REVIEW

CURRENT
OPINION Connectome and schizophrenia
Katherine L. Narr a,b and Amber M. Leaver a

Purpose of review
The neural connections, interconnections and organized networks of the central nervous system (CNS),
which represent the human connectome, are critical for intact brain function. Consequently, disturbances at
any level or juncture of these networks may alter behaviour and/or lead to brain dysfunction. In this
review, we focus on highlighting recent work using advanced imaging methods to address alterations in
the structural and functional connectome in patients with schizophrenia.
Recent findings
Using structural, diffusion, resting-state and task-related functional imaging and advanced computational
analysis methods such as graph theory, more than 200 publications have addressed different aspects of
structural and/or functional connectivity in schizophrenia over the last year. These studies have focused on
determining how brain networks differ from those in controls, interact with symptom profiles within and
across diagnoses, interface with disease-related cognitive impairments and confer genetic risk for the
disorder.
Summary
Much existing evidence supports the view that schizophrenia is a disorder of altered brain connectivity.
Recent and continued characterization of the structural and functional connectome in schizophrenia patients
have advanced our understanding of the neurobiology underlying clinical symptoms and cognitive
impairments in a particular patient, their overlaps with other neuropsychiatric disorders sharing common
features as well as the contributions of genetic risk factors. Although the clinical utility of the schizophrenia
connectome remains to be realized, recent findings provide further promise that research in this area may
lead to improved diagnosis, treatments and clinical outcomes.
Keywords
connectivity, diffusion imaging, graph theory, networks, resting state functional MRI

INTRODUCTION preventing neuropsychiatric illness. The current

The organization and interaction of molecules, cells,
fibre tracts and networks in the central nervous
system (CNS) act as the substrates of brain function
and dysfunction. As first introduced by Sporns et al.
[1] and Hagmann et al. [2], ‘the connectome’ refers
to the full micro and macroscale connectivity struc-
ture of all neural components within and across
individuals. At the macroscale (millimetre resol-
ution), brain systems can be reduced into anatom-
ically distinct nodes (or regions) to examine global
and local patterns of connectivity, mapping both
the brain’s structural architecture (or wiring) and
&
functional interconnections [3 ]. With advances in
noninvasive imaging technologies over the last
decade and sophisticated computational analysis
tools, new progress has been made towards mapping
the brain’s structural and functional connections.
In turn, these advances have provided new oppor-
tunities to study brain network abnormalities for
the purpose of better understanding, treating and
review focuses on selected neuroimaging findings
published over the last year seeking to advance these
goals in schizophrenia.
A wealth of evidence supports that disruptions
in brain connectivity contribute to schizophrenia
pathophysiology [4–10]. Indeed, near a century
ago, schizophrenia was termed and recognized by
Bleuler [11] as a neural disorder of connection or
conduction with varying clinical presentations [12].
Dysconnectivity in particular brain systems, or com-
ponents thereof, has since been implicated in many
a
Ahmanson-Lovelace Brain Mapping Center, Department of Neurology
and bDepartment of Psychiatry and Biobehavioral Sciences, University of
California at Los Angeles, Los Angeles, California, USA
Correspondence to Katherine L. Narr, PhD, 225 Neuroscience Research
Building, 635 Charles Young Drive South, Los Angeles, CA 90095, USA.
E-mail: narr@ucla.edu
Curr Opin Psychiatry 2015, 28:229–235
DOI:10.1097/YCO.0000000000000157

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Schizophrenia and related disorders
KEY POINTS
 Patients show disturbances in multiple large-scale neural
systems as well as more local network abnormalities
providing compelling evidence in favour of the
dysconnectivity hypothesis of schizophrenia.
 Disruptions in neural connectivity within particular brain
networks vary according to clinical, behavioural and
cognitive characteristics of patients.
 Structural and functional connectivity patterns in
patients with schizophrenia and bipolar disorder
suggest both common and unique underlying
mechanisms.
 Both static and dynamic changes in structural and
functional connectivity are linked with brain dysfunction
in schizophrenia.
 Mapping the schizophrenia connectome at the global
and local scale with advanced neuroimaging methods
show promise for developing improved diagnosis and
treatment strategies.
independent investigations. In accordance with
the guiding principles of the NIH/NIMH Research
Domain Criteria (RDoC) project [13,14] seeking to
build a dimensional classification system of diagno-
sis more closely linked to neurobiological dysfunc-
tion, recent studies have sought to identify global
and local patterns of connectivity associated with
different clinical or cognitive phenotypes in schizo-
phrenia, and their overlap with other psychiatric
disorders.
Over the last year, more than 200 publications
have addressed different aspects of structural and/or
functional connectivity in schizophrenia to deter-
mine how brain networks interact with symptom
profiles within and across diagnoses, interface with
disease-related cognitive impairments and confer
genetic risk for the disorder. In view of the number
of new studies in this area, the current review
focuses on summarizing representative findings
and those considered of most potential impact from
studies using resting-state functional MRI fMRI
(rfMRI), task-fMRI (tfMRI), diffusion MRI (dMRI)
and network-based methods to study the schizo-
phrenia connectome (Fig. 1).
RESTING-STATE FUNCTIONAL
CONNECTIVITY
Since the pioneering work of Biswal [15], Raichle
et al. [16] and others, resting-state neuroimaging
techniques have been widely applied to map the
brain’s functional connectivity. Using rfMRI, it is
230 www.co-psychiatry.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
possible to survey brain network activity associated
with sensory, motor and cognitive functions [17,18]
by determining blood-oxygenated level dependent
(BOLD)-related synchronous neural activity in
spatially distinct brain regions while an individual
is at rest. The investigation of resting state networks
(RSNs) typically identifies patterns of synchronous
BOLD activity with respect to a particular region-of-
interest (ROI) or seed, or by using data-driven
independent components analysis (ICA) to auto-
matically extract spatially independent patterns
of neural synchrony. These methods can address
whether disease processes impact the intrinsic func-
tional organization of large-scale networks, as well
as more localized neural circuitry, which can in turn
reflect mechanisms at the synaptic and cellular level
[19].
Existing evidence has shown that the organiz-
ation of the brain in schizophrenia is attributable to
both increased and decreased functional connec-
tivity amongst regions and RSNs. The default mode
network (DMN), encompassing the medial prefron-
tal cortex (PFC), precuneus/posterior cingulate,
lateral parietal cortex and hippocampus in the
medial temporal lobe (MTL), has been the most
widely studied RSN. Although findings are mixed,
as likely confounded by clinical and methodological
heterogeneity, the majority of evidence points to
schizophrenia-related DMN hypoconnectivity,
although both hypo and hyperconnectivity have
been reported with respect to non-DMN networks
[20,21] (see Fornito et al. [22] for a review). Recent
schizophrenia studies similarly report increased and
decreased functional connectivity between the
DMN, the insula and anterior-cingulate containing
salience network [23] and central executive network
(CEN), which includes the dorsolateral prefrontal
&
and posterior parietal cortex [24,25 ].
Overlaps in clinical, cognitive and genetic risk
factors are observed in patients with schizophrenia
&
and bipolar disorder [26–28,29 ], including reported
DMN hypoconnectivity. For example, a recent land-
mark investigation of 324 healthy controls, 296
schizophrenia and 300 psychotic bipolar disorder
probands, and 179 and 206 of their respective unaf-
fected relatives, used ICA to establish the utility of
DMN functional connectivity patterns as potential
biomarkers and endophenotypes within and across
&&
diagnoses [30 ]; imaging-genetic relationships were
examined in a subset of participants. Results showed
hypoconnectivity in three DMN components in both
diagnostic groups wherein the degree of functional
connectivity was associated with symptom dimen-
sions; similar patterns were observed in schizo-
phrenia relatives in one identified component.
Further, genes regulating neurodevelopmental
Volume 28  Number 3  May 2015
 Connectome and schizophrenia Narr and Leaver

Schizophrenia connectome: approaches

Functional: resting-state and task fMRI Structural: diffusion imaging

Network analysis

FIGURE 1. Current approaches for measuring the schizophrenia connectome. Functional connectivity analyses (upper left)
typically seek to identify networks with temporally coherent fMRI time courses either at rest (to probe spontaneous or intrinsic
activity) or during a task (to probe connectivity associated with specific sensory and/or cognitive-behavioural processes).
Studies of structural connectivity (upper right) typically make inferences regarding connectivity through diffusion MRI measures
of white matter integrity (microstructure) or use fibre tracking to measure differences in overall patterns of white matter
connections associated with schizophrenia and related mental disorders. Both functional and structural connectivity measures
have benefited from growing interest in applying network-level analyses (bottom panel), which use methods such as graph
theory to capture various, nuanced aspects of connectivity patterns (beyond differences in overall connectivity strength).

processes and neural transmission were found to
mediate disease-related DMN dysconnectivity. These
results provide compelling evidence that both
common and unique neurobiological mechanisms
extend across diagnoses and underscore the potential
of data-driven rfMRI approaches for identifying and
dissociating such mechanisms.
Recent data have implicated disruptions of con-
nectivity beyond the DMN in schizophrenia. Func-
tional interactions between the thalamus and
cortex, long implicated in the disorder [31,32], have
been the focus of continued research. A recent mul-
tisite study showed significant hyperconnectivity
between the thalamus and each sensory network
and reduced connectivity between sensory networks
&&
in schizophrenia [33 ]. Here, dynamic changes in
connectivity also pointed to weaker large-scale con-
nectivity patterns in patients similar to other recent
findings [34,35]. Investigators also report differ-
ences and similarities in functional connectivity
patterns within cortico-thalamic networks in
schizophrenia and psychotic bipolar disorder.
Examining functional connectivity at the level of
the thalamic subnuclei, both patient groups and
relatives of bipolar patients showed abnormal con-
nectivity in striatal-thalamo-cortical networks;
altered thalamo-insula connectivity was unique to
schizophrenia. Suggesting a common neural source,
altered functional connectivity was found more
similar between schizophrenia patients and bipolar
patients with a history of psychosis than those with-
&
out [36 ].
Much evidence implicates the MTL system in
schizophrenia [37,38], and altered connectivity
between MTL structures (amygdala and hippo-
campus) and prefrontal and parietal association areas
&
are reported in recent studies [39,40 ]. Findings show
decreased amygdala-orbitofrontal coupling in both
early course and chronic schizophrenia, but not in
individuals at a high risk, suggesting involvement of
&
disease-specific factors [40 ]. Further, observations of
differential functional connectivity between the
amygdala and dorsolateral PFC in schizophrenia
and between the amygdala and the ventral PFC in
bipolar disorder suggest a biological basis for dis-
tinguishing these disorders [39]. Cumulatively, find-
ings support that disturbances in functional
connectivity within cortico-limbic networks relate

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Schizophrenia and related disorders
to clinical features of schizophrenia and underlie
shared symptoms across psychiatric disorders.
Several new studies have addressed the neural
circuitry associated with hallucinations, a necessary
feature for schizophrenia diagnosis. Patients with
visual hallucinations are shown to exhibit hyper-
connectivity between the amygdala and visual cor-
& &&
tex [41 ]; auditory hallucinations associate with
temporo-parietal connectivity [42]. However, con-
nectivity within the mesolimbic pathway, linking
the nucleus accumbens and ventral tegmental area,
appear impacted regardless of the type of hallucina-
tion [43]. These findings and others [44] suggest
that sensory system specific connectivity patterns
underlie hallucinations, though functional connec-
tivity amongst brain regions including the ventral
striatum and medial PFC [43,45] are modulating
factors. Focusing on connections from primary
auditory cortex, new results further demonstrate
that both patients and their unaffected biological
relatives exhibit altered functional asymmetry and
temporo-limbic connectivity, which also associate
&
with a predisposition towards hallucinations [46 ].
A primary objective of patient-oriented research
is to enhance more successful treatment strategies.
As the striatum is a primary target of antipsychotic
treatments, a recent rfMRI study examined longi-
tudinal changes in functional connectivity seeded
from the striatum in patients with first-episode
psychosis treated with risperidone or aripiprazole.
Significant increases in functional connectivity
between the striatum and the anterior cingulate,
dorsolateral PFC, MTL regions and the insula, and
decreases of functional connectivity with parietal
cortex, occurred with improvements in psychotic
&&
symptoms for both medications [47 ]. These results
suggest that corticostriatal functional connectivity
is representative of clinical state and a potential
biomarker of treatment outcome. Another study
compared PFC connectivity in healthy individuals
after receiving the N-methyl-D-aspartate glutamate
receptor (NMDAR) antagonist, ketamine, and in
high risk, recent onset and chronic schizophrenia
&
patients not receiving ketamine [48 ]. Hypoconnec-
tivity in the PFC was observed in controls receiving
ketamine and in high-risk and recent onset schizo-
phrenia groups, but was absent in chronic schizo-
phrenia, suggesting that ketamine administration
better models the early phase of illness, information
that could be relevant for future drug development.
Using less traditional methodological appro-
aches to compare global whole-brain changes in
functional connectivity in schizophrenia, one study
[49] investigated the density of functional connec-
tivity to weight the regions most relevant to schizo-
phrenia diagnosis rather than selecting regions or
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networks to examine a priori. Here, results indicated
increased functional connectivity density for the
hippocampus and striatum independent of medi-
cation, illness duration or symptom severity. Another
study compared alterations in global brain signal (i.e.
signal averaged across all brain voxels, often disre-
garded in preprocessing) in two large schizophrenia
samples, controls and bipolar patients [50 ]. Results
showed elevated global brain signal variability in
schizophrenia and links with clinical symptoms,
but not in bipolar disorder, pointing to diagnostic
specificity of overall brain functional coherence.
TASK-BASED FUNCTIONAL
CONNECTIVITY
Schizophrenia is characterized by a generalized cog-
nitive impairment, though some functions, such as
attention, working and declarative memory, appear
particularly vulnerable. The investigation of task-
related functional connectivity provides important
information regarding the circuitry of particular cog-
nitive processes, enables validation of rfMRI findings
against brain networks engaged during overt behav-
iour and facilitates behaviour-based definition of
seeds for connectivity analyses [51]. Consequently,
sophisticated computational methods for measuring
functional connectivity have been applied to inves-
tigate the biological bases of cognitive impairments
(see [52] for review). With regard to working memory,
reductions in prefrontal-parietal functional connec-
tivity are most typically reported [53], appear to vary
with symptom severity [54] and are shown to dis-
tinguish schizophrenia and bipolar disorder in
particular network components [55]. New data also
show that antipsychotic-naive at-risk individuals
exhibit abnormal fronto-parietal connectivity during
working memory, suggesting that connectivity in
this functional system may serve as a potential
schizophrenia biomarker [56]. Notably, functional
connectivity in sensory pathways is also impacted
&
by task characteristics (e.g. verbal/nonverbal) [57 ], as
compatible with variations in task-related neural
activity patterns.
For declarative memory, new evidence demon-
strates that altered, effective fronto-temporal connec-
tivity originating in the hippocampus and observed
in unmedicated schizophrenia patients normalizes
&
after 1 week of antipsychotic treatment [58 ]. These
findings suggest that disturbances in specific system
components may be useful as a biomarker of treat-
ment response. Using a context processing task,
another new study used ICA methods to show that
similar to schizophrenia patients, unaffected
relatives of patients demonstrate altered connectivity
in a right lateralized executive fronto-parietal
Volume 28  Number 3  May 2015

network [59], suggesting that this deficit is attribu-
table to schizophrenia-related genetic vulnerability.
Together, these and other recently published studies
support that cognitive impairments in schizophrenia
are, to a meaningful extent, attributable to network-
specific disruptions in functional connectivity
[60,61].
STRUCTURAL CONNECTIVITY
The occurrence and strength of brain functional
connectivity is shown to reflect and be constrained
by structural connectivity [62]. Many studies have
used dMRI to characterize alterations in brain struc-
tural connectivity in schizophrenia [63,64]. Despite
different analysis methods and mixed regional
findings, schizophrenia-related disturbances in
structural connectivity have been reported within
almost all primary association and projection
pathways and interhemispheric tracts, for example
[65–68]. An updated review of dMRI findings in
schizophrenia, pointing to preferential involvement
of the corticospinal tracts, interhemispheric con-
nections, long association white matter tracts,
cerebello-thalamo-cortical circuit and limbic sys-
tem, also suggests that altered structural connec-
&
tivity occurs across all phases of illness [69 ].
In the context of the connectome, focus has
shifted towards comparing structural connections
within and across anatomic or functional networks
rather than solely on dMRI-derived measures of
white matter microstructural properties in particu-
lar pathways. This focus incorporates the use of
different imaging modalities and/or the application
of more complex brain network analyses (discussed
below) to understand disease mechanisms and
relationships with symptom dimensions. For
example, using rfMRI and dMRI to characterize
whole-brain differences in functional/structural
connectivity, patients with schizophrenia showed
decreased functional connectivity and impaired
white matter integrity in a distributed network
encompassing frontal, temporal, thalamic and stria-
tal regions and less inter-regional connectivity com-
pared with controls [70].
Another new study used dMRI and rfMRI to
examine functional connectivity in perisylvian
language areas in individuals at biological risk and
with recent-onset schizophrenia, with or without
auditory verbal hallucinations, and controls. Find-
ings, perhaps counter intuitively, suggested that
more severe disruptions in fronto-temporal connec-
tivity could act as a preventive mechanism for the
emergence of hallucinations early in the course of
illness [71]. However, another recent study showed
increased fractional anisotropy (an estimate of
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Connectome and schizophrenia Narr and Leaver
white matter integrity) in interhemispheric auditory
pathways in patients with hallucinations compared
with those without [72]. Although requiring clarifi-
cation, together, results support that altered con-
nectivity contributes to the pathophysiology of
auditory verbal hallucinations.
NETWORK ANALYSIS AND GRAPH
THEORY
Identifying neural elements and the interconnec-
tions amongst them, which constitutes the field of
connectomics, may provide a clearer understanding
of disease-related pathophysiology than investi-
gating altered brain structure or function alone
[73,74]. A graph can represent a dynamic network
in terms of a set of nodes and connections through
which the nodes interact. It is thus possible to
compute connectivity matrices and the small-world
network properties of connectivity in the human
brain. Graph theory based methods may capture
many features relevant to the topological organiz-
ation of the brain such as high local clustering (e.g.
cortical regions) combined with long-distance con-
nections between clusters (white matter tracts) [75].
An increasing number of studies have used
advanced computational approaches to separate
the brain into structural or functional compart-
ments or nodes to investigate disruptions in brain
&
network connectivity in schizophrenia [3 ].
As recently reviewed by van den Heuvel and
&&
Fornito [76 ], schizophrenia patients are typically
reported to show longer communication pathways
(path length) in frontal, temporal and parietal
regions and less network efficiency with fewer cen-
tral hubs with respect to controls. Adding to this
literature, a recent study seeking to identify the
source of schizophrenia-related alterations in brain
network efficiency identified a distributed set of
brain nodes associated with disease processes and
showed disease-related decentralization of this net-
work, suggesting less capacity to efficiently integrate
information [77]. Using a new framework for assess-
ing dynamic graph properties of time-varying
functional connectivity from rfMRI, another study
demonstrated that patients show decreased variance
in dynamic graph metrics, including strength,
clustering coefficient and global efficiency, over
time than controls. This evidence supports that
temporal connectivity patterns are altered in schizo-
phrenia and likely to impact brain function [78].
Methods extending the principles of functional con-
nectivity density mapping were also applied to
assess small-world network properties in schizo-
phrenia. Here, investigators showed weaker graph
theory metrics, including clustering and path
www.co-psychiatry.com 233
Schizophrenia and related disorders
length, in patients with schizophrenia than con-
trols, where disease effects were most prominent
in the thalamus and the midbrain. Decreased path
length was also observed in the PFC. These results
show distributed alterations in the schizophrenia
connectome and provide compelling evidence in
favour of the dysconnectivity hypothesis of schizo-
phrenia [4].
CONCLUSION
Studies published in the last year have helped
confirm that alterations of the human connectome
are central to the neurobiology of schizophrenia and
include multiple, large-scale neural systems as well
as more local network disturbances related to
particular clinical and cognitive phenotypes. This
work also emphasizes common biological links
between schizophrenia and bipolar disorder.
Although the schizophrenia connectome requires
further study, existing data support its future role for
refining diagnosis and treatment strategies.
Acknowledgements
None.
Financial support and sponsorship
Award Numbers R01MH092301 and K24MH102743
from the National Institute of Mental Health supported
this study. The content is solely the responsibility of the
authors and does not necessarily represent the official
views of the National Institute of Mental Health or the
National Institutes of Health.
Conflicts of interest
There are no conflicts of interest.
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