Cholinergic augmentation modulates visual task performance in sleep-deprived young adults

Abstract

Using 24 h of total sleep deprivation to perturb normal cognitive function, we conducted a double-blind, placebo-controlled crossover study to evaluate the effect of the acetylcholinesterase inhibitor, donepezil, on behavioral performance and task-related brain activation in 28 healthy, young, adult volunteers. The behavioral tasks involved the parametric manipulation of visual short-term memory load and perceptual load in separate experiments indirectly evaluating attention. Sleep deprivation significantly reduced posterior cortical activation (intraparietal sulcus and extrastriate cortex) at all levels of visual memory as well as perceptual load. Donepezil modulated an individual's performance in both tasks in accordance to whether accuracy declined after sleep deprivation without treatment. Critically, there were significant correlations between donepezil-induced increases in neural activation in the posterior cortical areas and improvement in accuracy. Reduced visual short-term memory after sleep deprivation may thus originate from a decline in visual attention and/or visual processing. Cholinergic augmentation can alleviate these deficits in individuals vulnerable to the effects of sleep deprivation, but it may have neutral or negative effects on those resistant to sleep deprivation.

Figures

Figure 1.

Schematic of the schedule and timeline of the study. B1, B2, and B3 denote briefing and screening sessions, whereas S1, S2, S3, and S4 denote scanning sessions. Treatment (placebo, donepezil) and state conditions (rested wakefulness, sleep deprivation) were counterbalanced across individuals.

Figure 2.

Schematic illustration of the VSTM (A) and VPC (B) tasks. For the VSTM task, subjects viewed and remembered arrays of up to eight colored squares. A single colored probe was presented 1 s later and subjects made a yes/no judgment as to whether the color was present in the most recently viewed array. There were four runs of the VSTM task and a total of 192 trials with 32 trials of each set size (1, 2, 3, 4, 6, and 8). The intertrial interval was randomized to be 5, 7.5, or 10 s with equal probability of occurrence. In the VPC task, subjects were presented with identical visual arrays, but the task was to press “yes” if a square appeared in the center of the array and “no” otherwise.

Figure 3.

Correlation between the decline in performance accuracy after sleep deprivation relative to rested wakefulness in the placebo condition (SDP-RWP) and the extent of improvement with donepezil relative to placebo when sleep-deprived (SDD-SDP) in the visual short-term memory (A) and visual perceptual control (B) tasks.

Figure 4.

A, B, Accuracy (±1 SEM) associated with the visual short-term memory (A) and visual perceptual control (B) tasks during RW and SD as a function of set size, drug (P, placebo; D, donepezil) and group (LV, low vulnerability; MV, moderate vulnerability; HV, high vulnerability). These groups were derived based on the extent of SD-related change in number of nonresponses in the placebo condition across both tasks (see supplemental material, available at www.jneurosci.org).

Figure 5.

Mean activation (±1 SEM) in the IPS and ventral occipital cortex (VO) associated with the VSTM and VPC tasks as a function of state (RW, SD) and set size. There were significant effects of state and set size for the VSTM task, and significant effects of state for the VPC task in the IPS. In the VO, there were significant effects of state and set size for both tasks. Taking into consideration the entire cohort of 28 individuals, there was no main effect of drug or interaction effect for either task in both regions.

Figure 6.

Top, The inflated brains show regions where activation tracked behavior decline after SD in the placebo condition (yellow). Regions in which activation tracked the effect of donepezil in the setting of SD are shown in red. The overlap of these regions appears in orange and data for the correlation plots that ensue were obtained from these regions. Bottom [left (L) to right (R)], The left panel shows the positive correlation between behavioral change elicited by SD in the placebo condition and the corresponding change in activation. The middle panel shows the correlation between how donepezil modulates performance and activation in the context of SD. The right panel shows the correlation between donepezil-induced changes in activation in the context of SD with SD-induced changes in activation when volunteers were on placebo. All correlations were significant at p < 0.05.

Figure 7.

Top, The inflated brains show regions in which activation tracked behavior decline after SD in the placebo condition (yellow). Regions in which activation tracked the effect of donepezil in the setting of SD are shown in red. The overlap of these regions appears in orange and data for the correlation plots that ensue were obtained from these regions. Bottom [left (L) to right (R)], The left panel shows the positive correlation between behavioral change elicited by SD in the placebo condition and the corresponding change in activation. The middle panel shows the correlation between how donepezil modulates performance and activation in the context of SD. The right panel shows the correlation between donepezil-induced changes in activation in the context of SD with SD-induced changes in activation when volunteers were on placebo. The right hemisphere was rotated slightly to expose the inferior surface of the occipital lobe. All correlations were significant at p < 0.05.