Cerebral Blood Flow Response Research Articles

Recent insights into mechanisms of hypoxia-induced vasodilatation in the human brain.

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in-flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro- and macrovascular dilatation. This contemporary review focuses on in vivo human work - with reference to seminal preclinical work where necessary - on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a - likely non-obligatory - combination of: (1) nitric oxide synthases, (2) deoxygenation-coupled S-nitrosothiols, (3) potassium channel-related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin-related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex-, heredity-, age-, and disease-related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury.

Initiation of combined antiretroviral therapy confers suboptimal beneficial effects on neurovascular function in people with HIV.

Due to advances in combined anti-retroviral treatment (cART), there is an increased burden of age-related cerebrovascular disease (CBVD), in people living with HIV (PWH). The underlying CNS injury can be assessed by measuring cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). 35 treatment-naïve PWH and 53 HIV negative controls (HC) were enrolled in this study. Study participants underwent T1-weighted anatomical, pseudo-continuous arterial spin labeling, and resting-state functional MRI to obtain measures of CBF and CVR prior to starting cART treatment and at two-time points (12 weeks and 2 years) post-cART initiation. Controls were scanned at the baseline and 2-year visits. We also measured plasma levels of microparticles of endothelial and glial origin and well-known endothelial inflammation markers, ICAM-1 and VCAM-1, to assess HIV-associated endothelial inflammation and the interaction of these peripheral markers with brain neurovascular function. HIV infection was found to be associated with reduced CVR and increased levels of endothelial and glial microparticles (MPs) prior to initiation of cART. Further, CVR correlated negatively with peripheral MP levels in PWH. Our results suggest that while cART treatment has a beneficial effect on the neurovascular function after initiation, these benefits are suboptimal over time.

Cerebral autoregulation and cerebral blood flow response to mean arterial pressure challenge following induction of general anaesthesia for neuroradiology procedure

IntroductionIntraoperative hypotension is common following general anaesthesia induction with propofol, but its impact on cerebral autoregulation (CA) remains unclear. We investigate the incidence and risk factors of impaired CApost-propofol induction and its recovery after a mean arterial pressure (mAP) challenge.MethodsWe included 40 non-emergency neuroradiology surgery patients [58 (47, 58)years old., 57% women]. We recorded mAP, mean blood flow velocity in the mean cerebral artery (MCAvmean), and regional cerebral oxygen saturation (rSO2). We computed the mean flow index (Mxa) pre and post mAP challenge. Mxa > 0.3 defined poor CA.ResultsAfter anaesthesia induction, 21 (53%) had impaired CBF autoregulation (CA−, Mxa > 0.3). The average mAP was 66 ± 9 mmHg, average MCAv was 39 ± 12 cm.s−1, and rSO2 was 63 ± 7%. We found no significant difference in age, norepinephrine infusion rate, and cardiovascular risks factors were similar between CA− and CA+ (Mxa ≤ 0.3) patients. Among the 22 patients (CA−: n = 14; CA+: n = 8) undergoing mAP challenge, there was a significant Mxa improvement and MCAv increase among CA− patients, (CA−: 0.63 ± 0.18 vs. 0.28 ± 0.20, p < 0.001), and [absolute variation: 1 (0.7–1.5) vs. 7 (3–9) cm.sec−1], respectively.ConclusionAfter induction of general anaesthesia for neuroradiology procedure, 53% of the patients had an impaired CA, regardless of age or medical history. Importantly, a mAP challenge effectively restored CA and improved CBF.Clinical Trial Registrationidentifier, NCT04288869

Distinct cortical haemodynamics during squat-stand and continuous aerobic exercise do not influence the magnitude of a postexercise executive function benefit

ABSTRACT A single bout of aerobic exercise benefits executive function (EF). A potential mechanism for this benefit is an exercise-mediated increase in cerebral blood flow (CBF) that elicits vascular endothelial shear-stress improving EF efficiency. Moderate intensity continuous aerobic exercise (MCE) asymptotically increases CBF, whereas continuous body weight squat-stand exercise (SSE) provides a large amplitude oscillatory response. Some work has proposed that an increase in CBF oscillation amplitude provides the optimal shear-stress for improving EF and brain health. We examined whether a large amplitude oscillatory CBF response associated with a single bout of SSE imparts a larger postexercise EF benefit than an MCE cycle ergometer protocol. Exercise changes in middle cerebral artery velocity (MCAv) were measured via transcranial Doppler ultrasound to estimate CBF, and pre- and postexercise EF was assessed via the antisaccade task. MCE produced a steady state increase in MCAv, whereas SSE produced a large amplitude MCAv oscillation. Both conditions produced a postexercise EF benefit that null hypothesis and equivalence tests showed to be comparable in magnitude. Accordingly, we provide a first demonstration that a single bout of SSE benefits EF; however, the condition’s oscillatory CBF response does not impart a larger benefit than a time- and intensity-matched MCE protocol.

Cerebral Autoregulation-guided Management of Adult and Pediatric Traumatic Brain Injury.

Cerebral autoregulation (CA) plays a vital role in maintaining cerebral blood flow in response to changes in systemic blood pressure. Impairment of CA following traumatic brain injury (TBI) may exacerbate the injury, potentially impacting patient outcomes. This focused review addresses 4 key questions regarding the measurement, natural history of CA after TBI, and potential clinical implications of CA status and CA-guided management in adults and children with TBI. We examine the feasibility and safety of CA assessment, its association with clinical outcomes, and the potential for reversing deranged CA following TBI. Finally, we discuss how the knowledge of CA status may affect TBI management and outcomes.

The effects of water temperature on cerebral blood flow during aquatic exercise

PurposeRecent studies suggest that episodic increases in cerebral blood flow (CBF) may contribute to the improvement in brain health associated with exercise training. Optimising CBF during exercise may enhance this benefit. Water immersion in ~ 30–32 °C augments CBF at rest and during exercise; however, the impact of water temperature on the CBF response has not been investigated. We hypothesised that cycle ergometry in water would increase CBF compared to land-based exercise, and that warm water would attenuate the CBF benefits.MethodsEleven young heathy participants (nine males; 23.8 ± 3.1 yrs) completed 30 min of resistance-matched cycle exercise in three separate conditions; non-immersion (Land), 32 °C and 38 °C water immersion up to the level of the waist. Middle cerebral artery velocity (MCAv), blood pressure, and respiratory measures were assessed throughout the exercise bouts.ResultsCore temperature was significantly higher in the 38 °C immersion than 32 °C (+ 0.84 ± 0.24 vs + 0.04 ± 0.16, P < 0.001), whilst mean arterial pressure was lower during 38 °C exercise compared to Land (84 ± 8 vs 100 ± 14 mmHg, P < 0.001) and 32 °C (92 ± 9, P = 0.03). MCAv was higher in 32 °C immersion compared to the Land and 38 °C conditions throughout the exercise bout (68 ± 10 vs 64 ± 11 vs 62 ± 12 cm/s, P = 0.03 and P = 0.02, respectively).ConclusionOur findings suggest that cycle exercise in warm water attenuates the beneficial impact of water immersion on CBF velocity due to redistribution of blood flow to subserve thermoregulatory demand. Our findings suggest that, whilst water-based exercise can have beneficial effects on cerebrovascular function, water temperature is a key determinant of this benefit.

Vicarious touch: Overlapping neural patterns between seeing and feeling touch

Simulation theories propose that vicarious touch arises when seeing someone else being touched triggers corresponding representations of being touched. Prior electroencephalography (EEG) findings show that seeing touch modulates both early and late somatosensory responses (measured with or without direct tactile stimulation). Functional Magnetic Resonance Imaging (fMRI) studies have shown that seeing touch increases somatosensory cortical activation. These findings have been taken to suggest that when we see someone being touched, we simulate that touch in our sensory systems. The somatosensory overlap when seeing and feeling touch differs between individuals, potentially underpinning variation in vicarious touch experiences. Increases in amplitude (EEG) or cerebral blood flow response (fMRI), however, are limited in that they cannot test for the information contained in the neural signal: seeing touch may not activate the same information as feeling touch. Here, we use time-resolved multivariate pattern analysis on whole-brain EEG data from people with and without vicarious touch experiences to test whether seen touch evokes overlapping neural representations with the first-hand experience of touch. Participants felt touch to the fingers (tactile trials) or watched carefully matched videos of touch to another person's fingers (visual trials). In both groups, EEG was sufficiently sensitive to allow decoding of touch location (little finger vs. thumb) on tactile trials. However, only in individuals who reported feeling touch when watching videos of touch could a classifier trained on tactile trials distinguish touch location on visual trials. This demonstrates that, for people who experience vicarious touch, there is overlap in the information about touch location held in the neural patterns when seeing and feeling touch. The timecourse of this overlap implies that seeing touch evokes similar representations to later stages of tactile processing. Therefore, while simulation may underlie vicarious tactile sensations, our findings suggest this involves an abstracted representation of directly felt touch.

Acceleration of the Development of Microcirculation Embolism in the Brain due to Capillary Narrowing.

Cerebral microvascular obstruction is critically involved in recurrent stroke and decreased cerebral blood flow with age. The obstruction must occur in the capillary with a greater resistance to perfusion pressure through the microvascular networks. However, little is known about the relationship between capillary size and embolism formation. This study aimed to determine whether the capillary lumen space contributes to the development of microcirculation embolism. To spatiotemporally manipulate capillary diameters in vivo, transgenic mice expressing the light-gated cation channel protein ChR2 (channelrhodopsin-2) in mural cells were used. The spatiotemporal changes in the regional cerebral blood flow in response to the photoactivation of ChR2 mural cells were first characterized using laser speckle flowgraphy. Capillary responses to optimized photostimulation were then examined in vivo using 2-photon microscopy. Finally, microcirculation embolism due to intravenously injected fluorescent microbeads was compared under conditions with or without photoactivation of ChR2 mural cells. Following transcranial photostimulation, the stimulation intensity-dependent decrease in cerebral blood flow centered at the irradiation was observed (14%-49% decreases relative to the baseline). The cerebrovascular response to photostimulation showed significant constriction of the cerebral arteries and capillaries but not of the veins. As a result of vasoconstriction, a temporal stall of red blood cell flow occurred in the capillaries of the venous sides. The 2-photon excitation of a single ChR2 pericyte demonstrated the partial shrinkage of capillaries (7% relative to the baseline) around the stimulated cell. With the intravenous injection of microbeads, the occurrence of microcirculation embolism was significantly enhanced (11% increases compared to the control) with photostimulation. Capillary narrowing increases the risk of developing microcirculation embolism in the venous sides of the cerebral capillaries.

Understanding recovery of language after stroke: insights from neurovascular MRI studies.

Stroke causes a disruption in blood flow to the brain that can lead to profound language impairments. Understanding the mechanisms of language recovery after stroke is crucial for the prognosis and effective rehabilitation of people with aphasia. While the role of injured brain structures and disruptions in functional connectivity have been extensively explored, the relationship between neurovascular measures and language recovery in both early and later stages has not received sufficient attention in the field. Fully functioning healthy brain tissue requires oxygen and nutrients to be delivered promptly via its blood supply. Persistent decreases in blood flow after a stroke to the remaining non-lesioned tissue have been shown to contribute to poor language recovery. The goal of the current paper is to critically examine stroke studies looking at the relationship between different neurovascular measures and language deficits and mechanisms of language recovery via changes in neurovascular metrics. Measures of perfusion or cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide complementary approaches to understanding neurovascular mechanisms post stroke by capturing both cerebral metabolic demands and mechanical vascular properties. While CBF measures indicate the amount of blood delivered to a certain region and serve as a proxy for metabolic demands of that area, CVR indices reflect the ability of the vasculature to recruit blood flow in response to a shortage of oxygen, such as when one is holding their breath. Increases in CBF during recovery beyond the site of the lesion have been shown to promote language gains. Similarly, CVR changes, when collateral vessels are recruited to help reorganize the flow of blood in hypoperfused regions, have been related to functional recovery post stroke. In the current review, we highlight the main findings in the literature investigating neurovascular changes in stroke recovery with a particular emphasis on how language abilities can be affected by changes in CBF and CVR. We conclude by summarizing existing methodological challenges and knowledge gaps that need to be addressed in future work in this area, outlining a promising avenue of research.

Placement of Extracranial Stimulating Electrodes and Measurement of Cerebral Blood Flow and Intracranial Electrical Fields in Anesthetized Mice.

The detection of cerebral blood flow (CBF) responses to various forms of neuronal activation is critical for understanding dynamic brain function and variations in the substrate supply to the brain. This paper describes a protocol for measuring CBF responses to transcranial alternating current stimulation (tACS). Dose-response curves are estimated both from the CBF change occurring with tACS (mA) and from the intracranial electric field (mV/mm). We estimate the intracranial electrical field based on the different amplitudes measured by glass microelectrodes within each side of the brain. In this paper, we describe the experimental setup, which involves using either bilateral laser Doppler (LD) probes or laser speckle imaging (LSI) to measure the CBF; as a result, this setup requires anesthesia for the electrode placement and stability. We present a correlation between the CBF response and the current as a function of age, showing a significantly larger response at higher currents (1.5 mA and 2.0 mA) in young control animals (12-14 weeks) compared to older animals (28-32 weeks) (p < 0.005 difference). We also demonstrate a significant CBF response at electrical field strengths <5 mV/mm, which is an important consideration for eventual human studies. These CBF responses are also strongly influenced by the use of anesthesia compared to awake animals, the respiration control (i.e., intubated vs. spontaneous breathing), systemic factors (i.e., CO2), and local conduction within the blood vessels, which is mediated by pericytes and endothelial cells. Likewise, more detailed imaging/recording techniques may limit the field size from the entire brain to only a small region. We describe the use of extracranial electrodes for applying tACS stimulation, including both homemade and commercial electrode designs for rodents, the concurrent measurement of the CBF and intracranial electrical field using bilateral glass DC recording electrodes, and the imaging approaches. We are currently applying these techniques to implement a closed-loop format for augmenting the CBF in animal models of Alzheimer's disease and stroke.

Reduced temporal lobe cerebral blood flow is associated with regional white matter damage among apolipoprotein E ε4 carriers

AbstractBackgroundReduced cerebral blood flow (CBF) is a risk factor for white matter damage. Apolipoprotein E (APOE) e4, a genetic risk factor for Alzheimer’s disease and vascular health modifier, is associated with lower CBF. However, it remains unknown if lower CBF is associated with more severe white matter damage among APOE‐e4 carriers. We examine whether associations among regional CBF, cerebrovascular reactivity (CVR), and white matter integrity are modified by APOE‐e4 status in older adults.MethodVanderbilt Memory and Aging Project participants (n = 313, 73±7 years) underwent 3T brain MRI. Resting grey matter CBF and CVR (CBF response to hypercapnic stimulus, ΔCBF/100*ΔCO2) were quantified in regions of interest from pseudo‐continuous arterial spin labeling (ASL). Fractional anisotropy (FA) was quantified from diffusion tensor imaging in tracts of interest derived from tractography templates. Linear regressions related regional CBF and CVR to tract‐specific FA, adjusting for demographic and vascular variables, regional tissue volume, cognitive status, and APOE‐e4 status. Follow‐up models tested an APOE‐ε4 status x ASL variable interaction term.ResultIn main models, lower temporal lobe CBF was associated with lower FA in the occipital lobe, suggesting compromised white matter integrity (p = 0.02). Lower CBF and higher CVR in the occipital lobe were associated with compromised lower FA in all lobes (all p‐values&lt;0.04). Temporal lobe CBF and CVR interacted with APOE‐e4 status, such that lower temporal lobe CBF related to lower FA in the frontal lobe (p = 0.01) and higher temporal lobe CVR related to lower FA in the frontal (p = 0.001) and temporal (p = 0.007) lobes among APOE‐e4 carriers only. Frontal lobe CVR interacted with APOE‐e4 status, such that higher CVR related to lower FA in the frontal (p&lt;0.001) and temporal lobes (p = 0.008) in APOE‐e4 carriers only.ConclusionAmong older adults, APOE‐e4 modifies associations between cerebral hemodynamics and white matter integrity, such that reduced CBF and greater CVR in the temporal lobe are associated with greater white matter damage in APOE‐e4 carriers. APOE‐e4 carriers may be more susceptible to changes in temporal lobe hemodynamics, and vascular changes in the temporal lobe may have a stronger impact on brain health outcomes for carriers compared to non‐carriers.

Brain responses to energy intake and its association with cognition in Alzheimer’s Disease

AbstractBackgroundTo evaluate the brain response to energy intake using cerebral blood flow(CBF) in Alzheimer’s disease (AD), mild cognitive impairment (MCI) and healthy controls (HC) and its relationship with cognition.MethodA self‐comparison design was used to test the effects of energy intake on brain activity in participants with AD (n = 30), MCI participants (n = 32), and HC (n = 30) and its relationship with cognitive function. Brain perfusion was measured using arterial spin labeling (ASL) functional brain imaging. Participants arrived at the site in the morning and underwent the ASL‐MRI with at least 10 hours fasting overnight. Then the second ASL‐MRI at 30 minutes after eating a standard breakfast was performed. Energy response ΔCBF was computed by subtracting the fasting CBF from the postprandial CBF obtained from ASL‐MRI. Whole brain grey matter voxel‐wise paired T test and linear regression analyses were used for statistical analysis.ResultAD and MCI group had different energy response ΔCBF pattern with HC group. In AD group, energy intake induced a significantly decreased CBF in temporal lobe including lateral inferior and superior temporal gyrus, right superior temporal gyrus, parietal lobe including bilateral superior and inferior parietal lobe, postcentral gyrus and precuneus, most of occipital lobe and frontal lobe including right rolandic operculum, right precentral gyrus and left middle frontal gyrus. (q &lt; 0.05, false discovery rate corrected). MCI had similar energy intake response pattern with AD. HC group had no significantly changed CBF response to energy intake. Energy response ΔCBF in the vicinity of the superior temporal gyrus showed significant negative correlation with Minimum Mental State Examination (MMSE) in all AD, MCI and HC groups.ConclusionThe different energy response ΔCBF pattern may help to characterize the energy disorder in AD and may indicate the different brain energy rescue effect in the three groups. Energy response ΔCBF in the superior temporal gyrus is an indicator of cognitive function in AD.

Genetic, vascular and amyloid components of cerebral blood flow in a preclinical population

Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and [18F]flutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses.

Nitric Oxide Production from Nitrite plus Ascorbate during Ischemia upon Hippocampal Glutamate NMDA Receptor Stimulation

Nitric oxide (•NO), a diffusible free radical, is an intercellular messenger, playing a crucial role in several key brain physiological processes, including in neurovascular coupling (NVC). In the brain, glutamatergic activation of the neuronal nitric oxide synthase (nNOS) enzyme constitutes its main synthesis pathway. However, when oxygen (O2) supply is compromised, such as in stroke, ischemia, and aging, such •NO production pathway may be seriously impaired. In this context, evidence suggests that, as already observed in the gastric compartment, the reduction of nitrite by dietary compounds (such as ascorbate and polyphenols) or by specific enzymes may occur in the brain, constituting an important rescuing or complementary mechanism of •NO production. Here, using microsensors selective for •NO, we show that nitrite enhanced the •NO production in a concentration-dependent manner and in the presence of ascorbate evoked by N-methyl-D-aspartate (NMDA) and glutamate stimulation of rat hippocampal slices. Additionally, nitrite potentiated the •NO production induced by oxygen-glucose deprivation (OGD). Overall, these observations support the notion of a redox interaction of ascorbate with nitrite yielding •NO upon neuronal glutamatergic activation and given the critical role of NO as the direct mediator of neurovascular coupling may represents a key physiological mechanism by which •NO production for cerebral blood flow (CBF) responses to neuronal activation is sustained under hypoxic/acidic conditions in the brain.

Cerebrovascular Reactivity and Concussion.

Cerebrovascular reactivity (CVR) reflects the change in cerebral blood flow in response to vasodilatory stimuli enabling assessment of the health of the cerebral vasculature. Recent advances in the quantitative delivery of CO2 stimuli with computer-controlled sequential gas delivery have enabled mapping of the speed and magnitude of response to flow stimuli. These CVR advances when applied to patients with acute concussion have unexpectedly shown faster speed and greater magnitude of responses unseen in other diseases that typically show the opposite effects. The strength of the CVR alterations have diagnostic potential in single subjects with AUC values in the 0.90-0.94 range.

Impact of intranasal insulin on cerebral blood flow and cerebrovascular reactivity in healthy young adults

Objective: Adults with obesity and insulin resistance exhibit impaired cerebrovascular reactivity and endothelial dysfunction, which increases the risk of dementia and Alzheimer’s disease. Impairments in cerebrovascular health have been attributed to vascular insulin resistance and emerging data support the use of intranasal insulin as a potential therapeutic intervention. Although mechanisms are unclear, the benefits of intranasal insulin may in part be mediated by changes in cerebral blood flow and/or cerebrovascular reactivity. Using intranasal administration of insulin, we examined the acute effect of central insulin on resting cerebral blood flow as well as reactivity to inhaled carbon dioxide. We hypothesized intranasal insulin would increase indices of cerebral blood flow and cerebrovascular reactivity in healthy young adults. Methods: Nineteen healthy young adults were randomized into time control [n=12 (5F/7M), 27±1 yrs, 25±3 kg/m2] or 160 IU of intranasal insulin administered over 5 min [n=7 (0F/7M), 27±3 yrs, 25±3 kg/m2]. Carotid artery blood flow (CBF, Doppler ultrasound) and middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) were measured prior to and 60 min following insulin administration and/or time control. In a subset of participants (time control, n=10; insulin, n=5), cerebrovascular reactivity was assessed as the relative (%) increase in MCAv and CBF from baseline during 3 min of carbon dioxide air breathing (+7.5±0.5 mmHg). Results: Blood glucose and plasma insulin remained unchanged throughout the protocol (both, p&gt;0.05). CBF (712±39 to 727±40 mL/min, p=0.45) and MCAv (50±3 to 52±3 cm/s, p=0.50) remained at baseline levels following the 60-min time control condition. Similarly, resting CBF (901±60 to 908±58 mL/min, p=0.78) and MCAv (54±5 to 52±5 cm/s, p=0.41) did not differ from baseline following intranasal insulin administration. Carbon dioxide breathing led to an elevation in CBF and MCAv, and their respective increases were unaffected by time control (33±5 to 37±7%, p=0.58; 49±6 to 58±9%, p=0.32) or intranasal insulin (25±3 to 24±5%, p=0.93; 39±6 to 46±6%, p=0.49). Conclusions: Contrary to our hypothesis, acute intranasal insulin administration had no effect on indices of cerebral blood flow and/or cerebrovascular reactivity in healthy young adults. Future studies should examine the cerebrovascular effects of intranasal administration in disease states ( e.g., obesity, insulin resistance, Alzheimer’s disease). CAFNR Joy of Discovery (JKL, JP) This is the full abstract presented at the American Physiology Summit 2023 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 responses to hyperoxia: exploring sex differences

Background: The administration of oxygen-rich gas (hyperoxia), is a common treatment in clinical medicine and various military occupations. Hyperoxia reduces cerebral blood flow (CBF), however, there exists substantial variability in the magnitude of its effect (0-33%), as well as an uncertainty regarding the role that hypocapnia may play in this vasoconstriction. Interestingly, hyperoxic vasoconstriction appears to be mediated by excessive reactive oxygen species (ROS) signaling. To our knowledge, no studies have directly assessed whether CBF regulation during hyperoxia is sex-specific. This is important since young females are broadly predicted to exhibit lower ROS stress and/or greater antioxidant capacity than males. Therefore, men and women may be differentially impacted. This led us to hypothesize hyperoxia will decrease CBF less in females than males. Methods: Healthy, young adults (n= 17; 7 F; 20 ± 6 yr; BMI: 20.7 ± 5) were studied after an 8 hour fast and 24 hours without caffeine or alcohol. Women were studied on days 1-5 of menstrual cycle. Subjects completed a single magnetic resonance imaging (MRI) visit. 2D phase contrast (2D PC) MRI was conducted to quantify flow through both internal carotid and vertebral arteries during normoxia, and then repeated during steady-state hyperoxia with subjects breathing 100% O 2 . Carbon dioxide (CO 2 ) was supplemented to maintain end-tidal CO 2 (ETCO 2 ) during hyperoxia. CBF was analyzed as absolute flow (mL/min), total change (ΔmL/min), and percent change (% ΔmL/min). In a subset (n=10; 3 F), arterial spin labeling (ASL) MRI was added to explore regional effects on perfusion (mL/100g/min) for an additional 5 mins of hyperoxia. The CAT12 toolbox extension for SPM12 was used to process ASL data. Significance was determined using a two-factor repeated measures ANOVA and was set at p≤0.05. Results: Results are mean±SD. Heart rate, mean arterial pressure, and ETCO 2 were similar between sexes and did not change between normoxia and hyperoxia (p&gt;0.05). When analyzing neck arteries using 2D PC MRI, hyperoxia did not have a significant effect on CBF (p&gt;0.1), and there was no differential effect between sexes (p&gt;0.1). In contrast, ASL data indicated hyperoxia significantly reduced perfusion in both sexes in all regions analyzed (gray matter, white matter, middle frontal gyrus, frontal operculum, anterior orbital gyrus, superior frontal gyrus, medial frontal cortex, accumbens area, and medial orbital gyrus (p≤0.013)). There was a trend towards a significantly smaller reduction in females in all regions (p≤0.101) except the anterior orbital gyrus (p=0.329). Conclusion: Contrary to our hypothesis, the CBF response to hyperoxia did not differ between men and women when examining the macrovasculature that supply blood to the brain. However, the smaller hyperoxic reductions in regional perfusion in females indicate that hyperoxia constriction may be sex-specific at the microvasculature level. NIH R01 HL150361 This is the full abstract presented at the American Physiology Summit 2023 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.

Microvascular Cerebral Blood Flow Monitoring Detects Response to Intrathecal Nicardipine Treatment for Vasospasm (S4.005)

<h3>Objective:</h3> Determining the effect of intrathecal nicardipine on microvascular cerebral blood flow <h3>Background:</h3> A common complication of subarachnoid hemorrhage is cerebral vasospasm, which is associated with delayed cerebral ischemia (DCI), a predictor of poor functional outcome. Intrathecal administration of nicardipine (ITn) upon detection of vasospasm holds promise as a treatment that reduces the incidence of secondary stroke. Herein, we utilize a novel non-invasive optical measurement of regional microvascular perfusion to determine the effect of ITn on microvascular cerebral blood flow (CBF). <h3>Design/Methods:</h3> In this observational study, we prospectively studied 20 patients with non-traumatic subarachnoid hemorrhage who were treated with ITn as part of usual care for evolving cerebral vasospasm. Regional microvascular CBF in the frontal cortex was measured with diffuse correlation spectroscopy for up to 90 min after the first treatment dose, and for a subset of patients, on days 2 and 3 of treatment as well. Outcome was assessed as the presence of DCI on imaging. <h3>Results:</h3> CBF increased significantly over the 90 min of monitoring after the first and subsequent doses (p&lt;0.001) in the absence of systemic hemodynamic changes. In general, the CBF response was heterogeneous across subjects. Using data from the first dose, a latent class mixture model was used to classify 19/20 patients into two distinct classes of cerebral blood flow response: patients in class 1 (n=6) showed a decrease or no change in CBF, while patients in class 2 (n=13) showed a pronounced increase in CBF in response to nicardipine. The incidence of DCI was 5/6 in class 1 and 0/13 in class 2 (p&lt;0.001). Similar significant differences in CBF response in patients with and without DCI were also observed on days 2 and 3 (both p&lt;0.001). <h3>Conclusions:</h3> Microvascular CBF monitoring is feasible in critically ill subarachnoid hemorrhage patients. CBF response may provide a valuable biomarker for treatment responsiveness. <b>Disclosure:</b> Dr. Sathialingam has nothing to disclose. Mr. Cowdrick has nothing to disclose. Ms. Urner has nothing to disclose. Ms. Liew has nothing to disclose. Dr. Sigman has nothing to disclose. Dr. Akbik has nothing to disclose. Dr. Samuels has received publishing royalties from a publication relating to health care. Dr. Kandiah has nothing to disclose. Dr. Buckley has received research support from Global Blood Therapeutics. Dr. Buckley has received research support from NIH. Ofer Sadan has received intellectual property interests from a discovery or technology relating to health care.

Impact of craniotomy area on improvement of cerebral blood flow in combined revascularization surgery for moyamoya disease

To investigate factors associated with improvements in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) after combined revascularization surgery for moyamoya disease, with special attention to the size of craniotomy. We retrospectively analyzed 35 hemispheres in 27 patients with adult and older pediatric moyamoya disease. CBF and CVR were measured separately in the MCA and ACA territories from acetazolamide-challenged single-photon emission computed tomography before and after 6 months postoperatively, and associations with various factors were analyzed. Postoperative CBF improved in patients with lower preoperative blood flow in both ACA and MCA territories. Postoperative CVR improved in 32 of 35 patients (91.4%) in the MCA territory and in 30 of 35 patients (85.7%) in the ACA territory, with more prominent improvement in the MCA territory than in the ACA territory (MCA territory 29.7% vs ACA territory 21.1%, p=0.015). Craniotomy area did not correlate with postoperative CBF and only MCA territory was associated with good (≥30%) CVR improvement (odds ratio 9.33, 95% confidence interval 1.91-45.6, p=0.003). Postoperative CBF improved in adult and older pediatric cases, reflecting preoperative CBF. Postoperative CVR improved in most cases, although the degree of improvement was more prominent in the MCA territory than in the ACA territory, suggesting a contribution of the temporal muscle. Large craniotomy area was not associated with improved blood flow in the ACA territory and should be applied prudently.

Comparing end-tidal CO2, respiration volume per time (RVT), and average gray matter signal for mapping cerebrovascular reactivity amplitude and delay with breath-hold task BOLD fMRI

Cerebrovascular reactivity (CVR), defined as the cerebral blood flow response to a vasoactive stimulus, is an imaging biomarker with demonstrated utility in a range of diseases and in typical development and aging processes. A robust and widely implemented method to map CVR involves using a breath-hold task during a BOLD fMRI scan. Recording end-tidal CO2 (PETCO2) changes during the breath-hold task is recommended to be used as a reference signal for modeling CVR amplitude in standard units (%BOLD/mmHg) and CVR delay in seconds. However, obtaining reliable PETCO2 recordings requires equipment and task compliance that may not be achievable in all settings. To address this challenge, we investigated two alternative reference signals to map CVR amplitude and delay in a lagged general linear model (lagged-GLM) framework: respiration volume per time (RVT) and average gray matter BOLD response (GM-BOLD). In 8 healthy adults with multiple scan sessions, we compare spatial agreement of CVR maps from RVT and GM-BOLD to those generated with PETCO2. We define a threshold to determine whether a PETCO2 recording has “sufficient” quality for CVR mapping and perform these comparisons in 16 datasets with sufficient PETCO2 and 6 datasets with insufficient PETCO2. When PETCO2 quality is sufficient, both RVT and GM-BOLD produce CVR amplitude maps that are nearly identical to those from PETCO2 (after accounting for differences in scale), with the caveat they are not in standard units to facilitate between-group comparisons. CVR delays are comparable to PETCO2 with an RVT regressor but may be underestimated with the average GM-BOLD regressor. Importantly, when PETCO2 quality is insufficient, RVT and GM-BOLD CVR recover reasonable CVR amplitude and delay maps, provided the participant attempted the breath-hold task. Therefore, our framework offers a solution for achieving high quality CVR maps in both retrospective and prospective studies where sufficient PETCO2 recordings are not available and especially in populations where obtaining reliable measurements is a known challenge (e.g., children). Our results have the potential to improve the accessibility of CVR mapping and to increase the prevalence of this promising metric of vascular health.