Mapping Lesions that Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target
Authors: Pines Andrew R. , Frandsen Summer B. , Drew William , Meyer Garance M. , Howard Calvin , Palm Stephan T. , Schaper Frederic L.W.V.J. , Lin Christopher , Butenko Konstantin , Ferguson Michael A. , Friedrich Maximilian U. , Grafman Jordan H. , Kappel Ari D. , Neudorfer Clemens , Rost Natalia S. , Sanderson Lauren L. , Taylor Joseph J. , Wu Ona , Kletenik Isaiah , Vogel Jacob W. , Cohen Alexander L. , Horn Andreas , Fox Michael D. , Silbersweig David , Siddiqi Shan H. 
Published: April 2024

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

This case-control study mapped functional connections of published cases of lesions causing secondary psychosis compared with control lesions unassociated with psychosis.

Setting

This study was conducted in a computational laboratory.

Participants

Published cases of lesion-induced psychosis were analyzed. Included subjects had documented brain lesions associated with new-onset psychotic symptoms without prior 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.

Exposures

Lesions causing secondary psychosis.

Main Outcomes and Measures

Psychosis or no psychosis.

Results

153 lesions from published cases were determined to be causal of psychosis (65 [42%] male; mean [SD] age, 50.0 [20.8] years), 42 of which were described as “schizophrenia” or “schizophrenia-like”. 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, pFWE<5 x 10-5). At a lower statistical threshold (75%> overlap, pFWE<5 x 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 (>75% overlap, pFWE<5x10-5), 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=0.025; unusual thought content, p=0.046). Voxels in the rostromedial prefrontal cortex (rmPFC) are highly correlated with this psychosis circuit (spatial r=0.82), suggesting the rmPFC as a promising TMS 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.

Key Points

Question

Do lesions that cause psychosis affect a common brain circuit?

Findings

This case-control study found that lesions causing psychosis specifically affected a common functional circuit aligning with the posterior subiculum of the hippocampus. This functional circuit was consistent across different psychotic symptoms, suggesting a shared neural substrate for psychosis. A similar circuit was derived when excluding lesions directly intersecting the hippocampus, indicating a circuit-level effect.

Meaning

Identifying a common brain circuit causally involved in psychotic symptoms suggests that the hippocampus may be pivotal in the pathophysiology and treatment targeting of psychotic disorders.