Human hippocampal CA3 damage disrupts both recent and remote episodic memories

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance.

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Please outline where this information can be found within the submission (e.g., sections or figure legends), or explain why this information doesn't apply to your submission: The statistical analysis methods applied to assess the data from the Autobiographical interview and output from 3-D whole-hippocampal subfield segmentation are described in a subsection at the end of Materials and Methods entitled, Statistical analyses. Statistical analysis methods applied to conduct whole-brain voxel-based morphometry are described in subsections of the Results, Materials and Methods and in the legend associated with Figure 3. Likewise, statistical analysis methods applied to conducted whole-brain resting-stating fMRI analyses are described in the appropriate subsections Results and Materials and Methods and in the legends associated with Renders included in Figure 7 and Figure 8 are depicted at the same threshold as used to assess significance (i.e., FDR-corrected p<0.05 (two-sided)).

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• Indicate how samples were allocated into experimental groups (in the case of clinical studies, please specify allocation to treatment method); if randomization was used, please also state if restricted randomization was applied • Indicate if masking was used during group allocation, data collection and/or data analysis Please outline where this information can be found within the submission (e.g., sections or figure legends), or explain why this information doesn't apply to your submission: Additional data files ("source data") • We encourage you to upload relevant additional data files, such as numerical data that are represented as a graph in a figure, or as a summary table • Where provided, these should be in the most useful format, and they can be uploaded as "Source data" files linked to a main figure or table • Include model definition files including the full list of parameters used • Include code used for data analysis (e.g., R, MatLab) • Avoid stating that data files are "available upon request" Please indicate the figures or tables for which source data files have been provided: No treatment protocols were included as part of experimental design that required random group allocation. Information about the criteria for group allocation (i.e., disease status) are provided in Material and Methods (subsection: Participants) Subject identity and group membership were masked when scoring the Autobiographical Interview (Materials and Methods, Behaviour, Scoring and Reliability). Likewise, raters were blinded to the identity and group membership of all scans when conducting 3-D quantitative hippocampal subfield morphometry (Material and Methods, Hippocampal subfield quantitative morphometry). Quantitative metrics were extracted automatically from raw image files for the voxel-based morphometry (subsection in the Result entitled, Whole-brain voxelbased morphometry) and graph theoretic analyses of resting-state data ( Fig. 7;  Fig. 8) conducted in both the amnesic group and the control group. Identical pre-processing and processing pipelines was applied to both groups.
Source data for Figure 6 is Table S1