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Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to provide effective cardiorenal protection, reducing mortality in conditions such as heart failure and chronic kidney disease. While several mechanisms have been identified, recent research has shed light on the drug’s ability to attenuate sympathetic nervous system (SNS) activity. Controversy exists on whether this is due to the extra-renal effects of the drug, or simply due to its renoprotective effects. However, recent trials have highlighted the persistent efficacy of SGLT2i despite declining renal function. Therefore, investigating the ability of SGLT2i to attenuate the SNS independently of the kidney could lead to more insight into its mechanism of action. So far, there has been limited research done on investigating the extra-renal effects of SGLT2i in human subjects on dialysis where the glycosuric renal effects of SGLT2i are negligible. This current study therefore aims to investigate the effects of SGLT2i on the SNS in anuric haemodialysis patients. Methods: We developed a protocol for a mechanistic study to investigate the extra-renal effects of SGLT2i on the SNS. The study will be an investigator-led, open-label, prospective study involving 20 adult (aged ≥18 years) haemodialysis patients with a residual urine output of ≤250 mL/day. Participants will be administered empagliflozin 25 mg/day for 6 weeks. Baseline SNS activity will be measured before and after administration by microneurography to assess central SNS outflow. Secondary outcomes such as changes from baseline in SNS stressor response, heart rate variability, and endothelial function will also be examined. We hypothesize that the use of empagliflozin will result in reduced sympathetic drive in anuric haemodialysis patients. Discussion: This will be the first study evaluating the effects of SGLT2i on the SNS in haemodialysis subjects. This study aims to enhance our understanding of the potential role of SGLT2i-induced SNS reduction in the setting of markedly reduced renal function. The study has received ethics approval from the Royal Perth Hospital Human Research Ethics Committee (RGS0000003840) (Australian New Zealand Clinical Trials Registry [ANZCTR] ID: ACTRN12623001237673). [ABSTRACT FROM AUTHOR]

Sympathetic and blood pressure (BP) hyper-reactivity to stress may contribute to increased cardiovascular disease (CVD) risk in adults with major depressive disorder (MDD); however, whether this is evident in young adults with MDD without comorbid disease remains unclear. We hypothesized that acute stress-induced increases in muscle sympathetic nerve activity (MSNA) and BP would be exaggerated in young adults with MDD compared to healthy non-depressed young adults (HA) and that, in adults with MDD, greater symptom severity would be positively related to MSNA and BP reactivity. In 28 HA (17 female) and 39 young adults with MDD of mild-to-moderate severity (unmedicated; 31 female), MSNA (microneurography) and beat-to-beat BP (finger photoplethysmography) were measured at rest and during the cold pressor test (CPT) and Stroop color word test (SCWT). There were no group differences in resting MSNA (p = 0.24). Neither MSNA nor BP reactivity to either the CPT [MSNA: ∆24 ± 10 HA vs. ∆21 ± 11 bursts/min MDD, p = 0.67; mean arterial pressure (MAP): ∆22 ± 7 HA vs. ∆21 ± 10 mmHg MDD, p = 0.46)] or the SCWT (MSNA: ∆-4 ± 6 HA vs. ∆-5 ± 8 bursts/min MDD, p = 0.99; MAP: ∆7 ± 8 HA vs ∆9 ± 5 mmHg MDD; p = 0.82) were different between groups. In adults with MDD, symptom severity predicted MAP reactivity to the CPT (β = 0.78, SE = 0.26, p = 0.006), but not MSNA (p = 0.42). The mild-to-moderate symptom severity reflects only part of the MDD spectrum. Neither sympathetic nor BP stress reactivity are exaggerated in young adults with MDD; however, greater symptom severity may amplify BP reactivity to stress, thereby increasing CVD risk. • Greater blood pressure (BP) reactivity to stress predicts cardiovascular risk. • BP reactivity to stress is not exaggerated in young adults with depression. • Symptom severity predicted BP reactivity to stress in young adults with depression. [ABSTRACT FROM AUTHOR]

Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia (S p O 2 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation. NEW & NOTEWORTHY: This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals. [ABSTRACT FROM AUTHOR]

Muscle sympathetic nerve responses to sudden sensory stimuli have been elucidated in several studies on young healthy men, showing reproducible interindividual differences ranging from varying degrees of inhibition to no significant change, with very few subjects showing significant excitation. These individual response patterns have been shown to predict the neural response to mental stress and coupled blood pressure responses. The aim of this study was to investigate whether premenopausal healthy women show similar neural and blood pressure responses. Muscle sympathetic nerve recordings from the peroneal nerve were performed in 34 healthy women (mean age 27 ± 8 yr) during sudden sensory stimuli (electrical stimuli to a finger) and 3 min of mental stress (forced arithmetics). After sensory stimuli, 18 women showed varying degrees of inhibition of muscle sympathetic nerve activity (burst amplitude mean reduction 60%, range 34–100%). The remaining 16 showed no inhibition (mean 5%, range –31 to 28%; one subject exhibiting excitation). During 3 min of mental stress, the normalized change in burst incidence for muscle sympathetic nerve activity correlated with the percentage change of muscle sympathetic nerve activity induced by the sensory stimulation protocol (r = 0.64, P = 0.0042). In contrast to men, the neural responses did not predict changes in blood pressure. Thus, premenopausal females show a similar range of individual differences in defense-related muscle sympathetic neural responses as men, but no associated differences in blood pressure responses. Whether these patterns are unchanged after menopause remains to be investigated. NEW & NOTEWORTHY: Muscle sympathetic neural responses to sudden sensory stimuli in premenopausal women showed interindividual differences and the distribution of sympathetic responses was similar to that previously found in men. Despite this similarity, the associated differences in transient blood pressure responses seen in men were not found in women. The increased risk of developing hypertension in postmenopausal women warrants an investigation of whether these response patterns are altered after menopause. [ABSTRACT FROM AUTHOR]

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to provide effective cardiorenal protection, reducing mortality in conditions such as heart failure and chronic kidney disease. While several mechanisms have been identified, recent research has shed light on the drug’s ability to attenuate sympathetic nervous system (SNS) activity. Controversy exists on whether this is due to the extra-renal effects of the drug, or simply due to its renoprotective effects. However, recent trials have highlighted the persistent efficacy of SGLT2i despite declining renal function. Therefore, investigating the ability of SGLT2i to attenuate the SNS independently of the kidney could lead to more insight into its mechanism of action. So far, there has been limited research done on investigating the extra-renal effects of SGLT2i in human subjects on dialysis where the glycosuric renal effects of SGLT2i are negligible. This current study therefore aims to investigate the effects of SGLT2i on the SNS in anuric haemodialysis patients. Methods: We developed a protocol for a mechanistic study to investigate the extra-renal effects of SGLT2i on the SNS. The study will be an investigator-led, open-label, prospective study involving 20 adult (aged ≥18 years) haemodialysis patients with a residual urine output of ≤250 mL/day. Participants will be administered empagliflozin 25 mg/day for 6 weeks. Baseline SNS activity will be measured before and after administration by microneurography to assess central SNS outflow. Secondary outcomes such as changes from baseline in SNS stressor response, heart rate variability, and endothelial function will also be examined. We hypothesize that the use of empagliflozin will result in reduced sympathetic drive in anuric haemodialysis patients. Discussion: This will be the first study evaluating the effects of SGLT2i on the SNS in haemodialysis subjects. This study aims to enhance our understanding of the potential role of SGLT2i-induced SNS reduction in the setting of markedly reduced renal function. The study has received ethics approval from the Royal Perth Hospital Human Research Ethics Committee (RGS0000003840) (Australian New Zealand Clinical Trials Registry [ANZCTR] ID: ACTRN12623001237673).

The present study investigated the impact of central α2‐adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2‐adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg−1; maintenance infusion of 0.1–0.5 µg kg h−1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats−1, P = 0.003) most strongly for medium‐sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats−1; P < 0.001). Dexmedetomidine progressively de‐recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de‐recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats−1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ –0.09 ± 0.07 to Δ –0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium‐sized APs (normalized cluster 2: –6.0 ± 5 to –1.6 ± 2 % mmHg−1; P = 0.008). These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. Key points: Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear.This microneurographic study investigated the impact of a dexmedetomidine infusion (α2‐adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns.Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre.Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre.These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. [ABSTRACT FROM AUTHOR]

Body posture and biological sex exhibit independent effects on the sympathetic neural responses to dynamic exercise. However, the neural mechanisms (e.g., baroreflex) by which posture impacts sympathetic outflow during rhythmic muscular contractions, and whether biological sex affects posture-mediated changes in efferent sympathetic nerve traffic during exercise, remain unknown. Thus, we tested the hypotheses that increases in muscle sympathetic nerve activity (MSNA) would be greater during upright compared with supine rhythmic handgrip (RHG) exercise, and that females would demonstrate smaller increases in MSNA during upright RHG exercise than males. Twenty young (30 [6] yr; means [SD]) individuals (9 males, 11 females) underwent 6 min of supine and upright (head-up tilt 45°) RHG exercise at 40% maximal voluntary contraction with continuous measurements of MSNA (microneurography), blood pressure (photoplethysmography), and heart rate (electrocardiogram). In the pooled group, absolute MSNA burst frequency (P < 0.001), amplitude (P = 0.009), and total MSNA (P < 0.001) were higher during upright compared with supine RHG exercise. However, body posture did not impact the peak change in MSNA during RHG exercise (range: P = 0.063–0.495). Spontaneous sympathetic baroreflex gain decreased from rest to RHG exercise (P = 0.006) and was not impacted by posture (P = 0.347). During upright RHG exercise, males demonstrated larger increases in MSNA burst amplitude (P = 0.002) and total MSNA (P = 0.001) compared with females, which coincided with greater reductions in sympathetic baroreflex gain among males (P = 0.004). Collectively, these data indicate that acute attenuation of baroreflex-mediated sympathoinhibition permits increases in MSNA during RHG exercise and that males exhibit a greater reserve for efferent sympathetic neural recruitment during orthostasis than females. NEW & NOTEWORTHY: The impact of posture and sex on cardiovascular control during rhythmic handgrip (RHG) exercise is unknown. We show that increases in muscle sympathetic nerve activity (MSNA) during RHG are partly mediated by a reduction in sympathetic baroreflex gain. In addition, males demonstrate larger increases in total MSNA during upright RHG than females. These data indicate that the baroreflex partly mediates increases in MSNA during RHG and that males have a greater sympathetic vasoconstrictor reserve than females. [ABSTRACT FROM AUTHOR]

This article examines the role of central α2-adrenergic activity in sympathetic outflow and its potential as a treatment for anxiety-related disorders. The study focuses on the effects of dexmedetomidine, an α2-adrenergic receptor agonist, on peripheral sympathetic outflow in healthy individuals. The results indicate that dexmedetomidine infusion reduces blood pressure and muscle sympathetic nerve activity (MSNA) by de-recruiting large action potentials and activating medium-sized action potentials. The study also suggests a complex relationship between cortical command, α2-adrenergic influences, and baroreflex-mediated mechanisms in controlling sympathetic discharge during stress. However, it is important to consider that dexmedetomidine can cause sedation, which may have influenced the results. The article discusses the role of central α2-adrenergic mechanisms in regulating sympathetic postganglionic discharge patterns and suggests that α2-agonists may be beneficial in reducing sympathetic hyperarousal and cardiovascular risk in individuals with anxiety and stress-related disorders. Overall, this study provides valuable insights into the neural aspects of peripheral sympathetic outflow and the potential therapeutic effects of α2-adrenergic agonists. [Extracted from the article]

In the peripheral nervous system, spontaneous activity in sensory neurons is considered to be one of the 2 main drivers of chronic pain states, alongside neuronal sensitization. Despite this, the precise nature and timing of this spontaneous activity in neuropathic pain is not well-established. Here, we have performed a systematic search and data extraction of existing electrophysiological literature to shed light on which fibre types have been shown to maintain spontaneous activity and over what time frame. We examined both in vivo recordings of preclinical models of neuropathic pain, as well as microneurography recordings in humans. Our analyses reveal that there is broad agreement on the presence of spontaneous activity in neuropathic pain conditions, even months after injury or years after onset of neuropathic symptoms in humans. However, because of the highly specialised nature of the electrophysiological methods used to measure spontaneous activity, there is also a high degree of variability and uncertainty around these results. Specifically, there are very few directly controlled experiments, with less directly comparable data between human and animals. Given that spontaneous peripheral neuron activity is considered to be a key mechanistic feature of chronic pain conditions, it may be beneficial to conduct further experiments in this space. [ABSTRACT FROM AUTHOR]

Microneurographic recordings of muscle sympathetic nerve activity (MSNA) and the succeeding changes in beat-to-beat blood pressure (i.e., sympathetic transduction) provide important insights into the neural control of the circulation in humans. Despite its widespread use, the reliability of this technique remains unknown. Herein, we assessed the intra- and interday test-retest reliability of signal-averaging sympathetic transduction to blood pressure. Data were analyzed from 15 (9 M/6 F) young, healthy participants who completed two baseline recordings of fibular nerve MSNA separated by 60 min (intraday). The interday reliability was obtained in a subset of participants (n = 13, 9 M/4 F) who completed a follow-up MSNA study. Signal-averaging sympathetic transduction was quantified as peak change in diastolic (DBP) and mean arterial pressure (MAP) following a burst of MSNA. Analyses were also computed considering different MSNA burst sizes (quartiles of normalized MSNA) and burst patterns (singlets, couplets, triplets, and quadruplets+), as well as nonburst responses. Intraclass-correlation coefficients (ICCs) were used as the main reliability measure. Peak changes in MAP [intraday: ICC = 0.76 (0.30–0.92), P = 0.006; interday: ICC = 0.91 (0.63–0.97), P < 0.001] demonstrated very good to excellent reliability. Sympathetic transduction of MSNA burst size displayed moderate to very good reliability, though the reliability of MSNA burst pattern was poor to very good. Nonburst responses revealed poor intraday [ICC = 0.37 (−1.05 to 0.80), P = 0.21], but very good interday [ICC = 0.76 (0.18–0.93), P = 0.01] reliability. Intraday reliability measures were consistently lower than interday reliability. Similar results were obtained using DBP. Collectively, these findings provide evidence that the burst-triggering signal-averaging technique is a reliable measure of sympathetic transduction to blood pressure in young, healthy adults. NEW & NOTEWORTHY: We found that signal-averaging sympathetic transduction to blood pressure displayed very good to excellent intra- and interday test-retest reliability in healthy, young adults. Reliability analyses according to muscle sympathetic burst size, burst pattern, and nonburst response were less consistent. Results were similar when using diastolic or mean arterial pressure in the transduction calculation. These findings suggest that the signal-averaging technique can be used with confidence to investigate sympathetic transduction to blood pressure in humans across time. [ABSTRACT FROM AUTHOR]

Sleep disturbance, one of the most common menopausal symptoms, contributes to autonomic dysfunction and is linked to hypertension and cardiovascular risk. Longitudinal studies suggest that hyperreactivity of blood pressure (BP) to a stressor can predict the future development of hypertension. It remains unknown if postmenopausal females who experience sleep disturbance (SDG) demonstrate greater hemodynamic and sympathetic neural hyperreactivity to a stressor. We hypothesized that postmenopausal females with reported sleep disturbance would exhibit increased hemodynamic and sympathetic reactivity to a stressor compared with postmenopausal females without sleep disturbance (non-SDG). Fifty-five postmenopausal females (age, 62 ± 4 yr old; SDG, n = 36; non-SDG; n = 19) completed two study visits. The Menopause-Specific Quality of Life Questionnaire (MENQOL) was used to assess the presence of sleep disturbance (MENQOL sleep scale, ≥2 units). Beat-to-beat BP (finger plethysmography), heart rate (HR; electrocardiogram), and muscle sympathetic nerve activity (MSNA; microneurography; SDG, n = 25; non-SDG, n = 15) were continuously measured during a 10-min baseline and 2-min stressor (cold pressor test; CPT) in both groups. Menopause age and body mass index were similar between groups (P > 0.05). There were no differences between resting BP, HR, or MSNA (P > 0.05). HR and BP reactivity were not different between SDG and non-SDG (P > 0.05). In contrast, MSNA reactivity had a more rapid increase in the first 30 s of the CPT in the SDG (burst incidence, Δ10.2 ± 14.8 bursts/100 hb) compared with the non-SDG (burst incidence, Δ4.0 ± 14.8 bursts/100 hb, time x group, P = 0.011). Our results demonstrate a more rapid sympathetic neural reactivity to a CPT in postmenopausal females with perceived sleep disturbance, a finding that aligns with and advances recent evidence that sleep disturbance is associated with sympathetic neural hyperactivity in postmenopausal females. [ABSTRACT FROM AUTHOR]

Abstract Hereditary sensory and autonomic neuropathy type III (HSAN III), also known as familial dysautonomia or Riley–Day syndrome, results from an autosomal recessive genetic mutation that causes a selective loss of specific sensory neurones, leading to greatly elevated pain and temperature thresholds, poor proprioception, marked ataxia and disturbances in blood pressure control. Stretch reflexes are absent throughout the body, which can be explained by the absence of functional muscle spindle afferents – assessed by intraneural microelectrodes inserted into peripheral nerves in the upper and lower limbs. This also explains the greatly compromised proprioception at the knee joint, as assessed by passive joint‐angle matching. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. Surprisingly, proprioception is normal at the elbow, suggesting that participants are relying more on sensory cues from the overlying skin; microelectrode recordings have shown that myelinated tactile afferents in the upper and lower limbs appear to be normal. Nevertheless, the lack of muscle spindles does affect sensorimotor control in the upper limb: in addition to poor performance in the finger‐to‐nose test, manual performance in the Purdue pegboard task is much worse than in age‐matched healthy controls. Unlike those rare individuals with large‐fibre sensory neuropathy, in which both muscle spindle and cutaneous afferents are absent, those with HSAN III present as a means of assessing sensorimotor control following the selective loss of muscle spindle afferents.

Abstract Background Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Methods Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens β-alanine, BAM 8-22 and cowhage extract. Results The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not β-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by β-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and β-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A “slow bursting discharge pattern” was evoked in 25% of CM-fibers by β-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. Conclusion Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade.

Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to greater activity of the sympathetic nervous system, which is associated with hypertensive disorders of pregnancy. We hypothesized that resting muscle sympathetic nerve activity (MSNA) would be greater in women with obesity during pregnancy when compared with normal-weight women. Blood pressure, heart rate, and MSNA were recorded during 5 min of supine rest in 14 normal-weight women [body mass index (BMI) 22.1 ± 2.1 (SD) kg/m²] and 14 women with obesity (BMI 33.9 ± 3.5 kg/m²) during (early and late) pregnancy and postpartum. All women had uncomplicated pregnancies. Resting MSNA burst frequency was not different between groups during early (normal weight 17 ± 10 vs. obesity 22 ± 15 bursts/min, P = 0.35) but was significantly greater in the obesity group during late pregnancy (23 ± 13 vs. 35 ± 15 bursts/min, P = 0.031) and not different postpartum (10 ± 6 vs. 9 ± 7 bursts/min, P = 0.74). These findings were also apparent when comparing burst incidence and total activity. Although still within the normotensive range, systolic blood pressure was greater in the obesity group across all time points (P = 0.002). Diastolic blood pressure was lower during pregnancy compared with postpartum (P < 0.001) and not different between groups (P = 0.488). Heart rate increased throughout pregnancy in both groups (P < 0.001). Our findings suggest that maternal obesity is associated with greater increases in sympathetic activity even during uncomplicated pregnancy. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy. NEW & NOTEWORTHY The impact of maternal obesity on resting muscle sympathetic nerve activity was examined during (early and late) and after uncomplicated pregnancy. Resting muscle sympathetic nerve activity is not different during early pregnancy or postpartum but is significantly elevated in women with obesity during late pregnancy when compared with normal-weight women. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy. [ABSTRACT FROM AUTHOR]

Hereditary sensory and autonomic neuropathy type III (HSAN III), also known as familial dysautonomia or Riley–Day syndrome, results from an autosomal recessive genetic mutation that causes a selective loss of specific sensory neurones, leading to greatly elevated pain and temperature thresholds, poor proprioception, marked ataxia and disturbances in blood pressure control. Stretch reflexes are absent throughout the body, which can be explained by the absence of functional muscle spindle afferents – assessed by intraneural microelectrodes inserted into peripheral nerves in the upper and lower limbs. This also explains the greatly compromised proprioception at the knee joint, as assessed by passive joint‐angle matching. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. Surprisingly, proprioception is normal at the elbow, suggesting that participants are relying more on sensory cues from the overlying skin; microelectrode recordings have shown that myelinated tactile afferents in the upper and lower limbs appear to be normal. Nevertheless, the lack of muscle spindles does affect sensorimotor control in the upper limb: in addition to poor performance in the finger‐to‐nose test, manual performance in the Purdue pegboard task is much worse than in age‐matched healthy controls. Unlike those rare individuals with large‐fibre sensory neuropathy, in which both muscle spindle and cutaneous afferents are absent, those with HSAN III present as a means of assessing sensorimotor control following the selective loss of muscle spindle afferents. What is the topic of this review?Hereditary sensory and autonomic neuropathy type III (HSAN III).What advances does it highlight?In individuals with (HSAN III) functional muscle spindles appear to be absent throughout the body, though myelinated cutaneous afferents are present. The former may explain the poor proprioception at the knee joint, while the latter may explain why increasing cutaneous feedback improves proprioception at the knee. Reaching and lifting small objects was greatly compromised, arguing for an important role of muscles spindles in sensorimotor control. [ABSTRACT FROM AUTHOR]

Objective: Patients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechanoinsensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans. We used an in-silico model to elucidate molecular causes of CMi dysfunction as observed in single nerve fiber recordings (microneurography) of SFN patients. Approach: We analyzed microneurography data from 97 CMi-fibers from healthy individuals and 34 of SFN patients to identify activity-dependent changes in conduction velocity. Using the NEURON environment, we adapted a biophysical realistic preexisting CMi-fiber model with ion channels described by HodgkinHuxley dynamics for identifying molecular mechanisms leading to those changes. Via a grid search optimization, we assessed the interplay between different ion channels, Na-K-pump, and resting membrane potential. Main results: Changing a single ion channel conductance, Na-K-pump or membrane potential individually is not sufficient to reproduce in-silico CMi-fiber dysfunction of unchanged activity-dependent conduction velocity slowing and quicker normalization of conduction velocity after stimulation as observed in microneurography. We identified the best combination of mechanisms: increased conductance of potassium delayed-rectifier and decreased conductance of NaK-pump and depolarized membrane potential. When the membrane potential is unchanged, opposite changes in Na-K-pump and ion channels generate the same effect. Significance: Our study suggests that not one single mechanism accounts for pain-relevant changes in CMi-fibers, but a combination of mechanisms. A depolarized membrane potential, as previously observed in patients with neuropathic pain, leads to changes in the contribution of ion channels and the Na-K-pump. Thus, when searching for targets for the treatment of neuropathic pain, combinations of several molecules in interplay with the membrane potential should be regarded. [ABSTRACT FROM AUTHOR]

Background: Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Methods: Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens β-alanine, BAM 8-22 and cowhage extract. Results: The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not β-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by β-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and β-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A "slow bursting discharge pattern" was evoked in 25% of CM-fibers by β-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. Conclusion: Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade. [ABSTRACT FROM AUTHOR]

ObjectivePatients with small fiber neuropathy (SFN) suffer from neuropathic pain, which is still a therapeutic problem. Changed activation patterns of mechano-insensitive peripheral nerve fibers (CMi) could cause neuropathic pain. However, there is sparse knowledge about mechanisms leading to CMi dysfunction since it is difficult to dissect specific molecular mechanisms in humans. We used an in-silico model to elucidate molecular causes of CMi dysfunction as observed in single nerve fiber recordings (microneurography) of SFN patients.ApproachWe analyzed microneurography data from 97 CMi-fibers from healthy individuals and 34 of SFN patients to identify activity-dependent changes in conduction velocity. Using the NEURON environment, we adapted a biophysical realistic preexisting CMi-fiber model with ion channels described by Hodgkin-Huxley dynamics for identifying molecular mechanisms leading to those changes. Via a grid search optimization, we assessed the interplay between different ion channels, Na-K-pump, and resting membrane potential.Main resultsChanging a single ion channel conductance, Na-K-pump or membrane potential individually is not sufficient to reproduce in-silico CMi-fiber dysfunction of unchanged activity-dependent conduction velocity slowing and quicker normalization of conduction velocity after stimulation as observed in microneurography. We identified the best combination of mechanisms: increased conductance of potassium delayed-rectifier and decreased conductance of Na-K-pump and depolarized membrane potential. When the membrane potential is unchanged, opposite changes in Na-K-pump and ion channels generate the same effect.SignificanceOur study suggests that not one single mechanism accounts for pain-relevant changes in CMi-fibers, but a combination of mechanisms. A depolarized membrane potential, as previously observed in patients with neuropathic pain, leads to changes in the contribution of ion channels and the Na-K-pump. Thus, when searching for targets for the treatment of neuropathic pain, combinations of several molecules in interplay with the membrane potential should be regarded.

We conducted a systematic review and meta-analysis to determine the effect of acute poikilocapnic, high-altitude, and acute isocapnia hypoxemia on muscle sympathetic nerve activity (MSNA) and cardiovascular function. A comprehensive search across electronic databases was performed until June 2021. All observational designs were included: population (healthy individuals); exposures (MSNA during hypoxemia); comparators (hypoxemia severity and duration); outcomes (MSNA; heart rate, HR; and mean arterial pressure, MAP). Sixty-one studies were included in the meta-analysis. MSNA burst frequency increased by a greater extent during high-altitude hypoxemia [P < 0.001; mean difference (MD), þ 22.5 bursts/min; confidence interval (CI) = 19.20 to 25.84] compared with acute poikilocapnic hypoxemia (P < 0.001; MD, þ 5.63 bursts/min; CI = 4.09 to 7.17) and isocapnic hypoxemia (P < 0.001; MD, þ 4.72 bursts/min; CI = 3.37 to 6.07). MSNA burst amplitude was only elevated during acute isocapnic hypoxemia (P = 0.03; standard MD, þ 0.46 au; CI = 0.03 to 0.90), and MSNA burst incidence was only elevated during high-altitude hypoxemia [P < 0.001; MD, 33.05 bursts/100 heartbeats; CI = 28.59 to 37.51]. Meta-regression analysis indicated a strong relationship between MSNA burst frequency and hypoxemia severity for acute isocapnic studies (P < 0.001) but not acute poikilocapnia (P = 0.098). HR increased by the same extent across each type of hypoxemia [P < 0.001; MD þ 13.81 heartbeats/min; 95% CI = 12.59-15.03]. MAP increased during high-altitude hypoxemia (P < 0.001; MD, þ 5.06 mmHg; CI = 3.14-6.99), and acute isocapnic hypoxemia (P < 0.001; MD, þ 1.91 mmHg; CI = 0.84-2.97), but not during acute poikilocapnic hypoxemia (P = 0.95). Both hypoxemia type and severity influenced sympathetic nerve and cardiovascular function. These data are important for the better understanding of healthy human adaptation to hypoxemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In the field of neuroscience, a considerable number of commercial data acquisition and processing solutions rely on proprietary formats for data storage. This often leads to data being locked up in formats that are only accessible by using the original software, which may lead to interoperability problems. In fact, even the loss of data access is possible if the software becomes unsupported, changed, or otherwise unavailable. To ensure FAIR data management, strategies should be established to enable long-term, independent, and unified access to data in proprietary formats. In this work, we demonstrate PyDapsys, a solution to gain open access to data that was acquired using the proprietary recording system DAPSYS. PyDapsys enables us to open the recorded files directly in Python and saves them as NIX files, commonly used for open research in the electrophysiology domain. Thus, PyDapsys secures efficient and open access to existing and prospective data. The manuscript demonstrates the complete process of reverse engineering a proprietary electrophysiological format on the example of microneurography data collected for studies on pain and itch signaling in peripheral neural fibers. [ABSTRACT FROM AUTHOR]

Aging augments resting muscle sympathetic nerve activity (MSNA) and sympatho‐inhibition during mild dynamic 1‐leg exercise. To elucidate which reflexes elicit exercise‐induced inhibition, we recruited 19 (9 men) healthy volunteers (mean age 56 ± 9 SD years), assessed their peak oxygen uptake (VO2peak), and, on another day, measured heart rate (HR), blood pressure (BP) and MSNA (microneurography) at rest and during 1‐leg cycling (2 min each at 0 load and 30%–40% VO2peak), 3 times: (1) seated +2 min of postexercise circulatory occlusion (PECO) (elicit muscle metaboreflex); (2) supine (stimulate cardiopulmonary baroreflexes);and (3) seated, breathing 32% oxygen (suppress peripheral chemoreceptor reflex). While seated, MSNA decreased similarly during mild and moderate exercise (p < 0.001) with no increase during PECO (p = 0.44). Supine posture lowered resting MSNA (main effect p = 0.01) BP and HR. MSNA fell further (p = 0.04) along with diastolic BP and HR during mild, not moderate, supine cycling. Hyperoxia attenuated resting (main effect p = 0.01), but not exercise MSNA. In healthy middle‐age, the cardiopulmonary baroreflex and arterial chemoreflex modulate resting MSNA, but contrary to previous observations in young subjects, without counter‐regulatory offset by the sympatho‐excitatory metaboreflex, resulting in an augmented sympatho‐inhibitory response to mild dynamic leg exercise. [ABSTRACT FROM AUTHOR]

This article discusses a study conducted by Farmer and colleagues that used vagal nerve microneurography to measure activity from single axons within the vagus nerve that synchronize with cardiac activity. The study involved 15 healthy human participants who underwent the insertion of a microelectrode into either the left or right vagus nerve. The researchers identified 44 patterns resembling axons that displayed cardiac rhythmicity. The findings of the study provide valuable insights into cardiac autonomic physiology in humans and have implications for understanding cardiac conditions. However, there are limitations to the study, including the small sample size and the inability to confirm afferent classification. Overall, this study contributes to the field of cardiac neuroscience and provides an opportunity to better understand cardiac interoception in health and disease. [Extracted from the article]

Abstract Aging augments resting muscle sympathetic nerve activity (MSNA) and sympatho‐inhibition during mild dynamic 1‐leg exercise. To elucidate which reflexes elicit exercise‐induced inhibition, we recruited 19 (9 men) healthy volunteers (mean age 56 ± 9 SD years), assessed their peak oxygen uptake (VO2peak), and, on another day, measured heart rate (HR), blood pressure (BP) and MSNA (microneurography) at rest and during 1‐leg cycling (2 min each at 0 load and 30%–40% VO2peak), 3 times: (1) seated +2 min of postexercise circulatory occlusion (PECO) (elicit muscle metaboreflex); (2) supine (stimulate cardiopulmonary baroreflexes);and (3) seated, breathing 32% oxygen (suppress peripheral chemoreceptor reflex). While seated, MSNA decreased similarly during mild and moderate exercise (p

In the field of neuroscience, a considerable number of commercial data acquisition and processing solutions rely on proprietary formats for data storage. This often leads to data being locked up in formats that are only accessible by using the original software, which may lead to interoperability problems. In fact, even the loss of data access is possible if the software becomes unsupported, changed, or otherwise unavailable. To ensure FAIR data management, strategies should be established to enable long-term, independent, and unified access to data in proprietary formats. In this work, we demonstrate PyDapsys, a solution to gain open access to data that was acquired using the proprietary recording system DAPSYS. PyDapsys enables us to open the recorded files directly in Python and saves them as NIX files, commonly used for open research in the electrophysiology domain. Thus, PyDapsys secures efficient and open access to existing and prospective data. The manuscript demonstrates the complete process of reverse engineering a proprietary electrophysiological format on the example of microneurography data collected for studies on pain and itch signaling in peripheral neural fibers.

Purpose: Orthostatic hypotension is a common condition with heterogeneous and, in many cases, unclear underlying pathophysiology. Frequent symptoms are syncope and falls with a strong impact on daily life. A two-generation family with eight individuals segregating early-onset severe orthostatic hypotension with persistent tachycardia in upright position and repeated faints was identified. Our aim was to elucidate the underlying pathophysiology. Methods: One severely affected individual underwent thorough investigation with neurophysiological and blood pressure (BP) measurements, including direct recording of baroreflex-governed sympathetic nerve signalling and induction of BP rise with phenylephrine. Family members underwent parts of the examination. Genetic analysis using exome sequencing was performed. Results: Marked postural hypotension with greatly reduced cardiac preload was observed, but without signs of autonomic nervous system dysfunction: sympathetic nerve signalling was normal, as were catecholamine levels, and phenylephrine stimulation revealed a normal increase in BP. The results of the genetic analysis using exome sequencing comprising all known genes associated with the regulation of BP and catecholamine metabolism were normal. Conclusion: The combined findings suggest an autosomal dominant form of early-onset orthostatic hypotension with variable clinical expression and without any additional autonomic dysfunction. It is possible that further investigation will reveal an as yet undescribed entity of orthostatic hypotension transmitted as an autosomal dominant trait. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Diabetic metabolism causes changes of the chemical milieu including accumulation of reactive carbonyl species, for example, methylglyoxal (MGO). MGO activates chemosensitive TRPA1 on nociceptors, but the contribution to neuronal pathophysiology causing pain and hyperalgesia in diabetic neuropathy is not fully understood. Methods: We employed single‐nerve‐fiber recordings in type 2 diabetes patients with (spDN) and without cutaneous pain (DN) and in streptozotocin‐diabetic and healthy mice. In mice, we measured Ca++ transients in cultured DRG neurons and stimulated CGRP release from hairy skin. Results: In diabetic patients, we recorded a large proportion of pathologically altered nerve C‐fibers (79%). In spDN patients we found a higher percentage (72%) of spontaneously active C‐nociceptors than in DN patients (15%). The proportion of spontaneous activity was highest among pathological fibers with mechanoinsensitive fiber properties which are particularly sensitive to MGO in contrast to mechanosensitive fibers. Mouse polymodal nociceptors, in contrast to purely mechanosensitive C‐fibers, showed highest prevalence of TRPA1‐related chemosensitivity. In diabetic mice about 37% of polymodal nociceptors developed spontaneous activity and exhibited significantly greater MGO responses, indicating sensitized TRPA1 receptors. Low‐threshold mechanosensitive Aδ‐fibers were vigorously activated by MGO but independently of TRPA1 activation. Interpretation: Our translational findings suggest that TRPA1‐expressing C‐nociceptors, which in human correspond to mechanoinsensitive and in mice to polymodal nociceptors, are especially vulnerable to develop spontaneous activity. Those two different nociceptor classes might share the functional role as dicarbonyl‐sensitive chemosensors and represent the critical nociceptor population that support the development of pain and hyperalgesia in diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Metadata is essential for handling medical data according to FAIR principles. Standards are well-established for many types of electrophysiological methods but are still lacking for microneurographic recordings of peripheral sensory nerve fibers in humans. Developing a new concept to enhance laboratory workflows is a complex process. We propose a standard for structuring and storing microneurography metadata based on odML and odML-tables. Further, we present an extension to the odML-tables GUI that enables user-friendly search functionality of the database. With our open-source repository, we encourage other microneurography labs to incorporate odML-based metadata into their experimental routines. [ABSTRACT FROM AUTHOR]

Dexterous object manipulation depends critically on information about forces normal and tangential to the fingerpads, and also on torque associated with object orientation at grip surfaces. We investigated how torque information is encoded by human tactile afferents in the fingerpads and compared them to 97 afferents recorded in monkeys (n =3; 2 females) in our previous study. Human data included slowly-adapting Type-II (SA-II) afferents, which are absent in the glabrous skin of monkeys. Torques of different magnitudes (3.5-7.5 mNm) were applied in clockwise and anticlockwise directions to a standard central site on the fingerpads of 34 human subjects (19 females). Torques were superimposed on a 2, 3, or 4 N background normal force. Unitary recordings were made from fastadapting Type-I (FA-I, n =39), and slowly-adapting Type-I (SA-I, n= 31) and Type-II (SA-II, n =13) afferents supplying the fingerpads via microelectrodes inserted into the median nerve. All three afferent types encoded torque magnitude and direction, with torque sensitivity being higher with smaller normal forces. SA-I afferent responses to static torque were inferior to dynamic stimuli in humans, while in monkeys the opposite was true. In humans this might be compensated by the addition of sustained SA-II afferent input, and their capacity to increase or decrease firing rates with direction of rotation. We conclude that the discrimination capacity of individual afferents of each type was inferior in humans than monkeys which could be because of differences in fingertip tissue compliance and skin friction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls. Methods and results: We compared data acquired in 177 conventionally‐treated, stable non‐diabetic patients in sinus rhythm, aged 18–79 years (149 males; 28 females; left ventricular ejection fraction [LVEF] 25 ± 11% [mean ± standard deviation]; range 5–60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; aged 18–81 years). In heart failure, MSNA ranged between 7 and 90 bursts·min−1, proportionate to heart rate (p < 0.0001) and body mass index (BMI) (p = 0.03), but was unrelated to age, blood pressure, or drug therapy. Mean MSNA, adjusted for age, sex, BMI, and heart rate, was greater in heart failure (+14.2 bursts·min−1; 95% confidence interval [CI] 12.1–16.3; p < 0.0001), but lower in women (−5.0 bursts·min−1; 95% CI 3.4–6.6; p < 0.0001). With spline modeling, LVEF accounted for 9.8% of MSNA variance; MSNA related inversely to LVEF below an inflection point of ∼21% (p < 0.006), but not above. Burst incidence was greater in ischaemic than dilated cardiomyopathy (p = 0.01), and patients with sleep apnoea (p = 0.03). Burst frequency correlated inversely with stroke volume (p < 0.001), cardiac output (p < 0.001), and peak oxygen consumption (p = 0.002), and directly with norepinephrine (p < 0.0001) and peripheral resistance (p < 0.001). Conclusion: Burst frequency and incidence exceeded normative values in only ∼53% and ∼33% of patients. Such diversity encourages selective deployment of sympatho‐modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation. [ABSTRACT FROM AUTHOR]

Sympathetic activation is a hallmark of pregnancy. However, longitudinal assessments of muscle sympathetic nerve activity (MSNA) in pregnancy are scarce and have primarily focused on burst occurrence (frequency) at rest, despite burst strength (amplitude) representing distinct characteristics of sympathetic outflow. Thus, we assessed MSNA burst amplitude distributions in healthy women to determine the impact of normal pregnancy on neural discharge patterns in response to orthostatic stress. Twenty-six women were studied longitudinally during pre-, early- (4-8 wk of gestation), and late (32-36 wk) pregnancy, as well as postpartum (6-10 wk after delivery). MSNA, blood pressure (BP), and heart rate (HR) were measured in the supine posture and during graded head-up tilt (30° and 60° HUT). Mean and median MSNA burst amplitudes were used to characterize burst amplitude distribution. In late pregnancy, women demonstrated smaller increases in HR (P < 0.001) during 60° HUT and larger increases in systolic BP (P = 0.043) throughout orthostasis, compared with prepregnancy. The increase in MSNA burst frequency during late-relative to prepregnancy (Late: D14[10] vs. Pre: D21[9] bursts/min; P = 0.001) was smaller during 60° HUT, whereas increases in burst incidence were smaller in late-relative to prepregnancy throughout orthostasis (P = 0.009). Nonetheless, median burst amplitude was smaller throughout orthostasis in late compared with prepregnancy (P = 0.038). Thus, while supine MSNA burst frequency was greater in late pregnancy, increases in burst frequency and strength during orthostasis were attenuated. These smaller, orthostatically induced MSNA increases may reflect natural adaptions of pregnancy serving to prevent sympathetic hyper-reactivity that is common in pathological states. [ABSTRACT FROM AUTHOR]

Introduction: Mechanistic studies suggested that excess sympathetic activity promotes arterial hypertension while worsening insulin sensitivity. Older patients with type 2 diabetes are at particularly high cardiovascular and metabolic risk. However, data on sympathetic activity in this population is scarce. Methods: We studied 61 patients with type 2 diabetes mellitus (22 women, 60.9 ± 1.4 years; 39 men, 60.9 ± 1.4 years). They had to have diabetes for at least 2 years, a hemoglobin A1c of 6.5-10%, a body-mass-index of 20-40 kg/m², and had to be treated with stable doses of metformin only. We recorded ECG, finger and brachial blood pressure, and muscle sympathetic nerve activity (MSNA). Results: MSNA was 37.5 ± 2.5 bursts/min in women and 39.0 ± 2.0 bursts/min in men (p = 0.55). MSNA expressed as burst incidence was 52.7 ± 2.0 bursts/100 beats in women and 59.2 ± 3.1 bursts/100 beats in men (p = 0.21). Five out of 39 men (12.8%) and two out of 22 women (9.1%) exhibited resting MSNA measurements above the 95th percentile for sex and age. In the pooled analysis, MSNA was not significantly correlated with systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, body composition, or HbA1c (r² < 0.02, p > 0.26 for all). Discussion: We conclude that relatively few older patients with type 2 diabetes mellitus exhibit increased MSNA. The large interindividual variability in MSNA cannot be explained by gender, blood pressure, body mass index, or glycemic control. [ABSTRACT FROM AUTHOR]

Normal pregnancy is associated with vast adjustments in cardiovascular autonomic control. Sympathetic baroreflex sensitivity has been reported to be attenuated during pregnancy in animal models, but most studies in humans are cross-sectional and findings from longitudinal case studies are inconclusive. It remains unclear how sympathetic baroreflex sensitivity is altered longitudinally during pregnancy within an individual in different body postures. Therefore, this study examined the impact of posture on sympathetic baroreflex sensitivity in 24 normal-weight normotensive pregnant women. Spontaneous sympathetic baroreflex sensitivity was assessed during early (6–11 weeks) and late (32–36 weeks) pregnancy and 6–10 weeks postpartum in the supine posture and graded head-up tilt (30° and 60°). In addition, data from the postpartum period were compared with (and no different to) 18 age-matched non-pregnant women to confirm that the postpartum period was reflective of a non-pregnant condition (online supplement). When compared with postpartum (−3.8 ± 0.4 bursts/100 heartbeats/mmHg), supine sympathetic baroreflex sensitivity was augmented during early pregnancy (−5.9 ± 0.4 bursts/100 heartbeats/mmHg, P < 0.001). However, sympathetic baroreflex sensitivity at 30° or 60° head-up tilt was not different between any phase of gestation (P > 0.05). When compared to supine, sympathetic baroreflex sensitivity at 60° head-up tilt was significantly blunted during early (Δ2.0 ± 0.7 bursts/100 heartbeats/mmHg, P = 0.024) and late (Δ1.5 ± 0.6 bursts/100 heartbeats/mmHg, P = 0.049) pregnancy but did not change postpartum (Δ0.4 ± 0.6 bursts/100 heartbeats/mmHg, P = 1.0). These data show that time-course changes in sympathetic baroreflex sensitivity are dependent on the posture it is examined in and provides a foundation of normal blood pressure regulation during pregnancy for future studies in women at risk for adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

IntroductionMechanistic studies suggested that excess sympathetic activity promotes arterial hypertension while worsening insulin sensitivity. Older patients with type 2 diabetes are at particularly high cardiovascular and metabolic risk. However, data on sympathetic activity in this population is scarce.MethodsWe studied 61 patients with type 2 diabetes mellitus (22 women, 60.9 ± 1.4 years; 39 men, 60.9 ± 1.4 years). They had to have diabetes for at least 2 years, a hemoglobin A1c of 6.5–10%, a body-mass-index of 20–40 kg/m2, and had to be treated with stable doses of metformin only. We recorded ECG, finger and brachial blood pressure, and muscle sympathetic nerve activity (MSNA).ResultsMSNA was 37.5 ± 2.5 bursts/min in women and 39.0 ± 2.0 bursts/min in men (p = 0.55). MSNA expressed as burst incidence was 52.7 ± 2.0 bursts/100 beats in women and 59.2 ± 3.1 bursts/100 beats in men (p = 0.21). Five out of 39 men (12.8%) and two out of 22 women (9.1%) exhibited resting MSNA measurements above the 95th percentile for sex and age. In the pooled analysis, MSNA was not significantly correlated with systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, body composition, or HbA1c (r2 < 0.02, p > 0.26 for all).DiscussionWe conclude that relatively few older patients with type 2 diabetes mellitus exhibit increased MSNA. The large interindividual variability in MSNA cannot be explained by gender, blood pressure, body mass index, or glycemic control.

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). [ABSTRACT FROM AUTHOR]

What is the purpose of sympathetic neuronal action potential (AP) discharge and recruitment patterns for human vascular regulation? This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. We used microneurography to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to detect sympathetic APs during a baseline condition and intravenous dexmedetomidine infusion (α 2 -adrenergic agonist, 10 min loading infusion of 0.225 µg kg -1 ; maintenance infusion of 0.1-0.5 µg kg h -1 ) in six healthy individuals (5 females, 27 ± 6 years). Arterial blood samples provided NPY (enzyme-linked immunosorbent assay) and norepinephrine (Liquid Chromatography Tandem Mass Spectrometry) levels during baseline and the dexmedetomidine maintenance infusion. Linear mixed model regressions assessed the relationships between AP discharge, recruitment, and neurotransmitter levels. Across baseline and the dexmedetomidine condition, NPY levels were positively related to mean arterial pressure (β = 1.63 [0.34], P = 0.002), total AP clusters (β = 0.90 [0.22], P = 0.005), and AP frequency (β = 0.11 [0.03], P = 0.003). Norepinephrine levels were not related to mean arterial pressure (β = 0.03 [0.02], P = 0.133) but were positively related to total AP clusters (β = 19.50 [7.07], P = 0.030) and AP frequency (β = 2.66 [0.81], P = 0.014). These data suggest that sympathetic neuronal discharge and recruitment patterns regulate NPY and norepinephrine bioavailability in healthy adults. As such, sympathetic neuronal firing strategies are important for human vascular regulation.

Fast-adapting type 1 (FA-1) and slow-adapting type 1 (SA-1) first-order neurons in the human tactile system have distal axons that branch in the skin and form many transduction sites, yielding receptive fields with many highly sensitive zones or ‘subfields.’ We previously demonstrated that this arrangement allows FA-1 and SA-1 neurons to signal the geometric features of touched objects, specifically the orientation of raised edges scanned with the fingertips. Here, we show that such signaling operates for fine edge orientation differences (5–20°) and is stable across a broad range of scanning speeds (15–180 mm/s); that is, under conditions relevant for real-world hand use. We found that both FA-1 and SA-1 neurons weakly signal fine edge orientation differences via the intensity of their spiking responses and only when considering a single scanning speed. Both neuron types showed much stronger edge orientation signaling in the sequential structure of the evoked spike trains, and FA-1 neurons performed better than SA-1 neurons. Represented in the spatial domain, the sequential structure was strikingly invariant across scanning speeds, especially those naturally used in tactile spatial discrimination tasks. This speed invariance suggests that neurons’ responses are structured via sequential stimulation of their subfields and thus links this capacity to their terminal organization in the skin. Indeed, the spatial precision of elicited action potentials rationally matched spatial acuity of subfield arrangements, which corresponds to a spatial period similar to the dimensions of individual fingertip ridges.

This work aims to improve FAIR-ness of the microneurography research by integrating the local (meta)data to existing research data infrastructures. In the previous work, we developed an odML based solution for local metadata storage of microneurography data. However, this solution is limited to a narrow community. As a next step, we propose the integration into the Local Data Hubs, data-sharing services within NFDI4Health infrastructure. We outline a first concept, that streams chosen data from the established odMLtables GUI. [ABSTRACT FROM AUTHOR]

Purpose: Spontaneous sympathetic transduction reflects the vascular and/or pressor responses to bursts of muscle sympathetic nerve activity (MSNA). Separately, signal-averaging and regression-based approaches have been implemented to quantify resting sympathetic transduction. It is unknown whether the outcomes of these analytical approaches provide (dis)similar information, which is imperative for between-study comparisons and the amalgamation of results for synthesis of multiple studies (i.e., meta-analyses). We explored the diastolic blood pressure (DBP) responses to spontaneous bursts of MSNA between these two methods of analysis. Methods: Resting beat-by-beat DBP (via finger photoplethysmography) and common peroneal nerve MSNA (via microneurography) were recorded in 52 healthy, normotensive adults (age 38 ± 20 years; 19 females). For the signal-averaged method, transduction was quantified as the mean peak increase in DBP (ΔDBP) during the 12 cardiac cycles following each MSNA burst. In addition, DBP was regressed to a moving two-cardiac-cycle window of normalized relative burst height (mmHg/relative %) to provide the regression-based transduction outcome. Results: The signal-averaged (1.2 ± 0.7 mmHg) and regression-based approaches (0.009 ± 0.016 mmHg/%) were unrelated (ρ = 0.03, p = 0.86). Adding to the discrepancy, only the signal-averaging approach demonstrated a lower transduction in middle-aged-older males versus younger males. Conclusions: The decision of which method to use when calculating sympathetic transduction influences study outcomes, with the two most common methods of determining transduction being unrelated. There are challenges of making sweeping conclusions across studies if different analysis strategies are implemented. An understanding of when to use each method is needed to adopt a harmonized approach to quantifying sympathetic transduction. [ABSTRACT FROM AUTHOR]

To understand neural encoding of neuropathic pain, evoked and resting activity of peripheral human C-fibers are studied via microneurography experiments. Before different spiking patterns can be analyzed, spike sorting is necessary to distinguish the activity of particular fibers of a recorded bundle. Due to single-electrode measurements and high noise contamination, standard methods based on spike shapes are insufficient and need to be enhanced with additional information. Such information can be derived from the activity-dependent slowing of the fiber propagation speed, which in turn can be assessed by introducing continuous "background" 0.125-0.25Hz electrical stimulation and recording the corresponding responses from the fibers. Each fiber's speed propagation remains almost constant in the absence of spontaneous firing or additional stimulation. This way, the responses to the "background stimulation" can be sorted by fiber. In this article, we model the changes in the propagation speed resulting from the history of fiber activity with polynomial regression. This is done to assess the feasibility of using the developed models to enhance the spike shape-based sorting. In addition to human microneurography data, we use animal in-vitro recordings with a similar stimulation protocol as higher signal-to-noise ratio data example for the models. [ABSTRACT FROM AUTHOR]