Background Converging evidence from clinical neuroimaging and animal models has strongly implicated dysfunction of thalamocortical circuits in the pathophysiology of schizophrenia. Preclinical models of genetic risk for schizophrenia have shown reduced synaptic transmission from auditory thalamus to primary auditory cortex, which may represent a correlate of auditory disturbances such as hallucinations. Human neuroimaging studies, however, have found a generalized increase in resting state functional connectivity (RSFC) between whole thalamus and sensorimotor cortex in people with schizophrenia (PSZ). We aimed to more directly translate preclinical findings by specifically localizing auditory and visual thalamic nuclei in unmedicated PSZ and measuring RSFC to primary sensory cortices. Methods In this case-control study, 82 unmedicated PSZ and 55 matched healthy controls (HC) completed RSFC functional magnetic resonance imaging (fMRI). Auditory and visual thalamic nuclei were localized for 55 unmedicated PSZ and 46 HC who additionally completed a sensory thalamic nuclei localizer fMRI task (N = 101). Using localized nuclei as RSFC seeds we assessed group differences in auditory and visual thalamocortical connectivity and associations with positive symptom severity. Results Auditory thalamocortical connectivity was not significantly different between PSZ and HC, but hyperconnectivity was associated with greater positive symptom severity in bilateral superior temporal gyrus. Visual thalamocortical connectivity was significantly greater in PSZ relative to HC in secondary and higher-order visual cortex, but not predictive of positive symptom severity. Conclusion These results indicate that visual thalamocortical hyperconnectivity is a generalized marker of schizophrenia, while hyperconnectivity in auditory thalamocortical circuits relates more specifically to positive symptom severity.

Mark Slifstein reports having served as a paid consultant for Neurocrine Biosciences, Inc. and for Yale University. Anissa Abi-Dargham received consulting fees from Neurocrine Biosciences, Inc., from Abbvie, Inc., and from MapLight Therapeutics, Inc. Anissa Abi-Dargham holds stock options in Herophilus, Inc. and in Terran Biosciences, Inc. All other authors declare that they have no known competing financial interests or personal relationships that could have influenced or appear to have influenced the work reported in this manuscript.

Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health (NIH) under award numbers K01MH107763 to J.X.V.S., K23MH101637 to G.H., R01MH109635 to A.A-D., F30MH122136 to J.C.W, and K23MH115291 to J.J.W. J.C.W. was also supported by a Research Supplement to Promote Diversity in Health-Related Research (3R01MH120293-04S1) and by the Stony Brook University Medical Scientist Training Program (Award No. T32GM008444; Principal Investigator: Dr. Michael A. Frohman). P.N.T. was supported by a Stony Brook University Department of Biomedical Engineering Graduate Assistance in Areas of National Need Fellowship (United States Department of Education Award No. P200A210006; Director: Dr. David Rubenstein) and the Stony Brook University Scholars in Biomedical Sciences Program (NIH Award No. T32GM148331; PI: Dr. Styliani-Anna [Stella] E. Tsirka). The Stony Brook high-performance SeaWulf computing system was supported by National Science Foundation (NSF) Award Nos. 1531492 (PI: Dr. Robert Harrison; co-PI: Dr. Yuefan Deng) and 2215987 (PI: Dr. Robert Harrison; co-PIs: Dr. Yuefan Deng, Dr. Eva Siegmann, and David Cyrille), and matching funds from the Empire State Development Division of Science, Technology and Innovation (NYSTAR) program contract C210148. The Stony Brook University Social, Cognitive, and Affective Neuroscience (SCAN) Center was supported by NSF Award No. 0722874 (PI: Dr. Turhan Canli). This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NSF, or NYSTAR.

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The Institutional Review Board of Stony Brook University gave ethical approval for this work. The Institutional Review Board of the New York State Psychiatric Institute gave ethical approval for this work.

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The sensory Thalamic Localizer task Presentation code is available from GitHub at https://github.com/CNaP-Lab/Sensory-Thalamic-Localizer, as well as the Neurobehavioral Systems Archives of Neurobehavioral Experiments and Stimuli at http://www.neurobs.com/ex_files/expt_view?id=302. The MATLAB task analysis code for producing MGN and LGN fROIs from BOLD fMRI Thalamic Localizer task data and Presentation task logs is available from GitHub at https://github.com/CNaP-Lab/Sensory-Thalamic-Localizer. All software associated with this manuscript is released under the GNU General Public License version 3. Data acquired from human participants used in the analyses detailed in this manuscript are available upon request from the corresponding author through a formal data sharing agreement.

https://github.com/CNaP-Lab/Sensory-Thalamic-Localizer

http://www.neurobs.com/ex_files/expt_view?id=302