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Disrupted cholinergic neurotransmission plays a central role in Alzheimer’s disease, medication-induced memory impairment, and delirium. At the systems level, this suggests anticholinergic drugs may alter the activity and interplay of anatomically distributed neural networks critical for memory function. Using a network-sensitive imaging technique (functional connectivity MRI) and a double-blind, crossover design, we examined the consequences of anticholinergic drug administration on episodic memory and functional network architecture in a group of clinically normal elderly. We observed that low-dose scopolamine (0.2 mg IV) decreased episodic memory performance and selectively decreased connectivity strength in 3 of 7 cortical networks. Both memory and connectivity effects were independent of β-amyloid burden. Drug-induced connectivity changes within the Default and Salience networks, as well as reductions in the strength of anticorrelation between these 2 networks, were sufficient to fully statistically mediate the effects of scopolamine on memory performance. These results provide experimental support for the importance of the Default and Salience networks to memory performance and suggest scopolamine-induced amnesia is underpinned by disrupted connectivity within and between these 2 networks. More broadly, these results support the potential utility of fcMRI as tool examine the systems-level pharmacology of psychoactive drugs.

Anticholinergic Amnesia is Mediated by Alterations in Human Network Connectivity Architecture