fMRI-behavioral Study of Cholinergic Augmentation With Donepezil in Healthy Sleep Deprived Adults

Sleep Deprivation Clinical Trial

Official title: The Neural and Behavioral Correlates of How Donepezil Modulates Memory and Inhibitory Efficiency in the Context of 24 Hours of Sleep Deprivation

Status Completed

Clinical Trial Summary

The purpose of this study was to characterize how the anti-cholinesterase inhibitor (AChE-I) donepezil modulates brain regions involved in visual short-term memory, episodic memory and inhibitory efficiency following 24 hours of total sleep deprivation using fMRI as an additional marker for drug effect.

Clinical Trial Description

Short-term total sleep deprivation (SD) can result in cognitive impairments (Durmer and Dinges, 2005) that contribute to industrial catastrophes, transportation accidents, and medical errors (Mitler et al., 1988; Dinges, 1995; Barger et al., 2006; Philip and Akerstedt, 2006). This has motivated the use of pharmacological countermeasures, the most widely used being caffeine (Bonnet et al., 2005). Functional imaging studies of sleep-deprived persons could provide information concerning the neural substrates associated with SD-induced cognitive decline and in addition, provide functional assays for assessing drug effects. However, despite the growing number of functional imaging studies involving SD (Chee and Chuah, 2008), neuropharmacological studies in this context are rare (Thomas and Kwong, 2006).

Impairment of attention in sleep-deprived persons (Lim and Dinges, 2008) is an important cognitive deficit that affects other 'higher' cognitive operations, for example, visual short-term memory (VSTM) (Chee and Chuah, 2007). VSTM is used in service of many higher cognitive operations and has a capacity limit (Luck and Vogel, 1997; Cowan, 2000) that has neuroimaging correlates (Linden et al., 2003; Majerus et al., 2007; Mitchell and Cusack, 2007). SD-induced decline in VSTM capacity has been shown to originate from depressed visual attention or visual processing (Chee and Chuah, 2007). This was inferred from observing state-dependent, but load-independent, attenuation of parieto-occipital activation elicited by two visual tasks in which memory and perceptual load were independently and parametrically varied. Critically, the load-independent manner in which SD affected parieto-occipital activation across the tasks signified that something more fundamental than memory was depressed.

We reasoned that the decline in attention/visual processing might arise from reduced noradrenergic and cholinergic drive, given that these neurotransmitters underlie the maintenance of wakefulness (Everitt and Robbins, 1997; Steriade and McCarley, 2005) as well as visuospatial attention (Everitt and Robbins, 1997; Phillips et al., 2000). Increasing cholinergic transmission may improve visual working memory by increasing the selectivity of perceptual processing in the visual cortex (Furey et al., 2000a). Other experiments on visual memory have suggested that behavioral benefit may be associated with increases in extrastriate (Furey et al., 2000a; Lawrence et al., 2002) and superior parietal (Mentis et al., 2001) regions. Conversely, cholinergic blockade using scopolamine may impair orienting responses that involve parietal regions (Davidson and Marrocco, 2000).

Of relevance to the present study, the concentration of cholinergic effects in the parieto-occipital region coincides with the locus of state effects in several functional imaging studies of short term memory (Habeck et al., 2004; Chee and Chuah, 2007; Lim et al., 2007) in sleep-deprived persons.

Collectively, these findings led us to hypothesize that SD-induced deficits in visual processing/attention might benefit from cholinergic augmentation. We anticipated that the neural correlates of such performance modulation could be tracked by observing task-related parieto-occipital activation. To evaluate these hypotheses, we conducted a double-blind, placebo-controlled, cross-over functional imaging study to characterize the effect of donepezil on healthy young adults. In this within-subjects design, volunteers were scanned four times, twice following a normal night's sleep and twice after 24 hours of total SD. ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Sleep Deprivation

• NCT number: NCT00800553
• Study type: Interventional
• Source: Duke-NUS Graduate Medical School
• Status: Completed
• Phase: Phase 4
• Start date: November 2006
• Completion date: May 2007