A network physiology framework investigated how coordinated interactions among multiple organ systems collectively support the preservation of cerebral bioenergetic function and better distinguish adaptive from maladaptive responses to hypoxia. Twelve healthy males were passively exposed to 6 h of normoxia (21% O2) and hypoxia (12% O2) in a randomised, single-blind, crossover design. Venous blood was assayed for oxidative-nitrosative stress (OXNOS, spectroscopy/chemiluminescence) and neurovascular unit (hs-ELISA) biomarkers. Global cerebral delivery of O2 and glucose were determined by duplex ultrasound. Clinical acute mountain sickness (AMS+) was diagnosed in five participants. Cerebral substrate delivery was well maintained in both hypoxia and AMS+ (p < 0.05 vs normoxia and AMS-) despite marked arterial hypoxemia. Bioenergetic defence coincided with pronounced elevations in the spectral amplitude and phase synchronisation of very low-frequency oscillations (VLFOs, 0.03-0.06 Hz), which were evident across multiple organ systems and most prominent within the cerebral network. Systemic VLFOs were further exaggerated and more functionally connected in AMS+ in the absence of exaggerated systemic OXNOS or structural damage/destabilisation of the neurovascular unit (both p < 0.05 vs normoxia and AMS-). Collectively, these findings suggest that AMS, while characterised by debilitating symptomatology, may reflect a neuroprotective adaptive as opposed to pathologically maladaptive phenotype.

Psychological stress is a recognised, yet mechanistically unresolved, risk factor for cardiovascular disease (CVD) partly through its association with a hypercoagulable state. Free radical-mediated oxidative stress has been proposed as a key upstream driver of this haemostatic imbalance. In this randomised cross-over study we investigated whether acute psychological stress promotes systemic radical formation and prothrombotic alterations in clot microstructure in eight healthy males. The Trier Social Stress Test was used to induce psychological stress. Antecubital venous blood was collected to measure the ascorbate free radical (A•-, electron paramagnetic resonance spectroscopy) and clot microstructure (Df, Fourier transform rheology), alongside standard coagulometry. Compared with the control condition (quiet sitting), psychological stress increased A•- (P = 0.042) and Df (P = 0.008), the latter reflecting larger, denser and more fibrin-rich networks. We also observed selective shortening of activated partial thromboplastin time (aPTT) (P = 0.018), indicating activation of the intrinsic coagulation pathway. This study provides the first in vivo evidence that acute psychological stress triggers systemic free radical formation and drives prothrombotic remodelling of clot architecture. These findings identify oxidative stress as a mechanistic link between psychological stress and CVD risk and highlight it as a compelling target for prevention and therapy. KEY POINTS: Although psychological stress is a recognised risk factor for cardiovascular disease (CVD), its mechanistic association with a hypercoagulable state remains unresolved. Acute psychological stress, induced by the Trier Social Stress Test (TSST), significantly increased systemic free radical formation, as measured by elevated levels of ascorbate free radical (A•-) via electron paramagnetic resonance (EPR) spectroscopy, and was associated with the formation of larger, denser, more fibrin-rich clots confirmed by increased fractal dimension (Df). The concurrent increase in A•- and Df suggests that free radical-mediated oxidative stress is an upstream driver of psychological stress-induced activation of haemostasis, specifically altering clot quality. The TSST selectively shortened activated partial thromboplastin time (aPTT), indicating activation of the intrinsic/contact coagulation pathway. There were no changes in prothrombin time (PT) or D-dimer, suggesting haemostatic activation occurred without engaging fibrinolysis. The findings demonstrate that even a brief episode of emotional stress can increase thrombotic potential in healthy individuals and identify oxidative stress as a key mechanistic link and a potential therapeutic target for treating stress-related CVD.

To what extent post-prandial hyperlipidaemia (PPH) impacts both systemic vascular function and dynamic cerebral autoregulation (dCA) is unknown. To address this, we recruited 20 healthy young males (24 ± 5 y) and compared them to 21 healthy older males (67 ± 6 y). In both groups, the following measurements were performed: systemic vascular function was assessed via flow-mediated dilation (FMD) using duplex ultrasound. Forced oscillations in mean arterial pressure (squat-stand manoeuvres) were used to assess dCA via transfer function analysis, with middle cerebral artery velocity recorded continuously. Venous samples were assayed for triglycerides, glucose and insulin. All measurements were completed following an overnight fast prior to and 4 h following consumption of a standardised high-fat meal. Older males exhibited comparable basal FMD (P = 0.635 vs. young) and dCA (P = 0.170–0.998), whereas cerebral perfusion was lower (P = <0.001–0.028). Triglycerides (P = < 0.001), glucose (P = 0.011) and insulin (P = < 0.001) increased in both groups post-prandially, resulting in impaired FMD (P = 0.032), increased cerebral pulsatility (P = < 0.001) and reduced dCA (P = 0.007–0.037), with the latter more marked in older participants. These findings are the first to demonstrate PPH impairs both systemic vascular function and dCA in both young and old male adults, with the older brain at greater risk.

To what extent sildenafil, a selective inhibitor of the type-5 phosphodiesterase modulates systemic redox status and cerebrovascular function during acute exposure to hypoxia remains unknown. To address this, 12 healthy males (aged 24 ± 3 y) participated in a randomized, placebo-controlled crossover study involving exposure to both normoxia and acute (60 min) hypoxia (FiO2 = 0.14), followed by oral administration of 50 mg sildenafil and placebo (double-blinded). Venous blood was sampled for the ascorbate radical (A•-: electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (NO: ozone-based chemiluminescence). Transcranial Doppler ultrasound was employed to determine middle cerebral artery velocity (MCAv), cerebral delivery of oxygen (CDO2), dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to hypo/hypercapnia (CVRCO2HYPO/HYPER). Cortical oxyhemoglobin (cO2Hb) and oxygenation index (OI) were assessed using pulsed continuous wave near infra-red spectroscopy. Hypoxia decreased total plasma NO (P = 0.008), CDO2 (P = <0.001) and cO2Hb (P = 0.005). In hypoxia, sildenafil selectively reduced A•- (P = 0.018) and MCAV (P = 0.018), and increased dCA metrics of low-frequency phase (P = 0.029) and CVRCO2HYPER (P = 0.007) compared to hypoxia-placebo. Collectively, these findings provide evidence for a PDE-5 inhibitory pathway that enhances select aspects of cerebrovascular function in hypoxia subsequent to a systemic improvement in redox homeostasis and independent of altered vascular NO bioavailability.

Objective To determine the molecular and cerebral haemodynamic biomarkers associated with sports-related concussion (SRC) and implications for cognition in retired rugby union players. We hypothesised that SRC would be associated with impaired cerebrovascular function and cognition, subsequent to elevated nitrosative stress in the absence of structural damage. Design Cross-sectional. Setting Laboratory. Participants 41 males were divided into two groups, 20 retired players aged 65 (mean) ± 5 (SD) years with 3 ± 3 self-reported SRC's and 21 age, fitness and education matched controls with no history of participation in contact sports or SRC. Interventions (or Assessment of Risk Factors) Recurrently concussed players were compared to controls. Outcome Measures Cerebral perfusion via middle cerebral artery velocity (MCAv) and cerebral delivery of oxygen (CDO2) were measured at rest and accompanied by venous assessment of NO bioactivity (nitrite [NO] and S-nitrosothiols [RSNO]), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and neurofilament light (NFL). Cognition was assessed via the Montreal Cognitive Assessment (MoCA). Main Results Players were characterised by lower NO bioactivity (P = 0.049, 95% CI = 1.02 – 1.22), perfusion (P = 0.007, 95% CI = 2.30 – 13.65) and CDO2 (P = 0.001, 95% CI = 82.67 – 308.02) that translated into mild cognitive impairment (MCI) versus controls (P = 0.020, 95% CI = 0.35 – 3.94). In contrast, no differences in NSE, GFAP or NFL were observed (P > 0.050). Conclusions Collectively, these findings provide a mechanistic basis to explain the observed decline in cognitive function that may be relevant for the future prediction of dementia.

What is the central question of this study? What are the molecular, cerebrovascular and cognitive biomarkers of retired rugby union players with concussion history? What is the main finding and its importance? Retired rugby players compared with matched controls exhibited lower systemic nitric oxide bioavailability accompanied by lower middle cerebral artery velocity and mild cognitive impairment. Retired rugby players are more susceptible to accelerated cognitive decline.

Abstract Hypoxia has the potential to impair cognitive function; however, it is still uncertain which cognitive domains are adversely affected. We examined the effects of acute hypoxia (∼7 h) on central executive (Go/No‐Go) and non‐executive (memory) tasks and the extent to which impairment was potentially related to regional cerebral blood flow and oxygen delivery (CDO2). Twelve male participants performed cognitive tasks following 0, 2, 4 and 6 h of passive exposure to both normoxia and hypoxia (12% O2), in a randomized block cross‐over single‐blinded design. Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities and corresponding CDO2 were determined using bilateral transcranial Doppler ultrasound. In hypoxia, MCA DO2 was reduced during the Go/No‐Go task (P = 0.010 vs. normoxia, main effect), and PCA DO2 was attenuated during memorization (P = 0.005 vs. normoxia) and recall components (P = 0.002 vs. normoxia) in the memory task. The accuracy of the memory task was also impaired in hypoxia (P = 0.049 vs. normoxia). In contrast, hypoxia failed to alter reaction time (P = 0.19 vs. normoxia) or accuracy (P = 0.20 vs. normoxia) during the Go/No‐Go task, indicating that selective attention and response inhibition were preserved. Hypoxia did not affect cerebral blood flow or corresponding CDO2 responses to cognitive activity (P > 0.05 vs. normoxia). Collectively, these findings highlight the differential sensitivity of cognitive domains, with memory being selectively vulnerable in hypoxia.

The speed and accuracy of decision-making may be an integral factor for superior sports performance. At rest, prolonged cognitive effort impairs reaction time (RT). However, to what extent prolonged cognitive effort in conjunction with sustained exercise (i.e., a dual-task with motor and cognitive demands) impacts RT an corresponding implications for decision-making is unknown. We hypothesised that decision-making (i.e., average and standard deviation (SD) of RT and accuracy) would be impaired to a greater extent during ‘dual-tasking’. PURPOSE: To test our hypothesis, we aimed to examine RT and accuracy following a 50-min aerobic exercise protocol with and without prolonged cognitive effort. METHODS: Twenty-one healthy males (aged 22 ± 2 yrs; VO2 peak = 46 ± 5 ml/kg/min) performed two trials [exercise only (EX) and prolonged cognitive effort + exercise (CE)] in a randomised-crossover design. Both EX and CE trials utilised a 50-min cycling exercise protocol (60% VO2 peak; 151 ± 16 W) and the prolonged cognitive effort in the CE trial was achieved via a 50-min Stroop task. In the first and final 5 min of both EX and CE trials, the Stroop task was utilised to examine decision-making. The interval between the stimulus of the Stroop task was randomly selected as either 3, 5, and 7 sec; namely, the 12 stimuli were presented per minute. A paired two-tailed t-test was used to compare the changes in scores between EX and CE trials. RESULTS: When compared to the EX trial, both RT (i.e., Δindividual Stroop interference ratio of averaged RT; EX -2.4 ± 8.4 vs. CE 4.7 ± 9.7, P < 0.05) and intraindividual variability (i.e., Δindividual SD of RT; EX -30 ± 47 msec vs. CE 25 ± 102 msec, P < 0.05) increased in response to the CE trial with no change in accuracy. CONCLUSIONS: These observations indicate that prolonged cognitive effort in conjunction with exercise impairs decision-making, implying that cognitive central fatigue may adversely impact sports performance.

Emergent evidence suggests that cyclic intermittent hypoxia increases cerebral arterial shear rate and endothelial function, whereas continuous exposure decreases anterior cerebral oxygen (O 2 ) delivery. To examine to what extent continuous hypoxia impacts cerebral shear rate, cerebral endothelial function, and consequent cerebral O 2 delivery (CDO 2 ), eight healthy males were randomly assigned single-blind to 7 h passive exposure to both normoxia (21% O 2 ) and hypoxia (12% O 2 ). Blood flow in the brachial and internal carotid arteries were determined using Duplex ultrasound and included the combined assessment of systemic and cerebral endothelium-dependent flow-mediated dilatation. Systemic (brachial artery) flow-mediated dilatation was consistently lower during hypoxia ( P = 0.013 vs . normoxia), whereas cerebral flow-mediated dilation remained preserved ( P = 0.927 vs . normoxia) despite a reduction in internal carotid artery antegrade shear rate ( P = 0.002 vs . normoxia) and CDO 2 ( P < 0.001 vs . normoxia). Collectively, these findings indicate that the reduction in CDO 2 appears to be independent of cerebral endothelial function and contrasts with that observed during cyclic intermittent hypoxia, highlighting the regulatory importance of (hypoxia) dose duration and flow/shear rate phenotype.

Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = < 0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = < 0.001 vs. CMS-) subsequent to liberation of free 'catalytic' iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = < 0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = < 0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = < 0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r =-0.692 to 0.595, P = < 0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+.

In many sports (e.g., football, lacrosse, rugby, etc.), the need to perform a dual-task (e.g., decision-making during exercise) is unavoidable. Purpose: Given that prolonged continuous performance of a cognitively demanding task increases mental fatigue, we hypothesized that a sustained cognitive effort superimposed during aerobic exercise would compound the increased rating of perceived exertion (RPE). Methods: Twenty-one healthy, young males (aged 22 ± 2 yrs; VO2 peak = 46 ± 5 ml/kg/min) performed two trials [i.e., exercise-cognition (EX-Cog) and exercise-only (EX)] in a randomised-crossover design. In EX-Cog trial, participants performed 50-min moderate-intensity (60% peak oxygen uptake) cycling exercise and sustained 50-min Stroop task, simultaneously. In EX trial, participants performed 50-min moderate-intensity cycling exercise. RPE was assessed via the Borg scale during the final 10 seconds of exercise in both conditions. Mental fatigue (visual analog scale) and heart rate (HR; HR monitor) in response to exercise were also recorded. RPE was analyzed using Wilcoxon signed-rank test. Changes in mental fatigue and HR in response to exercise were analyzed using a two-way (trial × time) repeated-measures analysis of variance. Results: The elevations in mental fatigue and HR were identical during both trials (both P < 0.05). In contrast, RPE was higher during EX-Cog (EX-Cog median 15; IQR 15.0 to 17.0 vs. EX median 15; IQR 14.0 to 16.5, P = 0.012). Conclusions: These findings indicate that dual-tasking increases perceived exertion yet fails to incur additional mental fatigue or cardiovascular demand which may have implications for decision-making during sport.

The speed and accuracy of decision-making ( i.e. , executive function (EF) domains) is an integral factor in many sports. At rest, prolonged cognitive load (pCL) impairs reaction time (RT). In contrast, exercise improves RT and EF. We hypothesized that RT and EF during exercise would be diminished by prolonged ‘dual tasking’ as a consequence of pCL. To test the hypothesis, twenty healthy male participants performed four conditions [resting control (Rest), pCL only (pCL Rest ), exercise only (EX), and pCL + exercise (pCL EX )] in a randomized-crossover design. Both exercise conditions utilized a 50-min cycling exercise protocol (60% VO 2 peak) and the pCL was achieved via a 50-min colour-word Stroop task (CWST). Compared with Rest, pCL Rest caused a slowed CWST RT ( P < 0.05) and a large SD ( i.e. , intraindividual variability) of CWST RT ( P < 0.01). Similarly, compared with EX, the slowed CWST RT ( P < 0.05) and large SD of CWST RT ( P < 0.01) were also observed in pCL EX . Whereas the reverse-Stroop interference was not affected in pCL Rest ( P = 0.46), it was larger ( i.e. , declined EF) in pCL EX than EX condition ( P < 0.05). These observations provide evidence that the effort of pCL impairs RT and EF even during exercise.

Football players are at increased risk of neurodegeneration, the likely consequence of repetitive mechanical trauma caused by heading the ball. However, to what extent a history of heading the ball affects cerebral blood flow (CBF) regulation and its potential relationship to cognitive impairment is unknown. To address this, we recruited 16 concussion‐free male amateur football players (age: 25 ± 6 y) with a history of heading the ball (18 ± 6 y) and 18 sex, age, education, and activity‐matched controls with no prior history of contact sport participation or concussion. Cerebral perfusion was measured at rest and in response to both hyper/hypocapnia to determine cerebrovascular reactivity to carbon dioxide (CVRCO2HYPER/HYPO) using transcranial Doppler ultrasound and capnography, with the sum reflecting the cerebral vasomotor range. Cognition and visuomotor coordination were assessed using the Montreal cognitive assessment (MoCA) and the Grooved Pegboard Dexterity Test (GPD), respectively. While no differences in cerebral perfusion were observed (p = 0.938), CVRCO2HYPER/HYPO (p = 0.038/p = 0.025), cerebral vasomotor range (p = 0.002), MoCA (p = 0.027), and GPD performance (dominant hand, P ≤ 0.001) were consistently lower in the players compared to controls. These findings are the first to demonstrate that CBF regulation and cognition are collectively impaired in male football players with history of heading the ball, which may contribute to neurodegeneration.

Recurrent contact and concussion in rugby union remains a significant public health concern given the potential increased risk of neurodegeneration in later life. This study determined to what extent prior‐recurrent contact impacts molecular‐hemodynamic biomarkers underpinning cognition in current professional rugby union players with a history of concussion. Measurements were performed in 20 professional rugby union players with an average of 16 (interquartile range [IQR] 13–19) years playing history reporting 3 (IQR 1–4) concussions. They were compared to 17 sex‐age‐physical activity‐and education‐matched non‐contact controls with no prior history of self‐reported concussion. Venous blood was assayed directly for the ascorbate free radical (A•−electron paramagnetic resonance spectroscopy) nitric oxide metabolites (NO reductive ozone‐based chemiluminescence) and select biomarkers of neurovascular unit integrity (NVU chemiluminescence/ELISA). Middle cerebral artery blood flow velocity (MCAv doppler ultrasound) was employed to determine basal perfusion and cerebrovascular reactivity (CVR) to hyper/hypocapnia (). Cognition was assessed by neuropsychometric testing. Elevated systemic oxidative‐nitrosative stress was confirmed in the players through increased A•−(p < 0.001) and suppression of NO bioavailability (p < 0.001). This was accompanied by a lower CVR range (;p = 0.045) elevation in neurofilament light‐chain (p = 0.010) and frontotemporal impairments in immediate‐memory (p = 0.001) delayed‐recall (p = 0.048) and fine‐motor coordination (p < 0.001). Accelerated cognitive decline subsequent to prior‐recurrent contact and concussion history is associated with a free radical‐mediated suppression of CVR and neuronal injury providing important mechanistic insight that may help better inform clinical management.

Dynamic autoregulation of cerebral oxygenation is altered in elderly persons with Alzheimer's disease, whereby the displacement in time of a cerebral oxygenation signal relative to cerebral blood flow (CBF) (i.e., transfer function phase shift) is larger in Alzheimer's patients than age-matched control subjects. Given that higher cardiorespiratory fitness may be associated with cognitive improvement, we hypothesized that dynamic autoregulation of cerebral oxygenation would be altered by regular exercise. PURPOSE: To test our hypothesis, we examined the relationship between dynamic autoregulation of cerebral oxygenation and cardiorespiratory fitness in both young and elderly participants. METHODS: Thirty-eight healthy males participated and were classified into 4 groups; elderly-trained (n = 11, age; 66 ± 6 yrs, maximal oxygen consumption (VO2 max); 38 ± 6 ml/kg/min), elderly-sedentary (n = 10, age; 66 ± 8 yrs, VO2 max; 22 ± 5 ml/kg/min), younger-trained (n = 7, age; 23 ± 3 yrs, VO2 max; 65 ± 11 ml/kg/min), and younger-sedentary men (n = 10, age; 25 ± 6 yrs, VO2 max; 36 ± 6 ml/kg/min). To determine dynamic autoregulation of cerebral oxygenation using transfer function analysis, blood flow velocity in the middle cerebral artery (MCA V; transcranial Doppler ultrasonography) and cortical tissue oxygenation index (TOI; continuous-wave near-infrared spectroscopy) were continuously measured during 0.05 Hz squat maneuver. RESULTS: While transfer function gain between normalized MCA Vmean and TOI was not affected (P = 0.33), the phase shift was smaller in trained-group than sedentary-group (P < 0.05). CONCLUSIONS: These observations indicate that regular exercise alters the time relationship between changes in CBF and cerebral oxygenation. Given that a larger phase shift is associated with cognitive decline in Alzheimer's disease, our findings suggest that regular exercise in these patients may provide therapeutic benefit in the form of improved cerebral microvascular function with the potential to improve cognitive function.

What is the central question of this study? To what extent do hypoxia‐induced changes in the peripheral and central respiratory chemoreflex modulate anterior and posterior cerebral oxygen delivery, with corresponding implications for susceptibility to acute mountain sickness? What is the main finding and its importance? We provide evidence for site‐specific regulation of cerebral blood flow in hypoxia that preserves oxygen delivery in the posterior but not the anterior cerebral circulation, with minimal contribution from the central respiratory chemoreflex. External carotid artery vasodilatation might prove to be an alternative haemodynamic risk factor that predisposes to acute mountain sickness.

New Findings What is the central question of this study? How does recurrent contact incurred across a season of professional rugby union impact molecular, cerebrovascular and cognitive function? What is the main findings and its importance? A single season of professional rugby union increases systemic oxidative-nitrosative stress (OXNOS) confirmed by a free radical-mediated suppression in nitric oxide bioavailability. Forwards encountered a higher frequency of contact events compared to backs, exhibiting elevated OXNOS and lower cerebrovascular function and cognition. Collectively, these findings provide mechanistic insight into the possible cause of reduced cognition in rugby union subsequent to impairment in the redox regulation of cerebrovascular function. 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(center dot-), 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(center dot-) (F-2,F-19 = 10.589, P = 0.004) and corresponding suppression of NO bioavailability (F-2,F-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 (cDO2, F-2,F-19 = 9.440, P = 0.006) and cognition (F-2,F-19 = 4.813, P = 0.041). Forwards exhibited a greater decline in the cerebrovascular reactivity range to changes in PETCO2 (CVRCO2RANG compared to backs (M-D 1.378; 95% CI, 0.74-2.02; P < 0.001).