (Hagmann et al., 2007; Iturria-Medina
et al., 2007; Zalesky and Fornito, 2009). Strictly speaking, a
connectome refers to a structural description of brain
connectivity (Sporns et al., 2005), though similar mapping
techniques have been applied to dynamical measures to
characterize the inter-regional functional interactions that
unfold on this anatomical backbone (Achard et al., 2006;
Eguiluz et al., 2005; Salvador et al., 2005).
Attempts to map the human connectome have used mag-
netic resonance imaging (MRI) because it provides an efcient,
cost-effective and non-invasive means for characterizing
structural and functional properties of the entire brain (though
techniques for comprehensive connectome mapping of ex vivo
specimens are also being developed; Axer et al., 2011; Chung
et al., 2013). In this work, diffusion-weighted imaging (DWI) is
typically used to map the macro-scale axonal structure (i.e.,
physical wiring) of the connectome while functional MRI (fMRI)
is used to characterize its dynamical properties (Bullmore and
Sporns, 2009; Fornito et al., 2013b). Advances in the acquisi-
tion, processing and analysis of MRI data for connectome
mapping (e.g., Essen and Ugurbil, 2012; Smith et al., 2013;
Sotiropoulos et al., 2013; Uurbil et al., 2013) are effecting a
paradigm shift in imaging neuroscience (Friston, 2011) as the
research emphasis moves from mapping regionally discrete
changes in activation patterns or tissue integrity to under-
standing the mechanisms underlying functional integration and
their disturbance in disease. Importantly, these approaches
are yielding new insights into brain disorders that would not
otherwise be possible using a regionally focused, segregation-
ist framework.
In this paper, we review some recent advances in the
burgeoning eld of imaging connectomics and consider their
contribution to understanding disease mechanisms using
specic examples taken from the literature. We focus in
particular on studies of Alzheimers disease and schizophre-
nia as these are disorders in which connectomic methods
are making rapid inroads, though we consider studies of
other disorders where relevant (extended treatments of
other disorders can be found elsewhere: Filippi et al., 2013;
Fornito and Bullmore, 2010; Menon, 2011; Zhang and
Raichle, 2010). We begin with a brief overview of some
basic concepts central to the eld.

Figure 1 Schematic pipeline for connectomic analysis with MRI. (a) Images are rst parcellated into distinct regions-of-interest to
represent network nodes. Shown here are examples of a parcellation based on sulcal/gyral landmarks (left) and functional regions-
of-interest (right). (b) Structural connectivity between these regions is then measured using diffusion tractography (left); functional
connectivity is estimated as a statistical dependence between regional time courses (right). (c) The connectivity between all
regional pairs can be succinctly represented in matrix form. Shown here are examples of an undirected, weighted and unthresholded
functional connectivity matrix (right) and the same matrix after thresholding and binarization (left) to retain only the strongest
connections. (d) Network connectivity can then be represented in graph form as a set of nodes linked by supra-threshold edges.
Shown here are examples of network graphs in an anatomical (left) and topological (right) embedding. The latter illustrates some
basic topological properties/measures used to characterize brain network organization: namely the presence of modules of nodes
highly connected with each than with other regions (yellow, magenta and cyan node groups); the presence of clustered connectivity,
as shown for nodes A, B and C (i.e., both nodes A and B connect to C while also connecting to each other); and the identication of
shortest paths between nodes (e.g., the blue path linking nodes A and D). Images adapted from Fornito et al. (2012b) with
permission. (For interpretation of the references to color in this gure caption, the reader is referred to the web version of this
paper.)
Connectomics: A new paradigm for understanding brain disease 735
736
1. Basic concepts in imaging connectomics
Mapping the connectome with MRI involves three major
steps: (1) dening regions; (2) measuring connectivity
between these regions; and (3) network analysis
(Figure 1). The rst step is deceptively challenging because
there are no clear boundaries visible with MRI that allow
precise delineation of functionally meaningful regional
borders (Wig et al., 2011). Consequently, several heuristic
methods have been employed, such as those based on a
priori anatomical templates (Desikan et al., 2006; Tzourio
et al., 1997), random parcellations of varying resolution
(Fornito et al., 2010; Hagmann et al., 2007; Zalesky et al.,
2010b), pre-determined functional criteria (Dosenbach
et al., 2010), data-driven parcellations (Power et al.,
2011; Yeo et al., 2011), voxel-wise mapping (van den
Heuvel et al., 2008), co-registration with histological data
(Eickhoff et al., 2005) or the quantitative mapping of
regional variations in specic imaging signals (Glasser and
Van Essen, 2011) (see also Figure 1a). Each approach has
strengths and limitations (Fornito et al., 2013b). As such,
the choice of a specic method should be based on its
ability to address the question(s) of interest.
The second step involves measuring connectivity between
regions. There are three broad classes of brain connectivity:
structural, functional and effective. Structural connectivity
refers to the anatomical (i.e., axonal, dendritic, synaptic)
connections between neural elementsthe physical wiring
of the brain. It is most commonly mapped using DWI, though
alternative methods such as the measurement of inter-
regional covariance in regional morphological properties
(e.g., gray matter volume, cortical thickness), have also
been used (Alexander-Bloch et al., 2013a). In DWI, tracto-
graphic algorithms (e.g., Behrens et al., 2007; Mori et al.,
1999) are employed to reconstruct putative ber pathways
linking discrete pairs of regions (e.g., Figure 1b, left), with
connectivity typically dened as either the number of
intersecting trajectories or some index of tissue microstruc-
ture (e.g., fractional anisotropy, mean diffusivity) averaged
over the putative ber tract. These trajectories are not
tantamount to axons, but instead reect an estimate of the
spatial location and course of large-scale axonal bundles
based on how white matter constrains water diffusion in the
brain. They thus represent an indirect index of actual
axonal connectivity. Moreover, DWI-derived microstructural
measures are susceptible to many effects, such as local
variations in ber organization and signal-to-noise, that
complicate interpretation (Fornito et al., 2013b; Jones
et al., 2012). The development of more physiologically
constrained, quantitative approaches (e.g., Alexander
et al., 2010), and multi-modal techniques attempting to
directly index important properties such as axonal myelin
content (van den Heuvel, 2010), may be particularly helpful
in this regard. Finally, although anatomical connectivity is
inherently directed (i.e., each axonal connection has a
source and a target), current DWI techniques cannot infer
directionality. Any resulting network thus constructed is
consequently undirected (i.e., symmetric).
Functional and effective connectivity are typically mea-
sured with fMRI but may also be studied using electo- and/or
magneto-encephalography (EEG and MEG, respectively) to
obtain a richer representation of temporal dynamics at the
A. Fornito, E.T. Bullmore
expense of spatial resolution (Bassett et al., 2006; Zalesky
et al., 2012a; Uhlhaas and Singer, 2006). Either type of
connectivity can be measured during task-free, so-called
resting-states to capture inter-relations between regional
spontaneous dynamics (Fox and Raichle, 2007), or during more
traditional task-driven experiments to quantify stimulus
evoked-changes in network organization (Fornito et al.,
2011a, 2012a). In these contexts, functional connectivity
refers to a statistical dependence between the neurophysio-
logical signals measured in each region (Friston, 1994). It is
most commonly quantied using a simple pair-wise Pearson
correlation between regional activity time courses (e.g.,
Figure 1b, right), though measures such as mutual information
(Salvador et al., 2007), coherence (Bassett et al., 2011) and
others (reviewed in Smith et al., 2011) have been used.
Effective connectivity refers to the inuence that one neural
system exerts over another and is based on a model of causal
interactions occurring at the neuronal level (Friston, 1994).
Functional connectivity has been studied more widely due to
its analytic simplicity and applicability to both small- and
large-scale brain networks. Modeling effective connectivity
with fMRI is more challenging and depends on an explicit
model of the neuronal dynamics causing the measured
hemodynamic signals (Friston, 2009). The high computational
burden of such an approach renders it applicable to networks
comprising only a few brain regions, though recent develop-
ments suggest scalability to larger systems in the near future
(Friston et al., 2011; Seghier and Friston, 2013). Though
functional connectivity is constrained by network anatomy,
the two are not isomorphic (Honey et al., 2009; Skudlarski et al.,
2008; Zalesky and Fornito, 2009). Understanding the relation-
ship between structure and function is an active area of
research (Goi et al., 2013; van den Heuvel and Sporns, 2013a).
Once connectivity between all regional pairs has been
dened, it can be represented succinctly in the form of a
connectivity matrix (Figure 1c). The connectome is an
intrinsically weighted and directed matrix (Fornito et al.,
2013a); i.e., connections are variably weighted in terms of
their strength and they are directed such that each
connection has a source and target. Moreover, the connec-
tome is dynamic. At the microscopic scale, spike-timing
dependent plasticity is evident over sub-second intervals. At
resolutions resolvable with MRI, dynamic changes in func-
tional interactions are evident over periods spanning from
seconds to minutes (Bassett et al., 2011; Chang and Glover,
2010; Fornito et al., 2012a) while changes in the strength
and topography of inter-regional structural connectivity, as
evident during development, ageing and experience-
dependent plasticity, evolve over periods ranging from days
to years (Hagmann et al., 2010; Scholz et al., 2009; Zatorre
et al., 2012). Finally, brain connectivity is heterogeneous
some connections are excitatory, some inhibitory, some
modulatory and so on. The capacity of MRI to capture each
of these features is limited. As a result, most studies have
traditionally analyzed unweighted (i.e., binary), undirected
and static matrices, resulting in a somewhat incomplete
description (Fornito et al., 2013b). Progress is being made
to address some of these limitations (Bassett et al., 2011;
Fornito et al., 2012a; Hutchison et al., 2012; Rubinov and
Sporns, 2011).
The connectivity matrix comprehensively describes the
connectional architecture of the brain. Once dened,
Connectomics: A new paradigm for understanding brain disease
analyses can be performed to examine either network
connectivity or topology (Fornito et al., 2012b). Connectiv-
ity analyses are concerned with understanding variations in
the type and strength of connectivity between brain
regions. Two types of connectivity analysis are possible:
candidate circuit analysis and connectome-wide analysis.
Candidate circuit analysis involves mapping the connectivity
of a specic circuit or sub-system within the connectome. It
does not strictly depend on constructing a comprehensive
connectomic map a priori. Indeed, in many cases, techni-
ques such as independent component analysis (ICA)
(Beckmann and Smith, 2004; Calhoun et al., 2001) or
seed-based tractographic or functional connectivity analysis
focused on the system in question are sufcient. Candidate
circuit analysis is particularly useful when there are strong
hypotheses concerning the localization of the effects under
investigation. In contrast, connectome-wide analysis
involves comprehensive mapping of experimental effects at
each and every element of the connectivity matrix. The
distinction between candidate circuit and connectome-wide
analyses is analogous to the difference between candidate
gene and genome-wide association analyses in genetics: the
former offers greater control and more detailed characteriza-
tion of a specic set of genetic variants (or brain regions) but
can be biased by a neglect of the wider genomic (or neural)
context; genome-wide (or connectome-wide) approaches
allow relatively unbiased identication of targets which must
then be scrutinized via more focused investigation.
Topological analyses are concerned with understanding
how connections are arranged with respect to each other
and are centered on the use of graph theorythe mathe-
matical study of systems of interacting elements (Bollobs,
1985; Bullmore and Sporns, 2009). A core assumption of this
approach is that any complex networkconnectomes
includedcan be represented as a graph of nodes (corre-
sponding to brain regions) connected by edges (some supra-
threshold structural or functional interaction between
regions) (e.g., Figure 1d, left). This representation enables
one to compute a diverse array of measures indexing
distinct organizational properties of the network, thus
providing a rich characterization of structural constraints
and their dynamical consequences. Accordingly, graph the-
oretical analysis of human MRI data has demonstrated that
the brain conforms to a so-called small-world architecture,
characterized by the simultaneous presence of highly clus-
tered connectivity (a topological substrate for functional
segregation) and a low average number of edges, or short
path length, linking any two brain regions (facilitating
functional integration) (Bassett and Bullmore, 2006). Brain
network organization also has a hierarchical, modular
architecture (Meunier et al., 2009b) in which sub-sets of
nodes, termed modules, are highly connected with each
other and sparsely connected with other modules (also
supporting functional segregation) (e.g., Figure 1d, right).
Though topological modules are not necessarily the neural
substrate of psychological modules (e.g., Fodor, 1983), it is
generally assumed that nodes belonging to the same module
possess some commonality of function. Some support for
this contention comes from meta-analytic network analysis
of task-based functional neuroimaging studies (Crossley
et al., 2013). These modules display pseudo-fractal proper-
ties, forming modules within modules, and so on (Bassett
737
et al., 2010; Meunier et al., 2011), and are organized
around a collection of highly interconnected hub-nodesa
so-called rich-clubwhich facilitates inter-module integra-
tion (van den Heuvel and Sporns, 2011; Bassett et al., 2010;
Bullmore and Sporns, 2012; Fornito et al., 2011b). Many of
these properties are conserved across species (Harriger
et al., 2012; Modha and Singh, 2010; Towlson et al., 2013)
suggesting that they represent the outcome of common
selection pressures on brain network evolution, a conten-
tion supported by evidence that similar properties are also
apparent in high performance computer chips, which have
also evolved in response to external pressures (Bassett
et al., 2010). Next, we consider how these three broad
classes of connectomic analysiscandidate circuit,
connectome-wide and topologicalare yielding new insights
into brain disease.
2. Candidate circuit analyses
Many early imaging studies of brain network connectivity
involved some form of candidate circuit analysis. Early
validation studies for DWI-tractography concentrated on
accurately reconstructing well-known anatomical circuits,
such as the cortico-spinal tract, arcuate, uncinate, superior
and longitudinal fasciculi, corpus callosum and thalamocor-
tical projection systems (Behrens et al., 2003; Catani et al.,
2002). Initial work applying multivariate decomposition
techniques to study functional connectivity in fMRI data
identied specic modes (networks) of regions showing
temporally coherent activity during performance of cogni-
tive tasks (Bullmore et al., 1996; Friston and Frith, 1995;
McIntosh et al., 2004). This work was a precursor to ICA-
based methods (Beckmann and Smith, 2004; Calhoun et al.,
2001), which have been widely used to identify a limited
number (typically about 10) of spatial networks that dom-
inate fMRI signals recorded under a diverse range of
experimental conditions (Smith et al., 2009). In parallel,
rudimentary techniques were being developed to study
effective connectivity between a single seed region and
the rest of the brain (Friston et al., 1997), which served as a
basis for the introduction of more sophisticated models
applicable to small sets of a priori dened regions-of-
interest (Friston et al., 2003).
The popularity of candidate circuit analysis increased
dramatically following seminal observations that the spon-
taneous activity of a seed region placed in primary motor
cortex, recorded in the absence of any explicit task,
strongly correlated with the dynamics of a spatially dis-
tributed set of brain regions known to be involved in motor
control (Biswal et al., 1995). Subsequent work showed that
this property extended beyond the motor system and could
be used to map the functional anatomy of numerous, well-
characterized neural systems, such as the dorsal and ventral
attention networks (Fox et al., 2006a), the fronto-parietal
executive control system (Vincent et al., 2008) and the so-
called default mode network (Greicius et al., 2003). Such
work led to the realization that patterns of inter-regional
co-activation commonly observed during cognitive task
performancethus dening major functional systems of
the brainare represented in the brains spontaneous,
so-called resting-state, dynamics (Smith et al., 2009; Toro
738 A. Fornito, E.T. Bullmore

Figure 2 The application of candidate circuit analysis to study neurodegeneration. Illustrated here is the correspondence between
syndrome-specic atrophy patterns (top) and healthy resting-state functional connectivity (middle) and gray matter covariance
networks (bottom) in Alzheimers disease (AD), behavioral-variant fronto-temporal dementia (bvFTD), semantic dementia (SD),
progressive non-uent aphasia (PNFA) and corticobasal syndrome (CBS). The functional connectivity and gray matter covariance
networks were dened using a seed region centered in the area of maximal gray matter atrophy for each syndrome, indicated by
circles in the top row. Figure adapted from Seeley et al. (2009) with permission.

et al., 2008). Moreover, these functional connectivity
patterns are found in different species and at various levels
of consciousness (Greicius et al., 2008; Vincent et al.,
2007), inuence task-evoked activity and behavior (Fox
et al., 2006b, 2007), are under strong genetic control
(Fornito et al., 2011b; Glahn et al., 2010; van den Heuvel
et al., 2012b) and correlate with underlying anatomical
connectivity (Honey et al., 2009; Skudlarski et al., 2008;
Vincent et al., 2007; Zalesky and Fornito, 2009), particu-
larly when low-frequency dynamics are recorded over long
time-scales (Honey et al., 2007). These observations led to
the view that inter-regional covariations in spontaneous
dynamics represent an intrinsic property of brain organiza-
tion (Fox and Raichle, 2007), resulting in the rapid applica-
tion of resting-state fMRI to understand circuit-level
dysfunction in brain disorders (Fornito and Bullmore, 2010;
Zhang and Raichle, 2010).
Impressive advances in this area have been made in the
study of neurodegeneration, particularly Alzheimers dis-
ease. For example, it is now known that patients show a
robust impairment of functional connectivity within the
default mode network, an ensemble of brain regions that
typically show reduced activation during performance of
cognitively demanding tasks (Shulman et al., 1997) and
increased activation during tasks requiring some degree of
introspection (Buckner and Carroll, 2007; Buckner et al.,
2008). The spatial anatomy of this system, which centres on
posterior and anterior medial cortex and lateral parietal
regions, bears striking correspondence to the distribution
and spread of amyloid pathology and gray matter atrophy in
the disease (Buckner et al., 2005). Moreover, impairments
of default mode network functional connectivity can be
seen in carriers of the 4 Alzheimers risk allele of the APOE
gene prior to the emergence of symptoms or any changes in
gray matter volume (Dennis et al., 2010; Machulda et al.,
2011; Sheline et al., 2010).
These ndings suggest that Alzheimers pathology spreads
throughout the interconnected default mode network and that
functional connectivity changes within this circuit may be a
particularly sensitive risk biomarker. Building on this idea, one
recent study used candidate circuit analysis to conrm that
neurodegeneration does indeed spread throughout intercon-
nected systems, albeit in a syndrome-specific way (Seeley
et al., 2009). After characterizing disease-specic patterns of
gray matter atrophy in Azheimers disease, frontotemporal
dementia, semantic dementia, progressive non-uent aphasia
and corticobasal syndrome, regions of peak atrophy in each
map were selected as seed regions for a candidate circuit
analysis of resting-state functional connectivity in an indepen-
dent sample of healthy individuals. The functional connectivity
of each seed region showed striking spatial overlap with the
syndrome-specic atrophy patterns observed in each patient
group (Figure 2). Such ndings support the hypothesis that
degenerative species may spread trans-synaptically, poten-
tially through a prion-like mechanism (Frost and Diamond,
2010), a hypothesis which has recently received direct experi-
mental support in animal models (de Calignon et al., 2012; Liu
et al., 2012b). Understanding how this spread also impacts
connectivity between regions will be an important avenue of
further work.
Connectomics: A new paradigm for understanding brain disease 739

Figure 3 Connectome-wide association analysis in amnestic mild cognitive impairment and schizophrenia. (a) Connectome-wide
analysis of resting-state functional connectivity in individuals with amnestic mild cognitive impairment identied two sub-networks
in which functional connectivity was reduced: one comprised inter-network links between sensorimotor and perceptual modules
(bottom left); the other comprised intra-network links within the default mode network (bottom right). Different node colors
represent visual (blue), default mode (orange), sensorimotor (green), auditory (yellow) and ventral attention (purple) modules.
(b) Connectome-wide analysis of task-related functional connectivity in people with schizophrenia performing a cognitive control
task revealed a widespread network showing reduced functional connectivity regardless of task condition, suggestive of a
generalized connectivity decit (top left). Functional connectivity reductions specically associated with the implementation of
cognitive control were restricted to a more circumscribed circuit (top right). Categorization of these edges into the broad regions of
the brain they connected indicated that the highest proportion of affected connections linked frontal and posterior areas (bottom).
The NBS was used to map connectome-wide changes in both analyses. Images adapted from Wang et al. (2013b) and Fornito et al.
(2011a) with permission. (For interpretation of the references to color in this gure caption, the reader is referred to the web
version of this paper.)

In schizophrenia, candidate circuit analyses have been
used to study a variety of well-dened systems (Hoffman
et al., 2011; White et al., 2010; Whiteld-Gabrieli et al.,
2009). One particular set of circuits subject to renewed
interest link the prefrontal cortex, striatum and thalamus
via a series of parallel yet integrated fronto-striato-
thalamic loops (Alexander et al., 1986). These circuits can
be readily mapped by examining the functional connectivity
of specic seed regions placed in different regions of the
striatum, covering the dorso-ventral and rostro-caudal
extent of the caudate and putamen (Di Martino et al.,
2008). The resulting networks bear a striking resemblance
to underlying anatomy. Using this method, it has been found
that patients with rst episode psychosis, their unaffected
relatives, and individuals experiencing a putative prodromal
at-risk mental state (AMRS) for psychosis display prominent
reductions of functional connectivity between a specic
seed region in the dorsal caudate and the dorsolateral
prefrontal cortex (Dandash et al., 2013; Fornito et al.,
2013a). In both patients and ARMS individuals, the magni-
tude of these reductions correlated with symptom severity.
Collectively, these ndings suggest that reduced functional
connectivity in dorsal frontostriatal circuitry may represent
a risk biomarker for psychotic illness. Importantly, these
connectivity changes can be directly linked to a candidate
molecular pathology, given recent evidence that both
patients and ARMS individuals display elevated dopamine
levels specically in the dorsal region of the striatum
(Howes et al., 2009; Kegeles et al., 2010). These dopamine
elevations correlate with altered prefrontal function
(Fusar-poli et al., 2010) and predict which ARMS individuals
subsequently transition to psychosis (Howes et al., 2011),
implying a central role for these abnormalities in disease
onset. Reduced functional connectivity in dorsal frontos-
triatal circuits is a predictable consequence of altered
dopamine signaling, since either too much or too little
dopamine is thought to increase noise in neural information-
processing systems (Winterer and Weinberger, 2004). Adding
noise to two variables (e.g., fMRI time series) will reduce
the correlation between them, thus resulting in a functional
connectivity reduction.
The identication of circuit-specic changes in brain
disorders raises the possibility of developing targeted
interventions aimed at selectively up- or down-regulating
functional connectivity within these systems. Indeed,
although traditional psychological and pharmacological
treatments are known to alter the activity of distributed
brain networks (Achard and Bullmore, 2007; Goldapple
et al., 2004; Lui et al., 2010), they are somewhat blunt
tools that cannot be used to target specic pathological
circuits. Combining imaging with brain stimulation techni-
ques may offer a more tailored and specic intervention
strategy. Such an approach has proven successful in guiding
the selection and validation of appropriate deep brain
stimulation targets for patients with treatment-resistant
depression (Mayberg et al., 2005) and obsessive-compulsive
disorder (Figee et al., 2013). Moreover, candidate circuit
analyses are proving useful for optimizing target-selection
740
for less invasive stimulation techniques such as transcranial
magnetic stimulation (TMS). Stimulation of focal points on
the cortical surface can modulate functional connectivity
within distributed neural systems (Eldaief et al., 2011) and
thus could be used to target deep brain structures that are
difcult to access without invasive surgery (Strafella et al.,
2001). Accordingly, one recent study has shown that the
treatment efcacy of prefrontal TMS in major depression
may be linked to the proximity of the stimulation site to
prefrontal areas whose spontaneous dynamics show strong
anti-correlation (i.e., negative correlation) with the sub-
genual cingulate cortex, a region known to play a major role
in emotion regulation (Fox et al., 2012). Notably, this region
is a primary target for invasive stimulation therapies in
treatment-resistant patients (Mayberg et al., 2005).
3. Connectome-wide analysis
In contrast to the specicity of candidate circuit analysis,
connectome-wide analyses involve relatively comprehensive
mapping of disease-related changes or experimental effects
of interest across the entire connectome. Such comprehen-
sive mapping immediately raises a multiple comparisons
problem: given a network of N regions, there are N(N 1)
connections in a directed network or N(N 1)/2 connections
in a symmetric, undirected network. For most MRI studies,
N ranges between 100 and 1000, meaning that any single
effect must surpass Bonferoni-corrected thresholds ranging
between po1.01  10 5 and po1.01  10 7 to be declared
signicant while retaining control over family-wise error.
Fortunately, techniques are being developed to enable
sensitive identication of statistically signicant effects
distributed throughout the connectome (Ginestet and
Simmons, 2011; Meskaldji et al., 2011; Zalesky et al.,
2010a, 2012a, 2012b). For example, one approach, termed
the network-based statistic (NBS), achieves major gains in
statistical power by evaluating the null hypothesis at the
level of interconnected sub-networks rather than each pair-
wise connection independently (Zalesky et al., 2010a).
Though the reliability of these methods has not yet been
comprehensively characterized, their development is lead-
ing to a rapid increase in the number of connectome-wide
maps of structural and functional effects reported, includ-
ing those associated with schizophrenia (Fornito et al.,
2011a; Zalesky et al., 2010a, 2011), depression (Bai et al.,
2012; Zhang et al., 2011), mild cognitive impairment (Wang
et al., 2013b), autism (Li et al., 2012a), attention-decit
hyperactivity disorder (Cocchi et al., 2012), amyotrophic
lateral sclerosis (Verstraete et al., 2011), migraine (Liu
et al., 2012a), multiple sclerosis (Li et al., 2012b), cannabis
use (Zalesky et al., 2012c), internet addiction (Hong et al.,
2013), and specialized training regimens (Wang et al.,
2013a).
The advantage of connectome-wide analyses lies in their
capacity to map effects of interest in an unbiased, model-
free manner. However, the results can often involve large
and distributed networks involving hundreds or thousands
of connections, creating problems for visualization and
interpretation. Consequently, it is often useful to combine
the results of such an analysis with a simpler, functionally
meaningful categorization of the nodes and/or edges
A. Fornito, E.T. Bullmore
involved in the affected sub-network. For example, one
resting-state fMRI study combined the NBS with an analysis
of the modular architecture of brain network functional
connectivity to report that, relative to healthy individuals,
people with amnestic mild cognitive impairment show
reduced functional connectivity in two discrete sub-net-
works: one involving intra-module connectivity between
elements of the default mode network and the other
implicating inter-module connectivity between sensorimo-
tor and perceptual systems (Wang et al., 2013b)
(Figure 3a). A similar approach, combined with measures
of event-related functional connectivity (Rissman et al.,
2004), was used to demonstrate that patients with rst
episode schizophrenia display a relatively circumscribed
impairment of fronto-parietal circuitry during the perfor-
mance of a cognitive control task, which is superimposed
on a more widespread and generalized network connectiv-
ity decit that was apparent regardless of task condition
(Fornito et al., 2011a) (Figure 3b). These network changes
parallel the neuropsychological prole of schizophrenia, in
which a generalized cognitive decit is coupled with
specic strengths and weaknesses in various specic cog-
nitive domains (Heinrichs and Zakzanis, 1998). Evidence
for structural decits in fronto-posterior connectivity in
schizophrenia has also been reported (Zalesky et al.,
2011), pointing to an anatomical basis for these functional
disturbances.
A particularly interesting development involves the com-
bination of connectome-wide and genome-wide analyses.
Using an extended twin design, one recent study mapped
the heritability of each specic connection on a
connectome-wide basis (Jahanshad et al., 2013). Genome-
wide associations with connectivity strength were then
tested within a restricted set of connections showing
heritability. A signicant association was found linking
variation at the rs2618516 allele of the SPON1 gene and
strength of connectivity between the posterior cingulate
cortex and the superior parietal lobule. Analysis of an
independent cohort found that the variant signicantly
impacted gray matter volume in the posterior cingulate
cortex and medial temporal areas and was correlated with
dementia severity in elderly patients. Interestingly, SPON1
is known to interact with APOE (Hoe and Rebeck, 2008). This
work illustrates how the integration of connectome- and
genome-wide methods can be used to identify novel treat-
ment targets for a wide range of connectomic disorders.
The combination of these two highly multivariate datasets
will however pose critical challenges for both analysis and
interpretation.
4. Topological analysis
Graph theory offers a diverse range of quantitative mea-
sures for characterizing the topology of brain structural
and functional networks (Rubinov and Sporns, 2010). To
date however, only a limited sub-set has been applied to
the study of brain disease. These measures largely relate
to three broad properties: topological integration, topolo-
gical segregation, and hub-dominance. Measures of inte-
gration include the characteristic path length, dened as
the mean number of connections on the shortest path
Connectomics: A new paradigm for understanding brain disease 741

Figure 4 Modeling brain functional network topology using simple growth models. (A) comparison of mean levels of clustering,
efciency and modularity in observed data (blue), a one-parameter model in which long-distance connections are penalized by an
exponential decay (green), a model that adds a bias to form connections preferentially with nodes showing higher connectivity
(orange), and an economical clustering model in which long-distance connectivity is penalized and clustered connectivity is favored
(red). Error bars represent 95% condence intervals. (B) The degree distribution for each of the networks. (C) The distribution of
connection distances in each type of network. (DG) Network connectivity of the right hemisphere of a single instantiation of each
model illustrated in anatomical space. The size of each node is proportional to its degree. Across all measures, the economical
clustering model provided the best t to the data. Moreover, tweaking model parameters such that the distance penalty and
clustering bias were reduced reproduced the topological alterations seen in patients with childhood onset schizophrenia. Images
adapted from Vertes et al. (2012) with permission. (For interpretation of the references to color in this gure caption, the reader is
referred to the web version of this paper.)

linking any pair of nodes (Figure 1D, left); and global
efciency, dened as the inverse path length. Measures of
segregation include the clustering coefcient, dened as
the probability that two nodes connected to a third are
also connected with each other (Figure 1D, left); local
efciency, dened as the efciency of sub-networks
dened by nodes directly connected to an index node,
after removal of that node; and modularity, which mea-
sures the degree to which the brain can be decomposed
into sub-sets of highly connected regions (Figure 1D, left).
Hubs are nodes that have a high degree of connectivity
and/or which play a central role in the connectome. The
extent to which a network is dominated by hubs can be
determined by analysis of its degree or strength distribu-
tionthe distribution of the number of connections
(degree) or total connectivity weight (strength) across
network nodes. In many complex networks, including the
brain, this distribution is fat-tailed and typically follows a
power law with an exponentially truncated cutoff at high
degree, pointing to the existence of a sub-set of nodes that
mediate a relatively large proportion of the total number
of edges in the network (Amaral et al., 2000; Barabasi and
Albert, 1999).
Hubs of the connectome are typically characterized by
high degree and/or strength, high betweenness centrality
(i.e., they exist on many shortest paths between brain
regions) and low clustering (i.e., they link brain regions
that are not directly connected to each other) (Harriger
et al., 2012; Sporns et al., 2007). Some hubs act as
connectors, linking nodes belonging to different modules.
They thus facilitate functional integration. Other nodes act
as provincial hubs, being strongly connected with other
regions located in the same module, thereby supporting
functional specialization or segregation (Fornito et al.,
2012a; Meunier et al., 2009a). Connector hubs from
different modules are often highly interconnected amongst
each other, forming a so-called rich-club of connectivity
that acts as a central distributor of network communica-
tion trafc (van den Heuvel and Sporns, 2011). Many of the
connections made by rich-club nodes span long-distances and
represent a major fraction of the total wiring cost of the
connectome (van den Heuvel et al., 2012a). They are thus
742
disproportionately costly. Nonetheless, rich-club connectivity
may offer a globally cost-effective solution for achieving
certain functional imperatives for the brain, such as efcient
integration between anatomically distinct and functionally
diverse network elements, given evidence that the total wiring
cost of the connectome may near-minimal relative to its
degree of topological complexity (Bassett et al., 2010).
It has recently been proposed that variations in the way
that the connectome negotiates the trade-off between
network wiring cost and topological complexity have impor-
tant implications for understanding brain disorders
(Bullmore and Sporns, 2012). Indeed, evidence that such
trade-offs in the brain are under strong genetic control
(Fornito et al., 2011b) indicates that they are a critical
constraint on connectome evolution and may represent
viable endophenotypes for brain disorders (Fornito and
Bullmore, 2012). Since hubs are metabolically costly, in
terms of their sustained high levels of activity, connectivity
and long-range projections (Liang et al., 2013; Tomasi
et al., 2013), they may be particularly sensitive to the
metabolic restrictions that can arise from pathological
insult. Indeed, one recent fMRI study found that patients
in a comatose state exhibit a profound impairment in the
functional connectivity of hub nodes (Achard et al., 2012),
suggesting that conscious awareness may be critically
dependent on the integrity of high-cost neural systems.
Similarly, major hub regions such as the posterior cingulate
cortex are among the rst to degenerate in Alzheimers
disease (Buckner et al., 2005) and the topological changes
observed in this patient group, characterized by combina-
tion of increased clustering and path length (Stam et al.,
2007)(He et al., 2008), coupled with reduced long-range
connectivity (Liu et al., 2013; Yao et al., 2010), suggest a
breakdown in the higher cost aspects of brain network
topology (Bullmore and Sporns, 2012). Conversely, neuro-
developmental disorders such as autism may reect a
failure of the maturation of these higher-cost network
properties, given evidence that certain hub regions in
prefrontal cortex may show excessive short-range and
impaired long-range connectivity (Courchesne and Pierce,
2005).
Patients with schizophrenia show a somewhat distinct
pattern of alterations. Though hub-regions are affected
(van den Heuvel et al., 2013), functional studies have found
reduced clustering (Lynall et al., 2010) and/or modularity
(Alexander-Bloch et al., 2010), coupled with an excess
proportion of long-distance connections (Alexander-Bloch
et al., 2013b) and either intact or increased functional or
topological integration (Lynall et al., 2010). These results
suggest that wiring cost in this patient group may be
increased at the expense of functional segregation; a shift
in the cost-efciency trade-off opposing the changes
observed in Alzheimers disease (Bullmore and Sporns,
2012). Accordingly, one recent study found that the emer-
gence of several key topological properties of brain func-
tional networks was reproduced by a simple model in which
networks develop to satisfy two competing constraints: a
bias towards clustered connectivity and a penalty on the
formation of long-distance connections (Vertes et al.,
2012). Moreover, the topological changes observed empiri-
cally in the functional networks of patients with childhood
onset schizophrenia could be reproduced by simply reducing
A. Fornito, E.T. Bullmore
the values of both model parameters (Figure 4). This
analysis demonstrates how a broad range of connectomic
disturbances in a given patient group are explicable in terms
of a relatively narrow set of parameters and how generative
models of network growth in particular may prove useful in
understanding constraints on connectome organization in
neurodevelopmental disorders.
Topological analyses can also offer insights into degen-
erative processes. One recent study found that the observed
pattern of gray matter atrophy in Alzheimers disease and
frontotemporal dementia could be reproduced by simulat-
ing a simple model of disease diffusion on network topolo-
gies obtained from DWI-derived connectomes in healthy
individuals (Raj et al., 2012). That is, the pattern of
observed disease spread was largely predicted by connec-
tome topology. In an independent study, gray matter
atrophy in Alzheimers disease, frontotemporal dementia,
semantic dementia, corticobasal syndrome and progressive
non-uent aphasia occurred in regions with a short topolo-
gical path length to putative disease-specic epicenters
representing focal (and possibly early) points of pathology in
each syndrome (Zhou et al., 2012). In other words, the
spatial distribution of atrophic changes was predicted by
the topological relation of each affected region to
syndrome-specic focal points of pathology.
These topological and model-based analyses illustrate the
potential power of connectomic techniques for uncovering
developmental mechanisms leading to aberrant brain net-
work organization, and for tracking the progression of
disease in degenerative disorders. An important goal for
future research will be the empirical validation of these
models with longitudinal designs following individuals as
they move from high-risk or prodromal states to frank
disorder. This work will be particularly useful for determin-
ing whether connectomic models offer any clinical utility in
predicting clinical outcomes. Importantly, mapping disease-
related brain changes from the earliest signs of illness will
be crucial for understanding whether the disorder is truly
connectomic, in the sense that it represents a primary
pathology of inter-regional connectivity (e.g., demyelinat-
ing disorders such as multiple sclerosis), or rather begins in
an isolated region of the brain and gradually spreads
throughout the network (e.g., the striatal pathology
preceding the more widespread changes seen in Parkinsons
disease and Huntingtons disease). This distinction is parti-
cularly critical for disorders such as schizophrenia and
Alzheimers disease, where early views of a focal origin
(e.g., Braak and Braak, 1991) must be reconciled with the
wide-range of spatially distributed brain abnormalities
discussed above.
5. Summary and conclusions
The brain is an extraordinarily complex network; it is thus
logical to study disorders of the brain from a network
perspective. In this review, we have considered how con-
nectomics can contribute to this endeavor by understanding
brain dysfunction at three distinct levels: candidate cir-
cuits, connectome-wide and at the level of network
topology.
Connectomics: A new paradigm for understanding brain disease
At the circuit-level, connectomic techniques afford a
powerful probe of the structural and functional integrity
of specic neural sub-systems. These techniques demon-
strate considerable sensitivity to brain disease (Fornito and
Bullmore, 2010; Zhang and Raichle, 2010). They have
yielded new insights into how degenerative processes
spread throughout interconnected networks (Seeley et al.,
2009; Zhou et al., 2012), and have identied candidate risk
biomarkers that can be linked to molecular pathologies
(Buckner et al., 2005; Fornito et al., 2013b). Preliminary
work also suggests that they may facilitate optimized
selection of patient-specic abnormalities for targeted
intervention (Fox et al., 2012).
Connectome-wide analyses afford an unbiased,
hypothesis-free means for comprehensively characterizing
brain network disturbances across the entire brain. Several
methods now exist for dealing with the statistical chal-
lenges posed by these approaches, and their application has
conrmed prevailing views about specic disorders, such as
the importance of fronto-posterior connectivity in schizo-
phrenia (Fornito et al., 2011a; Zalesky et al., 2011) and the
prominence of the default mode network in Alzheimers
disease (Wang et al., 2013b). The further development of
appropriate statistical and data mining techniques that
allow the integration of these methods with other omics
data will open new frontiers in discovery science (Biswal
et al., 2010).
Finally, analyses of network topology have contributed to
a new understanding of the fundamental principles guiding
connectome organization and its disruption by disease. They
have highlighted a central role for hub region disruption
across a range of brain disorders (van den Heuvel and
Sporns, 2013b), and suggest that disorders as diverse as
schizophrenia, autism and Alzheimers disease may be
recast in terms of the way in which topological costbenet
trade-offs mature and are maintained by the brain
(Bullmore and Sporns, 2012). A particular advantage of
these analyses is that they offer a range of quantitative
phenotypes that can be studied with the use of relatively
simple generative models. Preliminary attempts to model
aberrant developmental and degenerative processes have
had some success in capturing some of these features (Raj
et al., 2012; Vrtes et al., 2012). Further integration of
empirical and computational ndings will facilitate a shift
from phenomenological descriptions to formal, precisely
specied models of brain disease.
Role of funding source
None.
Contributors
A.F. and E.T.B. planned and co-wrote the paper.
Conict of interest
E.T.B. is employed half-time by G.S.K., half-time by the University
of Cambridge.
743
Author disclosure
A.F. was supported by a Monash University Larkins Fellow-
ship and National Health and Medical Research Council grant
(ID: 1050504). E.T.B. is employed half-time by G.S.K., half-
time by the University of Cambridge. The funding sources
had no further involvement in this paper.
Acknowledgments
We thank Drs William Seeley, Petra Vertes and Yong He for providing
high-resolution versions of some of the gures reproduced in this
paper.
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