Brain Advance Access originally published online on July 15, 2009
Brain 2009 132(9):2356-2371; doi:10.1093/brain/awp176
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Modulation of fusiform cortex activity by cholinesterase inhibition predicts effects on subsequent memory
1 Wellcome Centre for Neuroimaging at UCL, University College London, London WC1N 3BG, UK 2 Deparment of Clinical Neuroscience, Charing Cross Hospital, Imperial College London, London, W6 8RF, UK 3 UCL Institute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK
Correspondence to: Paul Bentley, Department of Clinical Neuroscience, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London, W6 8RF, UK E-mail: p.bentley{at}imperial.ac.uk
Cholinergic influences on memory are likely to be expressed at several processing stages, including via well-recognized effects of acetylcholine on stimulus processing during encoding. Since previous studies have shown that cholinesterase inhibition enhances visual extrastriate cortex activity during stimulus encoding, especially under attention-demanding tasks, we tested whether this effect correlates with improved subsequent memory. In a within-subject physostigmine versus placebo design, we measured brain activity with functional magnetic resonance imaging while healthy and mild Alzheimer's disease subjects performed superficial and deep encoding tasks on face (and building) visual stimuli. We explored regions in which physostigmine modulation of face-selective neural responses correlated with physostigmine effects on subsequent recognition performance. In healthy subjects physostigmine led to enhanced later recognition for deep- versus superficially-encoded faces, which correlated across subjects with a physostigmine-induced enhancement of face-selective responses in right fusiform cortex during deep- versus superficial-encoding tasks. In contrast, the Alzheimer's disease group showed neither a depth of processing effect nor restoration of this with physostigmine. Instead, patients showed a task-independent improvement in confident memory with physostigmine, an effect that correlated with enhancements in face-selective (but task-independent) responses in bilateral fusiform cortices. Our results indicate that one mechanism by which cholinesterase inhibitors can improve memory is by enhancing extrastriate cortex stimulus selectivity at encoding, in a manner that for healthy people but not in Alzheimer's disease is dependent upon depth of processing.
Key Words: fMRI; cholinergic; Alzheimer's disease; physostigmine; memory
Received December 5, 2008. Revised May 13, 2009. Accepted May 22, 2009.