J.A. Fisher

The cerebrovascular response to carbon dioxide in humans

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 CO2 and O2 is an important component of the latter. We used a specialised rebreathing technique to change CO2 over a wide range at constant O2, estimating brain blood flow responses from measurements of middle cerebral artery flow velocity. We found that below a threshold CO2, blood pressure was unchanged, but blood flow increased in response to CO2. This response had a sigmoidal shape, centred at a CO2 close to resting. Above the threshold, both blood flow and pressure increased with CO2. We concluded that this method measures the brain blood flow reactivity to CO2 without the confounding influence of blood pressure changes. The results obtained contribute to our understanding of brain blood flow regulation.

Measuring cerebrovascular reactivity: what stimulus to use?

Abstract  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 CO2 stimuli.

Quantitative Measurement of Cerebrovascular Reactivity by Blood Oxygen Level-Dependent MR Imaging in Patients with Intracranial Stenosis: Preoperative Cerebrovascular Reactivity Predicts the Effect of Extracranial-Intracranial Bypass Surgery

BACKGROUND AND PURPOSE: CVR is a measure of cerebral hemodynamic impairment. A recently validated technique quantifies CVR by using a precise CO2 vasodilatory stimulus and BOLD MR imaging. Our aim was to determine whether preoperative CO2 BOLD CVR predicts the hemodynamic effect of ECIC bypass surgery in patients with intracranial steno-occlusive disease. MATERIALS AND METHODS: Twenty-five patients undergoing ECIC bypass surgery for treatment of intracranial stenosis or occlusion were recruited. CVR was measured preoperatively and postoperatively and expressed as %ΔBOLD MR signal intensity per mm Hg ΔPetCO2. Using normative data from healthy subjects, we stratified patients on the basis of preoperative CVR into 3 groups: normal CVR, reduced CVR, and negative (paradoxical) CVR. Wilcoxon 2-sample tests (2-sided, α = 0.05) were used to determine whether the 3 groups differed with respect to change in CVR following bypass surgery. RESULTS: The group with normal preoperative CVR demonstrated no significant change in CVR following bypass surgery (mean, 0.22% ± 0.05% to 0.22% ± 0.01%; P = .881). The group with reduced preoperative CVR demonstrated a significant improvement following bypass surgery (mean, 0.08% ± 0.05% to 0.21 ± 0.08%; P < .001), and the group with paradoxical preoperative CVR demonstrated the greatest improvement (mean change, −0.04% ± 0.03% to 0.27% ± 0.03%; P = .028). CONCLUSIONS: Preoperative measurement of CVR by using CO2 BOLD MR imaging predicts the hemodynamic effect of ECIC bypass in patients with intracranial steno-occlusive disease. The technique is potentially useful for selecting patients for surgical revascularization.

Quantification of cerebrovascular reactivity by blood oxygen level-dependent MR imaging and correlation with conventional angiography in patients with Moyamoya disease.

BACKGROUND AND PURPOSE: BOLD MR imaging combined with a technique for precision control of end-tidal pCO2 was used to produce quantitative maps of CVR in patients with Moyamoya disease. The technique was validated against measures of disease severity by using conventional angiography; it then was used to study the relationship between CVR, vascular steal, and disease severity. MATERIALS AND METHODS: A retrospective analysis comparing conventional angiography with BOLD MR imaging was performed on 11 patients with Moyamoya disease. Iso-oxic cycling of end-tidal pCO2 between 2 target values was performed during BOLD MR imaging. CVR was calculated as the BOLD signal difference per ΔpCO2. CVR was correlated with the presence of Moyamoya or pial collaterals and the degree of Moyamaya disease as graded by using a modified Suzuki score. RESULTS: A good correlation between mean CVR and Suzuki score was found for the MCA and ACA territories (Pearson correlation coefficient, −0.7560 and −0.6140, respectively; P < .0001). A similar correlation was found between mean CVR and the presence of pial and Moyamoya collateral vessels for combined MCA and ACA territories (Pearson correlation coefficient, −0.7466; P < .0001). On a voxel-for-voxel basis, there was a greater extent of steal within vascular territories with increasing disease severity (higher modified Suzuki score). Mean CVR was found to scale nonlinearly with the extent of vascular steal. CONCLUSIONS: Quantitative measures of CVR show direct correlation with impaired vascular supply as measured by the modified Suzuki score and enable direct investigation of the physiology of autoregulatory reserve, including steal phenomenon, within a given vascular territory.

Mapping white matter diffusion and cerebrovascular reactivity in carotid occlusive disease

Objective: To characterize the relationship between cerebrovascular reactivity (CVR) and white matter (WM) diffusion in patients with internal carotid artery (ICA) occlusive disease. Methods: In this exploratory observational study, 41 patients with severe stenosis or occlusion of the extracranial ICA and 12 healthy control subjects underwent CVR mapping using the fMRI response to hypercapnia. Conventional anatomic and diffusion-weighted MRI sequences were used to calculate maps of the apparent diffusion coefficient (ADC) and to exclude areas of previous ischemic injury. In all subjects, ADC was compared between WM with positive and negative CVR. In 27 patients with unilateral ICA involvement, ADC and CVR were compared between ipsilateral and contralateral WM while covarying for relevant clinical risk factors. Results: In patients with bilateral disease and in the ipsilateral hemisphere of patients with unilateral disease, negative CVR was associated with increased WM ADC (p < 0.01 and p < 0.005, respectively). In patients with unilateral disease, the ipsilateral CVR deficit was correlated with the degree of hemispheric WM ADC elevation (p < 0.005). ADC elevation remained significant after correction for potential confounding risk factors. Conclusions: CVR impairment is associated with ADC elevation in normal-appearing WM of patients with severe stenosis or occlusion of the extracranial ICA. This finding is consistent with the presence of early, low-grade ischemic injury.

Central-peripheral respiratory chemoreflex interaction in humans.

We investigated the interaction between the central and peripheral chemoreflexes in humans using a temporal separation technique in three tests. In two tests hyperventilation was used to reduce central P(CO)₂ . In these tests the difference in the responses to the same step increases in P(CO)₂ to 45 mmHg at normoxic and hypoxic O(2) tensions provided a measure of the response to isocapnic hypoxia at a low central P(CO)₂. In a third test the response to a hypoxic step during sustained isocapnia at 45mmHg provided a measure of the response to isocapnic hypoxia at a high central P(CO)₂. The responses to isocapnic hypoxia at high and low central P(CO)₂were not significantly different, confirming the conclusion of previous studies that central and peripheral chemoreflex signals interact additively. This finding contrasts with those from recent animal experiments and emphasizes the need for caution when using animal experiments to make conclusions about the physiology of the respiratory chemoreflexes in humans.

Differences in the control of breathing between Himalayan and sea-level residents

We compared the control of breathing of 12 male Himalayan highlanders with that of 21 male sea‐level Caucasian lowlanders using isoxic hyperoxic (= 150 mmHg) and hypoxic (= 50 mmHg) Duffins rebreathing tests. Highlanders had lower mean ±s.e.m. ventilatory sensitivities to CO2 than lowlanders at both isoxic tensions (hyperoxic: 2.3 ± 0.3 vs. 4.2 ± 0.3 l min−1 mmHg−1, P= 0.021; hypoxic: 2.8 ± 0.3 vs. 7.1 ± 0.6 l min−1 mmHg−1, P < 0.001), and the usual increase in ventilatory sensitivity to CO2 induced by hypoxia in lowlanders was absent in highlanders (P= 0.361). Furthermore, the ventilatory recruitment threshold (VRT) CO2 tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 ± 0.9 vs. 48.9 ± 0.7 mmHg, P < 0.001; hypoxic: 31.2 ± 1.1 vs. 44.7 ± 0.7 mmHg, P < 0.001). Both groups had reduced ventilatory recruitment thresholds with hypoxia (P < 0.001) and there were no differences in the sub‐threshold ventilations (non‐chemoreflex drives to breathe) between lowlanders and highlanders at both isoxic tensions (P= 0.982), with a trend for higher basal ventilation during hypoxia (P= 0.052). We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea‐level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO2. Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO2‐independent increase in activity of peripheral chemoreceptor or hypoxia‐induced increase in [H+] at the central chemoreceptor. In some highlanders, the decrease in VRT was accompanied by an increase in sensitivity to CO2, while in others VRT remained unchanged and their sub‐threshold ventilations increased, although these were not statistically significant.

The effect of hypercarbia and hyperoxia on the total blood flow to the retina as assessed by magnetic resonance imaging.

PURPOSE The feasibility of measuring total blood flow to the retina with Arterial Spin Labeling Magnetic Resonance Imaging (ASL-MRI) has been described previously. In the present study, the hypothesis was that the reactivity that the ASL-MRI detects at the human retina is dominated by the choroidal blood flow, and thus it may serve as a useful tool for quantitative assessment of the choroidal vascular reactivity. METHODS Before imaging, the intraocular pressure (IOP) was measured in the study eye of nine clinically healthy subjects (four males) while the subject performed the ventilatory protocol subsequently imaged by the scanner. End-tidal CO₂ partial pressure (P(ET)CO₂) was increased to target 45 mm Hg, (baseline P(ET)CO₂ = 40 mm Hg and baseline P(ET)O₂ = 100 mm Hg). P(ET)O₂ was then increased to target 300 and 500 mm Hg while keeping P(ET)CO₂ constant at 45 mm Hg. A background-suppressed, pulsed-continuous ASL sequence was used for blood flow imaging. RESULTS The measured total blood flow increased significantly from 1.55 ± 0.17 μL/mm²/min at the baseline to 1.96 ± 0.18 μL/mm²/min during hypercarbia. With increasing P(ET)O₂, the measured blood flow did not change significantly relative to the hypercarbia condition but remained significantly elevated relative to the baseline. There were no significant changes in systolic, diastolic, or mean blood pressure, heart rate, or IOP during all four breathing conditions. CONCLUSIONS The lack of change in the ASL signal under hyperoxic conditions is consistent with the hypothesis that this noninvasive assessment technique is predominantly weighted by choroidal blood flow. The results indicate that a CO₂ provocation challenge, in combination with ASL-MRI, is a promising noninvasive approach for investigating choroidal vascular reactivity under normal and disease states.

Identifying Significant Changes in Cerebrovascular Reactivity to Carbon Dioxide

BACKGROUND AND PURPOSE: Changes in cerebrovascular reactivity can be used to assess disease progression and response to therapy but require discrimination of pathology from normal test-to-test variability. Such variability is due to variations in methodology, technology, and physiology with time. With uniform test conditions, our aim was to determine the test-to-test variability of cerebrovascular reactivity in healthy subjects and in patients with known cerebrovascular disease. MATERIALS AND METHODS: Cerebrovascular reactivity was the ratio of the blood oxygen level–dependent MR imaging response divided by the change in carbon dioxide stimulus. Two standardized cerebrovascular reactivity tests were conducted at 3T in 15 healthy men (36.7 ± 16.1 years of age) within a 4-month period and were coregistered into standard space to yield voxelwise mean cerebrovascular reactivity interval difference measures, composing a reference interval difference atlas. Cerebrovascular reactivity interval difference maps were prepared for 11 male patients. For each patient, the test-retest difference of each voxel was scored statistically as z-values of the corresponding voxel mean difference in the reference atlas and then color-coded and superimposed on the anatomic images to create cerebrovascular reactivity interval difference z-maps. RESULTS: There were no significant test-to-test differences in cerebrovascular reactivity in either gray or white matter (mean gray matter, P = .431; mean white matter, P = .857; paired t test) in the healthy cohort. The patient cerebrovascular reactivity interval difference z-maps indicated regions where cerebrovascular reactivity increased or decreased and the probability that the changes were significant. CONCLUSIONS: Accounting for normal test-to-test differences in cerebrovascular reactivity enables the assessment of significant changes in disease status (stability, progression, or regression) in patients with time.

Cerebral hyperperfusion and decreased cerebrovascular reactivity correlate with neurologic disease severity in MELAS.

OBJECTIVE To study the mechanisms underlying stroke-like episodes (SLEs) in MELAS syndrome. METHODS We performed a case control study in 3 siblings with MELAS syndrome (m.3243A>G tRNA(Leu(UUR))) with variable % mutant mtDNA in blood (35 to 59%) to evaluate regional cerebral blood flow (CBF) and arterial cerebrovascular reactivity (CVR) compared to age- and sex-matched healthy study controls and a healthy control population. Subjects were studied at 3T MRI using arterial spin labeling (ASL) to measure CBF; CVR was measured as a change in % Blood Oxygen Level Dependent signal (as a surrogate of CBF) to repeated 10 mmHg step increase in arterial partial pressure of CO2 (PaCO2). RESULTS MELAS siblings had decreased CVR (p ≤ 0.002) and increased CBF (p < 0.0026) compared to controls; changes correlated with disease severity and % mutant mtDNA (inversely for CVR: r = -0.82 frontal, r = -0.91 occipital cortex; directly for CBF: r = +0.85 frontal, not for occipital infarct penumbra). Mean CVR was reduced more in frontal (p < 0.001) versus occipital cortex (p = 0.002); mean CBF was increased more in occipital (p = 0.001) than frontal (p = 0.0026) cortices compared to controls. CBF correlated inversely with CVR (r = -0.99 in frontal; not in occipital infarct penumbra) suggesting that increased frontal resting flows are at the expense of flow reserve. INTERPRETATION MELAS disease severity and mutation load were inversely correlated with Interictal CVR and directly correlated with frontal CBF. These metrics offer further insight into the cerebrovascular hemodynamics in MELAS syndrome and may serve as noninvasive prognostic markers to stratify risk for SLEs. CLASSIFICATION OF EVIDENCE Class III.