Assessing changes in regional cerebral hemodynamics in adults with a high-density full-head coverage time-resolved near-infrared spectroscopy device.

Significance: Cerebral oximeters have the potential to detect abnormal cerebral blood oxygenation to allow for early intervention. However, current commercial systems have two major limitations: (1) spatial coverage of only the frontal region, assuming that surgery-related hemodynamic effects are global and (2) susceptibility to extracerebral signal contamination inherent to continuous-wave near-infrared spectroscopy (NIRS). Aim: This work aimed to assess the feasibility of a high-density, time-resolved (tr) NIRS device (Kernel Flow) to monitor regional oxygenation changes across the cerebral cortex during surgery. Approach: The Flow system was assessed using two protocols. First, digital carotid compression was applied to healthy volunteers to cause a rapid oxygenation decrease across the ipsilateral hemisphere without affecting the contralateral side. Next, the system was used on patients undergoing shoulder surgery to provide continuous monitoring of cerebral oxygenation. In both protocols, the improved depth sensitivity of trNIRS was investigated by applying moment analysis. A dynamic wavelet filtering approach was also developed to remove observed temperature-induced signal drifts. Results: In the first protocol (28±5 years; five females, five males), hair significantly impacted regional sensitivity; however, the enhanced depth sensitivity of trNIRS was able to separate brain and scalp responses in the frontal region. Regional sensitivity was improved in the clinical study given the age-related reduction in hair density of the patients (65±15 years; 14 females, 13 males). In five patients who received phenylephrine to treat hypotension, different scalp and brain oxygenation responses were apparent, although no regional differences were observed. Conclusions: The Kernel Flow has promise as an intraoperative neuromonitoring device. Although regional sensitivity was affected by hair color and density, enhanced depth sensitivity of trNIRS was able to resolve differences in scalp and brain oxygenation responses in both protocols.

Characterization of cerebral macro- and microvascular hemodynamics during transient hypotension.

The aim of the current study was to establish the interplay between blood flow patterns within a large cerebral artery and a downstream microvascular segment under conditions of transiently reduced mean arterial pressure (MAP). We report data from nine young, healthy participants (5 women; 26 ± 4 yr) acquired during a 15-s bout of sudden-onset lower body negative pressure (LBNP; -80 mmHg). Simultaneous changes in microvascular cerebral blood flow (CBF) and middle cerebral artery blood velocity (MCAvmean) were captured using diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound (TCD), respectively. Brachial blood pressure (finger photoplethysmography) and TCD waveforms were extracted at baseline and during the nadir blood pressure (BP) response to LBNP and analyzed using a modified Windkessel model to calculate indices of cerebrovascular resistance (Ri) and compliance (Ci). Compared with baseline, rapid-onset LBNP decreased MAP by 22 ± 16% and Ri by 14 ± 10% (both P ≤ 0.03). Ci increased (322 ± 298%; P < 0.01) but MCAvmean (-8 ± 16%; P = 0.09) and CBF (-2 ± 3%; P = 0.29) were preserved. The results provide evidence that changes in both vascular resistance and compliance preserve CBF, as indexed by no significant changes in MCAvmean or DCS microvascular flow, during transient hypotension.NEW & NOTEWORTHY To characterize the relationship between cerebrovascular patterns within the large middle cerebral artery (MCA) and a downstream microvascular segment, we used a novel combination of transcranial Doppler ultrasound of the MCA and optical monitoring of a downstream microvascular segment, respectively, under conditions of transiently reduced mean arterial pressure (i.e., lower body negative pressure, -80 mmHg). A rapid increase in vessel compliance accompanied the maintenance of MCA blood velocity and downstream microvascular flow.

Using depth-enhanced diffuse correlation spectroscopy and near-infrared spectroscopy to isolate cerebral hemodynamics during transient hypotension.

Significance: Combining diffuse correlation spectroscopy (DCS) and near-infrared spectroscopy (NIRS) permits simultaneous monitoring of multiple cerebral hemodynamic parameters related to cerebral autoregulation; however, interpreting these optical measurements can be confounded by signal contamination from extracerebral tissue. Aim: We aimed to evaluate extracerebral signal contamination in NIRS/DCS data acquired during transient hypotension and assess suitable means of separating scalp and brain signals. Approach: A hybrid time-resolved NIRS/multidistance DCS system was used to simultaneously acquire cerebral oxygenation and blood flow data during transient orthostatic hypotension induced by rapid-onset lower body negative pressure (LBNP) in nine young, healthy adults. Changes in microvascular flow were verified against changes in middle cerebral artery velocity (MCAv) measured by transcranial Doppler ultrasound. Results: LBNP significantly decreased arterial blood pressure (-18%±14%), scalp blood flow (>30%), and scalp tissue oxygenation (all p≤0.04 versus baseline). However, implementing depth-sensitive techniques for both DCS and time-resolved NIRS indicated that LBNP did not significantly alter microvascular cerebral blood flow and oxygenation relative to their baseline values (all p≥0.14). In agreement, there was no significant reduction in MCAv (8%±16%; p=0.09). Conclusion: Transient hypotension caused significantly larger blood flow and oxygenation changes in the extracerebral tissue compared to the brain. We demonstrate the importance of accounting for extracerebral signal contamination within optical measures of cerebral hemodynamics during physiological paradigms designed to test cerebral autoregulation.

Assessing the Sensitivity of Multi-Distance Hyperspectral NIRS to Changes in the Oxidation State of Cytochrome C Oxidase in the Brain.

Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO2) are frequently used during vascular and cardiac surgeries as a non-invasive means of assessing brain health; however, signal contamination from extracerebral tissues remains a concern. As an alternative, hyperspectral (hs)NIRS can be used to measure changes in the oxidation state of cytochrome c oxidase (ΔoxCCO), which provides greater sensitivity to the brain given its higher mitochondrial concentration versus the scalp. The purpose of this study was to evaluate the depth sensitivity of the oxCCO signal to changes occurring in the brain and extracerebral tissue components. The oxCCO assessment was conducted using multi-distance hsNIRS (source-detector separations = 1 and 3 cm), and metabolic changes were compared to changes in StO2. Ten participants were monitored using an in-house system combining hsNIRS and diffuse correlation spectroscopy (DCS). Data were acquired during carotid compression (CC) to reduce blood flow and hypercapnia to increase flow. Reducing blood flow by CC resulted in a significant decrease in oxCCO measured at rSD = 3 cm but not at 1 cm. In contrast, significant changes in StO2 were found at both distances. Hypercapnia caused significant increases in StO2 and oxCCO at rSD = 3 cm, but not at 1 cm. Extracerebral contamination resulted in elevated StO2 but not oxCCO after hypercapnia, which was significantly reduced by applying regression analysis. This study demonstrated that oxCCO was less sensitive to extracerebral signals than StO2.

Assessing the relationship between the cerebral metabolic rate of oxygen and the oxidation state of cytochrome-c-oxidase.

Significance: Hyperspectral near-infrared spectroscopy (hsNIRS) combined with diffuse correlation spectroscopy (DCS) provides a noninvasive approach for monitoring cerebral blood flow (CBF), the cerebral metabolic rate of oxygen ( CMRO 2 ) and the oxidation state of cytochrome-c-oxidase (oxCCO). CMRO 2 is calculated by combining tissue oxygen saturation ( S t O 2 ) with CBF, whereas oxCCO can be measured directly by hsNIRS. Although both reflect oxygen metabolism, a direct comparison has yet to be studied. Aim: We aim to investigate the relationship between CMRO 2 and oxCCO during periods of restricted oxygen delivery and lower metabolic demand. Approach: A hybrid hsNIRS/DCS system was used to measure hemodynamic and metabolic responses in piglets exposed to cerebral ischemia and anesthetic-induced reductions in brain activity. Results: Although a linear relationship was observed between CMRO 2 and oxCCO during ischemia, both exhibited a nonlinear relationship with respect to CBF. In contrast, linear correlation was sufficient to characterize the relationships between CMRO 2 and CBF and between the two metabolic markers during reduced metabolic demand. Conclusions: The observed relationship between CMRO 2 and oxCCO during periods of restricted oxygen delivery and lower metabolic demand indicates that the two metabolic markers are strongly correlated.

ETB receptor-mediated vasodilation is regulated by estradiol in young women.

The endothelin-B (ETB) receptor is a key regulator of vascular endothelial function in women. We have previously shown that the ETB receptor mediates vasodilation in young women, an effect that is lost after menopause. However, the direct impact of changes in estradiol (E2) on ETB receptor function in women remains unclear. Therefore, the purpose of this study was to test the hypothesis that E2 exposure modulates ETB receptor-mediated dilation in young women. Fifteen young women (24 ± 4 yr, 24 ± 3 kg/m2) completed the study. Endogenous sex hormone production was suppressed with daily administration of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) for 10 days; E2 (0.1 mg/day, Vivelle-Dot patch) was added back on days 4-10. We measured vasodilation in the cutaneous microcirculation (microvascular endothelial function) via local heating (42°C) on day 4 (GnRHant) and day 10 (GnRHant + E2) using laser Doppler flowmetry coupled with intradermal microdialysis during perfusions of lactated Ringer's (control) and ETB receptor antagonist (BQ-788, 300 nM). During GnRHant, vasodilatory responses to local heating were enhanced with ETB receptor blockade (control: 83 ± 9 vs. BQ-788: 90 ± 5%CVCmax, P = 0.004). E2 administration improved vasodilation in the control site (GnRHant: 83 ± 9 vs. GnRHant + E2: 89 ± 8%CVCmax, P = 0.036). Furthermore, cutaneous vasodilatory responses during ETB receptor blockade were blunted after E2 administration (control: 89 ± 8 vs. BQ-788: 84 ± 8%CVCmax, P = 0.047). These data demonstrate that ovarian hormones, specifically E2, modulate ETB receptor function and contribute to the regulation of microvascular endothelial function in young women.NEW & NOTEWORTHY The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.

Altered endothelial ETB receptor expression in postmenopausal women.

The endothelin system plays an important role in mediating vascular function. The endothelin-B receptor (ETBR) on endothelial cells mediates vasodilation via nitric oxide production. The vasodilatory effect of the ETBR is lost following menopause and may contribute to impaired vascular endothelial function in postmenopausal women (PMW). However, it is unclear if these functional changes are due to changes in ETBR expression on the endothelium. Therefore, the purpose of this study was to test the hypothesis that endothelial cell ETBR expression is lower in PMW compared with young women (YW). Primary endothelial cells were harvested from the antecubital vein of healthy PMW (n = 15, 60 ± 6 yr) and YW (n = 15, 22 ± 2 yr). Cells were identified as endothelial cells by staining for vascular endothelial cadherin, and nuclear integrity was assessed using 4',6-diamidino-2-phenylindole (DAPI). Within those cells, ETBR was quantified using immunocytochemistry; fluorescence intensity was measured in 30 cells and averaged for each participant. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Endothelial cell ETBR expression was lower in PMW [0.46 ± 0.11 arbitrary units (AU)] compared with YW (0.58 ± 0.14 AU; P = 0.02). Furthermore, significant correlations between ETBR expression and FMD (r = 0.47, P < 0.01), total cholesterol (r = -0.38, P = 0.04), and LDL cholesterol (r = -0.39, P = 0.03) were observed. These data demonstrate that endothelial cell ETBR expression is attenuated in PMW. These novel findings provide additional insight into the mechanisms underlying vascular endothelial dysfunction in PMW.NEW & NOTEWORTHY Our study provides novel data demonstrating attenuated endothelial ETBR expression in postmenopausal women. Furthermore, our data extend current knowledge by demonstrating a positive relation between ETBR expression and brachial artery flow-mediated dilation. These findings provide additional mechanistic insight into vascular endothelial dysfunction in postmenopausal women.

Acute exercise-related cognitive effects are not attributable to changes in end-tidal CO2 or cerebral blood velocity.

PURPOSE: Cognition, cerebral blood flow (CBF) and its major regulator (i.e., arterial CO2), increase with submaximal exercise and decline with severe exercise. These responses may depend on fitness. We investigated whether exercise-related changes in cognition are mediated in part by concomitant changes in CBF and CO2, in ten active (26 ± 3 years) and ten inactive (24 ± 6 years) healthy adults. METHODS: Participants completed two randomised sessions; exercise and a resting CO2-control-wherein end-tidal CO2 (PETCO2) was matched between sessions and clamped across conditions at exercise-associated increases (+ 3 mmHg) and hypercapnia (+ 10 mmHg). Exercise comprised inclined walking at submaximal and severe intensities. CBF was indexed using right middle cerebral artery blood velocity (MCAv). Cognition (visuomotor, switching and inhibitory response time) was measured before, during, and after exercise. RESULTS: MCAv and its inverted-U response to exercise were comparable between groups, whereas visuomotor performance improved during submaximal exercise in the active group only (p = 0.046). Submaximal, but not severe (p = 0.33), exercise increased MCAv (p ≤ 0.03). Hypercapnia increased MCAv during the CO2-control (27 ± 12%) and during submaximal exercise (39 ± 17%; p < 0.01). Despite the acute increases in MCAv, cognition was impaired during both levels of increased PETCO2 (3-6%; p ≤ 0.04), regardless of session. Overall, resting or exercise-related changes in PETCO2 and MCAv did not associate with changes in cognition (r ≤ 0.29 ± 0.34). Fitness ([Formula: see text]O2MAX) was associated with baseline cognition (r ≥ 0.50). CONCLUSION: Acute increases in PETCO2 and MCAv were not associated with improved cognition. In fact, cognitive performance was impaired at both levels of increased PETCO2, regardless of session. Finally, fitter people were found to have better cognition.

Swimming-related effects on cerebrovascular and cognitive function.

Both acute and regular exercise influence vascular and cognitive function. Upright aquatic exercise increases mean middle cerebral artery blood velocity (MCAvmean ) and has been suggested as favorable for cerebrovascular adaptations. However, MCAvmean has not been reported during swimming. Thus, we examined the cerebrovascular and cognitive effects of swimming. Ten land-based athletes (22 ± 5 years) and eight swimmers (19 ± 1 years) completed three cognitive tasks and four conditions that were used to independently and collectively delineate the swimming-related factors (i.e., posture, immersion, CO2 retention [end-tidal CO2 ; PETCO2 ], and motor involvement). Measurements of MCAvmean and PETCO2 were taken throughout each condition. Prone posture increased MCAvmean by 11% (P < 0.01 vs. upright land). Water immersion independently increased MCAvmean when upright (12%; P < 0.01) but not prone (P = 0.76). The consequent rise in PETCO2 during head-out, breast-stroke swimming (50% heart rate range) independently increased MCAvmean by 14% (P < 0.01), while the motor involvement of swimming per se did not significantly change MCAvmean (P = 0.32). While accounting for sex, swimmers had ~17% lower MCAvmean during all rest conditions (P ≤ 0.05). However, in a subset of participants, both groups had similar internal carotid artery diameters (P = 0.99) and velocities (P = 0.97). Water immersion per se did not alter cognition (P ≥ 0.15), but 20 min of moderate-intensity swimming improved visuomotor performance by 4% (P = 0.03), regardless of athlete group (P = 0.12). In conclusion, breast-stroke swimming increased MCAvmean mostly due to postural and PETCO2 effects, with minimal contributions from water immersion or motor activity. Lastly, swimming improved cognitive functioning acutely, regardless of athlete group. Future research should explore the chronic effects of swimming on cerebrovascular function and cognition, particularly in aging.

Cerebrovascular regulation is not blunted during mental stress.

NEW FINDINGS: What is the central question of the study? What are the effects of acute mental stress on the mechanisms regulating cerebral blood flow? What is the main finding and its importance? The major new findings are as follows: (i) high mental stress and hypercapnia had an interactive effect on mean middle cerebral artery blood velocity; (ii) high mental stress altered the regulation of cerebral blood flow; (iii) the increased cerebrovascular hypercapnic reactivity was not driven by changes in mean arterial pressure alone; and (iv) this increased perfusion with mental stress appeared not to be justified functionally by an increase in oxygen demand (as determined by near-infrared spectroscopy-derived measures). ABSTRACT: In this study, we examined the effects of acute mental stress on cerebrovascular function. Sixteen participants (aged 23 ± 4 years; five female) were exposed to low and high mental stress using simple arithmetic (counting backwards from 1000) and more complex arithmetic (serial subtraction of 13 from a rapidly changing four-digit number), respectively. During consecutive conditions of baseline, low stress and high stress, end-tidal partial pressure of CO2 ( PET,CO2 ) was recorded at normocapnia (37 ± 3 mmHg) and clamped at two elevated levels (P < 0.01): 41 ± 1 and 46 ± 1 mmHg. Mean right middle cerebral artery blood velocity (MCAvmean ; transcranial Doppler ultrasound), right prefrontal cortex haemodynamics (near-infrared spectroscopy) and mean arterial blood pressure (MAP; finger photoplethysmography) were measured continuously. Cerebrovascular hypercapnic reactivity (ΔMCAvmean /Δ PET,CO2 ), cerebrovascular conductance (CVC; MCAvmean /MAP), CVC CO2 reactivity (ΔCVC/Δ PET,CO2 ) and total peripheral resistance (MAP/cardiac output) were calculated. Acute high mental stress increased MCAvmean by 7 ± 7%, and more so at higher PET,CO2 (32 ± 10%; interaction, P = 0.03), illustrating increased sensitivity to CO2 (i.e. its major regulator). High mental stress also increased MAP (17 ± 9%; P ≤ 0.01), coinciding with increased near-infrared spectroscopy-derived prefrontal haemoglobin volume and saturation measures. High mental stress elevated both cerebrovascular hypercapnic and conductance reactivities (main effect of stress, P ≤ 0.04). These findings indicate that the cerebrovascular response to acute high mental stress results in a coordinated regulation between multiple processes.

Reactivity of larger intracranial arteries using 7 T MRI in young adults.

The larger intracranial conduit vessels contribute to the total cerebral vascular resistance, and understanding their vasoreactivity to physiological stimuli is required when attempting to understand regional brain perfusion. Reactivity of the larger cerebral conduit arteries remains understudied due to a need for improved imaging methods to simultaneously assess these vessels in a single stimulus. We characterized reactivity of basal intracranial conduit arteries (basilar, right and left posterior, middle and anterior cerebral arteries) and the right and left internal carotid arteries, to manipulations in end-tidal CO2 (PetCO2). Cross-sectional area changes (%CSA) were evaluated from high-resolution (0.5 mm isotropic) images collected at 7 T using a T1-weighted 3D SPACE pulse sequence, providing high contrast between vessel lumen and surrounding tissue. Cerebrovascular reactivity was calculated as %CSA/ΔPetCO2 in eight healthy individuals (18-23 years) during normocapnia (41 ± 4 mmHg), hypercapnia (48 ± 4 mmHg; breathing 5% CO2, balance oxygen), and hypocapnia (31 ± 8 mmHg; via hyperventilation). Reactivity to hypercapnia ranged from 0.8%/mmHg in the right internal carotid artery to 2.7%/mmHg in the left anterior cerebral artery. During hypocapnia, vasoconstriction ranged from 0.9%/mmHg in the basilar artery to 2.6%/mmHg in the right posterior cerebral artery. Heterogeneous cerebrovascular reactivity to hypercapnia and hypocapnia was characterized across basal intracranial conduit and internal carotid arteries.

Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress.

This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 ± 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 ± 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P < 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 ± 2; P < 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (HbSat: 56 ± 13 vs. 71 ± 6%; P < 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 ± 7; RBREnd: +11 ± 5) and total AP clusters (FRCApnea: +10 ± 2; RBREnd: +6 ± 4) (both P < 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P < 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress.NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress.