Rutgers study maps distinct patterns of brain connection loss in schizophrenia

Research involving a Rutgers professor sheds new light on the biological basis of schizophrenia by directly measuring synaptic connections in the human brain using specialized positron emission tomography (PET) imaging.

The study, published in Molecular Psychiatry, was led by senior authors Avram Holmes, associate professor of psychiatry at Robert Wood Johnson Medical School and core faculty member of the Center for Advanced Human Brain Imaging Research within the Rutgers Brain Health Institute, and Rajiv Radhakrishnan, associate professor of psychiatry and radiology and biomedical imaging at Yale University. First author Sidhant Chopra, formerly a postdoctoral fellow in the Holmes Lab, is a McKenzie Research Fellow at Orygen, Australia's Centre of Excellence in Youth Mental Health, and the University of Melbourne in Australia.

Synapses are the tiny connection points between brain cells that support communication across neural circuits. Disruptions to these connections are thought to contribute to the cognitive and emotional symptoms of schizophrenia, but detailed patterns of synaptic loss in living human brains have remained poorly understood as conventional brain scans such as magnetic resonance imaging aren't able to specifically measure synapses.

The study included a total of 122 individuals, including 29 individuals diagnosed with schizophrenia, and is one of the largest synaptic density PET imaging studies done to date. Researchers found that compared to healthy individuals, people with schizophrenia showed a prominent, widespread, lowering of synaptic connections across multiple brain regions, including frontal, temporal, memory and emotion-related areas. The left side of the brain was substantially more affected than the right.

This pattern of synaptic loss was distinct from the brain volume alterations commonly detected by standard MRI scans, suggesting these are two separate biological processes rather than the same problem measured in two ways.

The researchers also found that brain regions with the greatest synaptic loss were those normally rich in receptors for key neurotransmitters, including serotonin, gamma-aminobutyric acid and glutamate. This suggests the brain's molecular profile makes certain areas more vulnerable to damage in schizophrenia.

Using computer simulations of how synaptic loss spreads through the brain's structural network, the researchers identified a region in the left frontal lobe as a likely starting point from which synaptic loss may spread to connected brain regions.

These findings suggest that in schizophrenia, synaptic loss is not random. Rather, it follows the brain's molecular and connectivity architecture, which could eventually help identify where and how to intervene."

Sidhant Chopra, first author

 "This detailed mapping of synaptic vulnerability could eventually help identify where and how to intervene to preserve or restore brain function, such as emerging therapies to prevent and regrow synapses," Holmes added.

The researchers said future studies would build on these findings to further characterize how synaptic loss progresses over time and how it may respond to clinical interventions, to develop more precise and personalized approaches to care.