Effects of donepezil on cognitive performance after

human psychopharmacology Hum. Psychopharmacol Clin Exp 2011; 26: 578–587. Published online 8 December 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.1248

Effects of donepezil on cognitive performance after sleep deprivation Chris M. Dodds1*, Edward T. Bullmore1,2, Richard N. Henson3, Soren Christensen5, Sam Miller1, Marie Smith6, Odile Dewit1, Phil Lawrence1 and Pradeep J. Nathan1,2,4 1

Clinical Unit Cambridge, Medicines Discovery & Development, GlaxoSmithKline R&D, Cambridge, UK Brain Mapping Unit, Department of Psychiatry, University of Cambridge, UK 3 MRC Cognition and Brain Sciences Unit, Cambridge, UK 4 School of Psychology and Psychiatry, Monash University, Melbourne, Australia 5 Clinical Pharmacology and Pharmacokinetics, Lundbeck Pharmaceuticals, Denmark 6 Department of Psychological Sciences, Birkbeck, University of London, UK 2

Objectives To identify tasks that were sensitive to a temporary decline in cognitive performance after sleep deprivation and to investigate the ability of the acetylcholinesterase inhibitor donepezil to reverse any sleep deprivation-induced impairment. Methods Thirty healthy volunteers were administered either a 5-mg daily dose of donepezil or placebo for 14–17 days, in a double-blind parallel group design, then underwent either 24 h sleep deprivation or a normal night of sleep in non-blinded crossover, and were subsequently tested on a battery of cognitive tasks designed to measure different components of memory and executive function. Results Sleep deprivation selectively impaired performance on several memory tasks whilst also impairing non-memory function on these tasks. Performance on other tasks was spared. Despite partially reversing the decline in subjective alertness associated with sleep deprivation, treatment with donepezil failed to significantly reverse the decline in cognitive performance on any of the tasks. Conclusions The results demonstrate the sensitivity of certain tests, particularly those that measure memory function, to cognitive impairment after sleep deprivation. The inability of donepezil to reverse this performance decline suggests that the sleep deprivation model of cognitive impairment may not be suitable for detecting pro-cognitive effects of cholinergic augmentation. Copyright © 2011 John Wiley & Sons, Ltd. key words—donepezil; sleep deprivation; memory; executive function; cholinergic; cognitive

INTRODUCTION Impaired memory function is the core clinical symptom of Alzheimer’s disease (AD). Donepezil, an acetycholinesterase inhibitor, improves memory function in AD (Homma et al., 2000; Doody et al., 2001; Lopez-Pousa et al., 2001; Gauthier et al., 2002; Saine et al., 2002; Froelich et al., 2004; Foldi et al., 2005; Rockwood et al., 2007; Galvin et al., 2008). However, beneficial effects of donepezil on cognition in AD are only moderate and relatively short-lived (Harry and Zakzanis, 2005; Sun et al., 2008), and there is an urgent need for more effective and enduring memory-enhancing drugs. The evidence for pro-cognitive effects of donepezil in healthy, normal-performing volunteers is somewhat mixed. Using parallel group designs, several studies have found positive effects of a daily 5-mg dose of *Correspondence to: C. Dodds, CUC, Addenbrookes Centre for Clinical Investigation, Box 128, Hills Road, Cambridge CB2 0GG, UK. Tel: +44 (0) 1223 296182; Fax: +44 (0) 1223 296108. E-mail: [email protected]

Copyright © 2011 John Wiley & Sons, Ltd.

donepezil on cognitive function, with the treatment duration ranging from 30 to 42 days (Yesavage et al., 2002; Gron et al., 2005; Fitzgerald et al., 2008). Hutchison et al. (2001) also found positive effects of a single 5-mg dose in a crossover design. However, small negative effects of donepezil were found in two studies that administered a 5-mg daily dose for 14 days in a parallel group design (Beglinger et al., 2004, 2005). The lack of any consistent evidence for procognitive effects of donepezil in healthy volunteers may be due to methodological differences, or possibly high baseline performance and a resultant lack of sensitivity to further pharmacological enhancement. One way to increase sensitivity of experimental models is to induce a transient decline in cognitive function in healthy volunteers and then to test the ability of the drug to reverse any such impairment. Sleep deprivation is one method of inducing a transient, reversible decline in cognitive performance in healthy volunteers. Sleep deprivation impairs a range of cognitive functions (Morris et al., 1960;

Received 11 July 2011 Accepted 19 October 2011

sleep deprivation and donepezil

Gillberg and Akerstedt, 1998; Drummond et al., 2000; Harrison and Horne, 2000; Doran et al., 2001; Drummond et al., 2001; Jennings et al., 2003; Chee and Choo, 2004; Habeck et al., 2004; Choo et al., 2005; Nilsson et al., 2005; Chee et al., 2006; Chuah et al., 2006; Hsieh et al., 2007; Chee and Chuah, 2008; Chee et al., 2008; Tomasi et al., 2009). One previous study, published in two parts (Chuah and Chee, 2008, Chuah et al., 2009), examined the effects of donepezil on cognitive function and associated neural activation in sleep-deprived healthy adults. In terms of behavioural performance, donepezil reversed the sleep deprivation-induced decline in visual short-term memory, visual attention span and verbal episodic memory, but only in those participants whose performance was more susceptible to the effects of sleep deprivation. In the present study, we aimed to extend these findings by investigating the effects of sleep deprivation and donepezil on a wider range of cognitive tasks to examine more closely the cognitive specificity of the effects. We hypothesized that sleep deprivation would impair performance across multiple cognitive domains but that donepezil would reverse only the memory impairment. Another aim of the present study was to perform a more fine-grained analysis of the effects of sleep deprivation and donepezil on recollection and familiarity judgements, as well as an examination of the ‘memory illusion’ effect, whereby erroneous familiarity with, but not recollection of, a stimulus can be induced by the prior presentation of the same stimulus as a masked (not consciously perceived) prime (Jacoby and Whitehouse, 1989). We hypothesized that sleep deprivation would cause an overall memory impairment that would be more pronounced for recollection judgements than familiarity judgements and that this impairment would be reversed by donepezil. We also hypothesized that sleep deprivation would increase susceptibility to the memory illusion effect and that this increased susceptibility would be reversed by donepezil. In addition to behavioural testing, participants were scanned using magnetoencephalography (MEG) whilst performing some of the cognitive tasks. However, here we report only behavioural results, and the MEG results will be reported elsewhere.

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Committee (ref 07/H0306/120). All participants were free of medication (including nicotine and drugs of abuse) and had no physical or psychiatric illness as assessed by a physician. Smokers were only included if they smoked fewer than five cigarettes per day and were able to abstain from smoking for 24 h prior to each assessment session and for the duration of the assessment sessions. Psychiatric history was assessed using a semi-structured interview by a clinician. Participants were included in the study if they fulfilled the following criteria: a normal sleep pattern — as defined by a score of less than 5 in the Pittsburgh Sleep Quality Index; IQ greater than 90 as measured by the National Adult Reading Test (Nelson, 1982); no evidence of physical or mental impairment; body weight at least 50 kg and body mass index within the range 18.5–29.9 kg/m2 inclusive; and able to understand and comply with protocol requirements and instructions in English. Participants were also required to abstain from alcohol, tobacco and caffeine for at least 24 h prior to, and for the duration of, each assessment session. Design The study employed a randomized double-blind placebo-controlled parallel group design. Participants were randomized to 14–17 days dosing with placebo or donepezil, and the order of their rested wakefulness and sleep deprivation sessions was balanced (this aspect of the study was non-blinded and utilized a crossover design) (Figure 1). Dose rationale Donepezil is approved for treatment of AD at doses up to 10 mg daily, although the recommended starting dose is 5 mg/day. The terminal disposition half-life is

METHODS Participants Thirty healthy adults (six women) aged between 25 and 41 years (mean 29, SD 8) gave their informed consent to participate in the study. The study was approved by the Cambridgeshire Research Ethics Copyright © 2011 John Wiley & Sons, Ltd.

Figure 1.

Schematic of the study design

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approximately 80 h. Thus, steady state for 5-mg daily dosing is reliably achieved after 14 to 21 days of once daily administration (Rogers et al., 1998). Therefore, we used 5 mg/day for a 14- to 17-day period. Procedure Each participant attended the GSK Clinical Unit Cambridge (CUC) at Addenbrooke’s Hospital for screening (visit 1), two assessment sessions (visits 3 and 5) (which included an overnight stay), two dosing visits (visits 2 and 4) and a follow-up visit (visit 6) (Figure 2). All assessment sessions were separated by a minimum of 4 weeks. For the rested session, participants slept in the CUC. Participants practised the cognitive tasks during the screening visit. Assessment sessions followed 14–17 days after start of dosing. At the dosing visits, participants received, in random order, donepezil during one visit and placebo during the other, or placebo for both visits, depending on the randomization schedule. The randomization code for the study was produced using the GSK clinical trial randomization system such that the study team (other than the pharmacist) was blind to treatment. Dispensing of the individual doses into individual subject pots according to the randomization code was performed by the pharmacy at the CUC. All work within the pharmacy is carried out to Good Manufacturing Practice and is audited by both the internal company regulators and the Medicines and Healthcare products Regulatory Agency. Thereafter, the participants took study medication, at home, every evening (for a total of 14 to 17 days dosing) before the assessment sessions. Participants did not take any study drug between visits 3 to 4 and visits 5 to 6. These intervals were intended as ‘washout’. For visits 3 and 5, participants underwent sleep deprivation or they were allowed to sleep, depending on their randomization. Sleep deprivation sessions Sleep deprivation in this study was defined as the total absence of sleep for 24 h from arrival on day 14 or 42 to the morning of the test period on day 15 or 43 (visits 3 and 5). During sleep deprivation, the participants

Figure 2.

Schematic of study procedure for a single participant


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were allowed to engage in non-strenuous activity. The staff at the CUC kept the participants under continuous surveillance to ensure that they did not fall asleep. During the sleep deprivation periods, each participant arrived at the CUC at approximately 08:00 h on day 14 or 42. Participants then completed a Bond and Lader visual analogue scale (VAS) (1974) and the Pittsburgh Sleep Quality Index test. The VAS was repeated every 2 h until testing next morning. Participant was dosed at approximately 20:00 h. On the following day (after sleep deprivation) (at approximately 08:00 h on day 15 or 43), the participants were driven to the nearby Cognition and Brain Sciences Unit (CBU) for MEG scanning. In the MEG scanner, the participants performed a number of cognitive tasks including the N-back working memory and the verbal recognition memory tasks. In the present paper, only the behavioural results of the latter tasks are reported. On completion of the MEG scanning, the participants were driven back to the CUC. This included the VAS and a set of CANTAB cognitive tasks. Rested session For the test under rested conditions, the participants arrived in the CUC the night before testing at approximately 20:00 h (day 14 or 42). The participants first completed the VAS and were subsequently dosed with placebo. At 23:00 h, the lights were turned out, and the participants went to sleep until 07:30 h on the following morning (day 15 or 43). At approximately 09:00 h, the participants were driven to the CBU for MEG scanning. Following testing at the CBU, the participants were driven back to the CUC for CANTAB cognitive testing. Cognitive tests Several tasks were taken from the CANTAB computer-administered battery (www.camcog.com), including the following tests of executive function: intradimensional–extradimensional set shifting; stop signal; stockings of Cambridge; and Cambridge gamble; and the following tests of memory function: spatial span; and pattern recognition memory. These tasks are all described in detail elsewhere (Owen et al., 1995; Rahman et al., 1999; Rogers et al., 1999). Two non-CANTAB tasks were also used: the N-back task, a test of working memory with different levels of cognitive load in which participants are required to report either the number currently on the screen (0-back), the number on the screen on the previous trial (1-back) or the number on the screen Hum. Psychopharmacol Clin Exp 2011; 26: 578–587. DOI: 10.1002/hup


on the trial before the previous trial (2-back); and a recognition memory test based on a prior EEG experiment by Woollams et al. (2008) in which participants perform a lexical decision task on a list of words (study phase) and are subsequently required to judge whether words are old (previously studied) or new (test phase). In addition, if the participants responded that the word was previously studied, they indicated whether they ‘remembered’ (R) it or just ‘knew’ (K) it (a paradigm developed by Tulving, 1985), allowing estimates of the probability of recollection and familiarity in each condition (e.g., Yonelinas et al., 1996). Further, half of the old items and half of the new items were preceded by the same word (primed) or by a different word of the same study status (unprimed). Statistical analysis All measures were analyzed using a mixed-effects, repeated measures analysis of variance (ANOVA). If necessary, transformations (e.g. log) were applied before analysis to ensure normality and homogeneity of variance. Fixed effects were included for visit, sleep deprivation (sleep deprived versus rested) and treatment (donepezil versus placebo), with a random effect for participant. Additional fixed effects were included if appropriate, where interactions between sleep deprivation, drug and relevant task-related factors were examined. Two principal contrasts were examined, with an additional supportive contrast: (i) Sleep deprivation versus rested (within-participant contrast) across all participants, irrespective of treatment during sleep deprivation. (ii) Donepezil versus placebo (between-participant contrast) across all participants during the sleep-deprived session. (iii) (Supportive) Sleep deprivation versus rested (withinparticipant contrast) across only those participants who received placebo during their sleep-deprived session. The Kenward–Roger method was applied for adjusting the degrees of freedom for small sample sizes (Kenward and Roger, 1997), which can result in non-integer degrees of freedom. The statistical significance level was set at 5%, with no adjustment for multiplicity. For the recognition memory task, independent effects of sleep deprivation on remember/know judgements were also examined by including this factor in the ANOVA. However, some have argued that recollection and familiarity are independent processes, in which case they are not necessarily estimated directly from the proportion of remember and know judgements, respectively. Rather, if one assumes that recollection always produces a remember judgement, then familiarity is better estimated by the proportion Copyright © 2011 John Wiley & Sons, Ltd.

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of studied items given a know judgement that remain after adjusting for the proportion given a remember judgement (Yonelinas et al., 1996), that is, familiarity, F, is estimated by F = K / (1 R). Therefore, we also repeated the overall ANOVA using this ‘independence scoring’ instead. RESULTS Note that in all graphs the data in the well-rested session is divided into separate bars for placebo and drug groups. Although we did not examine effects of drug in the rested session, this division is made so that readers can compare the sleep-deprived (placebo and drug) groups against the same subjects in the rested session. Subjective alertness There was a significant effect of sleep deprivation on subjective alertness, F(1, 27.3) = 47.19, p < 0.0001. Participants reported feeling significantly less alert after the sleep deprivation session relative to the rested session, t(27.3) = 6.87, p < 0.0001. Donepezil partially reversed this sleep deprivation-induced decline in alertness such that participants in the sleep deprivation–donepezil group reported feeling significantly more alert than participants in the sleep deprivation–placebo group, t(41) = 2.15, p < 0.05, but significantly less alert than after the rested session, t(33.2) = 3.54, p < 0.01. Stop signal task. There were no significant effect of sleep deprivation on stop signal reaction time (SSRT) (p = 0.14) and no significant effect of drug within the sleep-deprived session (p = 0.94). Mean correct go trial reaction time was significantly slower in the sleep-deprived session (384 ms) relative to the rested session (345 ms), t(28) = 4.8, p < 0.001, but there was no significant effect of drug within the sleep deprivation session (p = 0.89). Intra–extradimensional set shift. There were no significant difference between extra-dimensional shift (EDS) errors in the sleep-deprived and rested sessions (sleep deprived versus rested, p = 0.64) and no significant difference between placebo and drug (p = 0.19). For total errors (adjusted), there was no significant difference between sleep-deprived and rested sessions (p = 0.54) or between drug and placebo (p = 0.38). Stockings of Cambridge. There were no significant differences in the mean number of moves or mean initial thinking time for 4 or 5 move problems between Hum. Psychopharmacol Clin Exp 2011; 26: 578–587. DOI: 10.1002/hup

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the sleep-deprived and rested sessions or between placebo and drug (rested versus sleep deprived, all p > 0.15; donepezil versus placebo, all p > 0.22). Cambridge gamble task. There were significant effects of ascending versus descending sequence (p < 0.001) and ratio (p < 0.001), and an interaction between the two (p = 0.0011) (more bet descending than ascending and more bet on higher ratios than lower). However, there were no significant main effects of sleep deprivation or treatment, or interactions involving these. Spatial span. There were no significant difference in ‘span length’ between the rested and sleep-deprived sessions (rested versus sleep deprived, p = 0.14) and no significant effect of drug (p = 0.84). Pattern recognition memory. The difference between accuracy in the rested and sleep deprivation sessions was marginal (rested: 98.2% versus sleep deprivation: 96.6%, F(1, 27.2) = 3.76, p = 0.063), but there was no significant difference between donepezil and placebo within the sleep-deprived session (p = 0.25). ‘Mean correct latency’ was significantly different between the rested and sleep-deprived sessions (rested: 1450 ms vs sleep deprived: 1520 ms, F(1, 27.2) = 5.08, p = 0.033) but not between donepezil and placebo (p = 0.74). N-back accuracy. There were a significant main effect of sleep deprivation (F(1, 26) = 17.84, p < 0.001), a significant main effect of cognitive load (F(1.328, 34.54) = 33.36, p < 0.001) and a significant interaction between sleep deprivation and cognitive load (F(1.8, 46.73) = 3.73, p = 0.036). Whilst participants performed more poorly in the sleep-deprived session relative to the rested session at all levels of N, this effect was strongest in the N = 1 condition (N = 0: 97% vs 94% t(27) = 2.3, p = 0.028; N = 1: 92% vs 84% t(27) = 4.4, p = 0.001; N = 2: 79% vs 73% t(27) = 2.73, p = 0.019; chance = 25%) (Figure 3). There were no significant interactions with drug (p > 0.16). To examine whether individual differences in sensitivity to sleep deprivation masked an overall drug effect, we repeated the analysis of the 1-back data, excluding those subjects who did not show a sleep deprivation-induced decline in accuracy. However, there was still no task drug interaction (p = 0.58). N-back reaction times. There were a significant main effect of sleep deprivation (F(1, 26) = 9.27, p = 0.005), Copyright © 2011 John Wiley & Sons, Ltd.

Figure 3. Visual analogue scale subjective alertness scores in the rested and sleep-deprived sessions, for placebo and donepezil groups. Error bars represent SEM. The division of the well-rested session into placebo-group and drug-group participants in the figure is provided for illustrative purposes

a significant main effect of N (F(1.54, 40.04) = 39.84, p < 0.001) and a trend for an interaction between sleep deprivation and N (F(1.786, 46.43) = 3.155, p = 0.057). At N = 0 and N = 1, there were significant effects of sleep deprivation in increasing reaction times (N = 0: t(27) = 2.79, p = 0.01; N = 1: t(27) = 3.95, p < 0.001), but this was not significant at N = 2 (t(27) = 1.73, p = 0.09) (Figure 4). There were no significant interactions with drug (p > 0.59), although there was a trend for an N drug interaction (p = 0.08). Recognition memory test. Participants who did not perform above chance in the lexical decision task of

Figure 4. N-back task performance: mean accuracy for N = 0, N = 1 and N = 2 conditions in the rested and sleep-deprived sessions, for placebo and donepezil groups. Error bars represent SEM. The division of the well-rested session into placebo-group and drug-group participants in the figure is provided for illustrative purposes



the study phase were removed. This led to removal of two participants in the placebo group, leaving N = 28 (n = 14 per drug condition) for both groups for the study phase. Any participant who failed to perform above chance in overall recognition memory performance, or who scored above 2 on an R/K confusion metric (defined as [R false alarms / R hits] / [K false alarms / K hits], Woollams et al., 2008) was removed. Under this criterion, four participants were removed. This left N = 24 (n = 12 per drug condition) for the test phase. Study phase accuracy. Performance accuracy on the study phase, in which participants performed a lexical decision task on words and pseudo-words, was assessed via ‘Pr’ scores, where Pr is the proportion of ‘hits’ (words that the participant labelled ‘words’) minus the proportion of ‘false alarms’ (pseudo-words that the participant labelled ‘words’). A Pr score of 0 thus indicates chance performance. There was a significant main effect of sleep deprivation (F(1, 26) = 34.7, p < 0.001), with sleep-deprived participants performing worse than rested participants (Pr(rested) = 0.94, Pr(sleep deprived) = 0.87, t(27) = 6, p < 0.001). There was no significant interaction of sleep deprivation and drug (p = 0.85). Study phase reaction time. There were a significant main effect of sleep deprivation (F(1, 26) = 5.05, p = 0.033), with slower responses in the sleep-deprived session (724 ms) relative to the rested session (752 ms), and a significant main effect of condition (F(1, 26) = 100.87, p < 0.001) with faster responses for words (682 ms) relative to pseudo-words (795 ms), but no significant interaction of sleep deprivation with drug (p > 0.3). Test phase accuracy. Performance accuracy on the test phase, in which participants reported whether they thought words were old or new, was assessed via ‘Pr’ scores, where Pr is the proportion of ‘hits’ (previously studied words called ‘old’) minus the proportion of ‘false alarms’ (previously unstudied words called ‘old’). Collapsing across remember/know and priming manipulations, there was a significant main effect of sleep deprivation (F(1, 22) = 20.10, p < 0.001), with participants performing worse in the sleep-deprived session (Pr = 0.31) than in the rested session (Pr = 0.43, t(23) = 4.54, p < 0.001). There was no significant interaction of this effect with drug (p = 0.54). To investigate more subtle effects of sleep deprivation on memory, specifically on recollection, familiarity and Copyright © 2011 John Wiley & Sons, Ltd.

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priming, an ANOVA was expanded to include factors of remember/know and priming, as well as the factor of hits and false alarms. An interaction between any factor and the hits/false alarms factor is equivalent to an effect of that factor on the Pr score considered earlier; its inclusion in the ANOVA, however, allows investigation of separate effects of other factors on hits and/or false alarms. The resulting five-way ANOVA showed two, three-way interactions that reached significance of sleep deprivation remember/know hits/false alarms (F(1, 22) = 6.647, p = 0.017) and of sleep deprivation remember/know priming (F(1, 22) = 6.134, p = 0.021). These interactions are explored further in the following two sections. No interactions between sleep deprivation and drug reached significance (p > 0.12). Three-way interaction between sleep deprivation remember/know hits/false alarms Looking at remember and know judgements separately (and collapsing across the factors of drug group and priming), there was a highly significant interaction of sleep deprivation with hits/false alarms for remember judgements only (F(1, 23) = 20.64, p < 0.001). This interaction results from a significant reduction in remember hits (rested: 0.31, sleep deprivation: 0.23, t(23) = 3.14, p = 0.005) and a concurrent increase in remember false alarms (rested: 0.024, sleep deprivation: 0.05, t(23) = 2.07, p = 0.05) following sleep deprivation. There was no significant effect of sleep deprivation on know judgements (p > 0.4) (Figure 5). These results potentially support prior claims (see Introduction) that sleep deprivation selectively impairs

Figure 5. N-back task performance: mean reaction time (RT) in milliseconds for N = 0, N = 1 and N = 2 conditions in the rested and sleep-deprived sessions, for placebo and donepezil groups. Error bars represent SEM. The division of the well-rested session into placebo-group and drug-group participants in the figure is provided for illustrative purposes


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recollection as opposed to familiarity. However, when the ANOVA was repeated using the method of independent scoring for remember/know judgements (see Methods section), the critical interaction between sleep deprivation and recollection/familiarity (rather than between sleep deprivation and remember/know) was no longer reliable (F(1, 23) = 1.734, p = 0.201). In this case, sleep deprivation affected both recollection and familiarity estimates similarly, that is, sleep deprivation affected recollection and familiarity estimates similarly. Three-way interaction between sleep deprivation remember/know priming To investigate this modulation of the effect of priming on remember/know judgements by sleep deprivation, rested and sleep-deprived sessions were analyzed separately (collapsing drug group and hits/false alarms). For the rested session, there was a significant interaction of remember/know and priming (F(1, 11) = 11.7, p < 0.01). As in Woollams et al. (2008), this interaction reflects an effect of priming on know judgements, increasing hits/false alarms (t(11) = 5.77, p < 0.001), but no effect of priming on remember judgements (t = 0.08, p = 0.94) (Figure 6). In the sleepdeprived session, however, there was no interaction between priming and R/K judgements (F < 1, p = 0.95) (similar results obtained using the abovementioned independent estimate of F in place of the proportion of K judgements) (Figure 7). Test phase reaction time. Collapsing across remember/ know and priming manipulations, there was a significant main effect of sleep deprivation (F(22, 1) = 9.96, p = 0.005),

Figure 6. Recognition task performance: Pr scores (proportion of hits minus proportion of false alarms) in the rested and sleep-deprived sessions, for placebo and donepezil groups. Error bars represent SEM. The division of the well-rested session into placebo-group and drug-group participants in the figure is provided for illustrative purposes


Figure 7. Recognition task performance: effects of priming and remember/know judgements (collapsed across drug group) on average hits and false alarm (FA) rate in the rested and sleep-deprived sessions. Error bars represent SEM. The division of the well-rested session into placebo-group and drug-group participants in the figure is provided purely for illustrative purposes

with participants responding faster in the rested session (884 ms) than in the sleep-deprived session (948 ms). DISCUSSION Twenty-four hours of total sleep deprivation in healthy volunteers led to significant performance impairments on the N-back working memory and recognition memory tasks and an almost significant impairment on the CANTAB Pattern Recognition Test. Performance on all of the remaining tasks was not significantly affected. We did not observe any significant effect of donepezil on performance on any of the tasks. Sparing of cognitive performance in certain domains after sleep deprivation could be related to the relatively short duration of sleep deprivation (24 h) and/or the particular time of day chosen for testing (morning), when, due to circadian factors, cognitive performance may increase up to the levels of the previous day. However, 24 h sleep deprivation is a standard protocol in the literature and has been shown previously to produce impairments in cognitive function with studies employing a variety of testing times (Thomas et al., 2000; Kim et al., 2001; Chee and Choo, 2004; Nilsson et al., 2005; Tomasi et al., 2009). Moreover, given the task selectivity of the effects of sleep deprivation in the present study, these findings are more likely to be due to measurement factors. The finding that effects of sleep deprivation were specific to memory tasks is consistent with many previous studies showing that sleep plays an important role in memory (Morris et al., 1960; Harrison and Horne, 2000; Drummond et al., 2000; Sei et al., Hum. Psychopharmacol Clin Exp 2011; 26: 578–587. DOI: 10.1002/hup


2000; Davis et al., 2003; McDermott et al., 2003; Habeck et al., 2004; Bell-McGinty et al., 2004; Chee et al., 2006, 2008; Choo et al., 2005). Previous studies have also found impairments on attention and executive function tasks after sleep deprivation (Gillberg and Akerstedt, 1998; Doran et al., 2001; Drummond et al., 2001; Jennings et al., 2003; Nilsson et al., 2005; Chuah et al., 2006; Hsieh et al., 2007; Chee et al., 2008; Tomasi et al., 2009), suggesting that effects of sleep deprivation are not restricted to memory function. Moreover, in the present study, sleep deprivation also affected non-memory related processes. For example, in the N-back task, there were a significant decline in accuracy and a significant increase in reaction time in the 0-back condition, essentially an attentional task with no memory demand. Thus, whilst the present results provide novel information about which tasks and processes are most sensitive to the effects of sleep deprivation, they do not necessarily reflect a process-specific effect of sleep deprivation on memory function. The apparent specificity of the present results may also be due to the fact that certain tasks are inherently more sensitive to the effects of sleep deprivation, perhaps due to their length and monotony. A related factor is the power provided by any particular task to detect an effect of sleep deprivation. In the tasks that showed the most robust effects of sleep deprivation (N-back and recognition memory), performance measures were obtained by averaging across multiple repetitions of each trial type, thereby maximizing the ability to make a precise and reliable measurement of task performance (i.e. increasing signal-to-noise). In contrast, in several of the tasks that did not show an effect of sleep deprivation, measures were obtained by observing performance at a specific stage in the task, for example the number of errors made at the extradimensional shift stage. The fact that these measurements are obtained over a much smaller number of trials potentially renders them noisier and less reliable and consequently less sensitive to subtle changes in performance across testing sessions. We also investigated the effects of sleep deprivation and donepezil on different components of recognition memory — recollection, familiarity and priming. When analyzing raw proportions of remember and know judgements, we confirmed previous claims that sleep deprivation affects recollection to a greater extent than familiarity (Drosopoulos et al., 2005; Atienza and Cantero, 2008; though note that the present study investigated the effect of sleep on the encoding and retrieval of memories rather than consolidation of memories). However, when the remember and know Copyright © 2011 John Wiley & Sons, Ltd.

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proportions were scored under the assumption that recollection and familiarity are independent processes (Yonelinas et al., 1996), the data suggested that sleep deprivation affected both recollection and familiarity. Thus, whether or not sleep deprivation selectively affects recollection depends on one’s theory of how recollection and familiarity combine to generate remember and know judgements: according to theories in which recollection and familiarity are exclusive, it does; according to theories in which they are independent, it does not (see Mayes et al., 2007 for review). We also found that sleep deprivation affected the Jacoby and Whitehouse (1989) ‘memory illusion’; whereby, a masked repetition prime presented immediately prior to the test cue increases the probability that people call that test cue old, regardless of whether it was studied (i.e. a hit) or not (i.e. a false alarm). We replicated this effect in the rested sessions — in particular that the memory illusion only occurs for know rather than remember judgements (as in Woollams et al., 2008) — but found a reduced memory illusion after sleep deprivation. We had hypothesized that sleep deprivation would increase the likelihood of memory illusions, but this opposite finding suggests instead that sleep-deprived individuals are less prone to such priming effects. Donepezil did not significantly reverse the impairments in cognitive function induced by sleep deprivation despite causing a moderate increase in subjective alertness. Whilst there is some prior evidence for a pro-cognitive effect of donepezil in healthy volunteers (Hutchison et al., 2001; Yesavage et al., 2002; Gron et al., 2005; Fitzgerald et al., 2008; Ginani et al., 2011), other studies have found negative effects (Beglinger et al., 2004, 2005), and a recent systematic review of studies investigating the cognitive effects of donepezil in healthy volunteers concluded that there is insufficient evidence to conclude that donepezil has beneficial effects on cognition in healthy people (Repantis et al., 2010). One study, published in two parts, previously examined the effects of donepezil on cognitive performance after sleep deprivation. Chuah et al. (2008, 2009) found that donepezil only exerted a beneficial effect in subjects who were cognitively impaired by sleep deprivation, suggesting high inter-subject variability in the pro-cognitive effects of donepezil. However, these findings were based on post-hoc analyses of the data involving the use of a median split to divide subjects according to their vulnerability to sleep deprivation. Moreover, some of the findings from that study may have been due to regression to the mean. With regard to individual differences in the present study, in Hum. Psychopharmacol Clin Exp 2011; 26: 578–587. DOI: 10.1002/hup

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the 1-back task, only five subjects did not show a sleep deprivation-induced impairment of performance, and excluding these five subjects did not change the results. Therefore, it seems unlikely that the lack of effect of donepezil was due to individual differences in sensitivity to sleep deprivation. Thus, the present results are broadly consistent with the previous literature on donepezil in demonstrating a lack of firm evidence for beneficial effects of the drug on cognitive performance, even under conditions of sleep deprivation. Discrepancies between studies relating to the cognitive-enhancing effects of donepezil may be due to the use of different doses. A recent study (Ginani et al., 2011) found that 7.5 mg but not 5 mg donepezil produced cognitive-enhancing effects in healthy volunteers. Thus, whilst a 5-mg daily dose of donepezil is sufficient to produce cognitive-enhancing effects in patients with AD (Birks and Harvey, 2006), a larger dose may be required to demonstrate similar effects in healthy volunteers. Nevertheless, even if donepezil can improve cognition in healthy people, it may be unable to overcome the widespread changes in multiple neurotransmitter systems associated with sleep deprivation, including serotonin, noradrenaline, dopamine, acetylcholine, GABA and adenosine (for a review, see Longordo et al., 2009). Consistent with this, stimulants such as modafanil and amphetamine, which modulate multiple neurotransmitter systems, have been shown more consistently to attenuate sleep deprivation-induced deficits in cognitive function (Killgore et al., 2009). Limitations of the present study include the following: A relatively small sample size was used for the placebo versus drug comparison such that the study may have been underpowered to detect an effect (although note that drug effects were not even close to significance). The study was not balanced for gender. We did not measure plasma levels and could not ensure compliance because of subjects taking the treatment at home (although this limitation is somewhat mitigated by the finding of an effect of donepezil on subjective alertness). Finally, subjects slept in the research facility for the well-rested session and therefore may have experienced some disruption to their normal sleep patterns. In summary, we observed a selective impairment in cognitive function on several memory tasks, including impairments on non-memory function, after 24 h total sleep deprivation, in the absence of any detectable effect on the primary measures of executive function. Despite showing a moderately positive effect on subjective alertness, donepezil failed to significantly Copyright © 2011 John Wiley & Sons, Ltd.

ET AL.

reverse the sleep deprivation-induced cognitive impairment. These findings suggest that the sleep deprivation model of cognitive impairment may be a reliable method for inducing a decline in cognitive function in healthy volunteers on specific tasks but that it may not be an effective model for predicting the efficacy of potential new memory-enhancing compounds in dementia. CONFLICTS OF INTEREST C. Dodds, E. Bullmore, S. Miller, O. Dewit, P. Lawrence and P. Nathan work for GlaxoSmithKline Pharmaceuticals. S. Christensen works for Lundbeck Pharmaceuticals. ACKNOWLEDGEMENTS This work was supported by GSK and by the UK Medical Research Council (WBSE U.1055.05.012.00001).

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