Cholinergic neurotransmission underlying visual hallucinations in Parkinson's disease: Integration of multimodal evidence and translational approaches

Abstract

Visual hallucinations (VH) represent a prevalent and clinically significant non-motor manifestation in Parkinson’s disease (PD), often leading to accelerated cognitive decline, increased caregiver burden, and reduced quality of life. Despite their impact, the neurobiological basis of VH remains poorly defined, and effective treatments are limited. This review systematically synthesizes evidence from neuropathology, multimodal neuroimaging (PET, DTI, fMRI), neurophysiology, and computational modeling to establish a coherent mechanism of VH rooted in cholinergic system failure. We demonstrate that selective degeneration of cholinergic circuits—notably the basal forebrain-cortical and brainstem-basal forebrain pathways—induces VH through multiple convergent pathways: disruption of thalamocortical sensory gating, breakdown in predictive coding, and maladaptive functional connectivity, particularly hypercoupling between the default mode network (DMN) and visual cortex. Imaging studies further delineate a posterior-anterior gradient of cholinergic denervation, quantified by AChE-PET as reduced k₃ values in occipito-temporal regions, while dynamic interactions with dopaminergic fluctuations amplify perceptual noise and computational imbalance. Beyond conventional cholinesterase inhibitors, novel interventions are emerging. These include α7-nAChR agonists, M4 receptor-positive allosteric modulators, and occipital tDCS. They represent circuit-specific strategies with the potential to restore cholinergic modulation and normalize network dynamics. This review integrates multimodal insights into a translational framework, thereby clarifying the cholinergic etiology of PD-VH and outlines a personalized therapeutic roadmap. We also urge future research to bridge molecular mechanisms with clinical innovation in hallucination management.