Increase In Cerebral Blood Flow Research Articles

Hot head-out water immersion increases internal carotid artery shear rate but does not alter intracranial vascular reactivity to carbon dioxide

Acute head-out water immersion (HOWI) in hot water increases cerebral blood flow (CBF) until core temperature rises by ~1.0°C. The increase in CBF may promote increases in arterial shear rate that could enhance cerebrovascular reactivity to CO2 (CVRCO2) as a result of elevated nitric oxide (NO) bioavailability. An increase in NO bioavailability improves peripheral vasodilator function, and therefore, a similar response may occur in the cerebral vasculature. This likely only aids in cerebral vasodilation during hypercapnia, and not cerebral vasoconstriction during hypocapnia. However, it is unclear if a single session of hot HOWI alters cerebral artery shear rate and CVRCO2 to hyper- and hypocapnia. Purpose: We tested the hypotheses that during a single session of hot HOWI (39°C), cerebral artery shear rate and hypercapnic CVRCO2 would be greater and hypocapnic CVRCO2 would be lower compared to temperate HOWI (35°C). Methods: Eighteen healthy participants (age: 25±5 y, 6 women) completed two experimental visits. Middle and posterior cerebral artery blood velocities (transcranial Doppler; MCAv and PCAv) were continuously recorded. Blood velocities and diameters of the right internal carotid artery (ICA) and vertebral artery (VA) were obtained via dual-mode Doppler ultrasound to calculate shear rate. Hypocapnic and hypercapnic CVRCO2 were assessed in the MCA and PCA during self-paced hyperventilation (until PETCO2 decreased by 10 mmHg from baseline) and during 30 s of 7% CO2 inhalation, respectively. Measures were completed before immersion (PRE) and after a +1.0°C increase in core temperature during hot HOWI and time-matched during temperate HOWI. Data are reported as mean ± SD. Results: There were no differences between conditions at PRE. MCAv (55±9 vs. 64±12 cm/s; P=0.01) and PCAv (29±5 vs. 39±7 cm/s; p<0.01) were lower in hot vs. temperate HOWI at +1.0°C. ICA shear rate was greater in hot vs. temperate HOWI at +1.0°C (247±51 vs. 180±43 s−1; p<0.01) but VA shear rate did not differ between conditions (P=0.78). There were no differences between conditions for hypercapnic CVRCO2 (MCA: P =0.48, PCA: P=0.43) or hypocapnic CVRCO2 (MCA: P=0.18). A condition effect was observed for PCA hypocapnic CVRCO2 (p<0.01), but multiple comparisons did not reveal where differences occurred (all P≥0.10). Conclusion: Hot head out water immersion elicits similar changes in hemodynamics and CVRCO2 in intracranial arteries (i.e., MCA and PCA) as temperate head out water immersion. Hot head out water immersion produces a greater shear rate in the ICA compared to temperate water, which may be beneficial for cerebrovascular health if done recurrently. This study was partially supported by the Mark Diamond Research Fund at the University at Buffalo and the Offce of Naval Research Director of Research Early Career Grant (N00014-17-1-2878). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Treatment of Hypotension with Phenylephrine Increases Cerebral Microvascular Perfusion in a Rat Model of Acute Hemodilution

Intraoperative blood loss is associated with reduced mean arterial blood pressure (MAP), which may endanger vital organ perfusion, including the brain. Phenylephrine (PE), an α1-receptor agonist, is clinically utilized to treat intraoperative hypotension through vasoconstriction of resistance arterioles. Clinical studies suggest that raising MAP with PE may decrease perfusion to vital organs such as the brain. Experimental studies suggest that lower α-receptor density in the cerebral resistance arteries may lead to preserved brain perfusion after PE administration. We hypothesize that treatment of hypotension with PE will result in preserved brain perfusion due to different microvascular blood flow and tissue oxygen tension (pO2) responses in the brain and skeletal muscle in an experimental rat model. With Animal Care and Use Committee approval in accordance with ARRIVE-2 guidelines, spontaneously breathing anesthetized rats (1.5% isoflurane) underwent hemodilution by exchanging 40-50% estimated blood volume 1:1 with saline over 10 minutes to achieve a 10-20 mmHg drop in MAP. MAP (tail artery) was measured continuously. Hypotension was treated with PE (10-20 μg/kg/min iv) to increase MAP to a target above baseline MAP. Shed blood was re-infused after stopping the PE infusion. Microvascular blood flow (Oxyflo; Oxford Optronix, Oxford, UK, n=7) or microvascular pO2 (OxyLED, Oxyphor G4, Oxygen Enterprises Ltd., Philadelphia, PA, n=6) were measured continuously in the cerebral cortex (burr hole) and biceps femoris muscle simultaneously in each rat. Results were analyzed via one or two-way ANOVA, with significance achieved at p<0.05. Baseline and post-hemodilution MAP values were comparable in both groups. PE infusion increased MAP to a mean level near 100 mmHg in both groups (p<0.05). Microvascular blood flow and tissue pO2 were greater in the brain as compared to the muscle at all time points (p<0.01 for both). PE infusion resulted in an increase in cerebral microvascular blood flow from baseline (1465±689 vs. 687±453 blood perfusion units (BPU); p<0.001) that was sustained after discontinuing PE and during blood reinfusion. No changes in muscle microvascular flow were observed after PE infusion (294±129 vs. 168±113 BPU). A sustained increase in cerebral microvascular pO2 was measured following PE infusion (50.2±8.6 vs. 40.6±4.6 mmHg; p=0.02), whereas muscle tissue pO2 did not change (22.2±5.6 vs. 25.0±2.5 mmHg). A differential blood flow and microvascular pO2 response was observed following PE infusion in brain and skeletal muscle. Both cerebral microvascular blood flow and tissue pO2 demonstrated sustained increases after PE infusion. By contrast, no changes were observed in muscle microvascular blood flow and pO2. These results suggest that treatment of hypotension with PE administration preferentially increased cerebral vs. muscle perfusion in an experimental model of acute blood loss and fluid resuscitation. Canadian Anesthesiologists’ Society and University of Toronto Merit Award Support. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Global hyperperfusion after successful endovascular thrombectomy is linked to worse outcome in acute ischemic stroke

Patients with stroke may develop hyperperfusion after a successful endovascular thrombectomy (EVT). However, the relationship between post-EVT hyperperfusion and clinical outcomes remains unclear and requires further clarification. We reviewed consecutive patients with anterior circulation occlusion who were successfully recanalized with EVT. Based on post-EVT arterial spin-labeling images, hyperperfusion was categorized as follows: global hyperperfusion (GHP), increased cerebral blood flow (CBF) in ≥ 50% of the culprit vessel territory; focal hyperperfusion (FHP), increased CBF in < 50% of the culprit vessel territory; no hyperperfusion (NHP), no discernible CBF increase. Factors associated with hyperperfusion were assessed, and clinical outcomes were compared among patients under different hyperperfusion categories. Among 131 patients, 25 and 40 patients developed GHP and FHP, respectively. Compared to other groups, the GHP group had worse National Institutes of Health Stroke Scale score (GHP vs. NHP/FHP, 18.1 ± 7.4 vs. 12.3 ± 6.0; p < 0.001), a larger post-EVT infarct volume (98.9 [42.3–132.7] vs. 13.5 [5.0–34.1] mL; p < 0.001), and a worse 90-day outcome (modified Rankin Scale, 3 [1–4] vs. 2 [0–3]; p = 0.030). GHP was independently associated with infarct volume (B = 0.532, standard error = 0.163, p = 0.001), and infarct volume was a major mediator of the association of GHP with unfavorable outcomes (total effect: β = 0.176, p = 0.034; direct effect: β = 0.045, p = 0.64; indirect effect: β = 0.132, p = 0.017). Patients presenting with post-EVT GHP had poorer neurological prognosis, which is likely mediated by a large infarct volume.

Elevated plasma aldosterone impairs functional hyperemia and cognitive function

Aldosterone, a steroid hormone, plays an important role in blood pressure homeostasis and the maintenance of plasma electrolyte levels by activating the mineralocorticoid receptor (MR) in renal distal tubule and collecting duct epithelial cells. Recent studies revealed that MRs are also expressed in other tissues, including cardiac myocytes, vascular smooth muscle cells, and vascular endothelial cells (EC), and that elevated plasma aldosterone, termed hyperaldosteronemia (HA), has deleterious effects on the cardiovascular system. HA is present in 10-30% of hypertensive patients and unrecognized and asymptomatic HA is estimated to occur in &gt; 10% of individuals with normal blood pressure. Despite the high prevalence of HA, little is known about its impact on cerebral blood flow (CBF) regulation and brain health. This study focused on the physiological processes that support the on-demand delivery of blood to regions of heightened neuronal activity (functional hyperemia). Specifically, we examined the impact of HA on the recently discovered novel mechanism, termed capillary-to-arteriole signaling, through which capillaries and their strong inward rectifier K+ (Kir 2.1) channels play a significant role in functional hyperemia. Importantly, early deficits in functional hyperemia are a hallmark of small vessel diseases of the brain, which are significant contributors to cognitive impairment and dementia. Employing HA model mice, we examined the impact of HA on functional hyperemia, capillary-to-arteriole signaling, Kir2.1 channel activity in freshly isolated capillary ECs (cECs), and cognitive function. Functional hyperemia, measured as whisker stimulation-induced CBF increases using laser Doppler flowmetry, was impaired in HA animals compared to vehicle-treated animals. Retrograde capillary-to-arteriole signaling, evaluated as upstream arteriolar dilation in response to capillary stimulation with 10 mM K+ in Capillary-Parenchymal Arteriole (CaPA), preparations was significantly attenuated in HA mice. Furthermore, cEC Kir2.1 channel currents, recorded using the conventional whole-cell configuration of the patch-clamp technique, were significantly smaller in HA mice compared to vehicle-treated mice. Further, HA model animals obtained lower scores in the Novel Object Recognition test, indicating that cognitive function in the form of memory retention may be impacted by elevated plasma aldosterone. These data suggest that HA impairs functional hyperemia and cognitive function, and that HA may be a novel risk factor for vascular cognitive impairment. This work was supported by The National Institute of Health (P20-GM-135007 to MK and R01-HL-142888 to GCW). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cerebral blood flow regulation in hypobaric hypoxia: role of haemoconcentration.

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty-three healthy lowlanders (12 females) completed two identical 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1h (P=0.001) but similar at all later time points (all P>0.199). Haemoglobin concentration was higher in HH than NX from 12h to 96h (all P<0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2g·dl-1 (P<0.001), it did not increase CBF (974 ± 282 to 872 ± 200ml·min-1; P=0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO2. KEY POINTS: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes. We investigated whether hypoxia-induced haemoconcentration contributes to the normalization of CBF during extended hypoxia. Following 4 days of hypobaric hypoxic exposure (corresponding to 3500m altitude), we measured CBF before and after abolishing hypoxia-induced haemoconcentration by hypervolaemic haemodilution. Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia. Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia.

Statin treatment intensity and cerebral vasomotor reactivity response in patients with ischemic stroke.

Cerebral vasomotor reactivity (VMR) is vital for regulating brain blood flow and maintaining neurological function. Impaired cerebral VMR is linked to a higher risk of stroke and poor post-stroke outcomes. This study explores the relationship between statin treatment intensity and VMR in patients with ischemic stroke. Seventy-four consecutive patients (mean age 69.3 years, 59.4% male) with recent ischemic stroke were included. VMR levels were assessed 4 weeks after the index stroke using transcranial Doppler, measuring the breath-holding index (BHI) as an indicator of the percentage increase in middle cerebral artery blood flow (higher BHI signifies higher VMR). Multistep multivariable regression models, adjusted for demographic and cerebrovascular risk factors, were employed to examine the association between statin intensity treatment and BHI levels. Forty-one patients (55%) received high-intensity statins. Patients receiving high-intensity statins exhibited a mean BHI of 0.85, whereas those on low-intensity statins had a mean BHI of 0.67 (mean difference 0.18, 95% confidence interval: 0.13-0.22, p-value<.001). This significant difference persisted in the fully adjusted model (adjusted mean values: 0.84vs. 0.68, p-value:.008). No significant differences were observed in BHI values within patient groups on high-intensity or low-intensity statin therapy (all p-values>.05). Furthermore, no significant association was found between baseline low-density lipoprotein (LDL) levels and BHI. High-intensity statin treatment post-ischemic stroke is linked to elevated VMR independent of demographic and clinical characteristics, including baseline LDL level. Further research is needed to explore statin therapy's impact on preserving brain vascular function beyond lipid-lowering effects.

A mathematical model for temporal cerebral blood flow response to acetazolamide evaluated in patients with Moyamoya disease

Background: Paired cerebral blood flow (CBF) measurement is usually acquired before and after vasoactive stimulus to estimate cerebrovascular reserve (CVR). However, CVR may be confounded because of variations in time-to-maximum CBF response (tmax) following acetazolamide injection. With a mathematical model, CVR can be calculated insensitive to variations in tmax, and a model offers the possibility to calculate additional model-derived parameters. A model that describes the temporal CBF response following a vasodilating acetazolamide injection is proposed and evaluated. Methods: A bi-exponential model was adopted and fitted to four CBF measurements acquired using arterial spin labelling before and initialised at 5, 15 and 25 min after acetazolamide injection in a total of fifteen patients with Moyamoya disease. Curve fitting was performed using a non-linear least squares method with a priori constraints based on simulations. Results: Goodness of fit (mean absolute error) varied between 0.30 and 0.62 ml·100 g-1·min-1. Model-derived CVR was significantly higher compared to static CVR measures. Maximum CBF increase occurred earlier in healthy- compared to diseased vascular regions. Conclusions: The proposed mathematical model offers the possibility to calculate CVR insensitive to variations in time to maximum CBF response which gives a more detailed characterisation of CVR compared to static CVR measures. Although the mathematical model adapts generally well to this dataset of patients with MMD it should be considered as experimental; hence, further studies in healthy populations and other patient cohorts are warranted.

Waveform Analysis of STA-MCA Bypass graft in Revascularization Surgery for Moyamoya Disease.

Postoperative hyperperfusion syndrome (PHS) is a well-known complication following superficial temporal artery (STA)-middle cerebral artery (MCA) bypass for moyamoya disease (MMD). The early detection of postoperative radiological hyperperfusion (PRH), characterized by a transient increase in local cerebral blood flow (CBF), is crucial for the early diagnosis of PHS. This study aimed to investigate the effectiveness of waveform analysis for early PRH detection. We reviewed 52 consecutive patients who underwent STA-MCA bypass for MMD. Patients were divided into PRH and non-PRH groups based on the postoperative/preoperative CBF ratio. We collected the intraoperative bypass graft waveform and bypass flow data using a flowmeter. The pulsatile index (PI), an indicator of peripheral vascular resistance (PVR), was calculated from bypass flow data. Next, the newly proposed index of PVR, the ratio of the time from peak to 50% decay and to 100% decay (RT50), was calculated through waveform analysis. The values were then compared between the PRH and non-PRH groups. Twenty-seven of the 52 patients met the inclusion criteria. Fourteen of these 27 patients showed PRH. The RT50, but not the PI, was significantly higher in the PRH group. Linear regression analysis revealed a significant correlation between the RT50 and PI. In the receiver operating characteristic for predicting PRH, the area under the curve of RT50 was 0.750, with a cutoff value of 0.255, a sensitivity of 0.928, and a specificity of 0.500. The RT50 obtained from waveform analysis is associated with PVR and can be useful for the early detection of PRH in patients with MMD.

Cardiac output-mediated regulation of cerebral blood flow during exercise: Clinical perspectives on the indirect impact of muscle metaboreflex.

The muscle metaboreflex stimulates the elevation of arterial blood pressure, aiming to rectify the oxygen deficit by enhancing oxygen delivery to support muscle activity. Moreover, activating the muscle metaboreflex significantly increases cardiac output (CO) by increasingfactors such as heart rate, ventricular contractility, preload, stroke volume and mobilization of central blood volume. Previous studies indicate that ageing and cardiovascular diseases modify the muscle metaboreflex during exercise, limiting the ability to increase CO during physical activity. Alongside reduced exercise capacity, the attenuated rise in CO due to abnormal muscle metaboreflex in these patients impedes the increase in cerebral blood flow during exercise. Considering that CO plays a pivotal role in regulating cerebral blood flow adequately during exercise, this occurrence might contribute to an elevated risk of cerebral diseases, and it could also, at least, reduce the effective role of exercise in preventing cerebral disease and dementia among elderly individuals and patients with cardiovascular conditions. Therefore, it is important to consider this phenomenon when optimizing the effectiveness of exercise rehabilitation in patients with cardiovascular disease to prevent cerebral diseases and dementia.

Hemorrhage at high altitude: impact of sustained hypobaric hypoxia on cerebral blood flow, tissue oxygenation, and tolerance to simulated hemorrhage in humans.

With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4M) participated in LBNP protocols to presyncope at LA (1130m) and 5-7days following ascent to HA (3800m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304s vs. HA: 1208 ± 306s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained.

Transcranial Photobiomodulation and Chronic Traumatic Brain Injury

Traumatic brain injury (TBI) is a common cause of neurologic morbidity for which few effective therapies exist, especially during the chronic stage. A potential therapy for chronic TBI is transcranial photobiomodulation (tPBM). tPBM is a noninvasive neuromodulation technique that uses light to stimulate the cortex and increase blood flow and metabolism while also enhancing cognition and improving affect. There has been much work focusing on the efficacy of tPBM in acute TBI in small animals, but much less work has focused on chronic TBI. Patients with chronic TBI manifest microvascular injury, which may serve as a modifiable treatment target for tPBM. There is a need to study and improve tPBM, as the currently implemented protocols targeting microvascular injury have been relatively unsuccessful. This review includes 16 studies, which concluded that after tPBM application, there were improvements in neuropsychological outcomes in addition to increases in cerebral blood flow. However, these conclusions are confounded by differing tPBM parameters, small sample sizes, and heterogenous TBI populations. While these results are encouraging, there is a need to further understand the therapeutic potential of tPBM in chronic TBI.

Perfusion tomography in early follow-up of acute traumatic subdural hematoma: a case series.

Perfusion Computed Tomography (PCT) is an alternative tool to assess cerebral hemodynamics during trauma. As acute traumatic subdural hematomas (ASH) is a severe primary injury associated with poor outcomes, the aim of this study was to evaluate the cerebral hemodynamics in this context. Five adult patients with moderate and severe traumatic brain injury (TBI) and ASH were included. All individuals were indicated for surgical evacuation. Before and after surgery, PCT was performed and cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were evaluated. These parameters were associated with the outcome at 6 months post-trauma with the extended Glasgow Outcome Scale (GOSE). Mean age of population was 46 years (SD: 8.1). Mean post-resuscitation Glasgow coma scale (GCS) was 10 (SD: 3.4). Mean preoperative midline brain shift was 10.1mm (SD: 1.8). Preoperative CBF and MTT were 23.9ml/100g/min (SD: 6.1) and 7.3s (1.3) respectively. After surgery, CBF increase to 30.7ml/100g/min (SD: 5.1), and MTT decrease to 5.8s (SD:1.0), however, both changes don't achieve statistically significance (p = 0.06). Additionally, CBV increase after surgery, from 2.34 (SD: 0.67) to 2.63ml/100g (SD: 1.10), (p = 0.31). Spearman correlation test of postoperative and preoperative CBF ratio with outcome at 6 months was 0.94 (p = 0.054). One patient died with the highest preoperative MTT (9.97s) and CBV (4.51ml/100g). CBF seems to increase after surgery, especially when evaluated together with the MTT values. It is suggested that the improvement in postoperative brain hemodynamics correlates to favorable outcome.

Association between Preoperative Cortical Magnetic Susceptibility and Postoperative Changes in the Cerebral Blood Flow on Cognitive Improvement following Carotid Endarterectomy

Introduction: While patients who experience improved cognition following carotid endarterectomy (CEA) typically demonstrate restored brain perfusion after the procedure, it is worth noting that less than 50% of patients in whom postoperative cerebral blood flow (CBF) restoration is achieved actually show improved cognition after postoperatively. This suggests that factors beyond the mere restoration of CBF may play a role in postoperative cognitive improvement. Increased iron deposition in the cerebral cortex may cause neural damage, and quantitative susceptibility mapping (QSM) obtained using magnetic resonance imaging (MRI) quantifies magnetic susceptibility in the cerebral cortex, allowing for the assessment of iron deposition in vivo. The purpose of the present study was to determine whether preoperative cortical magnetic susceptibility as well as postoperative changes in CBF are associated with cognitive improvement after CEA. Methods: Brain MRI with a three-dimensional gradient echo sequence was preoperatively performed in 53 patients undergoing CEA for ipsilateral internal carotid artery stenosis (≥70%), and QSM with brain surface correction and vein removal was obtained. Cortical magnetic susceptibility was measured in the cerebral hemisphere ipsilateral to surgery on QSM. Preoperatively and at 2 months after the surgery, brain perfusion single-photon emission computed tomography and neuropsychological assessments were conducted. Using these collected data, we evaluated alterations in CBF within the affected hemisphere and assessed cognitive improvements following the operation. Results: A logistic regression analysis showed that a postoperative greater increase in CBF (95% confidence interval [CI], 1.06–1.90; p = 0.0186) and preoperative lower cortical magnetic susceptibility (95% CI, 0.03–0.74; p = 0.0201) were significantly associated with postoperatively improved cognition. Although sensitivity, specificity, and positive and negative predictive values with the cutoff value lying closest to the upper left corner of a receiver operating characteristic curve for the prediction of postoperatively improved cognition did not differ between postoperative changes in CBF and preoperative cortical magnetic susceptibility, the specificity and the positive predictive value were significantly greater for the combination of postoperative changes in CBF and preoperative cortical magnetic susceptibility (specificity, 95% CI, 93–100%; positive predictive value 95% CI, 68–100%) than for the former parameter alone (specificity, 95% CI, 63–88%; positive predictive value 95% CI, 20–64%). Conclusion: Preoperative cortical magnetic susceptibility as well as postoperative changes in CBF are associated with cognitive improvement after CEA.

Abstract TMP10: Children With Sickle Cell Anemia Have Impaired Cerebrovascular Reactivity

Introduction: Sickle Cell Anemia (SCA) causes lower hemoglobin, leading to increased cerebral blood flow (CBF) to maintain cerebral oxygen metabolism (CMRO 2 ). Although CBF rises in childhood to meet higher CMRO 2 demands, further compensatory increases in CBF in children with SCA may tap into a limited hemodynamic reserve, increasing risk for infarct. Cerebrovascular reactivity (CVR) reflects hemodynamic reserve by measuring the vasculature’s response to vasoactive stimuli, particularly in the gray matter (GM). We hypothesized that children with SCA have lower GM CVR, regardless of CMRO 2 . Methods: We used magnetic resonance imaging of children with and without SCA to collect pseudocontinuous arterial spin labeling (pCASL) for CBF, asymmetric spin echo for oxygen extraction fraction (OEF) and blood oxygen level dependent (BOLD) data correlated with hypercapnic challenges for CVR. Lab draws confirmed Hemoglobin (Hb) values. CMRO 2 was calculated as CBF x OEF x Arterial Oxygen Content (1.36 x Hb x SpO 2 ). Continuous variable differences between groups were analyzed using the Mann-Whitney U test, and categorical variables using the Fisher’s exact test. Linear regression assessed the relationship between CVR and Hb. Reported significant relationships survived multiple comparisons correction. Results: A total of 35 participants, ages 8–22 years had quality CVR data [9 SCA subjects (5 male) and 26 controls (9 male)]. Of these, 8 SCA and 20 controls had adequate quality metabolic data. The groups are matched by age (p=0.56) and sex (p=0.43). Children with SCA had higher GM CBF (62.0 v 49.3 mL/100g/min; p=0.03), but similar GM CMRO 2 (1.81 v 1.42 mL/100g/min; p=0.07) than controls. GM CVR was significantly lower in SCA than controls (0.17 v 0.27 %/mmHg; p=0.0003). Lower CVR was associated with lower Hb (Figure) after adjusting for age and sex (p &lt;0.0001). Conclusion: Lower GM CVR in children with SCA indicates a lower hemodynamic reserve, likely related to the degree of anemia.

The conducted vascular response as a mediator of hypercapnic cerebrovascular reactivity: A modelling study

It is well established that the cerebral blood flow (CBF) shows exquisite sensitivity to changes in the arterial blood partial pressure of CO2 (Pa,CO2), which is reflected by an index termed cerebrovascular reactivity. In response to elevations in Pa,CO2 (hypercapnia), the vessels of the cerebral microvasculature dilate, thereby decreasing the vascular resistance and increasing CBF. Due to the challenges of access, scale and complexity encountered when studying the microvasculature, however, the mechanisms behind cerebrovascular reactivity are not fully understood. Experiments have previously established that the cholinergic release of the Acetylcholine (ACh) neurotransmitter in the cortex is a prerequisite for the hypercapnic response. It is also known that ACh functions as an endothelial-dependent agonist, in which the local administration of ACh elicits local hyperpolarization in the vascular wall; this hyperpolarization signal is then propagated upstream the vascular network through the endothelial layer and is coupled to a vasodilatory response in the vascular smooth muscle (VSM) layer in what is known as the conducted vascular response (CVR). Finally, experimental data indicate that the hypercapnic response is more strongly correlated with the CO2 levels in the tissue than in the arterioles. Accordingly, we hypothesize that the CVR, evoked by increases in local tissue CO2 levels and a subsequent local release of ACh, is responsible for the CBF increase observed in response to elevations in Pa,CO2. By constructing physiologically grounded dynamic models of CBF and control in the cerebral vasculature, ones that integrate the available knowledge and experimental data, we build a new model of the series of signalling events and pathways underpinning the hypercapnic response, and use the model to provide compelling evidence that corroborates the aforementioned hypothesis. If the CVR indeed acts as a mediator of the hypercapnic response, the proposed mechanism would provide an important addition to our understanding of the repertoire of metabolic feedback mechanisms possessed by the brain and would motivate further in-vivo investigation. We also model the interaction of the hypercapnic response with dynamic cerebral autoregulation (dCA), the collection of mechanisms that the brain possesses to maintain near constant CBF despite perturbations in pressure, and show how the dCA mechanisms, which otherwise tend to be overlooked when analysing experimental results of cerebrovascular reactivity, could play a significant role in shaping the CBF response to elevations in Pa,CO2. Such in-silico models can be used in tandem with in-vivo experiments to expand our understanding of cerebrovascular diseases, which continue to be among the leading causes of morbidity and mortality in humans.

Cool head-out water immersion does not alter cerebrovascular reactivity to hypercapnia despite elevated middle cerebral artery blood velocity: A pilot study.

Episodic increases in cerebral blood flow (CBF) are thought to contribute to improved cerebrovascular function and health. Head-out water immersion (HOWI) may be a useful modality to increase CBF secondary to the hydrostatic pressure placed on the body. However, it is unclear whether water temperatures common to the general public elicit similar cerebrovascular responses. We tested the hypothesis that mean middle cerebral artery blood velocity (MCAvmean) and cerebrovascular reactivity to CO2 (CVRCO2) would be higher during an acute bout of thermoneutral (TN; 35°C) vs. cool (COOL; 25°C) HOWI. Ten healthy participants (age: 23±3 y; 4 women) completed two randomized HOWI visits. Right MCAvmean, end-tidal CO2 (PETCO2) mean arterial pressure (MAP), and MCA conductance (MCAvmean/MAP) were continuously recorded. CVRCO2 was assessed using a stepped hypercapnia protocol before (PRE), at 30 minutes of HOWI (HOWI), immediately after HOWI (POST-1), and 45 minutes after HOWI (POST-2). Absolute values are reported as mean ± SD. MCAvmean, PETCO2, MAP, and CVRCO2 were not different between conditions at any timepoint (all P≥0.17). In COOL, MCAvmean increased from PRE (61±9 cm/s) during HOWI (68±11 cm/s), at POST-1 (69±11 cm/s), and POST-2 (72±8 cm/s) (all P<0.01), and in TN from PRE to POST-1 (66±13 vs. 71±14 cm/s; P = 0.05). PETCO2 did not change over time in either condition. In COOL, MAP increased from PRE (85±5 mmHg) during HOWI (101±4 mmHg), at POST-1 (97±7 mmHg), and POST-2 (96±9 mmHg), and in TN from PRE (88±5 mmHg) at HOWI (98±7 mmHg) and POST-1 (99±8 mmHg) (all P<0.01). In COOL, CVRCO2 increased from PRE to HOWI (1.66±0.55 vs. 1.92±0.52 cm/s/mmHg; P = 0.04). MCA conductance was not different between or within conditions. These data indicate that 30 minutes of cool HOWI augments MCAvmean and that the increase in MCAvmean persists beyond cool HOWI. However, cool HOWI does not alter CVRCO2 in healthy young adults.

Characteristics of donor vessels and cerebral blood flow in the chronic phase after combined revascularization surgery for moyamoya disease

ObjectiveThis study aimed to analyze whether the development of donor vessels after combined revascularization surgery for moyamoya disease (MMD) is related to cerebral blood flow (CBF) changes. MethodsWe retrospectively reviewed the charts of 11 adult (12 hemispheres) and 13 pediatric (19 hemispheres) patients who underwent combined revascularization in our department. The total vessel cross-sectional area (TVA) was the sum of the cross-sectional areas of the superficial temporal, middle meningeal, and deep temporal arteries imaged using time-of-flight magnetic resonance angiography. The ipsilateral relative CBF (RCBF) on the brain surface in the craniotomy area was calculated by single-photon emission computed tomography. ΔTVA and ΔRCBF were defined as the preoperative and postoperative ratios of TVA and RCBF, and their correlations were analyzed in adult and pediatric patients. ResultsThe TVA and RCBF showed a significant increase after surgery, regardless of the age group. However, there was no significant correlation between ΔTVA and ΔRCBF in either the adult or pediatric groups. While the adult group exhibited significantly higher ΔRCBF values compared to the pediatric group (p < 0.01, r = −0.44), the ΔTVA values were higher in the pediatric group compared to the adult group (p = 0.06). ConclusionsIn the chronic phase after combined revascularization surgery for MMD, the development of measurable TVA of donor vessels does not necessarily correlate with an increase in CBF around the craniotomy area.

Analysis of potassium ion diffusion from neurons to capillaries: Effects of astrocyte endfeet geometry.

Neurovascular coupling (NVC) refers to a local increase in cerebral blood flow in response to increased neuronal activity. Mechanisms of communication between neurons and blood vessels remain unclear. Astrocyte endfeet almost completely cover cerebral capillaries, suggesting that astrocytes play a role in NVC by releasing vasoactive substances near capillaries. An alternative hypothesis is that direct diffusion through the extracellular space of potassium ions (K+ ) released by neurons contributes to NVC. Here, the goal is to determine whether astrocyte endfeet present a barrier to K+ diffusion from neurons to capillaries. Two simplified 2D geometries of extracellular space, clefts between endfeet, and perivascular space are used: (i) a source 1μm from a capillary; (ii) a neuron 15 μm from a capillary. K+ release is modelled as a step increase in [K+ ] at the outer boundary of the extracellular space. The time-dependent diffusion equation is solved numerically. In the first geometry, perivascular [K+ ] approaches its final value within 0.05 s. Decreasing endfeet cleft width or increasing perivascular space width slows the rise in [K+ ]. In the second geometry, the increase in perivascular [K+ ] occurs within 0.5s and is insensitive to changes in cleft width or perivascular space width. Predicted levels of perivascular [K+ ] are sufficient to cause vasodilation, and the rise time is within the time for flow increase in NVC. These results suggest that direct diffusion of K+ through the extracellular space is a possible NVC signalling mechanism.

Assessing cerebrovascular reactivity (CVR) in rhesus macaques (Macaca mulatta) using a hypercapnic challenge and pseudo-continuous arterial spin labeling (pCASL)

Cerebrovascular reactivity (CVR) is a measure of cerebral small vessels’ ability to respond to changes in metabolic demand and can be quantified using magnetic resonance imaging (MRI) coupled with a vasoactive stimulus. Reduced CVR occurs with neurodegeneration and is associated with cognitive decline. While commonly measured in humans, few studies have evaluated CVR in animal models. Herein, we describe methods to induce hypercapnia in rhesus macaques (Macaca mulatta) under gas anesthesia to measure cerebral blood flow (CBF) and CVR using pseudo-continuous arterial spin labeling (pCASL). Fifteen (13 M, 2 F) adult rhesus macaques underwent pCASL imaging that included a baseline segment (100% O2) followed by a hypercapnic challenge (isoflurane anesthesia with 5% CO2, 95% O2 mixed gas). Relative hypercapnia was defined as an end-tidal CO2 (ETCO2) ≥5 mmHg above baseline ETCO2. The mean ETCO2 during the baseline segment of the pCASL sequence was 34 mmHg (range: 23–48 mmHg). During this segment, mean whole-brain CBF was 51.48 ml/100g/min (range: 21.47–77.23 ml/100g/min). Significant increases (p<0.0001) in ETCO2 were seen upon inspiration of the mixed gas (5% CO2, 95% O2). The mean increase in ETCO2 was 8.5 mmHg and corresponded with a mean increase in CBF of 37.1% (p<0.0001). The mean CVR measured was 4.3%/mmHg. No anesthetic complications occurred as a result of the CO2 challenge. Our methods were effective at inducing a state of relative hypercapnia that corresponds with a detectable increase in whole brain CBF using pCASL MRI. Using these methods, a CO2 challenge can be performed in conjunction with pCASL imaging to evaluate CBF and CVR in rhesus macaques. The measured CVR in rhesus macaques is comparable to human CVR highlighting the translational utility of rhesus macaques in neuroscience research. These methods present a feasible means to measure CVR in comparative models of neurodegeneration and cerebrovascular dysfunction.

Goreisan regulates cerebral blood flow according to barometric pressure fluctuations in female C57BL/6J mice

Goreisan is a Kampo medicine used to treat headaches associated with climate change. Here, by using an implantable complementary metal-oxide-semiconductor (CMOS) device, we evaluated the effects of Goreisan and loxoprofen on cerebral blood flow (CBF) dynamics associated with barometric pressure fluctuations in freely moving mice. In the vehicle group, decreasing barometric pressure increased CBF that was prevented by Goreisan and loxoprofen. Notably, Goreisan, but not loxoprofen, reduced CBF after returning to atmospheric pressure. These results indicate that, unlike the mechanism of action of antipyretic analgesics, Goreisan normalizes CBF abnormalities associated with barometric pressure fluctuations by actively reducing CBF increase.