Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease.

Background and Purpose- Cerebral small vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate whether chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods- Consecutive patients with middle cerebral artery or internal carotid artery occlusion presenting within 6 hours after stroke symptom onset who underwent thrombectomy from 2012 to 2017 were included. The prespecified primary outcome was poor collateral flow, which was assessed on baseline computed tomographic angiography (poor, ≤50% filling; good, >50% filling). Markers of chronic SVD on brain magnetic resonance imaging were rated for the extent of white matter hyperintensities, enlarged perivascular spaces, chronic lacunar infarctions and cerebral microbleeds using the Standards for Reporting Vascular Changes on Neuroimaging criteria. Severity of SVD was quantified by adding the presence of each SVD feature, with a total possible score of 0 to 4; each SVD type was also evaluated separately. Multivariable logistic regression analyses were performed to evaluate the relationships between SVD and poor collaterals, with adjustment for potential confounders. Results- Of the 100 eligible patients, the mean age was 65±16 years, median National Institutes of Health Stroke Scale score was 15, and 68% had any SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals than patients without SVD (aOR, 1.9 [95% CI, 1.1-3.2]). Of the SVD types, poor collaterals were significantly associated with white matter hyperintensities (aOR, 2.9 per Fazekas increment [95% CI, 1.6-5.3]) but not with enlarged perivascular spaces (adjusted odds ratio [aOR], 1.3 [95% CI, 0.4-4.0]), lacunae (aOR, 2.1 [95% CI, 0.6-7.1]), or cerebral microbleeds (aOR, 2.1 [95% CI, 0.6-7.8]). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend P<0.001; adjusted P=0.056). There was a dose-dependent relationship between white matter hyperintensity burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1 to 3 (Ptrend=0.015). No patient with an SVD score of 4 had good collaterals. Conclusions- Chronic cerebral SVD is associated with poor recruitment of collaterals in large vessel occlusive stroke. A prospective study to elucidate the potential mechanism of how SVD may impair the recruitment of collaterals is ongoing.

Slowed Temporal and Parietal Cerebrovascular Response in Patients with Alzheimer's Disease.

BACKGROUND: Recent investigations now suggest that cerebrovascular reactivity (CVR) is impaired in Alzheimer's disease (AD) and may underpin part of the disease's neurovascular component. However, our understanding of the relationship between the magnitude of CVR, the speed of cerebrovascular response, and the progression of AD is still limited. This is especially true in patients with mild cognitive impairment (MCI), which is recognized as an intermediate stage between normal aging and dementia. The purpose of this study was to investigate AD and MCI patients by mapping repeatable and accurate measures of cerebrovascular function, namely the magnitude and speed of cerebrovascular response (τ) to a vasoactive stimulus in key predilection sites for vascular dysfunction in AD. METHODS: Thirty-three subjects (age range: 52-83 years, 20 males) were prospectively recruited. CVR and τ were assessed using blood oxygen level-dependent MRI during a standardized carbon dioxide stimulus. Temporal and parietal cortical regions of interest (ROIs) were generated from anatomical images using the FreeSurfer image analysis suite. RESULTS: Of 33 subjects recruited, 3 individuals were excluded, leaving 30 subjects for analysis, consisting of 6 individuals with early AD, 11 individuals with MCI, and 13 older healthy controls (HCs). τ was found to be significantly higher in the AD group compared to the HC group in both the temporal (p = 0.03) and parietal cortex (p = 0.01) following a one-way ANCOVA correcting for age and microangiopathy scoring and a Bonferroni post-hoc correction. CONCLUSION: The study findings suggest that AD is associated with a slowing of the cerebrovascular response in the temporal and parietal cortices.

The efficiency of the brain connectome is associated with cerebrovascular reactivity in persons with white matter hyperintensities.

The purpose of this study was to determine the relationship between the organization of the brain connectome and cerebrovascular reactivity (CVR) in persons with white matter hyperintensities. Diffusion tensor and CVR mapping 3T MRI scans were acquired in 31 participants with white matter hyperintensities. In each participant, the connectome was assessed by reconstructing all white matter tracts with tractography and segmenting the whole brain into multiple regions. Graph theory analysis was performed to quantify how effectively tracts connected brain regions by measuring the global and local efficiency of the connectome. CVR in white matter and gray matter was correlated with the global and local efficiency of the connectome, while adjusting for age, gender, and gray matter volume. For comparison, white matter hyperintensity volume was also correlated with global and local efficiency. White matter CVR was positively correlated with the global efficiency (coefficient: 23.3, p = .005) and local efficiency (coefficient: 2850, p = .004) of the connectome. Gray matter CVR was positively correlated with the global efficiency (coefficient: 21.3, p < .001) and local efficiency (coefficient: 2670, p < .001) of the connectome. White matter hyperintensity volume was negatively correlated with global efficiency (coefficient: -0.0002, p = .003) and local efficiency (coefficient: -0.024, p = .003) of the connectome. The association between CVR and the brain connectome suggests that impaired cerebrovascular function may be part of the pathophysiology of the disruption of the brain connectome in persons with white matter hyperintensities.

The aging brain and cerebrovascular reactivity.

Cerebrovascular reactivity (CVR) is a measure of vascular response to a vasoactive stimulus, and can be used to assess the health of the brain vasculature. In this current study we used different analyses of BOLD fMRI responses to CO2 to provide a number of metrics including ramp and step CVR, speed of response and transfer function analysis (TFA). 51 healthy control volunteers between the ages of 18-85 (26 males) were recruited and scanned at 3T field strength. Atlases reflecting voxel-wise means and standard deviations were compiled to assess possible differences in these metrics between four age cohorts. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm, and monitoring end-tidal partial pressures of CO2 (PETCO2) and O2 (PETO2). No significant differences were found for resting PETCO2 values between cohorts. Ramp CVR decreased significantly with age in white matter frontal regions comprising the ACA-MCA watershed area, a finding that may be indicative of age related changes. Similarly, TFA showed that gain was reduced in the left white matter ACA-MCA watershed area as well as the posterior and anterior cingulate cortex, and superior frontal gyrus in the oldest compared to youngest cohort. These findings, detailing changes in cerebrovascular regulation in the healthy aging brain should prove useful in mapping areas of dysregulated blood flow in individuals with vascular risk factors especially those at risk for developing vascular dementia.

Impact of white matter hyperintensities on surrounding white matter tracts.

PURPOSE: It is unclear how white matter hyperintensities disrupt surrounding white matter tracts. The aim of this tractography study was to determine the spatial relationship between diffusion characteristics along white matter tracts and the distance from white matter hyperintensities. METHODS: Diffusion tensor 3-T MRI scans were acquired in 29 participants with white matter hyperintensities. In each subject, tractography by the fiber assignment by continuous tracking method was used to segment corticospinal tracts. Mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy were measured along corticospinal tracts in relation to white matter hyperintensities. Diffusion characteristics along tracts were correlated with distance from white matter hyperintensities and were also compared between tracts traversing and not traversing white matter hyperintensities. RESULTS: In tracts not traversing through white matter hyperintensities, increasing distance from white matter hyperintensities was associated with decreased mean diffusivity (p = 0.002) and increased fractional anisotropy (p = 0.006). In tracts traversing white matter hyperintensities, compared to tracts not traversing white matter hyperintensites, the mean diffusivity was higher at 6-8 voxels, axial diffusivity higher at 4-8 voxels, and radial diffusivity higher at 7 voxels away from white matter hyperintensities (all p < 0.006). CONCLUSION: White matter hyperintensities are associated with two patterns of altered diffusion characteristics in the surrounding white matter tract network. Diffusion characteristics along white matter tracts improve further away from white matter hyperintensities suggestive of a local penumbra pattern. Also, altered diffusion extends further along tracts traversing white matter hyperintensities suggestive of a Wallerian-type degenerative pattern.

Measurement of Cerebrovascular Reactivity as Blood Oxygen Level-Dependent Magnetic Resonance Imaging Signal Response to a Hypercapnic Stimulus in Mechanically Ventilated Patients.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) is an important prognostic marker of stroke. Most measures of CVR lack (1) a reproducible vasoactive stimulus and (2) a high time and spatial resolution measure of cerebral blood flow (CBF), particularly for mechanically ventilated patients. The aim of our study was to investigate the feasibility of measuring CVR using sequential gas delivery circuit and gas blender for precise targeting of end-tidal PCO2 (PetCO2), and blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) signal as a surrogate of CBF, in mechanically ventilated patients. METHODS: Four patients with known moyamoya disease requiring preoperative CVR measurements under general anesthesia were studied. All patients had standard anesthesia induction and maintenance with intravenous propofol and rocuronium. Patients were intubated and manually ventilated with a self-inflating bag connected to a sequential breathing circuit. A computer-controlled gas blender supplied the gas mixture in proportions to attain target PetCO2. BOLD-MRI was performed at 3.0 Tesla magnet. Changes in signal per change in PetCO2 were calculated, and their magnitude color-coded and mapped onto the anatomic scan to form CVR maps. RESULTS: CVR studies were successfully performed on all patients, and the CVR values were lower in both gray and white matter bilaterally when compared with healthy volunteers. In addition, CVR maps in 3 patients showed intracerebral steal phenomenon in spite of having had cerebral revascularization procedures, indicating that they are still at risk of cerebral ischemia. CONCLUSIONS: BOLD-MRI CVR studies are feasible in mechanically ventilated patients anesthetized with propofol.

Assessing cerebrovascular reactivity by the pattern of response to progressive hypercapnia.

Cerebral blood flow responds to a carbon dioxide challenge, and is often assessed as cerebrovascular reactivity, assuming a linear response over a limited stimulus range or a sigmoidal response over a wider range. However, these assumed response patterns may not necessarily apply to regions with pathophysiology. Deviations from sigmoidal responses are hypothesised to result from upstream flow limitations causing competition for blood flow between downstream regions, particularly with vasodilatory stimulation; flow is preferentially distributed to regions with more reactive vessels. Under these conditions, linear or sigmoidal fitting may not fairly describe the relationship between stimulus and flow. To assess the range of response patterns and their prevalence a survey of healthy control subjects and patients with cerebrovascular disease was conducted. We used a ramp carbon dioxide challenge from hypo- to hypercapnia as the stimulus, and magnetic resonance imaging to measure the flow responses. We categorized BOLD response patterns into four types based on the signs of their linear slopes in the hypo- and hypercapnic ranges, color coded and mapped them onto their respective anatomical scans. We suggest that these type maps complement maps of linear cerebrovascular reactivity by providing a better indication of the actual response patterns. Hum Brain Mapp 38:3415-3427, 2017. © 2017 Wiley Periodicals, Inc.

The role of vascular resistance in BOLD responses to progressive hypercapnia.

The ability of the cerebral vasculature to regulate vascular diameter, hence resistance and cerebral blood flow (CBF), in response to metabolic demands (neurovascular coupling), and perfusion pressure changes (autoregulation) may be assessed by measuring the CBF response to carbon dioxide (CO2 ). In healthy individuals, the CBF response to a ramp CO2 stimulus from hypocapnia to hypercapnia is assumed sigmoidal or linear. However, other response patterns commonly occur, especially in individuals with cerebrovascular disease, and these remain unexplained. CBF responses to CO2 in a vascular region are determined by the combined effects of the innate vascular responses to CO2 and the local perfusion pressure; the latter ensuing from pressure-flow interactions within the cerebral vascular network. We modeled this situation as two vascular beds perfused in parallel from a fixed resistance source. Our premise is that all vascular beds have a sigmoidal reduction of resistance in response to a progressive rise in CO2 . Surrogate CBF data to test the model was provided by magnetic resonance imaging of blood oxygen level-dependent (BOLD) signals. The model successfully generated all the various BOLD-CO2 response patterns, providing a physiological explanation of CBF distribution as relative differences in the network of vascular bed resistance responses to CO2 . Hum Brain Mapp 38:5590-5602, 2017. © 2017 Wiley Periodicals, Inc.

Development of White Matter Hyperintensity Is Preceded by Reduced Cerebrovascular Reactivity.

OBJECTIVE: White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH. METHODS: We examined 45 subjects (age range = 50-91 years; 25 males) with moderate-severe WMH, and measured their baseline CVR using the blood oxygen level-dependent magnetic resonance imaging signal response to a standardized step change in the end-tidal partial pressure of carbon dioxide. Diffusion tensor imaging and transverse relaxation time (T2) relaxometry were performed at baseline and 1-year follow-up, with automated coregistration between time points. Baseline fractional anisotropy (FA), mean diffusivity (MD), T2, and CVR were measured in areas that progressed from normal-appearing white matter (NAWM) to WMH over the 1-year period. RESULTS: CVR and FA values in baseline NAWM that progressed to WMH were lower by mean (standard deviation) = 26.5% (23.2%) and 11.0% (7.2%), respectively, compared to the contralateral homologous NAWM that did not progress (p < 0.001). T2 and MD were higher by 8.7% (7.9%) and 17.0% (8.5%), respectively, compared to the contralateral homologous NAWM (p < 0.001). INTERPRETATION: Areas of reduced CVR precede the progression from NAWM to WMH, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of age-related white matter disease. Ann Neurol 2016;80:277-285.

Invalidation of fMRI experiments secondary to neurovascular uncoupling in patients with cerebrovascular disease.

PURPOSE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a technique used to infer neuronal activity from the observed changes in blood flow. Cerebrovascular reactivity (CVR) is the ability of arterioles to increase blood flow in response to vasodilatory stimulus. We hypothesize that in areas of disease where there is exhausted vascular reserve and impaired CVR there will be diminished blood flow response following neuronal activation, and that these areas would appear as false-negative tests on BOLD fMRI. MATERIALS AND METHODS: Patients with steno-occlusive disease and unilateral hemodynamic impairment received a standardized hypercapnic stimuli while being imaged with BOLD fMRI to generate CVR maps. These were compared to traditional BOLD fMRI maps of neuronal activation in the motor cortex in response to a motor task. RESULTS: Neuronal activation from the motor task was found to be linearly correlated with CVR (n = 11 patients, R = 0.82). Regions with positive (normal) CVR showed positive activation on BOLD fMRI, while regions with negative CVR had attenuated neuronal activation on BOLD fMRI. CONCLUSION: In areas with cerebrovascular disease where CVR is impaired, there is uncoupling of neuronal activation and blood flow that confounds traditional BOLD fMRI. CVR mapping is a noninvasive MRI-based imaging technique that can provide information about the vascular reactivity of the brain that is important to consider when interpreting traditional BOLD fMRI studies. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1448-1455.

Reduced contralateral cerebrovascular reserve in patients with unilateral steno-occlusive disease.

UNLABELLED: The purpose of this study was to evaluate cerebrovascular reactivity (CVR) of major arterial vascular territories, particularly in the contralateral hemodynamically unaffected hemisphere, in patients with unilateral internal carotid artery (ICA) steno-occlusive disease compared to control subjects with risk factors for cerebrovascular disease. METHODS: In this retrospective observational study, twenty-seven patients with right-sided unilateral ICA steno-occlusive disease (age range, 25 to 91 years; 17 males) and twenty-one patients with left-sided unilateral ICA steno-occlusive disease (age range, 24 to 83 years; 14 males) and 41 control subjects were studied. CVR was quantitated as the change in blood oxygen level dependent (BOLD) MRI signal (as a surrogate of cerebral blood flow), in response to a consistently applied step change in the arterial partial pressure of carbon dioxide (PaCO2). The CVR of each major arterial vascular territory was assessed in the ipsilateral hemodynamically affected hemisphere and compared to the corresponding territory in the contralateral hemisphere. RESULTS: In patients, a significant reduction in CVR was observed in the ipsilateral anterior circulation compared to that of the corresponding territory on the contralateral side (0.027 ± 0.083 vs. 0.109 ± 0.066% BOLD change/​mm Hg, p < 0.0001) and to controls (0.195 ± 0.054% BOLD change/mm Hg, p < 0.0001). The CVR of the contralateral anterior circulation was reduced on average by 50% compared to controls (p < 0.0001). CONCLUSIONS: The implication of these findings is that unilateral carotid stenosis affects the vascular reserve of both sides of the brain compared to control subjects. This indicates that the collateral blood flow support from the contralateral to the ipsilateral hemisphere comes at a cost of reduced reserve capacity in the contralateral hemisphere. The findings suggest that there may be a reduction in functional hyperemia associated with neuronal activation, not only affecting the hemisphere ipsilateral to an occlusion, but also the hemisphere contralateral to an occlusion. It remains to be determined if 'stealing' from the 'rich' to support the 'poor' has clinical consequences over the long term.

CO2 blood oxygen level-dependent MR mapping of cerebrovascular reserve in a clinical population: safety, tolerability, and technical feasibility.

PURPOSE: To evaluate the safety, tolerability, and technical feasibility of mapping cerebrovascular reactivity (CVR) in a clinical population by using a precise prospectively targeted CO(2) stimulus and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging. MATERIALS AND METHODS: A chart review was performed of all CVR studies from institutional review board-approved projects at a tertiary care hospital between January 1, 2006, and December 1, 2010. Informed consent was obtained. Records were searched for the incidence of adverse events and failed examinations. CVR maps were evaluated for diagnostic quality by two blinded observers and were categorized as good, diagnostic but suboptimal, or nondiagnostic. Outcomes were presented as raw data and descriptive statistics (means ± standard deviations). Intraclass correlation coefficient was used to determine interobserver variability. RESULTS: Four hundred thirty-four consecutive CVR examinations from 294 patients (51.8% female patients) were studied. Patient age ranged from 9 to 88 years (mean age, 45.9 years ± 20.6). Transient symptoms, such as shortness of breath, headache, and dizziness, were reported in 48 subjects (11.1% of studies) during hypercapnic phases only. There were no neurologic ischemic events, myocardial infarctions, or other major complications. The success rate in generating CVR maps was 83.9% (364 of 434). Of the 70 (16.1%) failed examinations, 25 (35.7%) were due to discomfort; eight (11.4%), to head motion; two (2.9%), to inability to cooperate; seven (10.0%), to technical difficulties with equipment; and 28 (40.0%), to unknown or unspecified conditions. Among the 364 remaining successful examinations, good quality CVR maps were obtained in 340 (93.4%); diagnostic but suboptimal, in 12 (3.3%); and nondiagnostic, in 12 (3.3%). CONCLUSION: 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.

A Novel Window Into Human Vascular Remodeling and Diagnosing Carotid Flow Impairment: The Petro-Occipital Venous Plexus.

Background Adaptive arterial remodeling caused by flow reduction from downstream stenosis has been demonstrated in animal studies. The authors sought to determine whether inward remodeling from downstream stenosis also occurs in humans and is detectable by ex vacuo expansion of the Rektorzik venous plexus (RVP) surrounding the petrous internal carotid artery. Methods and Results The authors analyzed 214 intracranial magnetic resonance imaging examinations that included contrast-enhanced vessel wall imaging. RVP symmetry was qualitatively assessed on vessel wall imaging. RVP thickness (RVPT) was measured on the thicker side if asymmetric or randomly assigned side if symmetric. Maximum stenosis (M1 or intracranial internal carotid artery) was measured. Posterior communicating artery and A1 diameters (>1.0 mm and 1.5 mm, respectively) defined adequate collateral outflow when proximal to the stenosis. Seventy-two patients had stenosis downstream from RVPT measurements. For those without adequate outflow (38 of 72), 95.0% with RVPT ≥1.0 mm had ≥50% stenosis compared with only 5.6% with RVPT <1.0 mm. For these 72 patients, higher RVPT (RVPT ≥1.0 mm versus <1.0 mm) and absent adequate outflow were associated with greater downstream stenosis (P<0.001) using multivariate regression. For patients with downstream stenosis without adequate outflow, asymmetric RVP thickening was associated with greater ipsilateral stenosis (P<0.001, all had ≥46% stenosis) when stenosis was unilateral and greater differences in stenosis between sides (P=0.005) when stenosis was bilateral. Conclusions Inward internal carotid artery remodeling measured by RVPT or RVP asymmetry occurs as downstream stenosis approaches 50%, unless flow is preserved through a sufficiently sized posterior communicating artery or A1, and may serve as a functional measure of substantial flow reduction from downstream stenosis.

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.

The Reproducibility of Cerebrovascular Reactivity Across MRI Scanners.

Cerebrovascular reactivity (CVR) is defined as the ratio of the cerebral blood flow (CBF) response to an increase in a vasoactive stimulus. We used changes in blood oxygenation level-dependent (BOLD) MRI as surrogates for changes of CBF, and standardized quantitative changes in arterial partial pressure of carbon dioxide as the stimulus. Despite uniform stimulus and test conditions, differences in voxel-wise BOLD changes between testing sites may remain, attributable to physiologic and machine variability. We generated a reference atlas of normal CVR metrics (voxel-wise mean and SD) for each of two sites. We hypothesized that there would be no significant differences in CVR between the two atlases enabling each atlas to be used at any site. A total of 69 healthy subjects were tested to create site-specific atlases, with 20 of those individuals tested at both sites. 38 subjects were scanned at Site 1 (17F, 37.5 ± 16.8 y) and 51 subjects were tested at Site 2 (22F, 40.9 ± 17.4 y). MRI platforms were: Site 1, 3T Magnetom Skyra Siemens scanner with 20-channel head and neck coil; and Site 2, 3T HDx Signa GE scanner with 8-channel head coil. To construct the atlases, test results of individual subjects were co-registered into a standard space and voxel-wise mean and SD CVR metrics were calculated. Map comparisons of z scores found no significant differences between white matter or gray matter in the 20 subjects scanned at both sites when analyzed with either atlas. We conclude that individual CVR testing, and atlas generation are compatible across sites provided that standardized respiratory stimuli and BOLD MRI scan parameters are used. This enables the use of a single atlas to score the normality of CVR metrics across multiple sites.

The Effect of CO2 on Resting-State Functional Connectivity: Isocapnia vs. Poikilocapnia.

The normal variability in breath size and frequency results in breath-to-breath variability of end-tidal PCO2 (PETCO2), the measured variable, and arterial partial pressure of carbon dioxide (PaCO2), the independent variable affecting cerebral blood flow (CBF). This study examines the effect of variability in PaCO2 on the pattern of resting-state functional MRI (rs-fMRI) connectivity. A region of interest (ROI)-to-ROI and Seed-to-Voxel first-level bivariate correlation, hemodynamic response function (hrf)-weighted analysis for measuring rs-fMRI connectivity was performed during two resting-state conditions: (a) normal breathing associated with breath-to-breath variation in PaCO2 (poikilocapnia), and (b) normal breathing with breath-to-breath variability of PETCO2 dampened using sequential rebreathing (isocapnia). End-tidal PCO2 (PETCO2) was used as a measurable surrogate for fluctuations of PaCO2. During poikilocapnia, enhanced functional connections were found between the cerebellum and inferior frontal and supramarginal gyrus (SG), visual cortex and occipital fusiform gyrus; and between the primary visual network (PVN) and the hippocampal formation. During isocapnia, these associations were not seen, rather enhanced functional connections were identified in the corticostriatal pathway between the putamen and intracalacarine cortex, supracalcarine cortex (SCC), and precuneus cortex. We conclude that vascular responses to variations in PETCO2, account for at least some of the observed resting state synchronization of blood oxygenation level-dependent (BOLD) signals.

Accelerated ethanol elimination via the lungs.

Ethanol poisoning is endemic the world over. Morbidity and mortality depend on blood ethanol levels which in turn depend on the balance between its rates of absorption and clearance. Clearance of ethanol is mostly at a constant rate via enzymatic metabolism. We hypothesized that isocapnic hyperpnea (IH), previously shown to be effective in acceleration of clearance of vapour anesthetics and carbon monoxide, would also accelerate the clearance of ethanol. In this proof-of-concept pilot study, five healthy male subjects were brought to a mildly elevated blood ethanol concentration (~ 0.1%) and ethanol clearance monitored during normal ventilation and IH on different days. IH increased elimination rate of ethanol in proportion to blood levels, increasing the elimination rate more than three-fold. Increased veno-arterial ethanol concentration differences during IH verified the efficacy of ethanol clearance via the lung. These data indicate that IH is a nonpharmacologic means to accelerate the elimination of ethanol by superimposing first order elimination kinetics on underlying zero order liver metabolism. Such kinetics may prove useful in treating acute severe ethanol intoxication.

Cerebrovascular Reactivity Assays Collateral Function in Carotid Stenosis.

In patients with carotid artery stenosis (CAS), the risk of stroke, its severity, and response to revascularization are strongly related to the availability of collateral blood flow. Unfortunately, there is poor agreement between observers in assessing collateral flow using flow-based imaging. We used changes in blood-oxygen-level-dependent (BOLD) MRI as a surrogate of changes in regional cerebral blood flow in response to a hypercapnic stimulus [i.e., cerebrovascular reactivity (CVR)] as indicating flow reserve ipsilateral to CAS. We hypothesized that some patients with hemodynamically significant CAS develop functional collateral flow as indicated by normalization of ipsilateral CVR. We identified 55 patients in our CVR database with various degrees of CAS assessed by angiography and classed them as <50% stenosis, 50-69% stenosis, 70-90% stenosis, >90% stenosis, and full occlusion. CVR was measured as the change in BOLD signal in response to changes in end-tidal partial pressure of CO2 (Δ BOLD/Δ PETCO2) and normalized voxel-wise relative to the mean and standard deviation of the CVR in the corresponding voxels of an atlas of 46 healthy controls (CVR z scores). CVR and z scores were then averaged over gray matter (GM) and white matter (WM) on each side of the middle cerebral artery (MCA) territory. As hypothesized, CVR varied for each severity of CAS. Ipsilateral MCA territory CVR was less than normal in each class, including that with <50% stenosis (Student t-test, two-tailed; p = 0.0014 for GM and p = 0.030 for WM), with a trend of decreasing average CVR with increasing stenosis. Remarkably, the considerable individual variability in MCA CVR included some patients with normal CVR in each class - including that with complete occlusion. We conclude that, in general, CAS depresses downstream vascular reserve, but the extent of collateralization is highly variable and not predictable from the degree of stenosis, including both <50% stenosis and complete occlusion. CVR may be the more reliable marker for recruitable collateral blood flow than degree of CAS.

Cerebrovascular Resistance in Healthy Aging and Mild Cognitive Impairment.

Measures of cerebrovascular reactivity (CVR) are used to judge the health of the brain vasculature. In this study, we report the use of several different analyses of blood oxygen dependent (BOLD) fMRI responses to CO2 to provide a number of metrics of CVR based on the sigmoidal resistance response to CO2. To assess possible differences in these metrics with age, we compiled atlases reflecting voxel-wise means and standard deviations for four different age ranges and for a group of patients with mild cognitive impairment (MCI) and compared them. Sixty-seven subjects were recruited for this study and scanned at 3T field strength. Of those, 51 healthy control volunteers between the ages of 18-83 were recruited, and 16 (MCI) subjects between the ages of 61-83 were recruited. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm while monitoring end-tidal partial pressures of CO2. Surprisingly, some resistance sigmoid parameters in the oldest control group were increased compared to the youngest control group. Resistance amplitude maps showed increases in clusters within the temporal cortex, thalamus, corpus callosum and brainstem, and resistance reserve maps showed increases in clusters within the cingulate cortex, frontal gyrus, and corpus callosum. These findings suggest that some aspects of vascular reactivity in parts of the brain are initially maintained with age but then may increase in later years. We found significant reductions in all resistance sigmoid parameters (amplitude, reserve, sensitivity, midpoint, and range) when comparing MCI patients to controls. Additionally, in controls and in MCI patients, amplitude, range, reserve, and sensitivity in white matter (WM) was significantly reduced compared to gray matter (GM). WM midpoints were significantly above those of GM. Our general conclusion is that vascular regulation in terms of cerebral blood flow (CBF) responsiveness to CO2 is not significantly affected by age, but is reduced in MCI. These changes in cerebrovascular regulation demonstrate the value of resistance metrics for mapping areas of dysregulated blood flow in individuals with MCI. They may also be of value in the investigation of patients with vascular risk factors at risk for developing vascular dementia.

Cerebrovascular Resistance: The Basis of Cerebrovascular Reactivity.

The cerebral vascular network regulates blood flow distribution by adjusting vessel diameters, and consequently resistance to flow, in response to metabolic demands (neurovascular coupling) and changes in perfusion pressure (autoregulation). Deliberate changes in carbon dioxide (CO2) partial pressure may be used to challenge this regulation and assess its performance since CO2 also acts to change vessel diameter. Cerebrovascular reactivity (CVR), the ratio of cerebral blood flow (CBF) response to CO2 stimulus is currently used as a performance metric. However, the ability of CVR to reflect the responsiveness of a particular vascular region is confounded by that region's inclusion in the cerebral vascular network, where all regions respond to the global CO2 stimulus. Consequently, local CBF responses reflect not only changes in the local vascular resistance but also the effect of changes in local perfusion pressure resulting from redistribution of flow within the network. As a result, the CBF responses to CO2 take on various non-linear patterns that are not well-described by straight lines. We propose a method using a simple model to convert these CBF response patterns to the pattern of resistance responses that underlie them. The model, which has been used previously to explain the steal phenomenon, consists of two vascular branches in parallel fed by a major artery with a fixed resistance unchanging with CO2. One branch has a reference resistance with a sigmoidal response to CO2, representative of a voxel with a robust response. The other branch has a CBF equal to the measured CBF response to CO2 of any voxel under examination. Using the model to calculate resistance response patterns of the examined branch showed sigmoidal patterns of resistance response, regardless of the measured CBF response patterns. The sigmoid parameters of the resistance response pattern of examined voxels may be mapped to their anatomical location. We show an example for a healthy subject and for a patient with steno-occlusive disease to illustrate. We suggest that these maps provide physiological insight into the regulation of CBF distribution.