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

Abstract

Summary 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, which 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 non-human primate model. Unexpectedly, intermittent stimulation proved to be most beneficial (60 pulses per second, for 20 seconds 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.

Central cholinergic system mediates working memory deficit induced by anesthesia/surgery in adult mice

“…In present study, we demonstrated that donepezil pretreatment could improve the performance of working memory in adult mice after anesthesia and surgery, which showed similar results to Ruifeng Liu's findings in adult monkeys (Liu et al, 2017). Donepezil is a medicine approved by the FDA and could improve cognition for the patients with Alzheimer's disease and stroke traumatic brain injury and even for normal older adults (Berthier, Hinojosa, Martin Mdel, & Fernandez, 2003;Black et al, 2007;Yesavage et al, 2002;Zhang, Plotkin, Wang, Sandel, & Lee, 2004).…”

Nucleus Basalis Stimulation Enhances Working Memory by Stabilizing Attractor Networks in Prefrontal Cortex

“…Our study demonstrated that intermittent NB stimulation improves performance of monkeys in a working memory task that requires selective maintenance of a stimulus in memory, in agreement with recent studies that showed similar effects for other memory and attention tasks Liu et al, 2017Liu et al, , 2018. We additionally show that the effect was associated with changes in the firing rate of neurons in the dorsolateral prefrontal cortex, most often increasing it.…”

“…At the end of the trial that exceed the 45 s threshold, stimulation was applied anew and the cycle was repeated. This pattern of stimulation was elected based on recent results demonstrating the intermittent stimulation improves working memory and attention performance Liu et al, 2017Liu et al, , 2018. Behavioral performance in our task generally improved with intermittent stimulation ( Fig.…”

“…Improvement in cognitive functions can also be achieved by stimulation of the Nucleus Basalis (NB) of Meynert, the sole source of neocortical acetylcholine in primates and humans (Mesulam et al, 1983;Hendry et al, 1987). Recent studies in primates suggest that intermittent NB stimulation is equally or more effective in improving cognitive performance task as high doses of acetylcholinesterase inhibitors, with further effects that aggregate over time Liu et al, 2017Liu et al, , 2018.…”

Cognitive Improvements after Intermittent Deep Brain Stimulation of the Nucleus Basalis of Meynert in a Transgenic Rat Model for Alzheimer’s disease; a Preliminary Approach

“…The stimulation is likely to drive the dense population of cholinergic neurons of the NBM, functionally associated with control of attention and maintenance of arousal, both key functions for learning and memory formation (6–11). Studies in aged rhesus monkeys show intermittent NBM stimulation to induce supranormal working memory and sustained attention (12,13), suggesting that the current pattern of stimulation used in the clinic may not be optimal (14). Accordingly, in the present study, we aimed at comparing the cognitive benefits elicited by intermittent and continuous NBM stimulation in an animal model for AD (TgF344-AD rat line; TG), i.e.…”