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

Abstract

Dysfunction in the brain's cholinergic systems results in working memory and executive function impairments. The source of acetylcholine for the neocortex is the Nucleus Basalis of Meynert. We tested whether electrical activation of this nucleus would improve executive function in young adult monkeys. Continuous stimulation led to consistent performance impairments. In contrast, intermittent stimulation led to supranormal working memory performance. Optimal performance was achieved with delivery of 200 microsecond biphasic pulses at a frequency of 60 pulses per second, for 20 seconds every minute. Effects onset and offset within three minutes. Pharmacological experiments suggested both intermittent and continuous stimulation effects depended on cholinergic activation. Donepezil, a cholinesterase inhibitor, improved performance to supranormal levels in animals already impaired by continuous electrical stimulation. The same treatment did not impact performance while animals received intermittent stimulation. Administration of either nicotinic or muscarinic acetylcholine receptor antagonists prevented intermittent stimulation from altering performance. In the months after stimulation testing began, animal performance, measured in sessions without stimulation, improved. Over these months, the working memory delay at which animals achieved 80% correct performance increased three to fivefold. Our results show that cholinergic activation by deep brain stimulation enhances working memory performance and is a candidate treatment for losses in executive function in aging and Alzheimer's Disease.