Aerobic fitness is associated with hippocampal volume in elderly humans

Deterioration of the hippocampus occurs in elderly individuals with and without dementia, yet individual variation exists in the degree and rate of hippocampal decay. Determining the factors that influence individual variation in the magnitude and rate of hippocampal decay may help promote lifestyle changes that prevent such deterioration from taking place. Aerobic fitness and exercise are effective at preventing cortical decay and cognitive impairment in older adults and epidemiological studies suggest that physical activity can reduce the risk for developing dementia. However, the relationship between aerobic fitness and hippocampal volume in elderly humans is unknown. In this study, we investigated whether individuals with higher levels of aerobic fitness displayed greater volume of the hippocampus and better spatial memory performance than individuals with lower fitness levels. Furthermore, in exploratory analyses, we assessed whether hippocampal volume mediated the relationship between fitness and spatial memory. Using a region‐of‐interest analysis on magnetic resonance images in 165 nondemented older adults, we found a triple association such that higher fitness levels were associated with larger left and right hippocampi after controlling for age, sex, and years of education, and larger hippocampi and higher fitness levels were correlated with better spatial memory performance. Furthermore, we demonstrated that hippocampal volume partially mediated the relationship between higher fitness levels and enhanced spatial memory. Our results clearly indicate that higher levels of aerobic fitness are associated with increased hippocampal volume in older humans, which translates to better memory function. © 2009 Wiley‐Liss, Inc.     

Improving fitness increases dentate gyrus/CA3 volume in the hippocampal head and enhances memory in young adults

Converging evidence suggests a relationship between aerobic exercise and hippocampal neuroplasticity that interactively impacts hippocampally dependent memory. The majority of human studies have focused on the potential for exercise to reduce brain atrophy and attenuate cognitive decline in older adults, whereas animal studies often center on exercise‐induced neurogenesis and hippocampal plasticity in the dentate gyrus (DG) of young adult animals. In the present study, initially sedentary young adults (18–35 years) participated in a moderate‐intensity randomized controlled exercise intervention trial ( ClinicalTrials.gov ; NCT02057354) for a duration of 12 weeks. The aims of the study were to investigate the relationship between change in cardiorespiratory fitness (CRF) as determined by estimated _MAX, hippocampally dependent mnemonic discrimination, and change in hippocampal subfield volume. Results show that improving CRF after exercise training is associated with an increased volume in the left DG/CA3 subregion in young adults. Consistent with previous studies that found exercise‐induced increases in anterior hippocampus in older adults, this result was specific to the hippocampal head, or most anterior portion, of the subregion. Our results also demonstrate a positive relationship between change in CRF and change in corrected accuracy for trials requiring the highest level of discrimination on a putative behavioral pattern separation task. This relationship was observed in individuals who were initially lower‐fit, suggesting that individuals who show greater improvement in their CRF may receive greater cognitive benefit. This work extends animal models by providing evidence for exercise‐induced neuroplasticity specific to the neurogenic zone of the human hippocampus.     

The effects of memory training on behavioral and microstructural plasticity in young and older adults

Age differences in human brain plasticity are assumed, but have not been systematically investigated. In this longitudinal study, we investigated changes in white matter (WM) microstructure in response to memory training relative to passive and active control conditions in 183 young and older adults. We hypothesized that (i) only the training group would show improved memory performance and microstructural alterations, (ii) the young adults would show larger memory improvement and a higher degree of microstructural alterations as compared to the older adults, and (iii) changes in memory performance would relate to microstructural alterations. The results showed that memory improvement was specific to the training group, and that both the young and older participants improved their performance. The young group improved their memory to a larger extent compared to the older group. In the older sample, the training group showed less age‐related decline in WM microstructure compared to the control groups, in areas overlapping the corpus callosum, the cortico‐spinal tract, the cingulum bundle, the superior longitudinal fasciculus, and the anterior thalamic radiation. Less microstructural decline was related to a higher degree of memory improvement. Despite individual adaptation securing sufficient task difficulty, no training‐related group differences in microstructure were found in the young adults. The observed divergence of behavioral and microstructural responses to memory training with age is discussed within a supply‐demand framework. The results demonstrate that plasticity is preserved into older age, and that microstructural alterations may be part of a neurobiological substrate for behavioral improvements in older adults. Hum Brain Mapp 38:5666–5680, 2017. © 2018 The Authors Human Brain Mapping Published byWiley Periodicals, Inc.     

Cognitive dysfunction and multiple sclerosis: developing a rationale for considering the efficacy of exercise training

Cognitive impairment is a prevalent, disabling, and poorly managed consequence of multiple sclerosis (MS). This underscores the importance of considering alternative approaches, such as exercise training, for managing cognitive impairment in persons with MS. The consideration of exercise training is warranted based on evidence summarized in literature reviews and meta-analyses that (1) aerobic fitness, physical activity, and exercise training are associated with better cognitive function in older adults; and (2) exercise training has comparable effects on mobility and quality of life outcomes in older adults and persons with MS. To date, research examining aerobic fitness, physical activity, and exercise training effects on cognition in MS is nascent and mostly includes cross-sectional designs that provide preliminary evidence for a well-designed randomized controlled trial (RCT). We believe that a future RCT should adopt research methodologies and practices from gerontology when examining exercise training and cognition in MS. This will maximize the potential for successfully generating a body of knowledge on exercise training and cognition with the potential for impacting the lives of persons with MS.     

Improving Everyday Functioning in the Old-Old with Working Memory Training

ObjectiveThe aim of this study was to assess gains related to working memory (WM) training, in the short and long term (9 months after the training), in abilities required in everyday life, and in cognitive measures in old-old adults (aged ≥ 75 years).MethodsThirty-two community-dwelling older adults (aged 75–85 years) were randomly assigned to a training or an active control group. In addition to testing for any specific gains in a WM task similar to the one used in the training (criterion task), we sought transfer effects to: 1) abilities involved in everyday life using objective performance-based tasks (the Everyday Problem Test [EPT] and the Timed Instrumental Activities of Daily Living [TIADL] scale; 2) tasks demanding the comprehension and recall of spatial information and pairing names with faces; and 3) a measure of inhibitory control, that is, recall errors (intrusion errors).ResultsOnly the trained group showed specific gains in the criterion task, and in the TIADL in the short term. At follow-up, the trained group maintained gains in the criterion task, and showed transfer effects to everyday problem-solving (in the EPT), and in constructing spatial representations of an environment. The trained group also improved in a cognitive inhibition measure (intrusion errors) at follow-up. No such improvements were seen in the active control group.ConclusionWM training may be a valid way to help old-old adults preserve at least some abilities related to everyday functioning.     

Effects of working memory training on cognitive functions and neural systems

Working memory (WM) is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. WM plays a key role in a wide range of higher order cognitive functions and its impairment is observed in a wide range of psychiatric or neurological disorders, making it clinically important. Intensive adaptive training of WM has been shown to enhance individual WM. In this article, we review the studies and describe the methodologies of WM training, along with the psychological, clinical, and neuroimaging findings related to WM training. Training of WM is associated with a wide range of cognitive improvements in non-clinical and clinical subjects, although, on certain points, the results are divided. In clinical studies, training of WM was associated with an improvement of clinical symptoms outside the laboratory. Neuroimaging studies of WM training revealed the effect of WM training on the neural systems of the fronto-parietal network, which play a key role in WM. Still, a number of important issues remain uninvestigated, and we anticipate that future studies will solve these issues.     

Guiding research and practice: a conceptual model for aerobic exercise training in Alzheimer's disease

Alzheimer's disease is a global, epidemic problem affecting mainly older adults with tremendous social and financial burdens. Older adults with Alzheimer's disease showed reduced physical activity and cognitive changes that are probably amenable to aerobic exercise training. The purpose of this paper is to develop a conceptual model to guide future aerobic exercise research and practice by synthesizing the current state of the science on aerobic exercise training in older adults with AD. The literature review found 12 qualified studies that met the eligibility criteria for inclusion in this review and revealed six constructs (aerobic exercise training, physical fitness, physical performance, activities of daily living limitations, cognition, and psychological and behavioral symptoms), which composed the Functional Impact of aerobic exercise Training in Alzheimer's disease (FIT-AD) model. The state of science on each construct in older adults with Alzheimer's disease is reviewed and summarized. The emerging evidence suggests that aerobic exercise training might positively impacts all five other constructs. The implications of the FIT-AD model for future research and practice are discussed highlighted.     

Cardiorespiratory fitness predicts effective connectivity between the hippocampus and default mode network nodes in young adults

Rodent and human studies examining the relationship between aerobic exercise, brain structure, and brain function indicate that the hippocampus (HC), a brain region critical for episodic memory, demonstrates striking plasticity in response to exercise. Beyond the hippocampal memory system, human studies also indicate that aerobic exercise and cardiorespiratory fitness (CRF) are associated with individual differences in large‐scale brain networks responsible for broad cognitive domains. Examining network activity in large‐scale resting‐state brain networks may provide a link connecting the observed relationships between aerobic exercise, hippocampal plasticity, and cognitive enhancement within broad cognitive domains. Previously, CRF has been associated with increased functional connectivity of the default mode network (DMN), specifically in older adults. However, how CRF relates to the magnitude and directionality of connectivity, or effective connectivity, between the HC and other DMN nodes remains unknown. We used resting‐state fMRI and conditional Granger causality analysis (CGCA) to test the hypothesis that CRF positively predicts effective connectivity between the HC and other DMN nodes in healthy young adults. Twenty‐six participants (ages 18–35 years) underwent a treadmill test to determine CRF by estimating its primary determinant, maximal oxygen uptake (V^.O_2max), and a 10‐min resting‐state fMRI scan to examine DMN effective connectivity. We identified the DMN using group independent component analysis and examined effective connectivity between nodes using CGCA. Linear regression analyses demonstrated that CRF significantly predicts causal influence from the HC to the ventromedial prefrontal cortex, posterior cingulate cortex, and lateral temporal cortex and to the HC from the dorsomedial prefrontal cortex. The observed relationship between CRF and hippocampal effective connectivity provides a link between the rodent literature, which demonstrates a relationship between aerobic exercise and hippocampal plasticity, and the human literature, which demonstrates a relationship between aerobic exercise and CRF and the enhancement of broad cognitive domains including, but not limited to, memory.     

Structured exercise does not stabilize cognitive function in individuals with mild cognitive impairment residing in a structured living facility

Exercise has been shown to have positive effects on the brain and cognition in healthy older adults, though no study has directly examined possible cognitive benefits of formal exercise programs in persons with mild cognitive impairment (MCI) living in structured facilities. Thirty-one participants completed neuropsychological testing and measures of cardiovascular fitness at baseline and after 6 months of a structured exercise program that included aerobic and resistance training. While exercise improved cardiovascular fitness in persons with MCI, there was no improvement in cognitive function. Rather, MCI patients in this sample declined in performance on several tests sensitive to Alzheimer's disease. Examined in the context of past work, it appears exercise may be beneficial prior to the onset of MCI, though less helpful after its onset.     

Structural integrity of the corpus callosum predicts long‐term transfer of fluid intelligence‐related training gains in normal aging

Although cognitive training usually improves cognitive test performance, the capability to transfer these training gains into respective or functionally related cognitive domains varies significantly. Since most studies demonstrate rather limited transfer effects in older adults, aging might be an important factor in transfer capability differences. This study investigated the transfer capability of logical reasoning training gains to a measure of Fluid Intelligence (Gf) in relation to age, general intelligence, and brain structural integrity as measured by diffusion tensor imaging. In a group of 41 highly educated healthy elderly, 71% demonstrated successful transfer immediately after a 4‐week training session (i.e. short‐term transfer). In a subgroup of 22% of subjects transfer maintained over a 3‐month follow‐up period (i.e. long‐term transfer). While short‐term transfer was not related to structural integrity, long‐term transfer was associated with increased structural integrity in corpus and genu of the corpus callosum. Since callosal structural integrity was also related to age (in the present and foregoing studies), previously observed associations between age and transfer might be moderated by the structural integrity. Surprisingly, age was not directly associated with transfer in this study which could be explained by the multi‐dependency of the structural integrity (modulating factors beside age, e.g. genetics). In this highly educated sample, general intelligence was not related to transfer suggesting that high intelligence is not sufficient for transfer in normal aging. Further studies are needed to reveal the interaction of transfer, age, and structural integrity and delineate mechanisms of age‐dependent transfer capabilities. Hum Brain Mapp 35:309–318, 2014. © 2012 Wiley Periodicals, Inc.     

The gains of a 4‐week cognitive training are not modulated by novelty

Cognitive training should not only improve performance of the trained task, but also untrained abilities. Exposure to novelty can improve subsequent memory performance, suggesting that novelty exposure might be a critical factor to promote the effects of cognitive training. Therefore, we combined a 4‐week working memory training with novelty exposure. Neuropsychological tests and MRI data were acquired before and after training to analyze behavior and changes in gray matter volume, myelination, and iron levels. In total, 83 healthy older humans participated in one of three groups: Two groups completed a 4‐week computerized cognitive training of a two‐back working memory task, either in combination with novel or with familiarized nature movies. A third group did not receive any training. As expected, both training groups showed improvements in task specific working memory performance and reaction times. However, there were no transfer or novelty effects on fluid intelligence, verbal memory, digit‐span, and executive functions. At the neural level, no significant micro‐ or macrostructural changes emerged in either group. Our findings suggest that working memory training in healthy older adults is associated with task‐specific improvements, but these gains do not transfer to other cognitive domains, and it does not lead to structural brain changes.     

Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults

Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43–87 years. Whole‐brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol‐associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular‐related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Age differences in functional network reconfiguration with working memory training

Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task‐related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default‐mode network for younger adults, it enhanced efficiency within a task‐specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default‐mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between‐network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age‐related trajectories in functional network reorganization with WM training.     

Low‐intensity daily walking activity is associated with hippocampal volume in older adults

Hippocampal atrophy is associated with memory impairment and dementia and serves as a key biomarker in the preclinical stages of Alzheimer's disease. Physical activity, one of the most promising behavioral interventions to prevent or delay cognitive decline, has been shown to be associated with hippocampal volume; specifically increased aerobic activity and fitness may have a positive effect on the size of the hippocampus. The majority of older adults, however, are sedentary and have difficulty initiating and maintaining exercise programs. A modestly more active lifestyle may nonetheless be beneficial. This study explored whether greater objectively measured daily walking activity was associated with larger hippocampal volume. We additionally explored whether greater low‐intensity walking activity, which may be related to leisure‐time physical, functional, and social activities, was associated with larger hippocampal volume independent of exercise and higher‐intensity walking activity. Segmentation of hippocampal volumes was performed using Functional Magnetic Resonance Imaging of the Brain's Software Library (FSL), and daily walking activity was assessed using a step activity monitor on 92, nondemented, older adult participants. After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men. These relationships were specific to hippocampal volume, compared with the thalamus, used as a control brain region, and remained significant for low‐intensity walking activity, independent of moderate‐ to vigorous‐intensity activity and self‐reported exercise. This is the first study, to our knowledge, to explore the relationship between objectively measured daily walking activity and hippocampal volume in an older adult population. Findings suggest the importance of examining whether increasing nonexercise, lifestyle physical activities may produce measurable cognitive benefits and affect hippocampal volume through molecular pathways unique to those related to moderate‐intensity exercise. © 2014 Wiley Periodicals, Inc.     

Neuroticism and conscientiousness respectively constrain and facilitate short‐term plasticity within the working memory neural network

Individual differences in cognitive efficiency, particularly in relation to working memory (WM), have been associated both with personality dimensions that reflect enduring regularities in brain configuration, and with short‐term neural plasticity, that reflects task‐related changes in brain connectivity. To elucidate the relationship of these two divergent mechanisms, we tested the hypothesis that personality dimensions, which reflect enduring aspects of brain configuration, inform about the neurobiological framework within which short‐term, task‐related plasticity, as measured by effective connectivity, can be facilitated or constrained. As WM consistently engages the dorsolateral prefrontal (DLPFC), parietal (PAR), and anterior cingulate cortex (ACC), we specified a WM network model with bidirectional, ipsilateral, and contralateral connections between these regions from a functional magnetic resonance imaging dataset obtained from 40 healthy adults while performing the 3‐back WM task. Task‐related effective connectivity changes within this network were estimated using Dynamic Causal Modelling. Personality was evaluated along the major dimensions of Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. Only two dimensions were relevant to task‐dependent effective connectivity. Neuroticism and Conscientiousness respectively constrained and facilitated neuroplastic responses within the WM network. These results suggest individual differences in cognitive efficiency arise from the interplay between enduring and short‐term plasticity in brain configuration. Hum Brain Mapp 36:4158–4163, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

The association between aerobic fitness and executive function is mediated by prefrontal cortex volume

Aging is marked by a decline in cognitive function, which is often preceded by losses in gray matter volume. Fortunately, higher cardiorespiratory fitness (CRF) levels are associated with an attenuation of age-related losses in gray matter volume and a reduced risk for cognitive impairment. Despite these links, we have only a rudimentary understanding of whether fitness-related increases in gray matter volume lead to elevated cognitive function. In this cross-sectional study, we examined whether the association between higher aerobic fitness levels and elevated executive function was mediated by greater gray matter volume in the prefrontal cortex (PFC). One hundred and forty-two older adults (mean age=66.6 years) completed structural magnetic resonance imaging (MRI) scans, CRF assessments, and performed Stroop and spatial working memory (SPWM) tasks. Gray matter volume was assessed using an optimized voxel-based morphometry approach. Consistent with our predictions, higher fitness levels were associated with: (a) better performance on both the Stroop and SPWM tasks, and (b) greater gray matter volume in several regions, including the dorsolateral PFC (DLPFC). Volume of the right inferior frontal gyrus and precentral gyrus mediated the relationship between CRF and Stroop interference while a non-overlapping set of regions bilaterally in the DLPFC mediated the association between CRF and SPWM accuracy. These results suggest that specific regions of the DLPFC differentially relate to inhibition and spatial working memory. Thus, fitness may influence cognitive function by reducing brain atrophy in targeted areas in healthy older adults.     

Reorganization of functional brain networks mediates the improvement of cognitive performance following real‐time neurofeedback training of working memory

Working memory (WM) is essential for individuals' cognitive functions. Neuroimaging studies indicated that WM fundamentally relied on a frontoparietal working memory network (WMN) and a cinguloparietal default mode network (DMN). Behavioral training studies demonstrated that the two networks can be modulated by WM training. Different from the behavioral training, our recent study used a real‐time functional MRI (rtfMRI)‐based neurofeedback method to conduct WM training, demonstrating that WM performance can be significantly improved after successfully upregulating the activity of the target region of interest (ROI) in the left dorsolateral prefrontal cortex (Zhang et al., [2013]: PloS One 8:e73735); however, the neural substrate of rtfMRI‐based WM training remains unclear. In this work, we assessed the intranetwork and internetwork connectivity changes of WMN and DMN during the training, and their correlations with the change of brain activity in the target ROI as well as with the improvement of post‐training behavior. Our analysis revealed an “ROI‐network‐behavior” correlation relationship underlying the rtfMRI training. Further mediation analysis indicated that the reorganization of functional brain networks mediated the effect of self‐regulation of the target brain activity on the improvement of cognitive performance following the neurofeedback training. The results of this study enhance our understanding of the neural basis of real‐time neurofeedback and suggest a new direction to improve WM performance by regulating the functional connectivity in the WM related networks. Hum Brain Mapp 36:1705–1715, 2015. © 2014 Wiley Periodicals, Inc.     

Differential age-related gray and white matter impact mediates educational influence on elders’ cognition

High education, as a proxy of cognitive reserve (CR), has been associated with cognitive advantage amongst old adults and may operate through neuroprotective and/or compensation mechanisms. In neuromaging studies, indirect evidences of neuroprotection can be inferred from positive relationships between CR and brain integrity measures. In contrast, compensation allows high CR elders to sustain greater brain damage. We included 100 cognitively normal old-adults and investigated the associations and interactions between education, speed of processing (SP), memory and two brain integrity measures: cortical thickness (CTh) of gray matter (GM) and fractional anisotropy (FA) in the white matter (WM). High education was associated with better cognitive performance, enlarged CTh in frontal lobe areas and reduced measures of FA in several areas. Better SP performance in higher educated subjects was related to more preserved GM and WM, while memory status amongst high educated elders was better explained by a putative compensatory mechanism and independently from cerebrovascular risk indicators. Moreover, we analyzed the direct effect of age on measures of brain integrity and found a stronger negative effect on WM than in CTh, which was accentuated amongst the high CR sample. Our study suggests that the cognitive advantage associated to high education among healthy aging is related to the coexistence of both neuroprotective and compensatory mechanisms. In particular, high educated elders seem to have greater capacity to counteract a more abrupt age impact on WM integrity.     

Benefits of exercise training on cerebrovascular and cognitive function in ageing

Derangements in cerebrovascular structure and function can impair cognitive performance throughout ageing and in cardiometabolic disease states, thus increasing dementia risk. Modifiable lifestyle factors that cause a decline in cardiometabolic health, such as physical inactivity, exacerbate these changes beyond those that are associated with normal ageing. The purpose of this review was to examine cerebrovascular, cognitive and neuroanatomical adaptations to ageing and the potential benefits of exercise training on these outcomes in adults 50 years or older. We systematically searched for cross-sectional or intervention studies that included exercise (aerobic, resistance or multimodal) and its effect on cerebrovascular function, cognition and neuroanatomical adaptations in this age demographic. The included studies were tabulated and described narratively. Aerobic exercise training was the predominant focus of the studies identified; there were limited studies exploring the effects of resistance exercise training and multimodal training on cerebrovascular function and cognition. Collectively, the evidence indicated that exercise can improve cerebrovascular function, cognition and neuroplasticity through areas of the brain associated with executive function and memory in adults 50 years or older, irrespective of their health status. However, more research is required to ascertain the mechanisms of action.     

Water maze experience and prenatal choline supplementation differentially promote long‐term hippocampal recovery from seizures in adulthood

Status epilepticus (SE) in adulthood dramatically alters the hippocampus and produces spatial learning and memory deficits. Some factors, like environmental enrichment and exercise, may promote functional recovery from SE. Prenatal choline supplementation (SUP) also protects against spatial memory deficits observed shortly after SE in adulthood, and we have previously reported that SUP attenuates the neuropathological response to SE in the adult hippocampus just 16 days after SE. It is unknown whether SUP can ameliorate longer‐term cognitive and neuropathological consequences of SE, whether repeatedly engaging the injured hippocampus in a cognitive task might facilitate recovery from SE, and whether our prophylactic prenatal dietary treatment would enable the injured hippocampus to more effectively benefit from cognitive rehabilitation. To address these issues, adult offspring from rat dams that received either a control (CON) or SUP diet on embryonic days 12–17 first received training on a place learning water maze task (WM) and were then administered saline or kainic acid (KA) to induce SE. Rats then either remained in their home cage, or received three additional WM sessions at 3, 6.5, and 10 weeks after SE to test spatial learning and memory retention. Eleven weeks after SE, the brains were analyzed for several hippocampal markers known to be altered by SE. SUP attenuated SE‐induced spatial learning deficits and completely rescued spatial memory retention by 10 weeks post‐SE. Repeated WM experience prevented SE‐induced declines in glutamic acid decarboxylase (GAD) and dentate gyrus neurogenesis, and attenuated increased glial fibrilary acidic protein (GFAP) levels. Remarkably, SUP alone was similarly protective to an even greater extent, and SUP rats that were water maze trained after SE showed reduced hilar migration of newborn neurons. These findings suggest that prophylactic SUP is protective against the long‐term cognitive and neuropathological effects of KA‐induced SE, and that rehabilitative cognitive enrichment may be partially beneficial. © 2010 Wiley‐Liss, Inc.