Recruitment Strategies In Human Sympathetic Nerve Activity

The overall objectives of the current dissertation were to 1) establish the neural coding principles employed by the sympathetic nervous system (SNS) in response to acute physiological stress; and 2) to determine the various mechanisms of control underlying these sympathetic neural recruitment strategies. This research tested the working hypothesis that efferent post-ganglionic muscle sympathetic nerve activity exhibits neural coding patterns reflecting increased firing of lower-threshold axons, recruitment of latent sub-populations of higher-threshold axons, as well as malleable synaptic delays, and further, that these strategies are governed by factors such as reflex-specificity, stress severity, perception of effort or stress, age, and cardiovascular disease. Specifically, we utilized a novel signal processing approach to study sympathetic action potential discharge patterning during periods of acute reflex-mediated sympathoexcitation. Overall, these studies support the working hypothesis and confirm that neural coding principles operate within the SNS. Specifically, in response to acute homeostatic perturbation, the SNS has options to increase the firing rate of already-active, lower-threshold axons, recruit sub-populations of previously silent (i.e., not present at baseline), larger-sized and faster conducting sympathetic axons, as well as modify acutely synaptic delays. Study 1 demonstrated that the ability to recruit latent neural sub-populations represents a fixed, reflex-independent recruitment strategy, as this pattern was observed during chemoreflex- and baroreflex-mediated sympathoexcitation. In turn, this option appears reserved for severe stress scenarios. Furthermore, study 2 suggests that central, perceptual features may play a specific role in modifying the synaptic delay aspect of efferent discharge timing, whereas peripheral-reflex mechanisms mediate the recruitment of latent axons. Study 3 demonstrates that, while the ability to acutely modify synaptic delays appears preserved, the ability to increase firing frequency of already-active axons, and importantly, the capacity of the SNS to recruit latent sub-populations of higher-threshold axons are reduced with healthy aging and perhaps lost altogether with cardiovascular disease. Finally, study 4 suggests that the lack of ventilation itself, rather than the ever-increasing chemical drive, mediates the robust sympathetic neural recruitment observed during apnea. In conclusion, the series of studies contained herein confirm the presence of neural coding patterns in human efferent post-ganglionic sympathetic nerve activity

Impact of age on cerebrovascular dilation versus reactivity to hypercapnia.

This study quantified the effect of age on cerebrovascular reactivity and cerebrovascular conductance while accounting for differences in grey matter volume in younger (YA: n = 12; 24 ± 4 years, six females) and older adults (OA: n = 10; 66 ± 7 years; five females). Cerebral blood flow velocity (CBFV; transcranial Doppler) in the middle cerebral artery (MCA), MCA cross-sectional area (CSA), intracranial volumes (magnetic resonance imaging), and mean arterial pressure (MAP; Finometer), were measured under normocapnic and hypercapnic (6% carbon dioxide) conditions. Cerebral blood flow (CBF) was quantified from CBFV and MCA CSA and normalized to grey matter volume. Grey matter volume was 719 ± 98 mL in YA and 622 ± 50 mL in OA (P = 0.009). Cerebrovascular reactivity (%ΔCBF/Δ

Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans

As a primary component of homeostasis, the sympathetic nervous system enables rapid adjustments to stress through its ability to communicate messages among organs and cause targeted and graded end organ responses. Key in this communication model is the pattern of neural signals emanating from the central to peripheral components of the sympathetic nervous system. But what is the communication strategy employed in peripheral sympathetic nerve activity (SNA)? Can we develop and interpret the system of coding in SNA that improves our understanding of the neural control of the circulation? In 1968, Hagbarth and Vallbo (Hagbarth KE, Vallbo AB. Acta Physiol Scand 74: 96–108, 1968) reported the first use of microneurographic methods to record sympathetic discharges in peripheral nerves of conscious humans, allowing quantification of SNA at rest and sympathetic responsiveness to physiological stressors in health and disease. This technique also has enabled a growing investigation into the coding patterns within, and cardiovascular outcomes associated with, postganglionic SNA. This review outlines how results obtained by microneurographic means have improved our understanding of SNA outflow patterns at the action potential level, focusing on SNA directed toward skeletal muscle in conscious humans

Effects of aging and coronary artery disease on sympathetic neural recruitment strategies during end-inspiratory and end-expiratory apnea

In response to acute physiological stress, the sympathetic nervous system modifies neural outflow through increased firing frequency of lower-threshold axons, recruitment of latent subpopulations of higher-threshold axons, and/or acute modifications of synaptic delays. Aging and coronary artery disease (CAD) often modify efferent muscle sympathetic nerve activity (MSNA). Therefore, we investigated whether CAD (n = 14; 61 ± 10 yr) and/or healthy aging without CAD (OH; n = 14; 59 ± 9 yr) modified these recruitment strategies that normally are observed in young healthy (YH; n = 14; 25 ± 3 yr) individuals. MSNA (microneurography) was measured at baseline and during maximal voluntary end-inspiratory (EI) and end-expiratory (EE) apneas. Action potential (AP) patterns were studied using a novel AP analysis technique. AP frequency increased in all groups during both EI- and EE-apnea (all P \u3c 0.05). The mean AP content per integrated burst increased during EI- and EE-apnea in YH (EI: Δ6 ± 4 APs/burst; EE: Δ10 ± 6 APs/burst; both P \u3c 0.01) and OH (EI: Δ3 ± 3 APs/burst; EE: Δ4 ± 5 APs/burst; both P \u3c 0.01), but not in CAD (EI: Δ1 ± 3 APs/burst; EE: Δ2 ± 3 APs/burst; both P = NS). When APs were binned into clusters according to peak-to-peak amplitude, total clusters increased during EI- and EE-apnea in YH (EI: Δ5 ± 2; EE: Δ6 ± 4; both P \u3c 0.01), during EI-apnea only in OH (EI: Δ1 ± 2; P \u3c 0.01; EE: Δ1 ± 2; P = NS), and neither apnea in CAD (EI: Δ -2 ± 2; EE: Δ -1 ± 2; both P = NS). In all groups, the AP cluster size-latency profile was shifted downwards for every corresponding cluster during EI- and EE-apnea (all P \u3c 0.01). As such, inherent dysregulation exists within the central features of apnea-related sympathetic outflow in aging and CAD

Acute changes in forearm vascular compliance during transient sympatho-excitation

The study of vascular regulation often omits important information about the elastic properties of arteries under conditions of pulsatile flow. The purpose of this study was to examine the relationship between muscle sympathetic nerve activity (MSNA), vascular bed compliance, and peripheral blood flow responses in humans. We hypothesized that increases in MSNA would correlate with reductions in vascular compliance, and that changes in compliance would correspond with changes in peripheral blood flow during sympatho-excitation. MSNA (microneurography), blood pressure (Finopres), and brachial artery blood flow (Doppler ultrasound), were monitored in six healthy males at baseline and during the last 15 s of voluntary end-inspiratory, expiratory apneas and 5 min of static handgrip exercise (SHG; 20% maximum voluntary contraction) and 3 min of post-exercise circulatory occlusion (SHG + PECO; measured in the non-exercising arm). A lumped Windkessel model was employed to examine vascular bed compliance. During apnea, indices of MSNA were inversely related with vascular compliance, and reductions in compliance correlated with decreased brachial blood flow rate. During SHG, despite increased MSNA, compliance also increased, but was unrelated to increases in blood flow. Neither during SHG nor PECO did indices of MSNA correlate with forearm vascular compliance nor did vascular compliance correlate with brachial flow. However, during PECO, a linear combination of blood pressure and total MSNA was correlated with vascular compliance. These data indicate the elastic components of the forearm vasculature are regulated by adrenergic and myogenic mechanisms during sympatho-excitation, but in a reflex-dependent manner

Exploring Cerebrovascular Function in Osteoarthritis: Heads-up

ndividuals with osteoarthritis (OA) are at greater risk of cardiovascular and cerebrovascular incidents; yet, cerebrovascular control remains uncharacter- ized. Our primary outcome was to acquire cerebrovascular control metrics in patients with OA and compare measures to healthy control adults (CTL) without OA or cardiovascular complications. Our primary covariate was a 10- year risk factor for cardiovascular and stroke incidents, and secondary covari- ates were other cardiovascular disease risk factors (i.e., body mass index, caro- tid intima media thickness, and brachial flow-mediated dilation). Our secondary outcomes were to assess anatomical and functional changes that may be related to cerebrovascular reactivity were also acquired such as white matter lesion volume and brief cognitive assessments. In 25 adults (n = 13 CTL, n = 12 OA), under hypercapnia, magnetic resonance imaging (3T) was used to acquire a “Global Cerebrovascular Reactivity” index across the larger intracranial cerebral arteries and white matter lesions, and transcranial Doppler was used for both middle cerebral artery hemodynamic responses to hypercapnia and to assess autoregulation via a sit-to-stand task. Compared to CTL, OA had lower “Global Cerebrovascular Reactivity” index responses to hypercapnia, autoregulatory responses, and greater white matter lesions (P \u3c 0.05). These differences persisted after covarying for the outlined primary and secondary covariates. Patients with OA, in the absence of known cardio- vascular disease, can exhibit pre-clinical and impaired (compared to CTL) peripheral and cerebrovascular control metrics

Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress

© 2017 the American Physiological Society. 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 \u3c 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (Hb-Sat: 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 \u3c 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P \u3c 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

Influence of Sex and Age on Muscle Sympathetic Nerve Activity of Healthy Normotensive Adults

As with blood pressure, age-related changes in muscle sympathetic nerve activity (MSNA) may differ nonlinearly between sexes. Data acquired from 398 male (age: 39±17; range: 18-78 years [mean±SD]) and 260 female (age: 37±18; range: 18-81 years) normotensive healthy nonmedicated volunteers were analyzed using linear regression models with resting MSNA burst frequency as the outcome and the predictors sex, age, MSNA, blood pressure, and body mass index modelled with natural cubic splines. Age and body mass index contributed 41% and 11%, respectively, of MSNA variance in females and 23% and 1% in males. Overall, changes in MSNA with age were sigmoidal. At age 20, mean MSNA of males and females were similar, then diverged significantly, reaching in women a nadir at age 30. After 30, MSNA increased nonlinearly in both sexes. Both MSNA discharge and blood pressure were lower in females until age 50 (17±9 versus 25±10 bursts·min-1; P\u3c1×10-19; 106±11/66±8 versus 116±7/68±9 mm Hg; P\u3c0.01) but converged thereafter (38±11 versus 35±12 bursts·min-1; P=0.17; 119±15/71±13 versus 120±13/72±9 mm Hg; P\u3e0.56). Compared with age 30, MSNA burst frequency at age 70 was 57% higher in males but 3-fold greater in females; corresponding increases in systolic blood pressure were 1 (95% CI, -4 to 5) and 12 (95% CI, 6-16) mm Hg. Except for concordance in females beyond age 40, there was no systematic change with age in any resting MSNA-blood pressure relationship. In normotensive adults, MSNA increases after age 30, with ascendance steeper in women

Cardiac Baroreflex Variability and Resetting during Sustained Mild Effort

This exploratory study assessed the pattern of closed-loop baroreflex resetting using multi-logistic-curve analysis. Operating point gain and ranges of RR-interval (RRI) and systolic blood pressure (SBP) are derived to examine how these relate to sympathetic activation. Sustained low-intensity isometric handgrip exercise, with a period of post-exercise circulatory occlusion (PECO), provided a model to study baroreflex resetting because the progression toward fatigue at constant tension induces a continuous increase in volitional contribution to neuro-cardiovascular control. Continuous measurements of muscle sympathetic nerve activity (MSNA), blood pressure, and RRI were made simultaneously throughout the experimental session. Spontaneous sequence analysis was used to detect episodes of baroreflex “engagements”, but the results are examined with a view to the fundamental difference between experimental conditions that isolate the carotid sinus (open-loop) and intact physiological conditions (closed-loop). While baroreflex function under open-loop conditions can be described in terms of a single logistic curve, intact physiologic conditions require a family of logistic curves. The results suggest that the baroreflex is in a “floating” state whereby it is continuously resetting during the timeline of the experiment but with minute-by-minute average values that mimic the less complex step-wise resetting pattern reported under open-loop conditions. Furthermore, the results indicate that baroreflex function and resetting of the operating point gain is reflected not in terms of change in the values of blood pressure or RR-interval but in terms of change in the range of values of these variables prevailing under different experimental conditions

Effects of 6 Months of Exercise-Based Cardiac Rehabilitation on Autonomic Function and Neuro-Cardiovascular Stress Reactivity in Coronary Artery Disease Patients

Background Autonomic dysregulation represents a hallmark of coronary artery disease (CAD). Therefore, we investigated the effects of exercise-based cardiac rehabilitation (CR) on autonomic function and neuro-cardiovascular stress reactivity in CAD patients. Methods and Results Twenty-two CAD patients (4 women; 62±8 years) were studied before and following 6 months of aerobic- and resistance-training-based CR. Twenty-two similarly aged, healthy individuals (CTRL; 7 women; 62±11 years) served as controls. We measured blood pressure, muscle sympathetic nerve activity, heart rate, heart rate variability (linear and nonlinear), and cardiovagal (sequence method) and sympathetic (linear relationship between burst incidence and diastolic blood pressure) baroreflex sensitivity during supine rest. Furthermore, neuro-cardiovascular reactivity during short-duration static handgrip (20s) at 40% maximal effort was evaluated. Six months of CR lowered resting blood pressure (P\u3c0.05), as well as muscle sympathetic nerve activity burst frequency (48±8 to 39±11 bursts/min; P\u3c0.001) and burst incidence (81±7 to 66±17 bursts/100 heartbeats; P\u3c0.001), to levels that matched CTRL and improved sympathetic baroreflex sensitivity in CAD patients (P\u3c0.01). Heart rate variability (all P\u3e0.05) and cardiovagal baroreflex sensitivity (P=0.11) were unchanged following CR, yet values were not different pre-CR from CTRL (all P\u3e0.05). Furthermore, before CR, CAD patients displayed greater blood pressure and muscle sympathetic nerve activity reactivity to static handgrip versus CTRL (all P\u3c0.05); yet, responses were reduced following CR (all P\u3c0.05) to levels observed in CTRL. Conclusions Six months of exercise-based CR was associated with marked improvement in baseline autonomic function and neuro-cardiovascular stress reactivity in CAD patients, which may play a role in the reduced cardiac risk and improved survival observed in patients following exercise training