Inactivation of the hippocampus by electrical stimulation to preview post-surgical verbal recognition memory deficits

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PROJECT SUMMARY Patients who have undergone hippocampal resection to treat mesial temporal lobe epilepsy (MTLE) frequently experience memory deficits. Clinicians have few tools to preview these deficits when planning surgeries; the Wada test, which anesthetizes each hemisphere to test memory function available in the contralateral hemisphere, is the current medical standard. It was developed when temporal lobectomy was the primary surgical treatment for MTLE. In contrast, modern surgical techniques such as open selective amygdalohippocampectomy (AH) and laser interstitial thermal therapy (LITT) enable precise, selective lesions while minimizing damage to surrounding tissue. The difference in scale between the preview and the resection is one variable contributing to inconsistency in the utility of the Wada test to accurately preview memory deficits. Clinicians need a test which more precisely targets the tissue to be removed, and thus more accurately predicts functional consequences of losing the tissue. We propose using electrical stimulation (ES) through stereoelectroencephalography (SEEG) depth electrodes, placed in the hippocampus for clinical seizure monitoring, to generate temporary memory deficits at the spatial scale of intended surgical resection. Although ES of the hippocampus has been frequently employed to study the hippocampus' role in memory processes, its clinical utility to preview the memory deficits after hippocampectomy is less studied. Because the Wada test remains the clinical standard, we have designed our study to match its testing paradigm. Within this framework, our proposal will study where (Aim 1), when (Aim 2), and how (Aim 3) to stimulate the hippocampus to produce memory impairment. While the involvement of the hippocampus in memory function is undisputed, it is not clear which subregion(s) of the hippocampus should be stimulated to impair memory function. We believe stimulating both the head and body of the hippocampus will lead to impairment, but in Aim 1 we will also test stimulation of the head and body individually to see whether more localized stimulation can produce the desired effect. Similarly, the hippocampus has been implicated in both encoding and retrieval memory processes, but it is not known which of these processes should be disrupted by ES to impair memory function. In Aim 2 we will test stimulation in these phases individually and in both phases to determine which leads to the best impairment. Finally, in Aim 3 we will examine how the frequency of stimulation affects impairment of memory function. The literature reports studies using a wide range of frequencies, from 5 to 200 Hz. Because higher frequencies are more likely to generate epileptic activity, we limit our testing to a lower range of frequencies. We will evaluate ES at 5 Hz, which matches endogenous neurophysiological modulation within the hippocampus, and 50 Hz, which has long been a clinical standard used to disrupt function throughout neural tissue. This proposal, a new research direction, will establish the baseline results needed to translate ES of the hippocampus into a clinically viable tool to preview memory deficits resulting from resection of the hippocampus in the treatment of MTLE.