Jorn Fierstra

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.

Steal physiology is spatially associated with cortical thinning

Background The physiological impact of severely impaired cerebral autoregulatory vascular reactivity on cortical integrity is unknown. The purpose of this study is to determine the relationship between severe impairment of autoregulatory flow control associated with steal phenomenon and its impact on cortical thickness. Methods 250 blood oxygen level dependent (BOLD) MRI cerebrovascular reactivity (CVR) studies were reviewed in order to identify subjects with severe unilateral exhausted cerebrovascular reserve demonstrating steal physiology but with normal appearing cortex on fluid attenuated inversion recovery imaging. 17 patients meeting the inclusion criteria were identified. A reconstructed inflated cortical surface map was created for every subject using Freesurfer software (http://surfer.nmr.mgh.harvard.edu/). The region of interest (ROI) reflecting the steal physiology was determined by overlaying the subjects CVR map on to the cortical surface map. This ROI was compared with the corresponding area in the healthy hemisphere which provided control cortical thickness measurement in each subject. Results The hemisphere with steal physiology showed an 8% thinner cortex (2.23±0.28 mm) than the corresponding healthy hemisphere (2.42±0.23 mm) (p=0.0005). Conclusions Our findings indicate that a spatial correspondence exists between impairment of autoregulatory capacity with steal physiology and cortical thinning.

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.

Impaired Cerebrovascular Reactivity With Steal Phenomenon Is Associated With Increased Diffusion in White Matter of Patients With Moyamoya Disease

Background and Purpose— Reduced cerebrovascular reactivity (CVR) with steal phenomenon is an independent predictor for stroke and may indicate tissue exposed to episodic low-grade ischemia. The apparent diffusion coefficient (ADC) calculated using diffusion-weighted MRI is effective in characterizing focal brain ischemia and subtle structural changes in normal-appearing white matter (WM). We hypothesized that regions of steal phenomenon are associated with increased ADC in normal-appearing WM of patients with Moyamoya disease. Methods— Twenty-two patients with unilateral CVR impairment secondary to Moyamoya disease and 12 healthy control subjects underwent diffusion-weighted MRI and functional MRI mapping of the cerebrovascular response to hypercapnia. Parametric maps of ADC and CVR were calculated, coregistered, and segmented using automated image processing methods. ADC of normal-appearing WM was compared between hemispheres, and between WM with negative CVR (ie, steal phenomenon) and WM with positive CVR. Results— In patients, ADC of normal-appearing WM was elevated in the hemisphere ipsilateral to the CVR impairment compared with the contralateral hemisphere (P<0.005) and in WM with negative CVR compared with WM with positive CVR (P<0.001). WM in regions of steal phenomenon within the affected hemisphere had higher ADC than homologous contralateral WM (P<0.005). In control subjects, negative CVR in WM was not associated with elevated ADC. Conclusions— Regions of steal phenomenon are spatially correlated with elevated ADC in normal-appearing WM of patients with Moyamoya disease. This structural abnormality may reflect low-grade ischemic injury after exhaustion of the cerebrovascular reserve capacity.

Impaired peri-nidal cerebrovascular reserve in seizure patients with brain arteriovenous malformations

Epileptic seizures are a common presentation in patients with newly diagnosed brain arteriovenous malformations, but the pathophysiological mechanisms causing the seizures remain poorly understood. We used magnetic resonance imaging-based quantitative cerebrovascular reactivity mapping and conventional angiography to determine whether seizure-prone patients with brain arteriovenous malformations exhibit impaired cerebrovascular reserve or morphological angiographic features predictive of seizures. Twenty consecutive patients with untreated brain arteriovenous malformations were recruited (10 with and 10 without epileptic seizures) along with 12 age-matched healthy controls. Blood oxygen level-dependent MRI was performed while applying iso-oxic step changes in end-tidal partial pressure of CO(2) to obtain quantitative cerebrovascular reactivity measurements. The brain arteriovenous malformation morphology was evaluated by angiography, to determine to what extent limitations of arterial blood supply or the presence of restricted venous outflow and tissue congestion correlated with seizure susceptibility. Only patients with seizures exhibited impaired peri-nidal cerebrovascular reactivity by magnetic resonance imaging (0.11 ± 0.10 versus 0.25 ± 0.07, respectively; P < 0.001) and venous drainage patterns suggestive of tissue congestion on angiography. However, cerebrovascular reactivity changes were not of a magnitude suggestive of arterial steal, and were probably compatible with venous congestion in aetiology. Our findings demonstrate a strong association between impaired peri-nidal cerebrovascular reserve and epileptic seizure presentation in patients with brain arteriovenous malformation. The impaired cerebrovascular reserve may be associated with venous congestion. Quantitative measurements of cerebrovascular reactivity using blood oxygen level-dependent MRI appear to correlate with seizure susceptibility in patients with brain arteriovenous malformation.

Surgical Revascularization Reverses Cerebral Cortical Thinning in Patients With Severe Cerebrovascular Steno-Occlusive Disease

Background and Purpose— Chronic deficiencies in regional blood flow lead to cerebral cortical thinning without evidence of gross tissue loss at the same time as potentially negatively impacting on neurological and cognitive performance. This is most pronounced in patients with severe occlusive cerebrovascular disease in whom affected brain areas exhibit “steal physiology,” a paradoxical reduction of cerebral blood flow in response to a global vasodilatory stimulus intended to increase blood flow. We tested whether surgical brain revascularization that eliminates steal physiology can reverse cortical thinning. Methods— We identified 29 patients from our database who had undergone brain revascularization with pre- and postoperative studies of cerebrovascular reactivity using blood oxygen(ation) level-dependent MRI and whose preoperative study exhibited steal physiology without MRI-evident structural abnormalities. Cortical thickness in regions corresponding to steal physiology, and where applicable corresponding areas in the normal hemisphere, were measured using Freesurfer software. Results— At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere (n=30). Mean cortical thickness in the revascularized regions increased by 5.1% (from 2.40±0.03 to 2.53±0.03; P<0.0001). Conclusions— Successful regional revascularization and reversal of steal physiology is followed by restoration of cortical thickness.

Assessing cerebrovascular reactivity abnormality by comparison to a reference atlas.

Attribution of vascular pathophysiology to reductions in cerebrovascular reactivity (CVR) is confounded by subjective assessment and the normal variation between anatomic regions. This study aimed to develop an objective scoring assessment of abnormality. CVR was measured as the ratio of the blood-oxygen-level-dependent magnetic resonance signal response divided by an increase in CO2, standardized to eliminate variability. A reference normal atlas was generated by coregistering the CVR maps from 46 healthy subjects into a standard space and calculating the mean and standard deviation (s.d.) of CVR for each voxel. Example CVR studies from 10 patients with cerebral vasculopathy were assessed for abnormality, by normalizing each patients CVR to the same standard space as the atlas, and assigning a z-score to each voxel relative to the mean and s.d. of the corresponding atlas voxel. Z-scores were color coded and superimposed on their anatomic scans to form CVR z-maps. We found the CVR z-maps provided an objective evaluation of abnormality, enhancing our appreciation of the extent and distribution of pathophysiology compared with CVR maps alone. We concluded that CVR z-maps provide an objective, improved form of evaluation for comparisons of voxel-specific CVR between subjects, and across tests sites.

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.

Neuroimaging Assessment of Cerebrovascular Reactivity in Concussion: Current Concepts, Methodological Considerations, and Review of the Literature

Concussion is a form of traumatic brain injury (TBI) that presents with a wide spectrum of subjective symptoms and few objective clinical findings. Emerging research suggests that one of the processes that may contribute to concussion pathophysiology is dysregulation of cerebral blood flow (CBF) leading to a mismatch between CBF delivery and the metabolic needs of the injured brain. Cerebrovascular reactivity (CVR) is defined as the change in CBF in response to a measured vasoactive stimulus. Several magnetic resonance imaging (MRI) techniques can be used as a surrogate measure of CBF in clinical and laboratory studies. In order to provide an accurate assessment of CVR, these sequences must be combined with a reliable, reproducible vasoactive stimulus that can manipulate CBF. Although CVR imaging currently plays a crucial role in the diagnosis and management of many cerebrovascular diseases, only recently have studies begun to apply this assessment tool in patients with concussion. In order to evaluate the quality, reliability, and relevance of CVR studies in concussion, it is important that clinicians and researchers have a strong foundational understanding of the role of CBF regulation in health, concussion, and more severe forms of TBI, and an awareness of the advantages and limitations of currently available CVR measurement techniques. Accordingly, in this review, we (1) discuss the role of CVR in TBI and concussion, (2) examine methodological considerations for MRI-based measurement of CVR, and (3) provide an overview of published CVR studies in concussion patients.

Severely impaired cerebrovascular reserve in patients with cerebral proliferative angiopathy

OBJECT Cerebral proliferative angiopathy (CPA) has been morphologically distinguished from classically appearing brain arteriovenous malformations (AVMs) by exhibition of functional brain parenchyma that is intermingled with abnormal vascular channels. The presence of oligemia in this intralesional brain tissue may suggest ischemia, which is not detected in classic brain AVMs. The authors hypothesized that patients with CPA would exhibit a greater impairment of cerebrovascular reserve in neuronal tissue surrounding the true nidus compared with those with brain AVMs. METHODS Four patients with CPA, 10 patients with brain AVMs and seizures, and 12 young healthy individuals were studied. The 4 patients with CPA underwent blood oxygen level-dependent MR imaging examinations while applying normoxic step changes in end-tidal CO(2) to obtain quantitative cerebrovascular reactivity measurements. RESULTS Patients with a CPA lesion exhibited severely impaired perilesional cerebrovascular reserve in comparison with patients with brain AVMs and seizures (0.10 ± 0.03 vs 0.16 ± 0.03, respectively; p < 0.05), and young healthy individuals (0.10 ± 0.03 vs 0.21 ± 0.06, respectively; p < 0.01). CONCLUSIONS This study demonstrated severely impaired cerebrovascular reserve in the perilesional brain tissue surrounding the abnormal vessels of patients with CPA. This finding may provide an additional means to distinguish CPA from classic brain AVMs.