Cerebrovascular compliance within the rigid confines of the skull

© 2018 Zamir, Moir, Klassen, Balestrini and Shoemaker. Pulsatile blood flow is generally mediated by the compliance of blood vessels whereby they distend locally and momentarily to accommodate the passage of the pressure wave. This freedom of the blood vessels to exercise their compliance may be suppressed within the confines of the rigid skull. The effect of this on the mechanics of pulsatile blood flow within the cerebral circulation is not known, and the situation is compounded by experimental access difficulties. We present an approach which we have developed to overcome these difficulties in a study of the mechanics of pulsatile cerebral blood flow. The main finding is that while the innate compliance of cerebral vessels is indeed suppressed within the confines of the skull, this is compensated somewhat by compliance provided by other extravascular elements within the skull. The net result is what we have termed intracranial compliance, which we argue is more pertinent to the mechanics of pulsatile cerebral blood flow than is intracranial pressure

Regulation of cerebrovascular compliance compared with forearm vascular compliance in humans:a pharmacological study

Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance (C(i)) was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (experiment 1, phentolamine; 10 adults), cholinergic blockade (experiment 2, glycopyrrolate; 9 adults), and myogenic blockade (experiment 3, nicardipine; 14 adults). In experiment 1, phentolamine increased C(i) similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular C(i) (72 ± 61%) and forearm vascular C(i) (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased C(i) but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; P = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm. NEW & NOTEWORTHY Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain

Impaired dynamic cerebral autoregulation in trained breath-hold divers

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation. The current investigation tested the hypothesis that breathhold diving impairs dynamic autoregulation to a transient hypotensive stimulus. Seventeen BHD (3 women, 11 ± 9 yr of diving) and 15 healthy controls (2 women) completed two or three repeated sit-tostand trials during spontaneous breathing and poikilocapnic conditions. Heart rate (HR), finger arterial blood pressure (BP), and cerebral blood flow velocity (BFV) from the right middle cerebral artery were measured continuously with three-lead electrocardiography, finger photoplethysmography, and transcranial Doppler ultrasonography, respectively. End-tidal carbon dioxide partial pressure was measured with a gas analyzer. Offline, an index of cerebrovascular resistance (CVRi) was calculated as the quotient of mean BP and BFV. The rate of the drop in CVRi relative to the change in BP provided the rate of regulation [RoR; (δCVRi/δT)/δBP]. The BHD demonstrated slower RoR than controls (P ≤ 0.001, d = 1.4). Underlying the reduced RoR in BHD was a longer time to reach nadir CVRi compared with controls (P = 0.004, d = 1.1). In concert with the longer CVRi response, the time to reach peak BFV following standing was longer in BHD than controls (P = 0.01, d = 0.9). The data suggest impaired dynamic autoregulatory mechanisms to hypotension in BHD. NEW & NOTEWORTHY Impairments in dynamic cerebral autoregulation to hypotension are associated with breath-hold diving. Although weakened autoregulation was observed acutely in this group during apneic stress, we are the first to report on chronic adaptations in cerebral autoregulation. Impaired vasomotor responses underlie the reduced rate of regulation, wherein breath-hold divers demonstrate a prolonged dilatory response to transient hypotension. The slower cerebral vasodilation produces a longer perturbation in cerebral blood flow velocity, increasing the risk of cerebral ischemia

Rapid changes in vascular compliance contribute to cerebrovascular adjustments during transient reductions in blood pressure in young, healthy adults

Copyright © 2020 the American Physiological Society Rapid changes in vascular compliance contribute to cerebrovascular adjustments during transient reductions in blood pressure in young, healthy adults. J Appl Physiol 129: 27–35, 2020. First published May 28, 2020; doi:10.1152/japplphysiol.00272.2020.—Characterization of dynamic cerebral autoregulation has focused primarily on adjustments in cerebrovascular resistance in response to blood pressure (BP) alterations. However, the role of vascular compliance in dynamic autoregulatory processes remains elusive. The present study examined changes in cerebrovascular compliance and resistance during standing-induced transient BP reductions in nine young, healthy adults (3 women). Brachial artery BP (Finometer) and middle cerebral artery blood velocity (BV; Multigon) waveforms were collected. Beginning 20 beats before standing and continuing 40 beats after standing, individual BP and BV waveforms of every second heartbeat were extracted and input into a four-element modified Windkessel model to calculate indexes of cerebrovascular resistance (Ri) and compliance (Ci). Standing elicited a transient reduction in mean BP of 20 ± 9 mmHg. In all participants, a large increase in Ci (165 ± 84%; P \u3c 0.001 vs. seated baseline) occurred 2 ± 2 beats following standing. Reductions in Ri occurred 11 ± 3 beats after standing (Ci vs. Ri delay: P \u3c 0.001). The increase in Ci contributed to maintained systolic BV before the decrease in Ri. The present results demonstrate rapid, large but transient increases in Ci that precede reductions in Ri, in response to standing-induced reductions in BP. Therefore, Ci represents a discreet component of cerebrovascular responses during acute decreases in BP and, consequently, dynamic autoregulation. NEW & NOTEWORTHY Historically, dynamic cerebral autoregulation has been characterized by adjustments in cerebrovascular resistance following systematic changes in blood pressure. However, with the use of Windkessel modeling approaches, this study revealed rapid and large increases in cerebrovascular compliance that preceded reductions in cerebrovascular resistance following standing-induced blood pressure reductions. Importantly, the rapid cerebrovascular compliance response contributed to preservation of systolic blood velocity during the transient hypotensive phase. These results broaden our understanding of dynamic cerebral autoregulation

Heterogeneous baroreflex control of sympathetic action potential subpopulations in humans

© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society Key points: Emission patterns in muscle sympathetic nerve activity stem from differently sized action potential (AP) subpopulations that express varying discharge probabilities. The mechanisms governing these firing behaviours are unclear. This study investigated the hypothesis that the arterial baroreflex exerts varying control over the different AP subpopulations. During baseline, medium APs expressed the greatest baroreflex slopes, while small and large APs exhibited weaker slopes. On going from baseline to lower body negative pressure (LBNP; simulated orthostatic stress), baroreflex slopes for some clusters of medium APs expressed the greatest increase, while slopes for large APs also increased but to a lesser degree. A subpopulation of previously silent larger APs was recruited with LBNP but these APs expressed weak baroreflex slopes. The arterial baroreflex heterogeneously regulates sympathetic AP subpopulations, exerting its strongest effect over medium APs. Weak baroreflex mechanisms govern the recruitment of latent larger AP subpopulations during orthostatic stress. Abstract: Muscle sympathetic nerve activity (MSNA) occurs primarily in bursts of action potentials (AP) with subpopulations that differ in size and discharge probabilities. The mechanisms determining these discharge patterns remain unclear. This study investigated the hypothesis that variations in AP discharge are due to subpopulation-specific baroreflex control. We employed multi-unit microneurography and a continuous wavelet analysis approach to extract sympathetic APs in 12 healthy individuals during baseline (BSL) and lower body negative pressure (LBNP; -40, -60, -80 mmHg). For each AP cluster, the baroreflex threshold slope was measured from the linear regression between AP probability (%) and diastolic blood pressure (mmHg). During BSL, the baroreflex exerted non-uniform regulation over AP subpopulations: medium-sized AP clusters expressed the greatest slopes while clusters of small and large APs expressed weaker slopes. On going from BSL to LBNP, the baroreflex slopes for each AP subpopulation were modified differently. Baroreflex slopes (%/mmHg) for some medium APs (cluster 5: −4.4 ± 4 to −9.1 ± 5) expressed the greatest increase with LBNP, while slopes for large APs (cluster 9: −1.3 ± 1 to −2.6 ± 2) also increased, but to a lesser degree. Slopes for small APs present at BSL exhibited reductions with LBNP (cluster 2: −3.9 ± 3 to −2.2 ± 3). Larger previously silent AP clusters recruited with LBNP expressed weak baroreflex regulation (cluster 14: −0.9 ± 1%/mmHg). The baroreflex exerts the strongest control over medium-sized APs. Augmenting baroreflex gain and upward resetting of discrete AP subpopulations active at BSL, as well as recruiting larger previously silent APs with weak baroreflex control, facilitates elevated MSNA during orthostatic stress

Impaired Dynamic Cerebral Autoregulation to Postural Stress Following Concussive Injuries in Adolescents

Concussions disproportionately affect adolescents and ongoing maturation places this population at increased risk for prolonged recovery and long-term impairments in neurologic functioning. Although cerebrovascular impairments are believed to contribute to concussion symptoms and recovery, little information exists regarding brain vasomotor control in adolescent concussion, particularly during rapid changes in blood pressure that demand a dynamic cerebral autoregulatory response. The current investigation tested the hypothesis that adolescent concussion is marked by impaired dynamic cerebral autoregulation (CA). Twenty-two adolescents diagnosed with a concussion (CONC; 13 females; 15 ± 1 years; 26 ± 20 days post-injury, SCAT3 symptom score = 12 ± 6) and twenty-seven healthy controls (CTRL; 15 females; 14 ± 2 years; SCAT3 symptom score = 6 ± 4) completed two repeated sit-to-stand trials. CONC were followed through their rehabilitation for up to 12-weeks. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), end-tidal carbon dioxide partial pressure (PetCO2), and heart rate (HR) were measured continuously with finger photoplethysmography (Finapres Medical Systems BV), transcranial Doppler ultrasound (Multigon Industries), a gas analyzer (AD Instruments), and a standard 3-lead electrocardiogram (ECG), respectively. Furthermore, cardiac output (CO) was provided via the Model flow algorithm and cerebrovascular resistance (CVR) was calculated. The rate of the drop in CVR relative to the change in ABP provided the rate of regulation (RoR). The drop in ABP with standing was similar between CONC and CTRL (25 ± 8 vs. 24 ± 7 mmHg; p = 0.62) although the time to ABP nadir was longer in CONC compared with CTRL (7.2 ± 1.1 vs. 6.1 ± 1.3 sec; p = 0.002). Similarly, time to CBFV nadir was longer in CONC compared with CTRL (5.9 ± 1.4 vs. 4.4 ± 2.0 sec; p = 0.003). Compared to CTRL, RoR was reduced in CONC at study entry (0.21 ± 0.06 vs. 0.16 ± 0.04 sec−1; p = 0.005). However, at the time of CONC final visit (SCAT3 symptom score = 4 ± 5), RoR improved to levels similar to CTRL (0.20 ± 0.08 vs. 0.21 ± 0.06 sec−1; p = 0.55). During sitting and standing, CONC and CTRL had similar PetCO2. The change in heart rate with standing was similar between CONC and CTRL (30 ± 6 vs. 26 ± 9 bpm; p = 0.09) although the time to peak HR was longer in CONC compared with CTRL (10.8 ± 2.5 vs. 9.4 ± 2.0 sec; p = 0.004). Furthermore, a similar increase in CO was witnessed with standing in CONC and CTRL (1.4 ± 1.6 vs. 1.7 ± 0.7 L/min; p = 0.28). Impairments in dynamic CA are evident in adolescents following a concussive injury which recover in accordance with clinical symptoms. Therefore, RoR may aid decisions regarding diagnosis, rehabilitation, and recovery of adolescent concussion

Vasodilatation by carbon dioxide and sodium nitroglycerin reduces compliance of the cerebral arteries in humans.

NEW FINDINGS: What is the central question of this study? Vascular compliance importantly contributes to the regulation of cerebral perfusion and complex mechanisms are known to influence compliance of a vascular bed: while vasodilatation mediates changes in vascular resistance, does it also affect compliance, particularly in the cerebral vasculature? What is the main finding and its importance? Cerebral vasodilatation, elicited by hypercapnia and sodium nitroglycerin administration, reduced cerebrovascular compliance by approximately 26% from baseline. This study provides new insight into mechanisms mediating cerebrovascular compliance. ABSTRACT: Changes in vascular resistance and vascular compliance contribute to the regulation of cerebral perfusion. While changes in vascular resistance are known to be mediated by vasodilatation, the mechanisms contributing to changes in vascular compliance are complex. In particular, whether vasodilatation affects compliance of the vasculature within the cranium remains unknown. Therefore, the present study examined the impact of two vasodilatation pathways on cerebrovascular compliance in humans. Fifteen young, healthy adults (26 ± 5 years, seven females) completed two protocols: (i) sublingual sodium nitroglycerin (SNG; 0.4 mg) and (ii) hypercapnia (5-6% carbon dioxide gas mixture for 4 min). Blood pressure waveforms (finger photoplethysmography) and middle cerebral artery blood velocity waveforms (transcranial Doppler ultrasound) were input into a modified Windkessel model and an index of cerebrovascular compliance (Ci) was calculated. During the SNG protocol, Ci decreased 24 ± 17% from baseline ((5.0 ± 2.3) × 10-4 cm s-1 mmHg-1 ) to minute 10 ((3.6 ± 1.2) × 10-4 cm s-1 mmHg-1 ; P = 0.009). During the hypercapnia protocol, Ci decreased 28 ± 9% from baseline ((4.4 ± 1.9) × 10-4 cm s-1 mmHg-1 ) to minute 4 ((3.1 ± 1.4) × 10-4 cm s-1 mmHg-1 ; P \u3c 0.001). Cerebral vasodilatory stimuli induced by nitric oxide and carbon dioxide mechanisms reduced compliance of the cerebral vascular bed by approximately 26% from supine baseline values

Autonomic Dysregulation in Adolescent Concussion: Characterization and Temporal Resolution of Neurological Outcomes

Although incidence is at epidemic levels, objective indicators of neurologic damage in adolescent concussion remain poorly described. Autonomic markers such as heart rate variability (HRV) have provided equivocal results; however, these predominantly are made under conditions of minimal physiologic stress. The current investigation employs postural stressors to examine underlying neurological outcomes associated with acute concussion and clinical recovery to test the hypothesis that concussion impairs dynamic autonomic adjustments in adolescents. We examined concussed adolescents (CONC; n = 35; 14 males; age 15 ± 1 yrs, range = 12–18 yrs) for up to 6 weekly visits from diagnosis. A group of age and activity level-matched non-concussed adolescents (CTRL; n = 35; 19 males; age 14 ± 2 yrs, range = 12–18 yrs) formed the reference control. HRV (root mean square of successive differences in R-R intervals (RMSSD)) and heart rate were assessed during a sit-to-stand protocol (two trials of seated posture (three minutes), followed by two minutes of standing). Measurements were taken during the last minute of sitting and standing, the ten second period following the postural stress of standing, as well as the ten second period from maximum HR. While seated, RMSSD was lower in CONC (41 ± 24 msec) compared with CTRL (60 ± 40 msec; p \u3c 0.05). 31 patients provided weekly data until clinical discharge. Compared with the first visit (43 ± 25 msec), seated RMSSD in CONC increased (51 ± 36 msec; p = 0.05) at the time of clinical discharge. Upon standing (10 seconds following postural change to standing), RMSSD was lower in CONC versus CTRL (13 ± 7 vs. 18 ± 12 msec; p \u3c 0.05). Compared with the first visit, RMSSD following the induced postural stress did not improve in CONC over the six week recovery period. Following maximal HR, CTRL had increased RMSSD versus CONC (46 ± 30 vs. 34 ± 19 msec; p \u3c 0.05). Compared with CTRL, seated HR was higher in CONC. This tachycardia effect persisted throughout the sit-to-stand protocol (78 ± 12 vs. 72 ± 12 bpm; p \u3c 0.05) and was maintained until the time of clinical discharge (79 ± 13 vs. 72 ± 12 bpm; p \u3c 0.05). In adolescent concussion, autonomic cardiac impairment is demonstrated by reduced RMSSD in the seated position and throughout the adjustment period in response to postural stress. Further, seated HR is increased following acute concussion and remains elevated by the time of clinical discharge. Seated HRV, but not HR, recovered to levels seen in the control population within three to six weeks. Thus, cardiac adjustments to modest postural stress may represent a measurable neurological impairment in adolescent acute concussion which can be objectively monitored throughout clinical recovery

An Investigation of Dynamic Cerebral Autoregulation in Adolescent Concussion.

Purpose Although cerebrovascular impairments are believed to contribute to concussion symptoms, little information exists regarding brain vasomotor control in adolescent concussion, particularly autoregulatory control that forms a fundamental response mechanism during changes in blood pressure. This research tested the hypothesis that adolescent concussion is marked by impaired dynamic cerebral autoregulation. Methods Nineteen concussed adolescents (15 ± 2 yr, 13 females) and 18 healthy controls (15 ± 2 yr, 9 females) completed two sit-to-stand trials. Brachial artery blood pressure and cerebral blood flow velocity in the right middle cerebral artery were measured continuously. Dynamic rate of regulation was calculated as the rate of change in cerebrovascular resistance relative to the change in arterial blood pressure. The concussed adolescents were followed through their rehabilitation for up to 12 wk. Results At the first visit, the concussed adolescents demonstrated reduced rate of regulation compared with the healthy controls (0.12 ± 0.04 vs 0.19 ± 0.06 s, P ≤ 0.001). At the concussed adolescents final visit, after symptom resolution, the rate of regulation improved to levels that were not different from the healthy controls (n = 9; 0.15 ± 0.08 vs 0.19 ± 0.06 s, P= 0.06). Two distinct groups were observed at the final visit with some individuals experiencing recovery of dynamic cerebral autoregulation and others showing no marked change from the initial visit. Conclusion Adolescents demonstrate an impairment in dynamic cerebral autoregulation after concussion that improves along with clinical symptoms in some individuals and remains impaired in others despite symptom resolution

Asynchronous action potential discharge in human muscle sympathetic nerve activity

© 2019 the American Physiological Society. What strategies are employed by the sympathetic system to communicate with the circulation? Muscle sympathetic nerve activity (MSNA) occurs in bursts of synchronous action potential (AP) discharge, yet whether between-burst asynchronous AP firing exists remains unknown. Using multiunit microneurography and a continuous wavelet transform to isolate APs, we studied AP synchronicity within human MSNA. Asynchronous APs were defined as those which occurred between bursts. Experiment 1 quantified AP synchronicity in eight individuals at baseline (BSL), -10 mmHg lower body negative pressure (LBNP), -40 mmHg LBNP, and end-expiratory apnea (APN). At BSL, 33 ± 12% of total AP activity was asynchronous. Asynchronous discharge was unchanged from BSL (67 ± 37 AP/min) to -10 mmHg LBNP (69 ± 33 AP/min), -40 mmHg LBNP (83 ± 68 AP/min), or APN (62 ± 39 AP/min). Across all conditions, asynchronous AP probability and frequency decreased with increasing AP size. Experiment 2 examined the impact of the ganglia on AP synchronicity by using nicotinic blockade (trimethaphan). The largest asynchronous APs were derecruited from BSL (11 ± 4 asynchronous AP clusters) to the last minute of the trimethaphan infusion with visible bursts (7 ± 2 asynchronous AP clusters). However, the 6 ± 2 smallest asynchronous AP clusters could not be blocked by trimethaphan and persisted to fire 100 ± 0% asynchronously without forming bursts. Nonnicotinic ganglionic mechanisms affect some, but not all, asynchronous activity. The fundamental behavior of human MSNA contains between- burst asynchronous AP discharge, which accounts for a considerable amount of BSL activity. NEW & NOTEWORTHY Historically, sympathetic nerve activity destined for the blood vessels supplying skeletal muscle (MSNA) has been characterized by spontaneous bursts formed by synchronous action potential (AP) discharge. However, this study found a considerable amount (~30% during baseline) of sympathetic AP discharge to fire asynchronously between bursts of human MSNA. Trimethaphan infusion revealed that nonnicotinic ganglionic mechanisms contribute to some, but not all, asynchronous discharge. Asynchronous sympathetic AP discharge represents a fundamental behavior of MSNA