Rapid changes in cerebrovascular compliance during vasovagal syncope.

PURPOSE: The compensatory mechanisms supporting cerebral perfusion throughout head-up tilt (HUT) in patients with vasovagal syncope (VVS) remain unclear. We tested the hypothesis that increased cerebrovascular compliance (Ci) and decreased cerebrovascular resistance (CVR) support cerebral blood velocity (CBV) during pre-syncope in VVS. METHODS: Finger arterial blood pressure (ABP) and right middle cerebral artery blood velocity (CBV) were recorded in 15 individuals diagnosed with VVS (n = 11 female, mean age: 40 ± 16 years, mean body mass index: 24.9 ± 4.0 kg/m2) at supine rest and during HUT (80 degree angle). Individual ABP and CBV waveforms during VVS were input into a modified Windkessel model to calculate Ci and ohmic CVR. Gosling's pulsatility index (Pi; pulse amplitude/mean CBV) was calculated. RESULTS: Diastolic ABP, systolic ABP, mean ABP (72 ± 11 to 51 ± 12 mmHg), and CVR decreased progressively during presyncope (all P ≤ 0.04). As expected, systolic CBV was sustained (all P ≥ 0.29) while diastolic and mean CBV (51 ± 13 to 38 ± 13 mmHg) fell during presyncope (all P ≤ 0.04). Both Ci and Pi increased during presyncope (128 ± 97 and 60 ± 41%, respectively; all P ≤ 0.049) and were positively correlated (R2 = 0.79, P < 0.01). Increased Ci contributed to changes in mean CBV (P < 0.01) but decreased CVR did not (P = 0.28). CONCLUSIONS: These data provide evidence that Ci increases during presyncope in patients with VVS and is likely involved in the maintenance of systolic CBV during a fall in diastolic CBV. However, this regulation is not sufficient to preserve CBV in the presence of such extreme and progressive reductions in ABP.

A century of exercise physiology: key concepts in neural control of the circulation.

Early in the twentieth century, Walter B. Cannon (1871-1945) introduced his overarching hypothesis of "homeostasis" (Cannon 1932)-the ability to sustain physiological values within a narrow range necessary for life during periods of stress. Physical exercise represents a stress in which motor, respiratory and cardiovascular systems must be integrated across a range of metabolic stress to match oxygen delivery to oxygen need at the cellular level, together with appropriate thermoregulatory control, blood pressure adjustments and energy provision. Of these, blood pressure regulation is a complex but controlled variable, being the function of cardiac output and vascular resistance (or conductance). Key in understanding blood pressure control during exercise is the coordinating role of the autonomic nervous system. A long history outlines the development of these concepts and how they are integrated within the exercise context. This review focuses on the renaissance observations and thinking generated in the first three decades of the twentieth century that opened the doorway to new concepts of inquiry in cardiovascular regulation during exercise. The concepts addressed here include the following: (1) exercise and blood pressure, (2) central command, (3) neurovascular transduction with emphasis on the sympathetic nerve activity and the vascular end organ response, and (4) tonic neurovascular integration.

The interactive effects of age and sex on the neuro-cardiovascular responses during fatiguing rhythmic handgrip exercise.

The impact of age on exercise pressor responses is equivocal, likely because of sex-specific neuro-cardiovascular changes with age. However, assessments of the interactive effects of age and sex on muscle sympathetic nerve activity (MSNA) responses to exercise are lacking. We tested the hypothesis that older females would exhibit exaggerated increases in blood pressure (BP) and MSNA discharge patterns during handgrip exercise compared with similarly aged males and young adults. Twenty-five young (25 (2) years; mean (SD)) males (YM; n = 12) and females (YF; n = 13) and 23 older (71 (5) years) males (OM; n = 11) and females (OF; n = 12) underwent assessments of BP, total peripheral resistance (TPR; Modelflow) and MSNA action potential (AP) discharge patterns (microneurography) during incremental rhythmic handgrip exercise and post-exercise circulatory occlusion (PECO). OM demonstrated larger ∆BP and ∆TPR from baseline than YM (both P < 0.001) despite smaller increases in ∆APs/burst (OM: 0.4 (3) vs. YM: 5 (3) spikes/burst, P < 0.001) and ∆AP clusters/burst (OM: 0.1 (1) vs. YM: 1.8 (1) clusters/burst, P < 0.001) during exercise. Testosterone was lower in OM than YM (P < 0.001) and was inversely related to ∆BP but positively related to ∆AP clusters/burst in males (both P = 0.03). Conversely, YF and OF demonstrated similar ∆BP and ∆AP discharge during exercise (range: P = 0.75-0.96). Age and sex did not impact haemodynamics or AP discharge during PECO (range: P = 0.08-0.94). Altogether, age-related changes in neuro-cardiovascular reactivity exist in males but not females during fatiguing exercise and seem to be related to testosterone. This sex-specific impact of age underscores the importance of considering biological sex when assessing age-related changes in neuro-cardiovascular control during exercise. KEY POINTS: Older males have the largest increase in blood pressure despite having the smallest increases in sympathetic vasomotor outflow during rhythmic handgrip exercise. Young males demonstrate greater increases in sympathetic action potential (AP) discharge compared with young females during rhythmic handgrip exercise. Older adults (regardless of sex) demonstrate smaller increases in muscle sympathetic nerve activity (MSNA) burst amplitude and total AP clusters compared with young adults during exercise, as well as smaller increases in integrated MSNA burst frequency, incidence and total MSNA activity during post-exercise circulatory occlusion (i.e. independent effect of age). Males, but not females (regardless of age), reflexively modify AP conduction velocity during exercise. Our results indicate that age and sex independently and interactively impact the neural and cardiovascular homeostatic adjustments to fatiguing small muscle mass exercise.

Baroreflex resetting of human sympathetic action potential subpopulations during exercise.

This study tested the hypothesis that during fatiguing volitional exercise in humans, descending cortical signals and ascending skeletal muscle metaboreflex signals exert divergent control over baroreflex resetting of sympathetic action potential (AP) discharge. We quantified the baroreflex gain for sympathetic AP clusters within the muscle sympathetic nerve activity neurogram (peroneal microneurography and continuous wavelet transform) during baseline (BSL), the first 2-min of a 5-min isometric handgrip (20% of maximal effort; IHG1), the last 2-min of IHG (IHG2), and during postexercise circulatory occlusion (PECO) in seven healthy participants. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability (%) versus diastolic blood pressure (DBP; mmHg) for 10 normalized AP clusters. Compared with BSL, during IHG1, AP baroreflex threshold functions were only reset to greater DBP and baroreflex gain was unaffected. Compared with BSL, during IHG2 and PECO, baroreflex functions were reset to greater DBP and to greater AP firing probabilities, with medium-sized APs demonstrating the largest upward resetting (e.g., cluster 3 BSL: 26 ± 7%, cluster 3 IHG2: 78 ± 22%, cluster 3 PECO: 88 ± 46%). Compared with BSL, AP baroreflex threshold gain was not different during IHG2 but was increased during PECO, with medium-sized APs demonstrating the largest increase in baroreflex gain (e.g., cluster 3 BSL: -6.31 ± 3.1%/mmHg, cluster 3 IHG2: -6.18 ± 5.4%/mmHg, cluster 3 PECO: -12.13 ± 6.5%/mmHg). These findings indicate that during IHG exercise, descending cortical signaling and ascending skeletal muscle metaboreceptor signals differentially affect baroreflex resetting of subpopulations of human muscle sympathetic postganglionic neurons.NEW & NOTEWORTHY This study provides new insight to baroreflex resetting of MSNA during exercise in humans. Both fatiguing IHG and PECO reset baroreflex control of sympathetic APs to higher blood pressures and greater MSNA. However, only PECO increased baroreflex threshold gain of medium-sized sympathetic APs, an effect that was concealed when focusing on the integrated MSNA neurogram to quantify baroreflex gain. These data suggest that descending central versus ascending muscle metaboreflex mechanisms differentially affect baroreflex resetting of sympathetic APs.

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 (Ci) 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 Ci similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; P = 0.45). In experiment 2, glycopyrrolate increased cerebrovascular Ci (72 ± 61%) and forearm vascular Ci (74 ± 64%) to a similar extent (P = 0.88). In experiment 3, nicardipine increased Ci 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.

Age- and sex-related differences in sympathetic vascular transduction and neurohemodynamic balance in humans.

Bursts of muscle sympathetic nerve activity (MSNA) and the ensuing vasoconstriction are pivotal determinants of beat-by-beat blood pressure regulation. Although age and sex impact blood pressure regulation, how these factors affect the central and peripheral arcs of the baroreflex remains unclear. In 27 young [25 (SD 3) yr] males (YM; n = 14) and females (YF; n = 13) and 23 older [71 (SD 5) yr] males (OM; n = 11) and females (OF; n = 12), femoral artery blood flow, blood pressure, and MSNA were recorded for 10 min of supine rest. Sympathetic baroreflex sensitivity (i.e., central arc) was quantified as the relationship between diastolic blood pressure and MSNA burst incidence. Signal averaging was used to determine sympathetic vascular transduction into leg vascular conductance (LVC) for 12 cardiac cycles following MSNA bursts (i.e., peripheral arc). Older adults demonstrated attenuated sympathetic transduction into LVC (both P < 0.001) following MSNA bursts, and smaller increases in sympathetic transduction as a function of MSNA burst size and firing pattern compared with young adults (range, P = 0.004-0.032). YM (r2 = 0.36; P = 0.032) and OM (r2 = 0.51; P = 0.014) exhibited an inverse relationship between the central and peripheral arcs of the baroreflex, whereas females did not (YF, r2 = 0.03, P = 0.621; OF, r2 = 0.06, P = 0.445). MSNA burst incidence was inversely related to sympathetic transduction in YM and OF (range, P = 0.03-0.046) but not in YF or OM (range, P = 0.360-0.603). These data indicate that age is associated with attenuated sympathetic vascular transduction, whereas age- and sex-specific changes are present in the relationship between the central and peripheral arcs of the baroreflex regulation of blood pressure.NEW & NOTEWORTHY Sympathetic vascular transduction is attenuated in older compared with young adults, regardless of biological sex. Males, but not females (regardless of age), demonstrate an inverse relationship between central (sympathetic baroreflex sensitivity) and peripheral (sympathetic vascular transduction) components of the baroreflex arc. Young males and older females exhibit an inverse relationship between resting sympathetic outflow and sympathetic vascular transduction. Our results indicate that age and sex exert independent and interactive effects on sympathetic vascular transduction and sympathetic neurohemodynamic balance in humans.

Sympathetic transduction to blood pressure during euglycemic-hyperinsulinemia in young healthy adults: role of burst amplitude.

Insulin acts centrally to stimulate sympathetic vasoconstrictor outflow to skeletal muscle and peripherally to promote vasodilation. Given these divergent actions, the "net effect" of insulin on the transduction of muscle sympathetic nerve activity (MSNA) into vasoconstriction and thus, blood pressure (BP) remains unclear. We hypothesized that sympathetic transduction to BP would be attenuated during hyperinsulinemia compared with baseline. In 22 young healthy adults, MSNA (microneurography), and beat-to-beat BP (Finometer or arterial catheter) were continuously recorded, and signal-averaging was performed to quantify the mean arterial pressure (MAP) and total vascular conductance (TVC; Modelflow) responses following spontaneous bursts of MSNA at baseline and during a euglycemic-hyperinsulinemic clamp. Hyperinsulinemia significantly increased MSNA burst frequency and mean burst amplitude (baseline: 46 ± 6 au; insulin: 65 ± 16 au, P < 0.001) but did not alter MAP. The peak MAP (baseline: 3.2 ± 1.5 mmHg; insulin: 3.0 ± 1.9 mmHg, P = 0.67) and nadir TVC (P = 0.45) responses following all MSNA bursts were not different between conditions indicating preserved sympathetic transduction. However, when MSNA bursts were segregated into quartiles based on their amplitudes at baseline and compared with similar amplitude bursts during hyperinsulinemia, the peak MAP and TVC responses were blunted (e.g., largest burst quartile: MAP, baseline: Δ4.4 ± 1.7 mmHg; hyperinsulinemia: Δ3.0 ± 0.8 mmHg, P = 0.02). Notably, ∼15% of bursts during hyperinsulinemia exceeded the size of any burst at baseline, yet the MAP/TVC responses to these larger bursts (MAP, Δ4.9 ± 1.4 mmHg) did not differ from the largest baseline bursts (P = 0.47). These findings indicate that increases in MSNA burst amplitude contribute to the overall maintenance of sympathetic transduction during hyperinsulinemia.

Effects of biological sex and oral contraception on the sympathetic neurocirculatory adjustments to static handgrip exercise in humans.

While biological sex affects the neurocirculatory adjustments to exercise, the effects of sex hormones on sympathetic action potential (AP) patterns and ensuing vascular transduction remain unknown. We tested the hypothesis that males, and females using oral contraceptive pills (OCPs), would demonstrate larger increases in sympathetic activation and sympathetic vascular transduction compared with naturally menstruating females during static handgrip exercise (SHG) and postexercise circulatory occlusion (PECO). Young males [n = 14, 25 (5) yr], females using OCPs [n = 16, 24 (6) yr], and naturally menstruating females [n = 18, 26 (4) yr] underwent assessments of multiunit muscle sympathetic nerve activity (MSNA)/AP discharge patterns (microneurography) and femoral artery blood flow (ultrasound) during fatiguing SHG at 40% maximum voluntary contraction and 2-min PECO. Sympathetic vascular transduction was determined as the quotient of the change in leg vascular conductance (LVC) and MSNA/AP discharge. Males demonstrated greater increases in APs/burst [males: Δ7 (6) vs. midluteal: Δ2 (3), P = 0.028] and total AP clusters [males: Δ5 (3) vs. midluteal: Δ2 (3), P = 0.008] compared with naturally menstruating females only but not those using OCPs during exercise (APs/burst: P = 0.171, total clusters: P = 0.455). Sympathetic vascular transduction of MSNA burst amplitude, APs/burst, and total AP clusters was greater in males and females using OCPs compared with naturally menstruating females (range: P = 0.004-0.044). In contrast, during PECO no group differences were observed in AP discharge (range: P = 0.510-0.872), and AP discharge was not related to LVC during PECO (range: P = 0.08-0.949). These data indicate that biological sex and OCP use impact the central generation of AP discharge, as well as the transduction of these neuronal messages into peripheral vasoconstriction during static exercise.

Sympathetic activity is not a main cause of blood pressure reduction with exercise training in un-medicated middle-aged/older men.

BACKGROUND: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men. METHODS: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55 ± 3 years; n = 13) and normotensive controls (mean age 60 ± 5 years; n = 12) participated in 8 weeks of supervised high-intensity interval spinning training. Before and after training, muscle sympathetic nerve activity (MSNA) and blood pressure were measured at rest and during a sympatho-excitatory cold pressor test (CPT). Based on the measurements, baroreceptor sensitivity and baroreceptor threshold were calculated. RESULTS: Resting MSNA and baroreceptor sensitivity were similar for the hypertensive and the normotensive groups. Training lowered MSNA (p < 0.05), expressed as burst frequency (burst/min), overall, and to a similar extent, in both groups (17% and 27%, respectively, in hypertensive and normotensive group), whereas blood pressure was only significantly (p < 0.05) lowered (by 4 mmHg in both systolic and diastolic pressure) in the hypertensive group. Training did not (p > 0.05) alter the MSNA or blood pressure response to CPT or increase baroreceptor sensitivity but reduced (p < 0.05) the baroreceptor threshold with a main effect for both groups. Training adherence and intensity were similar in both groups yet absolute maximal oxygen uptake increased by 15% in the normotensive group only. CONCLUSION: The dissociation between the training induced changes in resting MSNA, lack of change in baroreflex sensitivity and the change in blood pressure, suggests that MSNA is not a main cause of the blood pressure reduction with exercise training in un-medicated middle-aged/older men.

Cerebral haemodynamics during arrhythmia in health, ischaemic heart disease and heart failure with reduced ejection fraction, and in a preclinical swine model.

Ventricular arrhythmias are associated with neurological impairment and could represent a source of cerebral hypoperfusion. In the present study, data from healthy individuals (n = 11), patients with ischaemic heart disease (IHD; ejection fraction >40%; n = 9) and patients with heart failure with reduced ejection fraction (HFrEF; EF = 31 (5)%, n = 11), as well as data from swine surgeries, where spontaneous ventricular arrhythmias were observed during cerebrovascular examination (transcranial Doppler ultrasound in humans and laser Doppler in swine) were analysed retrospectively to investigate the effect of arrhythmia on cerebral microvascular haemodynamics. A subset of participants also completed the Montreal Cognitive Assessment (MoCA). Middle cerebral artery mean blood velocity (MCAVmean ) decreased during premature ventricular contraction (PVC) in all groups, and data from swine indicate PVCs reduced cerebral microvascular perfusion. Overall MCAVmean was decreased in the HFrEF vs. control group. Further, %∆MCAVmean /%∆mean arterial pressure during the PVC was greater in the HFrEF vs. control group and was correlated with decreased MoCA scores. Subanalysis of HFrEF data revealed that during bigeminy MCAVmean decreased owing to reductions during irregular beats only. During non-sustained ventricular tachycardia, MCAVmean decreased but recovered above baseline upon return to sinus rhythm. Also, haemodynamic perturbations during and following the PVC were greater in the brachial artery vs. the MCA. Therefore, ventricular arrhythmias decreased indices of cerebral perfusion irrespective of IHD or HFrEF. The relative magnitude of arrhythmia-induced haemodynamic perturbations appears to be population specific and arrhythmia type and organ dependent. The cumulative burden of arrhythmia-induced deficits may exacerbate existing cerebral hypoperfusion in HFrEF and contribute to neurological abnormalities in this population. KEY POINTS: Irregular heartbeats are often considered benign in isolation, but individuals who experience them frequently have a higher prevalence of cerebrovascular and/or cognitive associated disorders. How irregular heartbeats affect blood pressure and cerebral haemodynamics in healthy and cardiovascular disease patients, those with and without reduced ejection fraction, remains unknown. Here it was found that in the absence of symptoms associated with irregular heartbeats, such as dizziness or hypotension, single, multiple non-sustained and sustained irregular heartbeats influence cerebral haemodynamics in a population-specific, arrhythmia-type and organ-dependent manner. Relative deficits in the index of cerebral blood flow normalized to relative deficits in blood pressure were greatest in patients with heart failure with reduced ejection and inversely related with cognitive performance. Chronic arrhythmias may exacerbate existing cerebral hypoperfusion in heart failure with reduced ejection fraction, thereby providing a mechanistic link between otherwise benign irregular heartbeats and cognitive dysfunction, independent of embolism.

Interactive effects of apneic and baroreflex stress on neuronal coding strategies in human muscle sympathetic nerve activity.

The sympathetic nervous system exhibits patterns of action potential (AP) discharge in human muscle sympathetic nerve activity that suggest coding strategies express reflex specificity. This study explored the interactive effects of baroreceptor unloading using lower body negative pressure (LBNP) and volitional end-expiratory apnea (APN) on sympathetic postganglionic neuronal discharge patterns inferred from the firing patterns of differently sized sympathetic AP clusters. Seven individuals were studied using multiunit microneurography (fibular) and a continuous wavelet approach to quantify AP discharge probability, recruitment, and latency during APN performed under ambient conditions, -10, and -40 mmHg LBNP. Compared with the ambient condition, LBNP increased AP discharge rate at -10 and -40 mmHg and recruited larger previously silent sympathetic neurons at -40 mmHg. Compared with spontaneous breathing, APN increased AP discharge when performed during the ambient condition (Δ351 ± 132 AP/min), -10 mmHg (Δ423 ± 184 AP/min), and -40 mmHg (Δ355 ± 278 AP/min; main effect APN: P < 0.01; LBNP-by-APN interaction: P = 0.55). APN recruited larger previously silent AP clusters during the ambient condition (Δ4 ± 3; P < 0.02) and -10 mmHg (Δ4 ± 3; P < 0.01), but not -40 mmHg (Δ0 ± 2; P = 0.53; LBNP-by-APN: P < 0.01). LBNP did not affect AP latency. However, APN reduced AP latency similarly during all conditions (ambient pressure: Δ-0.04 ± 0.04s, -10 mmHg: Δ-0.03 ± 0.03s, -40 mmHg: Δ-0.03 ± 0.04s; main effect APN: P < 0.01; LBNP-by-APN: P = 0.48). These data indicate that apneic and baroreflex mechanisms appear to additively modify the axonal discharge rate of previously active sympathetic postganglionic neurons and interact to affect recruitment of previously silent sympathetic neurons. Reductions in AP latency due to apneic stress were not impacted by baroreflex unloading.NEW & NOTEWORTHY Discrete physiological stressors differentially affect sympathetic postganglionic neuronal rate-, population-, and temporal-coding strategies. When performing end-expiratory apnea (APN) during graded baroreflex unloading via lower body negative pressure (LBNP), we found: 1) augmented sympathetic axonal firing probability, 2) recruitment of larger and previously silent sympathetic postganglionic neurons at ambient and -10 mmHg, but not -40 mmHg LBNP, and 3) APN reduced axonal discharge latency similarly across all conditions, independent of the level of baroreflex unloading.

Influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity in healthy adults.

We examined the influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity (MSNA) in healthy adults. Data were assessed from 224 volunteers (88 females), aged 18-76 yr, in whom resting MSNA (microneurography) and peak oxygen uptake (V̇o2peak; incremental exercise test) were evaluated. When separated into younger (<50 yr) and older (≥50 yr) subgroups, there were inverse relationships between relative V̇o2peak (mL·kg-1·min-1) and MSNA burst frequency in younger males (R2 = 0.21, P < 0.0001) and older females (R2 = 0.36, P < 0.01), but not older males (R2 = 0.05, P = 0.08) or younger females (R2 = 0.03, P = 0.14). Similar patterns were observed with absolute V̇o2peak (L·min-1) and percent-predicted (based on age, sex, weight, height, and modality), and with burst incidence. Sex and age influence the relationship between aerobic fitness and resting MSNA, and, thus, must be considered as key variables when studying these potential associations; inverse relationships are strongest in younger males and older females.NEW & NOTEWORTHY Our data reveal for the first time that associations between aerobic fitness and resting muscle sympathetic nerve activity are sex and age specific; inverse relationships are evident in younger males (<50 yr) and older females (≥50 yr), but absent in younger females (<50 yr) and older males (≥50 yr).

Forebrain Network Associated With Cardiovascular Control in Exercising Humans.

This article describes the forebrain neurocircuitry associated with rapid heart rate response at the exercise onset with attention to ascending somatosensory information from the Type I and II afferents from the contracting muscle and potential influence of sensory information related to blood pressure and changes in heart rate.

Impaired sympathetic neural recruitment during exercise pressor reflex activation in women with post-traumatic stress disorder.

Muscle sympathetic nerve activity (MSNA) increases during isometric exercise via increased firing of low-threshold action potentials (AP), recruitment of larger, higher-threshold APs, and synaptic delay modifications. Recent work found that women with post-traumatic stress disorder (PTSD) demonstrate exaggerated early-onset MSNA responses to exercise; however, it is unclear how PTSD affects AP recruitment patterns during fatiguing exercise. We hypothesized that women with PTSD (n = 11, 43 [11] [SD] years) would exhibit exaggerated sympathetic neural recruitment compared to women without PTSD (controls; n = 13, 40 [8] years). MSNA and AP discharge patterns (via microneurography and a continuous wavelet transform) were measured during 1 min of baseline, isometric handgrip exercise (IHG) to fatigue, 2 min of post-exercise circulatory occlusion (PECO), and 3 min of recovery. Women with PTSD were unable to increase AP content per burst compared to controls throughout IHG and PECO (main effect of group: P = 0.026). Furthermore, relative to controls, women with PTSD recruited fewer AP clusters per burst during the first (controls: ∆1.3 [1.2] vs. PTSD: ∆-0.2 [0.8]; P = 0.016) and second minute (controls: ∆1.2 [1.1] vs. PTSD: ∆-0.1 [0.8]; P = 0.022) of PECO, and fewer subpopulations of larger, previously silent axons during the first (controls: ∆5 [4] vs. PTSD: ∆1 [2]; P = 0.020) and second minute (controls: ∆4 [2] vs. PTSD: ∆1 [2]; P = 0.021) of PECO. Conversely, PTSD did not modify the AP cluster size-latency relationship during baseline, the end of IHG, or PECO (all P = 0.658-0.745). Collectively, these data indicate that women with PTSD demonstrate inherent impairments in the fundamental neural coding patterns elicited by the sympathetic nervous system during IHG and exercise pressor reflex activation.

The impact of 6 months of exercise-based cardiac rehabilitation on sympathetic neural recruitment during apneic stress.

The current study evaluated the hypothesis that 6 mo of exercise-based cardiac rehabilitation (CR) would improve sympathetic neural recruitment in patients with ischemic heart disease (IHD). Microneurography was used to evaluate action potential (AP) discharge patterns within bursts of muscle sympathetic nerve activity (MSNA), in 11 patients with IHD (1 female; 61 ± 9 yr) pre (pre-CR) and post (post-CR) 6 mo of aerobic and resistance training-based CR. Measures were made at baseline and during maximal voluntary end-inspiratory (EI-APN) and end-expiratory apneas (EE-APN). Data were analyzed during 1 min of baseline and the second half of apneas. At baseline, overall sympathetic activity was less post-CR (all P < 0.01). During EI-APN, AP recruitment was not observed pre-CR (all P > 0.05), but increases in both within-burst AP firing frequency (Δpre-CR: 2 ± 3 AP spikes/burst vs. Δpost-CR: 4 ± 3 AP spikes/burst; P = 0.02) and AP cluster recruitment (Δpre-CR: -1 ± 2 vs. Δpost-CR: 2 ± 2; P < 0.01) were observed in post-CR tests. In contrast, during EE-APN, AP firing frequency was not different post-CR compared with pre-CR tests (Δpre-CR: 269 ± 202 spikes/min vs. Δpost-CR: 232 ± 225 spikes/min; P = 0.54), and CR did not modify the recruitment of new AP clusters (Δpre-CR: -1 ± 3 vs. Δpost-CR: 0 ± 1; P = 0.39), or within-burst firing frequency (Δpre-CR: 3 ± 3 AP spikes/burst vs. Δpost-CR: 2 ± 2 AP spikes/burst; P = 0.21). These data indicate that CR improves some of the sympathetic nervous system dysregulation associated with cardiovascular disease, primarily via a reduction in resting sympathetic activation. However, the benefits of CR on sympathetic neural recruitment may depend upon the magnitude of initial impairment.

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 < 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.

Heterogeneous baroreflex control of sympathetic action potential subpopulations in humans.

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.

Increased cerebral blood flow supports a single-bout postexercise benefit to executive function: evidence from hypercapnia.

A single bout of aerobic exercise improves executive function; however, the mechanism for the improvement remains unclear. One proposal asserts that an exercise-mediated increase in cerebral blood flow (CBF) enhances the efficiency of executive-related cortical structures. To examine this, participants completed separate 10-min sessions of moderate- to heavy-intensity aerobic exercise, a hypercapnic environment (i.e., 5% CO2), and a nonexercise and nonhypercapnic control condition. The hypercapnic condition was included because it produces an increase in CBF independent of metabolic demands. An estimate of CBF was achieved via transcranial Doppler ultrasound and near-infrared spectroscopy that provided measures of middle cerebral artery blood velocity (BV) and deoxygenated hemoglobin (HHb), respectively. Exercise intensity was adjusted to match participant-specific changes in BV and HHb associated with the hypercapnic condition. Executive function was assessed before and after each session via antisaccades (i.e., saccade mirror-symmetrical to a target) because the task is mediated via the same executive networks that demonstrate task-dependent modulation following single and chronic bouts of aerobic exercise. Results showed that hypercapnic and exercise conditions were associated with comparable BV and HHb changes, whereas the control condition did not produce a change in either metric. In terms of antisaccade performance, the exercise and hypercapnic, but not control, conditions demonstrated improved postcondition reaction times (RT), and the magnitude of the hypercapnic and exercise-based increase in estimated CBF was reliably related to the postcondition improvement in RT. Accordingly, results evince that an increase in CBF represents a candidate mechanism for a postexercise improvement in executive function.NEW & NOTEWORTHY Single-bout aerobic exercise "boosts" executive function, and increased cerebral blood flow (CBF) has been proposed as a mechanism for the benefit. In this study, participants completed 10 min of aerobic exercise and 10 min of inhaling a hypercapnic gas, a manipulation known to increase CBF independently of metabolic demands. Both exercise and hypercapnic conditions improved executive function for at least 20 min. Accordingly, an increase in CBF is a candidate mechanism for the postexercise improvement in executive function.

Does vascular stiffness predict white matter hyperintensity burden in ischemic heart disease with preserved ejection fraction?

The survival rate of patients with ischemic heart disease (IHD) is increasing. However, survivors experience increased risk for neurological complications. The mechanisms for this increased risk are unknown. We tested the hypothesis that patients with IHD have greater carotid and cerebrovascular stiffness, and these indexes predict white matter small vessel disease. Fifty participants (age, 40-78 yr), 30 with IHD with preserved ejection fraction and 20 healthy age-matched controls, were studied using ultrasound imaging of the common carotid artery (CCA) and middle cerebral artery (MCA), as well as magnetic resonance imaging (T1, T2-FLAIR), to measure white matter lesion volume (WMLv). Carotid ß-stiffness provided the primary measure of peripheral vascular stiffness. Carotid-cerebral pulse wave transit time (ccPWTT) provided a marker of cerebrovascular stiffness. Pulsatility index (PI) and resistive index (RI) of the MCA were calculated as measures of downstream cerebrovascular resistance. When compared with controls, patients with IHD exhibited greater ß-stiffness [8.5 ± 3.3 vs. 6.8 ± 2.2 arbitrary units (AU); P = 0.04], MCA PI (1.1 ± 0.20 vs. 0.98 ± 0.18 AU; P = 0.02), and MCA RI (0.66 ± 0.06 vs. 0.62 ± 0.07 AU; P = 0.04). There was no difference in WMLv between IHD and control groups (0.95 ± 1.2 vs. 0.86 ± 1.4 mL; P = 0.81). In pooled patient data, WMLv correlated with both ß-stiffness (R = 0.34, P = 0.02) and cerebrovascular ccPWTT (R = -0.43, P = 0.02); however, ß-stiffness and ccPWTT were not associated (P = 0.13). In multivariate analysis, WMLv remained independently associated with ccPWTT (P = 0.02) and carotid ß-stiffness (P = 0.04). Patients with IHD expressed greater ß-stiffness and cerebral microvascular resistance. However, IHD did not increase risk of WMLv or cerebrovascular stiffness. Nonetheless, pooled data indicate that both carotid and cerebrovascular stiffness are independently associated with WMLv.NEW & NOTEWORTHY This study found that patients with ischemic heart disease (IHD) with preserved ejection fraction and normal blood pressures exhibit greater carotid ß-stiffness, as well as middle cerebral artery pulsatility and resistive indexes, than controls. White matter lesion volume (WMLv) was not different between vascular pathology groups. Cerebrovascular pulse wave transit time (ccPWTT) and carotid ß-stiffness independently associate with WMLv in pooled participant data, suggesting that regardless of heart disease history, ccPWTT and ß-stiffness are associated with structural white matter damage.

Abnormal sympathetic neural recruitment patterns and hemodynamic responses to cold pressor test in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is more prevalent in women and associated with greater risk of major forms of cardiovascular disease, but physiological mechanisms underlying this association remain unknown. We hypothesized that abnormal sympathetic responses to sympathoexcitatory stimuli might predispose PTSD patients to a greater risk of cardiovascular disease. We examined changes in integrated muscle sympathetic nerve activity (MSNA) burst and multiunit action potential (AP) recruitment patterns as well as hemodynamic responses during cold pressor test (CPT) in 14 women with PTSD and 14 healthy control subjects. Data were collected during 1-min baseline, 2-min CPT, and 3-min recovery. At baseline, blood pressure (BP) was not different between groups; however, heart rate and sympathetic neural activity were greater in women with PTSD [MSNA burst frequency (BF): 27 ± 13 vs. 18 ± 14 bursts/min (P = 0.04); AP frequency: 272 ± 152 vs. 174 ± 146 spikes/min (P = 0.03)]. In response to CPT, BP responses exhibited a significant group × time interaction (P = 0.01) highlighted by a significant diastolic BP main group effect (P = 0.048) despite the finding that increases in integrated MSNA burst responses were not different between groups (P > 0.05). However, compared with control subjects, AP firing frequency (group × time interaction P = 0.0001, group P = 0.02) and AP per burst (group × time interaction P = 0.03, group P = 0.03) were augmented in women with PTSD. Collectively, women with PTSD exhibited a greater pressor response and an exaggerated sympathetic neural recruitment pattern during sympathoexcitatory stimuli that may, in part, explain the propensity toward developing hypertension and cardiovascular disease later in life.NEW & NOTEWORTHY The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.