Modulation Of Muscle Sympathetic Nerve Activity Research Articles

Electrical stimulation of the ventromedial prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure.

We recently showed that transcranial alternating current stimulation of the dorsolateral prefrontal cortex modulates spontaneous bursts of muscle sympathetic nerve activity, heart rate, and blood pressure (Sesa-Ashton G, Wong R, McCarthy B, Datta S, Henderson LA, Dawood T, Macefield VG. Stimulation of the dorsolateral prefrontal cortex modulates muscle sympathetic nerve activity and blood pressure in humans. Cereb Cortex Comm. 2022:3:2tgac017.). Stimulation was delivered between scalp electrodes placed over the nasion and electroencephalogram (EEG) electrode site F3 (left dorsolateral prefrontal cortex) or F4 (right dorsolateral prefrontal cortex), and therefore the current passed within the anatomical locations underlying the left and right ventromedial prefrontal cortices. Accordingly, we tested the hypothesis that stimulation of the left and right ventromedial prefrontal cortices would also modulate muscle sympathetic nerve activity, although we predicted that this would be weaker than that seen during dorsolateral prefrontal cortex stimulation. We further tested whether stimulation of the right ventromedial prefrontal cortices would cause greater modulation of muscle sympathetic nerve activity, than stimulation of the left ventromedial prefrontal cortices. In 11 individuals, muscle sympathetic nerve activity was recorded via microelectrodes inserted into the right common peroneal nerve, together with continuous blood pressure, electrocardiogram, and respiration. Stimulation was achieved using transcranial alternating current stimulation, +2 to -2mA, 0.08Hz, 100cycles, applied between electrodes placed over the nasion, and EEG electrode site FP1, (left ventromedial prefrontal cortices) or FP2 (right ventromedial prefrontal cortices); for comparison, stimulation was also applied over F4 (right dorsolateral prefrontal cortex). Stimulation of all three cortical sites caused partial entrainment of muscle sympathetic nerve activity to the sinusoidal stimulation, together with modulation of blood pressure and heart rate. We found a significant fall in mean blood pressure of ~6mmHg (P = 0.039) during stimulation of the left ventromedial prefrontal cortices, as compared with stimulation of the right. We have shown, for the first time, that transcranial alternating current stimulation of the ventromedial prefrontal cortices modulates muscle sympathetic nerve activity and blood pressure in awake humans at rest. However, it is unclear if this modulation occurred through the same brain pathways activated during transcranial alternating current stimulation of the dorsolateral prefrontal cortex.

GABAA Receptors Modulate Muscle Sympathetic Nerve Activity and Pressor Responses to Skeletal Muscle Metaboreflex Activation in Humans

The cardiovascular responses to exercise are mediated by several interactive neural mechanisms including central command, arterial baroreflex and the exercise pressor reflex (EPR). Although all three neural mechanisms are relevant for cardiovascular regulation during exercise, considerable attention has been given to the EPR due to its importance determining the magnitude of sympathoexcitation during exercise. The sensory component of the EPR is comprised of group III and IV skeletal muscle afferents that respond to both mechanical (i.e., muscle mechanoreflex) and metabolic (i.e., muscle metaboreflex) stimuli. Despite it is well accepted that EPR is one of the principal mediators of the cardiovascular response to exercise, the possible neurotransmitters involved during EPR activation are not fully understood. Recently, we showed that central GABAergic mechanisms are involved in the muscle mechanoreflex‐mediated cardiac vagal withdrawal at the onset of exercise in humans (Am J Physiol Heart Circ Physiol 2018;314:H716–H723). However, whether GABAergic mechanisms are involved in the neurocardiovascular responses evoked by the metabolic component of EPR remains unknown. Therefore, the present study was undertaken to test the hypothesis that GABAA receptors modulate muscle sympathetic nerve activity (MSNA) and arterial blood pressure (BP) responses to skeletal muscle metaboreflex activation in humans. Eight healthy subjects (2 women) aged between 18 to 24 years were enrolled. Experiments were conducted in a randomized, double‐blinded, placebo‐controlled, and crossover design, whereby each subject performed 2 min of ischemic isometric handgrip (IHG) exercise at 30% of maximal voluntary contraction followed by 2 min of post‐exercise ischemia (PEI) to isolate the muscle metaboreflex. Trials were randomly conducted before and after oral administration of placebo or diazepam (10 mg), a benzodiazepine that produces an enhancement in GABAA activity. The MSNA (microneurography), BP (finger photoplethysmography) and heart rate (HR – electrocardiogram) were continuously measured at rest, during IHG, PEI and recovery. During IHG, MSNA bursts frequency and diastolic BP increased from rest before diazepam administration (Δ11 ± 6 bursts/min and Δ26 ± 10 mmHg, respectively) and further increased after diazepam (Δ31 ± 14 bursts/min and Δ34 ± 9 mmHg, respectively) (P<0.05). During PEI, MSNA and diastolic BP remained elevated from baseline before diazepam administration (Δ9 ± 5 bursts/min and Δ25 ± 11 mmHg, respectively) and this elevation was increased after diazepam (Δ19 ± 10 bursts/min and Δ28 ± 11 mmHg, respectively) (P<0.05). Systolic BP and HR responses to IHG and PEI were similar before and after diazepam (P>0.05). Importantly, oral administration of placebo pill had no effect on any neurocardiovascular variables (all P>0.05). In summary, these findings demonstrate for the first time that GABAA receptors modulate MSNA and pressor responses to activation of metabolically sensitive skeletal muscle afferents in healthy subjects. These findings allow us to suggest that muscle metaboreflex is a potential source of synaptic drive to GABAergic neurons in humans.Support or Funding InformationCNPq, FAPDF and CAPES.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cutaneous Mechanoreceptor Feedback from the Hand and Foot Can Modulate Muscle Sympathetic Nerve Activity

Stimulation of high threshold mechanical nociceptors on the skin can modulate efferent sympathetic outflow. Whether low threshold mechanoreceptors from glabrous skin are similarly capable of modulating autonomic outflow is unclear. Therefore, the purpose of this study was to examine the effects of cutaneous afferent feedback from the hand palm and foot sole on efferent muscle sympathetic nerve activity (MSNA). Fifteen healthy young participants (9 male; 25 ± 3 years [range: 22–29]) underwent microneurographic recording of multi-unit MSNA from the right fibular nerve during 2 min of baseline and 2 min of mechanical vibration (150 Hz, 220 μm peak-to-peak) applied to the left hand or foot. Each participant completed three trials of both hand and foot stimulation, each separated by 5 min. MSNA burst frequency decreased similarly during the 2 min of both hand (20.8 ± 8.9 vs. 19.3 ± 8.6 bursts/minute [Δ −8%], p = 0.035) and foot (21.0 ± 8.3 vs. 19.5 ± 8.3 bursts/minute [Δ −8%], p = 0.048) vibration but did not alter normalized mean burst amplitude or area (All p > 0.05). Larger reductions in burst frequency were observed during the first 10 s (onset) of both hand (20.8 ± 8.9 vs. 17.0 ± 10.4 [Δ −25%], p < 0.001) and foot (21.0 ± 8.3 vs. 18.3 ± 9.4 [Δ −16%], p = 0.035) vibration, in parallel with decreases in normalized mean burst amplitude (hand: 0.45 ± 0.06 vs. 0.36 ± 0.14% [Δ −19%], p = 0.03; foot: 0.47 ± 0.07 vs. 0.34 ± 0.19% [Δ −27%], p = 0.02) and normalized mean burst area (hand: 0.42 ± 0.05 vs. 0.32 ± 0.12% [Δ −25%], p = 0.003; foot: 0.47 ± 0.05 vs. 0.34 ± 0.16% [Δ −28%], p = 0.01). These results demonstrate that tactile feedback from the hands and feet can influence efferent sympathetic outflow to skeletal muscle.

Vestibular modulation of muscle sympathetic nerve activity by the utricle during sub-perceptual sinusoidal linear acceleration in humans

We assessed the capacity for the vestibular utricle to modulate muscle sympathetic nerve activity (MSNA) during sinusoidal linear acceleration at amplitudes extending from imperceptible to clearly perceptible. Subjects (n = 16) were seated in a sealed room, eliminating visual cues, mounted on a linear motor that could deliver peak sinusoidal accelerations of 30 mG in the antero-posterior direction. Subjects sat on a padded chair with their neck and head supported vertically, thereby minimizing somatosensory cues, facing the direction of motion in the anterior direction. Each block of sinusoidal motion was applied at a time unknown to subjects and in a random order of amplitudes (1.25, 2.5, 5, 10, 20 and 30 mG), at a constant frequency of 0.2 Hz. MSNA was recorded via tungsten microelectrodes inserted into muscle fascicles of the common peroneal nerve. Subjects used a linear potentiometer aligned to the axis of motion to indicate any perceived movement, which was compared with the accelerometer signal of actual room movement. On average, 67 % correct detection of movement did not occur until 6.5 mG, with correct knowledge of the direction of movement at ~10 mG. Cross-correlation analysis revealed potent sinusoidal modulation of MSNA even at accelerations subjects could not perceive (1.25–5 mG). The modulation index showed a positive linear increase with acceleration amplitude, such that the modulation was significantly higher (25.3 ± 3.7 %) at 30 mG than at 1.25 mG (15.5 ± 1.2 %). We conclude that selective activation of the vestibular utricle causes a pronounced modulation of MSNA, even at levels well below perceptual threshold, and provides further evidence in support of the importance of vestibulosympathetic reflexes in human cardiovascular control.

Vestibular modulation of muscle sympathetic nerve activity during sinusoidal linear acceleration in supine humans.

The utricle and saccular components of the vestibular apparatus preferentially detect linear displacements of the head in the horizontal and vertical planes, respectively. We previously showed that sinusoidal linear acceleration in the horizontal plane of seated humans causes a pronounced modulation of muscle sympathetic nerve activity (MSNA), supporting a significant role for the utricular component of the otolithic organs in the control of blood pressure. Here we tested the hypothesis that the saccule can also play a role in blood pressure regulation by modulating lower limb MSNA. Oligounitary MSNA was recorded via tungsten microelectrodes inserted into the common peroneal nerve in 12 subjects, laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal linear accelerations-decelerations (peak acceleration ±4 mG) were applied in the rostrocaudal axis (which predominantly stimulates the saccule) and in the mediolateral axis (which also engages the utricle) at 0.08 Hz. The modulation of MSNA in the rostrocaudal axis (29.4 ± 3.4%) was similar to that in the mediolateral axis (32.0 ± 3.9%), and comparable to that obtained by stimulation of the utricle alone in seated subjects with the head vertical. We conclude that both the saccular and utricular components of the otolithic organs play a role in the control of arterial pressure during postural challenges.

Neck proprioceptors contribute to the modulation of muscle sympathetic nerve activity to the lower limbs of humans

Several different strategies have now been used to demonstrate that the vestibular system can modulate muscle sympathetic nerve activity (MSNA) in humans and thereby contribute to the regulation of blood pressure during changes in posture. However, it remains to be determined how the brain differentiates between head-only movements that do not require changes in vasomotor tone in the lower limbs from body movements that do require vasomotor changes. We tested the hypothesis that neck movements modulate MSNA in the lower limbs of humans. MSNA was recorded in 10 supine young adult subjects, at rest, during sinusoidal stretching of neck muscles (100 cycles, 35° peak to peak at 0.37 ± 0.02 Hz) and during a ramp-and-hold (17.5° for 54 ± 9 s) static neck muscle stretch, while their heads were held fixed in space. Cross-correlation analysis revealed cyclical modulation of MSNA during sinusoidal neck muscle stretch (modulation index 45.4 ± 5.3 %), which was significantly less than the cardiac modulation of MSNA at rest (78.7 ± 4.2 %). Interestingly, cardiac modulation decreased significantly during sinusoidal neck displacement (63.0 ± 9.3 %). By contrast, there was no significant difference in MSNA activity during static ramp-and-hold displacements of the neck to the right or left compared with that with the head and neck aligned. These data suggest that dynamic, but not static, neck movements can modulate MSNA, presumably via projections of muscle spindle afferents to the vestibular nuclei, and may thus contribute to the regulation of blood pressure during orthostatic challenges.

Vestibular modulation of muscle sympathetic nerve activity by the utricle during sub-perceptual sinusoidal linear acceleration in humans

We assessed the capacity for the vestibular utricle to modulate muscle sympathetic nerve activity (MSNA) during sinusoidal linear acceleration at amplitudes extending from imperceptible to clearly perceptible. Subjects (n = 16) were seated in a sealed room, eliminating visual cues, mounted on a linear motor that could deliver peak sinusoidal accelerations of 30 mG in the antero-posterior direction. Subjects sat on a padded chair with their neck and head supported vertically, thereby minimizing somatosensory cues, facing the direction of motion in the anterior direction. Each block of sinusoidal motion was applied at a time unknown to subjects and in a random order of amplitudes (1.25, 2.5, 5, 10, 20 and 30 mG), at a constant frequency of 0.2 Hz. MSNA was recorded via tungsten microelectrodes inserted into muscle fascicles of the common peroneal nerve. Subjects used a linear potentiometer aligned to the axis of motion to indicate any perceived movement, which was compared with the accelerometer signal of actual room movement. On average, 67% correct detection of movement did not occur until 6.5 mG, with correct knowledge of the direction of movement at ~10 mG. Cross-correlation analysis revealed potent sinusoidal modulation of MSNA even at accelerations subjects could not perceive (1.25-5 mG). The modulation index showed a positive linear increase with acceleration amplitude, such that the modulation was significantly higher (25.3 ± 3.7%) at 30 mG than at 1.25 mG (15.5 ± 1.2%). We conclude that selective activation of the vestibular utricle causes a pronounced modulation of MSNA, even at levels well below perceptual threshold, and provides further evidence in support of the importance of vestibulosympathetic reflexes in human cardiovascular control.

Competitive interactions between vestibular and cardiac rhythms in the modulation of muscle sympathetic nerve activity

We tested the hypothesis that vestibular and cardiac rhythms compete to modulate muscle sympathetic nerve activity (MSNA) in human subjects. Sinusoidal galvanic vestibular stimulation was applied across the mastoid processes at each subject's cardiac frequency and at ± 0.1, ± 0.2, ± 0.3 and ± 0.6 Hz. Cyclic modulation of MSNA was weakest at this central frequency (44.8 ± 2.3%; n = 8); significantly lower than when delivered 0.1 Hz lower (57.7 ± 3.3%) or 0.1 Hz higher (56.3 ± 3.3%) than this frequency. We conclude that vestibular inputs compete with baroreceptor inputs operating at the cardiac rhythm, with vestibular modulation of MSNA being lowest when competition with the baroreceptors is highest.

Dynamic arterial baroreflex function during high intensity exercise in humans: insights into sympathetic control

Dynamic arterial baroreflex function during high intensity exercise in humans: insights into sympathetic control

Sympathetic responses to vestibular activation in humans

Activation of sympathetic neural traffic via the vestibular system is referred to as the vestibulosympathetic reflex. Investigations of the vestibulosympathetic reflex in humans have been limited to the past decade, and the importance of this reflex in arterial blood pressure regulation is still being determined. This review provides a summary of sympathetic neural responses to various techniques used to engage the vestibulosympathetic reflex. Studies suggest that activation of the semicircular canals using caloric stimulation and yaw rotation do not modulate muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA). In contrast, activation of the otolith organs appear to alter MSNA, but not SSNA. Specifically, head-down rotation and off-vertical axis rotation increase MSNA, while sinusoidal linear accelerations decrease MSNA. Galvanic stimulation, which results in a nonspecific activation of the vestibule, appears to increase MSNA if the mode of delivery is pulse trained. In conclusion, evidence strongly supports the existence of a vestibulosympathetic reflex in humans. Furthermore, attenuation of the vestibulosympathetic reflex is coupled with a drop in arterial blood pressure in the elderly, suggesting this reflex may be important in human blood pressure regulation.

CAROTID BAROREFLEX CONTROL OF SKELETAL MUSCLE BLOOD FLOW IN HUMANS

Carotid baroreceptors (CBR) are known to modulate muscle sympathetic nerve activity and vascular tone in humans (measured by microneurography, plethsmography, and ultrasound technology). However, CBR control of skeletal muscle microcirculatory blood flow is not well defined. Thus, near-infrared spectroscopy (NIRS) was employed to evaluate changes in muscle tissue oxygenation (TOm) as a reflection of microcirculatory blood flow. METHODS: Heart rate (HR), arterial blood pressure (ABP), and TOm were measured at rest and during 5-sec +40 mmHg neck pressure (NP, a CBR hypotensive stimulus) in 5 healthy volunteers. Blood flow responses are expressed as a percent of total labile signal (TLS) established by 3-minute suprasystolic leg occlusion. RESULTS: HR and ABP increased (P < 0.01) following NP, indicating a significant reflex response to carotid baroreceptor hypotension. All subjects experienced a significant attenuation in skeletal muscle TOm following NP (6.5 ± 1.0% change, P < 0.01), indicating a measurable reduction in skeletal microcirculatory blood flow. The time delay from NP stimulus to TOm response was 10.5 ± 1.4 sec. CONCLUSION: These data provide evidence of direct carotid baroreflex control of resting skeletal muscle microcirculatory blood flow in humans, and indicate that the time course for changes in TOm is similar to the published time constant for CBR mediated changes in ABP.

Frequency domain characteristics of muscle sympathetic nerve activity in heart failure and healthy humans.

The purpose of this study was to characterize oscillations in muscle sympathetic nerve activity (MSNA) in the frequency domain in healthy subjects and patients with congestive heart failure (CHF) and to relate these to blood pressure (BP), heart rate (HR), and breathing frequency. MSNA burst frequency was significantly greater in CHF [52 +/- 21 (n = 12) vs. 35 +/- 11 (n = 19) bursts/min, P < 0.05], whereas breathing frequency and HR were similar. There was no significant difference between CHF and healthy subjects in total power, harmonic power, and nonharmonic power in the MSNA spectrum from 0 to 0.5 Hz, but low frequency power (LF, 0.05-0.15 Hz, P < 0.05) was reduced in heart failure patients. There was less coherence between BP and MSNA in the LF range, but similar spectral power in both groups in the very LF (VLF, 0-0.05 Hz) and high frequency (0.15-0.5 Hz) ranges. The transfer of MSNA oscillations into BP in the VLF (P < 0.05) and LF (P < 0.02) ranges was significantly lower in CHF, but gains in the transfer function and in the coherence between BP and MSNA and in the coherence between respiration and MSNA were similar in the two groups. These observations indicate that modulation of MSNA by the arterial baroreflex and respiration is preserved in CHF. The loss of LF power in the MSNA signal may be due to impaired neuroeffector transduction. The higher sympathetic nerve firing rate in CHF would therefore appear to be caused by factors other than the loss of regulation by these two inhibitory influences.