Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment

Abstract

Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment. Here, we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.

Figure 1. Task designed to tax hippocampal DG/CA3 function

(A) Participants were presented with pictures of everyday objects for 2500 ms each separated by a 500 ms inter stimulus interval 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 similar lure items served as the critical trials for assessing performance dependent on the dentate gyrus/CA3. (B) The entorhinal cortex (EC) provides input from the cortex, via layer II (EC2) neurons, to the dentate gyrus (DG) and distal dendrites of CA3 pyramidal neurons. The CA3 afferents, in addition to innervating CA1, have autoassociative collaterals, forming the majority of CA3 synaptic input. The EC2 neurons and their targets in the hippocampus comprise a system that rapidly encodes representations that are distinct from prior memories. The sparse connections onto granule cells in DG by EC afferents promote pattern separation, while the recurrent CA3 network promote pattern completion.

Figure 2. Levetiracetam treatment normalizes increased dentate gyrus/CA3 activity in patients with aMCI

(A) High-resolution anatomical scan, with the left medial temporal lobe demarcated. (B) Segmentation of medial temporal lobe structures, including the CA1, dentate gyrus/CA3 (DG/CA3) and subiculum (SUB) subregions of the hippocampal formation. The boundaries between the CA3 and dentate gyrus (DG) cannot be clearly defined in structural scans and, therefore, are combined as DG/CA3 for analysis. (C) Area of task related activity based on an ANOVA of task condition in the left DG/CA3. (D) Area of task related activity in the left DG/CA3 resulting from the confirmatory analysis in which voxel selection is based on ANOVA of task condition that includes only age-matched healthy control subjects. (E) Graphs show mean activity ± SEM on lure trials correctly called similar. Patients with aMCI on placebo show increased activity in the left DG/CA3 compared to healthy control subjects during the lure trials. (F) Levetiracetam treatment significantly reduced activity in the DG/CA3 in patients with aMCI compared to the placebo condition. (G) In the confirmatory analysis for drug treatment, patients with aMCI taking low dose levetiracetam again showed significantly reduced BOLD activation during lure trials correctly identified as similar relative to the activity during those trials under placebo treatment. * p < 0.05 group comparisons using independent and paired samples t-tests respectively. See also Figure S1.

Figure 3. Levetiracetam treatment improves task-related memory performance on critical lure items in patients with aMCI

(A) Patients with aMCI on placebo had impaired memory performance by more often incorrectly judging lure items as 'old' instead of 'similar' when compared to healthy control subjects. (B) Levetiracetam improved performance in aMCI patients, by reducing errors in which lures were incorrectly judged 'old', with more correct judgments of 'similar', when comparing aMCI performance on drug with placebo. * Two-way repeated measures ANOVA revealed a significant contrast for the interaction of group as a function of response type (old vs similar), p < 0.05. Values are means ± SEM. See also Figure S2.