Original Investigation


, Volume 228, Issue 4, pp 673-683

First online:

Effect of cholinergic neurotransmission modulation on visual spatial paired associate learning in healthy human adults

  • Brian T. HarelAffiliated withCogState, Ltd Email author 
  • , Robert H. PietrzakAffiliated withYale University School of Medicine
  • , Peter J. SnyderAffiliated withLifespan Hospital SystemDepartment of Neurology, Alpert Medical School of Brown University
  • , Paul MaruffAffiliated withCogState LtdCentre for Neuroscience, University of Melbourne

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Use of cross-species neuropsychological paradigms such as visual–spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities.


This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, “process-based” computerized measure of visual–spatial PAL.


In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual–spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual–spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil.


Acute scopolamine challenge can produce large and robust deficits in visual–spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual–spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.


Paired associate learning Cognition Scopolamine Acetylcholinesterase inhibitor Donepezil Memory Executive function