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1.  Physical Activity, Brain Plasticity, and Alzheimer’s Disease 
Archives of medical research  2012;43(8):615-621.
In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer’s disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer’s disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.
PMCID: PMC3567914  PMID: 23085449
2.  The Aging Hippocampus: Interactions between Exercise, Depression, and BDNF 
Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy.
PMCID: PMC3575139  PMID: 21531985
aging; BDNF; depression; exercise; hippocampus
3.  A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children 
Brain research  2010;1358:172-183.
Because children are becoming overweight, unhealthy, and unfit, understanding the neurocognitive benefits of an active lifestyle in childhood has important public health and educational implications. Animal research has indicated that aerobic exercise is related to increased cell proliferation and survival in the hippocampus as well as enhanced hippocampal-dependent learning and memory. Recent evidence extends this relationship to elderly humans by suggesting that high aerobic fitness levels in older adults are associated with increased hippocampal volume and superior memory performance. The present study aimed to further extend the link between fitness, hippocampal volume, and memory to a sample of preadolescent children. To this end, magnetic resonance imaging was employed to investigate whether higher- and lower-fit 9- and 10-year-old children showed differences in hippocampal volume and if the differences were related to performance on an item and relational memory task. Relational but not item memory is primarily supported by the hippocampus. Consistent with predictions, higher-fit children showed greater bilateral hippocampal volumes and superior relational memory task performance compared to lower-fit children. Hippocampal volume was also positively associated with performance on the relational but not the item memory task. Furthermore, bilateral hippocampal volume was found to mediate the relationship between fitness level (VO2 max) and relational memory. No relationship between aerobic fitness, nucleus accumbens volume, and memory was reported, which strengthens the hypothesized specific effect of fitness on the hippocampus. The findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.
PMCID: PMC3953557  PMID: 20735996
Brain; Children; Exercise; Hippocampus; MRI; Physical activity
4.  The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance 
Psychological science  2013;24(9):1770-1779.
Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition.
PMCID: PMC3947596  PMID: 23907543
BDNF; physical activity; working memory; executive function; genetics; visual memory; episodic memory
5.  Neurobiological markers of exercise-related brain plasticity in older adults 
The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age = 66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.
PMCID: PMC3544982  PMID: 23123199
exercise; aging; functional connectivity; fMRI; default mode network; aerobic fitness; growth factors
6.  A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: Evidence for a limited window of opportunity 
Neuropsychology  2010;24(1):68-76.
The influence of hormone treatment on brain and cognition in postmenopausal women has been a controversial topic. Contradictory patterns of results have prompted speculation that a critical period, or a limited window of opportunity, exists for hormone treatment to protect against cognitive and neural decline in older women. Consistent with this hypothesis, studies in both humans and rodents indicate that the latency between the time of menopause and the initiation of hormone treatment is an important factor in determining whether hormone treatment will prevent or exacerbate cognitive impairment. In this cross-sectional study of 102 postmenopausal women, we examined whether hippocampal, amygdala, or caudate nucleus volumes and spatial memory performance were related to the interval between menopause and the initiation of hormone treatment. Consistent with a critical period hypothesis, we found that shorter intervals between menopause and the initiation of hormone treatment, as determined by self-report, were associated with larger hippocampal volumes compared with longer intervals between menopause and treatment initiation. Initiation of hormone treatment at the time of menopause was also associated with larger hippocampal volumes when compared to peers who had never used hormone treatment. Furthermore, these effects were independent from potentially confounding factors such as age, years of education, the duration of hormone treatment, current or past use of hormone therapy, the type of therapy, and the age at menopause. Larger hippocampal volumes in women who initiated hormone treatment at the time of menopause failed to translate to improved spatial memory performance. There was no relationship between the timing of hormone initiation, spatial memory performance, and amygdala or caudate nucleus volume. Our results provide support for the idea that there is a limited window of opportunity at the time of menopause for hormone treatment to influence hippocampal volume, yet the degree to which these effects translate to improved memory performance is uncertain.
PMCID: PMC2843433  PMID: 20063947
8.  Aging Brain from a Network Science Perspective: Something to Be Positive About? 
PLoS ONE  2013;8(11):e78345.
To better understand age differences in brain function and behavior, the current study applied network science to model functional interactions between brain regions. We observed a shift in network topology whereby for older adults subcortical and cerebellar structures overlapping with the Salience network had more connectivity to the rest of the brain, coupled with fragmentation of large-scale cortical networks such as the Default and Fronto-Parietal networks. Additionally, greater integration of the dorsal medial thalamus and red nucleus in the Salience network was associated with greater satisfaction with life for older adults, which is consistent with theoretical predictions of age-related increases in emotion regulation that are thought to help maintain well-being and life satisfaction in late adulthood. In regard to cognitive abilities, greater ventral medial prefrontal cortex coherence with its topological neighbors in the Default Network was associated with faster processing speed. Results suggest that large-scale organizing properties of the brain differ with normal aging, and this perspective may offer novel insight into understanding age-related differences in cognitive function and well-being.
PMCID: PMC3819386  PMID: 24223147
9.  Physical Exercise and Brain Functions in Older Adults 
Journal of Aging Research  2013;2013:197326.
PMCID: PMC3791662  PMID: 24163767
10.  A Review of the Effects of Physical Activity and Exercise on Cognitive and Brain Functions in Older Adults 
Journal of Aging Research  2013;2013:657508.
Studies supporting the notion that physical activity and exercise can help alleviate the negative impact of age on the body and the mind abound. This literature review provides an overview of important findings in this fast growing research domain. Results from cross-sectional, longitudinal, and intervention studies with healthy older adults, frail patients, and persons suffering from mild cognitive impairment and dementia are reviewed and discussed. Together these finding suggest that physical exercise is a promising nonpharmaceutical intervention to prevent age-related cognitive decline and neurodegenerative diseases.
PMCID: PMC3786463  PMID: 24102028
11.  Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition? 
Neuropsychologia  2010;48(5):1394-1406.
Over the next twenty years the number of Americans diagnosed with dementia is expected to more than double (CDC 2007). It is, therefore, an important public health initiative to understand what factors contribute to the longevity of a healthy mind. Both default mode network (DMN) function and increased aerobic fitness have been associated with better cognitive performance and reduced incidence of Alzheimer’s disease among older adults. Here we examine the association between aerobic fitness, functional connectivity in the DMN, and cognitive performance. Results showed significant age-related deficits in functional connectivity in both local and distributed DMN pathways. However, in a group of healthy elderly adults, almost half of the age-related disconnections showed increased functional connectivity as a function of aerobic fitness level. Finally, we examine the hypothesis that functional connectivity in the DMN is one source of variance in the relationship between aerobic fitness and cognition. Results demonstrate instances of both specific and global DMN connectivity mediating the relationship between fitness and cognition. We provide the first evidence for functional connectivity as a source of variance in the association between aerobic fitness and cognition, and discuss results in the context of neurobiological theories of cognitive aging and disease.
PMCID: PMC3708614  PMID: 20079755
cognitive aging; fMRI; functional connectivity; aerobic exercise; executive function; spatial memory
12.  The association between aerobic fitness and executive function is mediated by prefrontal cortex volume 
Brain, Behavior, and Immunity  2011;26(5):811-819.
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.
PMCID: PMC3321393  PMID: 22172477
cardiorespiratory fitness; executive function; voxel-based morphometry; cortical volume; prefrontal cortex; mediation
13.  Increased Body Mass Index Is Associated With a Global and Distributed Decrease in White Matter Microstructural Integrity 
Psychosomatic medicine  2012;74(7):682-690.
Obesity and decreased physical health are linked to deficits in several cognitive domains. The broad range of cognitive problems linked to obesity suggests a global mechanism that may interfere with multiple neural systems. We examined how variation in body mass index (BMI) is associated with the microstructural integrity of fiber connections in the human brain.
White matter structure was measured using diffusion tensor imaging in 28 participants (mean age = 30 years) with BMI scores ranging from normal weight to obese (19.5–45.7 kg/m2) based on standard BMI criteria.
Using a whole-brain voxelwise analysis, we found that, across participants, the fractional anisotropy of white matter voxels parametrically decreased with increasing BMI (63% of white matter voxels). Midbrain and brainstem tracts were among the pathways most strongly associated with obesity (r = −0.18 to −0.33, df = 27, all p values < .05). We also observed a weaker overall diffusion signal in individuals with higher BMI than controls with normal weight (r = −0.14 to −0.71, df = 27, for 67% of fiber pathways tested, all p values < .05). After controlling for this decrease in general diffusivity, we found that decreases in fractional anisotropy stemmed from both a decrease in axial diffusivity (p < .05) and an increase in radial diffusivity (p < .05).
Our results show that increased BMI is globally associated with a reduction in white matter integrity throughout the brain, elucidating a potential mechanism by which changes in physical health may influence cognitive health.
PMCID: PMC3586991  PMID: 22879428
DTI; white matter; fractional anisotropy; body mass index; obesity
14.  Physical activity and brain plasticity in late adulthood 
The human brain shrinks with advancing age, but recent research suggests that it is also capable of remarkable plasticity, even in late life. In this review we summarize the research linking greater amounts of physical activity to less cortical atrophy, better brain function, and enhanced cognitive function, and argue that physical activity takes advantage of the brain's natural capacity for plasticity. Further, although the effects of physical activity on the brain are relatively widespread, there is also some specificity, such that prefrontal and hippocampal areas appear to be more influenced than other areas of the brain. The specificity of these effects, we argue, provides a biological basis for understanding the capacity for physical activity to influence neurocognitive and neuropsychiatric disorders such as depression. We conclude that physical activity is a promising intervention that can influence the endogenous pharmacology of the brain to enhance cognitive and emotional function in late adulthood.
PMCID: PMC3622473  PMID: 23576893
aging; physical activity; exercise; brain; plasticity; neuroplasticity
15.  Estrogens, hormone therapy, and hippocampal volume in postmenopausal women 
Maturitas  2012;73(3):186-190.
The brain atrophies in late life. However, there are many factors that either magnify or mitigate the rate of atrophy. Loss of estrogens during menopause and administration of hormone therapy have both been hypothesized as sources of individual variation in the prevalence of cortical and subcortical atrophy and loss of cognitive function in late adulthood. In this review we critically summarize and assess the extant rodent and human neuroimaging studies that examine the link between estrogens and hippocampal morphology and function and focus predominantly on human studies of the hippocampus in postmenopausal women. Several cross-sectional studies report that the size of the hippocampus is larger in women receiving hormone therapy while several other cross-sectional studies report either negligible effects or smaller volumes in women receiving hormone therapy. We suggest that these differences might be caused by the variation between studies in the age of the samples studied, the duration of therapy, and the age at which hormone therapy is initiated. Unfortunately, all of the human studies reviewed here are cross-sectional in nature. With the lack of well-controlled randomized trials with neuroimaging measures on postmenopausal women both before and after some exposure interval, the effect of hormone therapy on hippocampal atrophy will remain equivocal and poorly understood.
PMCID: PMC3576699  PMID: 22858056
Hormone therapy; Estrogen; Hippocampus; Volume; Brain
16.  The effects of physical activity on functional MRI activation associated with cognitive control in children: a randomized controlled intervention 
This study used functional magnetic resonance imaging (fMRI) to examine the influence of a 9-month physical activity program on task-evoked brain activation during childhood. The results demonstrated that 8- to 9-year-old children who participated in 60+ min of physical activity, 5 days per week, for 9 months, showed decreases in fMRI brain activation in the right anterior prefrontal cortex coupled with within-group improvements in performance on a task of attentional and interference control. Children assigned to a wait-list control group did not show changes in brain function. Furthermore, at post-test, children in the physical activity group showed similar anterior frontal brain patterns and incongruent accuracy rates to a group of college-aged young adults. Children in the wait-list control group still differed from the young adults in terms of anterior prefrontal activation and performance at post-test. There were no significant changes in fMRI activation in the anterior cingulate cortex (ACC) for either group. These results suggest that physical activity during childhood may enhance specific elements of prefrontal cortex function involved in cognitive control.
PMCID: PMC3594762  PMID: 23487583
activation; brain; children; fitness; fMRI; physical activity
17.  Potential Moderators of Physical Activity on Brain Health 
Journal of Aging Research  2012;2012:948981.
Age-related cognitive decline is linked to numerous molecular, structural, and functional changes in the brain. However, physical activity is a promising method of reducing unfavorable age-related changes. Physical activity exerts its effects on the brain through many molecular pathways, some of which are regulated by genetic variants in humans. In this paper, we highlight genes including apolipoprotein E (APOE), brain derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT) along with dietary omega-3 fatty acid, docosahexaenoic acid (DHA), as potential moderators of the effect of physical activity on brain health. There are a growing number of studies indicating that physical activity might mitigate the genetic risks for disease and brain dysfunction and that the combination of greater amounts of DHA intake with physical activity might promote better brain function than either treatment alone. Understanding whether genes or other lifestyles moderate the effects of physical activity on neurocognitive health is necessary for delineating the pathways by which brain health can be enhanced and for grasping the individual variation in the effectiveness of physical activity interventions on the brain and cognition. There is a need for future research to continue to assess the factors that moderate the effects of physical activity on neurocognitive function.
PMCID: PMC3523571  PMID: 23304508
18.  Cardiorespiratory Fitness, Hippocampal Volume and Frequency of Forgetting in Older Adults 
Neuropsychology  2011;25(5):545-553.
The purpose of this study was to extend our earlier work to determine the extent to which cardiorespiratory fitness is associated with the frequency of memory problems via its effects on the hippocampus and spatial working memory. We hypothesized that age, sex, education, body composition, and physical activity were direct determinants of fitness which, in turn, influenced frequency of forgetting indirectly through hippocampal volume and spatial working memory.
We conducted assessments of hippocampal volume, spatial working memory, frequency of forgetting, BMI, physical activity, demographic characteristics, and cardiorespiratory fitness in 158 older adults (M age = 66.49). Path analyses within a covariance modeling framework were used to examine relationships among these constructs.
Sex, age, BMI, and education were all significant determinants of cardiorespiratory fitness. The hypothesized path models testing the effects of fitness on frequency of forgetting through hippocampal volume and accuracy and speed of spatial working memory all fit the data well.
Our findings suggest that older adults with higher levels of fitness show greater preservation of hippocampal volume which, in turn, is associated with more accurate and faster spatial memory and fewer episodes of forgetting. Given the proportion of older adults reporting memory problems, it is necessary to determine whether improvements in fitness brought about by physical activity interventions can result in subsequent attenuation of memory problems or potentially improvements in memory.
PMCID: PMC3140615  PMID: 21500917
Frequency of Forgetting; Hippocampus Volume; Cardiorespiratory Fitness; Spatial Memory; Older Adults
19.  Age-Related Decline in Controlled Retrieval: The Role of the PFC and Sleep 
Neural Plasticity  2012;2012:624795.
Age-related cognitive impairments often include difficulty retrieving memories, particularly those that rely on executive control. In this paper we discuss the influence of the prefrontal cortex on memory retrieval, and the specific memory processes associated with the prefrontal cortex that decline in late adulthood. We conclude that preretrieval processes associated with preparation to make a memory judgment are impaired, leading to greater reliance on postretrieval processes. This is consistent with the view that impairments in executive control significantly contribute to deficits in controlled retrieval. Finally, we discuss age-related changes in sleep as a potential mechanism that contributes to deficiencies in executive control that are important for efficient retrieval. The sleep literature points to the importance of slow-wave sleep in restoration of prefrontal cortex function. Given that slow-wave sleep significantly declines with age, we hypothesize that age-related changes in slow-wave sleep could mediate age-related decline in executive control, manifesting a robust deficit in controlled memory retrieval processes. Interventions, like physical activity, that improve sleep could be effective methods to enhance controlled memory processes in late life.
PMCID: PMC3434414  PMID: 22970389
20.  Caudate Nucleus Volume Mediates the Link between Cardiorespiratory Fitness and Cognitive Flexibility in Older Adults 
Journal of Aging Research  2012;2012:939285.
The basal ganglia play a central role in regulating the response selection abilities that are critical for mental flexibility. In neocortical areas, higher cardiorespiratory fitness levels are associated with increased gray matter volume, and these volumetric differences mediate enhanced cognitive performance in a variety of tasks. Here we examine whether cardiorespiratory fitness correlates with the volume of the subcortical nuclei that make up the basal ganglia and whether this relationship predicts cognitive flexibility in older adults. Structural MRI was used to determine the volume of the basal ganglia nuclei in a group of older, neurologically healthy individuals (mean age 66 years, N = 179). Measures of cardiorespiratory fitness (VO2max), cognitive flexibility (task switching), and attentional control (flanker task) were also collected. Higher fitness levels were correlated with higher accuracy rates in the Task Switching paradigm. In addition, the volume of the caudate nucleus, putamen, and globus pallidus positively correlated with Task Switching accuracy. Nested regression modeling revealed that caudate nucleus volume was a significant mediator of the relationship between cardiorespiratory fitness, and task switching performance. These findings indicate that higher cardiorespiratory fitness predicts better cognitive flexibility in older adults through greater grey matter volume in the dorsal striatum.
PMCID: PMC3415086  PMID: 22900181
21.  A protocol for a randomized clinical trial of interactive video dance: potential for effects on cognitive function 
BMC Geriatrics  2012;12:23.
Physical exercise has the potential to affect cognitive function, but most evidence to date focuses on cognitive effects of fitness training. Cognitive exercise also may influence cognitive function, but many cognitive training paradigms have failed to provide carry-over to daily cognitive function. Video games provide a broader, more contextual approach to cognitive training that may induce cognitive gains and have carry over to daily function. Most video games do not involve physical exercise, but some novel forms of interactive video games combine physical activity and cognitive challenge.
This paper describes a randomized clinical trial in 168 postmenopausal sedentary overweight women that compares an interactive video dance game with brisk walking and delayed entry controls. The primary endpoint is adherence to activity at six months. Additional endpoints include aspects of physical and mental health. We focus this report primarily on the rationale and plans for assessment of multiple cognitive functions.
This randomized clinical trial may provide new information about the cognitive effects of interactive videodance. It is also the first trial to examine physical and cognitive effects in older women. Interactive video games may offer novel strategies to promote physical activity and health across the life span.
The study is IRB approved and the number is: PRO08080012 Identifier: NCT01443455
PMCID: PMC3404007  PMID: 22672287
22.  Non-Exercise Estimated Cardiorespiratory Fitness: Associations with Brain Structure, Cognition, and Memory Complaints in Older Adults 
There is increasing evidence that cardiorespiratory fitness (CRF) is associated with brain structure and function, and improvements in CRF through exercise training have been associated with neural and cognitive functioning in older adults. The objectives of this study were to validate the use of a non-exercise estimate of CRF, and to examine its association with cognitive function, brain structure and subjective memory complaints. Low active, older adults (N = 86; M age= 65.14) completed a physician-supervised maximal exercise test, a 1-mile timed walk, several measures of cognitive function, and a 3 Tesla structural MRI. Fitness was also calculated from an equation derived by (Jurca et al., 2005) based on age, sex, body mass index, resting heart rate, and self-reported physical activity level. Analyses indicated that all three measures of CRF were significantly correlated with one another. In addition, measures of cognitive function, hippocampus volume, and memory complaints were significantly correlated with each measure of fitness. These findings have implications for using a low-risk, low-cost, non-exercise estimate of CRF in determining fitness associations with brain structure and cognitive function in older adults. As such, this measure may have utility for larger population based studies. Further validation is required, as is determination of whether such relationships hold over the course of exercise interventions.
PMCID: PMC3146052  PMID: 21808657
Equation-derived CRF; cognitive function; hippocampus; older adults
23.  Beyond vascularization: aerobic fitness is associated with N-acetylaspartate and working memory 
Brain and Behavior  2012;2(1):32-41.
Aerobic exercise is a promising form of prevention for cognitive decline; however, little is known about the molecular mechanisms by which exercise and fitness impacts the human brain. Several studies have postulated that increased regional brain volume and function are associated with aerobic fitness because of increased vascularization rather than increased neural tissue per se. We tested this position by examining the relationship between cardiorespiratory fitness and N-acetylaspartate (NAA) levels in the right frontal cortex using magnetic resonance spectroscopy. NAA is a nervous system specific metabolite found predominantly in cell bodies of neurons. We reasoned that if aerobic fitness was predominantly influencing the vasculature of the brain, then NAA levels should not vary as a function of aerobic fitness. However, if aerobic fitness influences the number or viability of neurons, then higher aerobic fitness levels might be associated with greater concentrations of NAA. We examined NAA levels, aerobic fitness, and cognitive performance in 137 older adults without cognitive impairment. Consistent with the latter hypothesis, we found that higher aerobic fitness levels offset an age-related decline in NAA. Furthermore, NAA mediated an association between fitness and backward digit span performance, suggesting that neuronal viability as measured by NAA is important in understanding fitness-related cognitive enhancement. Since NAA is found exclusively in neural tissue, our results indicate that the effect of fitness on the human brain extends beyond vascularization; aerobic fitness is associated with neuronal viability in the frontal cortex of older adults.
PMCID: PMC3343297  PMID: 22574272
Aging; brain; exercise; fitness; human; N-acetylaspartate; working memory
24.  Striatal Volume Predicts Level of Video Game Skill Acquisition 
Cerebral Cortex (New York, NY)  2010;20(11):2522-2530.
Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.
PMCID: PMC3841463  PMID: 20089946
basal ganglia; caudate nucleus; cognitive flexibility; nucleus accumbens; procedural learning
25.  Basal Ganglia Volume Is Associated with Aerobic Fitness in Preadolescent Children 
Developmental Neuroscience  2010;32(3):249-256.
The present investigation is the first to explore the association between childhood aerobic fitness and basal ganglia structure and function. Rodent research has revealed that exercise influences the striatum by increasing dopamine signaling and angiogenesis. In children, higher aerobic fitness levels are associated with greater hippocampal volumes, superior performance on tasks of attentional and interference control, and elevated event-related brain potential indices of executive function. The present study used magnetic resonance imaging to investigate if higher-fit and lower-fit 9- and 10-year-old children exhibited differential volumes of other subcortical brain regions, specifically the basal ganglia involved in attentional control. The relationship between aerobic fitness, dorsal and ventral striatum volumes and performance on an attention and inhibition Eriksen flanker task was also examined. The results indicated that higher-fit children showed superior flanker task performance compared to lower-fit children. Higher-fit children also showed greater volumes of the dorsal striatum, and dorsal striatum volume was negatively associated with behavioral interference. The results support the claim that the dorsal striatum is involved in cognitive control and response resolution and that these cognitive processes vary as a function of aerobic fitness. No relationship was found between aerobic fitness, the volume of the ventral striatum and flanker performance. The findings suggest that increased childhood aerobic fitness is associated with greater dorsal striatal volumes and that this is related to enhanced cognitive control. Because children are becoming increasingly overweight, unhealthy and unfit, understanding the neurocognitive benefits of an active lifestyle during childhood has important public health and educational implications.
PMCID: PMC3696376  PMID: 20693803
Brain; Development; Exercise; MRI; Physical activity; Neurocognition; Neuroimaging; Striatum

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