Human Cerebral Circulation Research Articles

CYP450 Inhibition on Cerebral Hemodynamics in Healthy, Young Males and Females During Simulated Hypovolemia

Animal models have shown that cytochrome P450 2C9 (CYP450) is involved in vascular control within the cerebrovasculature. However, the role sex plays on CYP450 within human cerebral circulation has not been examined. PURPOSE: To determine the contribution of CYP450 to cerebrovascular hemodynamics between healthy young males and females at rest and during mild simulated hypovolemia. METHODS: 18 subjects (9 females, tested during days 1-5 of early follicular phase) participated in 1 familiarization and 2 experimental visits. During experimental visits, subjects ingested a CYP450 inhibitor (fluconazole, FLZ 150mg) or placebo (PLC, 250mg microcrystalline cellulose) in a randomized, single-blind, crossover design. Following ingestion and 120 minutes of supine rest, middle cerebral artery velocity (MCAv, cm/s, Transcranial Doppler) and mean arterial pressure (MAP, mmHg, finger photoplethysmography) were continuously measured during 5 minutes of supine rest and 5 minutes of lower-body negative pressure (LBNP, -20mmHg). Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. RESULTS: Means ± SD. Resting values for all variables were not different between treatments (p > 0.05). Therefore, all data are presented as a change (Δ) from rest to LBNP. There was no treatment*time*sex effect for MCAv or CVCi (p = 0.52, pη2 = 0.08; p = 0.34, pη2 = 0.06, respectively). MCAv responded similarly to LBNP between sexes within PLC and FLZ with a low-to-moderate effect (M -4.2 ± 5.2 vs. F -2.4 ± 7.3, p = 0.63, r = 0.11; M -4.2 ± 6.2 vs. F -8.1 ± 6.3, p = 0.06, r = 0.45, respectively). Similarly, male and female CVCi responses to LBNP were similar within treatments with a low effect (PLC M -0.04 ± 0.05 vs. -0.02 ± 0.08, p = 0.69, r = 0.09; FLZ M -0.06 ± 0.06 vs. -0.08 ± 0.05, p = 0.31, r = 0.24). Two one-sided testing (TOST) analysis, used to assess equivalence between groups (1), revealed that the differences between PLC and FLZ ΔMCAv and ΔCVCi were non-equivalent between the sexes (Mean = 5.67, t(13.84) = 0.42, p = 0.55; Mean = 0.05, t(15.02) = 0.34, p = 0.63, respectively). CONCLUSION: Although no significant differences were seen between sexes, small-to-moderate effect sizes and TOST analysis suggest male and female hemodynamic responses to LBNP are not equal following CYP450 inhibition. These data argue that CYP450 may have differential contributions to cerebral vascular control between the sexes and further exploration is warranted. 1. O’Brien MW, Kimmerly DS. Is “not different” enough to conclude similar cardiovascular responses across sexes? American Journal of Physiology-Heart and Circulatory Physiology 322: H355–H358, 2022. doi: 10.1152/ajpheart.00687.2021. 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.

Bond Graph Model of Cerebral Circulation: Toward Clinically Feasible Systemic Blood Flow Simulations

The primary paper Safaei et al. (2018) proposed an anatomically detailed model of the human cerebral circulation that runs faster than real-time on a desktop computer and is designed for use in clinical settings when the speed of response is important. Based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, a lumped parameter model was developed for 218 arterial segments. The proposed model improved simulation speed by approximately 200-fold while preserved accuracy. Bond graph formulation was used to ensure mass and energy conservation. The model predicted the pressure and flow signatures in the body.

Bond Graph Model of Cerebral Circulation: Toward Clinically Feasible Systemic Blood Flow Simulations

The primary paper Safaei et al. (2018) proposed an anatomically detailed model of the human cerebral circulation that runs faster than real-time on a desktop computer and is designed for use in clinical settings when the speed of response is important. Based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, a lumped parameter model was developed for 218 arterial segments. The proposed model improved simulation speed by approximately 200-fold while preserved accuracy. Bond graph formulation was used to ensure mass and energy conservation. The model predicted the pressure and flow signatures in the body.

A method for modelling the oxyhaemoglobin dissociation curve at the level of the cerebral capillary in humans.

What is the central question of this study? Can the change in haemoglobin's affinity for oxygen in the human cerebral circulation be modelled in vivo? What is the main finding and its importance? We provide a novel method for modelling the oxyhaemoglobin dissociation curve at the cerebral capillary level in humans, so that the cerebral capillary and mitochondrial oxygen tensions can reliably be estimated. This may be useful in future human-experimental studies on cerebral oxygen transport. We provide a method for modelling the oxyhaemoglobin dissociation curve (ODC) in the cerebral capillary in humans. In contrast to most previous approaches, our method involves the construction of an averaged ODC based on paired arterial-jugular venous blood gas values, which enables the estimation of oxygen parameters in cerebral capillary blood. The method was used to determine the mean cerebral capillary oxygen saturation and tension from data previously collected from 30 healthy volunteers. The averaged ODC provided systematically higher capillary oxygen tensions than when assuming a 'fixed' standard arterial ODC. When the averaged and measured arterial ODC were used for constructing the capillary ODC, similar values were obtained during resting breathing, but not when the arterial ODC was modulated by hypocapnia. The findings suggest that our method for modelling the cerebral capillary ODC provides robust and physiologically reliable estimates of the cerebral capillary oxygen tension, which may be of use in future studies of cerebral oxygen transport in humans.

Modeling of the Human Cerebral Collateral Circulation: Evaluation of the Impact on the Cerebral Perfusion in Case of Ischemic Stroke

Abstract Stroke is the third-most cause of death in developed countries. A new promising treatment method in case of an ischemic stroke is selective intracarotid blood cooling combined with mechanical artery recanalization. However, the control of the treatment requires invasive or MRI-assisted measurement of cerebral temperature. An auspicious alternative is the use of computational modeling. In this work, we extended an existing 1D hemodynamics model including the characteristics of the anterior, middle and posterior cerebral artery. Furthermore, seven ipsilateral anastomoses were additionally integrated for each hemisphere. A potential stenosis was placed into the M1 segment of the middle cerebral artery, due to the highest risk of occlusion there. The extended model was evaluated for various degrees of collateralization (“poor”, “partial” and “good”) and degrees of stenosis (0%, 50%, 75% and 99.9%). Moreover, cerebral autoregulation was considered in the model. The higher the degree of collateralization and the degree of stenosis, the higher was the blood flow through the collaterals. Hence, a patient with a good collateralization could compensate a higher degree of occlusion and potentially has a better outcome after an ischemic stroke. For a 99.9% stenosis, an increased summed mean blood flow through the collaterals of +97.7% was predicted in case of good collateralization. Consequently, the blood supply via the terminal branches of the middle cerebral artery could be compensated up to 44.4% to the physiological blood flow. In combination with a temperature model, our model of the cerebral collateral circulation can be used for tailored temperature prediction for patients to be treated with selective therapeutic hypothermia.

Reactive oxygen species and cyclooxygenase products explain the majority of hypoxic cerebral vasodilation in healthy humans.

The role of reactive oxygen species (ROS) in human cerebral blood flow (CBF) during hypoxia is largely unknown. Additionally, it is unknown whether ROS interact with cyclooxygenase-derived signals during hypoxia to increase CBF. We hypothesized ROS inhibition would reduce hypoxic CBF, and combined inhibition of cyclooxygenase (COX) and ROS would decrease hypoxic CBF more than ROS suppression alone. We measured middle cerebral artery velocity with transcranial Doppler ultrasound in 12 healthy adults during normoxia and 2 isocapnic hypoxia trials. Intravenous ascorbic acid infusion during the first hypoxia trial suppressed ROS. Oral indomethacin inhibited COX between hypoxia trials. The second bout of hypoxia tested the combined effects of ROS and COX inhibition. Middle cerebral artery velocity was normalized for blood pressure as cerebrovascular conductance index. Hypoxia increased cerebrovascular conductance index in both trials (P<0.05). Ascorbic acid infusion did not alter cerebrovascular conductance index during hypoxia. Combined ascorbic acid and indomethacin significantly reduced hypoxia-mediated increases in cerebrovascular conductance index from 17±2 to 4±1 cm s-1 100 mmHg-1 (P<0.05). ROS are not obligatory for hypoxic cerebral vasodilation. Current data indicate ROS and COX together may account for the majority of the increase in CBF through the middle cerebral artery during hypoxia. These data are the first to demonstrate compensatory hypoxic vasodilatory signalling in human cerebral circulation.

High resolution 7T and 9.4T-MRI of human cerebral arterial casts enables accurate estimations of the cerebrovascular morphometry

Quantitative data on the morphology of the cerebral arterial tree could aid in modelling and understanding cerebrovascular diseases, but is scarce in the range between 200 micrometres and 1 mm diameter arteries. Traditional manual measurements are difficult and time consuming. 7T-MRI and 9.4T-MRI of human cerebral arterial plastic casts could proof feasible for acquiring detailed morphological data of the cerebral arterial tree in a time efficient method. One cast of the complete human cerebral arterial circulation embedded in gadolinium-containing gelatine gel was scanned at 7T-MRI (0.1 mm isotropic resolution). A small section of another cast was scanned at 9.4T-MRI (30 µm isotropic resolution). Subsequent 3D-reconstruction was performed using a semi-automatic approach. Validation of 7T-MRI was performed by comparing the radius calculated using MRI to manual measurements on the same cast. As manual measurement of the small section was not feasible, 9.4T-MRI was validated by scanning the small section both at 7T-MRI and 9.4T MRI and comparing the diameters of arterial segments. Linear regression slopes were 0.97 (R-squared 0.94) and 1.0 (R-squared 0.90) for 7T-MRI and 9.4T-MRI. This data shows that 7T-MRI and 9.4T-MRI and subsequent 3D reconstruction of plastic casts is feasible, and allows for characterization of human cerebral arterial tree morphology.

Hypoxia compounds exercise-induced free radical formation in humans; partitioning contributions from the cerebral and femoral circulation

This study examined to what extent the human cerebral and femoral circulation contribute to free radical formation during basal and exercise-induced responses to hypoxia. Healthy participants (5♂, 5♀) were randomly assigned single-blinded to normoxic (21% O2) and hypoxic (10% O2) trials with measurements taken at rest and 30 min after cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled from the brachial artery (a), internal jugular and femoral veins (v) for non-enzymatic antioxidants (HPLC), ascorbate radical (A•-, electron paramagnetic resonance spectroscopy), lipid hydroperoxides (LOOH) and low density lipoprotein (LDL) oxidation (spectrophotometry). Cerebral and femoral venous blood flow was evaluated by transcranial Doppler ultrasound (CBF) and constant infusion thermodilution (FBF). With 3 participants lost to follow up (final n = 4♂, 3♀), hypoxia increased CBF and FBF (P = 0.041 vs. normoxia) with further elevations in FBF during exercise (P = 0.002 vs. rest). Cerebral and femoral ascorbate and α-tocopherol consumption (v < a) was accompanied by A•-/LOOH formation (v > a) and increased LDL oxidation during hypoxia (P < 0.043–0.049 vs. normoxia) implying free radical-mediated lipid peroxidation subsequent to inadequate antioxidant defense. This was pronounced during exercise across the femoral circulation in proportion to the increase in local O2 uptake (r = −0.397 to −0.459, P = 0.037–0.045) but unrelated to any reduction in PO2. These findings highlight considerable regional heterogeneity in the oxidative stress response to hypoxia that may be more attributable to local differences in O2 flux than to O2 tension.

Bond Graph Model of Cerebral Circulation: Toward Clinically Feasible Systemic Blood Flow Simulations.

We propose a detailed CellML model of the human cerebral circulation that runs faster than real time on a desktop computer and is designed for use in clinical settings when the speed of response is important. A lumped parameter mathematical model, which is based on a one-dimensional formulation of the flow of an incompressible fluid in distensible vessels, is constructed using a bond graph formulation to ensure mass conservation and energy conservation. The model includes arterial vessels with geometric and anatomical data based on the ADAN circulation model. The peripheral beds are represented by lumped parameter compartments. We compare the hemodynamics predicted by the bond graph formulation of the cerebral circulation with that given by a classical one-dimensional Navier-Stokes model working on top of the whole-body ADAN model. Outputs from the bond graph model, including the pressure and flow signatures and blood volumes, are compared with physiological data.

Sympathetic control of the brain circulation: Appreciating the complexities to better understand the controversy.

Although the human cerebral circulation is richly innervated with sympathetic nerve fibers, the role of sympathetic nerve activity (SNA) on the regulation of cerebral blood flow (CBF) remains debated. Several issues may be responsible for the conflicting conclusions reported in the animal vs. human literature in regards to the sympathetic control of the brain circulation. Furthermore, due to the physiological consequences associated with SNA blockade (e.g. changes in blood pressure and cardiac output), and differences in methodology (e.g. assessment of CBF), interpretation of the role of SNA in CBF regulation in humans is challenging. The goals of this brief review are to provide an overview of the role of neural control in the regulation of CBF, with a focus on SNA and discuss the likely reasons behind the controversial influence of SNA on CBF regulation. A final objective of this article is to critically review the various methods available to measure CBF and highlight their strengths and weaknesses to provide insight in SNA regulation of CBF.

Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation: Relationship to Basal and Exercise Blood Flow Responses to Hypoxia.

The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Differential properties of Van der Pol — Duffing mathematical model of cerebrovascular haemodynamics based on clinical measurements

The present paper discusses the method of identification (diseased/healthy) human cerebral vessels by using of mathematical model. Human cerebral circulation as a single tuned circuit, which consists of blood flow, elastic vessels and elastic brain gel tissue is under consideration. Non linear Van der Pol-Duffing equation is assumed as mathematical model of cerebrovascular circulation. Hypothesis of vascular pathology existence in some position of blood vessel, based on mathematical model properties for this position is formulated. Good reliability of hypothesis is proved statistically for 7 patients with arterial aneurysms.

Endovascular external carotid artery occlusion for brain selective targeting: a cerebrovascular swine model.

BackgroundThe choice of an animal model for cerebrovascular research is often determined by the disease subtype to be studied (e.g. ischemic stroke, hemorrhage, trauma), as well as the nature of the intervention to be tested (i.e. medical device or pharmaceutical). Many initial studies are performed in smaller animals, as they are cost-effective and their encephalic vasculature closely models that of humans. Non-human primates are also utilized when confirmation or validation is required on higher levels and to test larger devices. However, working with primates is complex and expensive. Intermediate sized animal models, such as swine and sheep, may represent a valuable compromise. Their cerebrovascular anatomy, however, comes with challenges because of the natural higher external carotid artery perfusion and the existence of a rete mirabile. We describe a modification to the traditional swine cerebrovascular model that significantly enhances selective brain hemispheric perfusion, limiting external carotid perfusion and dilution.ResultsWe investigated whether unilateral endovascular coil-embolization of external carotid artery branches in swine would lead to increased brain perfusion, altering cerebral circulation so that it more closely models human cerebral circulation. Equal amounts of approximately 4 °C cold saline were injected in 6 Yorkshire pigs into the ipsilateral common carotid artery before and after embolization. Hemispheric temperature changes from pre- and post-embolization were obtained as a measure of brain perfusion and averaged and compared using non-parametric statistical tests (Wilcoxon signed rank test, Mann–Whitney U Test). Graphs were plotted with absolute changes in hemispheric temperature over time to determine peak temperature drop (PTD) and corresponding time to peak (TTP) following the cold bolus injection. There was a 288 ± 90 % increase in ipsilateral brain cooling after embolization indicating improved selective blood flow to the brain due to this vascular modification.ConclusionWe have developed an effective, selective vascular brain model in swine that may be useful as a practical and cost-reducing intermediate step for evaluating target dose–responses for central nervous system drugs and brain selective interventions, such as local hypothermia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-015-1714-7) contains supplementary material, which is available to authorized users.

Human CaV1.2/CaV3.x channels mediate paradoxical vasomotor responses in the human cerebral circulation (677.11)

This study examined which voltage‐gated Ca2+ channels are expressed in the human cerebral circulation and investigated their electrical and functional properties. Using cerebral arteries collected from patients undergoing resection surgeries, quantitative PCR and Western blot analyses revealed the expression of both L‐ and T‐type channels in the smooth muscle cell layer. Analogous to rodent, we observed both CaV1.2 (L) and CaV3.2 (T); intriguingly, CaV3.1 isoform was replaced in humans with CaV3.3 (T). Patch‐clamp electrophysiology displayed a robust whole‐cell Ba2+ current whose amplitude varied inversely with the patients’ age. This inward current was subdivided into L‐ and T‐type components using standard pharmacological/electrical approaches. The T‐type conductance was further separated into CaV3.2 and CaV3.3 components by exploiting their differential sensitivity to Ni2+. Vessel myography revealed a key role for CaV1.2 and CaV3.3 channels in mediating cerebral arterial constriction with the former and latter predominating at depolarized and hyperpolarized voltages, respectively. Like the rodent, human CaV3.2 appears to drive a negative feedback response that antagonizes myogenic tone development. In conclusion, this study is the first to document three distinct Ca2+ channel isoforms in human cerebral arteries along with their unique contribution to arterial tone development.

Impaired hypoxic cerebral vasodilation in younger adults with metabolic syndrome

Metabolic syndrome (MetSyn) increases the risk of cerebrovascular disease and stroke; however, its impact on human cerebral circulation remains unclear. Reduced cerebral dilation is also associated with an increased risk of stroke and may occur in MetSyn adults. We hypothesised that MetSyn adults would exhibit reduced cerebral vasodilation to hypoxia and hypercapnia. Middle cerebral artery velocity (MCAv) was insonated with Doppler ultrasound in younger (approximately 35 years) MetSyn and healthy adults. We measured mean arterial blood pressure (MABP), arterial oxygen saturation (S(p)O(2)) and end tidal carbon dioxide (Pet (CO2)). Cerebrovascular conductance index (CVCi) was calculated as MCAv*100/MABP. Cerebral vasodilation (ΔCVCi) to hypoxia (S(p)O(2) = 90% and 80%) and hypercapnia (+10 mm Hg Pet (CO2)) was assessed. Baseline MCAv was similar, while adults with MetSyn had lower baseline CVCi. MetSyn adults demonstrated markedly reduced ΔCVCi compared to healthy adults in response to hypoxia (90% S(p)O(2): 1±2 vs 6±2; 80% S(p)O(2): 5±2 vs 15±3 cm/s/mmHg, p<0.05). Both groups demonstrated similar ΔCVCi to hypercapnia (18±2 vs 20±2 cm/s/mmHg). These data are the first to demonstrate that younger MetSyn adults have impaired hypoxia-mediated cerebral vasodilation prior to clinically overt cerebrovascular disease. These findings provide novel insight into cerebrovascular disease onset in MetSyn adults.

Unraveling the human cerebral circulation: insights from cerebral blood pressure and flow recordings

a.c. burton once commented that the relation of pressure to flow is the “central problem in hemodynamics” ([2][1]). This proposition remains true today, as it did more than 50 years ago when revolutionary concepts such as “vascular impedance” and “autoregulation” of regional organ

Study of the heterogeneity of cardiovascular function should extend to the human cerebral circulation

to the editor: In a recent issue of this journal, Charkoudian et al. ([3][1]) contended that variation between individuals is often regarded as a limitation on our ability to detect statistically significant differences. This dogma has been canonized through a preference for positive results and

Reply to Willie and Tzeng

### Interindividual Heterogeneity in Integrative Physiology to the editor: We were very pleased to read the letter from Willie and Tzeng ([12][1]) regarding our recent publication in this Journal and our focus on the importance of interindividual variability in hemodynamic variables in the control

Complexity of the human cerebral circulation

The cerebral circulation shows both structural and functional complexity. For time scales of a few minutes or more, cerebral blood flow (CBF) and other cerebrovascular parameters can be shown to follow a random fractal point process. Some studies, but not all, have also concluded that CBF is non-stationary. System identification techniques have been able to explain a substantial fraction of the CBF variability by applying linear and nonlinear multivariate models with classical determinants of flow (arterial blood pressure, arterial CO(2) and cerebrovascular resistance, CVR) as inputs. These findings raise the hypothesis that fractal behaviour is not inherent to CBF but might be simply transmitted from its determinants. If this is the case, future investigations could focus on the complexity of the residuals or the unexplained variance of CBF. In the low-frequency range (below 0.15 Hz), changes in CVR due to pressure and metabolic autoregulation represent an important contribution to CBF variability. A small body of work suggests that parameters describing cerebral autoregulation can also display complexity, presenting significant variability that might also be non-stationary. Fractal analysis, entropy and other nonlinear techniques have a role to play to shed light on the complexity of cerebral autoregulation.

Effect of Adrenomedullin on the Cerebral Circulation: Relevance to Primary Headache Disorders

Adrenomedullin (ADM) is closely related to calcitonin gene-related peptide, which has a known causative role in migraine. Animal studies have strongly suggested that ADM has a vasodilatory effect within the cerebral circulation. For these reasons, ADM is also likely to be involved in migraine. However, the hypothetical migraine-inducing property and effect on human cerebral circulation of ADM have not previously been investigated. Human ADM (0.08 microg kg(-1) min(-1)) or placebo (saline 0.9%) was administered as a 20-min intravenous infusion to 12 patients suffering from migraine without aura in a crossover double-blind study. The occurrence of headache and associated symptoms were registered regularly 24 h post infusion. Cerebral blood flow (CBF) was measured by (133)Xenon single-photon emission computed tomography, mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler and the diameter of peripheral arteries by transdermal ultrasound (C-scan). ADM did not induce significantly more headache or migraine compared with placebo (P = 0.58). CBF was unaffected by ADM infusion (global CBF, P = 0.32 and rCBF(MCA), P = 0.38) and the same applied for the V(MCA) (P = 0.18). The superficial temporal artery dilated compared with placebo (P < 0.001), and facial flushing was seen after ADM administration (P = 0.001). In conclusion, intravenous ADM is not a mediator of migraine headache and does not dilate intracranial arteries.