Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk.
OBJECTIVE
Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness.


OBJECTIVE
To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity.


METHODS
In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012.


METHODS
Whole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging.


RESULTS
Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10(-8), Spearman ρ = 0.27, P < 4.75 × 10(-5), 2-tailed).


CONCLUSIONS
Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut2National Institute of Alcohol Abuse and Alcoholism Center for the Translational Neuroscience of Alcoholism, New Haven, Connecticut3Abraham Ribicoff Research Facilities, C.
Alan
A
Anticevic
Department of Psychology, Yale University, New Haven, Connecticut.
Kristen
K
Haut
Center for Neural Science, New York University, New York.
John D
JD
Murray
Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
Grega
G
Repovs
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut3Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven5Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut.
Genevieve J
GJ
Yang
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut4Department of Psychology, Yale University, New Haven, Connecticut.
Caroline
C
Diehl
Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles.
Sarah C
SC
McEwen
Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles.
Carrie E
CE
Bearden
Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Jean
J
Addington
Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.
Bradley
B
Goodyear
Department of Psychiatry, University of California, San Diego, La Jolla.
Kristin S
KS
Cadenhead
Department of Psychiatry, University of California, San Diego, La Jolla.
Heline
H
Mirzakhanian
Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York.
Barbara A
BA
Cornblatt
Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York.
Doreen
D
Olvet
Department of Psychiatry, University of California, San Francisco.
Daniel H
DH
Mathalon
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Thomas H
TH
McGlashan
Department of Psychiatry, University of North Carolina, Chapel Hill.
Diana O
DO
Perkins
Department of Psychiatry, University of North Carolina, Chapel Hill.
Aysenil
A
Belger
Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts15Massachusetts General Hospital, Boston16Department of Psychiatry, Harvard Medical School, and Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel.
Larry J
LJ
Seidman
Department of Psychiatry, University of California, San Diego, La Jolla.
Ming T
MT
Tsuang
Department of Psychiatry and Human Behavior, University of California, Irvine.
Theo G M
TG
van Erp
Departments of Psychology and Radiology, Emory University, Atlanta, Georgia.
Elaine F
EF
Walker
Departments of Psychology and Radiology, Emory University, Atlanta, Georgia.
Stephan
S
Hamann
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
Scott W
SW
Woods
Department of Diagnostic Radiology and Magnetic Resonance Research Center, Yale University, New Haven, Connecticut.
Maolin
M
Qiu
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut4Department of Psychology, Yale University, New Haven, Connecticut.
Tyrone D
TD
Cannon
D000293:Adolescent; D000328:Adult; D001931:Brain Mapping; D016022:Case-Control Studies; D002531:Cerebellum / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology*; D002648:Child; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D062706:Prodromal Symptoms; D011618:Psychotic Disorders / Q000503:physiopathology*; D012306:Risk; D012559:Schizophrenia / Q000503:physiopathology*; D013788:Thalamus / Q000503:physiopathology*; D055815:Young Adult