Whole-brain cholinergic modulation following computerized cognitive training in healthy older adults: a [18F]FEOBV PET study

The cholinergic system is central to attention, learning, and neuroplasticity and undergoes progressive degeneration with aging. Neuroplasticity-based computerized cognitive training is a scalable, non-pharmacological strategy to support cognitive health in older adults, yet its neurobiological mechanisms remain unclear. [18F]Fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET) quantifies presynaptic cholinergic terminals via vesicular acetylcholine transporter (VACht) binding, providing an index of cholinergic integrity and neurotransmission capacity. This offers a unique opportunity to examine training-induced cholinergic plasticity. In the INHANCE double-blind, active-controlled randomized clinical trial, 92 cognitively intact older adults (≥ 65 years; mean age 71.9) were randomized to 35 h of speed-based cognitive training (BrainHQ; Double Decision and Freeze Frame) or a non-speeded active control (Double Klondike Solitaire and Bricks Breaking Hex) over 10 weeks. Participants underwent neuropsychological assessment and [18F]FEOBV PET imaging at baseline and post-intervention. Voxel-wise analyses using threshold-free cluster enhancement assessed training-related changes in cholinergic signal. Training significantly increased cholinergic binding in the anterior cingulate, medial prefrontal cortex, insula, and orbitofrontal cortex, with greater increases in the intervention group compared to controls, who showed no significant change. Exploratory cross-sectional analyses revealed age-related reductions in FEOBV binding across frontal, striatal, and parietotemporal regions, and higher baseline cholinergic binding in prefrontal and insular regions was associated with better baseline attentional performance. These findings provide the first in vivo evidence that computerized cognitive training can enhance cholinergic integrity in healthy aging, identifying cholinergic plasticity as a potential neurobiological mechanism of cognitive training and a target for interventions aimed at supporting cognitive resilience in aging.