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Objective Blood oxygenation can be measured using magnetic resonance using the paramagnetic effect of deoxy-haemoglobin, which decreases the $$\textit{T}_{2}$$ T 2 relaxation time of blood. This $$\textit{T}_{2}$$ T 2 contrast has been well characterised at the $$\textit{B}_{{0}}$$ B 0 fields used in MRI (1.5 T and above). However, few studies have characterised this effect at lower magnetic fields. Here, the feasibility of blood oximetry at low field based on $$\textit{T}_{2}$$ T 2 changes that are within a physiological relevant range is explored. This study could be used for specifying requirements for construction of a monitoring device based on low field permanent magnet systems. Methods A continuous flow circuit was used to control parameters such as oxygen saturation and temperature in a sample of blood. It flowed through a variable field magnet, where CPMG experiments were performed to measure its $$\textit{T}_{2}$$ T 2 . In addition, the oxygen saturation was monitored by an optical sensor for comparison with the $$\textit{T}_{2}$$ T 2 changes. Results These results show that at low $$\textit{B}_{{0}}$$ B 0 fields, the change in blood $$\textit{T}_{2}$$ T 2 due to oxygenation is small, but still detectable. The data measured at low fields are also in agreement with theoretical models for the oxy-deoxy $$\textit{T}_{2}$$ T 2 effect. Conclusion $$\textit{T}_{2}$$ T 2 changes in blood due to oxygenation were observed at fields as low as 0.1 T. These results suggest that low field NMR relaxometry devices around 0.3 T could be designed to detect changes in blood oxygenation.

Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)—termed cerebral autoregulation (CA)—bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to ‘ identify novel therapeutic targets for treatment and management in acute ischemic stroke’. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.

Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.

Accumulating evidence suggests asymmetrical responses of cerebral blood flow during large transient changes in mean arterial pressure. Specifically, the augmentation in cerebral blood flow is attenuated when mean arterial pressure acutely increases, compared with declines in cerebral blood flow when mean arterial pressure acutely decreases. However, common analytical tools to quantify dynamic cerebral autoregulation assume autoregulatory responses to be symmetric, which does not seem to be the case. Herein, we provide the rationale supporting the notion we need to consider the directional sensitivity of large and transient mean arterial pressure changes when characterizing dynamic cerebral autoregulation.

NEW FINDINGS What is the central question of this study? The pathophysiology of acute mountain sickness (AMS), involving the respiratory, renal and cerebrovascular systems, remains poorly understood. How do the early adaptations in these systems during a simulated altitude of 5000 m relate to AMS risk? What is the main finding and its importance? The rate of blood alkalosis and cerebral artery dilatation predict AMS severity during the first 10 h of exposure to a simulated altitude of 5000 m. Slow metabolic compensation by the kidneys of respiratory alkalosis attributable to a brisk breathing response together with excessive brain blood vessel dilatation might be involved in early development of AMS. ABSTRACT The complex pathophysiology of acute mountain sickness (AMS) remains poorly understood and is likely to involve maladaptive responses of the respiratory, renal and cerebrovascular systems to hypoxia. Using stepwise linear regression, we tested the hypothesis that exacerbated respiratory alkalosis, as a result of a brisk ventilatory response, sluggish renal compensation in acute hypoxia and dysregulation of cerebral perfusion predict AMS severity. We assessed the Lake Louise score (LLS, an index of AMS severity), fluid balance, ventilation, venous pH, bicarbonate, sodium and creatinine concentrations, body weight, urinary pH and cerebral blood flow [internal carotid artery (ICA) and vertebral artery (VA) blood flow and diameter], in 27 healthy individuals (13 women) throughout 10 h exposures to normobaric normoxia (fraction of inspired O2 = 0.21) and normobaric hypoxia (fraction of inspired O2 = 0.117, simulated 5000 m) in a randomized, single-blinded manner. In comparison to normoxia, hypoxia increased the LLS, ventilation, venous and urinary pH, and blood flow and diameter in the ICA and VA, while venous concentrations of both bicarbonate and creatinine were decreased (P

Accentuated blood pressure (BP) fluctuation and low cerebral blood flow (CBF) response to CO2 increase the risk of transient ischemic attack (TIA) recurrence and stroke in TIA patients. Improving cardio- and cerebrovascular function may reduce stroke risk. We found dietary nitrate lowered dynamic blood pressure variability (BPV) in rats and improved cerebrovascular CO2 reactivity in healthy individuals. In 30 TIA patients, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day-1) on cerebrovascular function using a randomized, single-blinded, placebo-controlled study design. We hypothesized that 7-day dietary nitrate supplementation would decrease variabilities in BP and CBF and improve CBF-CO2 slope and cerebral autoregulation (CA). We assessed beat-to-beat middle cerebral artery blood velocity (MCAv; index of CBF) and BP at rest and during CO2 breathing. Transfer function analysis was performed on beat-to-beat MCAv and BP to determine CA parameters (gain, phase, and coherence). Irrespective of treatment, high- and low-frequency BP-MCAv gain and MCAv-CO2 slope increased 7 days following TIA onset, while low-frequency BPV decreased (P 0.05). Concurrent with standard treatment, dietary nitrate supplementation reduces BP and CBF fluctuation and improves cerebral autoregulation in TIA patients, without affecting cerebrovascular CO2 reactivity.NEW & NOTEWORTHY We found dietary nitrate supplementation reduced blood pressure and brain blood flow fluctuations and improved the relationship between blood pressure and brain blood flow in transient ischemic attack patients. Meanwhile, dietary nitrate had no effects on the brain blood vessels' response to CO2. We attribute the improved brain blood flow stability to the improved myogenic control of blood pressure with dietary nitrate. Our findings indicate that dietary nitrate could be an effective strategy for stabilizing blood pressure and brain blood flow following transient ischemic attack.

OBJECTIVE: An imbalance in autonomic nervous system (ANS) activity may play a role in asthma, but it is unclear whether this is associated with specific pathophysiology. This study assessed ANS activity by measuring heart rate variability (HRV) in eosinophilic (EA) and non-eosinophilic asthma (NEA) and people without asthma. METHODS: HRV, combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), skin prick tests to measure atopy, and spirometry tests were conducted in teenagers and young adults (14-21 years) with (n = 96) and without (n = 72) generally well-controlled asthma. HRV parameters associated with sympathetic and parasympathetic ANS branches were analyzed. EA and NEA were defined using a 2.5% sputum eosinophil cut-point. Airway hyperreactivity (AHR) was defined as ≥15% reduction in FEV1 following saline challenge. RESULTS: HRV parameters did not differ between asthmatics and non-asthmatics or EA and NEA. They were also not associated with markers of inflammation, lung function or atopy. However, increased absolute low frequency (LFµs2; representing increased sympathetic nervous system (SNS) activity) was found in asthmatics who used β-agonist medication compared to those who did not (median: 1611, IQR 892-3036 vs 754, 565-1592; p

BackgroundNeural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics.MethodsThirty-eight asthmatics and 19 non-asthmatics (aged 14–21 years) underwent combined hypertonic saline challenge/sputum induction, fractional exhaled nitric oxide, atopy and spirometry tests, followed by capsaicin challenge. EA and NEA were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs.ResultsNon-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared with non-asthmatics (n=19) (geometric mean C5: 58.3 µM, 95% CI 24.1 to 141.5 vs 193.6 µM, 82.2 to 456.0; p1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control or treatment were observed.ConclusionNEA, but not EA, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of NEA.

We present a novel technique to overcome the use of vasoactive agents when studying cerebrovascular dynamics in the conscious rat. Our method of vena cava occlusion to reduce BP was associated with decreased iCBF and no change in iCVR. In contrast, comparable BP falls with intravenous SNP increased iCBF and reduced iCVR. Thus, the dynamic cerebral pressure-flow relationship shows a narrower, less level autoregulatory plateau than conventionally thought. We confirm our method allows repeatable assessment of cerebrovascular dynamics in conscious rats.

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg−1·day −1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% ( P < 0.001) and lowered gain ( d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment ( d = 0.7, P = 0.043), while coherence was unaffected ( P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men ( d = 1.0, P = 0.014 vs. placebo), but had no effect in women ( P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function. NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels’ response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.

Background: Neural mechanisms may play an important role in non-eosinophilic asthma. This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic and non-eosinophilic asthma and non-asthmatics. Methods: Thirty-eight asthmatics and nineteen non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), atopy, and spirometry tests, followed by capsaicin challenge. Eosinophilic (EA) and non-eosinophilic asthma (NEA) were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity (AHR) was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. Results: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared to non-asthmatics (n=19) (geometric mean C5: 58.3μM, 95% confidence interval 24.1-141.5 vs 193.6μM, 82.2-456.0; p

Blood pressure (BP) regulation is widely recognized as being integral to the control of end-organ perfusion, but it remains unclear whether end-organ perfusion also plays a role in driving changes in BP. A randomized and placebo-controlled study design was followed to examine feedback relationships between very-low-frequency fluctuations in BP and cerebral blood flow (CBF) in humans under placebo treatment and α1-adrenergic blockade. To determine the causal relations among hemodynamic variables, BP, middle cerebral artery blood velocity (MCAv), and end-tidal CO 2 time-series were decimated, low-pass filtered (1-adrenergic blockade results in the dominant causal direction from BP to MCAv. These results suggest that, between subjects, cerebral pressure-flow interactions at time scales < 0.07 Hz are frequently bidirectional, and that in the presence of an intact autonomic nervous system BP may be regulated by reflex pathways sensitive to changes in CBF.

BACKGROUND Gamma irradiation of red blood cells (RBCs) is well recognized to exacerbate storage lesion formation, but the effect of storage after irradiation on in vivo oxygen delivery capacity of transfused RBCs is currently not known. STUDY DESIGN AND METHODS In 24 preterm infants with anemia receiving nonurgent transfusion of irradiated RBCs, we examined cerebral regional tissue oxygenation (crSO2 ) and time spent with peripheral arterial saturation (SpO2 ) less than 88%. Physiologic data were obtained immediately before, immediately after, and 5 days after transfusion. RESULTS We observed linear negative moderate correlations between time since irradiation and the magnitude of change in crSO2 (r = -0.60; 95% CI, -0.81 to -0.27; p = 0.0018) and time spent with SpO2 of less than 88% (r = -0.42; 95% CI, -0.71 to 0.003; p = 0.04) immediately after transfusion. In infants (n = 9) who received fresher RBCs (irradiated

SummaryPurpose Blood pressure (BP) is commonly assessed by brachial oscillometry in clinical practice, whereas in physiological studies, finger plethysmography is often employed. This study assessed the limits of agreement between BP metrics obtained from each device. Methods In 96 participants, we simultaneously recorded BP by brachial oscillometry (BP+; Uscom, Sydney, NSW, Australia) and finger plethysmography (Finometer MIDI, MLE1054-V; Finapres Medical Systems B.V., Amsterdam, the Netherlands). Agreement between the two devices was assessed by correlation and Bland–Altman analysis. We assessed average BP differences between the two devices using the criteria of the Association for the Advancement of Medical Instruments (AAMI), which require systolic and diastolic BP differences to be within ≤5 ± 8 (mean ± SD). Results Bland–Altman analysis showed wide limits of agreement (±~17 mmHg or greater) between finger-derived brachial and oscillometric BP. Both systolic and mean BP exhibited positive proportional biases (both P

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg

The dynamic regulation of cerebral blood flow (CBF) is thought to involve myogenic and chemoreflex mechanisms, but the extent to which the sympathetic nervous system also plays a role remains debated. Here we sought to identify the role of human sympathetic neurovascular control by examining cerebral pressure-flow relations using linear transfer function analysis and multivariate wavelet decomposition analysis that explicitly accounts for the confounding effects of dynamic end-tidal Pco2 (PetCO2) fluctuations. In 18 healthy participants randomly assigned to the α1-adrenergic blockade group ( n = 9; oral Prazosin, 0.05 mg/kg) or the placebo group ( n = 9), we recorded blood pressure, middle cerebral blood flow velocity, and breath-to-breath PetCO2. Analyses showed that the placebo administration did not alter wavelet phase synchronization index (PSI) values, whereas sympathetic blockade increased PSI for frequency components ≤0.03 Hz. Additionally, three-way interaction effects were found for PSI change scores, indicating that the treatment response varied as a function of frequency and whether PSI values were PetCO2 corrected. In contrast, sympathetic blockade did not affect any linear transfer function parameters. These data show that very-low-frequency CBF dynamics have a composite origin involving, not only nonlinear and nonstationary interactions between BP and PetCO2, but also frequency-dependent interplay with the sympathetic nervous system.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) likely plays an important role in the prevention of stroke, which is three- to fourfold more common after spinal cord injury (SCI). Although the directional relationship between BP and cerebral blood flow (CBF) has traditionally been thought to travel solely from BP to CBF, a Cushing-like mechanism functioning in the inverse direction, in which changes in CBF influence BP, has recently been revealed using Granger causality analysis. Although both CBF buffering of BP and the Cushing- like mechanism are influenced by the sympathetic nervous system, we do not understand the impact of disruption of descending sympathetic pathways within the spinal cord, caused by cervical SCI on these regulatory systems. We hypothesized that people with cervical SCI would have greater BP to CBF transmission, as well as a reduced Cushing- like mechanism. The directional relationships between mean arterial BP (MAP ; Finometer((R)) PRO) and middle cerebral artery blood velocity (MCAv ; transcranial Doppler) were assessed at rest in 14 cervical SCI subjects and 16 uninjured individuals using Granger causality analysis, while also accounting for end-tidal CO2 tension. Those with SCI exhibited 66% increased forward MAPMCAv information transmission as compared with the uninjured group (p=0.0003), indicating reduced cerebrovascular buffering of BP, and did not have a predominant backward Cushing-like MCAvMAP phenotype. These results indicate that both forward and backward communication between BP and CBF are influenced by SCI, which may be associated with impaired cerebrovascular BP buffering after SCI as well as widespread BP instability.

It is known that high blood pressure variability (BPV) in acute ischemic stroke is associated with adverse outcomes, yet there are no therapeutic treatments to reduce BPV. Studies have found increasing nitric oxide (NO) bioavailability improves neurological function following stroke, but whether dietary nitrate supplementation could reduce BPV remains unknown. We investigated the effects of dietary nitrate supplementation on heart rate (HR), blood pressure (BP), and beat-to-beat BPV using wireless telemetry in a rat model of distal middle cerebral artery occlusion. Blood pressure variability was characterized by spectral power analysis in the low frequency (LF; 0.2–0.6 Hz) range prestroke and during the 7 days poststroke in a control group ( n = 8) and a treatment group ( n = 8, 183 mg/l sodium nitrate in drinking water). Dietary nitrate supplementation moderately reduced systolic BPV in the LF range by ~11% compared with the control group ( P = 0.03), while resting BP and HR were not different between the two groups ( P = 0.28 and 0.33, respectively). Despite systolic BPV being reduced with dietary nitrate, we found no difference in infarct volumes between the treatment and the control groups (1.59 vs. 1.62 mm3, P = 0.86). These findings indicate that dietary nitrate supplementation is effective in reducing systolic BPV following stroke without affecting absolute BP. In light of mounting evidence linking increased BPV with poor stroke patient outcome, our data support the role of dietary nitrate as an adjunct treatment following ischemic stroke. NEW & NOTEWORTHY Using a rat model of stroke, we found that dietary nitrate supplementation reduced low frequency blood pressure fluctuations following stroke without affecting absolute blood pressure values. Since blood pressure fluctuations are associated with poor clinical outcome in stroke patients, our findings indicate that dietary nitrate could be an effective strategy for reducing blood pressure fluctuations, which could help reduce stroke severity and improve patient recovery.

The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) is crucial to prevent stroke, the incidence of which is three- to fourfold elevated after spinal cord injury (SCI). Disruption of descending sympathetic pathways within the spinal cord due to cervical SCI may result in impaired cerebrovascular buffering. Only linear analyses of cerebrovascular buffering of BP, such as transfer function, have been used in SCI research. This approach does not account for inherent nonlinearity and nonstationarity components of cerebrovascular regulation, often depends on perturbations of BP to increase the statistical power, and does not account for the influence of arterial CO2 tension. Here, we used a nonlinear and nonstationary analysis approach termed wavelet decomposition analysis (WDA), which recently identified novel sympathetic influences on cerebrovascular buffering of BP occurring in the ultra-low-frequency range (ULF; 0.02–0.03Hz). WDA does not require BP perturbations and can account for influences of CO2 tension. Supine resting beat-by-beat BP (Finometer), middle cerebral artery blood velocity (transcranial Doppler), and end-tidal CO2 tension were recorded in cervical SCI ( n = 14) and uninjured ( n = 16) individuals. WDA revealed that cerebral blood flow more closely follows changes in BP in the ULF range ( P = 0.0021, Cohen’s d = 0.89), which may be interpreted as an impairment in cerebrovascular buffering of BP. This persisted after accounting for CO2. Transfer function metrics were not different in the ULF range, but phase was reduced at 0.07–0.2 Hz ( P = 0.03, Cohen’s d = 0.31). Sympathetically mediated cerebrovascular buffering of BP is impaired after SCI, and WDA is a powerful strategy for evaluating cerebrovascular buffering in clinical populations.

Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked.Twenty young adults (16 male, age: 26.7 ± 6.6 years, BMI: 24.9 ± 3.0 kg/mThere were main effects for both cardiac cycle and frequency for phase and gain metrics (p0.001). The systolic phase (mean ± SD) was elevated at 0.05 (1.07 ± 0.51 radians) and 0.10 Hz (0.70 ± 0.46 radians) compared to the diastolic phase (0.05 Hz: 0.59 ± 0.14 radians; 0.10 Hz: 0.33 ± 0.11 radians). Conversely, the systolic normalized gain was reduced (0.05 Hz: 0.49 ± 0.12%/%; 0.10 Hz: 0.66 ± 0.20%/%) compared to the diastolic normalized gain (0.05 Hz: 1.46 ± 0.43%/%; 0.10 Hz: 1.97 ± 0.48%/%).These findings indicate there are differential systolic and diastolic aspects of the cerebral pressure-flow relationship. The oscillations associated with systole are extensively buffered within the cerebrovasculature, whereas diastolic oscillations are relatively unaltered. This indicates that the brain is adapted to protect itself against large increases in systolic blood pressure, likely as a mechanism to prevent cerebral haemorrhages.

Evidence derived from spontaneous measures of cardiovagal baroreflex sensitivity (BRS) suggests that slow breathing at 6 breaths/min augments BRS. However, increases in BRS associated with slow breathing may simply reflect the frequency-dependent nature of the baroreflex rather than the modulation of baroreflex function by changes in breathing rate per se. To test this hypothesis we employed a crossover study design ( n = 14) wherein breathing rate and systolic arterial blood pressure (SAP) oscillation induced via the application of oscillating lower body negative pressure (OLBNP) were independently varied at fixed frequencies. Breathing rate was controlled at 6 or 10 breaths/min with the aid of a metronome, and SAP oscillations were driven at 0.06 Hz and 0.1 Hz using OLBNP. The magnitudes of SAP and R-R interval (cardiac period) oscillations were quantified using power spectral analysis, and the transfer function gain between SAP and R-R interval was used to estimate BRS. Linear mixed-effects models were used to examine the main effects and interactions between breathing rate and OLBNP frequency. There was no statistical interaction between breathing and OLBNP frequency ( P = 0.59), indicating that the effect of breathing rate on BRS did not differ according to OLBNP frequency (and vice versa). Additionally, there was no main effect for breathing rate ( P = 0.28). However, we observed a significant main effect for OLBNP frequency ( P = 0.01) consistent with the frequency-dependent nature of baroreflex. These findings suggest that increases in spectral indices of BRS reflect the frequency dependence of the baroreflex and are not due to slow breathing per se.

We examined the between-day reproducibility of active (squat-stand maneuvers)- and passive [oscillatory lower-body negative pressure (OLBNP) maneuvers]-driven oscillations in blood pressure. These relationships were examined in both younger ( n = 10; 25 ± 3 yr) and older ( n = 9; 66 ± 4 yr) adults. Each testing protocol incorporated rest (5 min), followed by driven maneuvers at 0.05 (5 min) and 0.10 (5 min) Hz to increase blood-pressure variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal partial pressure of CO2 were monitored. The pressure-flow relationship was quantified in the very low (0.02-0.07 Hz) and low (0.07–0.20 Hz) frequencies (LF; spontaneous data) and at 0.05 and 0.10 Hz (driven maneuvers point estimates). Although there were no between-age differences, very few spontaneous and OLBNP transfer function metrics met the criteria for acceptable reproducibility, as reflected in a between-day, within-subject coefficient of variation (CoV) of

Objective: Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked.

Gamma irradiation of red blood cells (RBCs) is well recognized to exacerbate storage lesion formation, but the effect of storage after irradiation on in vivo oxygen delivery capacity of transfused RBCs is currently not known.In 24 preterm infants with anemia receiving nonurgent transfusion of irradiated RBCs, we examined cerebral regional tissue oxygenation (crSOWe observed linear negative moderate correlations between time since irradiation and the magnitude of change in crSOOur findings indicate that storage after gamma irradiation may have a detrimental effect on the oxygen delivery capacity of RBCs given to anemic preterm infants.

BackgroundFunctional cerebrovascular regulatory mechanisms are important for maintaining constant cerebral blood flow and oxygen supply in heathy individuals and are altered in heart failure. We aim to examine whether pulmonary arterial hypertension (PAH) is associated with abnormal cerebrovascular regulation and lower cerebral oxygenation and their physiological and clinical consequences.Methods and ResultsResting mean flow velocity in the middle cerebral artery mean flow velocity in the middle cerebral artery (MCAvmean); transcranial Doppler), cerebral pressure‐flow relationship (assessed at rest and during squat‐stand maneuvers; analyzed using transfer function analysis), cerebrovascular reactivity toCO2, and central chemoreflex were assessed in 11 patients with PAH and 11 matched healthy controls. Both groups also completed an incremental ramp exercise protocol until exhaustion, during whichMCAvmean, mean arterial pressure, cardiac output (photoplethysmography), end‐tidal partial pressure ofCO2, and cerebral oxygenation (near‐infrared spectroscopy) were measured. Patients were characterized by a significant decrease in restingMCAvmean(PPCO2was reduced (P=0.03), whereas central chemoreceptor sensitivity was increased inPAH(PR2=0.47;P2production slope (V˙E/V˙CO2slope;R2=0.62;PMCAvmeanwere limited inPAH(PMCAvmeancontributed to impaired cerebral oxygen delivery and oxygenation (bothPR2=0.52;P=0.01).ConclusionsThese findings provide comprehensive evidence for physiologically and clinically relevant impairments in cerebral hemodynamic regulation and oxygenation inPAH.

Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R2 values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04–0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.

Stroke remains the leading cause of long-term disability with no pharmacological approaches available to limit the degree of damage or aid in recovery. Considerable effort has been made to minimize neuronal damage using neuroprotective compounds. However, attempts have so far failed to translate into the clinic. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase type B are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Further, BDNF has been shown to play a role in both protection and recovery of functions after stroke. This review focuses on the endogenous release of BDNF as well as activity-induced (pharmacological and physical) elevation in BDNF, and the role this plays during both acute (hours to days) and subacute (days to weeks) periods after stroke. Exogenous administration has previously been shown not to cross the blood-brain barrier; therefore, we have focused this review on approaches that allow us to directly stimulate, using pharmacological therapies and mimetics, physical activity and potential drug delivery systems that can be used to administer BDNF. Finally, we also discuss the role of BDNF polymorphisms and the influence of epigenetic regulation of BDNF on post-stroke recovery.

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60–150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research.

Cerebral autoregulation (CA) is integral to the delicate process of maintaining stable cerebral perfusion and brain tissue oxygenation against changes in arterial blood pressure. The last four decades has seen dramatic advances in understanding CA physiology, and the role that CA might play in the causation and progression of disease processes that affect the cerebral circulation such as stroke. However, the translation of these basic scientific advances into clinical practice has been limited by the maintenance of old constructs and because there are persistent gaps in our understanding of how this vital vascular mechanism should be quantified. In this review, we re-evaluate relevant studies that challenge established paradigms about how the cerebral perfusion pressure and blood flow are related. In the context of blood pressure being a major haemodynamic challenge to the cerebral circulation, we conclude that: (1) the physiological properties of CA remain inconclusive, (2) many extant methods for CA characterisation are based on simplistic assumptions that can give rise to misleading interpretations, and (3) robust evaluation of CA requires thorough consideration not only of active vasomotor function, but also the unique properties of the intracranial environment.

Aim The ability to maintain arterial blood pressure when faced with a postural challenge has implications for the occurrence of syncope and falls. It has been suggested that posture-induced declines in the mechanical component of the baroreflex response drive reductions in cardiovagal baroreflex sensitivity associated with postural stress. However, these conclusions are largely based upon spontaneous methods of baroreflex assessment, the accuracy of which has been questioned. Therefore, the aim was to engage a partially open-loop approach to explore the influence of posture on the mechanical and neural components of the baroreflex. Methods In nine healthy participants, we measured continuous blood pressure, heart rate, RR interval and carotid artery diameter during supine and standing postures. The modified Oxford method was used to quantify baroreflex sensitivity. Results In response to falling pressures, baroreflex sensitivity was similar between postures (P = 0.798). In response to rising pressures, there was an attenuated (P = 0.042) baroreflex sensitivity (mean ± SE) in the standing position (−0.70 ± 0.11 beats min−1 mmHg−1) compared with supine (−0.83 ± 0.06 beats min−1 mmHg−1). This was explained by a diminished (P = 0.016) neural component whilst standing (−30.17 ± 4.16 beats min−1 mm−1) compared with supine (−38.23 ± 3.31 beats min−1 mm−1). These effects were consistent when baroreflex sensitivity was determined using RR interval. Conclusion Cardiovagal baroreflex sensitivity in response to rising pressures is reduced in young individuals during postural stress. Our data suggest that the mechanical component is unaffected by standing, and the reduction in baroreflex sensitivity is driven by the neural component.

This study sought to determine whether models of cerebrovascular function based on Laguerre- Volterra kernels that account for nonlinear cerebral blood flow (CBF) dynamics can detect the effects of functional cerebral sympathetic blockade. We retrospectively analysed continuous beat-to-beat blood pressure, middle cerebral blood velocity, and partial-pressure of end-tidal CO2 (PETCO2) recordings from eighteen healthy individuals who were treated with either an oral dose of the alpha1-adrenergic receptor blocker Prazosin or a placebo treatment. The global principal dynamic modes (PDMs) were analysed using Laguerre-Volterra kernels to examine the nonlinear system dynamics. Our principal findings were: 1) very low frequency (

Autonomic dysfunction and diminished capacity for physical exercise are commonly implicated in the 3- to 4-fold increased risk of cerebrovascular disease after spinal cord injury (SCI). We assessed cerebrovascular function (transcranial Doppler; neurovascular coupling [NVC], and cerebral pressure-flow regulation) in elite national level wheelchair rugby players (n = 23), normally active SCI individuals (n = 12), and able-bodied controls (n = 13). Cognitive (Stroop test) and autonomic function (postural change) also were evaluated. SCI individuals demonstrated reduced posterior cerebral blood flow, as well as impaired cerebrovascular and cognitive function. Autonomic dysfunction but not physical activity was related to impaired NVC and cerebral pressure-flow regulation after SCI. Routine upper-body exercise, as utilized by elite wheelchair rugby athletes, may not elicit beneficial cerebrovascular effects. On the other hand, autonomic dysfunction needs to be considered a key culprit in cerebrovascular diseases after SCI.

Key points • Cerebral autoregulation maintains cerebral perfusion relatively constant in the face of slow changes in arterial pressure, but is less effective against more rapid changes (i.e. functions as a ‘high-pass’ filter). • While thought to be maintained mainly through myogenic adjustments to changes in transmural pressure, recent work has highlighted a possibility of active autonomic involvement in cerebral autoregulation. • In this study we examined the cerebrovascular effects of cholinergic blockade on nine healthy volunteers during the application of oscillatory lower body pressure at six frequencies from 0.03 to 0.08 Hz. • Cholinergic blockade impaired autoregulation at frequencies above 0.04 Hz, suggesting a role for active cholinergic vasodilatation in the maintenance of cerebral perfusion. Abstract Despite growing evidence of autonomic nervous system involvement in the regulation of cerebral blood flow, the specific contribution of cholinergic vasodilatation to cerebral autoregulation remains unknown. We examined cerebral and forearm blood flow responses to augmented arterial pressure oscillations with and without cholinergic blockade. Oscillatory lower body negative pressure was applied at six frequencies from 0.03 to 0.08 Hz in nine healthy subjects with and without cholinergic blockade via glycopyrrolate. Cholinergic blockade increased cross-spectral coherence between arterial pressure and cerebral flow at all frequencies except 0.03 Hz and increased the transfer function gain at frequencies above 0.05 Hz. In contrast, gain between pressure and forearm flow increased only at frequencies below 0.06 Hz. These data demonstrate that the cholinergic system plays an active and unique role in cerebral autoregulation. The frequency region and magnitude of effect is very similar to what has been seen with sympathetic blockade, indicating a possible balance between the two reflexes to most effectively respond to rising and falling pressure. These findings might have implications for the role of dysfunction in autonomic control of the vasculature in cerebrovascular disease states.

We sought to determine the influence of sympathoexcitation on dynamic cerebral autoregulation (CA), cerebrovascular reactivity, and ventilatory control in humans at high altitude (HA). At sea level (SL) and following 3–10 days at HA (5,050 m), we measured arterial blood gases, ventilation, arterial pressure, and middle cerebral blood velocity (MCAv) before and after combined α- and β-adrenergic blockade. Dynamic CA was quantified using transfer function analysis. Cerebrovascular reactivity was assessed using hypocapnia and hyperoxic hypercapnia. Ventilatory control was assessed from the hypercapnia and during isocapnic hypoxia. Arterial Pco2 and ventilation and its control were unaltered following blockade at both SL and HA. At HA, mean arterial pressure (MAP) was elevated ( P < 0.01 vs. SL), but MCAv remained unchanged. Blockade reduced MAP more at HA than at SL (26 vs. 15%, P = 0.048). At HA, gain and coherence in the very-low-frequency (VLF) range (0.02–0.07 Hz) increased, and phase lead was reduced (all P < 0.05 vs. SL). Following blockade at SL, coherence was unchanged, whereas VLF phase lead was reduced (−40 ± 23%; P < 0.01). In contrast, blockade at HA reduced low-frequency coherence (−26 ± 20%; P = 0.01 vs. baseline) and elevated VLF phase lead (by 177 ± 238%; P < 0.01 vs. baseline), fully restoring these parameters back to SL values. Irrespective of this elevation in VLF gain at HA ( P < 0.01), blockade increased it comparably at SL and HA (∼43–68%; P < 0.01). Despite elevations in MCAv reactivity to hypercapnia at HA, blockade reduced ( P < 0.05) it comparably at SL and HA, effects we attributed to the hypotension and/or abolition of the hypercapnic-induced increase in MAP. With the exception of dynamic CA, we provide evidence of a redundant role of sympathetic nerve activity as a direct mechanism underlying changes in cerebrovascular reactivity and ventilatory control following partial acclimatization to HA. These findings have implications for our understanding of CBF function in the context of pathologies associated with sympathoexcitation and hypoxemia.

Although the cerebrovasculature is known to be exquisitely sensitive to CO2, there is no consensus on whether the sympathetic nervous system plays a role in regulating cerebrovascular responses to changes in arterial CO2. To address this question, we investigated human cerebrovascular CO2 reactivity in healthy participants randomly assigned to the α1-adrenoreceptor blockade group (9 participants; oral prazosin, 0.05 mg/kg) or the placebo control (9 participants) group. We recorded mean arterial blood pressure (MAP), heart rate (HR), mean middle cerebral artery flow velocity (MCAV mean), and partial pressure of end-tidal CO2 (PetCO2) during 5% CO2 inhalation and voluntary hyperventilation. CO2 reactivity was quantified as the slope of the linear relationship between breath-to-breath PetCO2 and the average MCAvmean within successive breathes after accounting for MAP as a covariate. Prazosin did not alter resting HR, PetCO2, MAP, or MCAV mean. The reduction in hypocapnic CO2 reactivity following prazosin (−0.48 ± 0.093 cm·s−1·mmHg−1) was greater compared with placebo (−0.19 ± 0.087 cm·s−1·mmHg−1; P < 0.05 for interaction). In contrast, the change in hypercapnic CO2 reactivity following prazosin (−0.23 cm·s−1·mmHg−1) was similar to placebo (−0.31 cm·s−1·mmHg−1; P = 0.50 for interaction). These data indicate that the sympathetic nervous system contributes to CO2 reactivity via α1-adrenoreceptors; blocking this pathway with prazosin reduces CO2 reactivity to hypocapnia but not hypercapnia.

Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P

Cardioventilatory coupling (CVC) is a temporal alignment between the heartbeat and inspiratory activity caused by pulsatile baroreceptor afferent activity. However, although first described over a century ago, the functional significance of CVC has yet to be established. One hypothesis is that baroreceptor triggering of inspiration positions heartbeats into phases of the respiratory cycle that may optimize pulmonary gas exchange efficiency. To test this hypothesis, we recruited ten patients with permanently implanted fixed-rate cardiac pacemakers and instructed them to pace breathe at heart rate-to-respiratory rate (HR/f) ratios of 3·8, 4·0 and 4·2. This breathing protocol enabled us to simulate heartbeat distributions similar to those seen in the presence (4·0) and complete absence (3·8, 4·2) of CVC. Results showed that heart rate, mean arterial pressure, end-tidal carbon dioxide and tidal volume remained unchanged across the three conditions (P> 0·05). Pulmonary gas exchange efficiency, as determined by the ventilatory equivalents of carbon dioxide (V·E/V·CO2) and oxygen (V·E/V·O2) did not differ significantly by HR/f ratio (P = 0·29 and P = 0·70, respectively). These data suggest that CVC does not play a significant role in optimizing pulmonary gas exchange efficiency in humans.