Carbon dioxide induced changes in cerebral blood flow and flow velocity: role of cerebrovascular resistance and effective cerebral perfusion pressure

In addition to cerebrovascular resistance (CVR) zero flow pressure (ZFP), effective cerebral perfusion pressure (CPPe) and the resistance area product (RAP) are supplemental determinants of cerebral blood flow (CBF). Until now, the interrelationship of PaCO₂-induced changes in CBF, CVR, CPPe, ZFP, and RAP is not fully understood. In a controlled crossover trial, we investigated 10 anesthetized patients aiming at PaCO₂ levels of 30, 37, 43, and 50 mm Hg. Cerebral blood flow was measured with a modified Kety-Schmidt-technique. Zero flow pressure and RAP was estimated by linear regression analysis of pressure–flow velocity relationships of the middle cerebral artery. Effective cerebral perfusion pressure was calculated as the difference between mean arterial pressure and ZFP, CVR as the ratio CPPe/CBF. Statistical analysis was performed by one-way RM-ANOVA. When comparing hypocapnia with hypercapnia, CBF showed a significant exponential reduction by 55% and mean V_MCA by 41%. Effective cerebral perfusion pressure linearly decreased by 17% while ZFP increased from 14 to 29 mm Hg. Cerebrovascular resistance increased by 96% and RAP by 39% despite these concordant changes in mean CVR and Doppler-derived RAP correlation between these variables was weak (r=0.43). In conclusion, under general anesthesia hypocapnia-induced reduction in CBF is caused by both an increase in CVR and a decrease in CPPe, as a consequence of an increase in ZFP.     

Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion

The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level-dependent (BOLD) MRI was performed in 11 patients (65±7 years) and 14 controls (66±4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) were evaluated. The CBF was 34±5 and 36±11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44±20 and 53±10% per 10 mm Hg ▵EtCO₂ in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3±0.8 versus 2.2±0.4% per 10 mm Hg ▵EtCO₂, P<0.01). The OEF was 41±8% and 38±6%, and the CMRO₂ was 116±39 and 111±40 μmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2±0.6 versus 1.6±0.5% per 10 mmHg ▵EtCO₂, P<0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients.     

Cerebrovascular reactivity is increased with acclimatization to 3,454?m altitude

Controversy exists regarding the effect of high-altitude exposure on cerebrovascular CO₂ reactivity (CVR). Confounding factors in previous studies include the use of different experimental approaches, ascent profiles, duration and severity of exposure and plausibly environmental factors associated with altitude exposure. One aim of the present study was to determine CVR throughout acclimatization to high altitude when controlling for these. Middle cerebral artery mean velocity (MCAv_mean) CVR was assessed during hyperventilation (hypocapnia) and CO₂ administration (hypercapnia) with background normoxia (sea level (SL)) and hypoxia (3,454 m) in nine healthy volunteers (26±4 years (mean±s.d.)) at SL, and after 30 minutes (HA0), 3 (HA3) and 22 (HA22) days of high-altitude (3,454 m) exposure. At altitude, ventilation was increased whereas MCAv_mean was not altered. Hypercapnic CVR was decreased at HA0 (1.16%±0.16%/mm Hg, mean±s.e.m.), whereas both hyper- and hypocapnic CVR were increased at HA3 (3.13%±0.18% and 2.96%±0.10%/mm Hg) and HA22 (3.32%±0.12% and 3.24%±0.14%/mm Hg) compared with SL (1.98%±0.22% and 2.38%±0.10%/mm Hg; P<0.01) regardless of background oxygenation. Cerebrovascular conductance (MCAv_mean/mean arterial pressure) CVR was determined to account for blood pressure changes and revealed an attenuated response. Collectively our results show that hypocapnic and hypercapnic CVR are both elevated with acclimatization to high altitude.     

Hemodynamic impairments within individual watershed areas in asymptomatic carotid artery stenosis by multimodal MRI

Improved understanding of complex hemodynamic impairments in asymptomatic internal carotid artery stenosis (ICAS) is crucial to better assess stroke risks. Multimodal MRI is ideal for measuring brain hemodynamics and has the potential to improve diagnostics and treatment selections. We applied MRI-based perfusion and oxygenation-sensitive imaging in ICAS with the hypothesis that the sensitivity to hemodynamic impairments will improve within individual watershed areas (iWSA). We studied cerebral blood flow (CBF), cerebrovascular reactivity (CVR), relative cerebral blood volume (rCBV), relative oxygen extraction fraction (rOEF), oxygen extraction capacity (OEC) and capillary transit-time heterogeneity (CTH) in 29 patients with asymptomatic, unilateral ICAS (age 70.3 ± 7.0 y) and 30 age-matched healthy controls. In ICAS, we found significant impairments of CBF, CVR, rCBV, OEC, and CTH (strongest lateralization ΔCVR = –24%), but not of rOEF. Although the spatial overlap of compromised hemodynamic parameters within each patient varied in a complex manner, most pronounced changes of CBF, CVR and rCBV were detected within iWSAs (strongest effect ΔCVR = +117%). At the same time, CTH impairments were iWSA independent, indicating widespread dysfunction of capillary-level oxygen diffusivity. In summary, complementary MRI-based perfusion and oxygenation parameters offer deeper perspectives on complex microvascular impairments in individual patients. Furthermore, knowledge about iWSAs improves the sensitivity to hemodynamic impairments.     

Impaired dynamic cerebral autoregulation at extreme high altitude even after acclimatization

Cerebral blood flow (CBF) increases and dynamic cerebral autoregulation is impaired by acute hypoxia. We hypothesized that progressive hypocapnia with restoration of arterial oxygen content after altitude acclimatization would normalize CBF and dynamic cerebral autoregulation. To test this hypothesis, dynamic cerebral autoregulation was examined by spectral and transfer function analyses between arterial pressure and CBF velocity variabilities in 11 healthy members of the Danish High-Altitude Research Expedition during normoxia and acute hypoxia (10.5% O₂) at sea level, and after acclimatization (for over 1 month at 5,260 m at Chacaltaya, Bolivia). Arterial pressure and CBF velocity in the middle cerebral artery (transcranial Doppler), were recorded on a beat-by-beat basis. Steady-state CBF velocity increased during acute hypoxia, but normalized after acclimatization with partial restoration of SaO₂ (acute, 78%±2% chronic, 89%±1%) and progression of hypocapnia (end-tidal carbon dioxide: acute, 34±2 mm Hg; chronic, 21±1 mm Hg). Coherence (0.40±0.05 Units at normoxia) and transfer function gain (0.77±0.13 cm/s per mm Hg at normoxia) increased, and phase (0.86±0.15 radians at normoxia) decreased significantly in the very-low-frequency range during acute hypoxia (gain, 141%±24% coherence, 136%±29% phase, −25%±22%), which persisted after acclimatization (gain, 136%±36% coherence, 131%±50% phase, −42%±13%), together indicating impaired dynamic cerebral autoregulation in this frequency range. The similarity between both acute and chronic conditions suggests that dynamic cerebral autoregulation is impaired by hypoxia even after successful acclimatization to an extreme high altitude.     

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.     

Positron emission tomography/magnetic resonance hybrid scanner imaging of cerebral blood flow using 15O-water positron emission tomography and arterial spin labeling magnetic resonance imaging in newborn piglets

Abnormality in cerebral blood flow (CBF) distribution can lead to hypoxic–ischemic cerebral damage in newborn infants. The aim of the study was to investigate minimally invasive approaches to measure CBF by comparing simultaneous ¹⁵O-water positron emission tomography (PET) and single TI pulsed arterial spin labeling (ASL) magnetic resonance imaging (MR) on a hybrid PET/MR in seven newborn piglets. Positron emission tomography was performed with IV injections of 20 MBq and 100 MBq ¹⁵O-water to confirm CBF reliability at low activity. Cerebral blood flow was quantified using a one-tissue-compartment-model using two input functions: an arterial input function (AIF) or an image-derived input function (IDIF). The mean global CBF (95% CI) PET-AIF, PET-IDIF, and ASL at baseline were 27 (23; 32), 34 (31; 37), and 27 (22; 32) mL/100 g per minute, respectively. At acetazolamide stimulus, PET-AIF, PET-IDIF, and ASL were 64 (55; 74), 76 (70; 83) and 79 (67; 92) mL/100 g per minute, respectively. At baseline, differences between PET-AIF, PET-IDIF, and ASL were 22% (P<0.0001) and −0.7% (P=0.9). At acetazolamide, differences between PET-AIF, PET-IDIF, and ASL were 19% (P=0.001) and 24% (P=0.0003). In conclusion, PET-IDIF overestimated CBF. Injected activity of 20 MBq ¹⁵O-water had acceptable concordance with 100 MBq, without compromising image quality. Single TI ASL was questionable for regional CBF measurements. Global ASL CBF and PET CBF were congruent during baseline but not during hyperperfusion.     

Comparison of cerebral vascular reactivity measures obtained using breath-holding and CO2 inhalation

Stimulation of cerebral vasculature using hypercapnia has been widely used to study cerebral vascular reactivity (CVR), which can be expressed as the quantitative change in cerebral blood flow (CBF) per mm Hg change in end-tidal partial pressure of CO₂ (P_ETCO₂). We investigate whether different respiratory manipulations, with arterial spin labeling used to measure CBF, lead to consistent measures of CVR. The approaches included: (1) an automated system delivering variable concentrations of inspired CO₂ for prospective targeting of P_ETCO₂, (2) administration of a fixed concentration of CO₂ leading to subject-dependent changes in P_ETCO₂, (3) a breath-hold (BH) paradigm with physiologic modeling of CO₂ accumulation, and (4) a maneuver combining breath-hold and hyperventilation. When CVR was expressed as the percent change in CBF per mm Hg change in P_ETCO₂, methods 1 to 3 gave consistent results. The CVR values using method 4 were significantly lower. When CVR was expressed in terms of the absolute change in CBF (mL/100 g per minute per mm Hg), greater discrepancies became apparent: methods 2 and 3 gave lower absolute CVR values compared with method 1, and the value obtained with method 4 was dramatically lower. Our findings indicate that care must be taken to ensure that CVR is measured over the linear range of the CBF-CO₂ dose–response curve, avoiding hypocapnic conditions.     

Regulation of brain blood flow and oxygen delivery in elite breath-hold divers

The roles of involuntary breathing movements (IBMs) and cerebral oxygen delivery in the tolerance to extreme hypoxemia displayed by elite breath-hold divers are unknown. Cerebral blood flow (CBF), arterial blood gases (ABGs), and cardiorespiratory metrics were measured during maximum dry apneas in elite breath-hold divers (n=17). To isolate the effects of apnea and IBM from the concurrent changes on ABG, end-tidal forcing (‘clamp'') was then used to replicate an identical temporal pattern of decreasing arterial PO₂ (PaO₂) and increasing arterial PCO₂ (PaCO₂) while breathing. End-apnea PaO₂ ranged from 23  to 37 mm Hg (30±7 mm Hg). Elevation in mean arterial pressure was greater during apnea than during clamp reaching +54±24% versus 34±26%, respectively; however, CBF increased similarly between apnea and clamp (93.6±28% and 83.4±38%, respectively). This latter observation indicates that during the overall apnea period IBM per se do not augment CBF and that the brain remains sufficiently protected against hypertension. Termination of apnea was not determined by reduced cerebral oxygen delivery; despite 40% to 50% reductions in arterial oxygen content, oxygen delivery was maintained by commensurately increased CBF.     

Cerebrovascular reactivity in the brain white matter: magnitude,temporal characteristics,and age effects

White matter (WM) comprises about half of the brain and its dysfunction is implicated in many brain disorders. While structural properties in healthy and diseased WM have been extensively studied, relatively little is known about the physiology underlying these structural characteristics. Recent advances in magnetic resonance (MR) technologies provided new opportunities to better understand perfusion and microvasculature in the WM. Here, we aim to evaluate vasodilatory capacity of the WM vasculature, which is thought to be important in tissue ischemia and autoregulation. Fifteen younger and fifteen older subjects performed a CO₂ inhalation task while blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging (MRI) images were continuously collected. The cerebrovascular reactivity (CVR) index showed that the value of CVR in the WM (0.03±0.002%/mm Hg) was positive, but was significantly lower than that in the gray matter (GM) (0.22±0.01%/mm Hg). More strikingly, the WM response showed a temporal delay of 19±3 seconds compared with GM, which was attributed to the longer time it takes for extravascular CO₂ to change. With age, WM CVR response becomes greater and faster, which is opposite to the changes seen in the GM. These data suggest that characteristics of WM CVR are different from that of GM and caution should be used when interpreting pathologic WM CVR results.     

The vascular mean transit time: a surrogate for the penumbra flow threshold?

Depicting the salvageable tissue is increasingly used in the clinical setting following stroke. As absolute cerebral blood flow (CBF) is difficult to measure using perfusion magnetic resonance or computed tomography and has limitations as a penumbral marker, time-based variables, particularly the mean transit time (MTT), are routinely used as surrogates. However, a direct validation of MTT as a predictor of the penumbra threshold using gold-standard positron emission tomography (PET) is lacking. Using ¹⁵O-PET data sets obtained from two independent acute stroke samples (N=7 and N=30, respectively), we derived areas under the curve (AUCs), optimal thresholds (OTs), and 90%-specificity thresholds (90%-Ts) from receiver operating characteristic curves for absolute MTT, MTT delay, and MTT ratio to predict three penumbra thresholds (‘classic'': CBF <20 mL/100 g per min; ‘normalized'': CBF ratio <0.5; and ‘stringent'': both CBF <20 mL/100 g per min and oxygen extraction fraction >0.55). In sample 1, AUCs ranged from 0.79 to 0.92, indicating good validity; OTs ranged from 7.8 to 8.3 seconds, 2.8 to 4.7 seconds, and 151% to 267% for absolute MTT, MTT delay, and MTT ratio, respectively, while as expected, 90%-Ts were longer. There was no significant difference between sample 1 and sample 2 for any of the above measurements, save for a single MTT parameter with a single penumbra threshold. These consistent findings from gold-standard PET obtained in two independent cohorts document that MTT is a very good surrogate to CBF for depicting the penumbra threshold.     

Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness

The thalamus has been found to be activated during the early phase of moderate hypoglycemia. Here, we tested the hypothesis that this region is less activated during hypoglycemia in subjects with type 1 diabetes (T1DM) and hypoglycemia unawareness relative to controls. Twelve controls (5 F/7 M, age 40±14 years, body mass index 24.2±2.7 kg/m²) and eleven patients (7 F/4 M, age 39±13 years, body mass index 26.5±4.4 kg/m²) with well-controlled T1DM (A1c 6.8±0.4%) underwent a two-step hyperinsulinemic (2.0 mU/kg per minute) clamp. Cerebral blood flow (CBF) weighted images were acquired using arterial spin labeling to monitor cerebral activation in the midbrain regions. Blood glucose was first held at 95 mg/dL and then allowed to decrease to 50 mg/dL. The CBF image acquisition during euglycemia and hypoglycemia began within a few minutes of when the target blood glucose values were reached. Hypoglycemia unaware T1DM subjects displayed blunting of the physiologic CBF increase that occurs in the thalamus of healthy individuals during the early phase of moderate hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia, suggesting that this region may be involved in the coordination of the counter regulatory response to hypoglycemia.     

The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO₂ would affect cerebral metabolism more than hypoxia. PaO₂ and PaCO₂ were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial–jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO₂-H⁺ relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO₂ reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.     

Reduced blood flow in normal white matter predicts development of leukoaraiosis

The purpose of this study was to investigate whether low cerebral blood flow (CBF) is associated with subsequent development of white matter hyperintensities (WMH). Patients were included from a longitudinal magnetic resonance (MR) imaging study of minor stroke/transient ischemic attack patients. Images were co-registered and new WMH at 18 months were identified by comparing follow-up imaging with baseline fluid-attenuated inversion recovery (FLAIR). Regions-of-interest (ROIs) were placed on FLAIR images in one of three categories: (1) WMH seen at both baseline and follow-up imaging, (2) new WMH seen only on follow-up imaging, and (3) regions of normal-appearing white matter at both time points. Registered CBF maps at baseline were used to measure CBF in the ROIs. A multivariable model was developed using mixed-effects logistic regression to determine the effect of baseline CBF on the development on new WMH. Forty patients were included. Mean age was 61±11 years, 30% were female. Low baseline CBF, female sex, and presence of diabetes were independently associated with the presence of new WMH on follow-up imaging. The odds of having new WMH on follow-up imaging reduces by 0.61 (95% confidence interval=0.57 to 0.65) for each 1 mL/100 g per minute increase in baseline CBF. We conclude that regions of white matter with low CBF develop new WMH on follow-up imaging.     

Smoking normalizes cerebral blood flow and oxygen consumption after 12-hour abstention

Acute nicotine administration stimulates [¹⁴C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO₂) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO₂. At the end of the abstention period, global grey-matter CBF and CMRO₂ were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO₂ had increased by 11%. Regional analysis showed that CMRO₂ had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO₂ had increased by 11-12%. Thus, we find substantial and global impairment of CBF/CMRO₂ in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO₂ during acute abstention may mediate the cognitive changes described in chronic smokers.     

Rho-kinase inhibition improves ischemic perfusion deficit in hyperlipidemic mice

Hyperlipidemia is a major cardiovascular risk factor associated with progressive cerebrovascular dysfunction and diminished collateral perfusion in stroke. Rho-associated kinase (ROCK) may be an important mediator of hyperlipidemic vascular dysfunction. We tested the efficacy of acute or chronic ROCK inhibition on the size of dynamic perfusion defect using laser speckle flowmetry in hyperlipidemic apolipoprotein E knockout mice fed on a high-fat diet for 8 weeks. Mice were studied at an age before the development of flow-limiting atherosclerotic stenoses in aorta and major cervical arteries. Focal ischemia was induced by distal middle cerebral artery occlusion (dMCAO) during optical imaging. The ROCK inhibitor fasudil (10 mg/kg) was administered either as a single dose 1 hour before ischemia onset, or daily for 4 weeks. Fasudil decreased both baseline arterial blood pressure and cerebrovascular resistance (CVR) by ∼15%, and significantly improved tissue perfusion during dMCAO. Interestingly, peri-infarct depolarizations were also reduced. Chronic treatment did not further enhance these benefits compared with acute treatment with a single dose. These data show that ROCK inhibition improves CVR and ischemic tissue perfusion in hyperlipidemic mice.     

Physiological origin for the BOLD poststimulus undershoot in human brain: vascular compliance versus oxygen metabolism

The poststimulus blood oxygenation level-dependent (BOLD) undershoot has been attributed to two main plausible origins: delayed vascular compliance based on delayed cerebral blood volume (CBV) recovery and a sustained increased oxygen metabolism after stimulus cessation. To investigate these contributions, multimodal functional magnetic resonance imaging was employed to monitor responses of BOLD, cerebral blood flow (CBF), total CBV, and arterial CBV (CBV_a) in human visual cortex after brief breath hold and visual stimulation. In visual experiments, after stimulus cessation, CBV_a was restored to baseline in 7.9±3.4 seconds, and CBF and CBV in 14.8±5.0 seconds and 16.1±5.8 seconds, respectively, all significantly faster than BOLD signal recovery after undershoot (28.1±5.5 seconds). During the BOLD undershoot, postarterial CBV (CBV_pa, capillaries and venules) was slightly elevated (2.4±1.8%), and cerebral metabolic rate of oxygen (CMRO₂) was above baseline (10.6±7.4%). Following breath hold, however, CBF, CBV, CBV_a and BOLD signals all returned to baseline in ∼20 seconds. No significant BOLD undershoot, and residual CBV_pa dilation were observed, and CMRO₂ did not substantially differ from baseline. These data suggest that both delayed CBV_pa recovery and enduring increased oxidative metabolism impact the BOLD undershoot. Using a biophysical model, their relative contributions were estimated to be 19.7±15.9% and 78.7±18.6%, respectively.     

Persistent CO2 reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO₂ challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity_, and an impaired respiratory rate response to CO₂ challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO₂ brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.     

Endothelial SKCa and IKCa channels regulate brain parenchymal arteriolar diameter and cortical cerebral blood flow

Calcium-sensitive potassium (K_Ca) channels have been shown to modulate the diameter of cerebral pial arteries; however, little is known regarding their roles in controlling cerebral parenchymal arterioles (PAs). We explored the function and cellular distribution of small-conductance (SK_Ca) and intermediate-conductance (IK_Ca) K_Ca channels and large-conductance K_Ca (BK_Ca) channels in endothelial cells (ECs) and smooth muscle cells (SMCs) of PAs. Both SK_Ca and IK_Ca channels conducted the outward current in isolated PA ECs (current densities, ∼20 pA/pF and ∼28 pA/pF at +40 mV, respectively), but these currents were not detected in PA SMCs. In contrast, BK_Ca currents were prominent in PA SMCs (∼154 pA/pF), but were undetectable in PA ECs. Pressurized PAs constricted to inhibition of SK_Ca (∼16%) and IK_Ca (∼16%) channels, but were only modestly affected by inhibition of BK_Ca channels (∼5%). Blockade of SK_Ca and IK_Ca channels decreased resting cortical cerebral blood flow (CBF) by ∼15%. NS309 (6,7-dichloro-1H-indole-2,3-dione3-oxime), a SK_Ca/IK_Ca channel opener, hyperpolarized PA SMCs by ∼27 mV, maximally dilated pressurized PAs, and increased CBF by ∼40%. In conclusion, these data show that SK_Ca and IK_Ca channels in ECs profoundly modulate PA tone and CBF, whereas BK_Ca channels in SMCs only modestly influence PA diameter.     

Cerebrovascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a small vessel disease caused by TREX1 mutations. RVCL-S is characterized by retinal vasculopathy and brain white matter lesions with and without contrast enhancement. We aimed to investigate cerebrovascular reactivity (CVR) in RVCL-S. In this cross-sectional observational study, 21 RVCL-S patients, 23 mutation-negative family members, and 31 healthy unrelated controls were included. CVR to a hypercapnic challenge was measured using dual-echo arterial spin labeling magnetic resonance imaging. Stratified analyses based on age were performed. We found that CVR was decreased in gray and white matter of RVCL-S patients compared with family members and healthy controls (ANCOVA; P < 0.05 for all comparisons). This was most noticeable in RVCL-S patients aged ≥40 years (ANCOVA, P < 0.05 for all comparisons). In RVCL-S patients aged < 40 years, only CVR in white matter was lower when compared to healthy controls (P < 0.05). Gray matter CVR was associated with white matter lesion volume in RVCL-S patients (r = –0.527, P = 0.01). In conclusion, impaired cerebrovascular reactivity may play an important role in the pathophysiology of RVCL-S and may be an useful early biomarker of cerebrovascular disease severity.