The pathophysiology of sleep-dependent memory consolidation

01/01/2023 to 01/01/2025

A bidirectional dialogue between the hippocampus and neocortex constitutes the physiological basis of sleep-dependent memory consolidation. The hippocampus also reflects a predilection site for epilepsy; a network disorder characterized by impaired memory retention at the behavioral level and an imbalance between excitation and inhibition (E/I-balance) at the neuronal level. This imbalance leads to hyperexcitability and uncontrolled neural firing that results in interictal epileptiform discharges (IEDs) and seizures. Critically, IEDs preferentially occur during non-rapid-eye-movement (NREM) sleep, a physiologic state of altered E/I-balance, that facilitates hippocampalneocortical interactions and memory formation in the healthy brain. Hence, E/I-imbalance, IEDs, and impaired network interactions might be fundamental causes of memory impairments in patients with epilepsy. In addition, it remains unclear how physiological memory processes are implemented under pathologic network conditions. This project aims to unravel the network dynamics that facilitate memory consolidation through studying epilepsy as a network disorder of the human memory system. I specifically plan to study E/I-balance as an overarching framework for understanding the intricate three-way interactions between sleep, memory, and epilepsy. The key hypothesis is that epilepsy hijacks sleep networks and triggers epileptic activity in response to selective engagement of the hippocampal-neocortical dialogue that typically supports memory consolidation. To test this hypothesis, I will utilize both non-invasive imaging (high-density electroencephalography; EEG) as well as intracranial EEG recordings combined with behavioral testing in patients with pharmacoresistant epilepsy requiring pre-surgical invasive monitoring. By utilizing state-of-the-art analyses, I will dissect the interplay between epilepsy and the hippocampal-neocortical dialogue, and determine how physiologic as well as pathologic electrophysiological signatures interact with memory formation. This approach will conceptualize E/I-balance as a unifying framework to understand both sleep-dependent memory formation as well as impaired memory retention in epilepsy.