What is the central question of this study? We developed and validated a 'stimulus index' (SI; ratio of end-tidal partial pressures of CO and O ) method to quantify cerebrovascular reactivity (CVR) in anterior and posterior cerebral circulations during breath holding. We aimed to determine whether the magnitude of CVR is correlated with breath-hold duration. What is the main finding and its importance? Using the SI method and transcranial Doppler ultrasound, we found that the magnitude of CVR of the anterior and posterior cerebral circulations is not positively correlated with physiological or psychological break-point during end-inspiratory breath holding. Our study expands the ability to quantify CVR during breath holding and elucidates factors that affect break-point. The central respiratory chemoreflex contributes to blood gas homeostasis, particularly in response to accumulation of brainstem CO . Cerebrovascular reactivity (CVR) affects chemoreceptor stimulation inversely through CO washout from brainstem tissue. Voluntary breath holding imposes alterations in blood gases, eliciting respiratory chemoreflexes, potentially contributing to breath-hold duration (i.e. break-point). However, the effects of cerebrovascular reactivity on break-point have yet to be determined. We tested the hypothesis that the magnitude of CVR contributes directly to breath-hold duration in 23 healthy human participants. We developed and validated a cerebrovascular stimulus index methodology [SI; ratio of end-tidal partial pressures of CO and O (P ET ,CO2/P ET ,O2)] to quantify CVR by correlating measured and interpolated values of P ET ,CO2 (r = 0.95, P < 0.0001), P ET ,O2 (r = 0.98, P < 0.0001) and SI (r = 0.94, P < 0.0001) during rebreathing. Using transcranial Doppler ultrasound, we then quantified the CVR of the middle (MCAv) and posterior (PCAv) cerebral arteries by plotting cerebral blood velocity against interpolated SI during a maximal end-inspiratory breath hold. The MCAv CVR magnitude was larger than PCAv (P = 0.001; +70%) during breath holding. We then correlated MCAv and PCAv CVR with the physiological (involuntary diaphragmatic contractions) and psychological (end-point) break-point, within individuals. There were significant inverse but modest relationships between both MCAv and PCAv CVR and both physiological and psychological break-points (r < -0.53, P < 0.03). However, these relationships were absent when MCAv and PCAv cerebrovascular conductance reactivity was correlated with both physiological and psychological break-points (r > -0.42; P > 0.06). Although central chemoreceptor activation is likely to be contributing to break-point, our data suggest that CVR-mediated CO washout from central chemoreceptors plays no role in determining break-point, probably because of a reduced arterial-to-tissue CO gradient during breath holding.

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Both voluntary breath‐holding and rebreathing of expired air elicit changes in respiratory gas chemostimuli (CO2 and O2) at the metabolic rate. These chemostimuli elicit increases in cerebral blood flow (CBF), proportional to the magnitude of concomitant increases in CO2 and reductions in O2. These chemostimuli also activate the sympathetic nervous system, which increases systemic blood pressure. Although blood pressure responses appear small during rebreathing, evidence from obstructive sleep apnea (OSA) patients suggests higher mean blood pressure during sleep in those with worse OSA. We aimed to assess how superimposed changes in blood gases and increases in blood pressure affect the CBF responses during breath holding vs. rebreathing. We recruited 23 healthy participants (12 females) and instrumented them with a finometer (for beat‐by‐beat mean arterial blood pressure; MAP), transcranial Doppler ultrasound (middle and posterior cerebral artery velocity; MCAv, PCAv) and a pneumotachometer with gas sampling via a dual gas analyzer to assess the pressure of end‐tidal (PET)CO2 and O2. Participants carried out two protocols in randomized order: (a) a maximal, voluntary end‐inspiratory breath hold (BH) and (b) a rebreathing (RB) test. A breath‐by‐breath stimulus index (SI) was calculated as PETCO2/PETO2 during rebreathing, whereas the end‐tidal gas values used to calculate SI were interpolated during breath holding from initial and break point values. During both BH and RB, cerebrovascular reactivity (CVR) was calculated as the MCAv or PCAv/SI. MAP reactivity (MAPR) was calculated as the slope of the MAP/SI response. Cerebrovascular conductance (CVC; MCA or PCA/MAP) reactivity (CVCR) was calculated as the slope of the MCACVC or PCACVC/SI responses. We found that (a) CVR was larger during BH vs. RB (MCA: 167.5±102.0 vs. 38.8±20.5 cm/s/SI, P<0.0001, n=23; PCA: 76.3±40.1 vs. 26.0±11.0 cm/s/SI, P<0.0001, n=19), (b) MAPR during BH was significantly higher than during RB (134.0±102.7 vs. 31.0±12.6 mmHg/SI, P=0.0001, n=23). and (c) CVCR during BH vs. RB (MCA: 0.75±0.69 vs. 0.16±0.15 cm/s/mmHg/SI, P<0.001, n=22; PCA: 0.26±0.29 vs. 0.12±0.09 cm/s/SI, cm/s/mmHg/SI, P=0.03, n=19). Our data demonstrate that breath holding elicited ~4‐fold increases in MAP, translating to a larger anterior and posterior CVR compared to rebreathing. These findings suggest that the sympathetic responses during voluntary breath holding were larger than those during rebreathing across similar chemostimuli, potentially due to the differential sympathetic effects of struggling against a closed glottis during breath holding. This is the first evidence that voluntary apnea has larger effects on brain blood flow beyond that elicited by blood gas stimuli alone. Our data may have implications for understanding stroke risk in clinical populations with obstructive sleep apnea, whereby patients experience intermittent breath holds throughout the night, with associated spikes in arterial blood pressure.

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