Andrew Pines, MD, MA, a resident in the Department of Psychiatry at Brigham and Women's Hospital and a researcher in the Center for Brain Circuit Therapeutics , is the lead author of a paper published in JAMA Psychiatry, Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target.
Shan Siddiqi, MD, Assistant Professor of Psychiatry at Harvard Medical School and Director of Psychiatric Neuromodulation Research at the BWH Center for Brain Circuit Therapeutics, is the senior author of this paper.
How would you summarize your study for a lay audience?
Our study investigated the brain circuits involved in psychosis—a condition characterized by delusions, hallucinations, disorganized thinking and detachment from reality. Psychosis is the classic symptom of schizophrenia, a serious mental illness that causes marked disability in otherwise young and healthy patients. We analyzed published cases in which focal brain damage caused psychosis, with the idea that if damaging a brain circuit causes a symptom, then mapping that circuit might tell us about how to treat that symptom.
We discovered that these psychosis-inducing lesions, although located in different parts of the brain, all connected to a common brain circuit. The peak in that circuit was in a brain region called the hippocampus, which is believed to be involved in constructing memory and reality.
This finding suggests that this hippocampal circuit plays a crucial role in causing psychotic symptoms, which could help guide new treatments for conditions like schizophrenia.
What question were you investigating?
Can we localize a circuit in the brain that can be targeted with brain stimulation therapy for schizophrenia? Our group has previously shown that analyzing lesions can identify these targets.
In other words, if damaging a brain circuit causes a symptom, then stimulating the same circuit can relieve the same symptom. Here, we sought to determine if the brain lesions that cause psychosis, despite occurring in different parts of the brain, affect a common circuit.
What methods or approach did you use?
We identified 153 published cases where patients with no prior history of psychotic symptoms developed acute psychosis following a brain lesion. We manually traced each patient's lesion onto a standard atlas, enabling us to compare them. Then, we mapped the circuits connected to each lesion using the human connectome, a large-scale wiring diagram of the human brain. We then identified which connections were common to lesions that cause psychosis, and distinct from lesions that cause other symptoms. We also validated our results with an independent brain lesion dataset of 181 patients.
What did you find?
We discovered that lesions causing psychosis, regardless of their location in the brain, were functionally connected to a common brain circuit centered in the hippocampus. The most specific region was the posterior aspect of a subfield of the hippocampus called the subiculum.
This finding held true even when we excluded lesions that directly touched the hippocampus, suggesting the symptoms were caused by the disruption of a brain circuit instead of a specific brain region.
An area in the rostromedial prefrontal cortex is highly correlated with this circuit and is a promising target to modulate this circuit with transcranial magnetic stimulation (TMS), a treatment that is highly effective for major depression but has shown mixed success for schizophrenia, potentially because previous trials did not know which circuit to target.
What are the implications?
For decades, studies have implicated the hippocampus in schizophrenia, but it was unclear if this was a cause of the disease, a compensatory process, or an incidental consequence of some other part of the disease process. Our study provides the first systematic evidence for a common brain circuit causally involved in psychosis.
This has important implications for understanding how psychosis develops, as we consider how the disruption of a circuit known to be involved in memory can result in psychotic symptoms.
More importantly, the identification of this circuit provides a promising TMS target. TMS has been shown to be safe with few side effects in patients with schizophrenia, a disorder whose current treatments involve medications that often incompletely resolve symptoms or have intolerable side effects.
What are the next steps?
The next step is to test whether targeting the identified brain circuit through the rostromedial prefrontal cortex can improve symptoms in patients with psychosis. We are now launching a clinical trial to test this target in patients with schizophrenia. For more details about the trial, please visit http://siddiqi.bwh.harvard.edu/clinical-trials/
Authorship: In addition to Pines and Siddiqi, Mass General Brigham authors include: Garance M. Meyer, Calvin Howard, Frederic L.W.V.J. Schaper, Michael A. Ferguson, Ari D. Kappel, Clemens Neudorfer, Natalia S. Rost, Lauren L. Sanderson, Joseph J. Taylor, Ona Wu, Isaiah Kletenik, Andreas Horn, Michael D. Fox, and David Silbersweig. Other authors include: Summer B. Frandsen, William Drew, Stephan T. Palm, Christopher Lin, Konstantin Butenko, Maximilian U. Friedrich, Jordan H. Grafman, Jacob W. Vogel, and Alexander L. Cohen.
Paper cited: Pines A R et al "Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target" JAMA Psychiatry doi:10.1001/jamapsychiatry.2024.4534
Funding: There was no funding for this study, and no funding entity or sponsor had a role in the no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication
Disclosures: MDF has served as a scientific consultant for Magnus Medical and is owner of intellectual property involving the use of functional connectivity to target TMS, which was not used in the present study. SS is an owner of intellectual property involving the use of brain connectivity to target TMS; has served as a scientific consultant for Magnus Medical; has received investigator-initiated research funding from Neuronetics and Brainsway; has received speaking fees from Brainsway and Otsuka (for PsychU.org); and is a shareholder in Brainsway (publicly traded) and Magnus Medical (not publicly traded). All other authors declare they have no competing interests. ARP had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
