The Role of Medial Temporal Lobe Regions in Incidental and Intentional Retrieval of Item and Relational Information in Aging

Considerable neuropsychological and neuroimaging work indicates that the medial temporal lobes are critical for both item and relational memory retrieval. However, there remain outstanding issues in the literature, namely the extent to which medial temporal lobe regions are differentially recruited during incidental and intentional retrieval of item and relational information, and the extent to which aging may affect these neural substrates. The current fMRI study sought to address these questions; participants incidentally encoded word pairs embedded in sentences and incidental item and relational retrieval were assessed through speeded reading of intact, rearranged, and new word‐pair sentences, while intentional item and relational retrieval were assessed through old/new associative recognition of a separate set of intact, rearranged, and new word pairs. Results indicated that, in both younger and older adults, anterior hippocampus and perirhinal cortex indexed incidental and intentional item retrieval in the same manner. In contrast, posterior hippocampus supported incidental and intentional relational retrieval in both age groups and an adjacent cluster in posterior hippocampus was recruited during both forms of relational retrieval for older, but not younger, adults. Our findings suggest that while medial temporal lobe regions do not differentiate between incidental and intentional forms of retrieval, there are distinct roles for anterior and posterior medial temporal lobe regions during retrieval of item and relational information, respectively, and further indicate that posterior regions may, under certain conditions, be over‐recruited in healthy aging. © 2016 Wiley Periodicals, Inc.     

Recalling the firedog: Individual differences in associative memory for unitized and nonunitized associations among older adults

Memory deficits in aging are characterized by impaired hippocampus‐mediated relational binding—the formation of links between items in memory. By reducing reliance on relational binding, unitization of two items into one concept enhances associative recognition among older adults. Can a similar enhancement be obtained when probing memory with recall? This question has yet to be examined, because recall has been assumed to rely predominantly on relational binding. Inspired by recent evidence challenging this assumption, we investigated individual differences in older adults' recall of unitized and nonunitized associations. Compared with successfully aging individuals, older adults with mild memory deficits, typically mediated by the hippocampus, were impaired in recall of paired‐associates in a task which relies on relational binding (study: “PLAY–TUNNEL”; test: PLAY–T?). In stark contrast, the two groups showed similar performance when items were unitized into a novel compound word (study: “LOVEGIGGLE”; test: LOVEG?). Thus, boosting nonrelational aspects of recall enhances associative memory among aging individuals with subtle memory impairments to comparable levels as successfully aging older adults.     

The medial temporal lobes distinguish between within‐item and item‐context relations during autobiographical memory retrieval

During autobiographical memory retrieval, the medial temporal lobes (MTL) relate together multiple event elements, including object (within‐item relations) and context (item‐context relations) information, to create a cohesive memory. There is consistent support for a functional specialization within the MTL according to these relational processes, much of which comes from recognition memory experiments. In this study, we compared brain activation patterns associated with retrieving within‐item relations (i.e., associating conceptual and sensory‐perceptual object features) and item‐context relations (i.e., spatial relations among objects) with respect to naturalistic autobiographical retrieval. We developed a novel paradigm that cued participants to retrieve information about past autobiographical events, non‐episodic within‐item relations, and non‐episodic item‐context relations with the perceptuomotor aspects of retrieval equated across these conditions. We used multivariate analysis techniques to extract common and distinct patterns of activity among these conditions within the MTL and across the whole brain, both in terms of spatial and temporal patterns of activity. The anterior MTL (perirhinal cortex and anterior hippocampus) was preferentially recruited for generating within‐item relations later in retrieval whereas the posterior MTL (posterior parahippocampal cortex and posterior hippocampus) was preferentially recruited for generating item‐context relations across the retrieval phase. These findings provide novel evidence for functional specialization within the MTL with respect to naturalistic memory retrieval. © 2015 Wiley Periodicals, Inc.     

Impaired inference in a case of developmental amnesia

Amnesia is associated with impairments in relational memory, which is critically supported by the hippocampus. By adapting the transitivity paradigm, we previously showed that age‐related impairments in inference were mitigated when judgments could be predicated on known pairwise relations, however, such advantages were not observed in the adult‐onset amnesic case D.A. Here, we replicate and extend this finding in a developmental amnesic case (N.C.), who also shows impaired relational learning and transitive expression. Unlike D.A., N.C.'s damage affected the extended hippocampal system and diencephalic structures, and does not extend to neocortical areas that are affected in D.A. Critically, despite their differences in etiology and affected structures, N.C. and D.A. perform similarly on the task. N.C. showed intact pairwise knowledge, suggesting that he is able to use existing semantic information, but this semantic knowledge was insufficient to support transitive expression. The present results suggest a critical role for regions connected to the hippocampus and/or medial prefrontal cortex in inference beyond learning of pairwise relations. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Transitivity performance,relational hierarchy knowledge and awareness: Results of an instructional framing manipulation

The transitive inference (TI) paradigm has been widely used to examine the role of the hippocampus in generalization. Here we consider a surprising feature of experimental findings in this task: the relatively poor transitivity performance and levels of hierarchy knowledge achieved by adult human subjects. We focused on the influence of the task instructions on participants' subsequent performance—a single‐word framing manipulation which either specified the relation between items as transitive (i.e., OLD‐FRAME: choose which item is “older”) or left it ambiguous (i.e., NO‐FRAME: choose which item is “correct”). We show a marked but highly specific effect of manipulating prior knowledge through instruction: transitivity performance and levels of relational hierarchy knowledge were enhanced, but premise performance unchanged. Further, we show that hierarchy recall accuracy, but not conventional awareness scores, was a significant predictor of inferential performance across the entire group of participants. The current study has four main implications: first, our findings establish the importance of the task instructions, and prior knowledge, in the TI paradigm—suggesting that they influence the size of the overall hypothesis space (e.g., to favor a linear hierarchical structure over other possibilities in the OLD‐FRAME). Second, the dissociable effects of the instructional frame on premise and inference performance provide evidence for the operation of distinct underlying mechanisms (i.e., an associative mechanism vs. relational hierarchy knowledge). Third, our findings suggest that a detailed measurement of hierarchy recall accuracy may be a more sensitive index of relational hierarchy knowledge, than conventional awareness score—and should be used in future studies investigating links between awareness and inferential performance. Finally, our study motivates an experimental setting that ensures robust hierarchy learning across participants—therefore facilitating study of the neural mechanisms underlying the learning and representation of linear hierarchies. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Cardiorespiratory fitness and hippocampal volume predict faster episodic associative learning in older adults

Declining episodic memory is common among otherwise healthy older adults, in part due to negative effects of aging on hippocampal circuits. However, there is significant variability between individuals in severity of aging effects on the hippocampus and subsequent memory decline. Importantly, variability may be influenced by modifiable protective physiological factors such as cardiorespiratory fitness (CRF). More research is needed to better understand which aspects of cognition that decline with aging benefit most from CRF. The current study evaluated the relation of CRF with learning rate on the episodic associative learning (EAL) task, a task designed specifically to target hippocampal‐dependent relational binding and to evaluate learning with repeated occurrences. Results show higher CRF was associated with faster learning rate. Larger hippocampal volume was also associated with faster learning rate, though hippocampal volume did not mediate the relationship between CRF and learning rate. Furthermore, to support the distinction between learning item relations and learning higher‐order sequences, which declines with aging but is largely reliant on extra‐hippocampal learning systems, we found learning rate on the EAL task was not related to motor sequence learning on the alternating serial reaction time task. Motor sequence learning was also not correlated with hippocampal volume. Thus, for the first time, we show that both higher CRF and larger hippocampal volume in healthy older adults are related to enhanced rate of relational memory acquisition.     

Reduced specificity of hippocampal and posterior ventrolateral prefrontal activity during relational retrieval in normal aging

Neuroimaging studies of episodic memory in young adults demonstrate greater functional neural activity in ventrolateral pFC and hippocampus during retrieval of relational information as compared with item information. We tested the hypothesis that healthy older adults--individuals who exhibit behavioral declines in relational memory--would show reduced specificity of ventrolateral prefrontal and hippocampal regions during relational retrieval. At study, participants viewed two nouns and were instructed to covertly generate a sentence that related the words. At retrieval, fMRIs were acquired during item and relational memory tasks. In the relational task, participants indicated whether the two words were previously seen together. In the item task, participants indicated whether both items of a pair were previously seen. In young adults, left posterior ventrolateral pFC and bilateral hippocampal activity was modulated by the extent to which the retrieval task elicited relational processing. In older adults, activity in these regions was equivalent for item and relational memory conditions, suggesting a reduction in ventrolateral pFC and hippocampal specificity with normal aging.     

The human ventromedial prefrontal cortex is critical for transitive inference

We hypothesized that the ventromedial pFC (vmPFC) is critical for making transitive inferences (e.g., the logical operation that if A > B and B > C, then A > C). To test this, participants with focal vmPFC damage, brain-damaged comparison participants, and neurologically normal participants completed a transitive inference task consisting an ordered set of arbitrary patterns. Participants first learned through trial-and-error the relationships of the patterns (e.g., Pattern A > Pattern B, Pattern B > Pattern C). After initial learning, participants were presented with novel pairings, some of which required transitive inference (e.g., Pattern A > Pattern C from the relationship above). We observed that vmPFC damage led to a specific deficit in transitive inference, suggesting that an intact vmPFC is necessary for making normal transitive inferences. Given the usefulness of transitivity in inferring social relationships, this deficit may be one of the basic features of social conduct problems associated with vmPFC damage.     

Memory for relations in the short term and the long term after medial temporal lobe damage

A central idea about the organization of declarative memory and the function of the hippocampus is that the hippocampus provides for the coding of relationships between items. A question arises whether this idea refers to the process of forming long‐term memory or whether, as some studies have suggested, memory for relations might depend on the hippocampus even at short retention intervals and even when the task falls within the province of short‐term (working) memory. The latter formulation appears to place the operation of relational memory into conflict with the idea that working memory is independent of medial temporal lobe (MTL) structures. In this report, the concepts of relational memory and working memory are discussed in the light of a simple demonstration experiment. Patients with MTL lesions successfully learned and recalled two word pairs when tested directly after learning but failed altogether when tested after a delay. The results do not contradict the idea that the hippocampus has a fundamental role in relational memory. However, there is a need for further elaboration and specification of the idea in order to explain why patients with MTL lesions can establish relational memory in the short term but not in long‐term memory. © 2017 Wiley Periodicals, Inc.     

Focusing on what matters: Modulation of the human hippocampus by relational attention

Hippocampal episodic memory is fundamentally relational, comprising links between events and the spatiotemporal contexts in which they occurred. Such relations are also important over shorter timescales, during online perception. For example, how do we assess the relative spatial positions of objects, their temporal order, or the relationship between their features? Here, we investigate the role of the hippocampus in online relational processing by manipulating attention to different kinds of relations. While undergoing fMRI, participants viewed two images in rapid succession on each trial and performed one of three relational tasks, judging the images’ relative: spatial positions, temporal onsets, or sizes. Additionally, they sometimes judged whether one image was tilted, irrespective of the other. This served as a baseline item task with no demands on relational processing. The hippocampus showed reliable deactivation when participants attended to relational vs. item information. Attention to temporal relations was associated with the most robust deactivation. One interpretation of such deactivation is that it reflects hippocampal disengagement. If true, there should be reduced information content and noisier activity patterns for the temporal vs. other tasks. Instead, multivariate pattern analysis revealed more stable hippocampal representations in the temporal task. This increased pattern similarity was not simply a reflection of lower univariate activity. Thus, the hippocampus differentiates between relational and item processing even during online perception, and its representations of temporal relations are particularly robust. These findings suggest that the relational computations of the hippocampus extend beyond long‐term memory, enabling rapid extraction of relational information in perception.     

Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age‐related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age‐related neural changes in the human hippocampus using high‐resolution (1.5 mm isotropic) blood‐oxygenation level‐dependent fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared with young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging. © 2010 Wiley‐Liss, Inc.     

Reconstructing relational information

Hippocampal involvement in learning and remembering relational information has an extensive history, often focusing specifically on spatial information. In humans, spatial reconstruction (SR) paradigms are a powerful tool for evaluating an individuals' spatial‐relational memory. In SR tasks, participants study locations of items in space and subsequently reconstruct the studied display after a short delay. Previous work has revealed that patients with hippocampal damage are impaired both in overall placement accuracy as well as on a specific measure of relational memory efficacy, “swaps” (i.e., when the relative location of two items is reversed). However, the necessity of the hippocampus for other types of spatial‐relational information involved in reconstruction behaviors (e.g., where in the environment and relative to which other items an item was located) have not yet been investigated systematically. In this work, three patients with hippocampal damage and nine healthy matched comparison participants performed an SR task. An analysis framework was developed to independently assess three first‐order types of relations: (1) memory for the binding of specific item identities to locations, (2) memory for arrangement of items in relation to each other or the environment bounds, regardless of memory for the item identity, and (3) higher‐order, compound relational errors (i.e., errors involving multiple pieces of relational information). Reconstruction errors were evaluated to determine the degree to which patients and comparisons differed (or not) on each type of spatial‐relational information. Data revealed that the primary group difference in performance was for identity‐location information. However, when the locations of items were evaluated without regarding the identities, no group difference was found in the number of item placements to studied locations. The present work provides a principled approach to analysis of SR data and clarifies our understanding of the types of spatial relations impaired in hippocampal damaged.     

Aging affects spatial reconstruction more than spatial pattern separation performance even after extended practice

Although the hippocampus experiences age‐related anatomical and functional deterioration, the effects of aging vary across hippocampal‐dependent cognitive processes. In particular, whether or not the hippocampus is known to be required for a spatial memory process is not an accurate predictor on its own of whether aging will affect performance. Therefore, the primary objective of this study was to compare the effects of healthy aging on a test of spatial pattern separation and a test of spatial relational processing, which are two aspects of spatial memory that uniquely emphasize the use of multiple hippocampal‐dependent processes. Spatial pattern separation supports spatial memory by preserving unique representations for distinct locations. Spatial relational processing forms relational representations of objects to locations or between objects and other objects in space. To test our primary objective, 30 young (18–30 years; 21F) and 30 older participants (60–80 years; 21F) all completed a spatial pattern separation task and a task designed to require spatial relational processing through spatial reconstruction. To ensure aging effects were not due to inadequate time to develop optimal strategies or become comfortable with the testing devices, a subset of participants had extended practice across three sessions on each task. Results showed that older adults performed more poorly than young on the spatial reconstruction task that emphasized the use of spatial relational processing, and that age effects persisted even after controlling for pattern separation performance. Further, older adults performed more poorly on spatial reconstruction than young adults even after three testing sessions each separated by 7–10 days, suggesting effects of aging are resistant to extended practice and likely reflect genuine decline in hippocampal memory abilities.     

Older adults can learn to learn new motor skills

Many studies have demonstrated that aging is associated with declines in skill acquisition. In the current study, we tested whether older adults could acquire general, transferable knowledge about skill learning processes. Older adult participants learned five different motor tasks. Two older adult control groups performed the same number of trials, but learned only one task. The experimental group exhibited faster learning than that seen in the control groups. These data demonstrate that older adults can learn to learn new motor skills.     

Age-differences in cognitive flexibility when overcoming a preexisting bias through feedback

Introduction: Older adults are often worse than younger adults at adapting to changing situational demands, and this difference is commonly attributed to an age-related decline in acquiring and updating information. Previous research on aging and cognitive flexibility has used measures that require adapting to novel associations learned during a laboratory task (e.g., choice X led to positive outcomes but now leads to negative outcomes). However, in everyday life people must frequently overcome associations based on preexisting beliefs and biases (e.g., you like to eat cake, but your doctor said to limit your sugar intake). The goal of the present study was to examine possible age-differences in overcoming a preexisting bias and determine whether age-related changes in the acquisition and updating of information influence this form of flexibility.

Method: Older (n = 20) and younger (n = 20) adults completed a novel task in which repeated choices were made between a sure option (gain or loss) and one of two risky options that were initially ambiguous. Optimal performance required overcoming a framing bias toward being risk seeking to avoid a sure loss and risk averse when offered a sure gain. Probe questions assessed knowledge of choice outcomes, while skin conductance assessed physiological reactions to choices and choice outcomes.

Results: Both older and younger adults demonstrated flexibility by reducing the impact of bias over trials, but younger adults had better performance overall. Age-differences were associated with distinct aspects of processing. Young adults had more precise knowledge of choice outcomes and developed skin conductance responses in anticipation of bad choices that were not apparent in older adults.

Conclusions: Older adults showed significant improvement over trials in their ability to decrease bias-driven choices, but younger showed greater flexibility. Age-differences in task performance were based on differences in learning and corresponding representations of task-relevant information.     

The effects of attention on age-related relational memory deficits: fMRI evidence from a novel attentional manipulation

Numerous studies have documented that older adults (OAs) do not perform as well as young adults (YAs) when task demands require the establishment or retrieval of a novel link between previously unrelated information (relational memory: RM). Nonetheless, the source of this age-related RM deficit remains unspecified. One of the most widely investigated factors is an age-related reduction in attentional resources. To investigate this factor, previous researchers have tested whether dividing YAs' attention during encoding equated their RM performance to that of OAs. However, results from these studies failed to replicate the age-related RM impairment observed in aging. The current study investigated whether a reduction in attentional resources for processing of relational information (i.e., relational attention) underlies age-related RM deficits. Using fMRI, we examined whether the effect of reduced attentional resources for processing of relational information is similar to that observed in aging at both behavioral and neural levels. The behavioral results showed that reduced attentional resources for relational information during encoding equated YAs RM performance to that of OAs. Furthermore, the fMRI results demonstrated that both aging, as well as reductions in relational attention in YAs, significantly reduced activity in brain areas associated with successful RM formation, namely, the ventrolateral and dorsolateral PFC, superior and inferior parietal regions, and left hippocampus. Such converging evidence from behavioral and neuroimaging studies suggests that a reduction in attentional resources for relational information is a critical factor for the RM deficit observed in aging.     

Transitivity,flexibility, conjunctive representations,and the hippocampus. I. An empirical analysis

After training on a set of four ordered, simultaneous, odor discrimination problems (A+B-, B+C-, C+D-, D+E), intact rats display transitivity: When tested on the novel combination BD, they choose B. Rats with damage to the hippocampus, however, do not show transitivity (Dusek and Eichenbaum, 1997. Proc Natl Acad Sci U S A 94:7109-7114). These results have been interpreted as support for the idea that the hippocampus is a relational memory storage system that enables the subject to make comparisons among representations of the individual problems and choose based on inferential logic. We provide evidence for a simpler explanation. Specifically, subjects make their choices based on the absolute excitatory value of the individual stimuli. This value determines the ability of that stimulus to attract a response. This conclusion emerged because after training on a five-problem set (A+B-, B+C-, C+D-, D+E-, E+F-) rats preferred B when tested with BE, but not when tested with BD. The implication of these results for how to conceptualize the role of the hippocampus in transitive-like phenomena is discussed.     

An FMRI analysis of the human hippocampus: inference, context, and task awareness

The hippocampus is critical for encoding and retrieving semantic and episodic memories. Animal studies indicate that the hippocampus is also required for relational learning tasks. A prototypical relational learning task, and the one investigated in this experiment, using event-related functional magnetic resonance imaging, is the transitive inference (TI) task. In the TI task, participants were to choose between A and B (A?B) and learned by trial and error to choose A (A > B). There were four such premise pairs during a training (A > B, B > C, C > D, D > E). These can be acquired distinctly or can be organized into a superordinate hierarchy (A > B > C > D > E), which would efficiently represent all the learned relations and allow inferences (e.g., B > D). At test there was no reinforcement: In addition to premise pairs, untrained pairings were introduced (e.g., A?E, B?D). Correctly inferring that B > D is taken as evidence for the formation of a superordinate hierarchy; several alternatives to the superordinate hierarchy hypothesis are considered. Awareness of the formation of this hierarchy was measured by a postscan questionnaire. Four main findings are reported: (1) Inferential performance and task awareness dissociated behaviorally and at the level of hemodynamic response; (2) As expected, performance on the inferred relation, B > D, corresponded to the ability to simultaneously acquire B > C and C > D premise pairs during training; (3) Interestingly, acquiring these "inner pairs" corresponded to greater hippocampal activation than the "outer pairs" (A > B, D > E) for all participants. However, a distinct pattern of hippocampal activity for these inner pairs differentiated those able to perform the inferential discrimination, B > D, at test. Because these inner premise pairs require contextual discrimination (e.g., C is incorrect in the context of B but correct in the context of D), we argue that the TI task is hippocampal-dependent because the premise pair acquisition necessary for inference is hippocampal-dependent; (4) We found B > D related hippocampal activity at test that is anatomically consistent with preconsolidation recall effects shown in other studies.     

Increased Hippocampal Excitability and Altered Learning Dynamics Mediate Cognitive Mapping Deficits in Human Aging

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain''s navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain''s navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.     

Contributions of the hippocampus and entorhinal cortex to rapid visuomotor learning in rhesus monkeys

The hippocampus and adjacent structures in the medial temporal lobe are essential for establishing new associative memories. Despite this knowledge, it is not known whether the hippocampus proper is essential for establishing such memories, nor is it known whether adjacent regions like the entorhinal cortex might contribute. To test the contributions of these regions to the formation of new associative memories, we trained rhesus monkeys to rapidly acquire arbitrary visuomotor associations, i.e., associations between visual stimuli and spatially directed actions. We then assessed the effects of reversible inactivations of either the hippocampus (Experiment 1) or entorhinal cortex (Experiment 2) on the within‐session rate of learning. For comparison, we also evaluated the effects of the inactivations on performance of problems of the same type that had been well learned prior to any inactivations. We found that inactivation of the entorhinal cortex but not hippocampus produced impairments in acquiring novel arbitrary associations. The impairment did not extend to the familiar, previously established associations. These data indicate that the entorhinal cortex is causally involved in establishing new associations, as opposed to retrieving previously learned associations. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.