Memory enhancement and deep-brain stimulation of the entorhinal area

Abstract

Background: The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.

Methods: We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).

Results: Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.

Conclusions: Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.).

Figures

Figure 1. High-Resolution Magnetic Resonance Imaging (MRI) in Two Subjects with Implanted Electrodes

Coronal high-resolution MRI scans show electrodes imaged on postoperative computed tomographic (CT) scans coregistered to the MRI scans. The two most distal electrodes (numbered 1 and 2, with 1 marking the most distal electrode) are shown in the left entorhinal region in one subject (Panel A) and the ipsilateral hippocampus in another subject (Panel B). For all subjects, the two most distal electrodes were used for stimulation.

Figure 2. Behavioral Performance on Spatial Learning Tasks

The graphs show the behavioral performance of six subjects on spatial learning tasks during stimulation and nonstimulation of the entorhinal region (Panels A and C) and the hippocampus (Panels B and D). Shown is the latency (Panels A and B) and excess path length (Panels C and D) across the six spatial learning trials for blocks 1 through 4 during stimulation and nonstimulation. I bars indicate standard errors for mean values among subjects for each condition.

Figure 3. Reduction in Excess Path Length

The percentage reduction in excess path length is shown for each subject during block 4 (i.e., retention) for store locations that had been learned during stimulation of the entorhinal region (Panel A) and hippocampus (Panel B) in blocks 1, 2, and 3, as compared with store locations that had been learned without stimulation. The maximum reduction that could occur was 100%, which is an excess path length of zero. The six sessions of entorhinal stimulation in all subjects (except Subject 5, who did not receive entorhinal stimulation) showed improvement in memory (reduced excess path length). The six sessions of hippocampal stimulation were from Subjects 2, 3, 4, 5, and 7; Subject 5 was tested for the right (5R) and left (5L) hippocampi separately. There was no consistent effect of stimulation of the hippocampus across subjects.

Figure 4. Average Theta-Phase Resetting in the Hippocampus in Four Subjects with Entorhinal and Ipsilateral Hippocampal Electrodes

Shown is the percentage change in theta power of the average waveform (i.e., theta-phase resetting) from the 5-second period before trial onset to the 5-second period after trial onset for stimulation and nonstimulation trials. Stimulation induced a mean increase of 44.3±6.9% in theta-phase resetting, as compared with the 5-second period before stimulation-trial onset. In the nonstimulation trials, there was no significant change in theta-phase resetting after the trial onset. I bars indicate standard errors for the mean values among the subjects for each condition.