Examining the relationship between fitness, cortical excitability, and neurochemistry of the brain (GABA, glutamate, and NAA)

L'exercice aérobique (AE) est associé à de nombreuses modifications fonctionnelles et anatomiques dans le cerveau humain. Par exemple, il a été démontré que l'EA modulait l'excitabilité corticale et la neurochimie immédiatement après l'exercice. Les effets d'une activité physique répétée et soutenue sur les fonctions cérébrales restent toutefois mal compris. En effet, peu de données sont disponibles permettant de déterminer si les personnes ayant une bonne condition physique présentent des modifications persistantes de l'excitabilité corticale et du métabolisme cérébral malgré les changements rapportés dans la matière grise et la matière blanche. Dans la présente étude, 20 personnes sédentaires en bonne santé ( 6 heures/semaine d'activité physique) sur la base de mesures de l'excitabilité corticale (rMT, courbe I/O, SICI, ICF) et de la concentration de métabolites (GABA, Glx, NAA) dans la représentation corticale de la main droite. L'épaisseur corticale de la représentation du cortex moteur primaire de la main droite et la densité apparente des fibres de la voie corticospinale (CST) ont également été évaluées. L'aptitude cardiorespiratoire (VO2max) était significativement plus élevée chez les athlètes que chez les sédentaires, ce qui n'était pas le cas de l'indice de masse corporelle. Aucune différence entre les groupes n'a été constatée en ce qui concerne les mesures du rMT, du SICI et de l'ICF. Les valeurs de la courbe I/O étaient significativement plus élevées et la courbe I/O était plus prononcée chez les individus actifs. Aucune différence significative n'a été observée pour l'épaisseur corticale, la concentration de métabolites et les valeurs de diffusion de la CST. La pente de la courbe I/O était positivement corrélée à la VO2max. Les présentes données suggèrent que des niveaux élevés de capacité aérobique sont associés à une excitabilité corticale accrue dans la représentation de la main du cortex moteur primaire.Aerobic exercise is associated with widespread functional and anatomical modifications in the human brain. For example, AE has been shown to modulate cortical excitability and neurochemistry immediately after exercise. The effects of repeated and sustained physical activity on brain function, however, remain poorly understood. Indeed, little is known about whether individuals with high levels of fitness display persistent modifications in cortical excitability and brain metabolism despite reported changes in grey and white matter. In the present study, 20 healthy sedentary individuals ( 6 hours/week AE) on measures of cortical excitability (rMT, I/O curve, SICI, ICF) and metabolite concentration (GABA, Glx, NAA) in the cortical representation of the right hand. Cortical thickness of the primary motor cortex representation of the right hand and corticospinal tract (CST) apparent fiber density (AFD) were also assessed. Cardiorespiratory fitness (VO2max) was significantly higher in athletes compared to sedentary individuals whereas body mass index was not. No group differences were found on measures of rMT, SICI and ICF. I/O curve values were significantly higher, and the I/O curve was steeper in active individuals. No significant differences were observed between the groups for cortical thickness, metabolite concentration and CST diffusion values. I/O curve slope was positively correlated with VO2max. The present data suggest that high levels of aerobic fitness are associated with increased cortical excitability in the hand representation of the primary motor cortex

Longitudinal study of the effect of a 5-year exercise intervention on structural brain complexity in older adults. A Generation 100 substudy

Physical inactivity has been identified as an important risk factor for dementia. High levels of cardiorespiratory fitness (CRF) have been shown to reduce the risk of dementia. However, the mechanism by which exercise affects brain health is still debated. Fractal dimension (FD) is an index that quantifies the structural complexity of the brain. The purpose of this study was to investigate the effects of a 5-year exercise intervention on the structural complexity of the brain, measured through the FD, in a subset of 105 healthy older adults participating in the randomized controlled trial Generation 100 Study. The subjects were randomized into control, moderate intensity continuous training, and high intensity interval training groups. Both brain MRI and CRF were acquired at baseline and at 1-, 3- and 5-years follow-ups. Cortical thickness and volume data were extracted with FreeSurfer, and FD of the cortical lobes, cerebral and cerebellar gray and white matter were computed. CRF was measured as peak oxygen uptake (VO2peak) using ergospirometry during graded maximal exercise testing. Linear mixed models were used to investigate exercise group differences and possible CRF effects on the brain's structural complexity. Associations between change over time in CRF and FD were performed if there was a significant association between CRF and FD. There were no effects of group membership on the structural complexity. However, we found a positive association between CRF and the cerebral gray matter FD (p < 0.001) and the temporal lobe gray matter FD (p < 0.001). This effect was not present for cortical thickness, suggesting that FD is a more sensitive index of structural changes. The change over time in CRF was associated with the change in temporal lobe gray matter FD from baseline to 5-year follow-up (p < 0.05). No association of the change was found between CRF and cerebral gray matter FD. These results demonstrated that entering old age with high and preserved CRF levels protected against loss of structural complexity in areas sensitive to aging and age-related pathology

Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer\u27s disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65–85) cognitively intact adults. A cross-sectional design was used with four groups (n = 17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous\u3eunfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline

Dementia risk and dynamic response to exercise: A non-randomized clinical trial

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the Apolipoprotein epsilon 4 (APOE4) allele, a genetic risk factor for developing Alzheimer’s. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. Methods Sixty-two older adults (73±5 years old, 41 female [67%]) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). Results Genotyping failed in one individual (n = 23 APOE4 carriers and n = 38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellum across both groups. Among high inter-individual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. Conclusions Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study provide an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer’s disease

Associations Between Cardiorespiratory Fitness, Adiposity, and White Matter Integrity

White matter (WM) is essential for transmitting neural signal between brain regions, and supporting healthy brain aging and cognitive function. Risk for WM deterioration is heightened in overweight and obesity, whereas increasing cardiorespiratory fitness may promote WM integrity. However, there is a lack of research comparing adiposity and cardiorespiratory fitness with WM. Further, it is not clear whether increasing cardiorespiratory fitness may outweigh the influence of excess adiposity on WM integrity in middle adulthood. In a sample of adults with overweight and obesity, we examined whether cardiorespiratory fitness and adiposity associate with WM integrity, both independently and jointly. We assessed WM pathways sensitive to cardiorespiratory fitness, adiposity, or both, and tested potential interactions. Baseline data from 125 middle-aged participants (Mage = 44.33 ± 8.60), with overweight or obesity (MBMI = 32.45 ± 4.19), were included in the study. Fitness was assessed via a submaximal graded exercise test. To quantify adiposity, whole body estimates of body fat % were calculated using dual-energy X-ray absorptiometry. Diffusion weighted images were acquired during an MRI protocol. We conducted whole-brain voxelwise analyses using the FMRIB’s Software Library randomise function to examine main effects of adiposity and fitness, as well as the interaction term, on WM integrity. After controlling for age, gender, and years of education, there were no significant main effects of adiposity or cardiorespiratory fitness on FA (all p > .05). There was a significant interaction (p = .03) such that with higher fitness levels, greater adiposity was associated with higher WM integrity, whereas with lower fitness levels greater adiposity was negatively associated with WM integrity. This pattern of findings was unexpected, and may be a function of the unique nature of the sample or related to the confounding effects of WM lesions or local inflammation. Future work may focus on accounting for the influence of WM lesions, and extending the analysis to older adults and patient populations

Cardiorespiratory fitness and virtual navigation in healthy older adults

One of the earliest symptoms of Alzheimer’s disease (AD) and age-related cognitive decline is topographical disorientation or impairment to spatial navigation. Furthermore, aging and AD are associated with cortical gray-matter thinning, particularly in the medial temporal and posterior cingulate regions, which have been associated with spatial navigation. Aerobic exercise has been well-established as a beneficial intervention to curtail the neurodegenerative effects of aging. This study aims to explore the relationship between cardiorespiratory fitness (CRF), and two markers of AD and cognitive aging, virtual navigation ability and cortical thickness of the entorhinal, parahippocampal and retrosplenial regions. Cross-sectional data utilized in this study was collected from 23 healthy older adults (60-80 years). Measures included in our analyses consisted of estimated VO2max, T1-weighted structural MR images, and behavioral performance on a virtual navigation task, measured as numbers of objects located during recall. Cortical thickness of the regions of interest (ROIs) was determined by processing T1-weighted MR images in FreeSurfer. We hypothesized that greater CRF would correlate with improved virtual navigation performance and greater cortical thickness of ROIs. Our analyses did not reveal statistically significant relationships between CRF and navigation performance or CRF and cortical thickness. However, Pearson’s correlations found right retrosplenial cortical (RSC) thickness and navigation performance to be significantly related. Multiple regression models of right RSC thickness and navigation performance were performed controlling for age, sex, education and task version. These analyses revealed that greater right RSC thickness predicted navigation performance. Additionally, this model showed that older age predicts decline in navigation performance. Our findings did not survive multiple comparisons correction; nonetheless, the results provide promising insight to the relationship between cortical thickness and navigation performance in healthy aging. Further cross-sectional and longitudinal investigations with a larger sample size are required to assess the impact of CRF and exercise on cortical thickness and navigation abilities in healthy aging. Understanding these relationships would contribute to the expansive body of literature that has linked CRF and exercise to neuroprotective mechanisms in the aging brain

Sex Differences in the Influence of Brain and Lifestyle Factors on Neurocognitive Aging

Declines in executive functioning (EF) are a hallmark of neurocognitive aging. Much research has focused on the impact of exercise, brain structure, and brain function on neurocognitive aging, yet their relative predictive weights had not been evaluated. Further, the impact of sex differences on the influence of these factors had not yet been investigated. Fifty-one older adults participated in this study evaluating the outcome of cardiorespiratory fitness (CRF), prefrontal cortex volume, and global efficiency of functional brain networks on EF. A stratified, multiple hierarchical regression was performed to identify the best predictors of EF for each sex. For females, a model containing solely CRF served as the best predictor of EF. A model containing both CRF and network efficiency best predicted EF in males. These results demonstrate that CRF and metrics of structural and functional brain health in older adulthood are independently associated with EF in a sex-dependent manner

Associations Between Physical Fitness and Brain Structure in Young Adulthood

A comprehensive analysis of associations between physical fitness and brain structure in young adulthood is lacking, and further, it is unclear the degree to which associations between physical fitness and brain health can be attributed to a common genetic pathway or to environmental factors that jointly influences physical fitness and brain health. This study examined genotype-confirmed monozygotic and dizygotic twins, along with non-twin full-siblings to estimate the contribution of genetic and environmental factors to variation within, and covariation between, physical fitness and brain structure. Participants were 1,065 young adults between the ages of 22 and 36 from open-access Young Adult Human Connectome Project (YA-HCP). Physical fitness was assessed by submaximal endurance (2-min walk test), grip strength, and body mass index. Brain structure was assessed using magnetic resonance imaging on a Siemens 3T customized ‘Connectome Skyra’ at Washington University in St. Louis, using a 32-channel Siemens head coil. Acquired T1-weighted images provided measures of cortical surface area and thickness, and subcortical volume following processing by the YA-HCP structural FreeSurfer pipeline. Diffusion weighted imaging was acquired to assess white matter tract integrity, as measured by fractional anisotropy, following processing by the YA-HCP diffusion pipeline and tensor fit. Following correction for multiple testing, body mass index was negatively associated with fractional anisotropy in various white matter regions of interest (all | z| statistics > 3.9) and positively associated with cortical thickness within the right superior parietal lobe (z statistic = 4.6). Performance-based measures of fitness (i.e., endurance and grip strength) were not associated with any structural neuroimaging markers. Behavioral genetic analysis suggested that heritability of white matter integrity varied by region, but consistently explained >50% of the phenotypic variation. Heritability of right superior parietal thickness was large (∼75% variation). Heritability of body mass index was also fairly large (∼60% variation). Generally, 12 to 23 of the correlation between brain structure and body mass index could be attributed to heritability effects. Overall, this study suggests that greater body mass index is associated with lower white matter integrity, which may be due to common genetic effects that impact body composition and white matter integrity

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

Long-term high-effort endurance exercise in older adults: diminishing returns for cognitive and brain aging

While there is evidence that age-related changes in cognitive performance and brain structure can be offset by increased exercise, little is known about the impact on these of long-term high-effort endurance exercise. In a cross-sectional design with 12-month follow-up, we recruited older adults engaging in high-effort endurance exercise over at least twenty years, and compared their cognitive performance and brain structure with a non-sedentary control group similar in age, sex, education, IQ, and lifestyle factors. Our findings showed no differences on measures of speed of processing, executive function, incidental memory, episodic memory, working memory, or visual search for older adults participating in long-term high-effort endurance exercise, when compared without confounds to non-sedentary peers. On tasks that engaged significant attentional control, subtle differences emerged. On indices of brain structure, long-term exercisers displayed higher white matter axial diffusivity than their age-matched peers, but this did not correlate with indices of cognitive performance