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. 2018 Jul 15;137:202-210.
doi: 10.1016/j.neuropharm.2018.04.026. Epub 2018 Apr 27.

Intermittent Stimulation in the Nucleus Basalis of Meynert Improves Sustained Attention in Rhesus Monkeys

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Intermittent Stimulation in the Nucleus Basalis of Meynert Improves Sustained Attention in Rhesus Monkeys

Ruifeng Liu et al. Neuropharmacology. .
Free PMC article

Abstract

Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance.

Keywords: Acetylcholine; Deep brain stimulation; Nonhuman primate; Nucleus basalis of meynert; Sustained attention.

Figures

Fig. 1
Fig. 1
The experimental paradigm. A white square was presented on the center of the screen at the beginning of the testing. Five successive taps on the white square started a CPT testing stimulus stream. Each stimulus duration was 600 ms. White squares in the stimulus stream were target stimuli. Any two adjacent target stimuli were separated by at least three non-target stimuli, and all colors were arranged pseudo-randomly. If the animal touched the target, food slurry reward was delivered to its mouth. Omission errors did not affect the stimulus stream, but inappropriate taps on the screen, errors of commission or false alarms, led to a 2–3 s timeout, after which a new stream was started. One testing session lasted 10 min. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig.2.
Fig.2.
Intermittent stimulation improved animals’ performance. A. Comparison of hit rates in control vs. stimulation. Left bars: animal Chf, right bars: animal Dit. B. Similar to A, but shows comparison of rates of commission errors (false alarms) in both animals. C. Distribution of false alarms on non-target to target stimulus. The horizontal axis indicates the position of the error of commission stimulus following a target stimulus. Solid line: data collected under the control condition, dotted line: data collected under stimulation. D. Data from animal Dit was shown as similar as section C. Error bars indicate the standard errors. The asterisks indicate the paired t-test results between any pair wised conditions. Single asterisk means 0.001 < p < 0.05, and double asterisk means p < 0.001.
Fig. 3.
Fig. 3.
Donepezil decreased animals’ behavioral performance. A. The effect of a 200 mg/ kg dose donepezil on hit rate. B. The effect of 200 mg/kg dose donepezil on false alarm rate. C-D. The effects of a 100 mg/kg dose. Asterisks in the figure indicate the p values of paired t-test. Single asterisk means 0.001 < p < 0.05, and double asterisk means p < 0.001.
Fig. 4.
Fig. 4.
Impact of intermittent stimulation on performance of animals with 100 mg/kg donepezil. A. Comparison of hit rates under donepezil vs. donepezil þ stimulation forboth animals. B. Comparison of rates of commission errors under donepezil vs. donepezil þ stimulation from both animals. Error bars indicate the standard errors. Asterisks in the figure indicate the p values of paired t-test. Single asterisk means0.001 < p < 0.05, and double asterisk means p < 0.001.
Fig. 5.
Fig. 5.
Impacts of cholinergic antagonists on animals’ performance. A. Mecamylamine improved hit rates of animals. B. Mecamylamine decreased error of commission rates of animals. C. Scopolamine decreased hit rates of both animals. D. Scopolamine increased error of commission rates of both animals. Error bars indicate the standard errors. Asterisks in the figure indicate the p values of paired t-test. Single asterisk means 0.001 < p < 0.05, and double asterisk means p < 0.001.
Fig. 6.
Fig. 6.
Impacts of intermittent stimulation on animals’ performance with cholinergic antagonists. A. Hit rates of both animals with mecamylamine vs. mecamylamine þ stimulation. B. False alarm rates of both animals with mecamylaminevs. mecamylamine þ stimulation. C-D. Similar to A-B, comparisons under scopolaminevs. scopolamine þ stimulation. Error bars indicate the standard errors. Asterisks in thefigure indicate the p values of paired t-test. Single asterisk means 0.001 < p < 0.05, and double asterisk means p < 0.001.
Fig. 7
Fig. 7
Impacts of stimulation and methylphenidate on animals’ performance. A. comparison of hit rates of both animals under control, stimulation, methylphenidate and stimulation þ methylphenidate conditions. B. Comparison of false alarm rates ofboth animals under control, stimulation, methylphenidate and stimulation þ methylphenidate conditions. Error bars indicate the standard errors. Asterisks in the figure indicate the p values of paired t-test. Single asterisk means0.001 < p < 0.05, and double asterisk means p < 0.001. 2-way ANOVA shows significant difference between experimental conditions in both A and B.

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