The Volume of Hippocampal Subfields in Relation to Decline of Memory Recall Across the Adult Lifespan

Background: The hippocampus is an important limbic structure closely related to memory function. However, few studies have focused on the association between hippocampal subfields and age-related memory decline. We investigated the volume alterations of hippocampal subfields at different ages and assessed the correlations with Immediate and Delayed recall abilities.Materials and Methods: A total of 275 participants aged 20–89 years were classified into 4 groups: Young, 20–35 years; Middle-early, 36–50 years; Middle-late, 51–65 years; Old, 66–89 years. All data were acquired from the Dallas Lifespan Brain Study (DLBS). The volumes of hippocampal subfields were obtained using Freesurfer software. Analysis of covariance (ANCOVA) was performed to analyze alterations of subfield volumes among the 4 groups, and multiple comparisons between groups were performed using the Bonferroni method. Spearman correlation with false discovery rate correction was used to investigate the relationship between memory recall scores and hippocampal subfield volumes.Results: Apart from no significant difference in the left parasubiculum (P = 0.269) and a slight difference in the right parasubiculum (P = 0.022), the volumes of other hippocampal subfields were significantly different across the adult lifespan (P < 0.001). The hippocampal fissure volume was increased in the Old group, while volumes for other subfields decreased. In addition, Immediate recall scores were associated with volumes of the bilateral molecular layer, granule cell layer of the dentate gyrus (GC-DG), cornus ammonis (CA) 1, CA2/3, CA4, left fimbria and hippocampal amygdala transition area (HATA), and right fissure (P < 0.05). Delayed recall scores were associated with the bilateral molecular layer, GC-DG, CA2/3 and CA4; left tail, presubiculum, CA1, subiculum, fimbria and HATA (P < 0.05).Conclusion: The parasubiculum volume was not significantly different across the adult lifespan, while atrophy in dementia patients in some studies. Based on these findings, we speculate that volume changes in this region might be considered as a biomarker for dementia disorders. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the key role of the hippocampus in age-related memory decline. These regions could be used to assess the risk of memory decline across the adult lifespan

Distinct multivariate structural brain profiles are related to variations in short- and long-delay memory consolidation across children and young adults

From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to memory consolidation processes. The present study examined memory consolidation of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory retention rate were related to structural brain measures. Our results showed that children, in comparison to young adults, retained correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal head and subfield structures in the body was found to be associated with variation in short-delay memory retention. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), hippocampal head, and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory retention. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short-and long-delay memory consolidation across children and young adults

How does episodic memory develop in adolescence?

Key areas of the episodic memory (EM) network demonstrate changing structure and volume during adolescence. EM is multifaceted and yet studies of EM thus far have largely examined single components, used different methods and have unsurprisingly yielded inconsistent results. The Treasure Hunt task is a single paradigm that allows parallel investigation of memory content, associative structure, and the impact of different retrieval support. Combining the cognitive and neurobiological accounts, we hypothesized that some elements of EM performance may decline in late adolescence owing to considerable restructuring of the hippocampus at this time. Using the Treasure Hunt task, we examined EM performance in 80 participants aged 10-17 yr. Results demonstrated a cubic trajectory with youngest and oldest participants performing worst. This was emphasized in associative memory, which aligns well with existing literature indicating hippocampal restructuring in later adolescence. It is proposed that memory development may follow a nonlinear path as children approach adulthood, but that future work is required to confirm and extend the trends demonstrated in this study

Empathic responding and hippocampal volume in young children

©American Psychological Association, 2019. This paper is not the copy of record and may not exactly replicate the authoritative document published in the APA journal. The final article is available, upon publication, at: https://doi.org/10.1037/dev0000684Empathic responding—the capacity to understand, resonate with, and respond sensitively to others’ emotional experiences—is a complex human faculty that calls upon multiple social, emotional, and cognitive capacities and their underlying neural systems. Emerging evidence in adults has suggested that the hippocampus and its associated network may play an important role in empathic responding, possibly via processes such as memory of emotional events, but the contribution of this structure in early childhood is unknown. We examined concurrent associations between empathic responding and hippocampal volume in a sample of 78 children (ages 4–8 years). Larger bilateral hippocampal volume (adjusted for intracranial volume) predicted greater observed empathic responses toward an experimenter in distress, but only for boys. The association was not driven by a specific subregion of the hippocampus (head, body, tail), nor did it vary with age. Empathic responding was not significantly related to amygdala volume, suggesting specificity of relations with the hippocampus. Results support the proposal that hippocampal structure contributes to individual differences in children’s empathic responding, consistent with research in adults. Findings shed light on an understudied structure in the complex neural systems supporting empathic responding and raise new questions regarding sex differences in the neurodevelopment of empathy in early childhood. (PsycInfo Database Record (c) 2020 APA, all rights reserved)https://doi.org/10.1037/dev000068

Hippocampus

The hippocampus is a bicortical structure with extensive fiber connections with multiple brain regions. It is involved in several functions, such as learning, memory, attention, emotion, and more. This book covers various aspects of the hippocampus including cytoarchitecture, functions, diseases, and treatment. It highlights the most advanced findings in research on the hippocampus. It discusses circuits, pattern formation process of grid cells, and zinc dynamics of the hippocampus. The book also addresses the tau pathology and circRNAs related to Alzheimer’s disease and potential treatment strategies. It is a useful resource for general readers, students, and researchers

Plasticity in the human hippocampus

If we are to approach rehabilitation of memory-impaired patients in a systematic and efficacious way, then it is vital to know if the human memory system has the propensity for plasticity in adulthood, the limiting factors on such plasticity, and the timescales of any plastic change. This thesis was motivated by an attempt to develop a body of knowledge in relation to these questions. There is wide agreement that the hippocampus plays a key role in navigation and memory across species. Evidence from animal studies suggests that spatial memoryrelated hippocampal volume changes and experience-related hippocampal neurogenesis takes place throughout the lifespan. Previous studies in humans indicated that expert navigators, licensed London taxi drivers, have different patterns of hippocampal grey matter volume relative to control participants. In addition, preliminary evidence also suggested there may be functional consequences associated with this grey matter pattern. Using licensed London taxi drivers as a model for learning and memory, the work undertaken centered on four key issues: (1) In a set of studies, I characterised the neuropsychological profile of licensed London taxi drivers in detail, which included devising a number of new table-top associational memory tests. This enabled me to assess the functional consequences of their expertise and hippocampal grey matter pattern in greater depth than previous studies. (2) In order to explore the effects of taxi drivers’ expertise in more naturalistic settings, I also examined how well they could learn the layout of an unfamiliar town compared with a group of non-taxi drivers, and how effectively taxi drivers could integrate a new district into their existing spatial representation of London. (3) I then conducted a study on experts whose knowledge was much less spatial than taxi drivers in order to examine if the effects on hippocampal grey matter and neuropsychology were general or whether they were specific to the spatial domain. (4) Given that previous taxi driver studies were cross-sectional, the question of whether the human hippocampus can exhibit spatial memory-related structural plasticity in adulthood was uncertain. I therefore conducted a longitudinal study which assessed participants both pre and post taxi driver training using structural MRI and neuropsychological measures. This enabled me to investigate, within subjects, whether hippocampal volume changes can be acquired in response to intense spatial stimulation. In addition, I explored whether ceasing to be a taxi driver (i.e. retiring after many years on the job) resulted in ‘reverse’ plasticity. I found evidence for hippocampal plasticity within individuals as a result of their intense acquisition of spatial knowledge over a number of years that was associated with qualifying to be a licensed London taxi driver, and preliminary evidence of reverse plasticity when taxi drivers retire. This suggests that hippocampal structure and memory ability can be modified in response to environmental factors and are not necessarily hard-wired. However, my results also provide some insights into the boundaries within which human memory operates, as I identified both positive and negative cognitive consequences of being an expert navigator, and also established that the MRI and neuropsychology effects of expertise on the hippocampus may be restricted to the spatial domain

Episodic memory across the life span : evidence from infancy, childhood, adults and amnesia

PhD ThesisIt is vital to examine changes in hippocampal-dependent memory across the life-span, in order to understand both its ontogeny and subsequent decline with healthy aging. To the authors’ knowledge, earlier research has not used the same methodology to assess episodic memory processes in children and adults, yet comparisons in performance between these groups have been made regardless. Equally, there is a lack of robust evidence to indicate that episodic memory paradigms employed with young children are hippocampal-dependent. In this thesis, I aimed to address these important issues by assessing memory performance across the lifespan in children aged 7.5-months-old to 8-years-old (n= >500), young adults aged 18-25 years (n= >60), older adults aged 54-77 years (n= >60) and patients with selective hippocampal damage aged 52-75 years (n=5). Two tasks were used; 1) a deferred imitation task which measured memory for action sequences and 2) a faces and places task which measured memory for face-scene associations via eye-tracking and/or explicit recall. Comparisons between patients and adult controls permitted me to infer whether these paradigms are measuring hippocampal-dependent processes. Both tasks contained conditions that did not rely on instructions, in order to permit valid comparisons to be made between pre-verbal infants and adults and determine at what age task performance becomes adult-like and exceeds that of patients. When patient performance was examined on both tasks relative to adult controls, patients demonstrated significantly poorer memory for the action sequence (deferred imitation task) and significantly worse recall for face-scene associations (faces and places task). These findings suggest that both tasks appear to index hippocampal-dependent memory processes and the integrity of the hippocampus is needed to support successful performance. Subtle distinctions were found between memory for action information and memory for temporal order information across childhood. While both types of memory became adult-like by 4- years-old and remained relatively stable from this age onwards, memory for actions increased more incrementally with age from approximately 2-years-old whereas temporal order memory emerged more sharply around 4-years-old. Alongside supporting episodic memory, the hippocampus plays a specialised role in the processing of scenes (Hassabis & Maguire, 2007) and spatial memory (O’Keefe & Nadel, 1979). In order to examine whether hippocampal scene processes may be influencing memory development, memory for face-scene associations was assessed in all age groups when scene viewing perspective either remained the same or was shifted slightly between learning and test. We examined whether participants could tolerate the change in scene perspective, i.e. recognise that it is the same place albeit the view of the scene has shifted slightly, to retrieve the previously formed association between that scene and a face. While all groups aged between 7.5-month-old to 4-years-old, with the exception of 3-year-olds, demonstrated eye movements veridical of remembering face-scene pairs when scene view remained constant within a trial, this behaviour was eradicated when scene perspective was shifted between learning and test in all groups with the exception of 4-year-olds. Shifting scene perspective between learning and test had a detrimental effect on memory for previously presented facescene pairs in older adults and to a more significant extent in patients with selective iv hippocampal damage. In contrast, shifting scene perspective between learning and test did not impact on recall for face-pairs in young adults and children aged 5-8 years. In addition to age-related increases in memory across childhood, the acquisition of developmental milestones may also facilitate memory development. Previous literature has tentatively linked the attainment of independent locomotion (IL) with greater memory retrieval flexibility in infancy (Herbert et al., 2007), with suggestion that the greater experience in varying spatial contexts that accompanies this milestone may be providing scaffolding to support episodic memory processes (Rovee-Collier & Cuevas, 2009). Therefore, I aimed to not just explore age-related differences in memory performance within my tasks, but assessed whether attaining IL in early infancy provides mnemonic benefits compared to peers who develop this ability later in the first year. Performance was compared between infants who had achieved IL and age-matched non-locomotive peers (NIL) at 7.5- months-old. A sub group of these infants returned to participate when aged 9-months-old and performance was compared between infants who had acquired IL by 7.5 months of age compared to age-matched peers who only recently acquired this milestone. DI performance in 9-month-olds who had acquired IL by 7.5 months of age significantly outperformed their agematched peers who only recently acquired IL (i.e. IL was acquired between 7.5-9 months of age). Furthermore, only those infants who had acquired IL by 7.5-months-old demonstrated eye-movements veridical of remembering previously presented face-scene pairs. This collection of findings are discussed in terms of how using the same hippocampaldependent memory task across the life-span can inform current understanding of the developmental trajectory of this specific form of memory. I reflect upon how the additional onus of the hippocampus in spatial processing may be fundamentally intertwined with episodic memory development and how the acquisition of spatial knowledge through attaining IL may be providing a scaffold for this type of memory development in early childhood.The Garside Legac

Examining the co-development of episodic memory and hippocampal subfields – A longitudinal study

Episodic memory is a cornerstone ability that allows one to recall past events and the context in which they occur. Many different tasks have been used to assess the development of episodic memory during early childhood. Previous longitudinal work on individual tasks has noted accelerated changes from approximately 5 to 7 years, suggesting non-linear changes in memory ability during early childhood. However, the extent to which tasks relate to one another and are indicative of the latent construct of episodic memory is not known. Further, improvements in memory are thought to relate to underlying changes occurring in the functionally distinct subfields of the hippocampus (i.e., CA2-4/dentate gyrus (DG), CA1, and Subiculum) during this developmental period. This study examined changes in episodic memory ability, hippocampal subfield volume, and the relation between changes in episodic memory and volume of hippocampal subfields during early childhood (4 to 8 years) using longitudinal data and a structural equation modeling framework. Results suggest that episodic memory ability improves substantially during this period, with consistent improvements between 4 to 8 years. Further, there are robust increases in subiculum, CA1, and CA2-4/DG volume between 5 to 6 years of age. Finally, within this sample, there were relations between the development of hippocampal subfields and improvements on a single source memory task commonly used to assess episodic memory. Interestingly, this relation was most robust between subiculum and source memory. Overall, these results highlight the ability to use laboratory tasks to characterize developmental changes in episodic memory, highlight 5- to 6-years as a period of developmental change in hippocampal subfields, and further support a role of the hippocampus in supporting episodic memory

Antidepressant-like Effects of Peripheral Reelin Administration in a Preclinical Model of Depression

Depression is a serious psychiatric disorder characterized by a range of debilitating symptoms. Long-term exposure to stress is a significant risk factor for the onset and maintenance of depression. Rats exposed to repeated treatment with the stress hormone corticosterone (CORT), a well-established rodent model of depression, begin to display depression-like symptoms. The development of depression-like symptoms with prolonged exposure to CORT is accompanied by reductions in the number and maturation rate of immature dentate granule cells within the hippocampus. Furthermore, these changes are paralleled by gradual decreases in reelin-expressing cells in the dentate subgranular zone of the hippocampus. Reelin is a large extracellular matrix protein that has been implicated in a number of neuropsychiatric disorders, including szchiphrenia, bipolar disorder, autism, as well as major depression. It holds important roles in learning and memory, cell migration and integration, synaptic contact formation, and adult neurogenesis. Mice deficient in reelin are more susceptible to CORT-induced impairments in hippocampal neurogenesis and the development of a depressive phenotype. Previous work has shown that intra-hippocampal infusions of reelin into the hippocampus reverse CORT-induced increases in depression-like behavior in rats, while restoring accompanying impairments in hippocampal neurogenesis. Reelin is also expressed in peripheral organs and tissues, though its roles here are not well understood. However, reelin-deficient mice show peripheral alterations in the clustering pattern of the serotonin transporter (SERT) in membranes of blood lymphocytes. The serotonin transporter is one of the main targets of antidepressant action, and importantly, this altered pattern of SERT clustering in reelin-deficient mice is mirrored both in patients with depression and in rats exposed to prolonged CORT treatment. Based on the previous findings, we were motivated to examine whether peripheral injections of reelin could restore CORT-induced increases in depression-like behavior. To investigate possible mechanisms, we examined (i) the SERT clustering pattern in peripheral lymphocyte membranes, and (ii) the maturation rate of immature hippocampal neurons. 40mg/kg of CORT was administered subcutaneously once per day for 21 consecutive days. In conjunction, we utilized a novel reelin injection paradigm, where reelin was delivered via the lateral tail vein at either 3μg/ml or 5μg/ml every 5 or 10 days during the period of CORT injections. Depression-like behavior was measured using the forced swim test the day following the last CORT injection. The open field test was included as a measure of locomotive and anxiety-like behavior. Importantly, peripheral reelin at all dosages administered restored CORT-induced increases in depression-like behavior in the forced swim test, normalizing both immobility and swimming behaviors. Neither CORT nor reelin impacted open field behavior. As expected, CORT-treated rats displayed alterations in SERT membrane protein clustering, and importantly this was restored by all doses of reelin administered. Peripheral reelin did not significantly reverse the CORT-induced deficits in immature neuron maturation rate. These novel findings demonstrate that reelin has antidepressant-like actions when given peripherally and provide evidence for the regulation of serotonin transporter clustering in lymphocyte membranes as a mechanism for the antidepressant action of reelin