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. 2017 Sep 11;27(17):2640-2646.e4.
doi: 10.1016/j.cub.2017.07.021. Epub 2017 Aug 17.

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

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Free PMC article

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

Ruifeng Liu et al. Curr Biol. .
Free PMC article

Abstract

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.

Keywords: Alzheimer’s; Nucleus Basalis of Meynert; deep brain stimulation; executive function; nonhuman primate; working memory.

Conflict of interest statement

Conflict of interest: The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Task paradigm and electrical stimulation position in the brain
A. Macaque monkeys were trained to interact with a touchscreen. The first step in the task is touching the cue. B. After the cue is touched, the screen blanks during the delay period, followed by presentation of two potential matches. Three colors were used in training, and two were randomly selected as cue/match and distractor on each trial. C. Stimulation of the Nucleus Basalis of Meynert was used in experimental sessions. The position of the nucleus is shown by the dotted yellow rectangle, with the curved arrows approximating the pathways from the nucleus to neocortices[52]. D. An MRI coronal section of a Rhesus monkey brain with the implantation target outlined in red. The MRI was taken from the Macaque Scalable Brain Atlas[53,54]. See also Figure S1–S2.
Figure 2
Figure 2. Effects of NB stimulation on working memory behavior
A. The impact of continuous stimulation on performance. Monkeys performed the task with concurrent 80 Hz continuous stimulation, or under a control condition. B. The impact of intermittent stimulation on performance. The gray bars indicated intermittent stimulation condition distinct from continuous stimulation condition indicated by empty bars in A. C. Both monkeys were tested with 1200 stimulation pulses per minute, delivered in 10 seconds (120 Hz), 20 seconds (60 Hz), 40 seconds (30 Hz) or 60 seconds (20 Hz). The performance under the control, no stimulation, condition for this week is indicated with the dashed line, and its standard error is 1.8%. D. Performance as both monkeys were tested with 80 pulses per second for different fractions of a minute. The standard error in control condition is 1.7%. E. Delay performance curve with and without intermittent stimulation in Monkey CH. F. Delay performance curve with and without intermittent stimulation in Monkey DI. Up to 1000 trials were used to determine each point. See also Figure S3 –S4.
Figure 3
Figure 3. Pharmacological interactions with stimulation and effects on the animals’ appetite
A. On the left, the experimental conditions of intermittent stimulation (Inter) are compared to control (dashed line), donepezil (Don), and both stimulation and donepezil (Both). On the right, in a separate experiment, the same comparisons are applied with continuous stimulation (Cont). The gray bars indicated intermittent stimulation involved. Standard errors for control conditions (dashed lines) on the left and right are 1% and 1.1%, respectively. B. Effects of stimulation and acetylcholine receptor blockers. Mecamylamine (Mec) was given to animals prior to behavior, and working memory performance was assessed during intermittent stimulation, and without stimulation. Scopolamine (Sc) was similarly tested. Average of the two animals tested in each condition is displayed. Dashed line shows the baseline performance in control condition, and standard error is 1.6%. C. Effects of Mecamylamine and Scopolamine. Animals performed behavior in control condition (left Ctrl), then were given Mecamylamine (Mec), or Scopolamine (Sc). Then, animals performed washout behavior (right Ctrl, 72 h after drug application). D. Effects of stimulation and Donepezil on appetite. Food consumption under the experimental conditions of Control, Intermittent Stimulation, or Donepezil. Individual animal consumption under all conditions was normalized by mean Control consumption to allow pooling across animals for this plot. Food consumption data was collected from animal CH and DI.
Figure 4
Figure 4. Changes in working memory over time
A. The working memory delay and performance for Animal CH. Delay and performance are plotted against time relative to initiating intermittent stimulation. The delay was chosen to maintain performance range. The vertical line before week 6 indicates when intermittent stimulation was introduced. Left axis illustrates the delay which is marked by the circle symbols, while the right axis illustrated the performance plotted as triangles. All data in this figure are defined under no-stimulation control conditions. B. Data for Animal DI. C. Data for Animal PU.

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