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1.  The influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: Results of a one-year exercise intervention 
Human brain mapping  2012;34(11):2972-2985.
Cerebral white matter degeneration occurs with increasing age and is associated with declining cognitive function. Research has shown that cardiorespiratory fitness and exercise are effective as protective, even restorative, agents against cognitive and neurobiological impairments in older adults. In this study, we investigated whether the beneficial impact of aerobic fitness would extend to white matter integrity in the context of a one-year exercise intervention. Further, we examined the pattern of diffusivity changes to better understand the underlying biological mechanisms. Finally, we assessed whether training-induced changes in white matter integrity would be associated with improvements in cognitive performance independent of aerobic fitness gains. Results showed that aerobic fitness training did not affect group-level change in white matter integrity, executive function, or short-term memory, but that greater aerobic fitness derived from the walking program was associated with greater change in white matter integrity in the frontal and temporal lobes, and greater improvement in short-term memory. Increases in white matter integrity, however, were not associated with short-term memory improvement, independent of fitness improvements. Therefore, while not all findings are consistent with previous research, we provide novel evidence for correlated change in training-induced aerobic fitness, white matter integrity, and cognition among healthy older adults.
doi:10.1002/hbm.22119
PMCID: PMC4096122  PMID: 22674729
Diffusion tensor imaging; Anisotropy; Cerebrum; Cognition; Physical fitness; Aging
2.  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.
doi:10.1016/j.brainres.2010.08.049
PMCID: PMC3953557  PMID: 20735996
Brain; Children; Exercise; Hippocampus; MRI; Physical activity
3.  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.
doi:10.1016/j.bbi.2012.10.021
PMCID: PMC3544982  PMID: 23123199
exercise; aging; functional connectivity; fMRI; default mode network; aerobic fitness; growth factors
4.  Mindfulness disposition and default-mode network connectivity in older adults 
An extensive body of research defines the default-mode network (DMN) to be one of the critical networks of the human brain, playing a pivotal functional role in processes of internal mentation. Alterations in the connectivity of this network as a function of aging have been found, with reductions associated with functional ramifications for the elderly population. This study examined associations between integrity of the DMN and trait levels of mindfulness disposition, defined by our ability to exert attentional and emotional control in the present moment, and, thereby, bring awareness to immediate experiences. Twenty-five older adults participated in the study and underwent a brief functional magnetic resonance imaging session and filled out questionnaires related to their overall health and mindfulness disposition. Mindfulness disposition was associated with greater connectivity of the DMN, specifically, in the dorsal posterior cingulate cortex and the precuneus. Mindfulness disposition, thus, explains variance in the connectivity of one of the more intrinsic networks of the human brain, known to be critical for promoting self-relevant mental explorations and building cognitive and affective control.
doi:10.1093/scan/nss115
PMCID: PMC3541498  PMID: 23051900
mindfulness; default network connectivity; individual differences; aging
5.  Mindfulness and the aging brain: a proposed paradigm shift 
There has been a proliferation of cognitive training studies investigating the efficacy of various cognitive training paradigms as well as strategies for improving cognitive control in the elderly. While some have found support for the transfer of training, the majority of training studies show modest to no transfer effects. When transfer effects have been observed, the mechanisms contributing to enhanced functioning have been difficult to dissociate. In this review, we provide a theoretical rationale for the study of mindfulness in older adults as a particular type of training program designed to improve cognitive control by capitalizing on older adults’ acquired behavioral orientation toward higher socioemotional goals. Given the synergistic relationship between emotional and cognitive control processes, the paradoxical divergence in older adults’ functional trajectory in these respective domains, and the harmonious interplay of cognitive and emotional control embedded in the practice of mindfulness, we propose mindfulness training as an opportunistic approach to cultivating cognitive benefits in older adults. The study of mindfulness within aging, we argue, capitalizes on a fundamental finding of the socioemotional aging literature, namely the preferential change in motivational goals of older adults from ones involving future-oriented wants and desires to present-focused emotion regulation and gratification.
doi:10.3389/fnagi.2014.00120
PMCID: PMC4068288  PMID: 25009492
aging; mindfulness; emotional control; cognitive control; neuroimaging
6.  BDNF mediates improvements in executive function following a 1-year exercise intervention 
Executive function declines with age, but engaging in aerobic exercise may attenuate decline. One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor (BDNF), which also declines with age. The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults (mean age = 66.82). Participants were randomized to a stretching and toning control group or a moderate intensity walking intervention group. BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up. We found that age moderated the effect of intervention group on changes in BDNF levels, with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise (p = 0.036). The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy, but did so as a function of age, such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71. These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes, particularly in elderly populations.
doi:10.3389/fnhum.2014.00985
PMCID: PMC4263078  PMID: 25566019
BDNF; executive function; aging; exercise; physical activity; cognition; mediation analysis
7.  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.
doi:10.1371/journal.pone.0078345
PMCID: PMC3819386  PMID: 24223147
8.  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.
doi:10.1016/j.neuropsychologia.2010.01.005
PMCID: PMC3708614  PMID: 20079755
cognitive aging; fMRI; functional connectivity; aerobic exercise; executive function; spatial memory
9.  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.
doi:10.1016/j.bbi.2011.11.008
PMCID: PMC3321393  PMID: 22172477
cardiorespiratory fitness; executive function; voxel-based morphometry; cortical volume; prefrontal cortex; mediation
10.  Cardiorespiratory Fitness, Hippocampal Volume and Frequency of Forgetting in Older Adults 
Neuropsychology  2011;25(5):545-553.
Objective
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1037/a0022733
PMCID: PMC3140615  PMID: 21500917
Frequency of Forgetting; Hippocampus Volume; Cardiorespiratory Fitness; Spatial Memory; Older Adults
11.  Self-Regulatory Processes and Exercise Adherence in Older Adults 
Background
Self-efficacy and the use of self-regulatory strategies are consistently associated with physical activity behavior. Similarly, behavioral inhibition and cognitive resource allocation, indices of executive control function, have also been associated with this health behavior.
Purpose
The purpose of this study was to examine the hypothesis that self-efficacy mediates the relationship between self-regulatory processes, such as executive function, and sustained exercise behavior.
Methods
Older adults (N = 177, mean age = 66.44 years) completed measures of executive function, self-reported use of self-regulatory strategies and self-efficacy prior to and during the first month of a 12-month exercise intervention. Percentage of exercise classes attended over the following 11 months was used to represent adherence. Data were collected from 2007 to 2010 and analyzed in 2010–2011. Structural equation models were tested examining the effect of executive function and strategy use on adherence via efficacy.
Results
As hypothesized, results showed significant direct effects of two elements of executive function and of strategy use on self-efficacy and of efficacy on adherence. In addition, there were significant indirect effects of strategy use and executive function on adherence via self-efficacy.
Conclusions
Higher levels of executive function and use of self-regulatory strategies at the start of an exercise program enhance beliefs in exercise capabilities, which in turn leads to greater adherence.
doi:10.1016/j.amepre.2011.04.014
PMCID: PMC3160622  PMID: 21855742
12.  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.
doi:10.1155/2012/939285
PMCID: PMC3415086  PMID: 22900181
13.  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.
doi:10.1002/brb3.30
PMCID: PMC3343297  PMID: 22574272
Aging; brain; exercise; fitness; human; N-acetylaspartate; working memory
14.  Examining neural correlates of skill acquisition in a complex videogame training program 
Acquisition of complex skills is a universal feature of human behavior that has been conceptualized as a process that starts with intense resource dependency, requires effortful cognitive control, and ends in relative automaticity on the multi-faceted task. The present study examined the effects of different theoretically based training strategies on cortical recruitment during acquisition of complex video game skills. Seventy-five participants were recruited and assigned to one of three training groups: (1) Fixed Emphasis Training (FET), in which participants practiced the game, (2) Hybrid Variable-Priority Training (HVT), in which participants practiced using a combination of part-task training and variable priority training, or (3) a Control group that received limited game play. After 30 h of training, game data indicated a significant advantage for the two training groups relative to the control group. The HVT group demonstrated enhanced benefits of training, as indexed by an improvement in overall game score and a reduction in cortical recruitment post-training. Specifically, while both groups demonstrated a significant reduction of activation in attentional control areas, namely the right middle frontal gyrus, right superior frontal gyrus, and the ventral medial prefrontal cortex, participants in the control group continued to engage these areas post-training, suggesting a sustained reliance on attentional regions during challenging task demands. The HVT group showed a further reduction in neural resources post-training compared to the FET group in these cognitive control regions, along with reduced activation in the motor and sensory cortices and the posteromedial cortex. Findings suggest that training, specifically one that emphasizes cognitive flexibility can reduce the attentional demands of a complex cognitive task, along with reduced reliance on the motor network.
doi:10.3389/fnhum.2012.00115
PMCID: PMC3351675  PMID: 22615690
skill acquisition; training strategies; attentional control; functional MRI
15.  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.
doi:10.1093/cercor/bhp293
PMCID: PMC3841463  PMID: 20089946
basal ganglia; caudate nucleus; cognitive flexibility; nucleus accumbens; procedural learning
16.  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.
doi:10.1159/000316648
PMCID: PMC3696376  PMID: 20693803
Brain; Development; Exercise; MRI; Physical activity; Neurocognition; Neuroimaging; Striatum
17.  Aerobic Fitness is Associated with Gray Matter Volume and White Matter Integrity in Multiple Sclerosis 
Brain research  2009;1341C:41-51.
Alterations in gray and white matter have been well documented in individuals with multiple sclerosis. Severity and extent of such brain tissue damage have been associated with cognitive impairment, disease duration and neurological disability, making quantitative indices of tissue damage important markers of disease progression. In this study, we investigated the association between cardiorespiratory fitness and measures of gray matter atrophy and white matter integrity. Employing a voxel-based approach to analyses of gray matter and white matter, we specifically examined whether higher levels of fitness in multiple sclerosis participants were associated with preserved gray matter volume and integrity of white matter. We found a positive association between cardiorespiratory fitness and regional gray matter volumes and higher focal fractional anisotropy values. Statistical mapping revealed that higher levels of fitness were associated with greater gray matter volume in the midline cortical structures including the medial frontal gyrus, anterior cingulate cortex and the precuneus. Further, we also found increasing levels of fitness were associated with higher fractional anisotropy in the left thalamic radiation and right anterior corona radiata. Both preserved gray matter volume and white-matter tract integrity were associated with better performance on measures of processing speed. Taken together, these results suggest that fitness exerts a prophylactic influence on the cerebral atrophy observed early on preserving neuronal integrity in multiple sclerosis, thereby reducing long-term disability.
doi:10.1016/j.brainres.2009.06.063
PMCID: PMC2884046  PMID: 19560443
Cortical atrophy; normal appearing gray matter; normal appearing white matter; cardiorespiratory fitness; processing speed; relapsing-remitting multiple sclerosis; neuroplasticity
18.  Aerobic Fitness is Associated With Hippocampal Volume in Elderly Humans 
Hippocampus  2009;19(10):1030-1039.
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.
doi:10.1002/hipo.20547
PMCID: PMC3072565  PMID: 19123237
aging; MRI; spatial memory; cognition; brain
19.  BDNF is Associated With Age-Related Decline in Hippocampal Volume 
Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.
doi:10.1523/JNEUROSCI.6251-09.2010
PMCID: PMC3069644  PMID: 20392958
brain-derived neurotrophic factor; hippocampus; human; brain; caudate nucleus; aging
20.  Resting Hippocampal Blood Flow, Spatial Memory and Aging 
Brain research  2009;1315C:119.
Aging is accompanied by a general deterioration of fluid cognitive processes and a reduction in resting cerebral blood flow (CBF). While the two phenomena have been observed independently, it is uncertain whether individual differences in cerebral blood flow are reliably associated with cognitive functioning in older adults. Furthermore, previous studies have concentrated primarily on gross measures of cognition and global gray matter CBF, leaving open the possibility that perfusion of specific brain regions may relate differentially to distinct cognitive domains. The present study sought to provide a more focused treatment of CBF and cognitive function in the context of aging by investigating the relationships among aging, spatial memory and resting hippocampal blood flow, both between and within younger and older adult groups. Blood flow was quantified using a novel Flow-Enhanced Signal Intensity (FENSI) technique which provides a localized, functionally-relevant measure of volumetric flow across a given unit area. As expected, we found that aging was associated with poorer spatial memory and reduced resting CBF. Moreover, hippocampal blood flow was positively correlated with spatial memory performance in the older adult group, suggesting that increased blood flow to the hippocampus is associated with superior memory performance in older adults. These results demonstrate a region-specific CBF—cognition relationship and thereby offer new insight into the complex connection between the aging brain and behavior.
doi:10.1016/j.brainres.2009.12.020
PMCID: PMC2822086  PMID: 20026320
hippocampus; cerebral blood flow; brain perfusion; cognition; memory; aging
21.  Predicting Individuals' Learning Success from Patterns of Pre-Learning MRI Activity 
PLoS ONE  2011;6(1):e16093.
Performance in most complex cognitive and psychomotor tasks improves with training, yet the extent of improvement varies among individuals. Is it possible to forecast the benefit that a person might reap from training? Several behavioral measures have been used to predict individual differences in task improvement, but their predictive power is limited. Here we show that individual differences in patterns of time-averaged T2*-weighted MRI images in the dorsal striatum recorded at the initial stage of training predict subsequent learning success in a complex video game with high accuracy. These predictions explained more than half of the variance in learning success among individuals, suggesting that individual differences in neuroanatomy or persistent physiology predict whether and to what extent people will benefit from training in a complex task. Surprisingly, predictions from white matter were highly accurate, while voxels in the gray matter of the dorsal striatum did not contain any information about future training success. Prediction accuracy was higher in the anterior than the posterior half of the dorsal striatum. The link between trainability and the time-averaged T2*-weighted signal in the dorsal striatum reaffirms the role of this part of the basal ganglia in learning and executive functions, such as task-switching and task coordination processes. The ability to predict who will benefit from training by using neuroimaging data collected in the early training phase may have far-reaching implications for the assessment of candidates for specific training programs as well as the study of populations that show deficiencies in learning new skills.
doi:10.1371/journal.pone.0016093
PMCID: PMC3021541  PMID: 21264257
22.  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.
doi:10.1037/a0017292
PMCID: PMC2843433  PMID: 20063947
23.  Age-related differences in the involvement of the prefrontal cortex in attentional control 
Brain and cognition  2009;71(3):328-335.
We investigated the relative involvement of cortical regions supporting attentional control in older and younger adults during performance on a modified version of the Stroop task. Participants were exposed to two different types of incongruent trials. One of these, an incongruent-ineligible condition, produces conflict at the non-response level, while the second, an incongruent-eligible condition, produces conflict at both non-response and response levels of information processing. Greater attentional control is needed to perform the incongruent-eligible condition compared to other conditions. We examined the cortical recruitment associated with this task in an event-related functional magnetic resonance imaging paradigm in twenty-five older and twenty-five younger adults. Our results indicated that while younger adults demonstrated an increase in the activation of cortical regions responsible for maintaining attentional control in response to increased levels of conflict, such sensitivity and flexibility of the cortical regions to increased attentional control demands was absent in older adults. These results suggest a limitation in older adults’ capabilities for flexibly recruiting the attentional network in response to increasing attentional demands.
doi:10.1016/j.bandc.2009.07.005
PMCID: PMC2783271  PMID: 19699019
attentional control; aging; fMRI; flexibility; Stroop task; interference; inhibition
24.  Top-down attentional control in spatially coincident stimuli enhances activity in both task-relevant and task-irrelevant regions of cortex 
Behavioural brain research  2008;197(1):186-197.
Models of selective attention predict that focused attention to spatially contiguous stimuli may result in enhanced activity in areas of cortex specialized for processing task-relevant and task-irrelevant information. We examined this hypothesis by localizing color-sensitive areas (CSA) and word and letter sensitive areas of cortex and then examining modulation of these regions during performance of a modified version of the Stroop task in which target and distractors are spatially coincident. We report that only the incongruent condition with the highest cognitive demand showed increased activity in CSA relative to other conditions, indicating an attentional enhancement in target processing areas. We also found an enhancement of activity in one region sensitive to word/letter processing during the most cognitively demanding incongruent condition indicating greater processing of the distractor dimension. Correlations with performance revealed that top-down modulation during the task was critical for effective filtering of irrelevant information in conflict conditions. These results support predictions made by models of selective attention and suggest an important mechanism of top-down attentional control in spatially contiguous stimuli.
doi:10.1016/j.bbr.2008.08.028
PMCID: PMC2845993  PMID: 18804123
Attentional control; Top-down modulation; Stroop task; Color-sensitive; Visual word form area
25.  Plasticity of Brain Networks in a Randomized Intervention Trial of Exercise Training in Older Adults 
Research has shown the human brain is organized into separable functional networks during rest and varied states of cognition, and that aging is associated with specific network dysfunctions. The present study used functional magnetic resonance imaging (fMRI) to examine low-frequency (0.008 < f < 0.08 Hz) coherence of cognitively relevant and sensory brain networks in older adults who participated in a 1-year intervention trial, comparing the effects of aerobic and non-aerobic fitness training on brain function and cognition. Results showed that aerobic training improved the aging brain's resting functional efficiency in higher-level cognitive networks. One year of walking increased functional connectivity between aspects of the frontal, posterior, and temporal cortices within the Default Mode Network and a Frontal Executive Network, two brain networks central to brain dysfunction in aging. Length of training was also an important factor. Effects in favor of the walking group were observed only after 12 months of training, compared to non-significant trends after 6 months. A non-aerobic stretching and toning group also showed increased functional connectivity in the DMN after 6 months and in a Frontal Parietal Network after 12 months, possibly reflecting experience-dependent plasticity. Finally, we found that changes in functional connectivity were behaviorally relevant. Increased functional connectivity was associated with greater improvement in executive function. Therefore the study provides the first evidence for exercise-induced functional plasticity in large-scale brain systems in the aging brain, using functional connectivity techniques, and offers new insight into the role of aerobic fitness in attenuating age-related brain dysfunction.
doi:10.3389/fnagi.2010.00032
PMCID: PMC2947936  PMID: 20890449
exercise; aging; functional connectivity; fMRI; default mode network; executive function; aerobic fitness

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