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Schizophrenia Bulletin vol. 40 no. 4 pp. 904–913, 2014
doi:10.1093/schbul/sbt093 Advance Access publication July 16,
2013
© The Author 2013. Published by Oxford University Press on behalf
of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email:
[email protected]
Altered Striatal Functional Connectivity in Subjects With an
At-Risk Mental State for Psychosis
Orwa Dandash1, Alex Fornito1–4, Jimmy Lee5,6,
Richard S. E. Keefe7,8, Michael W. L. Chee8, R.
Alison Adcock9, Christos Pantelis1,10, Stephen
J. Wood*,1,11, and Ben J. Harrison1
1Melbourne Neuropsychiatry Centre, Department of Psychiatry, The
University of Melbourne, Melbourne, Australia; 2Centre for Neural
Engineering, The University of Melbourne, Melbourne, Australia;
3The Victorian Research Laboratory National ICT Australia Ltd,
Victoria, Australia; 4Monash Clinical and Imaging Neuroscience,
School of Psychology and Psychiatry and Monash Biomedical Imaging,
Monash University, Clayton, Australia; 5Department of General
Psychiatry 1 and Research Division, Institute of Mental Health,
Buangkok, Singapore; 6Office of Clinical Sciences, Graduate Medical
School, Duke-National University of Singapore, Singapore,
Singapore; 7Psychiatry and Behavioral Sciences, Duke University
Medical Center, Durham, NC; 8Neuroscience and Behavioral Disorders
Program, Graduate Medical School, Duke-National University of
Singapore, Singapore, Singapore; 9Department of Psychiatry and
Behavioral Sciences and Center for Cognitive Neuroscience, Duke
University, Durham, NC; 10Melbourne Health, Melbourne, Australia;
11School of Psychology, University of Birmingham, Edgbaston,
Birmingham, UK
*To whom correspondence should be addressed; School of Psychology,
University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK;
tel: 44 121 414 4917, fax: 44 121 414 4897, e-mail:
[email protected]
Recent functional imaging work in individuals experienc- ing an
at-risk mental state (ARMS) for psychosis has implicated dorsal
striatal abnormalities in the emergence of psychotic symptoms,
contrasting with earlier findings implicating the ventral striatum.
Our aims here were to characterize putative dorsal and ventral
striatal circuit- level abnormalities in ARMS individuals using
resting- state functional magnetic resonance imaging (fMRI) and to
investigate their relationship to positive psychotic symptoms.
Resting-state fMRI was acquired in 74 ARMS subjects and 35 matched
healthy controls. An established method for mapping ventral and
dorsal striatal func- tional connectivity was used to examine
corticostriatal functional integrity. Positive psychotic symptoms
were assessed using the Comprehensive Assessment of At-Risk Mental
State and the Positive and Negative Syndrome Scale. Compared with
healthy controls, ARMS subjects showed reductions in functional
connectivity between the dorsal caudate and right dorsolateral
prefrontal cortex, left rostral medial prefrontal cortex, and
thalamus, and between the dorsal putamen and left thalamic and
lenticu- lar nuclei. ARMS subjects also showed increased func-
tional connectivity between the ventral putamen and the insula,
frontal operculum, and superior temporal gyrus bilaterally. No
differences in ventral striatal (ie, nucleus accumbens) functional
connectivity were found. Altered functional connectivity in
corticostriatal circuits were significantly correlated with
positive psychotic symptoms. Together, these results suggest that
risk for psychosis is
mediated by a complex interplay of alterations in both dorsal and
ventral corticostriatal systems.
Key words: ARMS/fMRI/resting state/striatum
Introduction
The onset of psychosis is commonly preceded by a pro- dromal period
characterized by subthreshold symp- tomatology and functional
decline.1 These symptoms have been construed as reflecting an
at-risk mental state (ARMS), which is associated with an enhanced
risk of converting to frank psychosis within 2 years.2,3
A number of anatomical, functional, and neurochemi- cal brain
changes thought to be crucial to the patho- genesis of the disease
have been associated with the ARMS.4–6 Chief among these is
elevated dopamine transmission in the striatum,7,8 a brain region
rich in dopamine D2 receptors targeted by most antipsychotic
drugs.9,10
Many pathophysiological models of psychosis ascribe a prominent
role to the striatum, comprising the caudate and putamen, given its
rich interconnectivity with other regions known to be dysfunctional
in psychosis, such as the prefrontal cortex.11–14 In particular,
animal studies have emphasized dysfunction of a ventral (limbic)
circuit, linking ventral striatum (nucleus accumbens) with medial
prefrontal cortex, a system implicated in the mesolimbic
dopaminergic pathway.15,16
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Altered Striatal Connectivity in ARMS Subjects
Recently, however, in vivo positron emission tomo- graphy research
has demonstrated elevated dopaminergic activity in the dorsal but
not the ventral striatum of patients with established
schizophrenia17 and ARMS subjects.8 These elevations correlate with
the severity of positive psychotic symptoms8 and prefrontal
activation18,19 in the latter group. Thus, in contrast to animal
models,15,16 human data implicate dorsal striatal dysfunction in
the emergence of psychosis. They also suggest that abnormalities
may not be restricted to the striatum but propagate throughout
interconnected corticostriatal circuitry, consistent with the idea
that psychotic disorders arise as a result of aberrant brain
connectivity or “dysconnectivity.”20–22
Despite this possibility, no study to date has directly examined
corticostriatal dysfunction in ARMS individu- als from a
systems-level perspective in order to character- ize putative,
circuit-based risk biomarkers for psychosis. Resting-state
functional magnetic resonance imaging (fMRI) provides a powerful
probe of the functional integrity of corticostriatal circuitry by
mapping networks of brain regions showing coherent fluctuations of
spon- taneous neural activity.23–25 These fluctuations are under
strong genetic control26,27 and are thought to represent an
intrinsic property of brain functional organization.20,28 In this
study, we used this technique to investigate the functional
connectivity of dorsal and ventral striatal regions (caudate
nucleus and putamen) with the rest of the brain in a
well-characterized, relatively large sample of ARMS subjects
recruited in a community-based set- ting in Singapore.29
The aims of this study were 2-fold. First, we sought to
systematically examine functional connectivity within dorsal and
ventral corticostriatal circuits to evalu- ate whether the ARMS is
associated primarily with alterations in the dorsal circuit,
ventral circuit, or both. Second, we sought to characterize
circuit-level abnormal- ities related to psychotic symptoms,
independently of any covariance with depression and anxiety, which
are often present in ARMS individuals. Based on recent neuroim-
aging work,8,18 we hypothesized that participants would show
altered striatal functional connectivity in the dorsal circuit
compared with healthy controls. We also hypoth- esized that altered
functional connectivity would be asso- ciated with more severe
psychotic symptoms.
Methods
Participants
Eighty help-seeking individuals were recruited from the
Longitudinal Youth At Risk study,29 a research study based at the
Institute of Mental Health (IMH), Singapore. Individuals were
recruited from psychiat- ric clinics at IMH, the Singapore Armed
Forces, and from community mental health services run by
trained
counselors. Comprehensive Assessment of At-Risk Mental State
(CAARMS)30 was used to establish at- risk status for the
development of psychosis. Included individuals had no history of
psychotic disorder, neu- rological disorder, serious medical
disorders, or men- tal retardation and no current substance use.
Baseline symptoms were assessed with the Positive and Negative
Syndrome Scale (PANSS) of schizophrenia,31 the Calgary Depression
Scale for Schizophrenia (CDSS),32 and the Beck Anxiety Inventory
(BAI).33 Overall func- tioning was assessed using the Global
Assessment of Functioning34 (see online supplementary table 1
for fur- ther information). All assessments were carried out by
trained psychologists (N = 14, CAARMS interrater reli- ability κ =
0.99).
At intake, 25 ARMS subjects were receiving antide- pressants
(tricyclic or serotonin reuptake inhibitors); 2 were receiving
antianxiety treatment (benzodiazepines); 12 were receiving both
antidepressants and benzodiaz- epines; and 2 received low-dose
antipsychotic treatment (chlorpromazine 50 mg and seroquel 25 mg).
Repeating analyses after excluding the last 2 subjects did not
alter the findings, so we report on the full sample here.
Subsequent to MRI scan, 6 ARMS subjects made a transition to psy-
chosis as outlined by the CAARMS (see online supple- mentary
table 2 for further information).
Forty subjects with a similar sociodemographic background to ARMS
subjects matched for age, gender, handedness, and educational
attainment were recruited as healthy controls. Sample
characteristics were compared between the groups (table 1)
using univariate ANOVA in the Statistical Package for the Social
Sciences (v.20). Educational attainment was assessed by the Primary
School Leaving Examination, a standardized multidisciplinary test
of scholastic achievement. Exclusion criteria were history of
severe head injury, personal history of psychotic or neurologic
disorders, and substance or alcohol dependence assessed with the
Structured Clinical Interview for Diagnostic and Statistical Manual
of Mental Disorders, fourth edition.35 All participants gave their
written and informed consent approved by the ethics review board of
the Singaporean National Healthcare Group.
Image Acquisition
T2*-weighted echo-planar images were acquired for each subject in
the resting condition with a 3.0 T MRI scan- ner (Siemens Magnetom,
Trio Tim) that is equipped with a 12-channel array coil. Subjects
were instructed to lie still with their eyes closed and not to fall
asleep. Functional volumes were acquired in 3 mm3 voxel size, with
a time to repetition (TR) of 2000 ms, time to echo (TE) of 30 ms,
flip angle of 90° in 64 × 64 matrix size, and 192 mm field of view
(FOV). For 7 control subjects, 320 volumes were acquired with 28
slices each. For the remaining participants, 240 volumes comprising
36 slices
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O. Dandash et al
each were obtained. Repeating analyses after excluding the 7
subjects did not significantly alter the findings, so we report on
the full sample here. For registration of functional images,
high-resolution anatomical T1 images were acquired using a
3-dimensional magnetic-prepared rapid gradient echo (MPRAGE)
sequence and multiecho MPRAGE. One hundred and ninety-two
contiguous sag- ittal slices of 1.0 mm thickness using a TR of 2300
ms, TE of 2980 ms, flip angle of 9°, and a FOV of 256 mm in 256 ×
256 matrix were acquired with a voxel size of 1.0 mm3.
Preprocessing
A validated resting-state functional connectivity mapping procedure
was used to characterize ventral and dorsal corticostriatal systems
via primary seed regions of interest located in ventral and dorsal
areas of the caudate nucleus and putamen (see Di Martino et
al36 for anatomical delineation of these regions and Harrison
et al25 and online supplementary text for a full description
of the methodology implemented herein).
First-Level, Within-Subjects Analysis
Functional connectivity maps were estimated for each participant by
including the striatal region time series and nuisance signals as
predictors of interest/no-interest
in whole-brain, linear regression analyses in SPM8 for each
hemisphere. Prior to model estimation, a high-pass filter set
at 128 seconds was used to remove low-frequency drifts. Each of the
3 nuisance covariates were orthogo- nalized (using an iterative
Gram-Schmidt method) and then removed from each seed’s time series
along with 6 head-motion parameters (3 translation and 3 rotation)
by linear regression, resulting in a general linear model that
comprised “noise-cleaned” regions and 9 nuisance vari- ables.
Contrast images were generated for each partici- pant by estimating
the regression coefficient between all brain voxels and each
region’s time series.
Second-Level, Between-Group Analysis
For each striatal region, participants’ contrast images were
included in a random effects 2 × 2 factorial design (Group
[control, ARMS] by Hemisphere [left, right]) in SPM8. Within-group
statistical maps were thresholded at a false discovery rate of P
< .05 for the whole-brain volume (figure 1). Between-group
effects (main effects of group and group × hemisphere interactions)
were mapped by implicitly masking t contrasts (1 tailed) with a
global conjunction of the within-subjects effect calculated for
both groups for the combined left and right hemispheres. Nuisance
covariates included age, gender, and 4 addi- tional summary
measures of head motion to further
Table 1. Demographics and Clinical Characteristics of the
At-Risk Mental State (ARMS) Group and the Healthy Comparison
Group
ARMS Subjects (N = 74)
Characteristics Mean SD Mean SD t/χ2 p
Age (y) 21.4 3.57 22.8 3.94 −1.839 .068 Educational attainment
196.5 47.3 206.7 27.1 −1.40 .166
Gender N % N % χ2 p
Male 47 67 21 60 0.599 .439 Female 27 33 14 40
Handednessa N % N % χ2 p
Left 4 5.7 0 0 4.921 .178 Mixed 6 8.6 1 2.9 Right 60 85.7 34
97.1
Clinical scoresa Mean SD — — — —
CAARMS positive symptoms scaleb
Unusual thought content 4.0 3.4 — — — — Nonbizarre ideation 5.5 3.2
— — — — Perceptual abnormality 4.3 3.3 — — — — Disorganized speech
1.7 2.8 — — — — PANSS PANSS total 49.6 11.5 — — — — PANSS positive
11.0 2.8 — — — —
Note: CAARMS, Comprehensive Assessment of At-Risk Mental State;
PANSS, Positive and Negative Syndrome Scale. aThe data of 4 (5.4%)
ARMS subjects were not available at the time of the analysis.
bSummed across intensity and frequency measures.
907
remove residual head-motion effects37: (1) the number of
significant micromovements (instances of >0.10 mm rela- tive
displacement between adjacent volumes); (2) mean head displacement;
(3) maximum head displacement; and (4) mean head rotation.
Between-group statistical maps were thresholded using a P < .05
([family-wise error] FWE) cluster-wise corrected threshold
determined using a permutation-based framework38 (1000 permutations
with a cluster-forming threshold of P < .01 uncorrected), as
implemented in the REST toolbox.39
Symptom Correlates of Striatal Functional Connectivity
We investigated associations between striatal functional
connectivity and measures of positive symptom severity taken from
the CAARMS and PANSS positive symptom scale in ARMS subjects (N =
70). Secondary associations
with CDSS and BAI scales were also performed to test the
specificity of findings to positive symptoms. These scores were
entered as covariates into separate general linear models, which
also included age, gender, and the 4 head motion derivatives as
nuisance covariates. Correlations between clinical ratings and
connectivity measures were masked by the between-group difference
observed between ARMS and control subjects (figure 2) to
identify the symptom correlates of striatal functional
dysconnectivity observed in ARMS subjects. All results were
displayed at P < .05 (FWE) cluster-wise corrected, with
appropriate correction for the search volume employed.
Results
Across groups, functional connectivity of the dorsal and ventral
striatum (figure 1) recapitulated previous
Fig. 1. Significant within-group (seed effect) functional
connectivity maps of the dorsal caudate (DC), ventral
striatum/nucleus accumbens (VS), dorsal putamen (DP), and ventral
putamen (VP) seeds (in blue). Green indicates healthy comparison
subjects, while red indicates at-risk mental state subjects and
yellow indicates areas of overlap; R, right hemisphere; L, left
hemisphere. Sagittal slices are displayed at x = ±6 (DC
and VS); x = −3 and x = 4 (DP);
x = ±8 (VP). Results are displayed at P < .05 (false
discovery rate) corrected.
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O. Dandash et al
results25,36 and was consistent with known anatomical con-
nectivity.11,12 When functional connectivity was compared between
groups, significant differences were observed for the dorsal
caudate, dorsal putamen, and ventral putamen seed regions
(figure 2; table 2). With regard to the dor- sal caudate, ARMS
subjects demonstrated significantly reduced functional connectivity
with the right dorsolat- eral prefrontal cortex, left rostral
medial prefrontal cor- tex, and thalamus bilaterally
(figure 2A). For the dorsal putamen seed region, ARMS subjects
demonstrated reduced functional connectivity with the left
lenticular nucleus and the medial dorsal, ventral lateral, and ven-
tral anterior thalamic nuclei (figure 2B). ARMS subjects
demonstrated increased functional connectivity between ventral
putamen seeds and lateral superior temporal gyrus, frontal
operculum and the insula bilaterally (fig- ure 2C). There were
no significant group differences for the ventral striatal (nucleus
accumbens) seed, nor were there any significant group × hemisphere
interactions for any seed region.
Brain-Behavior Associations
In ARMS participants, higher scores on the CAARMS nonbizarre
ideation subscale predicted lower functional connectivity between
the dorsal caudate and the left ros- tromedial prefrontal cortex
(figure 3A). Higher scores on the perceptual abnormality
subscale predicted lower func- tional connectivity between the
dorsal caudate and right dorsolateral prefrontal cortex
(figure 3A). Additionally, higher unusual thought content
(CAARMS) and PANSS positive scores predicted lower functional
connectiv- ity between the dorsal putamen and the medial dorsal,
ventral lateral, and ventral anterior thalamic nuclei (fig-
ure 3B). Finally, higher unusual thought content scores
(CAARMS) predicted higher functional connectivity between ventral
putamen and language areas, superior temporal gyrus and the insula
bilaterally, whereas higher PANSS positive scores predicted higher
functional con- nectivity with the left inferior frontal gyrus
(figure 3C).
No further significant associations with CAARMS or PANSS positive
scores were identified.
Repeating the analysis while covarying for CDSS and BAI ratings did
not significantly alter the correlation between corticostriatal
functional connectivity and positive symptom severity. To control
for medication effects, we ran a separate analysis in which we
investigated differences in functional connectivity of striatal
seeds (that showed significant between-group differences) between
ARMS subjects receiving antidepressants (n = 34) and
those who did not (n = 36), masked by the observed
pattern of group differences. No significant differences were
found. To further exclude the effect of diagnosis and/or treatment,
we repeated the between- group analysis after excluding subjects
with Axis-I diagnosis of depressive and/or anxiety disorder in
addition to subjects receiving antidepressants and/or
benzodiazepines. Despite lower power, the same effects were
observed (P < .01 uncorrected), indicating our results are not
attributable to diagnosis or treatment effects (see online
supplementary figure 1).
Discussion
It remains controversial whether psychotic symptoms emanate from
primary alterations of dorsal or ventral corticostriatal circuitry.
To address this question, we systematically characterized the
functional integrity of dorsal and ventral corticostriatal circuits
at a systems level with resting-state fMRI in a large sample of
ARMS subjects experiencing attenuated psychotic symptoms. ARMS
subjects showed a selective reduction of functional connectivity in
dorsal corticostriatal circuits and increased functional
connectivity between ventral putamen and brain regions largely
involved in language, including the superior temporal and
transverse gyri, insula, and frontal operculum bilaterally. No
functional connectivity changes were found for the ventral
striatum/ nucleus accumbens seeds. The magnitude of both dorsal and
ventral circuit alterations correlated significantly with
Fig. 2. z score statistical maps of significant between-group
differences in functional connectivity of the (A) dorsal caudate
(DC); (B) dorsal putamen (DP); and (C) ventral putamen (VP) seeds.
Right hemisphere to the right of the image. At-risk mental state (N
=7 0), healthy controls (N = 35). Results are displayed at P <
.05 (FWE) cluster-wise corrected. See table 2 for more
information.
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Altered Striatal Connectivity in ARMS Subjects
the severity of positive psychotic symptoms as measured by the
positive symptoms scales of the CAARMS and the PANSS.
The alterations of corticostriatal functional connectivity in ARMS
subjects are in strong agreement with accumulat- ing evidence of
functional and neurochemical changes in these structures prior to
the onset of frank psychosis8,40–42
(reviewed in Fusar-Poli, McGuire, Borgwardt5) and their general
role in the pathophysiology of schizophrenia.13,43 In addition, our
findings confirm and extend the find- ings of resting-state fMRI
studies in first episode44 and established schizophrenia patients45
(reviewed in Fornito and Bullmore20 and Pettersson-Yeo et
al46) by show- ing that functional dysconnectivity is evident in
subjects
Table 2. Brain Regions Demonstrating Significant Between-Group
Differences in Functional Connectivity and Association With
Positive Psychotic Symptoms in ARMS Subjects
Main Effect Anatomical Region Hemisphere MNI Coordinates (x, y, z)
z (df = 1,208) Voxels
Dorsal caudate Rostral medial prefrontal cortex
Left −8, 74, 8 3.34 215
Dorsal lateral prefrontal cortex
Right 26, 18, 62 3.60 298
Thalamus Left −6, −12, 14 4.12 828 Thalamus Right 8, −22, 12
4.30
Dorsal putamen Lentiform nucleus Left −26, −8, 0 4.19 580 Thalamus
Left −12, −10, 16 3.07
Ventral putamen Operculum Right 58, −14, 10 4.59 629 Inferior
postcentral gyrus Left −58, −24, 24 3.83 238 Inferior frontal gyrus
Left −48, 18, −4 3.77 316 Operculum Left −56, −6, 6 3.64 239 Insula
Left −44, −6, −4 3.23
Positive Symptoms Association Anatomical Region Hemisphere
MNI Coordinates (x, y, z) z (df = 1,131) Voxels
Dorsal caudate Dorsal lateral prefrontal cortex
Right 32, 38, 44 3.10 35
Rostral medial prefrontal cortex
Left −10, 72, 8 3.04 17
Dorsal putamen Thalamus Left −12, −10, 16 3.40 27 Thalamus Left
−12, −12, 20 3.0 13
Ventral putamen Insula/operculum Right 48, −4, 4 3.32 8
Insula/operculum Left −44, −4, 2 2.72 9 Inferior frontal gyrus Left
−56, 10, 6 3.15 27
Note: ARMS, at-risk mental state; FWE, family-wise error. Results
are viewed at P < .05 (FWE) cluster-wise corrected.
Fig. 3. z scores statistical maps of significant
brain-behavior association between estimates of functional
connectivity of striatal seeds and positive psychotic symptoms on
the Comprehensive Assessment of At-Risk Mental States (unusual
thought contents, nonbizarre ideation, and perceptual abnormality)
and the PANSS positive scales in at-risk mental state subjects (N =
70). Results are masked with the between-group difference (main
effect) mask and displayed at a P < .05 (FWE) cluster-wise
corrected. See table 2 for more information and online
supplementary figure 2 for scatter plots.
910
experiencing positive psychotic symptoms characteristic of the
psychosis prodrome and that it is not a secondary effect of
antipsychotic treatment, comorbidity, or illness chronicity.
The involvement of dorsal corticostriatal circuitry is consistent
with recent reports indicating that the ARMS is associated with
elevation of dopamine transmission specifically in the dorsal, so
called “associative,” regions of the caudate nucleus.8,18,19 In
past work, this elevation was associated with severity of psychotic
symptoms8 and altered prefrontal function.18,19 Our findings extend
these results by demonstrating a functional dysconnection in the
form of reduced connectivity between dorsal striatal and prefrontal
regions while also highlighting an impor- tant role for the ventral
putamen in this circuit-level abnormality.
It is as yet unclear whether altered striatal dopamine is a cause
or consequence of the apparent functional dyscon- nectivity
reported herein. Certainly, there is evidence that pharmacological
manipulation of dopamine transmission can alter brain functional
connectivity. In one study, acute depletion of dopamine precursors
(tyrosine and phenyl- alanine) in healthy controls led to a
reduction in fronto- striatal functional connectivity,47 whereas
administration of l-Dopa, another dopamine precursor, enhanced
it.48 Neither of these agents represent pharmacological mod- els of
psychosis, thus the effects of these drugs need not necessarily
mimic our findings, though they do suggest that general increase in
dopamine leads to increased fron- tostriatal functional
connectivity. This observation seems to be at odds with our report
of reduced functional con- nectivity, coupled with other findings
of increased striatal dopamine in ARMS subjects.7,8 However, it is
well known that there is an inverted U-shaped relationship between
dopamine levels and optimal cortical function and behav- ior,49,50
and well-established models posit that deviations from optimal
dopamine levels in either direction (ie, too much or too little)
will increase the noise of informa- tion processing in neural
systems.51,52 Adding noise to 2 variables (eg, regional fMRI time
series) will generally decrease the correlation between them. Thus,
both abnor- mal increases and decreases in dopamine could plausibly
lead to reduced functional connectivity.
Accumulating neuroimaging evidence in subjects at clinical high
risk for psychosis shows significant neuroanatomical alterations in
cortical regions before the onset of psychosis.6,53,54 Similar
changes have generally not been observed in striatal55 or thalamic
regions (reviewed in Fusar-Poli et al4 and Fusar-Poli,
McGuire, Borgwardt5). The strong connectivity of cortical afferents
with the striatum11,12 and their role in controlling subcortical
dopaminergic pathways56,57 imply that cortical alterations may
precede and influence striatal dopamine transmission as a result of
disrupted functional connectivity between these regions.
Importantly, disinhibition of subcortical dopamine and the
concomitant emergence of psychotic
symptoms have historically been viewed as the final step in a
common pathway arising from aberrant cortical afferents.58–60 It is
therefore plausible that disruption of corticostriatal functional
connectivity is driven by cortical abnormality. Our observed
association between corticostriatal dysconnectivity and positive
psychotic symptoms (figure 3), as well as other work61–64
implicating the prefrontal cortex in mediating aspects of psychotic
symptoms, is in support of this notion, though further work is
required to establish causal influences of this perturbation.
Alterations in striatothalamic connectivity are con- sistent with
models implicating cortical disinhibition of subcortical dopamine
in the emergence of psychotic symptoms.60,65 These models posit
that disinhibition of subcortical dopamine increases the flow of
sensory information to the thalamus, which results in a failure of
the thalamus to “filter out” irrelevant stimuli before they reach
the cortex, thus predisposing an individual to psychotic symptoms.
Given that the thalamus receives the bulk of striatal output via
GABAergic projections to the medial dorsal, ventral anterior, and
ventral lateral nuclei,12 it was perhaps not surprising that ARMS
sub- jects experiencing more severe positive psychotic symp- toms
showed disrupted functional connectivity between the dorsal putamen
and these nuclei (figure 3B).
The selective localization of striatothalamic dyscon- nectivity to
the left hemisphere is also in agreement with previous reports
showing neurochemical abnormalities in the left thalamus in ARMS
subjects.41,66 Importantly, reduced thalamic glutamate correlated
with altered activation and electrophysiological response in the
pre- frontal cortex and superior temporal gyrus, as well as reduced
gray matter volume in the lateral temporal, inferior frontal, and
insular cortices,67 brain regions that showed increased functional
connectivity with the ven- tral putamen (figure 2C). These
findings suggest that the abnormal increase in functional
connectivity of the ventral putamen may reflect an abnormal
increase in cortical glutamatergic tone that could potentially be
caused by thalamocortical disinhibition of pyramidal cells.65,68
Alternatively, the ventral putamen could be in overdrive to
compensate for a primary dorsal corticos- triatal abnormality.
Recent evidence in ARMS subjects points to alteration in ventral
striatal and medial tempo- ral areas function that is not present
in control subjects,69 and our more recent observation in
unaffected siblings of first-episode psychosis patients shows
reduced dorsal and increased ventral corticostriatal
connectivity.70 Thus, dorsal frontostriatal hypoconnectivity may be
a generic risk biomarker for psychosis, while ventral system hyper-
connectivity may emerge as a compensatory response or secondary
consequence.
Despite the relatively large sample of ARMS sub- jects,
between-group differences in functional connec- tivity may be an
underestimate of the actual underlying
911
Altered Striatal Connectivity in ARMS Subjects
disturbance given the smaller sample size of healthy controls.
A major strength, however, is the absence of substance abuse
problems due to the generally low prevalence of substance use in
Singapore71–73 (see online supplementary table 1 for more
details). In particular, cannabis use, which is often more common
in ARMS individuals,74–76 can influence dopamine levels77,78 and
corticostriatal function79 and thus represents a major confound in
imaging studies. Though nearly half of our ARMS sample were taking
antidepressants, the asso- ciation we observed between
corticostriatal functional connectivity and psychotic symptoms was
evident inde- pendent of depressive symptom, and there were no dif-
ferences between participants on/off these medications. These
findings support a specific involvement of corti- costriatal
dysconnectivity in the emergence of psychotic symptoms. The lack of
outcome data in our analyses prevents any inferences concerning the
specific risk for psychosis in our sample. Nonetheless, the robust
associa- tion observed with positive symptom severity in individ-
uals deemed to be at risk for psychosis, as defined using
extensively validated operational criteria,3,30,80 suggests that
this circuit-level disruption is intimately related to the
expression of psychotic symptoms. This assertion is further
supported by our recent finding of similar dorsal circuit changes
in patients with first-episode psychosis and their unaffected
relatives.70 Six individuals in our ARMS group have since made the
transition to psycho- sis, and we are presently following up the
remainder of participants to clarify clinical outcomes and more
accu- rately characterize risk levels.
In summary, our results indicate that the ARMS is associated with a
disruption of dorsal and ventral cor- ticostriatal functional
connectivity and that this disrup- tion correlates with the
severity of positive psychotic symptoms. These findings converge
with recent evidence that dopamine elevations are present
specifically in dorsal striatal regions of ARMS subjects8 and
patients with schizophrenia17 while also highlighting a role for
ventral corticostriatal circuitry. Further work examin- ing the
utility of this phenotype in predicting transition to psychosis
will be critical in determining its clinical relevance.
Supplementary Material
Funding
National Research Foundation Singapore under the National Medical
Research Council Translational and Clinical Research Flagship
Program (NMRC/ TCR/003/2008). The Australian Postgraduate Award
(2010); the Melbourne Neuropsychiatry Centre Research
Higher Degree Award (2010) to O.D.; CR Roper Fellowship and
National Health and Medical Research Council Project Grant (1050504
to A.F.); Department of Veteran’s Affair; Feinstein Institute for
Medical Research; GlaxoSmithKline; National Institute of Mental
Health; Novartis; Psychogenics; Research Foundation for Mental
Hygiene, Inc; the Singapore National Medical Research Council (to
R.S.E.K.); National Health and Medical Research Counsel of
Australia Senior Principal Research Fellowship (628386 to C.P.);
National Health and Medical Research Counsel of Australia Program
Grant (566529 to C.P.); National Health and Medical Research
Council of Australia Clinical Career Development Award (628509 to
B.J.H.).
Acknowledgments
The authors have declared that there are no conflicts of interest
in relation to the subject of this study.
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