Effects of cholinergic potentiation on resting-state functional connectivity in healthy adults

Abstract

Acetylcholine is a key attentional neuromodulator, yet its effects on large-scale organisation of resting-state networks remain poorly understood. Here, we investigated whether acute cholinergic potentiation with the acetylcholinesterase inhibitor donepezil modulates functional connectivity within and between resting-state networks involved in attention. Nineteen healthy young adults completed a double-blind, placebo-controlled crossover study using 7T resting-state functional MRI (rs-fMRI), with imaging performed before and after administration of donepezil or placebo. We tested whether donepezil altered functional connectivity within and between the dorsal attention, ventral attention, default mode, and frontoparietal networks and whether it improved attentional orienting in the same volunteers. Voxel-wise analysis revealed a significant donepezil-related increase in dorsal attention network connectivity within the left inferior parietal cortex. We did not observe donepezil-related changes within the ventral attention, default mode, or frontoparietal networks. Network-level analyses did not identify significant global changes in network strength. Exploratory analyses indicated reduced coupling between the dorsal attention and default mode networks following donepezil relative to placebo, although this result did not survive correction for multiple comparisons. Donepezil did not significantly improve attentional orienting at the group level. However, exploratory analyses suggested that greater donepezil-related enhancement of functional connectivity within the identified left inferior parietal cluster was associated with greater improvement in attentional orienting. These findings suggest that acute cholinergic potentiation does not globally enhance resting-state connectivity across attentional networks in healthy young adults. Instead, donepezil may selectively modulate localised dorsal attention network circuitry, particularly within left inferior parietal cortex, a region implicated in sensory integration and externally oriented cognition.