Brain Lesions Linked to Psychosis Map to Hippocampal Circuit, Suggesting New Target

Brain lesions associated with secondary psychosis map to a distinct functional circuit centered in the hippocampus, according to study findings published in JAMA Psychiatry. These findings suggest this circuit may serve as a potential therapeutic target for neuromodulation in psychotic disorders.

Researchers conducted a case-control study to determine whether lesions leading to secondary psychosis share common functional connectivity. The study analyzed data from 153 published cases of lesion-induced psychosis, including 42 cases classified as schizophrenia-like, and compared them to a control cohort of 1156 individuals with brain lesions not linked to psychosis. To assess generalizability, researchers validated their findings using an independent dataset of 181 individuals with penetrating brain injuries who later underwent neurobehavioral assessments.

Participants included individuals with documented brain lesions leading to new-onset psychotic symptoms, such as delusions, hallucinations, or disorganized thought, without a prior history of psychosis. The control group consisted of individuals with brain lesions that were not associated with psychotic symptoms.

The primary outcome was the presence or absence of psychosis, with a focus on identifying common functional connectivity patterns among lesion locations. Researchers used lesion network mapping, a technique that correlates lesion locations with a normative brain connectivity dataset, to identify overlapping circuits affected by psychosis-inducing lesions.

The mean (SD) age of individuals with psychosis-inducing lesions was 50 (20.8) years, with a nearly equal sex distribution (54% women). The symptoms observed in the included cases were visual hallucinations (83 cases), auditory hallucinations (81), delusions (67), thought disorder (25), and negative symptoms (13).

Lesions linked to secondary psychosis exhibited an 84% overlap in functional connectivity to the posterior subiculum of the hippocampus (family-wise error [FWE]-corrected P<5 × 10⁻⁵), indicating a shared neural network. At a lower statistical threshold (>75% overlap, FWE-corrected P<5 × 10⁻⁴), this psychosis-associated circuit extended to the ventral tegmental area, retrosplenial cortex, cerebellar lobule IX, dentate nucleus, and the mediodorsal and midline nuclei of the thalamus.

Further analyses demonstrated that this circuit remained consistent even when excluding lesions directly intersecting the hippocampus (spatial correlation r=0.98), suggesting a circuit-wide effect rather than an isolated hippocampal dysfunction.

In the independent validation cohort (n=181), lesions linked to psychotic-like symptoms, including suspiciousness (P=.03) and unusual thought content (P=.046), showed significant connectivity with the lesion-derived psychosis circuit.

A voxel-wise analysis revealed a strong correlation (spatial r=0.82) between the rostromedial prefrontal cortex (rmPFC) and the psychosis circuit, highlighting the rmPFC as a compelling target for transcranial magnetic stimulation.

“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,” the researchers concluded.

The study is limited by potential selection bias from lesion case reports, variability in imaging protocols, and a lack of insight into the neurochemical or developmental mechanisms of psychosis.

Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

This article originally appeared on Psychiatry Advisor