OBJECTIVE An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1–3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD MRI scans of a single healthy adult human subject were acquired both at 3 Tesla and 7 Tesla. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

The rodent hippocampus represents different spatial environments distinctly via changes in the pattern of “place cell” firing. It remains unclear, though, how spatial remapping in rodents relates more generally to human memory. Here participants retrieved four virtual reality environments with repeating or novel landmarks and configurations during high-resolution functional magnetic resonance imaging (fMRI). Both neural decoding performance and neural pattern similarity measures revealed environment-specific hippocampal neural codes. Conversely, an interfering spatial environment did not elicit neural codes specific to that environment, with neural activity patterns instead resembling those of competing environments, an effect linked to lower retrieval performance. We find that orthogonalized neural patterns accompany successful disambiguation of spatial environments while erroneous reinstatement of competing patterns characterized interference errors. These results provide the first evidence for environment-specific neural codes in the human hippocampus, suggesting that pattern separation/completion mechanisms play an important role in how we successfully retrieve memories.DOI: http://dx.doi.org/10.7554/eLife.10499.001

Current evidence strongly supports the central involvement of the human medial temporal lobes (MTL) in storing and retrieving memories for recently experienced events. However, a critical remaining question regards exactly how the hippocampus and surrounding cortex represents spatiotemporal context defining an event in memory. Competing accounts suggest that this process may be accomplished by the following: (1) an overall increase in neural similarity of representations underlying spatial and temporal context, (2) a differentiation of competing spatiotemporal representations, or (3) a combination of the two processes, with different subregions performing these two functions within the MTL. To address these competing proposals, we used high-resolution functional magnetic resonance imaging targeting the MTL along with a multivariate pattern similarity approach with 19 participants. While undergoing imaging, participants performed a task in which they retrieved spatial and temporal contextual representations from a recently learned experience. Results showed that successfully retrieving spatiotemporal context defining an episode involved a decrease in pattern similarity between putative spatial and temporal contextual representations in hippocampal subfields CA2/CA3/DG, whereas the parahippocampal cortex (PHC) showed the opposite pattern. These findings could not be accounted for by differences in univariate activations for complete versus partial retrieval nor differences in correlations for correct or incorrect retrieval. Together, these data suggest that the CA2/CA3/DG serves to differentiate competing contextual representations, whereas the PHC stores a comparatively integrated trace of scene-specific context, both of which likely play important roles in successful episodic memory retrieval.

Damage to the medial temporal lobes produces profound amnesia, greatly impairing the ability of patients to learn about new associations and events. While studies in rodents suggest a strong link between damage to the hippocampus and the ability to navigate using distal landmarks in a spatial environment, the connection between navigation and memory in humans remains less clear. Past studies on human navigation have provided mixed findings about whether patients with damage to the medial temporal lobes can successfully acquire and navigate new spatial environments, possibly due, in part, to issues related to patient demographics and characterization of medial temporal lobe damage. Here, we report findings from a young, high functioning patient who suffered severe medial temporal lobe damage. Although the patient is densely amnestic, her ability to acquire and utilize new, but coarse, spatial “maps” appears largely intact. Specifically, a novel computational analysis focused on the precision of her spatial search revealed a significant deficit in spatial precision rather than spatial search strategy. These findings argue that an intact hippocampus in humans is not necessary for representing multiple external landmarks during spatial navigation of new environments. We suggest instead that the human hippocampus may store and represent complex high-resolution bindings of features in the environment as part of a larger role in perception, memory, and navigation.

While numerous studies indicate the involvement of the hippocampus in encoding and retrieval of spatial and temporal context, the neural basis of spatial and temporal processing within the hippocampal circuit remains unclear. We employed a novel paradigm in which participants encoded stores within a spatial layout by visiting them in a specific temporal order. Participants then underwent high-resolution functional magnetic resonance imaging (fMRI) targeting the hippocampus while retrieving details of the spatial or temporal context in alternating blocks. During retrieval, participants made judgments about either near or far intervals within the spatial layout or temporal sequence. Across both near and far intervals, we found that retrieving spatial layout and temporal order information resulted in comparable levels of activation in the hippocampus that was not preferentially localized to a specific subfield. Furthermore, using a multivariate approach called multivariate pattern similarity analysis (MPSA), we found that correct near judgments vs. correct far judgments differed in their patterns of activity for spatial vs. temporal order judgments. Despite these differences in MPSA patterns, we did not find any specific subfields differentially recruited for spatial vs. temporal order retrieval. We discuss our results in terms of their relation to computational models of hippocampal subfield function and suggest mechanisms by which the hippocampus could process space and temporal order without the need for specific contributions from hippocampal subfields.