Blood Flow Responses Research Articles

Mixed nut consumption improves brain insulin sensitivity: a randomized, single-blinded, controlled, crossover trial in older adults with overweight or obesity

BackgroundImproving brain insulin sensitivity, which can be assessed by measuring regional cerebral blood flow (CBF) responses to intranasal insulin, may prevent age-related metabolic and cognitive diseases. ObjectivesThis study aimed to investigate longer-term effects of mixed nuts on brain insulin sensitivity in older individuals with overweight/obesity. MethodsIn a randomized, single-blinded, controlled, crossover trial, 28 healthy adults (mean ± standard deviation: 65 ± 3 years; body mass index: 27.9 ± 2.3 kg/m2) received either daily 60-g mixed nuts (15 g of walnuts, pistachio, cashew, and hazelnuts) or no nuts (control) for 16 weeks, separated by an 8-week washout period. Throughout the study, participants were instructed to adhere to the Dutch food-based dietary guidelines. During follow-up, brain insulin action was assessed by quantifying acute effects of intranasal insulin on regional CBF using arterial spin labeling magnetic resonance imaging. Furthermore, effects on peripheral insulin sensitivity (oral glucose tolerance test), intrahepatic lipids, and cardiometabolic risk markers were assessed. ResultsBody weight and composition did not change. Compared with control, mixed nut consumption improved regional brain insulin action in 5 clusters located in the left (difference in CBF responses to intranasal insulin: −4.5 ± 4.7 mL/100 g/min; P < 0.001; −4.6 ± 4.8 mL/100 g/min; P < 0.001; and −4.3 ± 3.6 mL/100 g/min; P = 0.007) and right occipital lobes (−4.3 ± 5.6 mL/100 g/min; and −3.9 ± 4.9 mL/100 g/min; P = 0.028). A fifth cluster was part of the left frontal lobe (−5.0 ± 4.6 mL/100 g/min; P < 0.001). Peripheral insulin sensitivity was not affected. Intrahepatic lipid content (−0.7%-point; 95% CI: −1.3%-point to −0.1%-point; P = 0.027), serum low-density lipoprotein cholesterol concentration (−0.24 mmol/L; 95% CI: −0.44 to −0.04 mmol/L; P = 0.019), and systolic blood pressure (−5 mm Hg; 95% CI: −8 to −1 mm Hg; P = 0.006) were lower after the mixed nut intervention. ConclusionsLonger-term mixed nut consumption affected insulin action in brain regions involved in the modulation of metabolic and cognitive processes in older adults with overweight/obesity. Intrahepatic lipid content and different cardiometabolic risk markers also improved, but peripheral insulin sensitivity was not affected.This trial was registered at clinicaltrials.gov as NCT04210869.

Clinically uninvolved but not healthy-The skin of patients with atopic dermatitis is primed for itch and inflammation.

Atopic dermatitis (AD) is a highly prevalent inflammatory skin disorder characterized by episodic exacerbations and remissions. Why the clinically healthy skin of AD patients becomes rapidly inflamed and very pruritic is poorly understood. To investigate cowhage- and histamine-induced itch and skin expression levels of their target receptors in lesional and non-lesional skin of AD, compared to the skin of patients with psoriasis, chronic spontaneous urticaria (CSU) and healthy subjects. Patients with AD, psoriasis and chronic spontaneous urticaria (CSU) as well as healthy control subjects (HC) (n = 20 each) were assessed for differences in itch parameters, neurogenic flare reaction and local blood flow responses to skin provocations with cowhage and histamine. Skin biopsies from 10 AD, 10 psoriasis,11 CSU and 12 HC were obtained to assess expression of protease-activated receptors 2 and 4 (PAR-2, PAR-4), histamine H1 and H4 receptors (H1R, H4R), and mast cells. Provocation of non-lesional skin of AD patients with cowhage resulted in prolonged itch (p = 0.020), which was not observed in psoriasis and CSU. Significantly prolonged and more intense cowhage- and histamine-induced itch (for duration, peak and overall intensity) was also observed in lesional AD skin. Diminished neurogenic flare reaction and blood flow after histamine provocation were shown in AD and psoriasis patients. Non-lesional AD skin along with lesional AD and psoriasis skin showed an increased expression of PAR-2 and PAR-4, H1R and H4R. Mast cell number was higher in lesional AD and psoriasis skin (p = 0.006 and p = 0.006, respectively). The non-lesional skin of AD patients markedly differs from healthy skin in cowhage-induced itch responses and the expression of receptors for proteases and histamine. Proactive therapeutic interventions that downregulate these receptors may prevent episodic exacerbation in AD.

Coronary microvascular function in male physicians with burnout and job stress: an observational study

BackgroundAs a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that is at least as high as that of other professionals. This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events.MethodsThirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on coronary flow reserve (primary outcome) and two additional measures of coronary microvascular function in the same model while adjusting for age and body mass index.ResultsBurnout and job stress were significantly and independently associated with endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow response, and hyperemic myocardial blood flow (r partial = 0.28 to 0.35; p-value = 0.008 to 0.035). Effort-reward ratio (r partial = − 0.32 to − 0.38; p-value = 0.004 to 0.015) and overcommitment (r partial = − 0.30 to − 0.37; p-value = 0.005 to 0.022) showed inverse associations with these measures.ConclusionsIn male physicians, burnout and high job stress showed opposite associations with coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications and temporal relationships between work-related variables and coronary microvascular function. Future studies should include burnout and job stress for a more nuanced understanding of their potential role in cardiovascular health.

Measurement of Retrobulbar Blood Flow and Vascular Reactivity—Relevance for Ocular and Cardiovascular Diseases

Abnormal retrobulbar hemodynamics have been linked to the development of various ocular diseases, including glaucoma, age-related macular degeneration, and diabetic retinopathy. Additionally, altered retrobulbar blood flow has been observed in patients with severe cardiovascular diseases, including carotid artery occlusion, stroke, heart failure, and acute coronary syndrome. Due to the complex and intricate anatomy of retrobulbar blood vessels and their location behind the eyeball, measurement of retrobulbar blood flow and vascular reactivity, as well as the interpretation of the findings, are challenging. Various methods, such as color Doppler imaging, computed tomography angiography or magnetic resonance imaging, have been employed to assess retrobulbar blood flow velocities in vivo. Color Doppler imaging represents a fast and non-invasive method to measure retrobulbar blood flow velocities in vivo. While no information about vessel diameter can be gained performing this method, computed tomography angiography and magnetic resonance imaging provide information about vessel diameter and detailed information on the anatomical course. Additionally, ex vivo studies, such as myography, utilizing genetically modified animal models may provide high optical resolution for functional vascular investigations in these small vessels. To our best knowledge, this is the first review, presenting a detailed overview of methods aiming to evaluate retrobulbar blood flow and vascular reactivity in both humans and laboratory animals. Furthermore, we will summarize the disturbances observed in retrobulbar blood flow in retinal, optic nerve, and cardiovascular diseases.

PLACENTAL DYSFUNCTION, FETAL AND NEWBORN CONDITION WITH COVID-19 IN PREGNANCY

Purpose. To determine signs of placental dysfunction, to assess the condition of the fetus and newborn in case of Covid-19, transferred to a woman during any.&#x0D; Materials and methods. 50 pregnant women with a severe course of Covid-19 (group 1) and 150 pregnant women with moderate severity of the disease (group 2) were examined. The control group consisted of 50 pregnant women who did not suffer from Covid-19. The state of uterine-placental-fetal blood flow was determined by the Doppler method. To assess the condition of the fetus, a cardiotocogram was recorded, cardiotocogram analysis was performed according to the Dawes/Redman criteria, and the biophysical profile of the fetus was established. Pathomorphological examination of the placenta was conducted.&#x0D; Results. Established placental insufficiency in most cases (72.0%) of patients with a severe course of Covid-19, supports the growth of the fetus and its distress in 32.0% and 48.0% of women. The results of dopplerometry at 32-34 weeks revealed significant violations of maternal-placental-fetal blood flow. A decrease in the pulsatility index in the middle cerebral artery of the fetus and cerebro-placental ratio indicates the centralization of fetal blood flow in response to hypoxia. When the status of the fetus is reduced, a reduced assessment of the biophysical profile of the fetus is indicated (6.69±0.30). According to the Dawes/Redman criteria, fetal protein acidemia occurred in 48.0% of patients, critical condition - in 8.0% of pregnant women. Pathomorphological examination of the placenta reveals violations of various structures in the form of degenerative and alterative-degenerative changes, dysmucoidosis, circulatory disorders, damage to the endothelium and thrombus formation, ischemia, infarction, and vasculitis. Signs of chorioamnionitis are found in 18.0% of placentas. 44.0% of children are born asphyxiated, 36.0% have respiratory failure, and 16.0% have bilateral pneumonia. High frequency of neurological disorders (56.0%), gastrointestinal (50.0%), hypoglycemic (34.0%) and hemorrhagic (32.0%) syndromes. 22.0% of children needed care in the intensive care unit. Perinatal mortality was 0.4 ‰.&#x0D; Conclusion. Сhildren born to women whose pregnancy complicated their SARS-CoV-2 infection belong to the high-risk group and require final follow-up to monitor the status of developed clear care algorithms depending on the condition.

Epidermal Growth Factor Receptors in Vascular Endothelial Cells Contribute to Functional Hyperemia in the Brain.

Functional hyperemia-activity-dependent increases in local blood perfusion-underlies the on-demand delivery of blood to regions of enhanced neuronal activity, a process that is crucial for brain health. Importantly, functional hyperemia deficits have been linked to multiple dementia risk factors, including aging, chronic hypertension, and cerebral small vessel disease (cSVD). We previously reported crippled functional hyperemia in a mouse model of genetic cSVD that was likely caused by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) in capillary endothelial cells (EC) downstream of impaired epidermal growth factor receptor (EGFR) signaling. Here, using EC-specific EGFR-knockout (KO) mice, we directly examined the role of endothelial EGFR signaling in functional hyperemia, assessed by measuring increases in cerebral blood flow in response to contralateral whisker stimulation using laser Doppler flowmetry. Molecular characterizations showed that EGFR expression was dramatically decreased in freshly isolated capillaries from EC-EGFR-KO mice, as expected. Notably, whisker stimulation-induced functional hyperemia was significantly impaired in these mice, an effect that was rescued by administration of PIP2, but not by the EGFR ligand, HB-EGF. These data suggest that the deletion of the EGFR specifically in ECs attenuates functional hyperemia, likely via depleting PIP2 and subsequently incapacitating Kir2.1 channel functionality in capillary ECs. Thus, our study underscores the role of endothelial EGFR signaling in functional hyperemia of the brain.

Whole brain irradiation–induced endothelial dysfunction in the mouse brain

Whole brain irradiation (WBI), also known as whole brain radiation therapy (WBRT), is a well-established treatment for multiple brain metastases and as a preventive measure to reduce the risk of recurrence after surgical removal of a cerebral metastasis. However, WBI has been found to lead to a gradual decline in neurocognitive function in approximately 50% of patients who survive the treatment, significantly impacting their overall quality of life. Recent preclinical investigations have shed light on the underlying mechanisms of this adverse effect, revealing a complex cerebrovascular injury that involves the induction of cellular senescence in various components of the neurovascular unit, including endothelial cells. The emergence of cellular senescence following WBI has been implicated in the disruption of the blood-brain barrier and impairment of neurovascular coupling responses following irradiation. Building upon these findings, the present study aims to test the hypothesis that WBI-induced endothelial injury promotes endothelial dysfunction, which mimics the aging phenotype. To investigate this hypothesis, we employed a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks) on young mice. Both the WBI-treated and control mice were fitted with a cranial window, enabling the assessment of microvascular endothelial function. In order to evaluate the endothelium-dependent, NO-mediated cerebral blood flow (CBF) responses, we topically administered acetylcholine and ATP, and measured the resulting changes using laser Doppler flowmetry. We found that the increases in regional CBF induced by acetylcholine and ATP were significantly diminished in mice subjected to WBI. These findings provide additional preclinical evidence supporting the notion that WBI induces dysfunction in cerebrovascular endothelial cells, which in turn likely contributes to the detrimental long-term effects of the treatment. This endothelial dysfunction resembles an accelerated aging phenotype in the cerebrovascular system and is likely causally linked to the development of cognitive impairment. By integrating these findings with our previous results, we have deepened our understanding of the lasting consequences of WBI. Moreover, our study underscores the critical role of cerebromicrovascular health in safeguarding cognitive function over the long term. This enhanced understanding highlights the importance of prioritizing cerebromicrovascular health in the context of preserving cognitive abilities.

Abstract 17343: Coronary Microvascular Function in Physician Burnout and Job Stress

Background: As a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that seems more prevalent among male than female physicians. Aim: This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events. Methods: Thirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on measures of coronary microvascular function in the same model while adjusting for age and body mass index. Results: Burnout and job stress had significant and independent effects on endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow (MBF) response, and hyperemic MBF (r partial: 0.29 to 0.35; p-value: 0.008 to 0.027). Effort-reward ratio (r partial: -0.32 to -0.34; p-value: 0.009 to 0.017) and overcommitment (r partial: -0.29 to -0.35; p-value: 0.008 to 0.027) showed inverse associations with these measures. Conclusions: In male physicians, burnout and high job stress showed opposite effects on coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications. Future studies should include burnout and job stress for a more nuanced understanding of their potential impact on cardiovascular health.

Abstract 13886: Impaired Locomotor Muscle Blood Flow During Cycling Exercise in Heart Failure With Preserved Ejection Fraction

Introduction: Obesity and hypertension (HTN) are highly prevalent comorbid risk factors for heart failure with preserved ejection fraction (HFpEF). Obesity and HTN independently increase sympathetic nervous activity and impair muscle blood flow during exercise. Previous work has reported attenuated limb blood flow in patients with HFpEF; however, these findings were compared to controls with dissimilar comorbidities and during small muscle mass exercise. It is unclear if HFpEF alters muscle blood flow responses independent of the obesity- and HTN-mediated alterations. Hypothesis: We hypothesized the muscle blood flow response during cycling would be lower in HFpEF patients than age, sex, BMI, and HTN matched controls (CTL). Methods: HFpEF patients (n=14, 9M/5W, 71±7yrs, 32±4 kg/m 2 ) and CTL (n=12, 8M/4W, 69±7yrs, 31±4 kg/m 2 ) performed an incremental cycling test. Blood pressure was measured by manual sphygmomanometry, cardiac output (Q) by open-circuit acetylene wash-in technique, and systemic vascular resistance (SVR) was calculated. Vastus lateralis blood flow index (BFI) was measured by near-infrared spectroscopy and indocyanine green dye injections and venous norepinephrine concentration was measured. Changes from rest to 40 W of the incremental test are reported. Results: Resting Q, mean arterial pressure, SVR, and venous norepinephrine concentration were not statistically different between groups (p&gt;0.18). From rest to 40 W, the increases in Q (CTL: 3.9±0.8 vs. HFpEF: 3.6±0.7 L/min), mean arterial pressure (CTL: 5.7±2.7 vs. HFpEF: 6.6±6.1 mmHg), and SVR (CTL: -7.3±2.1 vs. HFpEF: -6.0±2.0 mmHg/L/min) were not statistically different between groups (all, p&gt;0.13). The HFpEF group had smaller increases in vastus lateralis BFI at 40 W compared to CTL (CTL: 7.2±3.6 vs. HFpEF: 4.2±2.6 fold-increase from rest) (p=0.02). The HFpEF group had greater increases in venous norepinephrine concentration from rest to 40 W than CTL (CTL: 164±216 vs. HFpEF: 377±247 pg/mL) (p=0.05). Conclusions: Our findings suggest that, compared to age, sex, BMI, and HTN matched controls, patients with HFpEF have an impaired locomotor muscle blood flow response during submaximal cycling exercise likely due to higher locomotor muscle vascular resistance.

Endothelial Hemoglobin Alpha Mediates Iron Regulation of Endothelial Nitric Oxide

Iron deficiency is associated with heart failure, chronic kidney disease, and chronic inflammation. All of these pathologies are associated with endothelial dysfunction and impaired nitric oxide (NO) signaling. Previous clinical studies have found iron deficiency anemia (IDA) increases endothelial NO signaling and attributed this change to the reduction in circulating hemoglobin. However, while free hemoglobin is a potent scavenger of NO, it has been shown in ex vivo preparations that endothelial NO signaling is unaffected by the presence of erythrocytes suggesting changes in circulating hemoglobin do not alter NO signaling. For these reasons we focused on endothelial iron regulation. Using single cell RNA sequencing data of isolated mesenteric and adipose endothelial cells generated by our lab, we have observed arterial endothelial cells have higher transferrin receptor expression compared to capillary, veinous, and lymphatic endothelial cells. This suggests that the arterial endothelium, which controls blood flow and is especially susceptible to endothelial dysfunction, may be particularly sensitive to changes in iron status. Additionally, our lab has previously shown the alpha chain of hemoglobin (Hbα) is expressed in the endothelium of small arteries and scavenges NO. We therefore hypothesized endothelial Hbα, rather than blood hemoglobin is responsible for the increased NO signaling in IDA. We first tested this hypothesis in a mouse model of IDA in which we were able to replete vascular iron stores. C57BL/6 mice were fed an iron deficient (2-6 ppm Fe) or nutrient matched control diet (48 ppm Fe) beginning at weaning. IDA mice underwent phlebotomies (10% blood volume) at 9 and 11 weeks old to aid in the progression of anemia. To restore vascular iron stores, a subset of IDA mice received a single i.p. injection of iron dextran (FeDex; 20 mg/kg) at 12 weeks. One week later complete blood counts were assessed, tissues were collected, and blood flow studies were performed. As expected, IDA mice had low blood hemoglobin (Con: 15.54 ± 0.43 vs. IDA: 6.04 ± 0.35 g/dL; p &amp;lt; 0.0001). FeDex did not rescue the anemia (8.55 ± 0.74 g/dL; p &amp;lt; 0.0001 vs. Con), but did rescue vascular iron stores as measured by ferritin light chain protein. To investigate NO signaling, we used laser speckle contrast imaging to measure changes in in vivo blood flow in response to the NO synthase inhibitor L-NAME. The magnitude of the response to L-NAME is an indicator of NO signaling. IDA mice exhibited an exaggerated response to L-NAME indicating increased NO signaling. Rescuing vascular iron stores with FeDex restored the L-NAME response back to control levels suggesting vascular iron stores, rather than the anemia itself increased NO signaling. In order to investigate the role of endothelial Hbα, we repeated these studies in endothelial specific Hbα knockout mice (Hba1 fl/fl-Cdh5-CreER T2+) developed by us. Lack of endothelial Hbα did not prevent the increased response to L-NAME in IDA mice, but did prevent the rescue by FeDex. These data suggest a model in which endothelial Hbα participates in regulating NO in response to iron, but not the increased NO in IDA.

Insulin resistance induces earlier initiation of cognitive dysfunction mediated by cholinergic deregulation in a mouse model of Alzheimer's disease.

Although insulin resistance increases the risk of Alzheimer's disease (AD), the mechanisms remain unclear, partly because no animal model exhibits the insulin-resistant phenotype without persistent hyperglycemia. Here we established an AD model with whole-body insulin resistance without persistent hyperglycemia (APP/IR-dKI mice) by crossbreeding constitutive knock-in mice with P1195L-mutated insulin receptor (IR-KI mice) and those with mutated amyloid precursor protein (AppNL-G-F mice: APP-KI mice). APP/IR-dKI mice exhibited cognitive impairment at an earlier age than APP-KI mice. Since cholinergic dysfunction is a major characteristic of AD, pharmacological interventions on the cholinergic system were performed to investigate the mechanism. Antagonism to a nicotinic acetylcholine receptor α7 (nAChRα7) suppressed cognitive function and cortical blood flow (CBF) response to cholinergic-regulated peripheral stimulation in APP-KI mice but not APP/IR-dKI mice. Cortical expression of Chrna7, encoding nAChRα7, was downregulated in APP/IR-dKI mice compared with APP-KI. Amyloid β burden did not differ between APP-KI and APP/IR-dKI mice. Therefore, insulin resistance, not persistent hyperglycemia, induces the earlier onset of cognitive dysfunction and CBF deregulation mediated by nAChRα7 downregulation. Our mouse model will help clarify the association between type 2 diabetes mellitus and AD.

Change in renal blood flow in response to intrarenal pressure alterations induced by ureteroscopy in an in-vivo porcine model.

High irrigation rates are commonly used during ureteroscopy and can increase intrarenal pressure (IRP) substantially. Concerns have been raised that elevated IRP may diminish renal blood flow (RBF) and perfusion of the kidney. Our objective was to investigate the real-time changes in RBF while increasing IRP during Ureteroscopy (URS) in an in-vivo porcine model. Four renal units in two porcine subjects were used in this study, three experimental units and one control. For the experimental units, RBF was measured by placing an ultrasonic flow cuff around the renal artery, while performing ureteroscopy in the same kidney using a prototype ureteroscope with a pressure sensor at its tip. Irrigation was cycled between two rates to achieve targeted IRPs of 30mmHg and 100mmHg. A control data set was obtained by placing the ultrasonic flow cuff on the contralateral renal artery while performing ipsilateral URS. At high IRP, RBF was reduced in all three experimental trials by 10-20% but not in the control trial. The percentage change in RBF due to alteration in IRP was internally consistent in each porcine renal unit and independent of slower systemic variation in RBF encountered in both the experimental and control units. RBF decreased 10-20% when IRP was increased from 30 to 100mmHg during ureteroscopy in an in-vivo porcine model. While this reduction in RBF is unlikely to have an appreciable effect on tissue oxygenation, it may impact heat-sink capacity in vulnerable regions of the kidney.

Towards high-resolution quantitative assessment of vascular dysfunction

Neurovascular alterations are increasingly recognized as a key feature of many brain diseases. They can manifest as a reduction in resting cerebral blood flow or cerebrovascular reactivity (CVR) in the whole brain or in specific regions, depending on the underlying condition. Neurovascular impairment is observed in hypertension, Alzheimer’s disease, stroke, multiple sclerosis and cerebral small vessel disease. Magnetic resonance imaging (MRI)-derived CVR mapping is a reliable marker of vascular dysfunction and has been performed mainly at standard functional MRI (fMRI) resolutions of 2–3 mm using the blood oxygen level dependent (BOLD) contrast. However, vascular alterations may occur at a finer scale (i.e., in the capillary bed) which would be better characterized with smaller voxel sizes. Capillaries in gray matter deliver oxygen and glucose to neural tissue and are arranged in a mesh structure, with variable density across the cortical depth. Given that the human cortex is, on average, 2.5 mm thick, submillimetric voxel sizes are effective in increasing the spatial specificity of measurements of hemodynamic and metabolic changes. Novel MRI sequences offer the possibility to map physiological parameters at high resolution with relatively simple experimental setups. In particular, pairing the BOLD acquisition with a contrast sensitive to blood volume changes, while administering a mild hypercapnic challenge, allows for simultaneous mapping of CVR, cerebral metabolic rate of oxygen consumption and other relevant parameters at a high resolution and can be performed at the clinical field strength of 3 T. We propose that this approach will help provide crucial insights into vascular impairment.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Cerebral blood flow and cerebrovascular reactivity are modified by maturational stage and exercise training status during youth.

What is the central question of this study? Gonadal hormones modulate cerebrovascular function while insulin-like growth factor 1 (IGF-1) facilitates exercise-mediated cerebral angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF-1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown. What is the main finding and its importance? Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise-induced improvements in cerebrovascular function are attainable as early as the first decade of life. Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia ( ) are modulated by gonadal hormone activity, while insulin-like growth factor 1 facilitates exercise-mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and in n=128 adolescents characterised as endurance-exercise trained (males: n=30, females: n=36) or untrained (males: n=29, females: n=33). Participants were further categorised as pre- (males: n=35, females: n=33) or post- (males: n=24, females: n=36) peak height velocity (PHV) to determine pubertal or 'maturity' status. Three-factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and . Data are reported as group means (SD). Pre-PHV youth demonstrated elevated gCBF and slower mean response times than post-PHV counterparts (both: P≤0.001). gCBF was only elevated in post-PHV trained males when compared to untrained counterparts (634(43) vs. 578(46)mlmin-1 ; P=0.007). However, mean response time was faster in pre- (72(20) vs. 95(29)s; P≤0.001), but not post-PHV (P=0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post-PHV youth (r2 =0.19; P≤0.001) and mean response time in pre-PHV youth (r2 =0.13; P=0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype.

Acute upper and lower limb hemodynamic responses during single sessions of low- versus high-intensity inspiratory muscle strength training.

Inspiratory muscle strength training (IMST) has shown potential to improve both respiratory and cardiovascular function in health and disease. Less is known about acute hemodynamic responses to a single IMST session, therefore we assessed upper and lower limb blood flow via Doppler ultrasound in the brachial and popliteal arteries, respectively. Mean, anterograde, and retrograde blood flow (BF) and shear rate (SR) were assessed relative to baseline during low-intensity (15% maximal inspiratory pressure - PImax) and high-intensity (75% PImax) IMST. During low-intensity IMST, popliteal BF and SR were reduced by ∼10%, and brachial BF and SR were reduced by ∼40%. During high-intensity IMST, popliteal BF and SR were reduced by ∼20%, and brachial BF and SR were reduced by ∼35%. BF and SR responses were not statistically different between low-intensity and high-intensity training for either blood vessel (P > 0.05). In addition, anterograde BF and SR were significantly decreased in the brachial artery for both low-intensity and high-intensity training (P < 0.05), but not the popliteal artery (P > 0.05). Finally, during IMST retrograde BF and SR were significantly increased in both the upper and lower limbs during low-intensity and high-intensity training (P < 0.05). These data provide novel insight into the acute BF and SR responses to a single bout of IMST and may enhance our understanding of the mechanism(s) by which IMST imparts its beneficial chronic effects on cardiovascular function.NEW & NOTEWORTHY Herein, we demonstrate for the first time that upper and lower limb blood flow and shear rate patterns are altered during a single bout of IMST, at low- and high-intensity training. Specifically, anterograde blood flow and shear rate are significantly reduced in the brachial artery, whereas retrograde blood flow is significantly elevated in both the brachial and popliteal arteries. These findings provide insight into the vascular impact of IMST, which may inform future mechanistic studies.

Deep-learning-based separation of shallow and deep layer blood flow rates in diffuse correlation spectroscopy.

Diffuse correlation spectroscopy faces challenges concerning the contamination of cutaneous and deep tissue blood flow. We propose a long short-term memory network to directly quantify the flow rates of shallow and deep-layer tissues. By exploiting the different contributions of shallow and deep-layer flow rates to auto-correlation functions, we accurately predict the shallow and deep-layer flow rates (RMSE = 0.047 and 0.034 ml/min/100 g of simulated tissue, R2 = 0.99 and 0.99, respectively) in a two-layer flow phantom experiment. This approach is useful in evaluating the blood flow responses of active muscles, where both cutaneous and deep-muscle blood flow increase with exercise.

Whisker-evoked neurovascular coupling is preserved during hypoglycemia in mouse cortical arterioles and capillaries

Hypoglycemia is a serious complication of insulin treatment of diabetes that can lead to coma and death. Neurovascular coupling, which mediates increased local blood flow in response to neuronal activity, increases glucose availability to active neurons. This mechanism could be essential for neuronal health during hypoglycemia, when total glucose supplies are low. Previous studies suggest, however, that neurovascular coupling (a transient blood flow increase in response to an increase in neuronal activity) may be reduced during hypoglycemia. Such a reduction in blood flow increase would exacerbate the effects of hypoglycemia, depriving active neurons of glucose. We have reexamined the effects of hypoglycemia on neurovascular coupling by simultaneously monitoring neuronal and vascular responses to whisker stimulation in the awake mouse somatosensory cortex. We find that neurovascular coupling at both penetrating arterioles and at 2nd order capillaries did not change significantly during insulin-induced hypoglycemia compared to euglycemia. In addition, we show that the basal diameter of both arterioles and capillaries increases during hypoglycemia (10.3 and 9.7% increases, respectively). Our results demonstrate that both neurovascular coupling and basal increases in vessel diameter are active mechanisms which help to maintain an adequate supply of glucose to the brain during hypoglycemia.

Comprehensive investigations of cerebral hemodynamic responses in CSVD patients with mental disorders: a pilot study.

Although a portion of patients with cerebral small vessel disease (CSVD) present mental disorders, there is currently a lack of appropriate technologies to evaluate brain functions that are relevant to neurovascular coupling. Furthermore, there are no established objective criteria for diagnosing and distinguishing CSVD-induced mental disorders and psychiatric diseases. In this study, we report the first comprehensive investigation of the cerebral hemodynamics of CSVD patients who also presented with mental disorders. Two CSVD patients with similar magnetic resonance imaging (MRI) outcomes but with non-identical mental symptoms participated in this study. The patients were instructed to perform the verbal fluency task (VFT), high-level cognition task (HCT), as well as voluntary breath holding (VBH). A functional near-infrared spectroscopy (fNIRS) was used to measure the cerebral oxygenation responses. Additionally, a diffuse correlation spectroscopy (DCS) was used to measure the cerebral blood flow (CBF) responses. Both technologies were also applied to a healthy subject for comparison. The fNIRS results showed that both CSVD patients presented abnormal cerebral oxygenation responses during the VFT, HCT, and VBH tasks. Moreover, the patient with cognition impairment showed fluctuations in CBF during these tasks. In contrast, the patient without cognition impairment mostly presented typical CBF responses during the tasks, which was consistent with the healthy subject. The cognitive impairment in CSVD patients may be due to the decoupling of the neurons from the cerebrovascular, subsequently affecting the autoregulation capacity. The results of the fNIRS and DCS combined provide a comprehensive evaluation of the neurovascular coupling and, hence, offer great potential in diagnosing cerebrovascular or psychiatric diseases.

Multifaceted neural and vascular pathologies after pediatric mild traumatic brain injury

Dynamic changes in neurodevelopment and cognitive functioning occur during adolescence, including a switch from reactive to more proactive forms of cognitive control, including response inhibition. Pediatric mild traumatic brain injury (pmTBI) affects these cognitions immediately post-injury, but the role of vascular versus neural injury in cognitive dysfunction remains debated. This study consecutively recruited 214 sub-acute pmTBI (8–18 years) and age/sex-matched healthy controls (HC; N = 186), with high retention rates (>80%) at four months post-injury. Multimodal imaging (functional MRI during response inhibition, cerebral blood flow and cerebrovascular reactivity) assessed for pathologies within the neurovascular unit. Patients exhibited increased errors of commission and hypoactivation of motor circuitry during processing of probes. Evidence of increased/delayed cerebrovascular reactivity within motor circuitry during hypercapnia was present along with normal perfusion. Neither age-at-injury nor post-concussive symptom load were strongly associated with imaging abnormalities. Collectively, mild cognitive impairments and clinical symptoms may continue up to four months post-injury. Prolonged dysfunction within the neurovascular unit was observed during proactive response inhibition, with preliminary evidence that neural and pure vascular trauma are statistically independent. These findings suggest pmTBI is characterized by multifaceted pathologies during the sub-acute injury stage that persist several months post-injury.