Differential Reorganization of Episodic and Semantic Memory Systems in Epilepsy-Related Mesiotemporal Pathology

Abstract

AbstractDeclarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, while semantic memory houses context-independent knowledge. Behavioral and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions and distributed neocortices. Here, we studied a population of patients with unilateral temporal lobe epilepsy (TLE) and variable degrees of MTL pathology as a human disease model to explore declarative memory system reorganization, and to examine neurocognitive associations. Our cohort included 20 patients with TLE as well as 60 age and sex-matched healthy controls, who underwent episodic and semantic retrieval tasks during a functional MRI session. Tasks were closely matched in terms of stimuli and trial design. Capitalizing on connectome gradient mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, both in the MTL and in neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed topographic reorganization during episodic but not semantic memory states, characterized by marked gradient compression in lateral temporal and midline parietal cortices in both hemispheres, cooccurring with an expansion of anterior-posterior hippocampal differentiation ipsilateral to the MTL pathology. These findings suggest that episodic processes are supported by a distributed network, implicating both hippocampus and neocortex, and such alterations can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage such as TLE. Leveraging microstructural and morphological MRI proxies of MTL pathology, we furthermore observed that pathological markers selective to the hippocampus are associated with TLE-related functional reorganization. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioral deficits in episodic memory in patients. Altogether, our findings point to a selective mesiotemporal and neocortical functional reorganization of episodic memory systems in patients with TLE, which consistently affects behavioral memory deficits. These findings point to consistent structure-function relationships in declarative memory and reaffirm the critical role of the MTL in episodic memory systems.