Atypical neural topographies underpin dysfunctional pattern separation in temporal lobe epilepsy

Episodic memory is the ability to accurately remember events from our past. The process of pattern separation is hypothesized to underpin this ability and is defined as the ability to orthogonalize memory traces, to maximize the features that make them unique. Contemporary cognitive neuroscience suggests that pattern separation entails complex interactions between the hippocampus and the neocortex, where specific hippocampal subregions shape neural reinstatement in the neocortex. To test this hypothesis, the current work studied both healthy controls and patients with temporal lobe epilepsy (TLE) who present with hippocampal structural anomalies. In all participants, we measured neural activity using functional magnetic resonance imaging (fMRI) while they retrieved memorized items compared to lure items which share features with the target. Behaviorally, TLE patients were less able to exclude lures than controls, and showed a reduction in pattern separation. To assess the hypothesized relationship between neural patterns in the hippocampus and the neocortex, we identified topographic gradients of intrinsic connectivity along neocortical and hippocampal subfield surfaces and identified the topographic profile of the neural activity accompanying pattern separation. In healthy controls, pattern separation followed a graded pattern of neural activity, both along the hippocampal long axis (and peaked in anterior segments that are more heavily engaged in transmodal processing) and along the neocortical hierarchy running from unimodal to transmodal regions (peaking in transmodal default mode regions). In TLE patients, however, this concordance between task-based functional activations and topographic gradients was markedly reduced. Furthermore, person specific measures of concordance between task-related activity and connectivity gradients in patients and controls related to inter-individual differences in behavioral measures of pattern separation and episodic memory, highlighting the functional relevance of the observed topographic motifs. Our work is consistent with an emerging understanding that successful discrimination between memories with similar features entails a shift in the locus of neural activity away from sensory systems, a pattern that is mirrored along the hippocampal long axis and with respect to neocortical hierarchies. More broadly, our study establishes topographic profiling using intrinsic connectivity gradients captures the functional underpinnings of episodic memory processes in manner that is sensitive to their reorganization in pathology.