Margaret L. Schlichting

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

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 T and 7 T. 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 hippocampus and inferential reasoning: building memories to navigate future decisions

A critical aspect of inferential reasoning is the ability to form relationships between items or events that were not experienced together. This review considers different perspectives on the role of the hippocampus in successful inferential reasoning during both memory encoding and retrieval. Intuitively, inference can be thought of as a logical process by which elements of individual existing memories are retrieved and recombined to answer novel questions. Such flexible retrieval is sub-served by the hippocampus and is thought to require specialized hippocampal encoding mechanisms that discretely code events such that event elements are individually accessible from memory. In addition to retrieval-based inference, recent research has also focused on hippocampal processes that support the combination of information acquired across multiple experiences during encoding. This mechanism suggests that by recalling past events during new experiences, connections can be created between newly formed and existing memories. Such hippocampally mediated memory integration would thus underlie the formation of networks of related memories that extend beyond direct experience to anticipate future judgments about the relationships between items and events. We also discuss integrative encoding in the context of emerging evidence linking the hippocampus to the formation of schemas as well as prospective theories of hippocampal function that suggest memories are actively constructed to anticipate future decisions and actions.

Learning-related representational changes reveal dissociable integration and separation signatures in the hippocampus and prefrontal cortex

The episodic memory system enables accurate retrieval while maintaining flexibility by representing both specific episodes and generalizations across events. Although theories suggest that the hippocampus (HPC) is dedicated to represent specific episodes while the medial prefrontal cortex (MPFC) generalizes, other accounts posit that HPC can also integrate related memories. Here we use high-resolution functional magnetic resonance imaging in humans to examine how representations of memory elements change to either differentiate or generalize across related events. We show that while posterior HPC and anterior MPFC maintain distinct memories for individual events, anterior HPC and posterior MPFC integrate across memories. Integration is particularly likely for established memories versus those encoded simultaneously, highlighting the greater impact of prior knowledge on new encoding. We also show dissociable coding signatures in ventrolateral PFC, a region previously implicated in interference resolution. These data highlight how memory elements are represented to simultaneously promote generalization across memories and protect from interference.

Color, context, and cognitive style: Variations in color knowledge retrieval as a function of task and subject variables

Neuroimaging tests of sensorimotor theories of semantic memory hinge on the extent to which similar activation patterns are observed during perception and retrieval of objects or object properties. The present study was motivated by the hypothesis that some of the seeming discrepancies across studies reflect flexibility in the systems responsible for conceptual and perceptual processing of color. Specifically, we test the hypothesis that retrieval of color knowledge can be influenced by both context (a task variable) and individual differences in cognitive style (a subject variable). In Experiment 1, we provide fMRI evidence for differential activity during color knowledge retrieval by having subjects perform a verbal task, in which context encouraged subjects to retrieve more- or less-detailed information about the colors of named common objects in a blocked experimental design. In the left fusiform, we found more activity during retrieval of more- versus less-detailed color knowledge. We also assessed preference for verbal or visual cognitive style, finding that brain activity in the left lingual gyrus significantly correlated with preference for a visual cognitive style. We replicated many of these effects in Experiment 2, in which stimuli were presented more quickly, in a random order, and in the auditory modality. This illustration of some of the factors that can influence color knowledge retrieval leads to the conclusion that tests of conceptual and perceptual overlap must consider variation in both of these processes.

CA1 subfield contributions to memory integration and inference

The ability to combine information acquired at different times to make novel inferences is a powerful function of episodic memory. One perspective suggests that by retrieving related knowledge during new experiences, existing memories can be linked to the new, overlapping information as it is encoded. The resulting memory traces would thus incorporate content across event boundaries, representing important relationships among items encountered during separate experiences. While prior work suggests that the hippocampus is involved in linking memories experienced at different times, the involvement of specific subfields in this process remains unknown. Using both univariate and multivariate analyses of high‐resolution functional magnetic resonance imaging (fMRI) data, we localized this specialized encoding mechanism to human CA1. Specifically, right CA1 responses during encoding of events that overlapped with prior experience predicted subsequent success on a test requiring inferences about the relationships among events. Furthermore, we employed neural pattern similarity analysis to show that patterns of activation evoked during overlapping event encoding were later reinstated in CA1 during successful inference. The reinstatement of CA1 patterns during inference was specific to those trials that were performed quickly and accurately, consistent with the notion that linking memories during learning facilitates novel judgments. These analyses provide converging evidence that CA1 plays a unique role in encoding overlapping events and highlight the dynamic interactions between hippocampal‐mediated encoding and retrieval processes. More broadly, our data reflect the adaptive nature of episodic memories, in which representations are derived across events in anticipation of future judgments.

Memory reactivation during rest supports upcoming learning of related content

Significance How our brains capture and store new information is heavily influenced by what we already know. While prior work demonstrates that existing memories are spontaneously reactivated and strengthened in the brain during passive rest periods, the prospective benefits of spontaneous offline reactivation for future learning remain unknown. Here, we use functional MRI to interrogate how reactivation and interregional coupling support the ability to learn related content in later situations. We find that offline processing of prior memories is associated with better subsequent learning. Our results provide a mechanistic account of the circumstances under which prior knowledge can come to facilitate—as opposed to interfere with—new learning, serving as a strong foundation upon which new content is encoded. Although a number of studies have highlighted the importance of offline processes for memory, how these mechanisms influence future learning remains unknown. Participants with established memories for a set of initial face–object associations were scanned during passive rest and during encoding of new related and unrelated pairs of objects. Spontaneous reactivation of established memories and enhanced hippocampal–neocortical functional connectivity during rest was related to better subsequent learning, specifically of related content. Moreover, the degree of functional coupling during rest was predictive of neural engagement during the new learning experience itself. These results suggest that through rest-phase reactivation and hippocampal–neocortical interactions, existing memories may come to facilitate encoding during subsequent related episodes.

Hippocampal-medial prefrontal circuit supports memory updating during learning and post-encoding rest.

Learning occurs in the context of existing memories. Encountering new information that relates to prior knowledge may trigger integration, whereby established memories are updated to incorporate new content. Here, we provide a critical test of recent theories suggesting hippocampal (HPC) and medial prefrontal (MPFC) involvement in integration, both during and immediately following encoding. Human participants with established memories for a set of initial (AB) associations underwent fMRI scanning during passive rest and encoding of new related (BC) and unrelated (XY) pairs. We show that HPC-MPFC functional coupling during learning was more predictive of trial-by-trial memory for associations related to prior knowledge relative to unrelated associations. Moreover, the degree to which HPC-MPFC functional coupling was enhanced following overlapping encoding was related to memory integration behavior across participants. We observed a dissociation between anterior and posterior MPFC, with integration signatures during post-encoding rest specifically in the posterior subregion. These results highlight the persistence of integration signatures into post-encoding periods, indicating continued processing of interrelated memories during rest. We also interrogated the coherence of white matter tracts to assess the hypothesis that integration behavior would be related to the integrity of the underlying anatomical pathways. Consistent with our predictions, more coherent HPC-MPFC white matter structure was associated with better performance across participants. This HPC-MPFC circuit also interacted with content-sensitive visual cortex during learning and rest, consistent with reinstatement of prior knowledge to enable updating. These results show that the HPC-MPFC circuit supports on- and offline integration of new content into memory.

Hippocampal structure predicts statistical learning and associative inference abilities during development

Despite the importance of learning and remembering across the lifespan, little is known about how the episodic memory system develops to support the extraction of associative structure from the environment. Here, we relate individual differences in volumes along the hippocampal long axis to performance on statistical learning and associative inference tasks—both of which require encoding associations that span multiple episodes—in a developmental sample ranging from ages 6 to 30 years. Relating age to volume, we found dissociable patterns across the hippocampal long axis, with opposite nonlinear volume changes in the head and body. These structural differences were paralleled by performance gains across the age range on both tasks, suggesting improvements in the cross-episode binding ability from childhood to adulthood. Controlling for age, we also found that smaller hippocampal heads were associated with superior behavioral performance on both tasks, consistent with this regions hypothesized role in forming generalized codes spanning events. Collectively, these results highlight the importance of examining hippocampal development as a function of position along the hippocampal axis and suggest that the hippocampal head is particularly important in encoding associative structure across development.

Feature diagnosticity affects representations of novel and familiar objects

Many features can describe a concept, but only some features define a concept in that they enable discrimination of items that are instances of a concept from (similar) items that are not. We refer to this property of some features as feature diagnosticity. Previous work has described the behavioral effects of feature diagnosticity, but there has been little work on explaining why and how these effects arise. In this study, we aimed to understand the impact of feature diagnosticity on concept representations across two complementary experiments. In Experiment 1, we manipulated the diagnosticity of one feature, color, for a set of novel objects that human participants learned over the course of 1 week. We report behavioral and neural evidence that diagnostic features are likely to be automatically recruited during remembering. Specifically, individuals activated color-selective regions of ventral temporal cortex (specifically, left fusiform gyrus and left inferior temporal gyrus) when thinking about the novel objects, although color information was never explicitly probed during the task. Moreover, multiple behavioral and neural measures of the effects of feature diagnosticity were correlated across participants. In Experiment 2, we examined relative color association in familiar object categories, which varied in feature diagnosticity (fruits and vegetables, household items). Taken together, these results offer novel insights into the neural mechanisms underlying concept representations by demonstrating that automatic recruitment of diagnostic information gives rise to behavioral effects of feature diagnosticity.

Memory allocation and integration in rodents and humans

In rodents, recent studies indicate that levels of neuronal excitability dictate which cell populations encode a memory for a particular event (i.e. memory allocation), and whether memories for multiple events become linked. In human subjects, imaging methods now allow for detection of brain responses to specific events, and therefore make it possible to address whether analogous processes are engaged. Similar to rodents, these studies reveal that neural engagement prior to learning influences encoding in humans. Furthermore, they provide evidence that events that share content, or occur close together in time, become linked during learning or during later ‘offline’ processing (i.e. memory integration). These concepts of memory allocation and memory integration provide a common mechanistic framework for considering how knowledge emerges in rodents and humans.