TY - JOUR
T1 - Intermittent Stimulation of the Nucleus Basalis of Meynert Improves Working Memory in Adult Monkeys
AU - Liu, Ruifeng
AU - Crawford, Jonathan
AU - Callahan, Patrick M.
AU - Terry, Alvin V.
AU - Constantinidis, Christos
AU - Blake, David T.
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/9/11
Y1 - 2017/9/11
N2 - 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.
AB - 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.
KW - Alzheimer's
KW - Nucleus Basalis of Meynert
KW - deep brain stimulation
KW - executive function
KW - nonhuman primate
KW - working memory
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U2 - 10.1016/j.cub.2017.07.021
DO - 10.1016/j.cub.2017.07.021
M3 - Article
C2 - 28823679
AN - SCOPUS:85027528509
SN - 0960-9822
VL - 27
SP - 2640-2646.e4
JO - Current Biology
JF - Current Biology
IS - 17
ER -