Abstract
Cholinesterase inhibitors are a clinically recognised option for managing the symptoms of apathy in neurodegenerative disease. While it is well established that cholinesterase inhibitors increase acetylcholine levels in the brain, the mechanism by which they enhance motivation remains unclear. One validated approach to understand changes in motivation is to investigate the way individuals weigh up effort and reward information, a process commonly altered in neurodegenerative apathy. To understand how cholinergic enhancement improves motivation, we investigated the effects of cholinesterase inhibitors (ChEIs) on effort-based decision-making (EBDM) using the Apple Gathering Task (AGT), a behavioural paradigm that presents sequential offers of reward contingent on physical effort. We hypothesised that ChEIs would directly affect sensitivity to the effort and reward decision variables, rather than acting indirectly via improved attention.
Patients starting ChEIs as part of routine management were recruited from an early-onset dementia clinic, assessed at baseline before treatment, and again after 6 weeks of therapy. Age and sex-matched healthy controls were tested twice across the same timeframe. Apathy was assessed using the self-rated Apathy Evaluation Scale (AES). AGT choice data were analysed using generalised linear mixed-effects models fitted to the decisions of patients (n = 12) and healthy controls (n = 37), respectively. In the patient group, ChEI treatment was associated with a non-uniform increase in offer acceptance (p < 0.001) and enhanced sensitivity to both effort (p < 0.001) and reward (p < 0.001) variables. In healthy controls, no significant change over time was observed in acceptance (p = 0.28), effort sensitivity (p = 0.52), or reward sensitivity (p = 0.90). At a group level, AES-apathy scores did not change significantly at follow-up for patients (mean change = -0.73 points; p = 0.74) or controls (mean change = 0.70 points; p = 0.33). Our findings suggest that cholinesterase inhibitors enhance the salience and integration of effort and reward information when deciding whether to act, with increased overall willingness to exert effort for reward.