fMRI-behavioral Study of Cholinergic Augmentation With Donepezil in Healthy Sleep Deprived Adults
Condition: Sleep Deprivation
MeSH terms: Sleep Deprivation
Study type: Interventional
Phase: Phase 4

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.
    

Detailed 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.
    

Intervention name(s): donepezil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 5mg o.m. p.o. for approx. 2 weeks; 5mg of placebo for approx. 2 weeks
Other intervention name(s): Aricept
Intervention MeSH terms: Donepezil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: sleep deprivation; fMRI; double blind crossover study