Hippocampal-cortical networks underlying memory retrieval of linguistic knowledge

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ABSTRACT Language and memory overlap heavily in brain circuitry and in our day-to-day lives. Both are also frequently disrupted in neurological conditions such as temporal lobe epilepsy and Alzheimer’s disease. We have a limited understanding of the mechanisms by which cortical language centers integrate with memory circuits; for example, to support the retrieval of linguistic knowledge. This limits our insight into disease pathophysiology and slows the development of more effective therapies for cognitive impairments. This K23 will support an investigation of how language and memory integrate in the human brain, by harnessing unique innovations and resources. First, we will use special high-density grid and depth electrodes to record from many hundreds of local neuronal populations distributed throughout memory and language centers, among patients undergoing intracranial monitoring for refractory epilepsy. Second, to target distinct moments of linguistic-mnemonic integration, we have customized an auditory naming behavioral task that combines controlled yet natural language stimuli with memory retrieval of linguistic knowledge. Third, I will apply state-of-the-art analyses with pattern classifiers and computational linguistics, an approach that could improve the framework of how we understand neural representations of deep language processing. I will first evaluate whether the activity patterns in cortical language centers and the hippocampus reveal neural signatures of dynamic integration during knowledge retrieval, and whether their activity patterns reflect mutual information sufficient to predict the linguistic content of task trials (Aim 1). I will then use electrical stimulation to selectively disrupt neural processing in these regions, to determine if and how they contribute to distinct stages of language and memory integration (Aim 2). This approach will also allow us to probe whether the hippocampus is required for semantic memory, a long-debated question arising from classic literature. My mentorship team has a constellation of expertise aligning with my training plan and the goals of this investigation, including cortical language neurophysiology, hippocampal memory neurophysiology, and investigative neurostimulation. This proposal builds upon my prior expertise in translational intracranial recordings and neural signal processing, and my long-term career goal of understanding and improving treatments for cognitive impairments in epilepsy. I will receive training, coursework, and direct mentorship in skillsets that I will continue to use throughout my scientific career, including language and memory neurophysiology, human neurostimulation, neuroethics, machine learning, computational linguistics, scientific communication, and independent laboratory management. The knowledge and training acquired during this award period will allow me to establish an independent laboratory and emerge as a leader in human intracranial neurophysiology, applying my expertise to unmet needs in epilepsy.