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bioRxiv · 10.64898/2025.12.02.690396

Grey matter embedding of the cholinergic system

Weuthen, A.·Chopra, S.·Helbing, D. L.·Li, M.·Besteher, B.·Walter, M.
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Abstract

Integrity of acetylcholine-producing basal forebrain nuclei Ch1-4 is crucial for neurocognitive functioning and grey matter decline represents a hallmark of neuropsychiatric disorders, including Alzheimers disease, Parkinsons disease and schizophrenia. Approaches that link brain-wide grey matter atrophy with diminished cholinergic innervation from Ch1-4 projections are required for neuroimaging of disease stages and pharmacological decisions addressing cholinergic deficits. The current study assessed human magnetic resonance imaging-based markers for cholinergic nucleus subregions and synaptic targets in healthy exploration (HCP, n = 1113) and replication (IXI, n = 587) cohorts. Ch1-3 and Ch4 were delineated at 50% cytoarchitectonic probability to determine their grey matter coupling patterns using structural covariance analyses. Spatial colocalization with vesicular acetylcholine transporter, M1-muscarinic and 4{beta}2-nicotinic receptor density quantified the correspondence with synaptic cholinergic markers. All individual-level cholinergic nucleus and target region indices showed good test-retest reliability (R [≥] 0.80) when restricted to voxels with at least 10% grey matter probability. Spatial colocalization with presynaptic acetylcholine transporters emphasized a cholinergic nature of Ch1-4 grey matter and its coupling with corticopetal projections such as amygdala, insula and cingulate cortices. Subcortical gradients of M1-muscarinic receptor density and the Ch1-3 structural covariance map, however, dominated in locations of striatal cholinergic interneurons, such as nucleus accumbens, caudate nucleus and putamen. Ch4 covaried with medial thalamus and hippocampus, while both subregions structural covariance networks converged in a posterolateral Ch4 extensions, potentially resembling subputaminal nucleus of Ayala. The results emphasize Ch1-4 morphometry as marker for acetylcholine-driven brain regions and describe neuroimaging strategies to indicate synaptic cholinergic involvement. Significance StatementPrevious studies have suggested that grey matter alterations in basal forebrain Ch1-4 nuclei indicate cholinergic deficits in neurodegenerative and psychiatric pathologies. However, the use of Ch1-4 volume as a marker of cholinergic system integrity has yet to be validated. Additionally, there is a lack of non-invasive procedures to quantify integrity of regions innervated by its cholinergic projections. Our results suggest that grey matter coupling with Ch1-4 is a sensitive cholinergic system marker, mimicking the density distribution of synaptic cholinergic innervation. Furthermore, we introduce grey matter-based target region indices, evaluate their robustness in individual participants and describe regional contributions to M1-muscarinic, 4{beta}2-nicotinic and vesicular acetylcholine transporter gradients. The study advances our understanding of cholinergic circuits in vivo using magnetic resonance imaging.

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Weuthen, A., Chopra, S., Helbing, D. L., Li, M., Besteher, B., Walter, M.. 2025-12-05. Grey matter embedding of the cholinergic system. https://doi.org/10.64898/2025.12.02.690396

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