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Original Investigation |

Functional Dysconnectivity of Corticostriatal Circuitry as a Risk Phenotype for Psychosis

Alex Fornito, PhD1,2,3,4; Ben J. Harrison, PhD1; Emmeline Goodby, PhD5,6; Anna Dean, PhD5,6; Cinly Ooi, PhD5,6; Pradeep J. Nathan, PhD6,7,8; Belinda R. Lennox, DM, MRCPsych5,6; Peter B. Jones, MD, PhD, MRCPsych5,8; John Suckling, PhD5,6; Edward T. Bullmore, PhD, MRCPsych, FMedSci5,6,7
[+] Author Affiliations
1Monash Clinical and Imaging Neuroscience Laboratory, School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia
2Centre for Neural Engineering, University of Melbourne, Parkville, Victoria, Australia
3NICTA Victorian Research Laboratory, University of Melbourne, Parkville, Victoria, Australia
4Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Parkville, Victoria, Australia
5Cambridge and Peterborough Foundation NHS Foundation Trust, Cambridge, United Kingdom
6Brain Mapping Unit, Department of Psychiatry, and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
7GlaxoSmithKline, Clinical Unit Cambridge, Addenbrooke’s Centre for Clinical Investigation, Cambridge, United Kingdom
8Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
JAMA Psychiatry. 2013;70(11):1143-1151. doi:10.1001/jamapsychiatry.2013.1976.
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Importance  Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious.

Objective  To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives.

Design, Setting, and Participants  This case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study.

Main Outcomes and Measures  Voxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions.

Results  Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms.

Conclusions and Relevance  First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they represent a putative risk phenotype for psychotic illness.

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Figure 1.
Disease-Related Corticostriatal Functional Dysconnectivity

Axial slices showing regions where functional connectivity with the dorsal caudate (DC), superior ventral caudate (sVC), inferior ventral caudate (iVC), dorsocaudal putamen (dcPT), dorsorostral putamen (drPT), and ventrorostral putamen (vrPT) showed significant differences between patients and control subjects (P < .05, clusterwise corrected). The red and yellow regions identify where striatal functional connectivity was reduced in patients; blue regions identify where connectivity was increased in patients. Left-most column depicts the locations of the seed regions. The left hemisphere is on the right.

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Figure 2.
Risk-Related Corticostriatal Functional Dysconnectivity

Representative rendered axial and coronal slices showing regions where both patients and relatives show common alterations of functional connectivity compared with control subjects with seeds placed in the dorsal caudate (DC), dorsocaudal putamen (dcPT), superior ventral caudate (sVC), and ventrorostral putamen (vrPT). Yellow and magenta colors indicate regions where striatal functional connectivity was reduced in patients and relatives compared with control subjects, respectively. Blue and green colors indicate regions where functional connectivity was increased in patients and relatives compared with control subjects, respectively. The left hemisphere is on the right in the axial slices. The left hemisphere is on the left in the coronal representations. The far left column illustrates the locations of seed regions.

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Figure 3.
Correlations Between Positive Symptom Severity in Patients and Functional Connectivity in Risk-Affected Dorsal Frontostriatal Circuitry

A, The location of the dorsal caudate (DC) seed region. B, Prefrontal regions in which individual differences in functional connectivity with the DC were correlated with positive symptom severity. The yellow regions indicate where more severe positive symptoms were associated with reduced striatal functional connectivity. The magenta regions highlight where positive symptom correlations spatially overlapped with regions showing significantly reduced functional connectivity in patients and relatives compared with control subjects. The arrow highlights a prefrontal region where reduced functional connectivity with the DC was also predicted by negative symptom severity. The left hemisphere is on the right. C, Scatterplot of the association between positive symptom scores and average functional connectivity between the DC and all prefrontal regions depicted in part A showing significant voxelwise correlations. In this plot, positive symptom scores were orthogonalized via linear regression, with respect to negative, depressive, and manic symptoms, to depict the specific association between positive symptoms and frontostriatal functional connectivity. Also shown is the Spearman rank correlation coefficient for the association. This correlation remained significant after removal of the potential outlier apparent in the bottom right-hand corner of the graph (P = −.46 and P = .04; see eAppendix in Supplement for further details).

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