Patterned Hippocampal Stimulation Facilitates Memory in Patients With a History of Head Impact and/or Brain Injury

Abstract

Rationale: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI).

Methods: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject's medical history was unknown to the experimenters until after individual subject memory retention results were scored.

Results: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment.

Conclusion: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients.

Keywords: deep brain stimulation; epilepsy; hippocampus; memory; memory decoding; memory encoding; non-linear dynamics; traumatic brain injury.

FIGURE 1

Statistical interaction plot for the ANOVA. An ANOVA (SAS GLM, SAS Institute, Cary, NC, United States) of control (Non-stimulated) delayed-match-to-sample with delayed recognition (DMS-DR) test performance per subject sorted according to age (<35, 35–49, >50 years of age) and sex (Male, Female). DMS-DR performance was the dependent variable, subject was a continuous variable, while sex and age were independent discrete classification variables. The statistical interaction plot for the two-way ANOVA is shown.

FIGURE 2

Statistical interaction plot for the ANOVA by model. Performance by interaction traumatic brain injury (TBI)*memory plots for ANOVAs performed for each of the stimulation models. DMS-DR performance per subject (dependent variable) was modeled with independent variables of TBI-type [(Control, TBI, repeated and/or mild-to-moderate brain injury (RMBI)] and memory status (Normal, Impaired).

FIGURE 3

Subject–Condition differences in non-stimulated DMS-DR performance. Individual subject DMS-DR results were normalized by subtracting overall non-stimulated trial performance from control performance (i.e., non-stim DMS-DR from Control/Normal subjects), and dividing by individual subject standard deviation. The resulting differences in performance for the RMBI/TBI by Impaired/Normal memory status is plotted as mean (±intersubject SEM) normalized difference from baseline, control performance in the absence of stimulation. As expected, memory impaired subject performance the DMS-DR task worse than non-impaired subjects. (Note, since control performance was aggregated from all Control/Normal subjects, the bar and SEM for Control/Normal indicate individual subject variability.)

FIGURE 4

Subject–Condition differences in stimulated DMS-DR performance. Individual subject DMS-DR results were normalized by subtracting mean within-subject NoStim positive and negative pattern stimulated trial performance, and dividing by individual subject standard deviation to produce standard scores. Scores were then sorted by TBI status, stimulation model and presence or absence of memory impairment, and plotted as normalized mean (±inter-subject SEM) differences in DMS-DR performance. Individual linear contrasts were computed using paired-differences and mean standard error (MSE) from the overall multi-factor ANOVA. Asterisks (*) indicate conditions with significant differences between positive stim and NoStim conditions. Daggers (†) indicate statistically significant differences between positive and negative stim conditions.