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The process of pattern separation is hypothesized to underpin this ability and is defined as the capacity 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 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 who presented with hippocampal structural anomalies. We measured neural activity in all participants using functional MRI while they retrieved memorized items or lure items, which shared features with the target. Behaviourally, patients with temporal lobe epilepsy 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 neocortex, we identified the topographic gradients of intrinsic connectivity along neocortical and hippocampal subfield surfaces and determined the topographic profile of the neural activity accompanying pattern separation. In healthy controls, pattern separation followed a graded topography 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 patients with temporal lobe epilepsy, 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 were related to inter-individual differences in behavioural 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, capturing the functional underpinnings of episodic memory processes in a manner that is sensitive to their reorganization in pathology.<\/jats:p>","DOI":"10.1093\/brain\/awab121","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T20:12:29Z","timestamp":1615839149000},"page":"2486-2498","source":"Crossref","is-referenced-by-count":35,"title":["Atypical neural topographies underpin dysfunctional pattern separation in temporal lobe epilepsy"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6989-2981","authenticated-orcid":false,"given":"Qiongling","family":"Li","sequence":"first","affiliation":[{"name":"Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, H3A 2B4, Canada"},{"name":"School of Biological 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H3A 2B4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6183-4493","authenticated-orcid":false,"given":"Danielle S","family":"Bassett","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Physics and Astronomy, College of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Electrical and Systems Engineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA"},{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, 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