Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 1;82(4):368-378.
doi: 10.1001/jamapsychiatry.2024.4534.

Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target

Andrew R Pines  1   2 , Summer B Frandsen  2 , William Drew  2 , Garance M Meyer  2   3 , Calvin Howard  2   3 , Stephan T Palm  2 , Frederic L W V J Schaper  2   3 , Christopher Lin  2 , Konstantin Butenko  2 , Michael A Ferguson  2   3 , Maximilian U Friedrich  2 , Jordan H Grafman  4   5 , Ari D Kappel  2   6 , Clemens Neudorfer  2   7   8 , Natalia S Rost  9 , Lauren L Sanderson  2 , Joseph J Taylor  1   2 , Ona Wu  10 , Isaiah Kletenik  2   3 , Jacob W Vogel  11 , Alexander L Cohen  2   12   13 , Andreas Horn  2   3 , Michael D Fox  2   3 , David Silbersweig  1   2   3 , Shan H Siddiqi  1   2
Affiliations

Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target

Andrew R Pines et al. JAMA Psychiatry. .

Abstract

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 < 5 × 10-5). At a lower statistical threshold (>75% overlap, FWE-corrected P < 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 (>75% overlap, FWE-corrected P < 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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fox reported serving as a scientific consultant for Magnus Medical and owning intellectual property involving the use of functional connectivity to target transcranial magnetic stimulation (TMS) outside the submitted work. Dr Siddiqi reported owning intellectual property involving the use of brain connectivity to target TMS, having served as a scientific consultant for Magnus Medical, investigator-initiated research funding from Neuronetics and Brainsway, speaking fees from Brainsway and Otsuka (for PsychU.org), and being a shareholder in Brainsway (publicly traded) and Magnus Medical (not publicly traded). No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Lesions That Cause Psychosis Mapped to a Common Circuit of Functional Connectivity
A, Each lesion traced manually onto a standard brain atlas. B, Normative connectivity of each lesion was determined using a normative connectome database (n = 1000). C, Sensitivity analysis showing the overlap of functional connectivity of more than 75% of lesions, thresholded at t > 7. D, Specificity analysis showing the results of a 2-sample t test (P for family-wise error <5 × 10-5) comparing functional connectivity of lesions that cause psychosis and control lesions. E, Convergence map depicting the posterior subiculum as the most sensitive and specific region affected by lesions that cause psychosis. Subiculum is defined by the CoBrALab Merged Atlas.
Figure 2.
Figure 2.. Functional Connections of Lesions That Cause Different Symptoms of Psychosis and Correlation Values
Functional connections of lesions that cause different symptoms of psychosis share a common functional connection to the posterior subiculum of the hippocampus, and are more correlated with each other. A, Each grouping of psychotic symptoms had peak sensitivity (overlap >75%) and specificity (P for family-wise error<5 × 10-4) in the posterior subiculum of the hippocampus (outlined in white). No individual voxels from the negative symptoms subgroup remained significant after correcting for multiple comparisons. B, Spatial correlation values between the psychosis circuit and each symptom group. When correlating between the psychosis circuit and each psychotic symptom group, lesions from the psychotic group being examined were excluded from the psychosis circuit they were being correlated with.
Figure 3.
Figure 3.. Different Symptoms of Psychosis Mapped to Common Circuitry
A, Representative example of functional connectivity of a lesion causing a psychotic symptom. B, Connectivity maps of each symptom group were correlated with a map of mean connectivity of lesions that cause psychosis without the symptom being tested and mean connectivity of control lesions. C, Distribution of correlations of each lesion to each of the two comparator groups. D, For each group of psychotic symptoms, lesion connectivity was more similar to other psychotic symptoms than to control symptoms.
Figure 4.
Figure 4.. Correlation Values Between Functional Maps of Lesions Causing Psychosis and Lesions Causing Specific Symptoms From an Independent Cohort
Functional connectivity maps specific to suspiciousness and unusual thought content are shown to illustrate similarity to the psychosis circuit.
Figure 5.
Figure 5.. Therapeutic Transcranial Magnetic Stimulation (TMS) Target Identified by Correlation With Each Voxel’s Intrinsic Functional Connectivity
A, Blood oxygen level–dependent (BOLD) correlations for each voxel in a 2-mm brain template. B, Correlated with unthresholded BOLD correlation for the 2-sample t test between lesions causing psychosis and controls. C, Identification of voxels with the strongest correlation between intrinsic resting-state BOLD signal and BOLD signal specific to lesions that cause psychosis. D, A simulated electric field measured in volts per meter overlaps peak nodal connectivity within the psychosis circuit, indicating that the psychosis circuit is sufficiently superficial to be targeted with TMS. E, Peak nodal connectivity of the psychosis circuit, identical to panel C, shown on a 3-dimensional (3-D) model., F, Placement of the TMS coil, halfway between Afz and Fpz. G, Magnetic field generated by the TMS coil in the position overlapping peak nodal connectivity within the psychosis circuit, identical to panel D, shown on a 3-D model.
See this image and copyright information in PMC

Comment in

References

    1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators . Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. doi: 10.1016/S0140-6736(18)32279-7 - DOI - PMC - PubMed
    1. Lieberman JA, Stroup TS, McEvoy JP, et al. ; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. doi: 10.1056/NEJMoa051688 - DOI - PubMed
    1. Jääskeläinen E, Juola P, Hirvonen N, et al. A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull. 2013;39(6):1296-1306. doi: 10.1093/schbul/sbs130 - DOI - PMC - PubMed
    1. Fox MD, Buckner RL, Liu H, Chakravarty MM, Lozano AM, Pascual-Leone A. Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proc Natl Acad Sci U S A. 2014;111(41):E4367-E4375. doi: 10.1073/pnas.1405003111 - DOI - PMC - PubMed
    1. Baker JT, Holmes AJ, Masters GA, et al. Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry. 2014;71(2):109-118. doi: 10.1001/jamapsychiatry.2013.3469 - DOI - PMC - PubMed