Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO 2 stimuli. Abbreviations ACZ, acetazolamide; ASL, arterial spin labeling; BOLD, blood oxygen level-dependent; CBF, cerebral blood flow; CVR, cerebrovascular reactivity; DEF, dynamic end-tidal forcing; MRI, magnetic resonance imaging; SGD, sequential gas delivery (circuit); TCD, trans-cranial Doppler.Jorn Fierstra is currently enrolled in a neurosurgical training program at the University Medical Center Zürich, Switzerland. His PhD degree from Utrecht University, was based on research done in the Department of Neurosurgery, Neuroradiology and Anesthesiology of the University Health Network, Toronto, Canada, and he recently received an MD degree from Utrecht University, the Netherlands. His research interests include clinical investigations of cerebral vasculature pathophysiology and fMRI related research. Olivia Sobczyk is currently a PhD student in the Institute of Medical Science at the University of Toronto and the University Health Network, Toronto, Canada. She obtained her MSc in Biomedical Physics from Ryerson University, Toronto, Canada. Her research interests include mathematical modeling and investigation in cerebral hemodynamic processes, specifically cerebral vascular reactivity, and clinical investigation in the application of functioning imaging tools to investigate neurological disorders.

Non-technical summary Two mechanisms control brain blood flow by changing blood vessel diameter: autoregulation maintains flow in the face of perfusion pressure changes, and brain metabolism adjusts flow to meet metabolic requirements. Brain blood vessel reactivity to CO 2 and O 2 is an important component of the latter. We used a specialised rebreathing technique to change CO 2 over a wide range at constant O 2 , estimating brain blood flow responses from measurements of middle cerebral artery flow velocity. We found that below a threshold CO 2 , blood pressure was unchanged, but blood flow increased in response to CO 2 . This response had a sigmoidal shape, centred at a CO 2 close to resting. Above the threshold, both blood flow and pressure increased with CO 2 . We concluded that this method measures the brain blood flow reactivity to CO 2 without the confounding influence of blood pressure changes. The results obtained contribute to our understanding of brain blood flow regulation.Abstract Carbon dioxide (CO 2 ) increases cerebral blood flow and arterial blood pressure. Cerebral blood flow increases not only due to the vasodilating effect of CO 2 but also because of the increased perfusion pressure after autoregulation is exhausted. Our objective was to measure the responses of both middle cerebral artery velocity (MCAv) and mean arterial blood pressure (MAP) to CO 2 in human subjects using Duffin-type isoxic rebreathing tests. Comparisons of isoxic hyperoxic with isoxic hypoxic tests enabled the effect of oxygen tension to be determined. During rebreathing the MCAv response to CO 2 was sigmoidal below a discernible threshold CO 2 tension, increasing from a hypocapnic minimum to a hypercapnic maximum. In most subjects this threshold corresponded with the CO 2 tension at which MAP began to increase. Above this threshold both MCAv and MAP increased linearly with CO 2 tension. The sigmoidal MCAv response was centred at a CO 2 tension close to normal resting values (overall mean 36 mmHg). While hypoxia increased the hypercapnic maximum percentage increase in MCAv with CO 2 (overall means from 76.5 to 108%) it did not affect other sigmoid parameters. Hypoxia also did not alter the supra-threshold MCAv and MAP responses to CO 2 (overall mean slopes 5.5% mmHg −1 and 2.1 mmHg mmHg −1 , respectively), but did reduce the threshold (overall means from 51.5 to 46.8 mmHg). We concluded that in the MCAv response range below the threshold for the increase of MAP with CO 2 , the MCAv measurement reflects vascular reactivity to CO 2 alone at a constant MAP.

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CVR mapping by using a prospectively targeted CO(2) stimulus and BOLD MR imaging is safe, well tolerated, and technically feasible in a clinical patient population.