A new study led by investigators from Mass General Brigham has identified a unique brain network that links varied patterns of brain atrophy, or shrinkage, associated with schizophrenia. By combining neuroimaging data from multiple studies involving more than 8,000 participants, the research team found a specific connectivity pattern of atrophy that was present across different stages and symptoms of schizophrenia — and distinct from brain networks associated with other psychiatric disorders. The findings will help to guide a clinical trial that will start recruiting patients soon and will assess brain stimulation sites connected to the schizophrenia network. Results are published in Nature Mental Health.
“We looked for common threads among reports on how schizophrenia affects the brain,” said corresponding author Ahmed T. Makhlouf, MD, of the Center for Brain Circuit Therapeutics and medical director of the Brigham and Women’s Hospital Psychosis Program. “We found that there's atrophy in places all over the brain, but they're all connected to a single network.”
Despite large-scale efforts to resolve the neuroanatomy of schizophrenia, varied results and methodological differences have limited experts’ understanding of circuits linked to brain atrophy.
“One explanation could be that everyone’s actually looking at the same thing from a different vantage point. If multiple people try to feel different parts of an elephant with their eyes closed, they’re going to describe different things,” said senior author Shan H. Siddiqi, MD, a psychiatrist at the Brigham’s Center for Brain Circuit Therapeutics. “Our approach with this study was to try to reconstruct the elephant.”
The research examined data from 90 studies involving atrophy in schizophrenia. The dataset included ??1,636 patients with recently diagnosed schizophrenia, 2,120 individuals with chronic disease and just over 6,000 healthy people. The study also examined results from 927 individuals and 580 individuals with genetic or clinical (based on early symptoms) high risk of developing schizophrenia, respectively.
First, the investigators constructed a common brain map combining the widespread locations of atrophy in schizophrenia. Then, they used a technique known as coordinate network mapping (CNM) to estimate the overlap between atrophy locations and functional brain networks. The resulting atrophy connectivity map overlapped with schizophrenia-associated brain regions, including the bilateral insula, hippocampus and fusiform cortex. Finally, the researchers showed that these maps differed from brain connectivity maps developed for aging patients or those with conditions like Alzheimer’s disease, major depressive disorder or substance use disorders — indicating the network was specific to schizophrenia.
The researchers found that the network was similar across patients with contrasting symptoms or at different stages of schizophrenia and did not significantly change with antipsychotic treatments. Patients at high risk of developing schizophrenia shared similarities in atrophy, but there was a unique connectivity pattern in patients who had progressed to clinical disease. The authors suggest that further understanding of atrophy patterns in high-risk individuals could help predict likelihood of developing schizophrenia. The researchers note that future studies with patient-specific connectomes could provide individualized insights. They also note that a clinical trial is planned that will use transcranial magnetic stimulation to assess connectivity of stimulation sites to the identified schizophrenia network.
“There is a debate in the field as to whether or not schizophrenia is a neurodegenerative disorder,” said Makhlouf. “Our study indicates that there is a unique and unified network that might be a core characteristic of schizophrenia.”
Authorship: In addition to Makhlouf and Siddiqi, Mass General Brigham authors include William Drew, Jacob L. Stubbs, Joseph J. Taylor, David Silbersweig, Michael D. Fox. Additional authors include Donato Liloia and Jordan Grafman.
Disclosures: Siddiqi holds intellectual property related to using individualized resting-state network mapping for targeting TMS, filed in 2016, which has not generated royalties and is unrelated to this work. Siddiqi also serves as a scientific consultant for Magnus Medical, has received investigator-initiated research funding from Neuronetics (2019) and Brainsway (2022), received speaking fees from Brainsway (2021) and Otsuka (for PsychU.org, 2021), and holds shares in Brainsway (publicly traded) and Magnus Medical (privately held). Fox is a scientific consultant for Magnus Medical and owns separate intellectual property related to using functional connectivity to target TMS for depression, filed in 2013, which has not generated royalties and is unrelated to this work.
Funding: Harvard Medical School (Dupont Warren Fellowship Award, Livingston Award), the NIH (grant no. R01MH113929, K23MH129829, R01MH113929, R21MH126271, R56AG069086, R01MH115949, R01AG060987, K23MH121657, R21MH126271, R01MH136248), Canadian Institutes of Health Research Vanier Scholarship and a University of British Columbia Friedman Award for Scholars in Health, Brain and Behavior Research Foundation Young Investigator Grant (no. 31081), Sidney R. Baer, Jr. Foundation, Baszucki Brain Research Fund, the Nancy Lurie Marks Foundation, the Kaye Family Research Endowment, the Baszucki Brain Research Fund, the Brain and Behavior Research Foundation Young Investigator Grant, and the Baszucki Brain Research Fund and the Department of Veterans Affairs (grant no.I01CX002293).
Paper cited: Makhlouf AT et al. “Heterogeneous Patterns of Brain Atrophy in Schizophrenia Localize to A Common Brain Network” Nature Mental Health DOI: 10.1038/s44220-024-00348-5
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