Representations of Complex Contexts: A Role for Hippocampus.

The hippocampus plays a critical role in supporting episodic memory, in large part by binding together experiences and items with surrounding contextual information. At present, however, little is known about the roles of different hippocampal subfields in supporting this item-context binding. To address this question, we constructed a task in which items were affiliated with differing types of context-cognitive associations that vary at the local, item level and membership in temporally organized lists that linked items together at a global level. Participants made item recognition judgments while undergoing high-resolution fMRI. We performed voxel pattern similarity analyses to answer the question of how human hippocampal subfields represent retrieved information about cognitive states and the time at which a past event took place. As participants recollected previously presented items, activity patterns in the CA23DG subregion carried information about prior cognitive states associated with these items. We found no evidence to suggest reinstatement of information about temporal context at the level of list membership, but exploratory analyses revealed representations of temporal context at a coarse level in conjunction with representations of cognitive contexts. Results are consistent with characterizations of CA23DG as a critical site for binding together items and contexts in the service of memory retrieval.

The hippocampus and orbitofrontal cortex jointly represent task structure during memory-guided decision making.

The hippocampus, well known for its role in episodic memory, might also be an important brain region for extracting structure from our experiences in order to guide future decisions. Recent evidence in rodents suggests that the hippocampus supports decision making by representing task structure in cooperation with the orbitofrontal cortex (OFC). Here, we examine how the human hippocampus and OFC represent task structure during an associative learning task that required learning of both context-determined and context-invariant probabilistic associations. We find that after learning, hippocampal and lateral OFC representations differentiated between context-determined and context-invariant task structures. The degree of this differentiation within the hippocampus and lateral OFC is highly correlated. These results advance our understanding of the hippocampus and suggest that the hippocampus and OFC support goal-directed behavior by representing information that guides the selection of appropriate decision strategies.

The Hippocampus Generalizes across Memories that Share Item and Context Information.

Episodic memory is known to rely on the hippocampus, but how the hippocampus organizes different episodes to permit their subsequent retrieval remains controversial. One major area of debate hinges on a discrepancy between two hypothesized roles of the hippocampus: differentiating between similar events to reduce interference and assigning similar representations to events that share overlapping items and contextual information. Here, we used multivariate analyses of activity patterns measured with fMRI to characterize how the hippocampus distinguishes between memories based on similarity at the level of items and/or context. Hippocampal activity patterns discriminated between events that shared either item or context information but generalized across events that shared similar item-context associations. The current findings provide evidence that, whereas the hippocampus can reduce mnemonic interference by separating events that generalize along a single attribute dimension, overlapping hippocampal codes may support memory for events with overlapping item-context relations. This lends new insights into the way the hippocampus may balance multiple mnemonic operations in adaptively guiding behavior.

Dynamic integration of conceptual information during learning.

The development and application of concepts is a critical component of cognition. Although concepts can be formed on the basis of simple perceptual or semantic features, conceptual representations can also capitalize on similarities across feature relationships. By representing these types of higher-order relationships, concepts can simplify the learning problem and facilitate decisions. Despite this, little is known about the neural mechanisms that support the construction and deployment of these kinds of higher-order concepts during learning. To address this question, we combined a carefully designed associative learning task with computational model-based functional magnetic resonance imaging (fMRI). Participants were scanned as they learned and made decisions about sixteen pairs of cues and associated outcomes. Associations were structured such that individual cues shared feature relationships, operationalized as shared patterns of cue pair-outcome associations. In order to capture the large number of possible conceptual representational structures that participants might employ and to evaluate how conceptual representations are used during learning, we leveraged a well-specified Bayesian computational model of category learning [1]. Behavioral and model-based results revealed that participants who displayed a tendency to link experiences in memory benefitted from faster learning rates, suggesting that the use of the conceptual structure in the task facilitated decisions about cue pair-outcome associations. Model-based fMRI analyses revealed that trial-by-trial integration of cue information into higher-order conceptual representations was supported by an anterior temporal (AT) network of regions previously implicated in representing complex conjunctions of features and meaning-based information.

Brain activity related to working memory for temporal order and object information.

Maintaining items in an appropriate sequence is important for many daily activities; however, remarkably little is known about the neural basis of human temporal working memory. Prior work suggests that the prefrontal cortex (PFC) and medial temporal lobe (MTL), including the hippocampus, play a role in representing information about temporal order. The involvement of these areas in successful temporal working memory, however, is less clear. Additionally, it is unknown whether regions in the PFC and MTL support temporal working memory across different timescales, or at coarse or fine levels of temporal detail. To address these questions, participants were scanned while completing 3 working memory task conditions (Group, Position and Item) that were matched in terms of difficulty and the number of items to be actively maintained. Group and Position trials probed temporal working memory processes, requiring the maintenance of hierarchically organized coarse and fine temporal information, respectively. To isolate activation related to temporal working memory, Group and Position trials were contrasted against Item trials, which required detailed working memory maintenance of visual objects. Results revealed that working memory encoding and maintenance of temporal information relative to visual information was associated with increased activation in dorsolateral PFC (DLPFC), and perirhinal cortex (PRC). In contrast, maintenance of visual details relative to temporal information was characterized by greater activation of parahippocampal cortex (PHC), medial and anterior PFC, and retrosplenial cortex. In the hippocampus, a dissociation along the longitudinal axis was observed such that the anterior hippocampus was more active for working memory encoding and maintenance of visual detail information relative to temporal information, whereas the posterior hippocampus displayed the opposite effect. Posterior parietal cortex was the only region to show sensitivity to temporal working memory across timescales, and was particularly involved in the encoding and maintenance of fine temporal information relative to maintenance of temporal information at more coarse timescales. Collectively, these results highlight the involvement of PFC and MTL in temporal working memory processes, and suggest a dissociation in the type of working memory information represented along the longitudinal axis of the hippocampus.

Functional connectivity based parcellation of the human medial temporal lobe.

Regional differences in large-scale connectivity have been proposed to underlie functional specialization along the anterior-posterior axis of the medial temporal lobe (MTL), including the hippocampus (HC) and the parahippocampal gyrus (PHG). However, it is unknown whether functional connectivity (FC) can be used reliably to parcellate the human MTL. The current study aimed to differentiate subregions of the HC and the PHG based on patterns of whole-brain intrinsic FC. FC maps were calculated for each slice along the longitudinal axis of the PHG and the HC. A hierarchical clustering algorithm was then applied to these data in order to group slices according to the similarity of their connectivity patterns. Surprisingly, three discrete clusters were identified in the PHG. Two clusters corresponded to the parahippocampal cortex (PHC) and the perirhinal cortex (PRC), and these regions showed preferential connectivity with previously described posterior-medial and anterior-temporal networks, respectively. The third cluster corresponded to an anterior PRC region previously described as area 36d, and this region exhibited preferential connectivity with auditory cortical areas and with a network involved in visceral processing. The three PHG clusters showed different profiles of activation during a memory-encoding task, demonstrating that the FC-based parcellation identified functionally dissociable sub-regions of the PHG. In the hippocampus, no sub-regions were identified via the parcellation procedure. These results indicate that connectivity-based methods can be used to parcellate functional regions within the MTL, and they suggest that studies of memory and high-level cognition need to differentiate between PHC, posterior PRC, and anterior PRC.

Algal toxin impairs sea lion memory and hippocampal connectivity, with implications for strandings.

Domoic acid (DA) is a naturally occurring neurotoxin known to harm marine animals. DA-producing algal blooms are increasing in size and frequency. Although chronic exposure is known to produce brain lesions, the influence of DA toxicosis on behavior in wild animals is unknown. We showed, in a large sample of wild sea lions, that spatial memory deficits are predicted by the extent of right dorsal hippocampal lesions related to natural exposure to DA and that exposure also disrupts hippocampal-thalamic brain networks. Because sea lions are dynamic foragers that rely on flexible navigation, impaired spatial memory may affect survival in the wild.

Cortico-hippocampal systems involved in memory and cognition: the PMAT framework.

In this chapter, we review evidence that the cortical pathways to the hippocampus appear to extend from two large-scale cortical systems: a posterior medial (PM) system that includes the parahippocampal cortex and retrosplenial cortex, and an anterior temporal (AT) system that includes the perirhinal cortex. This "PMAT" framework accounts for differences in the anatomical and functional connectivity of the medial temporal lobes, which may underpin differences in cognitive function between the systems. The PM and AT systems make distinct contributions to memory and to other cognitive domains, and convergent findings suggest that they are involved in processing information about contexts and items, respectively. In order to support the full complement of memory-guided behavior, the two systems must interact, and the hippocampal and ventromedial prefrontal cortex may serve as sites of integration between the two systems. We conclude that when considering the "connected hippocampus," inquiry should extend beyond the medial temporal lobes to include the large-scale cortical systems of which they are a part.

Functional subregions of the human entorhinal cortex.

The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC.

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.

Medial temporal lobe coding of item and spatial information during relational binding in working memory.

Several models have proposed that different medial temporal lobe (MTL) regions represent different kinds of information in the service of long-term memory. For instance, it has been proposed that perirhinal cortex (PRC), parahippocampal cortex (PHC), and hippocampus differentially support long-term memory for item information, spatial context, and item-context relations present during an event, respectively. Recent evidence has indicated that, in addition to long-term memory, MTL subregions may similarly contribute to processes that support the retention of complex spatial arrangements of objects across short delays. Here, we used functional magnetic resonance imaging and multivoxel pattern similarity analysis to investigate the extent to which human MTL regions independently code for object and spatial information, as well as the conjunction of this information, during working memory encoding and active maintenance. Voxel activity patterns in PRC, temporopolar cortex, and amygdala carried information about individual objects, whereas activity patterns in the PHC and posterior hippocampus carried information about the configuration of spatial locations that was to be remembered. Additionally, the integrity of multivoxel patterns in the right anterior hippocampus across encoding and delay periods was predictive of accurate short-term memory for object-location relationships. These results are consistent with parallel processing of item and spatial context information by PRC and PHC, respectively, and the binding of item and context by the hippocampus.

Complementary roles of human hippocampal subregions during retrieval of spatiotemporal context.

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.

Medial temporal lobe contributions to cued retrieval of items and contexts.

Several models have proposed that different regions of the medial temporal lobes contribute to different aspects of episodic memory. For instance, according to one view, the perirhinal cortex represents specific items, parahippocampal cortex represents information regarding the context in which these items were encountered, and the hippocampus represents item-context bindings. Here, we used event-related functional magnetic resonance imaging (fMRI) to test a specific prediction of this model-namely, that successful retrieval of items from context cues will elicit perirhinal recruitment and that successful retrieval of contexts from item cues will elicit parahippocampal cortex recruitment. Retrieval of the bound representation in either case was expected to elicit hippocampal engagement. To test these predictions, we had participants study several item-context pairs (i.e., pictures of objects and scenes, respectively), and then had them attempt to recall items from associated context cues and contexts from associated item cues during a scanned retrieval session. Results based on both univariate and multivariate analyses confirmed a role for hippocampus in content-general relational memory retrieval, and a role for parahippocampal cortex in successful retrieval of contexts from item cues. However, we also found that activity differences in perirhinal cortex were correlated with successful cued recall for both items and contexts. These findings provide partial support for the above predictions and are discussed with respect to several models of medial temporal lobe function.

Recollection and familiarity in schizophrenia: a quantitative review.

Recognition memory judgments can be based on recollection of qualitative information about an earlier study event or on assessments of stimulus familiarity. Schizophrenia is associated with pronounced deficits in overall recognition memory, and these deficits are highly predictive of global functioning. However, the extent to which these deficits reflect impairments in recollection or familiarity is less well understood. In the current article, we reviewed studies that used remember-know-new, process dissociation, and receiver operating characteristic procedures to investigate recollection and familiarity in schizophrenia. We also performed a quantitative reanalysis of these study results to obtain recollection and familiarity estimates that account for methodological differences between studies. Contrary to previous conclusions that recollection is selectively impaired in schizophrenia, we found evidence for both familiarity and recollection deficits across studies, suggesting multi-focal medial temporal lobe and/or prefrontal cortex dysfunction. The familiarity deficits were more variable with frequent small-to-medium rather than medium-to-large effect sizes, suggesting that familiarity could be potentially used as a compensatory ability, whereas recollection is conceptualized as a therapeutic target for new treatment development.

Differential connectivity of perirhinal and parahippocampal cortices within human hippocampal subregions revealed by high-resolution functional imaging.

Numerous studies support the importance of the perirhinal cortex (PRC) and parahippocampal cortex (PHC) in episodic memory. Theories of PRC and PHC function in humans have been informed by neuroanatomical studies of these regions obtained in animal tract-tracing studies, but knowledge of the connectivity of PHC and PRC in humans is limited. To address this issue, we used resting-state functional magnetic resonance imaging to compare the intrinsic functional connectivity profiles associated with the PRC and PHC both across the neocortex and within the subfields of the hippocampus. In Experiment 1, we acquired standard-resolution whole-brain resting-state fMRI data in 15 participants, and in Experiment 2, we acquired high-resolution resting-state fMRI data targeting the hippocampus in an independent sample of 15 participants. Experiment 1 revealed that PRC showed preferential connectivity with the anterior hippocampus, whereas PHC showed preferential connectivity with posterior hippocampus. Experiment 2 indicated that this anterior-posterior functional connectivity dissociation was more evident for subfields CA1 and subiculum than for a combined CA2/CA3/dentate gyrus region. Finally, whole-brain analyses from Experiment 1 revealed preferential PRC connectivity with an anterior temporal and frontal cortical network, and preferential PHC connectivity with a posterior medial temporal, parietal, and occipital network. These results suggest a framework for refining models of the functional organization of the human medial temporal lobes in which the PRC and PHC are associated with distinct neocortical pathways that, in turn, may differentially interact with regions along the anterior-posterior axis of the hippocampus.

FMRI as a measure of cognition related brain circuitry in schizophrenia.

Functional magnetic resonance imaging (fMRI) has played a prominent role in the quest to identify the brain systems responsible for cognitive dysfunction in schizophrenia. This chapter describes the evolution of these research efforts, which have alternated between efforts to localize specific cognitive impairments to work trying to understand broader network dysfunction. After a concise summary of localization efforts, the remainder of the chapter describes how different groups of scientists have developed and tested broader network theories. This includes a description of both task-activation and resting state studies, and involves a wide array of analytic techniques. The chapter closes with an understanding of how current default-mode and task-positive network theories grew out of these earlier resting-state and task-activation approaches, and provides some recommendations about future directions.

Non-peptide alpha(v)beta(3) antagonists. Part 3: identification of potent RGD mimetics incorporating novel beta-amino acids as aspartic acid replacements.

Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.