Control Of Cerebral Blood Flow Research Articles

Vasomotion and Cerebral Blood Flow in Patients With Traumatic Brain Injury and Subarachnoid Hemorrhage: Cerebrovascular Autoregulation Versus Autonomic Control.

This study compared the roles of extraparenchymal autonomic nervous system (ANS) control of cerebral blood flow (CBF) versus intraparenchymal cerebrovascular autoregulation in 487 patients with aneurysmal subarachnoid hemorrhage (SAH) and 413 patients with traumatic brain injury (TBI). Vasomotion intensity of extraparenchymal and intraparenchymal vessels were quantified as the amplitude of oscillations of arterial blood pressure (ABP) and intracranial pressure (ICP) in the very low frequency range of 0.02-0.07 Hz, or periods of 55-15 sec, computed with a bandpass filter. A version of the pressure reactivity index (PRx-55-15) was computed as the correlation of the filtered waveforms, ABP-55-15 and ICP-55-15. Since ABP-55-15 is measured in the radial artery, any influence of cerebral factors must be mediated by the ANS. ICP-55-15 is measured in the brain and is influenced by intraparenchymal chemical and metabolic factors in addition to the ANS. Patient outcome was assessed using the Extended Glasgow Outcome Score (GOSe). Ten-day mean cerebral perfusion pressure (CPP) was negatively correlated with GOSe in the TBI cohort (R = -0.13, p = 0.01) but positively correlated with GOSe in the SAH cohort, (R = 0.32, p < 0.00001), indicating a much greater dependence on ANS support in the form of elevated CPP in SAH. The optimal CPP range for TBI was 60-70 mmHg, but for SAH it was 110-120 mmHg. The percentage of monitoring time with PRx-55-15 < 0.8, indicating very pressure-active cerebral vessels that resist ANS influence via systemic ABP, is positively correlated with GOSe in the TBI cohort (R = 0.14, p = 0.003), but negatively correlated with GOSe in the SAH cohort (R = -0.10, p = 0.004). The TBI cohort optimal PRx-55-15 for patient outcome was -1.0, while the SAH optimum was 0.3. For the TBI cohort, the correlation of ABP-55-15 amplitude with 10-day mean ICP-55-15 amplitude was 0.29. For the SAH cohort the correlation was 0.51, which is stronger (p = 0.0001). The TBI cohort had a median GOSe of 5 (interquartile range [IQR] 3-7), while SAH had a median of 3 (IQR 3-5), which is worse (p < 0.00001). The higher optimal CPP in patients with SAH, more passive optimal pressure reactivity, and greater dependence of cerebral on systemic vasomotion indicate that they require more active support by the ANS and systemic circulation for CBF than patients with TBI. CBF in patients with TBI is more reliant on cerebrovascular autoregulation based on metabolic demand. This appears to be deficient following SAH, making the heightened ANS support necessary. Although this support is beneficial, it does not fully compensate for the loss of cerebrovascular autoregulation, as reflected in the problems in the SAH cohort with delayed cerebral ischemia and poor outcome.

Electrocalcium coupling in brain capillaries: Rapidly traveling electrical signals ignite local calcium signals

The routing of blood flow throughout the brain vasculature is precisely controlled by mechanisms that serve to maintain a fine balance between local neuronal demands and vascular supply of nutrients. We recently identified two capillary endothelial cell (cEC)-based mechanisms that control cerebral blood flow in vivo: 1) electrical signaling, mediated by extracellular K+-dependent activation of strong inward rectifying K+ (Kir2.1) channels, which are steeply activated by hyperpolarization and thus are capable of cell-to-cell propagation, and 2) calcium (Ca2+) signaling, which reflects release of Ca2+ via the inositol 1,4,5-trisphosphate receptor (IP3R)-a target of Gq-protein-coupled receptor signaling. Notably, Ca2+ signals were restricted to the cell in which they were initiated. Unexpectedly, we found that these two mechanisms, which were presumed to operate in distinct spatiotemporal realms, are linked such that Kir2.1-dependent hyperpolarization induces increases in the electrical driving force for Ca2+ entry into cECs through resident TRPV4 channels. This process, termed electrocalcium (E-Ca) coupling, enhances IP3R-mediated Ca2+ release via a Ca2+-induced Ca2+-release mechanism, and allows focally induced hyperpolarization, including that initiated by ATP-dependent K+ (KATP) channels, to travel cell-to-cell via activation of Kir2.1 channels in adjacent cells, providing a mechanism for the "pseudopropagation" of Ca2+ signals. Computational modeling supported the basic features of E-Ca coupling and provided insight into the intracellular processes involved. Collectively, these data provide strong support for the concept of E-Ca coupling and provide a mechanism for the spatiotemporal integration of diverse signaling pathways in the control of cerebral blood flow.

The role of endothelial frequency in the cerebral blood flow control during neonatal asphyxia: a retrospective longitudinal study

BackgroundCerebral blood flow dynamics can be explored through analysis of endothelial frequencies. Our hypothesis posits a disparity in endothelial activity among neonates with perinatal asphyxia, stratified by the presence or absence of neuronal lesions.MethodsWe conducted a retrospective longitudinal study involving newborns treated with hypothermia for moderate to severe asphyxia. Participants were grouped based on the presence or absence of neuronal damage to investigate temporal endothelial involvement in cerebral blood flow regulation. Regional cerebral oxygen saturation (rScO2) was measured using near-infrared spectroscopy (NIRS), and temporal series were analyzed in the frequency domain, utilizing the original frequency of the INVOS™ device.ResultsThe study included 88 patients, with 53% (47/88) being male and 33% (29/88) demonstrating brain lesions on magnetic resonance imaging. Among them, 86% (76/88) had a gestational age exceeding 37 weeks according to the Ballard scale, and 81% (71/88) had a birth weight exceeding 2500 g. Cohen’s d effect size was calculated to assess differences in endothelial frequency between groups, indicating a small effect size based on cerebral MRI findings (Cohen’s d values for Day 2 = 0.2351 and Day 3 = 0.2325).ConclusionNIRS represents a valuable tool for monitoring cerebral autoregulation in neonates affected by perinatal asphyxia, underscoring the utility of assessing endothelial frequency or energy on rScO2 measured by NIRS using the original INVOS™ device frequency.

Vascular Function and Ion Channels in Alzheimer's Disease.

This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression.

The phase coherence of the neurovascular unit is reduced in Huntington’s disease

Abstract Huntington’s disease is a neurodegenerative disorder in which neuronal death leads to chorea and cognitive decline. Individuals with ≥40 cytosine–adenine–guanine repeats on the interesting transcript 15 gene develop Huntington’s disease due to a mutated huntingtin protein. While the associated structural and molecular changes are well characterized, the alterations in neurovascular function that lead to the symptoms are not yet fully understood. Recently, the neurovascular unit has gained attention as a key player in neurodegenerative diseases. The mutant huntingtin protein is known to be present in the major parts of the neurovascular unit in individuals with Huntington’s disease. However, a non-invasive assessment of neurovascular unit function in Huntington’s disease has not yet been performed. Here, we investigate neurovascular interactions in presymptomatic (N = 13) and symptomatic (N = 15) Huntington’s disease participants compared to healthy controls (N = 36). To assess the dynamics of oxygen transport to the brain, functional near-infrared spectroscopy, ECG and respiration effort were recorded. Simultaneously, neuronal activity was assessed using EEG. The resultant time series were analysed using methods for discerning time-resolved multiscale dynamics, such as wavelet transform power and wavelet phase coherence. Neurovascular phase coherence in the interval around 0.1 Hz is significantly reduced in both Huntington’s disease groups. The presymptomatic Huntington’s disease group has a lower power of oxygenation oscillations compared to controls. The spatial coherence of the oxygenation oscillations is lower in the symptomatic Huntington’s disease group compared to the controls. The EEG phase coherence, especially in the α band, is reduced in both Huntington’s disease groups and, to a significantly greater extent, in the symptomatic group. Our results show a reduced efficiency of the neurovascular unit in Huntington’s disease both in the presymptomatic and symptomatic stages of the disease. The vasculature is already significantly impaired in the presymptomatic stage of the disease, resulting in reduced cerebral blood flow control. The results indicate vascular remodelling, which is most likely a compensatory mechanism. In contrast, the declines in α and γ coherence indicate a gradual deterioration of neuronal activity. The results raise the question of whether functional changes in the vasculature precede the functional changes in neuronal activity, which requires further investigation. The observation of altered dynamics paves the way for a simple method to monitor the progression of Huntington’s disease non-invasively and evaluate the efficacy of treatments.

Influence of Cholesterol Dysregulation and Cell Senescence on Hippocampal Neurovascular Integrity in Alzheimer’s Disease

The neurovascular unit (NVU) is an essential construct of cerebral blood flow control and contains neurons, astrocytes, microglia, smooth muscle, pericytes, and endothelial cells (ECs). This cellular ensemble, among other roles, balances cerebrovascular blood flow control with the metabolic demand of active neurons. Recent studies underscore the pivotal role of the NVU in Alzheimer’s disease (AD), particularly with molecular, cellular, and integrative evidence that vascular dysfunction precedes amyloid-beta (Aβ) plaque deposition. Cerebrovascular ECs are particularly vulnerable in the aging brain while central to regulation of the blood-brain barrier, hemodynamic flow, angiogenesis, and immunity. As a common characteristic of an array of cardiovascular and neurodegenerative diseases, interactions among dyslipidemia and EC health may establish cerebrovascular injury that precedes and accompanies AD. Furthermore, aberrant vascularization in the hippocampus coincides with development of mild cognitive impairment (MCI) and AD due to compromised oxygen and energy provisions in tandem with accumulation of metabolic waste and toxins. Thus, we hypothesize that interaction among cholesterol dysregulation and EC senescence signaling in the hippocampus contribute to progressive AD pathology. To test this hypothesis, we examine transgenic AD mice ( 3xTg-AD) demonstrating MCI (4-5 mo), presence of extracellular Aβ plaques (6-8 mo), and extracellular Aβ plaques with neurofibrillary tau tangles (≥12 mo) compared to young controls (1-2 mo). Our investigation employs an innovative tissue clearing method (iDISCO+), adapted for imaging on a confocal microscope, to probe three-dimensional vascular structure (CD31, Podocalyxin) and senescent cell aggregation (p16, β-Galactosidase) in the hippocampus. Second, Filipin III, selective blood vessel, and senescence markers are imaged in 25 μm coronal sections to examine broader spatial distribution of cholesterol around the hippocampus and cortex. Third, ex vivo blood vessel staining enables an in-depth analysis among membrane cholesterol inclusions and endothelial inward-rectifying K+ (KIR2.1) channels, an ion channel marker particularly sensitive to the distribution of membrane cholesterol while integral to cerebral blood flow control. As cholesterol dysregulation poses a significant risk to the integrity of the NVU including EC senescence and diminishment of KIR2.1 channel function, we anticipate that our results will ultimately highlight its potential role in the early to late stages of AD pathogenesis. This work was supported by the National Institutes of Health (R01AG073230). Imaging was performed in the LLUSM Advanced Imaging and Microscopy Core that is supported by NSF Grant No. MRI-DBI 0923559 and the Loma Linda University School of Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cerebral sympatholysis: experiments on in vivo cerebrovascular regulation and ex vivo cerebral vasomotor control.

Whether cerebral sympathetic-mediated vasomotor control can be modulated by local brain activity remains unknown. This study tested the hypothesis that the application or removal of a cognitive task during a cold pressor test (CPT) would attenuate and restore decreases in cerebrovascular conductance (CVC), respectively. Middle cerebral artery blood velocity (transcranial Doppler) and mean arterial pressure (finger photoplethysmography) were examined in healthy adults (n = 16; 8 females and 8 males) who completed a control CPT, followed by a CPT coupled with a cognitive task administered either 1) 30 s after the onset of the CPT and for the duration of the CPT or 2) at the onset of the CPT and terminated 30 s before the end of the CPT (condition order was counterbalanced). The major finding was that the CPT decreased the index of CVC, and such decreases were abolished when a cognitive task was completed concurrently and restored when the cognitive task was removed. As a secondary experiment, vasomotor interactions between sympathetic transduction pathways (α1-adrenergic and Y1-peptidergic) and compounds implicated in cerebral blood flow control [adenosine, and adenosine triphosphate (ATP)] were explored in isolated porcine cerebral arteries (wire myography). The data reveal α1-receptor agonism potentiated vasorelaxation modestly in response to adenosine, and preexposure to ATP attenuated contractile responses to α1-agonism. Overall, the data suggest a cognitive task attenuates decreases in CVC during sympathoexcitation, possibly related to an interaction between purinergic and α1-adrenergic signaling pathways.NEW & NOTEWORTHY The present study demonstrates that the cerebrovascular conductance index decreases during sympathoexcitation and this response can be positively and negatively modulated by the application or withdrawal of a nonexercise cognitive task. Furthermore, isolated vessel experiments reveal that cerebral α1-adrenergic agonism potentiates adenosine-mediated vasorelaxation and ATP attenuates α1-adrenergic-mediated vasocontraction.

ROLE OF MICROGLIA IN SEPSIS-ASSOCIATED ENCEPHALOPATHY PATHOGENESIS: AN UPDATE.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, which is characterized by cognitive dysfunction, a poor prognosis, and high incidences of morbidity and mortality. Substantial levels of systemic inflammatory factors induce neuroinflammatory responses during sepsis, ultimately disrupting the central nervous system's (CNS) homeostasis. This disruption results in brain dysfunction through various underlying mechanisms, contributing further to SAE's development. Microglia, the most important macrophage in the CNS, can induce neuroinflammatory responses, brain tissue injury, and neuronal dysregulation, resulting in brain dysfunction. They serve an important regulatory role in CNS homeostasis and can be activated through multiple pathways. Consequently, activated microglia are involved in several pathogenic mechanisms related to SAE and play a crucial role in its development. This article discusses the role of microglia in neuroinflammation, dysfunction of neurotransmitters, disruption of the blood-brain barrier, abnormal control of cerebral blood flow, mitochondrial dysfunction, and reduction in the number of good bacteria in the gut as main pathogenic mechanisms of SAE and focuses on studies targeting microglia to ameliorate SAE to provide a theoretical basis for targeted microglial therapy for SAE.

Internal Carotid Artery Blood Flow Response to Anaesthesia, Pneumoperitoneum and Head-Up Tilt During Laparoscopic Cholecystectomy: A Clinical Study

Background: Control of cerebral blood flow (CBF) is complex and is only beginning to be elucidated. There is paucity of information on how implementation of pneumoperitoneum and head-up tilt under general anaesthesia affects CBF. This study was designed to observe changes that occur in the internal carotid artery (ICA) blood flow with pneumoperitoneum and head-up position and corelate these changes with changes in cardiac output in patients undergoing laparoscopic cholecystectomy.Methods: ICA blood velocity and diameter was measured by Doppler ultrasound in 35 ASA grade I and II patients undergoing laparoscopic cholecystectomy, at four time points: awake, after anaesthesia induction, after induction of pneumoperitoneum, and after head-up tilt; and ICA blood flow was calculated. Simultaneously, heart rate, blood pressure, and end-tidal carbon dioxide (ETCO2) were recorded, and cardiac output was calculated.Results: ICA blood flow decreased upon anesthesia induction from 164 mL/minute to 151 ml/minute (p&gt;0.05). ICA blood flow increased with pneumoperitoneum (from 164 mL/minute to 179ml/minute p= 0.04). Head-up tilt resulted in decrease in ICA blood flow (from 164 mL/minute to 151ml/ minute, P = 0.09).Conclusion: ICA blood flow significantly increased after the creation of pneumoperitoneum in patients undergoing elective laparoscopic cholecystectomy under general anaesthesia. Induction of anaesthesia and head-up tilt, however, did not have any significant change in ICA blood flow. We suggest that ICA blood flow during anaesthesia is influenced by an interplay of actions of anaesthetic agents, positive pressure ventilation and patient position besides the changes in blood pressure, ETCO2 and cardiac output.

Single cell in vivo optogenetic stimulation by two-photon excitation fluorescence transfer

Optogenetic manipulation with single-cell resolution can be achieved by two-photon excitation. However, this frequently requires relatively high laser powers. Here, we developed a novel strategy that can improve the efficiency of current two-photon stimulation technologies by positioning fluorescent proteins or small fluorescent molecules with high two-photon cross-sections in the vicinity of opsins. This generates a highly localized source of endogenous single-photon illumination that can be tailored to match the optimal opsin absorbance. Through neuronal and vascular stimulation in the live mouse brain, we demonstrate the utility of this technique to achieve efficient opsin stimulation, without loss of cellular resolution. We also provide a theoretical framework for understanding the potential advantages and constrains of this methodology, with directions for future improvements. Altogether, this fluorescence transfer illumination method opens new possibilities for experiments difficult to implement in the live brain such as all-opticalneural interrogation and control of regional cerebral blood flow.

Neural control of cerebral blood flow: scientific basis of scalp acupuncture in treating brain diseases.

Scalp acupuncture (SA), as a modern acupuncture therapy in the treatment of brain diseases, especially for acute ischemic strokes, has accumulated a wealth of experience and tons of success cases, but the current hypothesized mechanisms of SA therapy still seem to lack significant scientific validity, which may not be conducive to its ultimate integration into mainstream medicine. This review explores a novel perspective about the mechanisms of SA in treating brain diseases based on its effects on cerebral blood flow (CBF). To date, abundant evidence has shown that CBF is significantly increased by stimulating specific SA points, areas or nerves innervating the scalp, which parallels the instant or long-term improvement of symptoms of brain diseases. Over time, the neural pathways that improve CBF by stimulating the trigeminal, the facial, and the cervical nerves have also been gradually revealed. In addition, the presence of the core SA points or areas frequently used for brain diseases can be rationally explained by the characteristics of nerve distribution, including nerve overlap or convergence in certain parts of the scalp. But such characteristics also suggest that the role of these SA points or areas is relatively specific and not due to a direct correspondence between the current hypothesized SA points, areas and the functional zones of the cerebral cortex. The above evidence chain indicates that the efficacy of SA in treating brain diseases, especially ischemic strokes, is mostly achieved by stimulating the scalp nerves, especially the trigeminal nerve to improve CBF. Of course, the mechanisms of SA in treating various brain diseases might be multifaceted. However, the authors believe that understanding the neural regulation of SA on CBF not only captures the main aspects of the mechanisms of SA therapy, but also facilitates the elucidation of other mechanisms, which may be of greater significance to further its clinical applications.

The Effect of Supine Cycling and Progressive Lower Body Negative Pressure on Cerebral Blood Velocity Responses.

Moderate-intensity aerobic exercise increases cerebral blood velocity (CBv) primarily due to hyperpnea-induced vasodilation; however, the integrative control of cerebral blood flow (CBF) allows other factors to contribute to vasodilation. Lower body negative pressure (LBNP) can reduce CBv, the exact LBNP-intensity required to blunt the aforementioned exercise-induced CBv response is unknown. This could hold utility for concussion recovery, allowing individuals to exercise at higher-intensities without symptom exacerbation. Thirty-two healthy adults (age: 20-33 years; 19 females) completed a stepwise maximal-exercise test to determine each participant's wattage associated with their exercise-induced maximal CBv increase. During the second visit, participants completed moderate-intensity exercise at their determined threshold, while progressive LBNP was applied at 0, -20, -40, -60, -70, -80, and ~88 Torr. Bilateral middle cerebral artery blood velocities (MCAv), mean arterial pressure (MAP), heart rate, respiratory rate, and end-tidal carbon dioxide levels were measured continuously. Two-way analysis of variance with effect sizes compared between sexes and stages. Compared to resting-supine baseline, averaged MCAv was elevated during 0 and -20 Torr LBNP (q-value>7.73; p<0.001); no differences were noted between baseline and -40 to -70 Torr (q-value<|4.24|; p>0.262). Differences were present between females and males for absolute MCAv measures (q-value>11.2; p<0.001), but not when normalized to baseline (q-value<0.03; p>0.951). Supine cycling-elicited increases in MCAv were blunted during the application of LBNP ranging from -40 to -70 Torr. The blunted CBv response demonstrates the potential benefit of allowing individuals to aerobically train (moderate-intensity supine cycling with LBNP) without exacerbating symptoms during concussion recovery.

Cerebrovascular pressure reactivity and brain tissue oxygen monitoring provide complementary information regarding the lower and upper limits of cerebral blood flow control in traumatic brain injury: a CAnadian High Resolution-TBI (CAHR-TBI) cohort study

BackgroundBrain tissue oxygen tension (PbtO2) and cerebrovascular pressure reactivity monitoring have emerged as potential modalities to individualize care in moderate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO2 and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity.MethodsA retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pressure (ICP), arterial blood pressure (ABP), and PbtO2 monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx).ResultsA total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact.ConclusionsIn this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO2 seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF.

DAILY EXERCISE DOES NOT ALTER CEREBRAL BLOOD FLOW REGULATION DURING TILT IN OLDER ADULTS AFTER TWO WEEKS OF BEDREST

Abstract Bedrest is associated with cardiovascular and cerebrovascular changes that are linked to a greater prevalence of orthostatic intolerance; however, much of what we know from bedrest trials comes from young adults. How older adults respond to extended periods of activity restriction is not well understood. The current work tested the hypothesis that impaired control of cerebral blood flow in older adults following bedrest could be attenuated by regular exercise. Twenty-two older adults (55-65 years, 11 women) participated in a randomized controlled trial involving 14 days of continuous 6-degree head-down bedrest. The cohort was randomized to an exercise intervention (EX), involving daily aerobic, high-intensity interval, and resistance training, or a control group (CON), involving passive manual therapy. Cerebral blood flow velocity, cardiac output, and arterial blood pressure were measured continuously during a passive 80-degree head-up tilt protocol for up to 15 minutes. Responses in the cerebral and peripheral vascular beds were quantified by vascular resistance (cerebral: resistance area product (RAP); peripheral: total peripheral resistance (TPR)). Following bedrest, both supine RAP and TPR were elevated (p&amp;lt; 0.01), with no effect of exercise training. In addition, the number of participants who could not complete 15 minutes of tilt increased from 3 to 15 (8 EX, 7 CON). In these non-finishers, RAP dropped ~20% and TPR dropped ~15% during the final 2 minutes of tilt, with no difference between groups. These data suggest that multimodal exercise training is insufficient to prevent changes in cardiovascular and cerebrovascular regulation in older adults observed during 14-day bedrest.

The role of the autonomic nervous system in cerebral blood flow regulation in dementia: A review.

In this review we will examine the role of the autonomic nervous system in the control of cerebral blood flow (CBF) in dementia. Worldwide, 55 million people currently live with dementia, and this figure will increase as the global population ages. Understanding the changes in vascular physiology in dementia could pave the way for novel therapeutic approaches. Reductions in CBF have been demonstrated in multiple dementia sub-types, in addition to increased cerebrovascular resistance and reduced vasoreactivity. Cerebral autoregulation (CA) is a key mechanism for the maintenance of cerebral perfusion, but remains largely intact in cognitive disorders, despite reductions in global and regional CBF. However, the tight coupling between neuronal activity and CBF (neurovascular coupling - NVC) is lost in dementia, which may be a key driver of cognitive dysfunction. Despite numerous studies investigating disturbances in the control of CBF in dementia, less is known about the specific mechanisms responsible for the observed changes. Disturbances could be related to one of a number of pathways and mechanisms including disruption of the autonomic component. In this review we will explore clinical and animal studies, which specifically investigated the autonomic component of CBF control in dementia, drawing on the clinical implications and potential for novel biomarker and therapeutic targets.

Effect of Hyperinsulinemia on Cerebral Autoregulation and Myogenic Control of Cerebral Blood Flow in Healthy Young Adults

ObjectiveHyperinsulinemia has marked vasodilatory effects within the skeletal muscle vasculature in healthy young adults; however, the magnitude of insulin‐stimulated cerebrovascular vasodilation is less clear. Differences between circulations may be due to a greater importance of the cerebral circulation to maintain a constant level of blood flow (i.e., cerebral autoregulation) during hyperinsulinemia. We hypothesized cerebral autoregulation would increase during hyperinsulinemia. Autoregulatory mechanisms, such as myogenic control, play important roles in mediating cerebral vasomotor responses. Thus, we further sought to examine the contribution of the myogenic mechanism to the control of cerebral blood flow during hyperinsulinemia.MethodsMiddle cerebral artery blood velocity (MCAv) and femoral artery blood velocity (FAV) were measured with Doppler ultrasound and femoral artery blood flow (FBF) was calculated in 17 healthy adults (11M/6F, 28±2 yrs, 24±1 kg/m2) at baseline and following a hyperinsulinemic (40 mU/m2body surface area/min), euglycemic infusion. Finger plethysmography was used to assess mean blood pressure (MBP). Normalized transfer function gain between changes in MBP and MCAv were estimated in the 0.02‐0.07 Hz (very low frequency, VLF) and 0.07–0.20 Hz (low frequency, LF) ranges using the Welch method. Interactions between MBP and MCAv or FAV were determined using cross‐correlation analyses.ResultsIntravenous insulin infusion increased plasma insulin concentrations (6±1 to 50±3 μIU/mL, p&lt;0.01) with blood glucose maintained at baseline levels (p=0.33). There was a significant increase in FBF (121±15 to 151±19 mL/min, p=0.03) during hyperinsulinemia, with no change in MCAv (61±4 to 59±4 cm/s, p=0.28) or MBP (86±2 to 89±2 mmHg, p=0.10). There was no effect of hyperinsulinemia on normalized transfer function gain in the VLF (p=0.25) or LF ranges (p=0.46). Hyperinsulinemia had no effect on the association between MBP and MCAv (p=0.15) or FAV (p=0.82).ConclusionsHyperinsulinemia in healthy young adults elicits peripheral vasodilation, but no change in MCAv. Contrary to our hypothesis, the sensitivity of the cerebrovascular circulation to changes in MBP (i.e., cerebral autoregulation) is not altered during systemic hyperinsulinemia in healthy adults. Furthermore, the contribution of the myogenic mechanism to the control of blood flow in the peripheral and cerebral circulations is unaffected by hyperinsulinemia. Whether these results translate to disease states (e.g., diabetes) and the implications for cerebrovascular health warrant further exploration.

Cerebrovascular Carbon Dioxide Reactivity with Hyperoxia and Hypoxia in Humans with Treated Hypertension

Hypertension increases the risk of cerebrovascular diseases such as stroke and dementia, but the underlying mechanisms are currently unclear. While chronic hypertension can lead to anatomical and functional adaptations within the cerebral circulation, its effect on cerebral blood flow (CBF) control remains poorly understood. We tested the hypothesis that the CBF responses to CO2 with either high or low oxygen levels are impaired in treated hypertensive patients compared to normotensive aged‐matched controls.In 14 treated hypertensive patients (age: 68±5 years, mean±SD) and 8 normotensive age‐matched controls (age: 66±6 years), we assessed cardiorespiratory and cerebrovascular variables at rest, during voluntary hyperventilation (partial pressure of end‐tidal CO2 [PETCO2] ~25 mmHg), and hyperoxic and hypoxic rebreathing. Using transcranial Doppler ultrasound and finger photoplethysmography, we measured beat‐to‐beat middle cerebral artery blood velocity (MCAv: index of CBF) and BP, respectively, while PETCO2 was assessed using a gas analyzer. Linear regression was used to determine the MCAv‐CO2 slope (i.e., cerebrovascular CO2 reactivity).At rest, mean BP was higher in the hypertensive patients (108±9 mmHg) compared to normotensive controls (93±10 mmHg, p=0.001), while MCAv (46.8±11.4 vs. 53.3±10.4 cm/s) and PETCO2 (41±4 vs. 42±3 mmHg) were not different between groups (p&lt;0.05). Hyperventilation‐induced hypocapnia elicited similar reductions in MCAv in the hypertensive and normotensive groups (Δ14.8±4.7 vs. Δ16.5±5.7 cm/s, p=0.484). Similarly, the MCAv‐CO2slope was not different between the hypertensive and normotensive groups during either hyperoxic rebreathing (1.53±1.05 vs. 1.98±0.56 cm/s/mmHg, p=0.320) or hypoxic rebreathing (1.94±1.04 vs. 2.21±1.13 cm/s/mmHg, p=0.815).These preliminary findings indicate that in treated hypertensive patients, the MCAv responses to hypocapnia, and hypercapnia administrated with either high or low oxygen levels, do not differ from that observed in age‐matched normotensive controls.

New Insights Into Cerebrovascular Pathophysiology and Hypertension.

Despite advances in acute management and prevention of cerebrovascular disease, stroke and vascular cognitive impairment together remain the world's leading cause of death and neurological disability. Hypertension and its consequences are associated with over 50% of ischemic and 70% of hemorrhagic strokes but despite good control of blood pressure (BP), there remains a 10% risk of recurrent cerebrovascular events, and there is no proven strategy to prevent vascular cognitive impairment. Hypertension evolves over the lifespan, from predominant sympathetically driven hypertension with elevated mean BP in early and mid-life to a late-life phenotype of increasing systolic and falling diastolic pressures, associated with increased arterial stiffness and aortic pulsatility. This pattern may partially explain both the increasing incidence of stroke in younger adults as well as late-onset, chronic cerebrovascular injury associated with concurrent systolic hypertension and historic mid-life diastolic hypertension. With increasing arterial stiffness and autonomic dysfunction, BP variability increases, independently predicting the risk of ischemic and intracerebral hemorrhage, and is potentially modifiable beyond control of mean BP. However, the interaction between hypertension and control of cerebral blood flow remains poorly understood. Cerebral small vessel disease is associated with increased pulsatility in large cerebral vessels and reduced reactivity to carbon dioxide, both of which are being targeted in early phase clinical trials. Cerebral arterial pulsatility is mainly dependent upon increased transmission of aortic pulsatility via stiff vessels to the brain, while cerebrovascular reactivity reflects endothelial dysfunction. In contrast, although cerebral autoregulation is critical to adapt cerebral tone to BP fluctuations to maintain cerebral blood flow, its role as a modifiable risk factor for cerebrovascular disease is uncertain. New insights into hypertension-associated cerebrovascular pathophysiology may provide key targets to prevent chronic cerebrovascular disease, acute events, and vascular cognitive impairment.

Autonomic arousals contribute to brain fluid pulsations during sleep

During sleep, slow waves of neuro-electrical activity engulf the human brain and aid in the consolidation of memories. Recent research suggests that these slow waves may also promote brain health by facilitating the removal of metabolic waste, possibly by orchestrating the pulsatile flow of cerebrospinal fluid (CSF) through local neural control over vascular tone. To investigate the role of slow waves in the generation of CSF pulsations, we analyzed functional MRI data obtained across the full sleep-wake cycle and during a waking respiratory task. This revealed a novel generating mechanism that relies on the autonomic regulation of cerebral vascular tone without requiring slow electrocortical activity or even sleep. Therefore, the role of CSF pulsations in brain waste clearance may, in part, depend on proper autoregulatory control of cerebral blood flow.

Importance of Pericytes in the Pathophysiology of Cerebral Ischemia.

Various cell types contribute to pathological changes observed in the brain following cerebral ischemia. Pericytes, as a component of neurovascular unit (NVU) and blood brain barrier (BBB), play a key role for cerebral blood flow control and regulation of vessel permeability. It was shown that pericytes can control cerebral blood flow at the level of capillaries, by their contractile property. Their role in BBB development and maintenance are crucial for guidance of brain vessel development, new vessel formation and stabilization of the newly formed vessels. Additionally, they can contribute to inflammation in response to inflammatory stimuli and can differentiate to various cell types by their multipotent differentiation properties. This cell type which is intimately associated with cerebral circulation also plays important roles during cerebral ischemia. Here, we review the properties and physiological functions of pericytes, how these functions change during ischemia to affect the pathophysiology of ischemic stroke and post stroke cognitive impairment. Pericytes are a neglected cell type and they are not unambiguously characterized which in turn led to contradictory findings in the literature. Clear characterization of pericytes by current methods will help better understanding of their role in the pathophysiology of stroke. With the information gained from these efforts it will be possible to develop pericyte specific therapeutic targets and achieve important breakthroughs in clinical recovery in ischemic stroke treatment.