Towards Causal Mapping of Episodic Memory iEEG Networks Via Multi-method Brain Stimulation

Episodic memory impairment occurs when diseases impact the hippocampus and its network of interacting brain areas. Better understanding of brain mechanisms for memory is required to development treatments. This project will develop experimental approaches that use stimulation to manipulate brain-behavior relationships in humans and thereby directly test how the hippocampal network supports memory. Intracranial electroencephalography (iEEG) provides opportunities to study the neural basis of memory with high spatial and temporal resolution. Many experiments have identified iEEG signals associated with memory, for instance by comparing instances of memory success to failure. However, the functional relevance of these signals remains unclear, as such comparisons can identify signals of extraneous, co-occurring, cognitive processes. A routine approach to address this limitation in the behavioral neurosciences is via bi-directional manipulations, i.e., exogenous enhancement or inhibition of the putative neural process and tests of corresponding enhancement or inhibition of behavioral performance. This approach has been underutilized in human iEEG memory research, in part due to difficulties in reliably influencing memory or neural signals given currently available manipulations, such as direct electrical stimulation (DES) through iEEG electrodes. As a route to achieve bi-directional manipulation experiments in human iEEG memory research, this project utilizes a noninvasive electromagnetic stimulation tool that reliably and robustly influences hippocampal network activity and memory performance, called "hippocampal indirectly targeted stimulation" (HITS). HITS will be used with iEEG for the first time to identify activity patterns of the hippocampal network related to memory behavioral performance enhancement versus impairment. To rigorously test for behavioral relevance, we will use a closed-loop machine-learning approach to identify DES parameters that reproduce the hippocampal-network iEEG activity patterns generated by HITS, and then test whether delivery of DES to enhance or inhibit these hippocampal-network iEEG activity patterns produces corresponding enhancement versus impairment of memory behavioral performance. Thus, bidirectional manipulation will be used to directly/causally test iEEG signals of memory behavior. Group-level modeling of DES parameters that mimic the effects of HITS will be used to broaden the accessibility of bidirectional manipulations for future research that tests memory mechanisms in larger iEEG samples across multiple sites that lack the technical capability for HITS. Across three sites, will test whether bi-directional manipulations of hippocampal-network activity involvement in memory performance are more successful for HITS-informed DES versus DES based on a priori hypotheses. This exploratory project will thus build a foundation for future studies to rigorously test hippocampal-network support of memory behavioral performance using bi-directional experimental manipulations and will establish a collaboration of multidisciplinary researchers across multiple institutions to perform this innovative mechanistic memory research.