Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target
Authors: Andrew R. Pines, Summer B. Frandsen, William Drew, Garance M. Meyer, Calvin Howard, Stephan T. Palm, Frederic L. W. V. J. Schaper, Christopher Lin, Konstantin Butenko, Michael A. Ferguson, Maximilian U. Friedrich, Jordan H. Grafman, Ari D. Kappel, Clemens Neudorfer, Natalia S. Rost, Lauren L. Sanderson, Joseph J. Taylor, Ona Wu, Isaiah Kletenik, Jacob W. Vogel, Alexander L. Cohen, Andreas Horn, Michael D. Fox, David Silbersweig, Shan H. Siddiqi
Journal: JAMA Psychiatry (2025)

Importance Identifying anatomy causally involved in psychosis could inform therapeutic neuromodulation targets for schizophrenia. Objective To assess whether lesions that cause secondary psychosis have functional connections to a common brain circuit. Design, Setting, and Participants This case-control study mapped functional connections of published cases of lesions causing secondary psychosis compared with control lesions unassociated with psychosis. Published cases of lesion-induced psychosis were analyzed in a computational laboratory. Participants had documented brain lesions associated with new-onset psychotic symptoms without a history of psychosis. Control cases included 1156 patients with lesions not associated with psychosis. Generalizability across lesional datasets was assessed using an independent cohort of 181 patients with brain lesions who subsequently underwent neurobehavioral testing. Data were analyzed from June 2022 to April 2024. Exposures Lesions causing secondary psychosis. Main Outcomes and Measures Psychosis or no psychosis. Results A total of 153 lesions from published cases were determined to be causal of psychosis, 42 of which were described as schizophrenia or schizophrenia-like (71 [46%] patients were male, 82 [54%] female; mean [SD] age, 50.0 [20.8] years). Lesions that caused secondary psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus (84% functional overlap, family-wise error [FWE] rate corrected P &amp;amp;lt; 5 × 10 −5 ). At a lower statistical threshold (&amp;amp;gt;75% overlap, FWE-corrected P &amp;amp;lt; 5 × 10 −4 ), this circuit included the ventral tegmental area, retrosplenial cortex, lobule IX and dentate nucleus of the cerebellum, and the mediodorsal and midline nuclei of the thalamus. This circuit was consistent when derived from schizophrenia-like cases (spatial r = 0.98). We repeated these analyses after excluding lesions intersecting the hippocampus (n = 47) and found a consistent functional connectivity profile (spatial r = 0.98) with the posterior subiculum remaining the center of connectivity (&amp;amp;gt;75% overlap, FWE-corrected P &amp;amp;lt; 5 × 10 −5 ), demonstrating a circuit-level effect. In an independent observational cohort of patients with penetrating head trauma (n = 181), lesions associated with symptoms of psychosis exhibited significantly similar connectivity profiles to the lesion-derived psychosis circuit (suspiciousness, P = .03; unusual thought content, P = .046). Voxels in the rostromedial prefrontal cortex are highly correlated with this psychosis circuit (spatial r = 0.82), suggesting the rostromedial prefrontal cortex as a promising transcranial magnetic stimulation target for psychosis. Conclusions and Relevance Lesions that cause secondary psychosis affect a common brain circuit in the hippocampus. These results can help inform therapeutic neuromodulation targeting.