Microstructural imaging and transcriptomics of the basal forebrain in first-episode psychosis

Area of Science:

• Neuroscience
• Psychiatry
• Genetics

Background:

• Cholinergic dysfunction is a key factor in psychosis, including schizophrenia, depression, and bipolar disorder.
• The basal forebrain (BF) cholinergic nuclei (Ch1-3, Nucleus Basalis of Meynert [NBM]) project widely throughout the brain.
• Understanding microstructural changes in these nuclei is crucial for elucidating psychosis pathophysiology.

Purpose of the Study:

• To investigate microstructural neuroimaging measures (myelin and axonal integrity) of BF cholinergic nuclei in untreated first-episode psychosis (FEP).
• To correlate neuroimaging findings with magnetic resonance spectroscopy (MRS) data, clinical symptoms, and transcriptomic profiles.
• To provide biological validity to neuroimaging measures through genetic enrichment analyses.

Main Methods:

• Utilized quantitative T1 (qT1) for myelin and axial diffusion (AxD) for axonal integrity in BF nuclei (Ch1-3, NBM) using a cytoarchitectonic atlas.
• Analyzed a clinical sample of 56 FEP patients and 29 healthy controls, alongside MRS and Allen Human Brain Atlas transcriptomic data.
• Correlated neuroimaging measures with clinical symptom severity (manic, negative symptoms) and performed gene enrichment analyses for psychiatric disorders.

Main Results:

• Observed increased qT1 (reduced myelin) and AxD (reduced axonal integrity) in Ch1-3 in FEP patients compared to controls.
• Found disrupted correlations between BF cholinergic nuclei myelin and brain choline levels in FEP, unlike in healthy controls.
• Identified significant genetic enrichment for schizophrenia and depression in cholinergic nuclei, linked to cholinergic receptor and cell type genes.

Conclusions:

• These findings provide robust neuroimaging, genetic, and clinical evidence supporting cholinergic dysfunction in schizophrenia and related psychoses.
• The study validates microstructural measures of BF cholinergic nuclei and their relevance to psychiatric disorders.
• The results underscore the importance of the cholinergic system in the pathophysiology of psychosis.