Data-driven MRI analysis reveals fitness-related functional change in default mode network and cognition following an exercise intervention.

Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.

Getting Fit to Counteract Cognitive Aging: Evidence and Future Directions.

Physical activity has shown tremendous promise for counteracting cognitive aging, but also tremendous variability in cognitive benefits. We describe evidence for how exercise affects cognitive and brain aging, and whether cardiorespiratory fitness is a key factor. We highlight a brain network framework as a valuable paradigm for the mechanistic insight needed to tailor physical activity for cognitive benefits.

Hippocampal acidity and volume are differentially associated with spatial navigation in older adults.

The hippocampus is negatively affected by aging and is critical for spatial navigation. While there is evidence that wayfinding navigation tasks are especially sensitive to preclinical hippocampal deterioration, these studies have primarily used volumetric hippocampal imaging without considering microstructural properties or anatomical variation within the hippocampus. T1ρ is an MRI measure sensitive to regional pH, with longer relaxation rates reflecting acidosis as a marker of metabolic dysfunction and neuropathological burden. For the first time, we investigate how measures of wayfinding including landmark location learning and delayed memory in cognitively normal older adults (N = 84) relate to both hippocampal volume and T1ρ in the anterior and posterior hippocampus. Regression analyses revealed hippocampal volume was bilaterally related to learning, while right lateralized T1ρ was related to delayed landmark location memory and bilateral T1ρ was related to the delayed use of a cognitive map. Overall, results suggest hippocampal volume and T1ρ relaxation rate tap into distinct mechanisms involved in preclinical cognitive decline as assessed by wayfinding navigation, and laterality influenced these relationships more than the anterior-posterior longitudinal axis of the hippocampus.

White matter plasticity in healthy older adults: The effects of aerobic exercise.

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer's disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60-79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter.

Cardiorespiratory fitness and hippocampal volume predict faster episodic associative learning in older adults.

Declining episodic memory is common among otherwise healthy older adults, in part due to negative effects of aging on hippocampal circuits. However, there is significant variability between individuals in severity of aging effects on the hippocampus and subsequent memory decline. Importantly, variability may be influenced by modifiable protective physiological factors such as cardiorespiratory fitness (CRF). More research is needed to better understand which aspects of cognition that decline with aging benefit most from CRF. The current study evaluated the relation of CRF with learning rate on the episodic associative learning (EAL) task, a task designed specifically to target hippocampal-dependent relational binding and to evaluate learning with repeated occurrences. Results show higher CRF was associated with faster learning rate. Larger hippocampal volume was also associated with faster learning rate, though hippocampal volume did not mediate the relationship between CRF and learning rate. Furthermore, to support the distinction between learning item relations and learning higher-order sequences, which declines with aging but is largely reliant on extra-hippocampal learning systems, we found learning rate on the EAL task was not related to motor sequence learning on the alternating serial reaction time task. Motor sequence learning was also not correlated with hippocampal volume. Thus, for the first time, we show that both higher CRF and larger hippocampal volume in healthy older adults are related to enhanced rate of relational memory acquisition.

Spx, the central regulator of the heat and oxidative stress response in B. subtilis, can repress transcription of translation-related genes.

Spx is a Bacillus subtilis transcription factor that interacts with the alpha subunits of RNA polymerase. It can activate the thiol stress response regulon and interfere with the activation of many developmental processes. Here, we show that Spx is a central player orchestrating the heat shock response by up-regulating relevant stress response genes as revealed by comparative transcriptomic experiments. Moreover, these experiments revealed the potential of Spx to inhibit transcription of translation-related genes. By in vivo and in vitro experiments, we confirmed that Spx can inhibit transcription from rRNA. This inhibition depended mostly on UP elements and the alpha subunits of RNA polymerase. However, the concurrent up-regulation activity of stress genes by Spx, but not the inhibition of translation related genes, was essential for mediating stress response and antibiotic tolerance under the applied stress conditions. The observed inhibitory activity might be compensated in vivo by additional stress response processes interfering with translation. Nevertheless, the impact of Spx on limiting translation becomes apparent under conditions with high cellular Spx levels. Interestingly, we observed a subpopulation of stationary phase cells that contains raised Spx levels, which may contribute to growth inhibition and a persister-like behaviour of this subpopulation during outgrowth.

Aerobic exercise promotes executive functions and impacts functional neural activity among older adults with vascular cognitive impairment.

BACKGROUND: Vascular cognitive impairment (VCI) results from cerebrovascular disease, and worldwide, it is the second most common type of cognitive dysfunction. While targeted aerobic training is a promising approach to delay the progression of VCI by reducing cardiometabolic risk factors, few randomised controlled trials to date have specifically assessed the efficacy of aerobic training on cognitive and brain outcomes in this group at risk for functional decline. AIM: To examine the effect of moderate-intensity aerobic training on executive functions and functional neural activity among older adults with mild subcortical ischaemic VCI (SIVCI). METHODS: Older adults with mild SIVCI were randomly assigned to: (1) 6-month, 3×/week aerobic training (n=10) or (2) usual care (control; n=11). Participants completed functional MRI (fMRI) at baseline and trial completion. During the fMRI sessions, behavioural performance on the Eriksen flanker task and task-evoked neural activity were assessed. RESULTS: At trial completion, after adjusting for baseline general cognition, total white matter lesion volume and flanker performance, compared with the control group, the aerobic training group significantly improved flanker task reaction time. Moreover, compared with the controls, the aerobic training group demonstrated reduced activation in the left lateral occipital cortex and right superior temporal gyrus. Reduced activity in these brain regions was significantly associated with improved (ie, faster) flanker task performance at trial completion. SUMMARY: Aerobic training among older adults with mild SIVCI can improve executive functions and neural efficiency of associated brain areas. Future studies with greater sample size should be completed to replicate and extend these findings.

Aging affects spatial reconstruction more than spatial pattern separation performance even after extended practice.

Although the hippocampus experiences age-related anatomical and functional deterioration, the effects of aging vary across hippocampal-dependent cognitive processes. In particular, whether or not the hippocampus is known to be required for a spatial memory process is not an accurate predictor on its own of whether aging will affect performance. Therefore, the primary objective of this study was to compare the effects of healthy aging on a test of spatial pattern separation and a test of spatial relational processing, which are two aspects of spatial memory that uniquely emphasize the use of multiple hippocampal-dependent processes. Spatial pattern separation supports spatial memory by preserving unique representations for distinct locations. Spatial relational processing forms relational representations of objects to locations or between objects and other objects in space. To test our primary objective, 30 young (18-30 years; 21F) and 30 older participants (60-80 years; 21F) all completed a spatial pattern separation task and a task designed to require spatial relational processing through spatial reconstruction. To ensure aging effects were not due to inadequate time to develop optimal strategies or become comfortable with the testing devices, a subset of participants had extended practice across three sessions on each task. Results showed that older adults performed more poorly than young on the spatial reconstruction task that emphasized the use of spatial relational processing, and that age effects persisted even after controlling for pattern separation performance. Further, older adults performed more poorly on spatial reconstruction than young adults even after three testing sessions each separated by 7-10 days, suggesting effects of aging are resistant to extended practice and likely reflect genuine decline in hippocampal memory abilities.

Fitness, but not physical activity, is related to functional integrity of brain networks associated with aging.

Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the default mode network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks.

White matter microstructure mediates the relationship between cardiorespiratory fitness and spatial working memory in older adults.

White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract-specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood.

Frontal and Temporal Structural Connectivity Is Associated with Social Communication Impairment Following Traumatic Brain Injury.

OBJECTIVES: Although it has been well documented that traumatic brain injury (TBI) can result in communication impairment, little work to date has examined the relationship between social communication skills and structural brain integrity in patients with TBI. The aim of the current study was to investigate the association between self- and other-perceived communication problems and white matter integrity in patients with mild to severe TBI. METHODS: Forty-four individuals (TBI=24) and people with whom they frequently communicate, as well as demographically matched normal healthy comparisons (NC) and their frequent communication partners, were administered, respectively, the La-Trobe Communication Questionnaire Self form (LCQ-SELF) and Other form (LCQ-OTHER). In addition, diffusion tensor imaging data were collected, and fractional anisotropy (FA) measures were extracted for each lobe in both hemispheres. RESULTS: Within the TBI group, but not within the NC group, participants who were perceived by their close others as having more communication problems had lower FA in the left frontal and temporal lobes (p<.01), but not in other brain regions. CONCLUSIONS: Frontotemporal white matter microstructural integrity is associated with social communication abilities in adults with TBI. This finding contributes to our understanding of the mechanisms leading to communication impairment following TBI and can inform the development of new neuromodulation therapies as well as diagnostic tools. (JINS, 2016, 22, 705-716).

Physical activity and cognitive vitality.

We examine evidence supporting the associations among physical activity (PA), cognitive vitality, neural functioning, and the moderation of these associations by genetic factors. Prospective epidemiological studies provide evidence for PA to be associated with a modest reduction in relative risk of cognitive decline. An evaluation of the PA-cognition link across the life span provides modest support for the effect of PA on preserving and even enhancing cognitive vitality and the associated neural circuitry in older adults, with the majority of benefits seen for tasks that are supported by the prefrontal cortex and the hippocampus. The literature on children and young adults, however, is in need of well-powered randomized controlled trials. Future directions include a more sophisticated understanding of the dose-response relationship, the integration of genetic and epigenetic approaches, inclusion of multimodal imaging of brain-behavior changes, and finally the design of multimodal interventions that may yield broader improvements in cognitive function.

Relating hippocampus to relational memory processing across domains and delays.

The hippocampus has been implicated in a diverse set of cognitive domains and paradigms, including cognitive mapping, long-term memory, and relational memory, at long or short study-test intervals. Despite the diversity of these areas, their association with the hippocampus may rely on an underlying commonality of relational memory processing shared among them. Most studies assess hippocampal memory within just one of these domains, making it difficult to know whether these paradigms all assess a similar underlying cognitive construct tied to the hippocampus. Here we directly tested the commonality among disparate tasks linked to the hippocampus by using PCA on performance from a battery of 12 cognitive tasks that included two traditional, long-delay neuropsychological tests of memory and two laboratory tests of relational memory (one of spatial and one of visual object associations) that imposed only short delays between study and test. Also included were different tests of memory, executive function, and processing speed. Structural MRI scans from a subset of participants were used to quantify the volume of the hippocampus and other subcortical regions. Results revealed that the 12 tasks clustered into four components; critically, the two neuropsychological tasks of long-term verbal memory and the two laboratory tests of relational memory loaded onto one component. Moreover, bilateral hippocampal volume was strongly tied to performance on this component. Taken together, these data emphasize the important contribution the hippocampus makes to relational memory processing across a broad range of tasks that span multiple domains.

Exercise training increases size of hippocampus and improves memory.

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

Educational Attainment Moderates Task-State Control Network Connectivity Relations to Response Conflict Among Healthy Older Adults.

OBJECTIVES: Older adult executive function varies widely due to brain and cognitive aging. Variance in older adult executive function is linked to increased response conflict from cognitive and brain aging. Cognitive reserve (CR) is a theoretical protective mechanism that lessens brain aging's impact on cognition and is associated with greater educational attainment. Recent work in rest-state functional magnetic resonance imaging (fMRI) suggests CR proxies moderate the relationship between functional connectivity (FC) and cognitive performance. Brain network FC in "control networks," including the salience (SN), dorsal attention and frontoparietal networks, are associated with cognitive processes in older adults. CR is hypothesized to maintain cognitive processing in part through changes in how brain networks respond to cognitive demands. However, it is unclear how CR proxies like educational attainment are related to control network FC during performance when cognitive demands are increased relative to rest. Because CR is expressed more in those with higher education, we hypothesized stronger control network FC would relate to better performance, where this relationship would be strongest among the most educated. METHODS: We collected flanker task data during fMRI to assess the impact of a CR proxy (i.e., educational attainment) on response conflict among older adult subjects (n = 42, age = 65-80). RESULTS: Linear mixed-effects models showed more educated older adults with greater SN-FC had a smaller flanker effect (i.e., less influence of distractors; p < .001) during task performance. DISCUSSION: For the first time, we show that educational attainment moderates the relationship between task-state SN-FC and executive function among older adults.

The Association of the 24-Hour Activity Cycle Profiles With Cognition in Older Adults With Mild Cognitive Impairment: A Cross-Sectional Study.

BACKGROUND: The relationship of cognition and the 24-h activity cycle (24-HAC), encompassing physical activity, sedentary behavior, and sleep, in older adults with mild cognitive impairment (MCI) remains uncertain. Distinct combinations of 24-HAC behaviors can characterize unique activity profiles and influence cognition. We aimed to characterize 24-HAC activity profiles in older adults with MCI and assess whether differences in cognition exist across profiles. METHODS: We conducted a cross-sectional analysis utilizing baseline data from 3 randomized controlled trials involving 253 community-dwelling older adults (55 + years) with MCI (no functional impairment, dementia diagnosis, and Montreal Cognitive Assessment score <26/30). Using MotionWatch8© wrist-worn actigraphy (+5 days), we captured the 24-HAC. Cognition was indexed by the Alzheimer's Disease Assessment Scale Cognitive Plus (ADAS-Cog-Plus). Compositional data and latent profile analyses identified distinct 24-HAC activity profiles. Analysis of covariance examined whether 24-HAC activity profiles differed in cognition. RESULTS: Four distinct activity profiles were identified. Profile 1 ("Average 24-HAC," n = 103) engaged in all 24-HAC behaviors around the sample average. Profile 2 ("Active Chillers," n = 70) depicted lower-than-average engagement in physical activity and higher-than-average sedentary behavior. Profile 3 ("Physical Activity Masters," n = 54) were the most active and the least sedentary. Profile 4 ("Sedentary Savants," n = 26) were the least active and the most sedentary. Sleep was similar across profiles. There were no significant differences in ADAS-Cog-Plus scores between 24-HAC activity profiles (p > .05). CONCLUSIONS: Older adults with MCI exhibited four 24-HAC activity profiles conforming to recommended physical activity and sleep guidelines. Nonetheless, cognition was similar across these profiles.

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans.

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

The Effects of Computerized Cognitive Training in Older Adults' Cognitive Performance and Biomarkers of Structural Brain Aging.

OBJECTIVES: Cognitive training (CT) has been investigated as a means of delaying age-related cognitive decline in older adults. However, its impact on biomarkers of age-related structural brain atrophy has rarely been investigated, leading to a gap in our understanding of the linkage between improvements in cognition and brain plasticity. This study aimed to explore the impact of CT on cognitive performance and brain structure in older adults. METHODS: One hundred twenty-four cognitively normal older adults recruited from 2 study sites were randomly assigned to either an adaptive CT (n = 60) or a casual game training (active control, AC, n = 64). RESULTS: After 10 weeks of training, CT participants showed greater improvements in the overall cognitive composite score (Cohen's d = 0.66, p < .01) with nonsignificant benefits after 6 months from the completion of training (Cohen's d = 0.36, p = .094). The CT group showed significant maintenance of the caudate volume as well as significant maintained fractional anisotropy in the left internal capsule and in left superior longitudinal fasciculus compared to the AC group. The AC group displayed an age-related decrease in these metrics of brain structure. DISCUSSION: Results from this multisite clinical trial demonstrate that the CT intervention improves cognitive performance and helps maintain caudate volume and integrity of white matter regions that are associated with cognitive control, adding to our understanding of the changes in brain structure contributing to changes in cognitive performance from adaptive CT. CLINICAL TRIAL REGISTRATION: NCT03197454.

The influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: results of a one-year exercise intervention.

Cerebral white matter (WM) 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 WM 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 WM 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 WM integrity, executive function, or short-term memory, but that greater aerobic fitness derived from the walking program was associated with greater change in WM integrity in the frontal and temporal lobes, and greater improvement in short-term memory. Increases in WM 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, WM integrity, and cognition among healthy older adults.

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.