Cerebrovascular Reactivity Values Research Articles

Baseline cerebrovascular reactivity predicts longitudinal enlarged perivascular space burden in the basal ganglia among cognitively normal older adults

AbstractBackgroundIncreasing evidence suggests that enlarged perivascular spaces (ePVS) on magnetic resonance images (MRIs) are associated with cognitive dysfunction in aging. However, the etiology of ePVS remains unknown. Here we tested the possibility that cerebrovascular dysfunction, as assessed by an MRI measure of cerebrovascular reactivity (CVR), may contribute to ePVS development.Method79 cognitively normal, older adults (46 women, age range 60‐84) were recruited to undergo baseline MRI scanning and follow‐up scanning approximately 2.5 years later. Of the 79 participants scanned at baseline, 50 returned for follow‐up. Participants were scanned on a 3T Siemens Prisma scanner with a 64‐channel head coil. All scanning methods were identical across time points and included collection of T1‐weighted, T2‐weighted FLAIR, and quantitative susceptibility mapping (QSM) images. Cerebrovascular dysfunction was assessed using CVR, a measure of the ability of cerebrovasculature to dilate in response to vasoactive stimuli. Participants underwent blocked administration of breathing either room air or hypercapnic gas, while blood‐oxygen‐level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) was performed. CVR values were computed for baseline scans in specific regions by dividing change in BOLD signal by change in end‐tidal CO2. Baseline and follow‐up ePVS counts were performed by a single rater who was blinded to participant demographics. ePVS were individually and manually counted using STRIVE criteria in a representative, axial slice of the basal ganglia (BGePVS) and centrum semiovale (CSePVS).ResultBGePVS and CSePVS significantly increased during the follow‐up period. Mixed effects models indicated that baseline basal ganglia CVR values significantly predicted increased BGePVS counts after controlling for age, sex, education, and time point (p = <0.001). Furthermore, this effect was present bilaterally: Baseline CVR in the left hemisphere predicted increased BGePVS in the left hemisphere (p = <0.001) and baseline CVR in the right hemisphere predicted increased BGePVS in the right hemisphere (p = <0.001). Conversely, there was no longitudinal relationship between baseline CVR and increased CSePVS (p = 0.449).ConclusionThese results demonstrate that low baseline CVR is a risk factor for later development of ePVS. Localization of these findings to the basal ganglia suggests that it is particularly vulnerable to cerebrovascular dysfunction.

Cerebrovascular reactivity in amnestic and non‐amnestic mild cognitive impairment

AbstractBackgroundCerebrovascular disease (CVD) is implicated in the pathogenesis and clinical presentation of Alzheimer’s Disease. Cerebrovascular reactivity (CVR) is considered a more direct estimate of cerebrovascular integrity. CVR is a potential promising biomarker for examining pathological cognitive decline in older adults though, to date, findings have been inconclusive, possibly partly due to variability in methodological approaches. In this study, we add to the limited literature on CVR in mild cognitive impairment (MCI). We provide preliminary evidence for CVR differences in MCI phenotypes compared to older adult cognitively normal controls. We hypothesized that they amnestic phenotype (aMCI) will have lower CVR than non‐amnestic (naMCI) and both groups will show lower CVR compared to controls. We also performed exploratory correlational analyses between CVR and neuropsychological test scores.MethodCVR was assessed in 22 controls, 11 aMCI, 9 naMCI cohorts using a breath‐holding task functional magnetic resonance imaging (fMRI). fMRI data were preprocessed and analyzed using AFNI. All participants underwent neuropsychological testing. T‐tests and ANOVA/ANCOVA analyses were conducted to compare controls to MCI groups on CVR metrics and cognitive tests of memory, language, processing speed, and executive functioning. Partial correlation analyses between CVR derived from regions‐of‐interest (Yeo 1‐7 ROIs) and different cognitive functions were conducted.ResultsCVR was found to be significantly lower in MCI compared to controls across all Yeo functional networks, ps < .001, which was mostly driven by the aMCI phenotype. naMCI showed intermediate patterns between aMCI and controls, though results were not significant, ps > .05. Regional CVR values along Yeo networks were positively correlated with cognitive measures of processing speed, executive functioning, and memory.ConclusionThis is the first study to evaluate CVR differences in MCI phenotypes. Consistent with previous research, we found that CVR is lower in MCI compared to controls. While group differences between naMCI and controls (also between naMCI and aMCI) did not reach statistical significance, visual inspection of CVR mean values showed preliminary evidence that naMCI had lower mean values across all ROIs compared to controls and higher mean values compared to aMCI. Future research is needed to examine differences in CVR between MCI phenotypes.

Hemodynamic imaging parameters in brain metastases patients – Agreement between multi-delay ASL and hypercapnic BOLD

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, rrm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF (rrm = −0.822) and longer arterial arrival time (AAT; rrm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR (rrm = −0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.

Severity Evaluation of Regional Cerebrovascular Reactivity in Acute Stroke Patients Using SPECT.

Cerebrovascular Reactivity (CVR), as measured using perfusion Single Photon Emission Computed Tomography (SPECT), is an important indicator for the treatment and prognosis of cerebrovascular disease, but there are a few studies on acute stroke or small vascular disease using SPECT. This study evaluated the regional severity with quantitatively determined CVR in patients with acute stroke. Fifty-eight patients who took brain SPECT images were selected to localize quantitative CVR values. The severity of the disease (Grade 1 to 4) was determined through image-based clinical assessment in the absence and presence of a CVR map, and their results were compared. In 1st diagnosis without the map, the mean CVR values of Grades 2 and 3 were -6.07 % and -9.12 %, respectively (P=0.034), while they were -4.78 % and -12.34 % in 2nd diagnosis with the map, respectively (P<0.001), suggesting that the CVR difference with the map was much more pronounced than without the map. Furthermore, in the ROC analysis, the diagnostic sensitivity between Grades 2 and 3 in the 2nd diagnosis (AUC=0.899, P<0.001) was substantially greater than the 1st diagnosis (AUC=0.646, P=0.048). This study demonstrated that the quantitative CVR maps could reinforce the clinical evaluation of cerebral severity by showing that they can provide statistically significant results between severity and CVR. Furthermore, this study was the first to evaluate the effectiveness of quantitative CVR by examining the difference in the presence or absence of CVR in patients with acute stroke.

Abstract TP168: Quantitative Cerebrovascular Reactivity Atlas In Children

Introduction: Cerebrovascular reactivity (CVR) can be measured by inducing carbon dioxide (CO 2 ) changes in the circulation and measuring subsequent changes in blood flow with functional MRI blood oxygen level dependent sequences (BOLD). In clinical practice, abnormalities in CVR imaging can serve as a biomarker of ischemic risk. To characterize pathological aberrations in CVR, it is essential to have quantitative reference data as to what constitutes normal CVR across brain regions at various stages of development. Methods: Prospective enrollment of healthy children ages 6 to 18. Target N of 40. Two datasets are being generated within the atlas using two different methods of administering the vasoactive stimulus (CO 2 ): a breath-hold CVR dataset (endogenous stimulus) and a RespirAct TM CVR dataset (exogenous). A test of normality is performed on CVR values for each voxel across subjects, with mean and standard deviation calculations. This will allow for generation of a Z-score for each CVR value per voxel in any clinical CVR study. Voxel-wide validation of breath-hold CVR values against the gold standard RespirAct TM CVR values will be performed using within subject t-test and between group comparisons. Subgroup analysis based on gender and age will also be performed. Results: Preliminary CVR data for 8 healthy right-handed children is presented (4 female, median age 13, range 9 -14 years). All participants tolerated CVR studies well and no side effects were reported. Group datasets acquired to date passed tests of normality with no significant differences in CVR values between the two methods found. Conclusions: This study will generate the first atlas of quantitative CVR-fMRI data in healthy children. Normative physiological data on CVR changes throughout childhood, and associations between CVR, blood pressure, age, and gender will be obtained. CVR imaging is performed clinically in patients with a risk of recurrent arterial ischemic stroke such as those with intracranial arteriopathies, sickle cell disease and other genetic and metabolic disorders. Our atlas can provide clinicians with objective measures regarding extent and distribution of CVR abnormalities, allow for stroke risk stratification, and aid in determining the optimal time for intervention.

Multi-vendor and multisite evaluation of cerebrovascular reactivity mapping using hypercapnia challenge

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain's vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials.

Assessment of Impaired Cerebrovascular Reactivity in Chronic Cerebral Ischemia using Intravoxel Incoherent Motion Magnetic Resonance Imaging

BackgroundThe severity of chronic cerebral ischemia can be assessed using cerebrovascular reactivity (CVR) to acetazolamide (ACZ) challenge, which is measured by single-photon emission computed tomography (SPECT); however, this is an invasive method. We investigated whether intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) can assess impaired CVR in preoperative patients with chronic cerebral ischemia and compared it to SPECT-CVR. MethodsForty-seven patients with unilateral cervical carotid artery stenosis underwent diffusion-weighted MRI with 11 b-values in the range of 0–800 s/mm2 and cerebral perfusion SPECT with the ACZ challenge. The perfusion fraction (f) and diffusion coefficient (D) of the IVIM parameters were calculated using a bi-exponential model. The f and D values and these ratios of the ipsilateral middle cerebral artery territory against the contralateral side were compared with the CVR values of the affected side calculated from the SPECT data. ResultsThe IVIM-f and D values in the affected side were significantly higher than those in the unaffected side (median: 7.74% vs. 7.45%, p = 0.027; 0.816 vs. 0.801 10−3mm2/s, p < 0.001; respectively). However, there were no significant correlations between the f or D values and SPECT-CVR values in the affected side. In contrast, the f ratio showed a moderate negative correlation with the SPECT-CVR values (r = -0.40, p = 0.006) and detected impaired CVR (< 18.4%) with a sensitivity/specificity of 0.71/0.90. ConclusionThe IVIM perfusion parameter, f, can noninvasively assess impaired CVR with high sensitivity and specificity in patients with unilateral cervical carotid artery stenosis.

A practical modification to a resting state fMRI protocol for improved characterization of cerebrovascular function

Cerebrovascular reactivity (CVR), defined here as the Blood Oxygenation Level Dependent (BOLD) response to a CO2 pressure change, is a useful metric of cerebrovascular function. Both the amplitude and the timing (hemodynamic lag) of the CVR response can bring insight into the nature of a cerebrovascular pathology and aid in understanding noise confounds when using functional Magnetic Resonance Imaging (fMRI) to study neural activity. This research assessed a practical modification to a typical resting-state fMRI protocol, to improve the characterization of cerebrovascular function. In 9 healthy subjects, we modelled CVR and lag in three resting-state data segments, and in data segments which added a 2–3 minute breathing task to the start of a resting-state segment. Two different breathing tasks were used to induce fluctuations in arterial CO2 pressure: a breath-hold task to induce hypercapnia (CO2 increase) and a cued deep breathing task to induce hypocapnia (CO2 decrease). Our analysis produced voxel-wise estimates of the amplitude (CVR) and timing (lag) of the BOLD-fMRI response to CO2 by systematically shifting the CO2 regressor in time to optimize the model fit. This optimization inherently increases gray matter CVR values and fit statistics. The inclusion of a simple breathing task, compared to a resting-state scan only, increases the number of voxels in the brain that have a significant relationship between CO2 and BOLD-fMRI signals, and improves our confidence in the plausibility of voxel-wise CVR and hemodynamic lag estimates. We demonstrate the clinical utility and feasibility of this protocol in an incidental finding of Moyamoya disease, and explore the possibilities and challenges of using this protocol in younger populations. This hybrid protocol has direct applications for CVR mapping in both research and clinical settings and wider applications for fMRI denoising and interpretation.

Normal BOLD Response to a Step CO2 Stimulus After Correction for Partial Volume Averaging.

Cerebrovascular reactivity (CVR) is defined as the change in cerebral blood flow induced by a change in a vasoactive stimulus. CVR using BOLD MRI in combination with changes in end-tidal CO2 is a very useful method for assessing vascular performance. In recent years, this technique has benefited from an advanced gas delivery method where end-tidal CO2 can be targeted, measured very precisely, and validated against arterial blood gas sampling (Ito et al., 2008). This has enabled more precise comparison of an individual patient against a normative atlas of healthy subjects. However, expected control ranges for CVR metrics have not been reported in the literature. In this work, we calculate and report the range of control values for the magnitude (mCVR), the steady state amplitude (ssCVR), and the speed (TAU) of the BOLD response to a standard step stimulus, as well as the time delay (TD) as observed in a cohort of 45 healthy controls. These CVR metrics maps were corrected for partial volume averaging for brain tissue types using a linear regression method to enable more accurate quantitation of CVR metrics. In brief, this method uses adjacent voxel CVR metrics in combination with their tissue composition to write the corresponding set of linear equations for estimating CVR metrics of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). After partial volume correction, mCVR and ssCVR increase as expected in gray matter, respectively, by 25 and 19%, and decrease as expected in white matter by 33 and 13%. In contrast, TAU and TD decrease in gray matter by 33 and 13%. TAU increase in white matter by 24%, but TD surprisingly decreased by 9%. This correction enables more accurate voxel-wise tissue composition providing greater precision when reporting gray and white matter CVR values.

Occipital artery to middle cerebral artery bypass in pediatric moyamoya disease: rescue therapy after failed revascularization.

Patients with pediatric moyamoya disease (PMMD) showing recurrent symptoms or decreased cerebral blood flow after initial revascularization therapy may require additional revascularization to improve their clinical condition. The authors evaluated the clinical and hemodynamic benefits of an occipital artery (OA)-middle cerebral artery (MCA) bypass for patients with PMMD who have undergone an initial revascularization procedure. The authors retrospectively identified 9 patients with PMMD who had undergone OA-MCA bypass between March 2013 and December 2017, and who had received a previous superficial temporal artery-MCA bypass. The following clinical data were collected: initial revascularization procedure, symptoms (presence or recurrence), pre- and postoperative cerebral blood flow and cerebrovascular reactivity (CVR) changes, posterior cerebral artery (PCA) stenosis, PCA-related and nonrelated symptoms, and latest follow-up. Preoperatively, all patients (n = 9) suffered non-PCA-related recurrent symptoms, and 4 had PCA-related symptoms. At 1-year follow-up, all patients with PCA-related symptoms showed complete recovery. Additionally, 8 (89%) patients with non-PCA symptoms experienced improvement. Only 1 (11%) patient showed no improvement after the surgical procedure. The mean pre- and postoperative CVR values of the MCA territory were 14.8% and 31.3%, respectively, whereas the respective mean CVR values of the PCA territory were 22.8% and 40.0%. The OA-MCA bypass is an effective rescue therapy to improve the clinical condition and hemodynamic changes caused by PMMD in patients who experience recurrent symptoms after initial revascularization.

Cerebrovascular Reactivity Mapping Using Resting-State BOLD Functional MRI in Healthy Adults and Patients with Moyamoya Disease.

Background Cerebrovascular reserve, the potential capacity of brain tissue to receive more blood flow when needed, is a desirable marker in evaluating ischemic risk. However, current measurement methods require acetazolamide injection or hypercapnia challenge, prompting a clinical need for resting-state (RS) blood oxygen level-dependent (BOLD) functional MRI data to measure cerebrovascular reactivity (CVR). Purpose To optimize and evaluate an RS CVR MRI technique and demonstrate its relationship to neurosurgical treatment. Materials and Methods In this HIPAA-compliant study, RS BOLD functional MRI data collected in 170 healthy controls between December 2008 and September 2010 were retrospectively evaluated to identify the optimal frequency range of temporal filtering on the basis of spatial correlation with the reference standard CVR map obtained with CO2 inhalation. Next, the optimized RS method was applied in a new, prospective cohort of 50 participants with Moyamoya disease who underwent imaging between June 2014 and August 2019. Finally, CVR values were compared between brain hemispheres with and brain hemispheres without revascularization surgery by using Mann-Whitney U test. Results A total of 170 healthy controls (mean age ± standard deviation, 51 years ± 20; 105 women) and 100 brain hemispheres of 50 participants with Moyamoya disease (mean age, 41 years ± 12; 43 women) were evaluated. RS CVR maps based on a temporal filtering frequency of [0, 0.1164 Hz] yielded the highest spatial correlation (r = 0.74) with the CO2 inhalation CVR results. In patients with Moyamoya disease, 77 middle cerebral arteries (MCAs) had stenosis. RS CVR in the MCA territory was lower in the group that did not undergo surgery (n = 30) than in the group that underwent surgery (n = 47) (mean, 0.407 relative units [ru] ± 0.208 vs 0.532 ru ± 0.182, respectively; P = .006), which is corroborated with the CO2 inhalation CVR data (mean, 0.242 ru ± 0.273 vs 0.437 ru ± 0.200; P = .003). Conclusion Cerebrovascular reactivity mapping performed by using resting-state blood oxygen level-dependent functional MRI provided a task-free method to measure cerebrovascular reserve and depicted treatment effect of revascularization surgery in patients with Moyamoya disease comparable to that with the reference standard of CO2 inhalation MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wolf and Ware in this issue.

The value of a shorter-delay arterial spin labeling protocol for detecting cerebrovascular impairment

The aim of this study was to determine the relationship between blood oxygen level dependent (BOLD) cerebrovascular reactivity (CVR) and cerebral blood flow (CBF) obtained from arterial spin labeling (ASL) using different post labeling delays (PLD). Forty-two patients with steno-occlusive diseases and impaired CVR were divided into two groups, one scanned with a 1.5-second (1.5-s) and the other with a 2.5-second (2.5-s) PLD ASL protocol. For all patients, a region of interest (ROI) was drawn around the CVR impairment. This affected ROI was then left-right flipped across the brain midline to obtain the control ROI. For both groups, the difference in grey matter CVR between affected and control ROI was first tested to confirm significance. The average grey matter CBF of affected and control ROIs were then compared. The same analysis method was used to compare affected and control hemispheres. In both groups of 1.5-s and 2.5-s PLD, CVR values in the affected ROI (-0.049±0.055 and -0.042±0.074%/mmHg, respectively) were significantly lower compared to that in the control ROI (0.152±0.054 and 0.152±0.053%/mmHg, respectively, P<0.0001). In the group with the 1.5-s PLD, CBF in the affected ROI (37.62±11.37 mL/100 g/min) was significantly lower compared to CBF in the control ROI (44.13±11.58 mL/100 g/min, P<0.05). However, in the group with the 2.5-s PLD, no significant differences could be seen between CBF in the affected ROI (40.50±14.82 mL/100 g/min) and CBF in the control ROI (39.68±12.49 mL/100 g/min, P=0.73). In the hemisphere-based analysis, CBF was significantly lower in the affected side than in the control side for the group with the 1.5-s PLD (P<0.05) when CVR was impaired (P<0.0001), but not for the group with the 2.5-s PLD (P=0.49). In conclusion, our study reveals and highlights the value of a shorter-PLD ASL protocol, which is able to reflect CVR impairment. At the same time, we offer a better understanding of the relationship between BOLD CVR and CBF obtained from ASL.

Cerebrovascular Reactivity Assessment during Carbon Dioxide Inhalation Using SPECT

Background: Perfusion single-photon emission computed tomography (SPECT) using an acetazolamide is an important clinical tool used to assess cerebrovascular reactivity (CVR) in patients, but its use has been limited to clinical diagnostics. This study aimed to preliminarily evaluate the feasibility of perfusion SPECT using carbon dioxide (CO2). Methods: Ten healthy subjects participated in two consecutive SPECT scans using CO2 inhalation. To evaluate brain perfusion after preprocessing, the voxel-by-voxel CVR values were averaged in 13 subgroup regions of interest (ROIs) based on a template. Subsequently, averaged CVR values of each ROI were analyzed based on both cerebellar hemispheres. Results: CVR values in the eight subgroup ROIs, which included vermis, both insula/cingulate, and frontal cortices, showed significant changes (p &lt; 0.05). CVR values were higher in vermis and right insula/cingulate by 3.34% and 3.15%, respectively. Conclusions: This study showed that quantitative SPECT with CO2 inhalation could be used to evaluate the voxel-based CVR in healthy subjects, which could be beneficial for elucidating induced hypercapnic states and for longitudinally investigating the healthy aging in brain vessels. Furthermore, the cerebrovascular hemodynamic parameters induced by CO2 could play an important role as a biomarker to evaluate treatment progress in patients with cerebrovascular disease.

Quantitative Cerebrovascular Reactivity in Normal Aging: Comparison Between Phase-Contrast and Arterial Spin Labeling MRI.

Purpose: Cerebrovascular reactivity (CVR) is an index of the dilatory function of cerebral blood vessels and has shown great promise in the diagnosis of risk factors in cerebrovascular disease. Aging is one such risk factor; thus, it is important to characterize age-related differences in CVR. CVR can be measured by BOLD MRI but few studies have measured quantitative cerebral blood flow (CBF)-based CVR in the context of aging. This study aims to determine the age effect on CVR using two quantitative CBF techniques, phase-contrast (PC), and arterial spin labeling (ASL) MRI.Methods: In 49 participants (32 younger and 17 older), CVR was measured with PC, ASL, and BOLD MRI. These CVR methods were compared across young and older groups to determine their dependence on age. PC and ASL CVR were also studied for inter-correlation and mean differences. Gray and white matter CVR values were also studied.Results: PC CVR was higher in younger participants than older participants (by 17%, p = 0.046). However, there were no age differences in ASL or BOLD CVR. ASL CVR was significantly correlated with PC CVR (p = 0.042) and BOLD CVR (p = 0.016), but its values were underestimated compared to PC CVR (p = 0.045). ASL CVR map revealed no difference between gray matter and white matter tissue types, whereas gray matter was significantly higher than white matter in the BOLD CVR map.Conclusion: This study compared two quantitative CVR techniques in the context of brain aging and revealed that PC CVR is a more sensitive method for detection of age differences, despite the absence of spatial information. The ASL method showed a significant correlation with PC and BOLD, but it tends to underestimate CVR due to confounding factors associated with this technique. Importantly, our data suggest that there is not a difference in CBF-based CVR between the gray and white matter, in contrast to previous observation using BOLD MRI.

Voxelwise optimization of hemodynamic lags to improve regional CVR estimates in breath-hold fMRI.

Cerebrovascular Reactivity (CVR), the responsiveness of blood vessels to a vasodilatory stimulus, is an important indicator of cerebrovascular health. Assessing CVR with fMRI, we can measure the change in the Blood Oxygen Level Dependent (BOLD) response induced by a change in CO2 pressure (%BOLD/mmHg). However, there exists a temporal offset between the recorded CO2 pressure and the local BOLD response, due to both measurement and physiological delays. If this offset is not corrected for, voxel-wise CVR values will not be accurate. In this paper, we propose a framework for mapping hemodynamic lag in breath-hold fMRI data. As breath-hold tasks drive task-correlated head motion artifacts in BOLD fMRI data, our framework for lag estimation fits a model that includes polynomial terms and head motion parameters, as well as a shifted variant of the CO2 regressor (±9 s in 0.3 s increments), and the hemodynamic lag at each voxel is the shift producing the maximum total model R2 within physiological constraints. This approach is evaluated in 8 subjects with multi-echo fMRI data, resulting in robust maps of hemodynamic delay that show consistent regional variation across subjects, and improved contrast-to-noise compared to methods where motion regression is ignored or performed earlier in preprocessing.Clinical Relevance- We map hemodynamic lag using breathhold fMRI, providing insight into vascular transit times and improving the regional accuracy of cerebrovascular reactivity measurements.

Cerebrovascular reactivity mapping using intermittent breath modulation

Cerebrovascular reactivity (CVR), an index of brain vessel’s dilatory capacity, is typically measured using hypercapnic gas inhalation or breath-holding as a vasoactive challenge. However, these methods require considerable subject cooperation and could be challenging in clinical studies. More recently, there have been attempts to use resting-state BOLD data to map CVR by utilizing spontaneous changes in breathing pattern. However, in subjects who have small fluctuations in their spontaneous breathing pattern, the CVR results could be noisy and unreliable. In this study, we aim to develop a new method for CVR mapping that does not require gas-inhalation yet provides substantially higher sensitivity than resting-state CVR mapping. This new method is largely based on resting-state scan, but introduces intermittent modulation of breathing pattern in the subject to enhance fluctuations in their end-tidal CO2 (EtCO2) level. Here we examined the comfort level, sensitivity, and accuracy of this method in two studies. First, in 8 healthy young subjects, we developed the intermittent breath-modulation method using two different modulation frequencies, 6 ​s per breath and 12 ​s per breath, respectively, and compared the results to three existing CVR methods, specifically hypercapnic gas inhalation, breath-holding, and resting-state. Our results showed that the comfort level of the 6-s breath-modulation method was significantly higher than breath-holding (p ​= ​0.007) and CO2-inhalation (p ​= ​0.015) methods, while not different from the resting-state, i.e. free breathing method (p ​= ​0.52). When comparing the sensitivity of CVR methods, the breath-modulation methods revealed higher Z-statistics compared to the resting-state scan (p ​< ​0.008) and was comparable to breath-holding results. Next, we tested the feasibility of breath-modulation CVR mapping (6 ​s per breath) in 21 cognitively normal elderly participants and compared quantitative CVR values to that obtained with the CO2-inhalation method. Whole-brain CVR was found to be 0.150 ​± ​0.055 and 0.154 ​± ​0.032 %ΔBOLD/mmHg for the breath-modulation and CO2-inhalation method, respectively, with a significant correlation between them (y ​= ​0.97x, p ​= ​0.007). CVR mapping with intermittent breath modulation may be a useful method that combines the advantages of resting-state and CO2-inhalation based approaches.

The CO2 stimulus duration and steady-state time point used for data extraction alters the cerebrovascular reactivity outcome measure.

What is the central question of this study? Cerebrovascular reactivity (CVR) is a common functional test to assess brain health, and impaired CVR has been associated with all-cause cardiovascular mortality: does the duration of the CO2 stimulus and the time point used for data extraction alter the CVR outcome measure? What is the main finding and its importance? This study demonstrated CVR measures calculated from 1 and 2min CO2 stimulus durations were significantly higher than CVR calculated from a 4min CO2 stimulus. CVRs calculated from the first 2min of the CO2 stimulus were significantly higher than CVR values calculated from the final minute if the duration was ≥4min. This study highlights the need for consistent methodological approaches. Cerebrovascular reactivity to carbon dioxide (CVR) is a common functional test to assess brain vascular health, though conflicting age and fitness effects have been reported. Studies have used different CO2 stimulus durations to induce CVR and extracted data from different time points for analysis. Therefore, this study examined whether these differences alter CVR and explain conflicting findings. Eighteen healthy volunteers (24±5years) inhaled CO2 for four stimulus durations (1, 2, 4 and 5min) of 5% CO2 (in air) via the open-circuit Douglas bag method, in a randomized order. CVR data were derived from transcranial Doppler (TCD) measures of middle cerebral artery blood velocity (MCAv), with concurrent ventilatory sensitivity to the CO2 stimulus ( ). Repeated measures ANOVAs compared CVR and measures between stimulus durations and steady-state time points. An effect of stimulus duration was observed (P=0.002, η²=0.140), with 1min (P=0.010) and 2min (P<0.001) differing from 4min, and 2min differing from 5min (P=0.019) durations. sensitivity increased ∼3-fold from 1min to 4 and 5min durations (P<0.001, η²=0.485). CVRs calculated from different steady-state time points within each stimulus duration were different (P<0.001, η²=0.454), specifically for 4min (P=0.001) and 5min (P<0.001), but not 2min stimulus durations (P=0.273). These findings demonstrate that methodological differences alter the CVR measure.

The association between BOLD-based cerebrovascular reactivity (CVR) and end-tidal CO2 in healthy subjects

Cerebrovascular reactivity (CVR) mapping using CO2-inhalation can provide important insight into vascular health. At present, blood-oxygenation-level-dependent (BOLD) MRI acquisition is the most commonly used CVR method due to its high sensitivity, high spatial resolution, and relatively straightforward processing. However, large variations in CVR across subjects and across different sessions of the same subject are often observed, which can cloud the ability of this promising measure in detecting diseases or monitoring treatment responses. The present work aims to identify the physiological components underlying the observed variability in CVR data. When studying the association between CVR value and the subject’s CO2 levels in a total of N = 253 healthy participants, we found that CVR was lower in individuals with a higher basal end-tidal CO2, EtCO2 (slope = −0.0036 ± 0.0008%/mmHg2, p < 0.001), or with a greater EtCO2 change (ΔEtCO2) with hypercapnic condition (slope = −0.0072 ± 0.0018%/mmHg2, p < 0.001). In a within-subject setting, when studying the CVR difference between two repeated scans (with repositioning) in relation to the corresponding differences in basal EtCO2 and ΔEtCO2 (n = 11), it was found that CVR values were lower if the basal EtCO2 or ΔEtCO2 during that particular scan session was greater. The present work suggests that basal physiological state and the level of hypercapnic stimulus intensity should be considered in application studies of CVR in order to reduce inter-subject and intra-subject variations in the data. Potential approaches to use these findings to reduce noise and augment sensitivity are proposed.

Influence of different isoflurane anesthesia protocols on murine cerebral hemodynamics measured with pseudo-continuous arterial spin labeling.

Arterial spin labeling (ASL)‐MRI can noninvasively map cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), potential biomarkers of cognitive impairment and dementia. Mouse models of disease are frequently used in translational MRI studies, which are commonly performed under anesthesia. Understanding the influence of the specific anesthesia protocol used on the measured parameters is important for accurate interpretation of hemodynamic studies with mice. Isoflurane is a frequently used anesthetic with vasodilative properties. Here, the influence of three distinct isoflurane protocols was studied with pseudo‐continuous ASL in two different mouse strains. The first protocol was a free‐breathing set‐up with medium concentrations, the second a free‐breathing set‐up with low induction and maintenance concentrations, and the third a set‐up with medium concentrations and mechanical ventilation. A protocol with the vasoconstrictive anesthetic medetomidine was used as a comparison. As expected, medium isoflurane anesthesia resulted in significantly higher CBF and lower CVR values than medetomidine (median whole‐brain CBF of 157.7 vs 84.4 mL/100 g/min and CVR of 0.54 vs 51.7% in C57BL/6 J mice). The other two isoflurane protocols lowered the CBF and increased the CVR values compared with medium isoflurane anesthesia, without obvious differences between them (median whole‐brain CBF of 138.9 vs 131.7 mL/100 g/min and CVR of 10.0 vs 9.6%, in C57BL/6 J mice). Furthermore, CVR was shown to be dependent on baseline CBF, regardless of the anesthesia protocol used.

Evaluation of cerebrovascular reserve in patients with cerebrovascular diseases using resting-state MRI: A feasibility study

PurposeTo demonstrate the feasibility of mapping cerebrovascular reactivity (CVR) using resting-state functional MRI (fMRI) data without gas or other challenges in patients with cerebrovascular diseases and to show that brain regions affected by the diseases have diminished vascular reactivity. Materials and methodsTwo sub-studies were performed on patients with stroke and Moyamoya disease. In Study 1, 20 stroke patients (56.3 ± 9.7 years, 7 females) were enrolled and resting-state blood‑oxygenation-level-dependent (rs-BOLD) fMRI data were collected, from which CVR maps were computed. CVR values were compared across lesion, perilesional and control ROIs defined on anatomic images. Reproducibility of the CVR measurement was tested in 6 patients with follow-up scans. In Study 2, rs-BOLD fMRI and dynamic susceptibility contrast (DSC) MRI scans were collected in 5 patients with Moyamoya disease (32.4 ± 8.2 years, 4 females). Cerebral blood flow (CBF), cerebral blood volume (CBV), and time-to-peak (TTP) maps were obtained from the DSC MRI data. CVR values were compared between stenotic brain regions and control regions perfused by non-stenotic arteries. ResultsIn stroke patients, lesion CVR (0.250 ± 0.055 relative unit (r.u.)) was lower than control CVR (0.731 ± 0.088 r.u., p = 0.0002). CVR was also lower in the perilesional regions in a graded manner (perilesion 1 CVR = 0.422 ± 0.051 r.u., perilesion 2 CVR = 0.492 ± 0.046 r.u.), relative to that in the control regions (p = 0.005 and 0.036, respectively). In the repeatability analysis, a strong correlation was observed between lesion CVR (r2 = 0.91, p = 0.006) measured at two time points, as well as between control CVR (r2 = 0.79, p = 0.036) at two time points. In Moyamoya patients, CVR in the perfusion deficit regions delineated by DSC TTP maps (0.178 ± 0.189 r.u.) was lower than that in the control regions (0.868 ± 0.214 r.u., p = 0.013). Furthermore, the extent of reduction in CVR was significantly correlated with the extent of lengthening in TTP (r2 = 0.91, p = 0.033). ConclusionOur findings suggested that rs-BOLD data can be used to reproducibly evaluate CVR in patients with cerebrovascular diseases without the use of any vasoactive challenges.