Summary: A new study utilized specialized Positron Emission Tomography (PET) imaging to measure synaptic connections in the living human brain. Evaluating one of the largest clinical cohorts of its kind to date, the research team unmasked a prominent, widespread reduction of synaptic density that follows the brain’s molecular blueprint, mapping a distinct structural starting point for how the disease progresses.
Key Facts
- Direct Synaptic Quantification: By shifting away from standard anatomical tissue mapping and employing highly specialized synaptic PET imaging, the researchers directly measured the density of microscopic connections across neural circuits in living human subjects.
- Widespread Structural Loss: Individuals diagnosed with schizophrenia exhibited a pronounced, systemic reduction of synaptic connections. This loss was identified across critical cognitive and emotional hubs, including the frontal cortex, temporal regions, and memory centers.
- The Left Hemisphere Vulnerability: The destruction of synaptic density was not uniformly balanced across the brain. The data revealed that the left hemisphere was substantially more degraded and impacted by synaptic loss than the right hemisphere.
- PET vs. MRI Discordance: The specific pattern of synaptic degradation caught by the PET scans did not overlap with the broad tissue volume alterations typically seen on standard MRI scans. This indicates that synaptic loss and brain tissue shrinkage are two separate, independent biological processes rather than two versions of the same mechanical failure.
- The Neurotransmitter Blueprint: Synaptic drop-offs were most severe in brain zones naturally rich in receptors for three core chemical messengers: serotonin, glutamate, and GABA (gamma-aminobutyric acid). This suggests that a region’s underlying molecular signature dictates its vulnerability to schizophrenia-related damage.
- Locating the Epicenter: Utilizing advanced network computer simulations to trace how synaptic loss propagates through the brain’s structural highways, the team identified a specific launchpad: a localized region within the left frontal lobe emerged as the primary origin point from which connection degradation spreads to neighboring, interconnected circuits.
Source: Rutgers
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,” 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.
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.
Key Questions Answered:
A: Think of an MRI scan like a satellite photograph of a city, it is excellent for mapping out the broad boundaries of neighborhoods, the sizes of parks, and the shrinkage of buildings (tissue volume). However, it cannot see the individual telephone wires running between houses. Synapses are the sub-microscopic connection points where brain cells communicate. Specialized Positron Emission Tomography (PET) imaging utilizes a targeted tracer that physically binds to synaptic proteins, allowing scientists to see and measure the density of these actual “wires” in a living human brain for the first time.
A: This means schizophrenia doesn’t attack the brain like a random explosion; it behaves like a targeted virus that selectively follows specific pre-existing pathways. Dr. Sidhant Chopra discovered that the areas suffering the worst synaptic damage are those that naturally contain high concentrations of receptors for key brain chemicals like serotonin, glutamate, and GABA. The disease exploits this molecular layout, meaning a brain area’s baseline chemistry dictates exactly how vulnerable it is to breaking down.
A: Currently, many psychiatric treatments are reactive, managing widespread emotional and cognitive symptoms after the illness has altered broad regions of the brain. By using computer models to trace the destruction back to a single origin point in the left frontal lobe, researchers can look toward a new era of preventive, proactive medicine. It gives neuroscientists a precise geographic target to deploy emerging, localized therapies designed to protect, regrow, or reinforce fragile synapses before the network damage spreads throughout the rest of the brain.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this schizophrenia research news
Author: Patti Zielinski
Source: Rutgers University
Contact: Patti Zielinski – Rutgers University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Widespread synaptic density loss in schizophrenia follows molecular and network architecture” by Sidhant Chopra, Patrick D. Worhunsky, Mika Naganawa, Xi-Han Zhang, Ashlea Segal, Loïc Labache, Edwina Orchard, Vanessa Cropley, Stephen Wood, Gustavo A. Angarita, Kelly Cosgrove, David Matuskey, Nabeel B. Nabulsi, Yiyun Huang, Richard E. Carson, Irina Esterlis, Patrick D. Skosnik, Deepak C. D’Souza, Avram J. Holmes & Rajiv Radhakrishnan. Molecular Psychiatry
DOI:10.1038/s41380-026-03717-x
Abstract
Widespread synaptic density loss in schizophrenia follows molecular and network architecture
Converging neuroimaging, genetic, and post-mortem evidence highlights the fundamental role of synaptic density reductions in schizophrenia pathogenesis. However, the brain-wide spatial pattern of these alterations and the mechanisms underlying this patterning remain to be established.
Here, using [11C]UCB-J radiotracer positron emission tomography (PET) imaging in individuals with schizophrenia (n = 29) and healthy controls (n = 93), we find a prominent and widespread pattern of lower synaptic density (0.58 < Cohen’s D < 1.47; pFWE < 0.05) in patients.
The left hemisphere is substantially more impacted than the right (Cohen’s D = 1.14; p < 0.001), with frontal, temporal, cingulate, thalamic, striatal and hippocampal areas particularly affected. Synaptic density alterations were not spatially aligned with grey matter volume alterations indexed using anatomical Magnetic Resonance Imaging. Lower synaptic density in the left hemisphere is associated with higher normative concentrations of GABAA/BZ, 5HT2A, mGluR5 and 5HT1B (rcca = 0.68; p = 0.022).
Simulation-based network diffusion models identified regions that may represent the initial sources of pathology, nominating left inferior frontal areas (pFWE < 0.05) as potential foci from which synaptic pathology initiates and then propagates to structurally connected and molecularly similar areas.
Overall, our findings provide in vivo evidence for widespread synaptic density deficits in schizophrenia that are left-lateralised, independent of grey matter volume alterations, aligned to specific neurochemical systems, and suggest that such synaptic pathology may propagate in a pattern consistent with axonal networks.
