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Exercise training has been proposed to counteract age-related cognitive decline through improvements in cardiorespiratory fitness (CRF hypothesis). Research has focused on cognitive domains like attention and processing speed, and one cross-sectional study reported a positive relationship between CRF and language production in older adults. In a randomized controlled trial, we investigated whether these benefits could extend to language comprehension in healthy older adults, and whether bilinguals, for whom language processing is more costly, would exhibit greater benefits than monolinguals. Eighty older English monolinguals and 80 older Norwegian-English bilinguals were randomized into either a 6-month exercise training group or into a passive control group. We assessed CRF (VO2 peak ) and language comprehension (reaction times to spoken word monitoring) in first (L1, all participants) and second language (L2, bilinguals only), before and after the intervention. We found that monolinguals in the exercise group (compared to the control group) were faster in comprehension following the intervention. Moreover, this effect was mediated by exercise-induced increases in VO2 peak , supporting the CRF hypothesis. This extends previous cross-sectional research and establishes a causal link between exercise training and speeded comprehension in older monolinguals. However, despite inducing increased VO2 peak , exercise training did not affect bilingual (L1 or L2) comprehension, and bilinguals in both groups were slower after the intervention period. Exploratory analyses suggested that this slowing may be driven by participants with low L2 proficiency, but further research is needed to examine whether bilingual language processing is in fact unaffected by exercise training and its consequent improvements in CRF.

Brain vascular health worsens with age, as is made evident by resting grey matter cerebral blood flow (CBF GM ) reductions and lengthening arterial transit time (ATT GM ). Exercise training can improve aspects of brain health in older adults, yet its effects on CBF GM and ATT GM remain unclear. This randomised controlled trial assessed responses of CBF GM and ATT GM to a 26 week exercise intervention in 65 healthy older adults (control: n = 33, exercise: n = 32, aged 60-81 years), including whether changes in CBF GM or ATT GM were associated with changes in cognitive functions. Multiple-delay pseudo-continuous arterial spin labelling data were used to estimate resting global and regional CBF GM and ATT GM . Results showed no between-group differences in CBF GM or ATT GM following the intervention. However, exercise participants with the greatest cardiorespiratory gains (n = 17; ∆V̇O 2peak >2 mL/kg/min) experienced global CBF GM reductions (-4.0 [-7.3, -0.8] mL/100 g/min). Cognitive functions did not change in either group and changes were not associated with changes in CBF GM or ATT GM . Our findings indicate that exercise training in older adults may induce global CBF GM reductions when high cardiorespiratory fitness gains are induced, but this does not appear to affect cognitive functions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katrien Segaert reports financial support was provided by the Research Council of Norway. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Endothelial dysfunction is an early predictor of atherosclerosis and cardiovascular disease. Flow-mediated dilation (FMD) is the gold standard to assess endothelial function in humans. FMD reproducibility has been mainly assessed in the brachial artery (BA) with limited research in lower limb arteries. The purpose of this study was to compare FMD reproducibility in the upper limb BA and lower limb superficial femoral artery (SFA) in young healthy adults.Fifteen young healthy adults (nine males; six females) underwent FMD, resting diameter, velocity, and shear rate measurements on three occasions to determine intra-and inter-day reproducibility in both BA and SFA, assessed by coefficient of variation (CV), intraclass correlation coefficient (ICC), and Bland-Altman plots.BA FMD CVs (intra-day: 4.2%; inter-day: 8.7%) and ICCs (intra-day: 0.967; inter-day: 0.903) indicated excellent reproducibility and reliability, while for SFA FMD, both CVs (intra-day: 11.6%; inter-day: 26.7%) and ICCs (intra-day: 0.898; inter-day: 0.651) showed good/moderate reproducibility and reliability. BA FMD was significantly more reproducible than SFA FMD (p < 0.05). Diameter reproducibility was excellent and similar between arteries, while resting velocity and shear rate have lower reproducibility in the BA compared to SFA. Bland-Altman plots displayed no proportional and fixed bias between measurements.In summary, SFA FMD is less reproducible than BA FMD, with identical volume of ultrasound training. Given the increasing interest in using SFA FMD to test the efficacy of interventions targeting lower limb's vascular health and as a potential biomarker for peripheral arterial disease risk, future studies should ensure higher levels of training for adequate reproducibility., (© 2024. The Author(s).)

Joyce, Kelsey E., Catherine A. Campbell, Arthur R. Bradwell, Samuel J.E. Lucas, Christopher T. Lewis, Rebekah A.I. Lucas, and Mark Edsell. The environmental impact of a high-altitude medical research expedition. High Alt Med Biol. 00:00-00, 2024. Introduction: Scientists must begin examining the environmental cost(s) of their research. The purpose of this study was to evaluate a component of the environmental impact of a high-altitude medical research expedition by totaling the carbon dioxide (CO 2 ) emissions calculated from as many direct and indirect sources as possible. Methods: Eighteen individuals flew from London to Bagdogra (via Delhi), and then drove onward to Lachung (via Gangtok) where they began their ascent on foot to 4,800 m (Kanchenjunga National Park, Sikkim). Several research experiments were conducted throughout the expedition, which required use of a laboratory centrifuge, solid CO 2 (specimen storage), rechargeable laptop computers and battery-powered oximeters. International Civil Aviation Organization calculators estimated aviation CO 2 production. Land emissions were calculated for Mahindra vehicles. Solid waste was weighed and CO 2 emissions estimated for its incineration. Results : Total CO 2 emissions equated to ∼16.7 tonnes from the following sources: air and land transportation of expedition team (87.3%); sublimation and transportation of solid CO 2 (7.7%), waste incineration (0.58%), generator transportation and gasoline (12 l) combustion (0.48%), and battery transportation (3.3%). Conclusions : Air travel contributed the most to the overall environmental cost of the research expedition. Further investigation is required to contextualize these findings in relation to lab-based alternative(s).

Cerebral blood flow (CBF) and arterial transit time (ATT), markers of brain vascular health, worsen with age. The primary aim of this cross-sectional study was to identify modifiable determinants of CBF and ATT in healthy older adults ( n = 78, aged 60-81 years). Associations between cardiorespiratory fitness and CBF or ATT were of particular interest because the impact of cardiorespiratory fitness is not clear within existing literature. Secondly, this study assessed whether CBF or ATT relate to cognitive function in older adults. Multiple post-labelling delay pseudo-continuous arterial spin labelling estimated resting CBF and ATT in grey matter. Results from multiple linear regressions found higher BMI was associated with lower global CBF (β = -0.35, P = 0.008) and a longer global ATT (β = 0.30, P = 0.017), global ATT lengthened with increasing age (β = 0.43, P = 0.004), and higher cardiorespiratory fitness was associated with longer ATT in parietal (β = 0.44, P = 0.004) and occipital (β = 0.45, P = 0.003) regions. Global or regional CBF or ATT were not associated with processing speed, working memory, or attention. In conclusion, preventing excessive weight gain may help attenuate age-related declines in brain vascular health. ATT may be more sensitive to age-related decline than CBF, and therefore useful for early detection and management of cerebrovascular impairment. Finally, cardiorespiratory fitness appears to have little effect on CBF but may induce longer ATT in specific regions.

Introduction: Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect hematopoietic stem and progenitor cells (HSPCs) for hematopoietic stem cell transplantation. Single bouts of exercise transiently enrich peripheral blood with HSPCs and cytolytic natural killer cells (CD56 dim ), which are important in preventing post-transplant complications. To provide a rationale to investigate the utility of exercise in a PBSC donation setting (≈3 h), this study aimed to establish whether interval cycling increased peripheral blood HSPC and CD56 dim concentrations to a greater degree than continuous cycling., Methods: In a randomised crossover study design, eleven males (mean ± SD: age 25 ± 7 years) undertook bouts of moderate intensity continuous exercise [MICE, 30 min, 65%-70% maximum heart rate (HR max )], high-volume high intensity interval exercise (HV-HIIE, 4 × 4 min, 80%-85% HR max ) and low-volume HIIE (LV-HIIE, 4 × 2 min, 90%-95% HR max ). The cumulative impact of each interval on circulating HSPC (CD34 + CD45 dim SSC low ) and CD56 dim concentrations (cells/µL), and the bone marrow homing potential of HSPCs (expression of CXCR-4 and VLA-4) were determined., Results: There was an increase in HSPC concentration after two intervals of LV-HIIE (Rest: 1.84 ± 1.55 vs. Interval 2: 2.94 ± 1.34, P = 0.01) and three intervals of HV-HIIE only (Rest: 2.05 ± 0.86 vs. Interval 3: 2.51 ± 1.05, P = 0.04). The concentration of all leukocyte subsets increased after each trial, with this greatest for CD56 dim NK cells, and in HIIE vs. MICE (LV-HIIE: 4.77 ± 2.82, HV-HIIE: 4.65 ± 2.06, MICE: 2.44 ± 0.77, P < 0.0001). These patterns were observed for concentration, not frequency of CXCR-4 + and VLA-4 + HSPCs, which was unaltered. There was a marginal decrease in VLA-4, but not CXCR-4 expression on exercise-mobilised HSPCs after all trials ( P < 0.0001)., Discussion: The results of the present study indicate that HIIE caused a more marked increase in HSPC and CD56 dim NK cell concentrations than MICE, with mobilised HSPCs maintaining their bone marrow homing phenotype. LV-HIIE evoked an increase in HSPC concentration after just 2 × 2-minute intervals. The feasibility and clinical utility of interval cycling in a PBSC donation context should therefore be evaluated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pradana, Nijjar, Cox, Morgan, Podlogar, Lucas, Drayson, Kinsella and Wadley.)

Introduction: Mild traumatic brain injury (TBI) affects a significant number of military personnel, primarily because of physical impact, vehicle incidents, and blast exposure. Post-traumatic headache (PTH) is the most common symptom reported following mild TBI and can persist for several years. However, the current International Classification of Headache Disorders lacks phenotypic characterization for this specific headache disorder. It is important to appropriately classify the headache sub-phenotypes as it may enable more targeted management approaches. This systematic review seeks to identify the most common sub-phenotype of headaches in military personnel with PTH attributed to mild TBI., Methods: We conducted a systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines, focusing on the military population. PubMed, Web of Science, Cochrane, and Clinicaltrials.gov databases were searched. Abstracts and full texts were independently reviewed by two authors using predefined inclusion and exclusion criteria. Data extraction was performed using a standardized form. The risk of bias was assessed using the Newcastle-Ottawa Scale., Results: Eight papers related to the military population were included in this review. Migraine was the most commonly reported headache sub-phenotype, with a prevalence ranging from 33 to 92%. Additionally, one military study identified tension-type headaches as the most prevalent headache phenotype. Although not the primary phenotype, one military cohort reported that approximately one-third of their cohort experienced trigeminal autonomic cephalalgias, which were associated with exposure to blast injuries and prior concussions., Conclusion: This systematic review demonstrated that PTH in the military population frequently exhibit migraine-like features. Tension-type headache and trigeminal autonomic cephalalgias also occur, although less commonly reported. Sub-phenotyping PTH may be important for initiating effective treatment since different phenotypes may respond differently to medications. The study populations analyzed in this systematic review display heterogeneity, underscoring the necessity for additional research features, more stringent criteria and comprehensive recording of baseline characteristics. Characterizing headaches following injury is crucial for an accurate diagnosis to enable effective management and rehabilitation planning for our armed forces., (© The Association of Military Surgeons of the United States 2024.)

Background: This study aimed to investigate the effectiveness of a 6-month home-based high-intensity interval training (HIIT) intervention to improve peak oxygen consumption (V̇O 2 peak) and lactate threshold (LT) in older adults., Methods: Two hundred thirty-three healthy older adults (60-84 years; 54% females) were randomly assigned to either 6-month, thrice-weekly home-based HIIT (once-weekly circuit training and twice-weekly interval training) or a passive control group. Exercise sessions were monitored using a Polar watch and a logbook for objective and subjective data, respectively, and guided by a personal coach. The outcomes were assessed using a modified Balke protocol combining V̇O 2 peak and LT measures. General linear regression models assessed between-group differences in change and within-group changes for each outcome., Results: There was a significant between-group difference in the pre-to-post change in V̇O 2 peak (difference: 1.8 [1.2; 2.3] mL/kg/min; exercise: +1.4 [1.0; 1.7] mL/kg/min [~5%]; control: -0.4 [-0.8; -0.0] mL/kg/min [approximately -1.5%]; effect size [ES]: 0.35). Compared with controls, the exercise group had lower blood lactate concentration (-0.7 [-0.9; -0.4] mmol/L, ES: 0.61), % of peak heart rate (-4.4 [-5.7; -3.0], ES: 0.64), and % of V̇O 2 peak (-4.5 [-6.1; -2.9], ES: 0.60) at the intensity corresponding to preintervention LT and achieved a higher treadmill stage (% incline) at LT (0.6 [0.3; 0.8]; ES: 0.47), following the intervention., Conclusion: This study highlights the effectiveness of a home-based HIIT intervention as an accessible and equipment-minimal strategy to induce clinically meaningful improvements in cardiorespiratory fitness in older adults. Over 6 months, the exercise group showed larger improvements in all outcomes compared with the control group. Notably, the LT outcome exhibited a more pronounced magnitude of change than V̇O 2 peak., (© 2024 The Author(s). Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research., (© 2024. The Author(s).)

Purpose: To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). "Controller-gain" sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep., Methods: Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2-5 μg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR)., Results: A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P < 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1)., Conclusion: Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR "controller gain," rather than "plant gain," because PaCO 2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Spinal cord injuries (SCI) often result in cardiovascular issues, increasing the risk of stroke and cognitive deficits., Objectives: This study assessed cerebrovascular reactivity (CVR) using functional magnetic resonance imaging (fMRI) during a hypercapnic challenge in SCI participants compared to noninjured controls., Methods: Fourteen participants were analyzed ( n = 8 with SCI [unless otherwise noted], median age = 44 years; n = 6 controls, median age = 33 years). CVR was calculated through fMRI signal changes., Results: The results showed a longer CVR component (tau) in the grey matter of SCI participants ( n = 7) compared to controls (median difference = 3.0 s; p < .05). Time since injury (TSI) correlated negatively with steady-state CVR in the grey matter and brainstem of SCI participants ( R S = -0.81, p = .014; R S = -0.84, p = .009, respectively). Lower steady-state CVR in the brainstem of the SCI group ( n = 7) correlated with lower diastolic blood pressure ( R S = 0.76, p = .046). Higher frequency of hypotensive episodes ( n = 7) was linked to lower CVR outcomes in the grey matter ( R S = -0.86, p = .014) and brainstem ( R S = -0.89, p = .007)., Conclusion: Preliminary findings suggest a difference in the dynamic CVR component, tau, between the SCI and noninjured control groups, potentially explaining the higher cerebrovascular health burden in SCI individuals. Exploratory associations indicate that longer TSI, lower diastolic blood pressure, and more hypotensive episodes may lead to poorer CVR outcomes. However, further research is necessary to establish causality and support these observations., (© 2024 American Spinal Injury Association.)

Aim: The present systematic review and meta-analysis aimed to compare the effect of moderate- versus high-intensity aerobic exercise on cardiorespiratory fitness (CRF) in older adults, taking into account the volume of exercise completed., Methods: The databases MEDLINE (Ovid), EMBASE (Ovid), and CENTRAL (Cochrane Library) were searched to identify randomized controlled trials (RCTs). Two reviewers extracted data and assessed bias. Comprehensive Meta-Analysis software calculated overall effect size, intensity differences, and performed meta-regression analyses using pre-to-post intervention or change scores of peak oxygen uptake (V̇O 2 peak). The review included 23 RCTs with 1332 older adults (intervention group: n = 932; control group: n = 400), divided into moderate-intensity (435 older adults) and high-intensity (476 older adults) groups., Results: Meta-regression analysis showed a moderate, but not significant, relationship between exercise intensity and improvements in V̇O 2 peak after accounting for the completed exercise volume (β = 0.31, 95% CI = [-0.04; 0.67]). Additionally, studies comparing moderate- versus high-intensity revealed a small, but not significant, effect in favor of high-intensity (Hedges' g = 0.20, 95% CI = [-0.02; 0.41]). Finally, no significant differences in V̇O 2 peak improvements were found across exercise groups employing various methods, modalities, and intensity monitoring strategies., Conclusion: Findings challenge the notion that high-intensity exercise is inherently superior and indicate that regular aerobic exercise, irrespective of the specific approach and intensity, provides the primary benefits to CRF in older adults. Future RCTs should prioritize valid and reliable methodologies for monitoring and reporting exercise volume and adherence among older adults., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Heat and cold stress influence cerebral blood flow (CBF) regulatory factors (e.g., arterial CO 2 partial pressure). However, it is unclear whether the CBF response to a CO 2 stimulus (i.e., cerebrovascular-CO 2 responsiveness) is maintained under different thermal conditions. This study aimed to compare cerebrovascular-CO 2 responsiveness between normothermia, passive heat, and cold stress conditions. Sixteen participants (8 females; 25 ± 7 yr) completed two experimental sessions (randomized) comprising normothermic and either passive heat or cold stress conditions. Middle and posterior cerebral artery velocity (MCA v , PCA v ) were measured during rest, hypercapnia (5% CO 2 inhalation), and hypocapnia (voluntary hyperventilation to an end-tidal CO 2 of 30 mmHg). The linear slope of the cerebral blood velocity (CB v ) response to changing end-tidal CO 2 was calculated to measure cerebrovascular-CO 2 responsiveness, and cerebrovascular conductance (CVC) was used to examine responsiveness independent of blood pressure. CB v -CVC-CO 2 responsiveness to hypocapnia was greater during heat stress compared with cold stress (MCA: +0.05 ± 0.08 cm/s/mmHg/mmHg, P = 0.04; PCA: +0.02 ± 0.02 cm/s/mmHg/mmHg, P = 0.002). CB v -CO 2 responsiveness to hypercapnia decreased during heat stress (MCA: -0.67 ± 0.89 cm/s/mmHg, P = 0.02; PCA: -0.64 ± 0.62 cm/s/mmHg; P = 0.01) and increased during cold stress (MCA: +0.98 ± 1.33 cm/s/mmHg, P = 0.03; PCA: +1.00 ± 0.82 cm/s/mmHg; P = 0.01) compared with normothermia. However, CB v -CVC-CO 2 responsiveness to hypercapnia was not different between thermal conditions ( P > 0.08). Overall, passive heat, but not cold, stress challenges the maintenance of cerebral perfusion. A greater cerebrovascular responsiveness to hypocapnia during heat stress likely reduces an already impaired cerebrovascular reserve capacity and may contribute to adverse events (e.g., syncope). NEW & NOTEWORTHY This study demonstrates that thermoregulatory-driven perfusion pressure changes, from either cold or heat stress, impact cerebrovascular responsiveness to hypercapnia. Compared with cold stress, heat stress poses a greater challenge to the maintenance of cerebral perfusion during hypocapnia, challenging cerebrovascular reserve capacity while increasing cerebrovascular-CO 2 responsiveness. This likely exacerbates cerebral hypoperfusion during heat stress since hyperthermia-induced hyperventilation results in hypocapnia. No regional differences in middle and posterior cerebral artery responsiveness were found with thermal stress.

Background: A low level of cardiorespiratory fitness [CRF; defined as peak oxygen uptake ([Formula: see text]O2peak) or peak power output (PPO)] is a widely reported consequence of spinal cord injury (SCI) and a major risk factor associated with chronic disease. However, CRF can be modified by exercise. This systematic review with meta-analysis and meta-regression aimed to assess whether certain SCI characteristics and/or specific exercise considerations are moderators of changes in CRF., Methods and Findings: Databases (MEDLINE, EMBASE, CENTRAL, and Web of Science) were searched from inception to March 2023. A primary meta-analysis was conducted including randomised controlled trials (RCTs; exercise interventions lasting >2 weeks relative to control groups). A secondary meta-analysis pooled independent exercise interventions >2 weeks from longitudinal pre-post and RCT studies to explore whether subgroup differences in injury characteristics and/or exercise intervention parameters explained CRF changes. Further analyses included cohort, cross-sectional, and observational study designs. Outcome measures of interest were absolute (A[Formula: see text]O2peak) or relative [Formula: see text]O2peak (R[Formula: see text]O2peak), and/or PPO. Bias/quality was assessed via The Cochrane Risk of Bias 2 and the National Institute of Health Quality Assessment Tools. Certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random effects models were used in all meta-analyses and meta-regressions. Of 21,020 identified records, 120 studies comprising 29 RCTs, 67 pre-post studies, 11 cohort, 7 cross-sectional, and 6 observational studies were included. The primary meta-analysis revealed significant improvements in A[Formula: see text]O2peak [0.16 (0.07, 0.25) L/min], R[Formula: see text]O2peak [2.9 (1.8, 3.9) mL/kg/min], and PPO [9 (5, 14) W] with exercise, relative to controls (p < 0.001). Ninety-six studies (117 independent exercise interventions comprising 1,331 adults with SCI) were included in the secondary, pooled meta-analysis which demonstrated significant increases in A[Formula: see text]O2peak [0.22 (0.17, 0.26) L/min], R[Formula: see text]O2peak [2.8 (2.2, 3.3) mL/kg/min], and PPO [11 (9, 13) W] (p < 0.001) following exercise interventions. There were subgroup differences for R[Formula: see text]O2peak based on exercise modality (p = 0.002) and intervention length (p = 0.01), but there were no differences for A[Formula: see text]O2peak. There were subgroup differences (p ≤ 0.018) for PPO based on time since injury, neurological level of injury, exercise modality, and frequency. The meta-regression found that studies with a higher mean age of participants were associated with smaller changes in A[Formula: see text]O2peak and R[Formula: see text]O2peak (p < 0.10). GRADE indicated a moderate level of certainty in the estimated effect for R[Formula: see text]O2peak, but low levels for A[Formula: see text]O2peak and PPO. This review may be limited by the small number of RCTs, which prevented a subgroup analysis within this specific study design., Conclusions: Our primary meta-analysis confirms that performing exercise >2 weeks results in significant improvements to A[Formula: see text]O2peak, R[Formula: see text]O2peak, and PPO in individuals with SCI. The pooled meta-analysis subgroup comparisons identified that exercise interventions lasting up to 12 weeks yield the greatest change in R[Formula: see text]O2peak. Upper-body aerobic exercise and resistance training also appear the most effective at improving R[Formula: see text]O2peak and PPO. Furthermore, acutely injured, individuals with paraplegia, exercising for ≥3 sessions/week will likely experience the greatest change in PPO. Ageing seemingly diminishes the adaptive CRF responses to exercise training in individuals with SCI., Registration: PROSPERO: CRD42018104342., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hodgkiss et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Idiopathic intracranial hypertension (IIH) is a disease characterised by elevated intracranial pressure (ICP). The impact of straining and exercise on ICP regulation is poorly understood yet clinically relevant to IIH patient care. We sought to investigate the impact of Valsalva manoeuvres (VMs) and exercise on ICP and cerebrovascular haemodynamics in IIH. People with IIH were prospectively enrolled and had an intraparenchymal telemetric ICP sensor inserted. Three participants (age [mean ± standard deviation]: 40.3 ± 13.9 years) underwent continuous real-time ICP monitoring coupled with cerebrovascular haemodynamic assessments during VMs and moderate exercise. Participants had IIH with supine ICP measuring 15.3 ± 8.7 mmHg (20.8 ± 11.8 cm cerebrospinal fluid (CSF)) and sitting ICP measuring -4.2 ± 7.9 mmHg (-5.7 ± 10.7 cmCSF). During phase I of a VM ICP increased by 29.4 ± 13.5 mmHg (40.0 ± 18.4 cmCSF) but returned to baseline within 16 seconds from VM onset. The pattern of ICP changes during the VM phases was associated to that of changes in blood pressure, the middle cerebral artery blood velocity and prefrontal cortex haemodynamics. Exercise led to minimal effects on ICP. In conclusion, VM-induced changes in ICP were coupled to cerebrovascular haemodynamics and showed no sustained impact on ICP. Exercise did not lead to prolonged elevation of ICP. Those with IIH experiencing VMs (for example, during exercise and labour) may be reassured at the brief nature of the changes. Future research must look to corroborate the findings in a larger IIH cohort., Competing Interests: AY reports receiving speaker fees from Teva, UK, outside the submitted work. SPM reports other Invex Therapeutics, other Heidelberg engineering during the conduct of the study; other from Chugai-Roche Ltd, other from Janssen, other from Allergan, other from Santen, other from Roche, and other from Neurodiem, outside the submitted work. AJS reports personal fees from Invex therapeutics in her role as Director with stock holdings, during the conduct of the study; other fees from Allergan, Novartis, Cheisi and Amgen outside the submitted work. The other authors report no conflicts of interest. The views expressed are those of the authors and not necessarily those of the UK National Health Service, MoD, NIHR, or the UK department of Health and Social Care. Role of Funder/Sponsor: The MoD, NIHR and the MRC had no role in the design or conduct of the study; no role in collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript; and no role in the decision to submit the manuscript for publication in the design, execution or write up of this sub-study of the trial., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Small extracellular vesicles (sEVs) are released from all cell types and participate in the intercellular exchange of proteins, lipids, metabolites and nucleic acids. Proteomic, flow cytometry and nanoparticle tracking analyses suggest sEVs are released into circulation with exercise. However, interpretation of these data may be influenced by sources of bias introduced by different analytical approaches. Seven healthy participants carried out a high intensity intermittent training (HIIT) cycle protocol consisting of 4 × 30 s at a work-rate corresponding to 200% of individual max power (watts) interspersed by 4.5 min of active recovery. EDTA-treated blood was collected before and immediately after the final effort. Platelet-poor (PPP) and platelet-free (PFP) plasma was derived by one or two centrifugal spins at 2500 g, respectively (15 min, room temperature). Platelets were counted on an automated haemocytometer. Plasma samples were assessed with the Exoview R100 platform, which immobilises sEVs expressing common tetraspanin markers CD9, CD63, CD81 and CD41a on microfluidic chips and with the aid of fluorescence imaging, counts their abundance at a single sEV resolution, importantly, without a pre-isolation step. There was a lower number of platelets in the PFP than PPP, which was associated with a lower number of CD9, CD63 and CD41a positive sEVs. HIIT induced an increase in fluorescence counts in CD9, CD63 and CD81 positive sEVs in both PPP and PFP. These data support the concept that sEVs are released into circulation with exercise. Furthermore, platelet-free plasma is the preferred, representative analyte to study sEV dynamics and phenotype during exercise. KEY POINTS: Small extracellular vesicles (sEV) are nano-sized particles containing protein, metabolites, lipid and RNA that can be transferred from cell to cell. Previous findings implicate that sEVs are released into circulation with exhaustive, aerobic exercise, but since there is no gold standard method to isolate sEVs, these findings may be subject to bias introduced by different approaches. Here, we use a novel method to immobilise and image sEVs, at single-vesicle resolution, to show sEVs are released into circulation with high intensity intermittent exercise. Since platelet depletion of plasma results in a reduction in sEVs, platelet-free plasma is the preferred analyte to examine sEV dynamics and phenotype in the context of exercise., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Mental stress has been associated with cardiovascular events and stroke, and has also been linked with poorer brain function, likely due to its impact on cerebral vasculature. During periods of stress, individuals often increase their consumption of unhealthy foods, especially high-fat foods. Both high-fat intake and mental stress are known to impair endothelial function, yet few studies have investigated the effects of fat consumption on cerebrovascular outcomes during periods of mental stress. Therefore, this study examined whether a high-fat breakfast prior to a mental stress task would alter cortical oxygenation and carotid blood flow in young healthy adults. In a randomised, counterbalanced, cross-over, postprandial intervention study, 21 healthy males and females ingested a high-fat (56.5 g fat) or a low-fat (11.4 g fat) breakfast 1.5 h before an 8-min mental stress task. Common carotid artery (CCA) diameter and blood flow were assessed at pre-meal baseline, 1 h 15 min post-meal at rest, and 10, 30, and 90 min following stress. Pre-frontal cortex (PFC) tissue oxygenation (near-infrared spectroscopy, NIRS) and cardiovascular activity were assessed post-meal at rest and during stress. Mental stress increased heart rate, systolic and diastolic blood pressure, and PFC tissue oxygenation. Importantly, the high-fat breakfast reduced the stress-induced increase in PFC tissue oxygenation, despite no differences in cardiovascular responses between high- and low-fat meals. Fat and stress had no effect on resting CCA blood flow, whilst CCA diameter increased following consumption of both meals. This is the first study to show that fat consumption may impair PFC perfusion during episodes of stress in young healthy adults. Given the prevalence of consuming high-fat foods during stressful periods, these findings have important implications for future research to explore the relationship between food choices and cerebral haemodynamics during mental stress.

The strength model of self-control purports to explain why brief cognitive response inhibition tasks impair subsequent isometric handgrip endurance. According to the model, ego depleting tasks requiring self-control resources impair performance on subsequent tasks that also require self-control resources. However, several lines of evidence challenge this model, including evidence of improved exercise performance following longer cognitive tasks. Our study investigated the effects of cognitive task duration on (1) subsequent physical endurance performance, (2) concurrent cognitive task performance, and (3) subsequent novel cognitive task performance. Adopting an experimental design, with Stroop task type (incongruent, congruent) and duration (5, 10, 20 min) as between-participant factors, participants (N = 180) completed a color word Stroop task, an isometric handgrip to exhaustion task, and a novel 5-min incongruent number word Stroop task. In the handgrip task, endurance performance was worse following incongruent word Stroop than congruent word Stroop for 10-min tasks but not 5-min and 20-min tasks. In the word Stroop task, accuracy was lower and speed was slower following incongruent word Stroop than congruent word Stroop. Importantly, reaction times improved with longer task durations. In the novel number Stroop task, accuracy was higher following incongruent word Stroop than congruent word Stroop. In conclusion, the finding that the ego depletion effect was moderated by cognitive task duration is better explained by the expected value of control model than the strength model., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and aims: Sex differences in the rate and occurrence of cerebrovascular diseases (e.g., stroke) indicate a role for female sex hormones (i.e., oestrogen and progesterone) in cerebrovascular function and regulation. However, it remains unclear how cerebrovascular function differs between the sexes, and between distinct phases of the menstrual cycle. This study aimed to compare cerebrovascular-CO 2 responsiveness in 1) females during the early follicular (EF), ovulatory (O) and mid-luteal (ML) phases of their menstrual cycle; and 2) males compared to females during phases of lower oestrogen (EF) and higher oestrogen (O). Methods: Eleven females (25 ± 5 years) complete experimental sessions in the EF ( n = 11), O ( n = 9) and ML ( n = 11) phases of the menstrual cycle. Nine males (22 ± 3 years) completed two experimental sessions, approximately 2 weeks apart for comparison to females. Middle and posterior cerebral artery velocity (MCAv, PCAv) was measured at rest, during two stages of hypercapnia (2% and 5% CO 2 inhalation) and hypocapnia (voluntary hyperventilation to an end-tidal CO 2 of 30 and 24 mmHg). The linear slope of the cerebral blood velocity response to changes in end-tidal CO 2 was calculated to measure cerebrovascular-CO 2 responsiveness.. Results: In females, MCAv-CO 2 responsiveness to hypocapnia was lower during EF (-.78 ± .45 cm/s/mmHg) when compared to the O phase (-1.17 ± .52 cm/s/mmHg; p < .05) and the ML phase (-1.30 ± .82; p < .05). MCAv-CO 2 responsiveness to hypercapnia and hypo-to-hypercapnia, and PCAv-CO 2 responsiveness across the CO 2 range were similar between menstrual phases ( p ≥ .20). MCAv-CO 2 responsiveness to hypo-to hypercapnia was greater in females compared to males (3.12 ± .91 cm/s/mmHg vs. 2.31 ± .46 cm/s/mmHg; p = .03), irrespective of menstrual phase (EF or O). Conclusion: Females during O and ML phases have an enhanced vasoconstrictive capacity of the MCA compared to the EF phase. Additionally, biological sex differences can influence cerebrovascular-CO 2 responsiveness, dependent on the insonated vessel., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Skinner, Weaver, Lucas and Lucas.)

The most common non-pharmacological intervention for both peripheral and cerebral vascular health is regular physical activity (e.g., exercise training), which improves function across a range of exercise intensities and modalities. Numerous non-exercising approaches have also been suggested to improved vascular function, including repeated ischemic preconditioning (IPC); heat therapy such as hot water bathing and sauna; and pneumatic compression. Chronic adaptive responses have been observed across a number of these approaches, yet the precise mechanisms that underlie these effects in humans are not fully understood. Acute increases in blood flow and circulating signalling factors that induce responses in endothelial function are likely to be key moderators driving these adaptations. While the impact on circulating factors and environmental mechanisms for adaptation may vary between approaches, in essence, they all centre around acutely elevating blood flow throughout the circulation and stimulating improved endothelium-dependent vascular function and ultimately vascular health. Here, we review our current understanding of the mechanisms driving endothelial adaptation to repeated exposure to elevated blood flow, and the interplay between this response and changes in circulating factors. In addition, we will consider the limitations in our current knowledge base and how these may be best addressed through the selection of more physiologically relevant experimental models and research. Ultimately, improving our understanding of the unique impact that non-pharmacological interventions have on the vasculature will allow us to develop superior strategies to tackle declining vascular function across the lifespan, prevent avoidable vascular-related disease, and alleviate dependency on drug-based interventions., (© 2022. The Author(s).)

Although mentally fatiguing cognitive tasks can impair subsequent physical endurance, the importance of cognitive task duration and the role of response inhibition remain unclear. This study compared the effects of a serial incongruent Stroop color-classification task (i.e., with response inhibition) and N-back memory updating task (i.e., without response inhibition) on mental fatigue and subsequent rhythmic handgrip exercise. Participants (N = 90) were randomly assigned to one of three cognitive task groups (Stroop, 2-back, control) and completed four 10-min blocks of one cognitive task followed by a 5-min physical endurance task (self-paced rhythmic handgrip exercise). Heart rate, heart rate variability, electromyographic forearm activity, and force were recorded throughout along with self-reported measures of fatigue, exertion, and motivation. From the start, the Stroop and 2-back tasks elicited higher heart rate and lower heart rate variability as well as greater fatigue, effort, and interest/enjoyment than the control task. From the second block onwards, the Stroop and 2-back groups produced less force than the control group. There were no group differences in forearm muscle activity. In sum, mental fatigue was induced after performing a cognitive task for 10 mins, whereas muscular endurance was impaired after performing a cognitive task for 20 mins. That these effects were observed for both types of cognitive task indicates that response inhibition is not a necessary condition. The cognitive task duration required to induce mental fatigue and impair rhythmic handgrip endurance performance lay between the durations reported previously for isometric (a few minutes) and whole-body (half an hour) endurance exercise., (© 2022 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

The growing prevalence of physical inactivity in the population highlights the urgent need for a more comprehensive understanding of how sedentary behaviour affects health, the mechanisms involved and what strategies are effective in counteracting its negative effects. Physical inactivity is an independent risk factor for different pathologies including atherosclerosis, hypertension and cardiovascular disease. It is known to progressively lead to reduced life expectancy and quality of life, and it is the fourth leading risk factor for mortality worldwide. Recent evidence indicates that uninterrupted prolonged sitting and short-term inactivity periods impair endothelial function (measured by flow-mediated dilation) and induce arterial structural alterations, predominantly in the lower body vasculature. Similar effects may occur in the cerebral vasculature, with recent evidence showing impairments in cerebral blood flow following prolonged sitting. The precise molecular and physiological mechanisms underlying inactivity-induced vascular dysfunction in humans are yet to be fully established, although evidence to date indicates that it may involve modulation of shear stress, inflammatory and vascular biomarkers. Despite the steady increase in sedentarism in our societies, only a few intervention strategies have been investigated for their efficacy in counteracting the associated vascular impairments. The current review provides a comprehensive overview of the evidence linking acute and short-term physical inactivity to detrimental effects on peripheral, central and cerebral vascular health in humans. We further examine the underlying molecular and physiological mechanisms and attempt to link these to long-term consequences for cardiovascular health. Finally, we summarize and discuss the efficacy of lifestyle interventions in offsetting the negative consequences of physical inactivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daniele, Lucas and Rendeiro.)

Talks, Benjamin James, Catherine Campbell, Stephanie J. Larcombe, Lucy Marlow, Sarah L. Finnegan, Christopher T. Lewis, Samuel J.E. Lucas, Olivia K. Harrison, and Kyle T.S. Pattinson. Baseline psychological traits contribute to Lake Louise Acute Mountain Sickness score at high altitude. High Alt Med Biol. 23:69-77, 2022. Background: Interoception refers to an individual's ability to sense their internal bodily sensations. Acute mountain sickness (AMS) is a common feature of ascent to high altitude that is only partially explained by measures of peripheral physiology. We hypothesized that interoceptive ability may explain the disconnect between measures of physiology and symptom experience in AMS. Methods: Two groups of 18 participants were recruited to complete a respiratory interoceptive task three times at 2-week intervals. The control group remained in Birmingham (140 m altitude) for all three tests. The altitude group completed test 1 in Birmingham, test 2 the day after arrival at 2,624 m, and test 3 at 2,728 m after an 11-day trek at high altitude (up to 4,800 m). Results: By measuring changes to metacognitive performance, we showed that acute ascent to altitude neither presented an interoceptive challenge, nor acted as interoceptive training. However, AMS symptom burden throughout the trek was found to relate to sea level measures of anxiety, agoraphobia, and neuroticism. Conclusions: This suggests that the Lake Louise AMS score is not solely a reflection of physiological changes on ascent to high altitude, despite often being used as such by researchers and commercial trekking companies alike.

Proteinuria is a transient physiological phenomenon that occurs with a range of physical activities and during ascent to altitude. Exercise intensity appears to dictate the magnitude of postexercise proteinuria; however, evidence also indicates the possible contributions from exercise-induced hypoxemia or reoxygenation. Using an environmental hypoxic chamber, this crossover-designed study aimed to evaluate urinary alpha-1 acid glycoprotein (α1-AGP) excretion pre/postexercise performed in hypoxia (HYP) and normoxia (NOR). Sixteen individuals underwent experimental sessions in normoxia (NOR, 20.9% O 2 ) and hypoxia (HYP, 12.0% O 2 ). Sessions began with a 2-h priming period before completing a graded maximal exercise test (GXT) on a cycle ergometer, which was followed by continuation of exposure for an additional 2 h. Physiological responses (i.e., blood pressure, heart rate, and peripheral oxygenation), Lake Louise Scores (LLSs), and urine specimens (analyzed for albumin and α1-AGP) were collected pre- and postexercise (after 30, 60, and 120 min). Peak power output was significantly reduced in HYP (193 ± 45 W) compared with NOR (249 ± 59 W, P < 0.01). Postexercise urinary α1-AGP was greater in NOR (20.04 ± 14.84 µg·min -1 ) than in HYP (15.08 ± 13.46 µg·min -1 ), albeit the difference was not significant ( P > 0.05). Changes in urinary α1-AGP from pre- to post-30 min were not related to physiological responses or performance outcomes observed during GXT in NOR or HYP. Despite profound systemic hypoxemia with maximal exercise in hypoxia, postexercise α1-AGP excretion was not elevated above the levels observed following normoxic exercise. NEW & NOTEWORTHY By superimposing hypoxic exposure and maximal exercise, we were able to investigate the impact of hypoxia on postexercise proteinuria. Urinalysis for α1-AGP (via particle-enhanced immunoturbidimetry) in specimens collected pre-/postexercise enabled the sensitive detection of altered glomerular permeability. Data indicated that exercise intensity, rather than the degree of exercise-induced hypoxemia, determines postexercise proteinuria.

In 1959, Niels Lassen illustrated the cerebral autoregulation curve in the classic review article entitled Cerebral Blood Flow and Oxygen Consumption in Man. This concept suggested a relatively broad mean arterial pressure range (~60-150 mmHg) wherein cerebral blood flow remains constant. However, the assumption that this wide cerebral autoregulation plateau could be applied on a within-individual basis is incorrect and greatly variable between individuals. Indeed, each data point on the autoregulatory curve originated from independent samples of participants and patients and represented interindividual relationships between cerebral blood flow and mean arterial pressure. Nonetheless, this influential concept remains commonly cited and illustrated in various high-impact publications and medical textbooks, and is frequently taught in medical and science education without appropriate nuances and caveats. Herein, we provide the rationale and additional experimental data supporting the notion we need to lose this dogmatic view of cerebral autoregulation., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: The purpose of this study was to investigate the effect of sex on the efficacy of intermittent post-exercise sauna bathing to induce heat acclimation and improve markers of temperate exercise performance in trained athletes., Methods: Twenty-six trained runners (16 female; mean ± SD, age 19 ± 1 years, V̇O 2max F: 52.6 ± 6.9 mL⋅kg -1 ⋅min -1 , M: 64.6 ± 2.4 mL⋅kg -1 ⋅min -1 ) performed a running heat tolerance test (30 min, 9 km⋅h -1 /2% gradient, 40 °C/40%RH; HTT) and temperate (18 °C) exercise tests (maximal aerobic capacity [V̇O 2max ] and lactate profile) pre and post 3 weeks of normal exercise training plus 29 ± 1 min post-exercise sauna bathing (101-108 °C) 3 ± 1 times per week., Results: Females and males exhibited similar reductions (interactions p > 0.05) in peak rectal temperature (- 0.3 °C; p < 0.001), skin temperature (- 0.9 °C; p < 0.001) and heart rate (- 9 beats·min -1 ; p = 0.001) during the HTT at post- vs pre-intervention. Only females exhibited an increase in active sweat glands on the forearm (measured via modified iodine technique; F: + 57%, p < 0.001; M: + 1%, p = 0.47). Conversely, only males increased forearm blood flow (measured via venous occlusion plethysmography; F: + 31%, p = 0.61; M: + 123%; p < 0.001). Females and males showed similar (interactions p > 0.05) improvements in V̇O 2max (+ 5%; p = 0.02) and running speed at 4 mmol·L -1 blood lactate concentration (+ 0.4 km·h -1 ; p = 0.001)., Conclusions: Three weeks of post-exercise sauna bathing effectively induces heat acclimation in females and males, though possibly amid different thermoeffector adaptations. Post-exercise sauna bathing is also an effective ergogenic aid for both sexes., (© 2021. The Author(s).)

Key Points: We investigated the influence of arterial PCO 2 (PaCO 2 ) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO 2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO 3 - ). Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO 3 - ] (i.e. buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H + ]/pH were consistent with the altered relationship between PaCO 2 and [H + ]/pH following ACZ at high altitude (i.e. leftward x-intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO 2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO 2 rather than arterial pH., Abstract: Alterations in acid-base balance with progressive acclimatization to high altitude have been well-established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid-base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ -0.07 ± 0.04 and base excess: Δ -5.7 ± 1.9 mEq⋅l -1 , trial effects: P < 0.001 and P < 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO 3 - ; pH: Δ -0.01 ± 0.04 and base excess: Δ -1.5 ± 2.1 mEq⋅l -1 , trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO 2 (PaCO 2 ), i.e. cerebrovascular CO 2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. Δ -3.4 ± 2.3 mmHg PaCO 2 , trial effect: P < 0.001) was sufficient to offset any elevations in CBF induced via the ACZ-mediated metabolic acidosis. Between trials at high altitude, we observed consistent leftward shifts in both the PaCO 2 -pH and CBV-pH responses across the CO 2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO 2 - rather than pH - the absolute CBV and sensitivity of CBV-PaCO 2 was unchanged between trials at high altitude. Taken together, following acclimatization, CO 2 -mediated changes in cerebrovascular tone rather than arterial [H + ]/pH is integral to CBF regulation at high altitude., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Introduction: Resting cerebral blood flow (CBF) and perfusion measures have been used to determine brain health. Studies showing variation in resting CBF with age and fitness level using different imaging approaches have produced mixed findings. We assess the degree to which resting CBF measures through transcranial Doppler (TCD) and arterial spin labeling (ASL) MRI provide complementary information in older and younger, fit and unfit cohorts., Methods: Thirty-five healthy volunteers (20 younger: 24 ± 7y; 15 older: 66 ± 7y) completed two experimental sessions (TCD/MRI). Aging and fitness effects within and between imaging modalities were assessed., Results: Middle cerebral artery blood velocity (MCAv, TCD) was lower and transit time (MRI) slower in older compared with younger participants (p < .05). The younger group had higher gray matter cerebral perfusion (MRI) than the older group, albeit not significantly (p = .13). Surprisingly, fitness effects in the younger group (decrease/increase in MCAv/transit time with fitness, respectively) opposed the older group (increase/decrease in MCAv/transit time). Whole cohort transit times correlated with MCAv (r=-0.63; p < .05), whereas tissue perfusion did not correlate with TCD measures., Conclusion: TCD and MRI modalities provide complementary resting CBF measures, with similar effects across the whole cohort and between subgroups (age/fitness) if metrics are comparable (e.g., velocity [TCD] versus transit time [MRI])., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Resistance exercise (RE) is a popular modality for the general population and athletes alike, due to the numerous benefits of regular participation. The acute response to dynamic RE is characterised by temporary and bidirectional physiological extremes, not typically seen in continuous aerobic exercise (e.g. cycling) and headlined by phasic perturbations in blood pressure that challenge cerebral blood flow (CBF) regulation. Cerebral autoregulation has been heavily scrutinised over the last decade with new data challenging the effectiveness of this intrinsic flow regulating mechanism, particularly to abrupt changes in blood pressure over the course of seconds (i.e. dynamic cerebral autoregulation), like those observed during RE. Acutely, RE can challenge CBF regulation, resulting in adverse responses (e.g. syncope). Compared with aerobic exercise, RE is relatively understudied, particularly high-intensity dynamic RE with a concurrent Valsalva manoeuvre (VM). However, the VM alone challenges CBF regulation and generates additional complexity when trying to dissociate the mechanisms underpinning the circulatory response to RE. Given the disparate circulatory response between aerobic and RE, primarily the blood pressure profiles, regulation of CBF is ostensibly different. In this review, we summarise current literature and highlight the acute physiological responses to RE, with a focus on the cerebral circulation.

Cerebrovascular reactivity (CVR) is used as an outcome measure of brain health. Traditionally, lower CVR is associated with ageing, poor fitness and brain-related conditions (e.g. stroke, dementia). Indeed, CVR is suggested as a biomarker for disease risk. However, recent findings report conflicting associations between ageing or fitness and CVR measures. Inconsistent findings may relate to different neuroimaging modalities used, which include transcranial Doppler (TCD) and blood-oxygen-level-dependant (BOLD) contrast magnetic resonance imaging (MRI). We assessed the relationship between CVR metrics derived from two common imaging modalities, TCD and BOLD MRI, within the same individuals and with expected significant differences (i.e., younger vs. older) to maximise the expected spread in measures. We conducted two serial studies using TCD- and MRI-derived measures of CVR (via inspired 5% CO 2 in air). Study 1 compared 20 younger (24 ± 7 years) with 15 older (66 ± 7 years) participants, Study 2 compared 10 younger (22 ± 2 years) with 10 older (72 ± 4 years) participants. Combining the main measures across studies, no significant correlation ( r = 0.15, p = 0.36) was observed between individual participant TCD- and BOLD-CVR measures. Further, these measures showed differential effects between age groups; with TCD-CVR higher in the older compared to younger group (4 ± 1 vs. 3 ± 1 %MCAv/mmHg P ET CO 2 ; p < 0.05, Hedges' g = 0.75), whereas BOLD-CVR showed no difference ( p = 0.104, Hedges' g = 0.38). In Study 2 additional measures were obtained to understand the origin of the discrepancy: phase contrast angiography (PCA) MRI of the middle cerebral artery, showed a significantly lower blood flow (but not velocity) CVR response in older compared with younger participants ( p > 0.05, Hedges' g = 1.08). The PCA CVR metrics did not significantly correlate with the BOLD- or TCD-CVR measures. The differing CVR observations between imaging modalities were despite expected, correlated ( r = 0.62-0.82), age-related differences in resting CBF measures across modalities. Taken together, findings across both studies show no clear relationship between TCD- and BOLD-CVR measures. We hypothesize that CVR differences between imaging modalities are in part due to the aspects of the vascular tree that are assessed (TCD:arteries; BOLD:venules/veins). Further work is needed to understand the between-modality CVR response differences, but caution is needed when comparing CVR metrics derived from different imaging modalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Burley, Francis, Thomas, Whittaker, Lucas and Mullinger.)

Objectives: Mental fatigue impairs endurance exercise. Brain endurance training (BET) - engaging in cognitively fatiguing tasks during exercise - can develop resilience to mental fatigue and improve physical performance over physical training alone. The mechanism for this effect is unknown. This experiment examines if BET enhances performance over physical training and investigates potential underlying physiological mechanisms., Design: A mixed design randomised control trial., Methods: Pre- and post-testing: 36 participants completed dynamic rhythmic muscular endurance handgrip tasks requiring generation of as much force as possible once a second for 300s, performed under 3 counterbalanced conditions: following 600s of a 2-back memory/attention task (subsequent); while performing a 2-back task (concurrent); and on its own (solo). Cardiac activity, electromyographic forearm activity, pre-frontal cerebral haemodynamics (near infrared spectroscopy), and force were recorded. Training: Participants (randomised to a Control or BET group) completed 24 (6 weeks) submaximal hand contractions sessions. The BET group also completed concurrent cognitive tasks (2-back, Stroop). Measures of motivation, physical and mental exertion and mental fatigue were collected throughout., Results: Endurance performance, across the 3 tasks, improved more following BET (32%) than Control (12%) (p<0.05). The better performance following BET occurred with a higher pre-frontal oxygenation during the post-training physical tasks over time relative to Control (p<0.05)., Conclusions: Concurrent BET improved endurance performance over physical training alone. This was accompanied by a training-induced maintenance of pre-frontal oxygenation, suggestive of reduced mental effort during physical activity., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Purpose: Red wine polyphenols (RWP) are plant-based molecules that have been extensively studied in relation to their protective effects on vascular health in both animals and humans. The aim of this review was to quantify and compare the efficacy of RWP and pure resveratrol on outcomes measures of vascular health and function in both animals and humans., Methods: Comprehensive database searches were carried out through PubMed, Web of Science and OVID for randomised, placebo-controlled studies in both animals and humans. Meta-analyses were carried out on acute and chronic studies of RWP in humans, alongside sub-group analysis where possible. Risk-of-bias assessment was carried out for all included studies based on randomisation, allocation, blinding, outcome data reporting, and other biases., Results: 48 animal and 37 human studies were included in data extraction following screening. Significant improvements in measures of blood pressure and vascular function following RWP were seen in 84% and 100% of animal studies, respectively. Human studies indicated significant improvements in systolic blood pressure overall (- 2.6 mmHg, 95% CI: [- 4.8, - 0.4]), with a greater improvement in pure-resveratrol studies alone (- 3.7 mmHg, 95% CI: [- 7.3, - 0.0]). No significant effects of RWP were seen in diastolic blood pressure or flow-mediated dilation (FMD) of the brachial artery., Conclusion: RWP have the potential to improve vascular health in at risk human populations, particularly in regard to lowering systolic blood pressure; however, such benefits are not as prevalent as those observed in animal models.

Purpose: This study investigated whether intermittent post-exercise sauna bathing across three-weeks endurance training improves exercise heat tolerance and exercise performance markers in temperate conditions, compared to endurance training alone. The subsidiary aim was to determine whether exercise-heat tolerance would further improve following 7-Weeks post-exercise sauna bathing., Methods: Twenty middle-distance runners (13 female; mean ± SD, age 20 ± 2 years, [Formula: see text]O 2max 56.1 ± 8.7 ml kg -1  min -1 ) performed a running heat tolerance test (30-min, 9 km h -1 /2% gradient, 40 °C/40%RH; HTT) and temperate (18 °C) exercise tests (maximal aerobic capacity [[Formula: see text]O 2max ], speed at 4 mmol L -1 blood lactate concentration ([La - ]) before (Pre) and following three-weeks (3-Weeks) normal training (CON; n = 8) or normal training with 28 ± 2 min post-exercise sauna bathing (101-108 °C, 5-10%RH) 3 ± 1 times per week (SAUNA; n = 12). Changes from Pre to 3-Weeks were compared between-groups using an analysis of co-variance. Six SAUNA participants continued the intervention for 7 weeks, completing an additional HTT (7-Weeks; data compared using a one-way repeated-measures analysis of variance)., Results: During the HTT, SAUNA reduced peak rectal temperature (T rec ; - 0.2 °C), skin temperature (- 0.8 °C), and heart rate (- 11 beats min -1 ) more than CON at 3-Weeks compared to Pre (all p < 0.05). SAUNA also improved [Formula: see text]O 2max (+ 0.27 L -1  min -1 ; p = 0.02) and speed at 4 mmol L -1 [La - ] (+ 0.6 km h -1 ; p = 0.01) more than CON at 3-Weeks compared to Pre. Only peak T rec (- 0.1 °C; p = 0.03 decreased further from 3-Weeks to 7-Weeks in SAUNA (other physiological variables p > 0.05)., Conclusions: Three-weeks post-exercise sauna bathing is an effective and pragmatic method of heat acclimation, and an effective ergogenic aid. Extending the intervention to seven weeks only marginally improved T rec .

Key Points: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. In the present study, we used a placebo-controlled, single-blinded, randomized cross-over design to test the hypothesis that acutely-reduced CBF (using a pharmacological aid; indomethacin) would impair cognition in young and older healthy adults. At baseline, older adults had lower cognitive performance and CBF, but similar cerebrovascular reactivity to CO 2 and dynamic cerebral autoregulation compared to young adults. In both young and older adults, cognitive performance on a mental switching task was slightly (7%) reduced after indomethacin, but not significantly associated with reductions in CBF (∼31%). These results indicate that cognitive performance is broadly resilient against a ∼31% reduction in CBF per se in healthy young and older adults., Abstract: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. Using a placebo-controlled, single-blinded, randomized cross-over design, we tested the hypothesis that acutely-reduced CBF (using indomethacin [1.2 mg kg -1 oral dose]) would impair cognition in young (n = 13; 25 ± 4 years) and older (n = 12; 58 ± 6 years) healthy adults. CBF and cerebrovascular control were measured using middle cerebral artery blood velocity (MCAv mean ) and its reactivity to hypercapnia (CVR HYPER ) and hypocapnia (CVR HYPO ), respectively. Cognitive function was assessed using a computerized battery including response time tasks. Baseline comparisons revealed that older adults had 14% lower MCAv mean and 15% lower cognitive performance (all P ≤ 0.048), but not lower CVR HYPER/HYPO (P ≥ 0.26). Linear and rank-based mixed models revealed that indomethacin decreased MCAv mean by 31% (95% confidence interval = -35 to -26), CVR HYPER by 68% [interquartile range (IQR) = -94 to -44] and CVR HYPO by 50% (IQR = -83 to -33) (treatment-effect; all P < 0.01), regardless of age. Baseline CVR HYPER/HYPO values were strongly associated with their indomethacin-induced reductions (r = 0.70 to 0.89, P < 0.01). Mental switching performance was impaired 7% (IQR = 0-19) after indomethacin (P = 0.04), but not significantly associated with reductions in MCAv mean (Young: rho = -0.31, P = 0.30; Older: rho = 0.06, P = 0.86). In conclusion, indomethacin reduced MCAv mean and impaired cognition slightly; however, no clear association was evident in younger or older adults. Older adults had poorer cognition and lower MCAv mean , but similar CVR HYPER/HYPO ., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

This study examined acute cerebral hemodynamic and circulating neurotrophic factor responses to moderate intensity continuous exercise (MICT), guideline-based high intensity interval exercise (HIIT), and sprint interval exercise (SIT). We hypothesized that the pattern of middle cerebral artery velocity (MCAv) response would differ between interval and continuous exercise, with SIT inducing the smallest increase from rest, while increases in neurotrophic factors would be intensity-dependent. In a randomized crossover design, 24 healthy adults (nine females) performed three exercise protocols: (i) MICT (30 min), (ii) HIIT (4 × 4 min at 85% HR max ), and (iii) SIT (4 × 30 s supramaximal). MCAv significantly increased from rest across MICT (Δ13.1 ± 8.5 cm⋅s -1 , p < 0.001) and all bouts of HIIT (Δ15.2 ± 9.8 cm⋅s -1 , p < 0.001), but only for the initial bout of SIT (Δ17.3 ± 11.6 cm⋅s -1 , p < 0.001). Immediately following each interval bout, MCAv increased (i.e., rebounded) for the SIT (9-14% above rest, p ≤ 0.04), but not HIIT protocol. SIT alone induced significant elevations from rest to end-exercise in vascular endothelial growth factor (VEGF; Δ28 ± 36%, p = 0.017) and brain-derived neurotrophic factor (BDNF, Δ149% ± 162%, p < 0.001) and there were greater increases in lactate than in either other protocol (>5-fold greater in SIT, p < 0.001), alongside a small significant reduction at the end of active recovery in insulin-like growth factor 1 (IGF-1, Δ22 ± 21%, p = 0.002). In conclusion, while the nature of the response may differ, both guideline-based and sprint-based interval exercise have the potential to induce significant changes in factors linked to improved cerebrovascular and brain health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Weaver, Skinner, Furlong, Lucas, Cable, Rendeiro, McGettrick and Lucas.)

Objective: Altitude-related and exercise-related elevations in blood pressure (BP) increase the likelihood of developing pulmonary hypertension and high-altitude illness during high-altitude sojourn. This study examined the antihypertensive effect and potential exercise benefit of the angiotensin II receptor antagonist losartan when taken at altitude., Methods: Twenty participants, paired for age and ACE genotype status, completed a double-blinded, randomised study, where participants took either losartan (100 mg/day) or placebo for 21 days prior to arrival at 5035 m (Whymper Hut, Mt Chimborazo, Ecuador). Participants completed a maximal exercise test on a supine cycle ergometer at sea level (4 weeks prior) and within 48 hours of arrival to 5035 m (10-day ascent). Power output, beat-to-beat BP, oxygen saturation (SpO 2 ) and heart rate (HR) were recorded during exercise, with resting BP collected from daily medicals during ascent. Before and immediately following exercise at 5035 m, extravascular lung water prevalence was assessed with ultrasound (quantified via B-line count)., Results: At altitude, peak power was reduced relative to sea level (p<0.01) in both groups (losartan vs placebo: down 100±29 vs 91±28 W, p=0.55), while SpO 2 (70±6 vs 70±5%, p=0.96) and HR (146±21 vs 149±24 bpm, p=0.78) were similar between groups at peak power, as was the increase in systolic BP from rest to peak power (up 80±37 vs 69±33 mm Hg, p=0.56). Exercise increased B-line count (p<0.05), but not differently between groups (up 5±5 vs 8±10, p=0.44)., Conclusion: Losartan had no observable effect on resting or exercising BP, exercise-induced symptomology of pulmonary hypertension or performance at 5035 m., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

The emergence of COVID-19 infection (caused by the SARS-CoV-2 virus) in Wuhan, China in the latter part of 2019 has, within a relatively short time, led to a global pandemic. Amidst the initial spread of SARS-CoV-2 across Asia, an epidemiologic trend emerged in relation to high altitude (HA) populations. Compared with the rest of Asia, SARS-CoV-2 exhibited attenuated rates of expansion with limited COVID-19 infection severity along the Tibetan plateau. These characteristics were soon evident in additional HA regions across Bolivia, central Ecuador, Nepal, Bhutan, and the Sichuan province of mainland China. This mini-review presents a discussion surrounding attributes of the HA environment, aspects of HA physiology, as well as, genetic variations among HA populations which may provide clues for this pattern of SARS-CoV-2 expansion and COVID-19 infection severity. Explanations are provided in the hypothetical, albeit relevant historical evidence is provided to create a foundation for future research.

The optimal exercise intensity and modality for maximizing cerebral blood flow (CBF) and hence potential exposure to positive, hemodynamically derived cerebral adaptations is yet to be fully determined. This study compared CBF velocity responses between running and cycling across a range of exercise intensities. Twenty-six participants (12 females; age: 26 ± 8 years) completed four exercise sessions; two mode-specific maximal oxygen consumption (VO 2max ) tests, followed by (order randomized) two incremental exercise protocols (3-min stages at 35%, 50%, 65%, 80%, 95% VO 2max ). Continuous measures of middle cerebral artery velocity (MCAv), oxygen consumption, end-tidal CO 2 (P ET CO 2 ), and heart rate were obtained. Modality-specific MCAv changes were observed for the whole group (interaction effect: p = .01). Exercise-induced increases in MCAv mean during cycling followed an inverted-U pattern, peaking at 65% VO 2max (Δ12 ± 7 cm/s from rest), whereas MCAv mean during running increased linearly up to 95% VO 2max (change from rest: Δ12 ± 13 vs. Δ7 ± 8 cm/s for running vs. cycling at 95% VO 2max ; p = .01). In contrast, both modalities had an inverted-U pattern for P ET CO 2 changes, although peaked at different intensities (running: 50% VO 2max , Δ6 ± 2 mmHg; cycling: 65% VO 2max , Δ7 ± 2 mmHg; interaction effect: p = .01). Further subgroup analysis revealed that the running-specific linear MCAv mean response was fitness dependent (Fitness*modality*intensity interaction effect: p = .04). Above 65% VO 2max , fitter participants (n = 16; male > 45 mL/min/kg and female > 40 mL/min/kg) increased MCAv mean up to 95% VO 2max , whereas in unfit participants (n = 7, male < mL/min/kg and female < 35 mL/min/kg) MCAv mean returned toward resting values. Findings demonstrate that modality- and fitness-specific profiles for MCAv mean are seen at exercise intensities exceeding 65% VO 2max ., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate-intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high-intensity interval training (HIIT) has since emerged as a more time-efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever-ageing population., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Purpose: Cognition, cerebral blood flow (CBF) and its major regulator (i.e., arterial CO 2 ), increase with submaximal exercise and decline with severe exercise. These responses may depend on fitness. We investigated whether exercise-related changes in cognition are mediated in part by concomitant changes in CBF and CO 2 , in ten active (26 ± 3 years) and ten inactive (24 ± 6 years) healthy adults., Methods: Participants completed two randomised sessions; exercise and a resting CO 2 -control-wherein end-tidal CO 2 (PETCO 2 ) was matched between sessions and clamped across conditions at exercise-associated increases (+ 3 mmHg) and hypercapnia (+ 10 mmHg). Exercise comprised inclined walking at submaximal and severe intensities. CBF was indexed using right middle cerebral artery blood velocity (MCAv). Cognition (visuomotor, switching and inhibitory response time) was measured before, during, and after exercise., Results: MCAv and its inverted-U response to exercise were comparable between groups, whereas visuomotor performance improved during submaximal exercise in the active group only (p = 0.046). Submaximal, but not severe (p = 0.33), exercise increased MCAv (p ≤ 0.03). Hypercapnia increased MCAv during the CO 2 -control (27 ± 12%) and during submaximal exercise (39 ± 17%; p < 0.01). Despite the acute increases in MCAv, cognition was impaired during both levels of increased PETCO 2 (3-6%; p ≤ 0.04), regardless of session. Overall, resting or exercise-related changes in PETCO 2 and MCAv did not associate with changes in cognition (r ≤ 0.29 ± 0.34). Fitness ([Formula: see text]O 2MAX ) was associated with baseline cognition (r ≥ 0.50)., Conclusion: Acute increases in PETCO 2 and MCAv were not associated with improved cognition. In fact, cognitive performance was impaired at both levels of increased PETCO 2 , regardless of session. Finally, fitter people were found to have better cognition.