Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance

Abstract

Studies of individuals with amnestic mild cognitive impairment (aMCI) have detected hyperactivity in the hippocampus during task-related functional magnetic resonance imaging (fMRI). Such elevated activation has been localized to the hippocampal dentate gyrus/CA3 (DG/CA3) during performance of a task designed to detect the computational contributions of those hippocampal circuits to episodic memory. The current investigation was conducted to test the hypothesis that greater hippocampal activation in aMCI represents a dysfunctional shift in the normal computational balance of the DG/CA3 regions, augmenting CA3-driven pattern completion at the expense of pattern separation mediated by the dentate gyrus. We tested this hypothesis using an intervention based on animal research demonstrating a beneficial effect on cognition by reducing excess hippocampal neural activity with low doses of the atypical anti-epileptic levetiracetam. In a within-subject design we assessed the effects of levetiracetam in three cohorts of aMCI participants, each receiving a different dose of levetiracetam. Elevated activation in the DG/CA3 region, together with impaired task performance, was detected in each aMCI cohort relative to an aged control group. We observed significant improvement in memory task performance under drug treatment relative to placebo in the aMCI cohorts at the 62.5 and 125 mg BID doses of levetiracetam. Drug treatment in those cohorts increased accuracy dependent on pattern separation processes and reduced errors attributable to an over-riding effect of pattern completion while normalizing fMRI activation in the DG/CA3 and entorhinal cortex. Similar to findings in animal studies, higher dosing at 250 mg BID had no significant benefit on either task performance or fMRI activation. Consistent with predictions based on the computational functions of the DG/CA3 elucidated in basic animal research, these data support a dysfunctional encoding mechanism detected by fMRI in individuals with aMCI and therapeutic intervention using fMRI to detect target engagement in response to treatment.

Keywords: Dentate gyrus; Entorhinal cortex; Levetiracetam; Memory; Mild cognitive impairment; fMRI.

Fig. 1

Schematic of the study design.

Fig. 2

Task designed to tax hippocampal DG/CA3 function. Participants were shown a series of pictures of every day objects and asked to judge if the item was new (seen for the first time), old (a repeated item) or similar (resembled a previously shown item). The lure items served as the critical trials for assessing performance dependent on the dentate gyrus/CA3.

Fig. 3

Increased hippocampal DG/CA3 activation is observed in the context of impaired memory performance in three aMCI cohorts. Task related activation and behavioral performance during the placebo condition in participants with aMCI in the (A) 62.5 mg BID treatment group, (B) 125 mg BID treatment group and (C) 250 mg BID treatment group. (A–C) Top left in A–C: sagittal view of the left medial temporal lobe. Green vertical lines identify slices through the hippocampus shown to the right. Top middle in A–C: segmentation of the structures of interest including the CA1, dentate gyrus/CA3 (DG/CA3), and subiculum (SUB) subregions of the hippocampus. Top right in A–C: coronal slices show statistical maps of the extent of task related activity in the left DG/CA3 from anterior to posterior. Bottom left in A–C: mean activity during lure trials correctly called similar. Participants with aMCI on placebo in each of the treatment groups show increased activity in the left DG/CA3 compared to healthy control subjects during lure trials based on independent samples t-tests. Bottom right in A–C: participants with aMCI on placebo in each of the treatment groups show impaired memory performance by more often incorrectly judging lure items as “old” instead of similar when compared to healthy control subjects. Statistics show p-values resulting from a planned post-hoc contrast for the interaction of group as a function of response type (old versus similar). Values are means ± SEM. *p < 0.05.

Fig. 4

Low dose levetiracetam normalizes DG/CA3 activation and improves task-related memory performance on critical lure items in participants with aMCI. Top graphs show mean fMRI activity during lure trials correctly called similar. Bottom graphs show behavioral performance as the proportion of lure trials called “old”, “new” and “similar”. For each cohort all analyses were within-subject comparing placebo with drug treatment. (A) In the 62.5 mg BID cohort levetiracetam did not significantly reduce activity in the DG/CA3 in participants with aMCI although activity under drug treatment was no longer significantly different from healthy control subjects. (B) In the 62.5 mg BID cohort levetiracetam improved memory performance in aMCI participants by reducing errors in which lures were incorrectly judged “old”, with more correct judgments of “similar”. (C) In the 125 mg BID cohort levetiracetam significantly reduced activation in the DG/CA3 and (D) significantly improved memory performance. (E) In the 250 mg BID cohort treatment levetiracetam did not reduce activity in the DG/CA3 and (F) did not alter memory performance in these patients. Values are means ± SEM. *p < 0.05.

Fig. 5

Low dose levetiracetam normalizes entorhinal cortex activity in participants with aMCI. Task-related activation in (A) 62.5 mg BID treatment group and (B) 125 mg BID treatment group. Top left in A–B: sagittal view of the left medial temporal lobe. Green vertical lines identify slices through the entorhinal cortex shown to the right. Top middle A–B: segmentation of the medial temporal lobe structures including the entorhinal (EC) and perirhinal (PRC) cortices. Top right A–B: coronal slices show statistical maps of the extent of task related activity in the left EC in the 62.5 mg BID treatment cohort and the 125 mg BID treatment cohort.