Jeremy J. Walsh

Neurotrophic growth factor responses to lower body resistance training in older adults

Resistance exercise is an efficacious stimulus for improving cognitive function in older adults, which may be mediated by the upregulation of blood-borne neurotrophic growth factors (NTFs) like brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). However, the NTF response to resistance exercise and training in older adults is poorly understood. Therefore, the purpose of this study was to characterize the timing and magnitude of the NTF response following an acute bout of resistance exercise before and after 8 weeks of resistance training. Ten cognitively normal, older adults (ages 60-77 years, five men) were examined. The acute NTF response to resistance exercise was assessed via serum samples drawn at designated time points following exercise. This procedure was then repeated following 8 weeks of resistance training. BDNF increased immediately post-exercise (Δ9% pre-training, Δ11% post-training) then returned to resting levels while IGF-1 remained stable following resistance exercise before and after 8 weeks of resistance training. Basal levels of both NTFs were unaffected by the 8 week training period. We report a transient increase in serum BDNF following a bout of resistance exercise in older adults, which could have implications for the design of interventions seeking to maximize cognitive function in older adults.

Effects of reaction time variability and age on brain activity during Stroop task performance

Variability in reaction time during task performance may reflect fluctuations in attention and cause reduced performance in goal-directed tasks, yet it is unclear whether the mechanisms behind this phenomenon change with age. Using fMRI, we tested young and cognitively healthy older adults with the Stroop task to determine whether aging affects the neural mechanisms underlying intra-individual reaction time variability. We found significant between-group differences in BOLD activity modulated by reaction time. In older adults, longer reaction times were associated with greater activity in frontoparietal attentional areas, while in younger adults longer reaction times were associated with greater activity in default mode network areas. Our results suggest that the neural correlates of reaction time variability change with healthy aging, reinforcing the concept of functional plasticity to maintain high cognitive function throughout the lifespan.

Fasting and exercise differentially regulate BDNF mRNA expression in human skeletal muscle

Brain-derived neurotrophic factor (BDNF) gene expression was measured in human skeletal muscle following 3 intensities of exercise and a 48-h fast. No change in BDNF mRNA was observed following exercise, while fasting upregulated BDNF by ∼ 3.5-fold. These changes were dissociated from changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) following exercise (+2- to 15-fold) and fasting (∼-25%). These results challenge our understanding of the response of BDNF to energetic stress and highlight the importance of future work in this area.

Individual susceptibility to hypoperfusion and reductions in exercise performance when perfusion pressure is reduced: evidence for vasodilator phenotypes

The primary objective of this study was to determine whether cardiovascular compensatory response phenotypes exist in the face of a reduced perfusion pressure challenge to exercising muscle oxygen delivery (O2D), and whether these responses might be exercise intensity (EI) dependent. Ten healthy men (19.5 ± 0.4 yr) completed two trials of progressive forearm isometric handgrip exercise to exhaustion (24.5 N increments every 3.5 min) in each of forearm above and below heart level [forearm arterial perfusion pressure (FAPP) difference of 29.5 ± 0.97 mmHg]. At the end of each EI, measurements of forearm blood flow (FBF; ml/min) via brachial artery Doppler and echo ultrasound, mean arterial blood pressure (MAP; mmHg) via finger photoplethysmography, and exercising forearm venous effluent via antecubital vein catheter revealed distinct cardiovascular response groups: n = 6 with compensatory vasodilation vs. n = 4 without compensatory vasodilation. Compensatory vasodilators were able to blunt the perfusion pressure-evoked reduction in submaximal O2D in the arm-above-heart condition, whereas nonvasodilators did not (-22.5 ± 13.6 vs. -65.4 ± 14.1 ml O2/min; P < 0.05), and in combination with being able to increase O2 extraction, nonvasodilators defended submaximal V̇o2 and experienced less of an accumulated submaximal O2D deficit (-80.7 ± 24.7 vs. -219.1 ± 36.0 ml O2/min; P < 0.05). As a result, the compensatory vasodilators experienced less of a compromise to peak EI than nonvasodilators (-24.5 ± 3.5 N vs. -52.1 ± 8.9 N; P < 0.05). In conclusion, in the forearm exercise model studied, vasodilatory response phenotypes exist that determine individual susceptibility to hypoperfusion and the degree to which aerobic metabolism and exercise performance are compromised.

Absence of compensatory vasodilation with perfusion pressure challenge in exercise: evidence for and implications of the noncompensator phenotype

Compromising oxygen delivery (O2D) during exercise requires compensatory vasodilatory and/or pressor responses to protect O2D:demand matching. The purpose of the study was to determine whether compensatory vasodilation is absent in some healthy young individuals in the face of a sudden reduction in exercising forearm perfusion pressure and whether this affects the exercise pressor response. Twenty-one healthy young men (21.6 ± 2.0 yr) completed rhythmic forearm exercise at a work rate equivalent to 70% of their own maximal exercise vasodilation. During steady-state exercise, the exercising arm was rapidly adjusted from below to above heart level, resulting in a reduction in forearm perfusion pressure of -30.7 ± 0.9 mmHg. Forearm blood flow (ml/min; brachial artery Doppler and echo ultrasound), mean arterial blood pressure (mmHg; finger photoplethysmography), and exercising forearm venous effluent (antecubital vein catheter) measurements revealed distinct compensatory vasodilatory differences. Thirteen individuals responded with compensatory vasodilation (509 ± 128 vs. 632 ± 136 ml·min-1·100 mmHg-1; P < 0.001), while eight individuals did not (663 ± 165 vs. 667 ± 167 ml·min-1·100 mmHg-1; P = 0.6). Compensatory pressor responses between groups were not different (5.5 ± 5.5 and 9.7 ± 9.5 mmHg; P = 0.2). Forearm blood flow, O2D, and oxygen consumption were all protected in compensators (all P > 0.05) but not in noncompensators, who therefore suffered compromises to exercise performance (6 ± 14 vs. -36 ± 29 N; P = 0.004). Phenotypic differences were not explained by potassium or nitric oxide bioavailability. In conclusion, both compensator and noncompensator vasodilator phenotype responses to a sudden compromise to exercising muscle blood flow are evident. Interindividual differences in the mechanisms governing O2D:demand matching should be considered as factors influencing exercise tolerance. NEW & NOTEWORTHY In healthy young individuals, compromising submaximally exercising muscle perfusion appears to evoke compensatory vasodilation to defend oxygen delivery. Here we report the absence of compensatory vasodilation in 8 of 21 such individuals, despite their vasodilatory capacity and increases in perfusion with increasing exercise intensity being indistinguishable from compensators. The absence of compensation impaired exercise tolerance. These findings suggest that interindividual differences in oxygen delivery:demand matching efficacy affect exercise tolerance and depend on the nature of a delivery:demand matching challenge.

Dietary nitrate restores compensatory vasodilation and exercise capacity in response to a compromise in oxygen delivery in the noncompensator phenotype

Recently, dietary nitrate supplementation has been shown to improve exercise capacity in healthy individuals through a potential nitrate-nitrite-nitric oxide pathway. Nitric oxide has been shown to play an important role in compensatory vasodilation during exercise under hypoperfusion. Previously, we established that certain individuals lack a vasodilation response when perfusion pressure reductions compromise exercising muscle blood flow. Whether this lack of compensatory vasodilation in healthy, young individuals can be restored with dietary nitrate supplementation is unknown. Six healthy (21 ± 2 yr), recreationally active men completed a rhythmic forearm exercise. During steady-state exercise, the exercising arm was rapidly transitioned from an uncompromised (below heart) to a compromised (above heart) position, resulting in a reduction in local pressure of -31 ± 1 mmHg. Exercise was completed following 5 days of nitrate-rich (70 ml, 0.4 g nitrate) and nitrate-depleted (70 ml, ~0 g nitrate) beetroot juice consumption. Forearm blood flow (in milliliters per minute; brachial artery Doppler and echo ultrasound), mean arterial blood pressure (in millimeters of mercury; finger photoplethysmography), exercising forearm venous effluent (ante-cubital vein catheter), and plasma nitrite concentrations (chemiluminescence) revealed two distinct vasodilatory responses: nitrate supplementation increased (plasma nitrite) compared with placebo (245 ± 60 vs. 39 ± 9 nmol/l; P < 0.001), and compensatory vasodilation was present following nitrate supplementation (568 ± 117 vs. 714 ± 139 ml ⋅ min-1 ⋅ 100 mmHg-1; P = 0.005) but not in placebo (687 ± 166 vs. 697 ± 171 min-1 ⋅ 100 mmHg-1; P = 0.42). As such, peak exercise capacity was reduced to a lesser degree (-4 ± 39 vs. -39 ± 27 N; P = 0.01). In conclusion, dietary nitrate supplementation during a perfusion pressure challenge is an effective means of restoring exercise capacity and enabling compensatory vasodilation.NEW & NOTEWORTHY Previously, we identified young, healthy persons who suffer compromised exercise tolerance when exercising muscle perfusion pressure is reduced as a result of a lack of compensatory vasodilation. The ability of nitrate supplementation to restore compensatory vasodilation in such noncompensators is unknown. We demonstrated that beetroot juice supplementation led to compensatory vasodilation and restored perfusion and exercise capacity. Elevated plasma nitrite is an effective intervention for correcting the absence of compensatory vasodilation in the noncompensator phenotype.

Short-Duration Maximal and Long-Duration Submaximal Effort Forearm Exercise Achieve Elevations in Serum Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is a major orchestrator of exercise-induced brain plasticity and circulating (peripheral) BDNF may have central effects. Approximately 99% of circulating BDNF is platelet-bound, and at rest ~30% of circulating platelets are stored in the spleen. Interestingly, forearm handgrip exercise significantly elevates sympathetic outflow and has been shown to induce splenic constriction, suggesting that small muscle mass exercise could stand as a viable strategy for increasing circulating BDNF; however, the BDNF response to handgrip exercise is currently unknown. Purpose: This study examined BDNF and platelet responses to short-duration maximal (ME) and prolonged submaximal (SE) effort handgrip exercise. Methods: Healthy males (n = 18; 21.4 ± 2.1 years, BMI 25.0 ± 1.0 kg/m2) performed 10 min of ME and 30 min of SE. Blood was sampled for the determination of serum BDNF and platelet count at rest and during the last minute of exercise. Results: Compared to rest, serum BDNF significantly increased during ME (21.2%) and SE (11.2%), which displayed a non-significant trend toward an intensity-dependent response. Platelets increased in an intensity-dependent fashion compared to rest with an 8.0% increase during ME and 3.1% during SE, and these responses were significantly correlated with diastolic blood pressure responses to handgrip exercise. Further, the amount of BDNF per platelet significantly increased compared to rest during ME (13.4%) and SE (8.7%). Conclusions: Handgrip exercise evokes significant increases in serum BDNF and platelets, implicating splenic constriction as a key mechanism and confirming efficacy of this exercise model for elevating circulating BDNF.

A multifaceted investigation into the effects of acute exercise on indices of brain function

Participation in regular exercise is important for the maintenance and improvement of brain health across the lifespan. These beneficial effects are realized almost immediately, as a single bout of exercise transiently improves cognitive function after cessation from exercise. This postexercise time period represents an opportunity to strategically prescribe cognitively stimulating activities for enhancing brain plasticity and function. Mechanistically, acute exercise is proposed to upregulate brain-derived neurotrophic factor (BDNF) expression and increase regional activation and arousal of brain areas involved in cognitive control; however, the specific mechanisms underlying this facilitation are poorly understood. The purpose of this study was to (i) investigate BDNF responses to small muscle mass exercise to probe a potential mechanism of BDNF release during exercise; (ii) create and validate an equipment-free exercise protocol for use in a magnetic resonance imaging (MRI) scanner, with the eventual goal of investigating brain responses during exercise that may underlie improved cognition; and (iii) determine the effect of a very brief bout of high-intensity interval exercise (HIIE) on neuroelectric indices of reinforcement learning in young adults. Serum BDNF, platelet, and the amount of BDNF per platelet responses were measured following short-duration, maximal effort and long-duration, submaximal effort forearm handgrip exercise. We assessed the magnitude and reliability of metabolic responses to a novel whole-body isometric contraction (WBI) exercise protocol. We also characterized the amount of head movement created by WBI. The event-related potential component associated with reward-based learning was assessed before and after a bout of HIIE. Forearm handgrip exercise significantly increased serum BDNF, platelets, and BDNF per platelet, suggesting the possibility of splenic and cellular contribution of BDNF in response to handgrip exercise. WBI reliably evokes metabolic responses that are similar in magnitude to previous in-MRI studies, and creates head movement suitable for MRI scanning. HIIE abolishes neuroelectric indices of reward learning, likely owing to incomplete recovery from exercise. These findings advance our understanding of neurochemical and neuroelectric responses to acute exercise and introduce a novel tool that stands to further elucidate the regional brain responses to exercise that may underlie enhanced cognition after exercise.