Donepezil improves episodic memory in young individuals vulnerable to the effects of sleep deprivation

Abstract

Study objectives: We investigated if donepezil, a long-acting orally administered cholinesterase inhibitor, would reduce episodic memory deficits associated with 24 h of sleep deprivation.

Design: Double-blind, placebo-controlled, crossover study involving 7 laboratory visits over 2 months. Participants underwent 4 functional MRI scans; 2 sessions (donepezil or placebo) followed a normal night's sleep, and 2 sessions followed a night of sleep deprivation.

Setting: The study took place in a research laboratory.

Participants: 26 young, healthy volunteers with no history of any sleep, psychiatric, or neurologic disorders.

Interventions: 5 mg of donepezil was taken once daily for approximately 17 days.

Measurements and results: Subjects were scanned while performing a semantic judgment task and tested for word recognition outside the scanner 45 minutes later. Sleep deprivation increased the frequency of non-responses at encoding and impaired delayed recognition. No benefit of donepezil was evident when participants were well rested. When sleep deprived, individuals who showed greater performance decline improved with donepezil, whereas more resistant individuals did not benefit. Accompanying these behavioral effects, there was corresponding modulation of task-related activation in functionally relevant brain regions. Brain regions identified in relation to donepezil-induced alteration in non-response rates could be distinguished from regions relating to improved recognition memory. This suggests that donepezil can improve delayed recognition in sleep-deprived persons by improving attention as well as enhancing memory encoding.

Conclusions: Donepezil reduced decline in recognition performance in individuals vulnerable to the effects of sleep deprivation. Additionally, our findings demonstrate the utility of combined fMRI-behavior evaluation in psychopharmacological studies.

Figure 1

A schematic of the study timeline. B1, B2, and B3 denote briefing and screening sessions while S1, S2, S3, and S4 denote scanning sessions. The drug (placebo, donepezil) and state (rested wakefulness, sleep deprivation) conditions were counterbalanced across individuals.

Figure 2

The extent to which donepezil modulated performance following sleep deprivation was dependent on the extent to which performance declined following sleep deprivation in the untreated condition. Volunteers whose task performance declined following sleep deprivation (Vulnerable) showed drug-related benefit, while those whose performance did not deteriorate following sleep deprivation (Resistant) showed little performance benefit and even marginal decline. No benefit of drug was present at rested wakefulness. RWP: rested wakefulness placebo; RWD: rested wakefulness donepezil; SDP: sleep deprivation placebo; SDD: sleep deprivation donepezil; NR: Non-responses; CR: Corrected Recognition.

Figure 3

Task-related activation associated with high confidence hits following a normal night of sleep (conjunction of RWP (rested wakefulness placebo) and RWD (rested wakefulness donepezil)). All clusters passed a voxel-level threshold of P < 0.0001 (uncorrected).

Figure 4

Regions that showed significant effects of state in a state by drug ANOVA. All clusters passed a voxel-level threshold of P < 0.005 (uncorrected). There were no significant effects of drug.

Figure 5

The graphs in the left panel depict encoding-related signal change (± 1 SEM) in brain regions depicted alongside. Task-related activity in these regions was altered during sleep deprivation. Sleep deprivation related change in the number of non-responses (SDP-RWP) at encoding correlated with sleep deprivation related change in activation in the left middle frontal gyrus, the left intraparietal sulcus and the left fusiform gyrus (right panel). Similar correlations were present in 2 ROIs within the inferior frontal gyrus (r = −0.47), the left pre-supplementary motor cortex (r = −0.64), and right fusiform gyrus (r = −0.47). RWP: rested wakefulness placebo; SDP: sleep deprivation placebo.

Figure 6

Declines in non-responses with donepezil following sleep deprivation (SDD–SDP) correlated (P < 0.05) with activation increases in (A) the left superior parietal cortex (r = −0.43), (B) right fusiform gyrus (r = −0.45), (C) left fusiform gyrus (r = −0.43) and left ventral occipital cortex (r = −0.44). SDD: sleep deprivation donepezil; SDP: sleep deprivation placebo. Note that N = 25 following the exclusion of an outlier.

Figure 7

Donepezil-related modulation in corrected recognition correlated (P < 0.05) with activation in (A) the left middle prefrontal cortex (r = 0.54), (B) the left inferior frontal gyrus (r = 0.53), and (C) the right fusiform gyrus (r = 0.39). The highlighted frontal regions overlapped (orange) with those showing a subsequent memory effect (yellow; Supplementary Figure 2 available at www.journalsleep.org). SDD: sleep deprivation donepezil; SDP: sleep deprivation placebo. Note that N = 25 following the exclusion of an outlier.

Supplementary Figure 1

A schematic illustrating how inter-individual differences in cholinergic transmission might affect behavioral responses to donepezil during rested wakefulness and following sleep deprivation. When young, healthy participants are well rested (top panel), cholinergic neurotransmission is likely to be within the optimal range and further modulation may not elicit further benefit (top panel). Following sustained wakefulness, cholinergic transmission may decline together with cognitive performance (red arrow, red open circle). As such, individuals who are vulnerable to cognitive decline when sleep deprived (middle panel) may benefit from exogenous cholinergic augmentation (middle panel, orange circle). In contrast, there are resistant individuals who show either no decline or minimal cognitive decline after sleep deprivation (bottom panel). Tolerance to the effects of sleep deprivation may be accompanied by elevated task-related brain activation. When sleep deprived, these individuals may manifest endogenous phasic elevation of cholinergic transmission (bottom panel, red solid circle). As such, further exogenous elevation of cholinergic transmission may result in no significant cognitive benefit or even a slight decline in behavioral performance. RWP: rested wakefulness placebo; RWD: rested wakefulness donepezil; SDP: sleep deprivation placebo; SDD: sleep deprivation donepezil.

Supplementary Figure 2

The subsequent memory effect (high confidence hits > high confidence misses) was present in the left lateral prefrontal cortex (middle and inferior frontal gyri) and left middle temporal gyrus for all four conditions. The low number of miss trials during rested wakefulness (approximately half the subjects had fewer than 10 % misses), precluded a random effects analysis and a fixed-effects analysis was performed. The left frontal regions showing this effect overlapped substantially with those described earlier in relation to corrected recognition (Figure 7).