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Importantly the researchers were able to distinguish brain changes associated with disease from those linked to the use of antipsychotic medication. Credit: Neuroscience News

Mapping Psychosis Reveals The Brain’s Epicentre of Schizophrenia

Summary: Researchers charted the brain’s response to psychosis, specifically how it spreads, revealing potential therapeutic targets. Their study, which examined 534 individuals across various stages of psychosis, identified the hippocampus as an initial site of change.

Utilizing MRI technology, the team observed that grey matter changes due to psychosis aren’t random but follow structural connections, similar to neurodegenerative diseases. Their findings could pave the way for targeted treatments that could minimize the disease’s progression.

Key Facts:

  1. The study pinpointed the hippocampus, vital for memory, as an early site for brain alterations in psychosis.
  2. The progression of psychosis, characterized by grey matter changes, seems to originate in the hippocampus, spreading through the brain’s axonal connections.
  3. The research method was able to separate brain changes due to antipsychotic medication from those directly resulting from the illness itself.

Source: Monash University

Psychoses like schizophrenia cost billions of dollars annually and derail the lives of people struggling with the disease.

Now Monash University researchers have modelled how the effects of psychosis spread through the brain, allowing them to isolate areas where these changes may originate from and which could be targeted by therapies designed to reduce the disease’s progression.

The study, published today in the prestigious Journal of the American Medical Association Psychiatry, details how the scientists were able to map and model the spread of brain changes in people with different stages of psychoses such as schizophrenia,from people newly diagnosed to those who have experienced psychosis for years.

The study, led by  Dr Sid Chopra , from the Turner Institute for Brain and Mental Health and Monash University’s School of Psychological Sciences,  identified the hippocampus, which is important for memory, as a possible  early site of brain changes in psychosis. “This finding could potentially guide  therapies that can target this area of the brain, potentially limiting the impact of the illness or perhaps even reducing the risk of psychosis onset,” he said

The study looked at 534 individuals from four groups, spanning early and late stages of psychotic illness. The researchers used MRI to examine changes in grey matter that occur at the different illness stages

They found that the evolution of psychoses, as measured by changes in great matter, may originate in the hippocampus and gradually  spread  across the brain, over time, via the nerve or axonal connections.

According to Dr Chopra, “we found that the pattern of grey matter change seen in psychosis is not randomly distributed across the brain, but is shaped by a complex network of structural connections – in a very similar way to how we see the progression of neurodegenerative diseases in the brain.”

The researchers used a mathematical model to predict  grey matter volume changes  in four different groups of people with schizophrenia, scanned at both early and late stages of illness.

According to Professor Alex Fornito, who led the research team, “we found consistent evidence that the hippocampus, an area important for memory and which is known to play an important role in schizophrenia, is a candidate epicentre of brain changes in the illness,” he said.

Importantly the researchers were able to distinguish brain changes associated with disease from those linked to  the use of antipsychotic medication. “Most research has taken place with people who are already taking antipsychotic medications, making it difficult to disentangle the effects of medication from those of  illness,” said Dr Chopra.

“Our network-based model was able to account for both medication-related and illness-related brain changes, meaning that brain network architecture represents a fundamental constraint on both types of brain changes in psychosis.” 

According to Dr Chopra, the new approach opens new possibilities for understanding the causes of brain changes in schizophrenia, and for forecasting how they might evolve in individual patients.

“Our work demonstrates that it is possible to investigate promising mechanisms behind widespread brain changes in schizophrenia, using fairly simple models” he said. “We hope to further extend these models to identify possible treatment targets and predict how the illness might evolve in individual people.”

About this schizophrenia research news

Author: Tania Ewing
Source: Monash University
Contact: Tania Ewing – Monash University
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Network-based spreading of grey matter changes across different stages of psychosis” by Sid Chopra et al. JAMA Psychiatry


Network-based spreading of grey matter changes across different stages of psychosis


Psychotic illness is associated with anatomically distributed gray matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown.


To test the hypothesis that brain network architecture constrains cross-sectional and longitudinal gray matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicenters from which volume loss spreads.

Design, Settings, and Participants  

This case-control study included 534 individuals from 4 cohorts, spanning early and late stages of psychotic illness. Early-stage cohorts included patients with antipsychotic-naive first-episode psychosis (n = 59) and a group of patients receiving medications within 3 years of psychosis onset (n = 121). Late-stage cohorts comprised 2 independent samples of people with established schizophrenia (n = 136).

Each patient group had a corresponding matched control group (n = 218). A sample of healthy adults (n = 356) was used to derive representative structural and functional brain networks for modeling of network-based spreading processes. In Longitudinal illness-related and antipsychotic-related gray matter changes over 3 and 12 months were examined using a triple-blind randomized placebo-control magnetic resonance imaging study of the antipsychotic-naive patients.

All data were collected between April 29, 2008, and January 15, 2020, and analyses were performed between March 1, 2021, and January 14, 2023.

Main Outcomes and Measures  

Coordinated deformation models were used to estimate the extent of gray matter volume (GMV) change in each of 332 parcellated areas by the volume changes observed in areas to which they were structurally or functionally coupled. To identify putative epicenters of volume loss, a network diffusion model was used to simulate the spread of pathology from different seed regions. Correlations between estimated and empirical spatial patterns of GMV alterations were used to quantify model performance.


Of 534 included individuals, 354 (66.3%) were men, and the mean (SD) age was 28.4 (7.4) years. In both early and late stages of illness, spatial patterns of cross-sectional volume differences between patients and controls were more accurately estimated by coordinated deformation models constrained by structural, rather than functional, network architecture (r range, >0.46 to <0.57; P < .01).

The same model also robustly estimated longitudinal volume changes related to illness (r ≥ 0.52; P < .001) and antipsychotic exposure (r ≥ 0.50; P < .004). Network diffusion modeling consistently identified, across all 4 data sets, the anterior hippocampus as a putative epicenter of pathological spread in psychosis. Epicenters of longitudinal GMV loss were apparent in posterior cortex early in the illness and shifted to the prefrontal cortex with illness progression.

Conclusion and Relevance  

These findings highlight a central role for white matter fibers as conduits for the spread of pathology across different stages of psychotic illness, mirroring findings reported in neurodegenerative conditions. The structural connectome thus represents a fundamental constraint on brain changes in psychosis, regardless of whether these changes are caused by illness or medication. Moreover, the anterior hippocampus represents a putative epicenter of early brain pathology from which dysfunction may spread to affect connected areas.

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