CAUSAL MECHANISMS OF DISTRIBUTED BRAIN NETWORK FUNCTION DURING EPISODIC MEMORY RETRIEVAL

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Project Summary This proposal follows from a previously approved K99 fellowship, with Northwestern University as the proposed R00-phase institution. Memory impairments are common to many neurological and psychiatric disorders, including Alzheimer’s disease and depression, which impose a heavy burden on society. Brain stimulation is a potentially powerful therapeutic strategy with the potential to elicit improvements in episodic memory. However, its efficacy depends on precise targeting of stimulation, in a manner that respects the idiosyncrasies of an individual’s functional brain anatomy. Recent advances in functional magnetic resonance imaging (fMRI) have allowed brain networks to be defined with precision within individuals. Of particular relevance to memory disorders, a distributed network was recently identified within individuals that includes regions of posterior parietal and parahippocampal cortices – prominent stimulation targets for modulation of memory – in combination with other regions distributed throughout frontal, parietal, temporal and midline cortices. It is not known whether stimulation of these additional distributed regions can lead to memory improvements. If so, this could provide additional and potentially more accessible targets for stimulation-based therapies. In this project, individual-level network mapping with fMRI will be performed on epilepsy patients who are scheduled to undergo intracranial monitoring. The distributed network which includes parahippocampal and posterior parietal cortex will be delineated with precision in individual patients and the resulting network maps will be used to select candidate implanted electrodes for stimulation. The involvement of the distributed brain network in episodic memory will be characterized at high temporal and spatial resolution through recordings obtained during an episodic memory task. Recordings will allow the exploration of electrophysiological properties of this network, as well as quantify its separation and interactions with neighboring networks, and direct cortical stimulation will be applied to individual sites with the aim of testing the causal influence of the network on episodic memory. To achieve this project, the PI will establish a research program at the Northwestern University Feinberg School of Medicine, building on procedures, protocols and experience gained at Stanford University during the K99 training, and in collaboration with neuroscientists (Joel Voss, Ph.D.) and epileptologists (Stephan Schuele, Ph. D.) at Northwestern University. The resulting data will refine the current understanding of the neural systems involved in episodic memory, and importantly provide a proof-of-principle for the use of individual-level network mapping to guide intracranial brain recording and stimulation, which could have important implications for stimulation therapies for a range of mental health disorders.