Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory

Abstract

Modulation of the cholinergic neurotransmitter system results in changes in memory performance, including working memory (WM), in animals and in patients with Alzheimer disease. To identify associated changes in the functional brain response, we studied performance measures and regional cerebral blood f low (rCBF) using positron emission tomography (PET) in healthy subjects during performance of a WM task. Eight control subjects received an infusion of saline throughout the study and 13 experimental subjects received a saline infusion for the first 2 scans followed by a continuous infusion of physostigmine, an acetylcholinesterase inhibitor, for the subsequent 8 scans. rCBF was measured using H 2 15 O and PET in a sequence of 10 PET scans that alternated between rest and task scans. During task scans, subjects performed the WM task for faces. Physostigmine both improved WM efficiency, as indicated by faster reaction times, and reduced WM task-related activity in anterior and posterior regions of right midfrontal gyrus, a region shown previously to be associated with WM. Furthermore, the magnitudes of physostigmine-induced change in reaction time and right midfrontal rCBF correlated. These results suggest that enhancement of cholinergic function can improve processing efficiency and thus reduce the effort required to perform a WM task, and that activation of right prefrontal cortex is associated with task effort.Working memory (WM) refers to processes that maintain temporary, active representations of information so that they are available for further processing or recall (1, 2). The cholinergic neurotransmitter system is associated with WM, insofar as cholinergic agonists improve performance (3-5) and antagonists impair performance (6, 7) on WM tasks. Physostigmine, an acetylcholinesterase inhibitor that increases the duration of action of acetylcholine at the synapse, also improves performance on WM tasks in animals and in patients with Alzheimer disease (3-5, 8, 9). Functional brain imaging studies of humans have identified brain regions involved in the performance of object and spatial WM tasks, including occipital, temporal, parietal, and prefrontal cortical areas (10 -13). On object WM tasks, functional imaging studies in humans, as well as lesion and single neuron recording studies in nonhuman primates, indicate that posterior occipitotemporal cortex is associated more with perceptual processing, whereas prefrontal cortex is associated more with maintaining an active representation of the stimulus after it has been removed from view (10, 14 -17). Although it has been shown that cholinergic modulation alters WM performance, the site of modulation in the distributed neural system that mediates WM has yet to be determined. Therefore, we decided to investigate changes in regional cerebral blood f low (rCBF) and behavioral performance (reaction time) associated with cholinergic stimulation during a WM task. MATERIALS AND METHODSTwenty-one right-handed healthy volunteers participated in the study. Each p...

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