Background and Purpose-Age-related impairments in cerebral blood flow and cerebrovascular reactivity to carbon dioxide (CVR CO2 ) are established risk factors for stroke that respond favorably to aerobic training. The present study examined to what extent cerebral hemodynamics are improved when training is sustained throughout the adult lifespan. Methods-Eighty-one healthy males were prospectively assigned to 1 of 4 groups based on their age (young, ≤30 years versus old, ≥60 years) and lifetime physical activity levels (trained, ≥150 minutes recreational aerobic activity/week versus sedentary, no activity

The present study examined to what extent professional boxing compromises cerebral haemodynamic function and its association with CTBI (chronic traumatic brain injury). A total of 12 male professional boxers were compared with 12 age-, gender- and physical fitness-matched non-boxing controls. We assessed dCA (dynamic cerebral autoregulation; thigh-cuff technique and transfer function analysis), CVRCO₂ (cerebrovascular reactivity to changes in CO₂: 5% CO₂ and controlled hyperventilation), orthostatic tolerance (supine to standing) and neurocognitive function (psychometric tests). Blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasound), mean arterial blood pressure (finger photoplethysmography), end-tidal CO₂ (capnography) and cortical oxyhaemoglobin concentration (near-IR spectroscopy) were continuously measured. Boxers were characterized by fronto-temporal neurocognitive dysfunction and impaired dCA as indicated by a lower rate of regulation and autoregulatory index (P<0.05 compared with controls). Likewise, CVRCO₂ was also reduced resulting in a lower CVRCO₂ range (P<0.05 compared with controls). The latter was most marked in boxers with the highest CTBI scores and correlated against the volume and intensity of sparring during training (r=-0.84, P<0.05). These impairments coincided with more marked orthostatic hypotension, cerebral hypoperfusion and corresponding cortical de-oxygenation during orthostatic stress (P<0.05 compared with controls). In conclusion, these findings provide the first comprehensive evidence for chronically impaired cerebral haemodynamic function in active boxers due to the mechanical trauma incurred by repetitive, sub-concussive head impact incurred during sparring training. This may help explain why CTBI is a progressive disease that manifests beyond the active boxing career.

Thomas A. Calverley became interested in physiology while studying for a Bachelor's degree in Sport and Exercise Science at the University of South Wales. Upon graduation, he enrolled as a PhD student investigating the neuroprotective benefits of high-intensity interval training in older adults under the auspices of Professor Bailey. Currently in the final year of his studentship, he enjoys playing cricket/rugby and is a keen guitarist making the most of his spare time. Damian M. Bailey trained at the

Key points Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative‐inflammatory‐nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS−) and low‐altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia‐induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. Abstract Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross‐sectional study examined to what extent exaggerated systemic oxidative‐inflammatory‐nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80 m, n = 17), and age‐ and gender‐matched HA dwellers born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 23) and without (CMS−, n = 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone‐based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P < 0.05 vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P < 0.05 vs. CMS−). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia‐induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

Various design and model selection methods are available for supersaturated designs having more factors than runs but little research is available on their comparison and evaluation. In this paper, simulated experiments are used to evaluate the use of E(s2)-optimal and Bayesian D-optimal designs, and to compare three analysis strategies representing regression, shrinkage Various design and model selection methods are available for supersaturated designs having more factors than runs but little research is available on their comparison and evaluation. In this paper, simulated experiments are used to evaluate the use of E(s 2 )-optimal and Bayesian D-optimal designs, and to compare three analysis strategies representing regression, shrinkage and a novel model-averaging procedure. Suggestions are made for choosing the values of the tuning constants for each approach. Findings include that (i) the preferred analysis is via shrinkage; (ii) designs with similar numbers of runs and factors can be effective for a considerable number of active effects of only moderate size; and (iii) unbalanced designs can perform well. Some comments are made on the performance of the design and analysis methods when effect sparsity does not hold.

Elevated cardiorespiratory fitness improves resting cerebral perfusion, although to what extent this is further amplified during acute exposure to exercise stress and the corresponding implications for cerebral oxygenation remain unknown. To examine this, we recruited 12 moderately active and 12 sedentary healthy males. Middle cerebral artery blood velocity (MCAv) and prefrontal cortical oxyhemoglobin (cO(2)Hb) concentration were monitored continuously at rest and throughout an incremental cycling test to exhaustion. Despite a subtle elevation in the maximal oxygen uptake (active: 52±9 ml/kg per minute versus sedentary: 33±5 ml/kg per minute, P<0.05), resting MCAv was not different between groups. However, more marked increases in both MCAv (+28±13% versus +18±6%, P<0.05) and cO(2)Hb (+5±4% versus -2±3%, P<0.05) were observed in the active group during the transition from low- to moderate-intensity exercise. Collectively, these findings indicate that the long-term benefits associated with moderate increase in physical activity are not observed in the resting state and only become apparent when the cerebrovasculature is challenged by acute exertional stress. This has important clinical implications when assessing the true extent of cerebrovascular adaptation.

The topic of this review is to consider innovative exercise strategies that optimize neuroprotection in order to combat cognitive decline and neurodegenerative disease in older age. r What advances does it highlight?The review summarizes current understanding around exercise mode, duration, frequency and intensity, and then highlights adaptive roles of select stressors that have equal if not indeed greater capacity than exercise per se to induce health-related adaptation in the brain. These stressors include, but are not exclusively limited to, hydrostatic and thermal stress, hypoxia, nutritional supplementation and cognitive loading, and are effective by targeting specific pathways that collectively contribute towards improved brain structure and function.The prevalence of cognitive decline and neurodegenerative diseases (e.g. stroke and dementia) is increasing. Numerous studies show that regular exercise has beneficial effects on brain health in clinical and non-clinical populations, yet adherence to public health exercise guidelines is notoriously poor. Recently, novel exercise strategies have been investigated to allow for more individualized and prescriptive approaches that target the key mechanistic pathways that allow exercise to mediate adaptation.

Contact events in rugby union remain a public health concern. We determined the molecular, cerebrovascular and cognitive consequences of contact events during a season of professional rugby. Twenty-one male players aged 25 (mean) ± 4 (SD) years were recruited from a professional rugby team comprising forwards (n = 13) and backs (n = 8). Data were collected across the season. Pre-and post-season, venous blood was assayed for the ascorbate free radical (A •-, electron paramagnetic resonance spectroscopy) and nitric oxide (NO, reductive ozone-based chemiluminescence) to quantify oxidative-nitrosative stress (OXNOS). Middle cerebral artery velocity (MCAv, Doppler ultrasound) was measured to assess cerebrovascular reactivity (CVR), and cognition was assessed using the Montreal Cognitive Assessment (MoCA). Notational analysis determined contact events over the season. Forwards incurred more collisions (Mean difference [M D ] 7.49; 95% CI, 2.58-12.40; P = 0.005), tackles (M D 3.49; 95% CI, 0.42-6.56; P = 0.028) and jackals (M D 2.21; 95% CI, 0.18-4.24; P = 0.034). Forwards suffered five concussions while backs suffered one concussion. An increase in systemic OXNOS, confirmed by elevated A •-(F 2,19 = 10.589, P = 0.004) and corresponding suppression of NO bioavailability (F 2,19 = 11.492, P = 0.003) was apparent in forwards and backs across the season. This was accompanied by a reduction in cerebral oxygen delivery (cD O 2 , F 2,19 = 9.440, P = 0.006) and cognition (F 2,19 = 4.813, P = 0.041).Forwards exhibited a greater decline in the cerebrovascular reactivity range to changes in PET CO2 (CVR CO 2 RANG compared to backs (M D 1.378; 95% CI, 0.74-2.02; P < 0.001).