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Corticolimbic Glutamate-Functional Connectivity Associations Found in Antipsychotic-Naive CHR-P IndividualsCould early brain changes in psychosis risk be linked to specific chemical connections?

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Key Takeaway
Note altered corticolimbic Glx-connectivity associations in antipsychotic-naive CHR-P individuals in observational study.

This observational study investigated associations between corticolimbic glutamatergic metabolites and functional connectivity in antipsychotic-naive individuals. The population included 22 participants at clinical high-risk for psychosis (CHR-P), 23 healthy controls (HC), and 10 first-episode psychosis (FEP) participants. The study measured Glx (glutamate + glutamine) levels and resting-state functional connectivity, comparing CHR-P participants against both HC and FEP groups.

The main finding was a significant interaction between group and anterior cingulate cortex (ACC) Glx for functional connectivity between the nucleus accumbens and bilateral amygdala and hippocampus (p-FDR=0.021). This was driven by a significant negative association specifically in the CHR-P group (p-FDR=0.005). Additional negative associations between ACC Glx and functional connectivity with the left middle temporal gyrus, and between hippocampal Glx and functional connectivity with parahippocampal and temporal fusiform cortices, were present in CHR-P individuals but absent in HC. Regarding Glx levels, FEP participants showed higher ACC and hippocampal Glx than HC (p=0.015), but no significant Glx differences were found between CHR-P and HC groups.

Safety and tolerability data were not reported. A key limitation was that FEP individuals were excluded from functional connectivity analyses due to insufficient sample size after quality control. The study design was observational, so causality cannot be inferred. The findings suggest that altered relationships between corticolimbic connectivity and glutamatergic function may be associated with increased psychosis risk, but further research is needed to determine clinical utility.

Imagine trying to understand a complex machine by looking at how its parts talk to each other. This study did exactly that for people at clinical high-risk for psychosis. Researchers measured levels of glutamate and glutamine, which are key chemicals in the brain, and how different brain regions connect. They compared these people to healthy individuals and those who had just started experiencing psychosis.

The team found a worrying pattern in the high-risk group. The connection between certain brain chemicals and how brain regions communicate was significantly weaker in these individuals compared to healthy people. This specific weakness was not seen in people who had already developed psychosis, suggesting these changes might happen very early in the process.

It is important to remember that this was an observational study, meaning it watched what happened without changing anything. Because of this, we cannot say these chemical changes cause the illness. Also, the group of people who had already developed psychosis was too small to include in some of the detailed brain connection analyses. These findings are a step forward, but they are not the final word on how to treat or predict the illness.

What this means for you:
Early brain chemical connections may differ in people at high risk for psychosis, but this study cannot prove cause and effect.

Study Details

Sample sizen = 22
EvidenceLevel 5
PublishedApr 2026
View Original Abstract ↓
Recent evidence suggests that psychosis involves glutamatergic dysfunction and altered activity/connectivity within corticolimbic circuitry. While altered relationships between corticolimbic glutamatergic metabolite levels and resting-state functional connectivity (FC) have been described in schizophrenia and first-episode psychosis (FEP), whether these disruptions are also present prior to psychosis onset remains unclear. We measured Glx (glutamate + glutamine) levels in the anterior cingulate cortex (ACC) and hippocampus with magnetic resonance spectroscopy (MRS), and resting-state FC between corticolimbic regions of interest (ACC, hippocampus, amygdala and nucleus accumbens (NAc)) in antipsychotic-naive participants at clinical high-risk for psychosis (CHR-P, n=22), compared to healthy controls (HC, n=23) and FEP participants (n=10). Primary analyses compared corticolimbic Glx-FC interactions between CHR-P and HC groups. FEP individuals were included in secondary Glx comparisons but were excluded from FC analyses due to insufficient sample size after quality control. There was a significant interaction between group and ACC Glx for FC between the NAc and the bilateral amygdala and hippocampus (p-FDR=0.021), which was driven by a significant negative association in the CHR-P group (p-FDR=0.005). Complementary seed-to-whole-brain analyses revealed additional negative associations between ACC Glx and FC with the left middle temporal gyrus, and between hippocampal Glx and FC with the parahippocampal and temporal fusiform cortices in CHR-P individuals, which were absent in HC. FEP showed higher Glx than HC across both regions (p=0.015), but there were no significant Glx differences between CHR-P and HC. These data suggest that increased risk for psychosis is associated with altered relationships between corticolimbic connectivity and glutamatergic function.
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