Schizophrenia’s lost brain connections follow a surprising pattern

Schizophrenia may erode the brain’s connections in a surprisingly organized pattern—one that researchers can now begin to trace back to where it may start.

Researchers, including a Rutgers professor, have gained a clearer view of the biological changes associated with schizophrenia by directly measuring synaptic connections in the living human brain. The team used specialized positron emission tomography (PET) imaging to examine these crucial points of communication between brain cells.

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.

Measuring the Brain's Synaptic Connections

Synapses are tiny junctions that allow brain cells to communicate with one another across neural circuits. Problems involving these connections are believed to play a role in the cognitive and emotional symptoms of schizophrenia. Until now, however, scientists have had a limited understanding of exactly where synaptic loss occurs in the brains of living people because conventional imaging methods such as magnetic resonance imaging cannot specifically measure synapses.

The research involved 122 people, including 29 diagnosed with schizophrenia, making it one of the largest synaptic density PET imaging studies conducted so far. Compared with healthy participants, people with schizophrenia showed a pronounced and widespread reduction in synaptic connections across several parts of the brain. These included frontal and temporal regions as well as areas involved in memory and emotion. The loss was also considerably greater on the left side of the brain than on the right.

Researchers found that this synaptic pattern did not match the changes in brain volume typically seen with standard MRI scans. That distinction suggests synaptic loss and changes in brain volume may reflect separate biological processes rather than two imaging methods capturing the same underlying change.

A Molecular Pattern Behind Synaptic Loss

The team also discovered that the brain regions showing the greatest synaptic losses tended to contain high concentrations of receptors for important neurotransmitters, including serotonin, gamma-aminobutyric acid and glutamate. The finding suggests that the molecular characteristics of individual brain regions may influence how vulnerable they are to changes associated with schizophrenia.

To explore how synaptic loss might move through the brain, the researchers used computer simulations based on the brain's structural connections. Their modeling identified an area in the left frontal lobe as a likely starting point from which synaptic loss could spread into connected regions.

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

"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.

Toward More Precise Schizophrenia Treatments

The researchers said future work will build on these results by investigating how synaptic loss changes over time and how it responds to clinical treatments. A better understanding of that progression could ultimately help researchers develop more precise and personalized approaches to schizophrenia care.