RT Journal Article SR Electronic T1 Schizophrenia Exhibits Bi-Directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits JF bioRxiv FD Cold Spring Harbor Laboratory SP 166728 DO 10.1101/166728 A1 Jie Lisa Ji A1 Caroline Diehl A1 Charles Schleifer A1 Carol A. Tamminga A1 Matcheri S. Keshavan A1 John A. Sweeney A1 Brett A. Clementz A1 S. Kristian Hill A1 Godfrey Pearlson A1 Genevieve Yang A1 Gina Creatura A1 John H. Krystal A1 Grega Repovs A1 John Murray A1 Anderson Winkler A1 Alan Anticevic YR 2018 UL http://biorxiv.org/content/early/2018/03/06/166728.abstract AB Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia, yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in schizophrenia. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in schizophrenia, calling into question accounts of exclusively focal functional disturbances.