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Cereb Cortex. 2019 Jun 3. pii: bhy306. doi: 10.1093/cercor/bhy306. [Epub ahead of print]

Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits.

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Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT, USA.
Department of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA.
Department of Psychology, BioImaging Research Center, University of Georgia, Athens, GA, USA.
Department of Neuroscience, BioImaging Research Center, University of Georgia, Athens, GA, USA.
Department of Psychology, Rosalind Franklin University of Medicine and Science, Chicago, IL, USA.
Department of Psychology, University of Ljubljana, Ljubljana, Slovenia.
Nuffield Department of Clinical Neurosciences, Oxford University, John Radcliffe Hospital, Oxford University, Headington, Oxford, UK.


Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), 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 SCZ. 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 SCZ, calling into question accounts of exclusively focal functional disturbances.


CSTC circuits; connectivity; fMRI; machine learning; resting-state


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