Unique Functional Neuroimaging Signatures of Genetic Versus Clinical High Risk for Psychosis

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• 22q11.2 deletion syndrome (22qDel) is linked to psychosis and neurodevelopmental disorders.
• Adolescents at clinical high risk for psychosis (CHR) exhibit subthreshold psychosis symptoms.
• The neural substrates underlying 22qDel and CHR populations are not well understood.

Purpose of the Study:

• To compare functional brain measures in 22qDel and CHR cohorts.
• To identify common or distinct neural substrates in these high-risk groups.
• To map functional brain alterations to biological pathways.

Main Methods:

• Analysis of two large, multisite resting-state functional magnetic resonance imaging (fMRI) cohorts: 22qDel (n=164) vs. controls (n=134) and CHR (n=240) vs. controls (n=149).
• Computation of global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions.
• Testing for case-control differences and relating group difference maps to biological gradients.

Main Results:

• Individuals with 22qDel showed significant disruptions in BSV, LC, and GBC compared to controls.
• Spatial maps of BSV and LC differences were highly correlated in the 22qDel group.
• The CHR group exhibited significant alterations only in LC, with a distinct spatial pattern compared to the 22qDel group.
• 22qDel effects were most pronounced in brain regions with high predicted blood flow and metabolism.

Conclusions:

• 22qDel carriers and CHR individuals display different functional brain alterations detectable by fMRI.
• Convergent disruptions in BSV and LC observed in 22qDel, but not CHR, suggest distinct underlying functional brain changes.
• These findings highlight unique neurobiological pathways in 22qDel and CHR.