Estradiol treatment altered anticholinergic-related brain activation during working memory in postmenopausal women

Abstract

Estradiol has been shown to affect cholinergic modulation of cognition in human and nonhuman animal models. This study examined the brain-based interaction of estradiol treatment and anticholinergic challenge in postmenopausal women during the performance of a working memory task and functional MRI. Twenty-four postmenopausal women were randomly and blindly placed on 1mg oral 17-β estradiol or matching placebo pills for three months after which they participated in three anticholinergic challenge sessions. During the challenge sessions, subjects were administered the antimuscarinic drug scopolamine, the antinicotinic drug mecamylamine, or placebo. After drug administration, subjects completed an fMRI session during which time they performed a visual verbal N-back test of working memory. Results showed that scopolamine increased activation in the left medial frontal gyrus (BA 10) and mecamylamine increased activation in the left inferior frontal gyrus (BA 46). Estradiol treatment compared to placebo treatment significantly reduced the activation in this left medial frontal region during scopolamine challenge. Estradiol treatment also increased activation in the precuneus (BA 31) during mecamylamine challenge. These data are the first to show that estradiol modulated antimuscarinic- and anitnicotinic-induced brain activity and suggest that estradiol affected cholinergic system regulation of cognition-related brain activation in humans.

Figure 1

Activation map for scopolamine minus placebo challenge (Figure 1a) and mecamylamine minus placebo challenge (Figure 1b) for the 3-back minus 0-back conditions of the N-back task (p < .05). These data are for subjects in the placebo treatment group only. Orange colors represent activation that is greater for the scopolamine or mecamylamine day relative to the placebo challenge day. Blue colors represent activation that is greater for the placebo relative to either challenge drug.

Figure 2

Activation map for estradiol treatment minus placebo treatment for the 3-back minus 0-back conditions of the N-back task for subjects on the scopolamine challenge day (Figure 2a) and the mecamylamine challenge day (Figure 2b; p < .05). Orange colors represent activation that is greater for the estradiol treatment group relative to the placebo treatment group. Blue colors represent activation that is greater for the placebo treatment group relative to the estradiol treatment group.

Figure 3

Sensitivity (d’ Figure 3a), percent correct (Figure 3b), and bias (C, Figure 3c) with standard errors on the 0- and 3-back conditions for the two treatment groups (E2 and PLC-TX) on each challenge day (SCOP, MECA, PLC).