Intermittent Stimulation of the Nucleus Basalis of Meynert Improves Working Memory in Adult Monkeys

Acetylcholine in the neocortex is critical for executive function [1–3]. Degeneration of cholinergic neurons in aging and Alzheimer’s dementia is commonly treated with cholinesterase inhibitors [4–7]; however, these are modestly effective and are associated with side effects that preclude effective dosing in many patients [8]. Electrical activation of the nucleus basalis (NB) of Meynert, the source of neocortical acetylcholine [9, 10], provides a potential method of improving cholinergic activation [11, 12]. Here we tested whether NB stimulation would improve performance of a working memory task in a nonhuman primate model. Unexpectedly, intermittent stimulation proved to be most beneficial (60 pulses per second, for 20 s every minute), whereas continuous stimulation often impaired performance. Pharmacological experiments confirmed that the effects depended on cholinergic activation. Donepezil, a cholinesterase inhibitor, restored performance in animals impaired by continuous stimulation but did not improve performance further during intermittent stimulation. Intermittent stimulation was rendered ineffective by either nicotinic or muscarinic receptor antagonists. In the months after stimulation began, performance also improved in sessions without stimulation. Our results reveal that intermittent NB stimulation can improve working memory, a finding that has implications for restoring cognitive function in aging and Alzheimer’s dementia. •Intermittent stimulation of nucleus basalis (NB) improves working memory performance•Continuous NB stimulation degrades performance in young adult monkeys•Donepezil provided no greater improvement than intermittent stimulation•Effects were blocked by nicotinic and muscarinic receptor antagonists Liu et al. show that an intermittent train of electrical stimulation in the nucleus basalis improves working memory in adult monkeys. The improvement depends on cholinergic receptors. The finding reveals a new mechanism to improve cognitive performance in conditions that compromise cholinergic action, including aging and Alzheimer’s disease.