Reminders activate the prefrontal-medial temporal cortex and attenuate forgetting of event memory.

Replicas of an aspect of an experienced event can serve as effective reminders, yet little is known about the neural basis of such reminding effects. Here we examined the neural activity underlying the memory-enhancing effect of reminders 1 week after encoding of naturalistic film clip events. We used fMRI to determine differences in network activity associated with recently reactivated memories relative to comparably aged, non-reactivated memories. Reminders were effective in facilitating overall retrieval of memory for film clips, in an all-or-none fashion. Prefrontal cortex and hippocampus were activated during both reminders and retrieval. Peak activation in ventro-lateral prefrontal cortex (vPFC) preceded peak activation in the right hippocampus during the reminders. For film clips that were successfully retrieved after 7 days, pre-retrieval reminders did not enhance the quality of the retrieved memory or the number of details retrieved, nor did they more strongly engage regions of the recollection network than did successful retrieval of a non-reminded film clip. These results suggest that reminders prior to retrieval are an effective means of boosting retrieval of otherwise inaccessible episodic events, and that the inability to recall certain events after a delay of a week largely reflects a retrieval deficit, rather than a storage deficit for this information. The results extend other evidence that vPFC drives activation of the hippocampus to facilitate memory retrieval and scene construction, and show that this facilitation also occurs when reminder cues precede successful retrieval attempts. The time course of vPFC-hippocampal activity during the reminder suggests that reminders may first engage schematic information meditated by vPFC followed by a recollection process mediated by the hippocampus.

Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions.

A wide range of cognitive deficits, including memory loss associated with hippocampal dysfunction, have been widely reported in cancer survivors who received chemotherapy. Changes in both white matter and gray matter volume have been observed following chemotherapy treatment, with reduced volume in the medial temporal lobe thought to be due in part to reductions in hippocampal neurogenesis. Pre-clinical rodent models confirm that common chemotherapeutic agents used to treat various forms of non-CNS cancers reduce rates of hippocampal neurogenesis and impair performance on hippocampally-mediated learning and memory tasks. We review the pre-clinical rodent literature to identify how various chemotherapeutic drugs affect hippocampal neurogenesis and induce cognitive impairment. We also review factors such as physical exercise and environmental stimulation that may protect against chemotherapy-induced neurogenic suppression and hippocampal neurotoxicity. Finally, we review pharmacological interventions that target the hippocampus and are designed to prevent or reduce the cognitive and neurotoxic side effects of chemotherapy.

Reminders reinstate context-specificity to generalized remote memories in rats: relation to activity in the hippocampus and aCC.

Conditioned fear memories that are context-specific shortly after conditioning generalize over time. We exposed rats to a context reminder 30 d after conditioning, which served to reinstate context-specificity, and investigated how this reminder alters retrieval-induced activity in the hippocampus and anterior cingulate cortex (aCC) relative to a no reminder condition. c-Fos expression in dorsal CA1 was observed following retrieval in the original context, but not in a novel context, whether or not the memory was reactivated, suggesting that dCA1 retains the context-specific representation. c-Fos was highly expressed in aCC following remote memory testing in both contexts, regardless of reminder condition, indicating that aCC develops generalized representations that are insensitive to memory reactivation.

Hippocampal and Retrosplenial Goal Distance Coding After Long-term Consolidation of a Real-World Environment.

Recent research indicates the hippocampus may code the distance to the goal during navigation of newly learned environments. It is unclear however, whether this also pertains to highly familiar environments where extensive systems-level consolidation is thought to have transformed mnemonic representations. Here we recorded fMRI while University College London and Imperial College London students navigated virtual simulations of their own familiar campus (>2 years of exposure) and the other campus learned days before scanning. Posterior hippocampal activity tracked the distance to the goal in the newly learned campus, as well as in familiar environments when the future route contained many turns. By contrast retrosplenial cortex only tracked the distance to the goal in the familiar campus. All of these responses were abolished when participants were guided to their goal by external cues. These results open new avenues of research on navigation and consolidation of spatial information and underscore the notion that the hippocampus continues to play a role in navigation when detailed processing of the environment is needed for navigation.

The hippocampus is critical for value-based decisions guided by dissociative inference.

The hippocampus supports flexible decision-making through memory integration: bridging across episodes and inferring associations between stimuli that were never presented together ('associative inference'). A pre-requisite for memory integration is flexible representations of the relationships between stimuli within episodes (AB) but also of the constituent units (A,B). Here we investigated whether the hippocampus is required for parsing experienced episodes into their constituents to infer their re-combined within-episode associations ('dissociative inference'). In three experiments male rats were trained on an appetitive conditioning task using compound auditory stimuli (AB+, BA+, CD-, DC-). At test either the compound or individual stimuli were presented as well as new stimuli. Rats with hippocampal lesions acquired and retained the compound discriminations as well as controls. Single constituent stimuli (A, B, C, D) were presented for the first time at test, so the only value with which they could be associated was the one from the compound to which they belonged. Controls inferred constituent tones' corresponding values while hippocampal rats did not, treating them as merely familiar stimuli with no associated value. This finding held whether compound training occurred before or after hippocampal lesions, suggesting that hippocampus-dependent inferential processes more likely occur at retrieval. The findings extend recent discoveries about the role of the hippocampus in intrinsic value representation, demonstrating hippocampal contributions to allocating value from primary rewards to individual stimuli. Importantly, we discovered that dissociative inferences serve to restructure or reparse patterns of directly acquired associations when animals are faced with environmental changes and need to extract relevant information from a multiplex memory. The hippocampus is critical for this fundamental flexible use of associations.

Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans.

The dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation.

Prior knowledge modulates the neural substrates of encoding and retrieving naturalistic events at short and long delays.

Congruence with prior knowledge and incongruence/novelty have long been identified as two prominent factors that, despite their opposing characteristics, can both enhance episodic memory. Using narrative film clip stimuli, this study investigated these effects in naturalistic event memories - examining behaviour and neural activation to help explain this paradox. Furthermore, we examined encoding, immediate retrieval, and one-week delayed retrieval to determine how these effects evolve over time. Behaviourally, both congruence with prior knowledge and incongruence/novelty enhanced memory for events, though incongruent events were recalled with more errors over time. During encoding, greater congruence with prior knowledge was correlated with medial prefrontal cortex (mPFC) and parietal activation, suggesting that these areas may play a key role in linking current episodic processing with prior knowledge. Encoding of increasingly incongruent events, on the other hand, was correlated with increasing activation in, and functional connectivity between, the medial temporal lobe (MTL) and posterior sensory cortices. During immediate and delayed retrieval the mPFC and MTL each demonstrated functional connectivity that varied based on the congruence of events with prior knowledge; with connectivity between the MTL and occipital regions found for incongruent events, while congruent events were associated with functional connectivity between the mPFC and the inferior parietal lobules and middle frontal gyri. These results demonstrate patterns of neural activity and connectivity that shift based on the nature of the event being experienced or remembered, and that evolve over time. Furthermore, they suggest potential mechanisms by which both congruence with prior knowledge and incongruence/novelty may enhance memory, through mPFC and MTL functional connectivity, respectively.

The influence of recollection and familiarity in the formation and updating of associative representations.

Prior representations affect future learning. Little is known, however, about the effects of recollective or familiarity-based representations on such learning. We investigate the ability to reuse or reassociate elements from recollection- and familiarity-based associations to form new associations. Past neuropsychological research suggests that hippocampal, and presumably recollective, representations are more flexible than extra-hippocampal, presumably familiarity-based, representations. We therefore hypothesize that the elements of recollective associations, as opposed to familiarity-based representations, may be more easily manipulated and decoupled from each other, and facilitate the formation of new associations. To investigate this hypothesis we used the AB/AC learning paradigm. Across two recall studies we observed an advantage in learning AC word pairs if AB word pairs were initially recollected. Furthermore, AB word pairs were more likely to intrude during a final AC test if those AB word pairs were initially familiarity-based. A third experiment using a recognition version of the AB/AC paradigm ruled out the possibility that our findings were due to memory strength. Our results support the idea that elements in recollective associative traces may be more discretely coded, leading to their flexible use, whereas elements in familiarity-based associative traces are less flexible.

Episodic Memory and Beyond: The Hippocampus and Neocortex in Transformation.

The last decade has seen dramatic technological and conceptual changes in research on episodic memory and the brain. New technologies, and increased use of more naturalistic observations, have enabled investigators to delve deeply into the structures that mediate episodic memory, particularly the hippocampus, and to track functional and structural interactions among brain regions that support it. Conceptually, episodic memory is increasingly being viewed as subject to lifelong transformations that are reflected in the neural substrates that mediate it. In keeping with this dynamic perspective, research on episodic memory (and the hippocampus) has infiltrated domains, from perception to language and from empathy to problem solving, that were once considered outside its boundaries. Using the component process model as a framework, and focusing on the hippocampus, its subfields, and specialization along its longitudinal axis, along with its interaction with other brain regions, we consider these new developments and their implications for the organization of episodic memory and its contribution to functions in other domains.

Recovering and preventing loss of detailed memory: differential rates of forgetting for detail types in episodic memory.

Episodic memories undergo qualitative changes with time, but little is known about how different aspects of memory are affected. Different types of information in a memory, such as perceptual detail, and central themes, may be lost at different rates. In patients with medial temporal lobe damage, memory for perceptual details is severely impaired, while memory for central details is relatively spared. Given the sensitivity of memory to loss of details, the present study sought to investigate factors that mediate the forgetting of different types of information from naturalistic episodic memories in young healthy adults. The study investigated (1) time-dependent loss of "central" and "peripheral" details from episodic memories, (2) the effectiveness of cuing with reminders to reinstate memory details, and (3) the role of retrieval in preventing forgetting. Over the course of 7 d, memory for naturalistic events (film clips) underwent a time-dependent loss of peripheral details, while memory for central details (the core or gist of events) showed significantly less loss. Giving brief reminders of the clips just before retrieval reinstated memory for peripheral details, suggesting that loss of details is not always permanent, and may reflect both a storage and retrieval deficit. Furthermore, retrieving a memory shortly after it was encoded prevented loss of both central and peripheral details, thereby promoting retention over time. We consider the implications of these results for behavioral and neurobiological models of retention and forgetting.

Forgetting Patterns Differentiate Between Two Forms of Memory Representation.

For decades, there has been controversy about whether forgetting is caused by decay over time or by interference from irrelevant information. We suggest that forgetting occurs because of decay or interference, depending on the memory representation. Recollection-based memories, supported by the hippocampus, are represented in orthogonal patterns and are therefore relatively resistant to interference from one another. Decay should be a major source of their forgetting. By contrast, familiarity-based memories, supported by extrahippocampal structures, are not represented in orthogonal patterns and are therefore sensitive to interference. In a study in which we manipulated the postencoding task-interference level and the length of the delay between study and testing, we provide direct evidence in support of our representation theory of forgetting. Recollection and familiarity were measured using the remember/know procedure. We show that the causes of forgetting depend on the nature of the underlying memory representation, which places the century-old puzzle of forgetting in a coherent framework.

Functional connectivity of hippocampal and prefrontal networks during episodic and spatial memory based on real-world environments.

Several recent studies have compared episodic and spatial memory in neuroimaging paradigms in order to understand better the contribution of the hippocampus to each of these tasks. In the present study, we build on previous findings showing common neural activation in default network areas during episodic and spatial memory tasks based on familiar, real-world environments (Hirshhorn et al. (2012) Neuropsychologia 50:3094-3106). Following previous demonstrations of the presence of functionally connected sub-networks within the default network, we performed seed-based functional connectivity analyses to determine how, depending on the task, the hippocampus and prefrontal cortex differentially couple with one another and with distinct whole-brain networks. We found evidence for a medial prefrontal-parietal network and a medial temporal lobe network, which were functionally connected to the prefrontal and hippocampal seeds, respectively, regardless of the nature of the memory task. However, these two networks were functionally connected with one another during the episodic memory task, but not during spatial memory tasks. Replicating previous reports of fractionation of the default network into stable sub-networks, this study also shows how these sub-networks may flexibly couple and uncouple with one another based on task demands. These findings support the hypothesis that episodic memory and spatial memory share a common medial temporal lobe-based neural substrate, with episodic memory recruiting additional prefrontal sub-networks.

An occupation-based strategy training approach to managing age-related executive changes: a pilot randomized controlled trial.

OBJECTIVE: To determine the feasibility of recruitment and retention of healthy older adults and the effectiveness of an intervention designed to manage age-related executive changes. DESIGN: A pilot randomized controlled trial. SETTING: Research centre and participants' homes. PARTICIPANTS: Nineteen healthy, community dwelling older adults with complaints of cognitive difficulties and everyday problems, but no evidence of mild cognitive impairment, dementia or depression on objective testing. INTERVENTIONS: Seventeen hours of group and individual training. Participants in the experimental arm received education about self-management, successful aging and an occupation-based meta-cognitive strategy-training program. Participants in the control arm received education about brain health and participated in cognitively stimulating exercises. MAIN MEASURES: Changes on untrained, everyday life goals were identified using the Canadian Occupational Performance Measure. Generalization of benefits was measured using the Stanford Chronic Disease Questionnaire, general self-efficacy and changes in executive function (Delis-Kaplan Executive Function System Tower Test, Word Fluency and Trail-Making Test). RESULTS: 20% (19/96) of healthy older adults approached were eligible, consented and were enrolled in the study, 90% (17/19) were retained to three-month follow-up. Participants in the experimental arm reported significantly more improvement on untrained goals (11/22 compared with 9/46, χ(2)=4.92, p<0.05), maintenance of physical activity (p<0.05) and better preparation for doctors' visits (p<0.05) relative to the control group. There were no significant between group differences on objective measures of executive function. CONCLUSIONS: These data support the feasibility of a larger trial where a sample of 72 (36 participants in each arm) would be required to confirm or refute these findings.

Hippocampal lesions produce both nongraded and temporally graded retrograde amnesia in the same rat.

Rats were administered contextual fear conditioning and trained on a water-maze, spatial memory task 28 days or 24 h before undergoing hippocampal lesion or control surgery. When tested postoperatively on both tasks, rats with hippocampal lesions exhibited retrograde amnesia for spatial memory at both delays but temporally graded retrograde amnesia for the contextual fear response. In demonstrating both types of retrograde amnesia in the same animals, the results parallel similar observations in human amnesics with hippocampal damage and provide compelling evidence that the nature of the task and the type of information being accessed are crucial factors in determining the pattern of retrograde memory loss associated with hippocampal damage. The results are interpreted as consistent with our transformation hypothesis (Winocur et al. (2010a) Neuropsychologia 48:2339-2356; Winocur and Moscovitch (2011) J Int Neuropsychol Soc 17:766-780) and at variance with standard consolidation theory and other theoretical models of memory.

Factors affecting graded and ungraded memory loss following hippocampal lesions.

This review evaluates three current theories--Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace-Transformation (Winocur, Moscovitch, & Bontempi, 2010)--in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed.

Differential contributions of executive and episodic memory functions to problem solving in younger and older adults.

The relationship of higher order problem solving to basic neuropsychological processes likely depends on the type of problems to be solved. Well-defined problems (e.g., completing a series of errands) may rely primarily on executive functions. Conversely, ill-defined problems (e.g., navigating socially awkward situations) may, in addition, rely on medial temporal lobe (MTL) mediated episodic memory processes. Healthy young (N = 18; M = 19; SD = 1.3) and old (N = 18; M = 73; SD = 5.0) adults completed a battery of neuropsychological tests of executive and episodic memory function, and experimental tests of problem solving. Correlation analyses and age group comparisons demonstrated differential contributions of executive and autobiographical episodic memory function to well-defined and ill-defined problem solving and evidence for an episodic simulation mechanism underlying ill-defined problem solving efficacy. Findings are consistent with the emerging idea that MTL-mediated episodic simulation processes support the effective solution of ill-defined problems, over and above the contribution of frontally mediated executive functions. Implications for the development of intervention strategies that target preservation of functional independence in older adults are discussed.

The hippocampus is involved in mental navigation for a recently learned, but not a highly familiar environment: a longitudinal fMRI study.

Functional magnetic resonance imaging (MRI) was used to investigate the hypothesis that memory for a large-scale environment is initially dependent on the hippocampus but is later supported by extra-hippocampal structures (e.g., precuneus, posterior parahippocampal cortex, and lingual gyrus) once the environment is well-learned. Participants were scanned during mental navigation tasks initially when they were newly arrived to the city of Toronto, and later after having lived and navigated within the city for 1 yr. In the first session, activation was observed in the right hippocampus, left precuneus, and postcentral gyrus. The second session revealed activation in the caudate and lateral temporal cortex, but not in the right hippocampus; additional activation was instead observed in the posterior parahippocampal cortex, lingual gyrus, and precuneus. These findings suggest that the right hippocampus is required for the acquisition of new spatial information but is not needed to represent this information when the environment is highly familiar.

Episodic Memory and Recollection Network Disruptions Following Chemotherapy Treatment in Breast Cancer Survivors: A Review of Neuroimaging Findings.

Long-term memory disturbances are amongst the most common and disruptive cognitive symptoms experienced by breast cancer survivors following chemotherapy. To date, most clinical assessments of long-term memory dysfunction in breast cancer survivors have utilized basic verbal and visual memory tasks that do not capture the complexities of everyday event memories. Complex event memories, including episodic memory and autobiographical memory, critically rely on hippocampal processing for encoding and retrieval. Systemic chemotherapy treatments used in breast cancer commonly cause neurotoxicity within the hippocampus, thereby creating a vulnerability to memory impairment. We review structural and functional neuroimaging studies that have identified disruptions in the recollection network and related episodic memory impairments in chemotherapy-treated breast cancer survivors, and argue for the need to better characterize hippocampally mediated memory dysfunction following chemotherapy treatments. Given the importance of autobiographical memory for a person's sense of identity, ability to plan for the future, and general functioning, under-appreciation of how this type of memory is impacted by cancer treatment can lead to overlooking or minimizing the negative experiences of breast cancer survivors, and neglecting a cognitive domain that may benefit from intervention strategies.

Right frontal lobe mediation of recollection- and familiarity-based verbal recognition memory: evidence from patients with tumor resections.

Medial-temporal, parietal, and pFC regions have been implicated in recollection and familiarity, but existing evidence from neuroimaging and patient studies is limited and conflicting regarding the role of specific regions within pFC in these memory processes. We report a study of 20 patients who had undergone resection of right frontal lobe tumors and 20 matched healthy control participants. The location and extent of lesions were traced on the patients' scans. A process dissociation procedure was employed to yield estimates of the contributions of recollection and familiarity in verbal recognition performance. Group comparisons revealed deficits in recollection but not familiarity in the patient group relative to their healthy counterparts. We found a positive relationship between estimates of familiarity and lesion sizes in the right inferior pFC (BA 11, 47) which was significant upon bootstrap resampling. These results are discussed in terms of prior work linking this area to an overextended sense of familiarity.

Memory transformation and systems consolidation.

With time and experience, memories undergo a process of reorganization that involves different neuronal networks, known as systems consolidation. The traditional view, as articulated in standard consolidation theory (SCT), is that (episodic and semantic) memories initially depend on the hippocampus, but eventually become consolidated in their original forms in other brain regions. In this study, we review the main principles of SCT and report evidence from the neuropsychological literature that would not be predicted by this theory. By comparison, the evidence supports an alternative account, the transformation hypothesis, whose central premise is that changes in neural representation in systems consolidation are accompanied by corresponding changes in the nature of the memory. According to this view, hippocampally dependent, episodic, or context-specific memories transform into semantic or gist-like versions that are represented in extra-hippocampal structures. To the extent that episodic memories are retained, they will continue to require the hippocampus, but the hippocampus is not needed for the retrieval of semantic memories. The transformation hypothesis emphasizes the dynamic nature of memory, as well as the underlying functional and neural interactions that must be taken into account in a comprehensive theory of memory.