Recording and quantifying sympathetic outflow to muscle and skin in humans : methods, caveats and challenges

The development of microneurography, in which the electrical activity of axons can be recorded via an intrafascicular microelectrode inserted through the skin into a peripheral nerve in awake human participants, has contributed a great deal to our understanding of sensorimotor control and the control of sympathetic outflow to muscle and skin. This review summarises the different approaches to recording muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA), together with discussion on the issues that determine the quality of a recording. Various analytical approaches are also described, with a primary emphasis on those developed by the author, aimed at maximizing the information content from recordings of postganglionic sympathetic nerve activity in awake humans

The role of central command in the increase in muscle sympathetic nerve activity to contracting muscle during high intensity isometric exercise

We previously demonstrated that muscle sympathetic nerve activity (MSNA) increases to contracting muscle as well as to non-contracting muscle, but this was only assessed during isometric exercise at ∼10% of maximum voluntary contraction (MVC). Given that high-intensity isometric contractions will release more metabolites, we tested the hypothesis that the metaboreflex is expressed in the contracting muscle during highintensity but not low-intensity exercise. MSNA was recorded continuously via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve in 12 participants, performing isometric dorsiflexion of the right ankle at 10, 20, 30, 40, and 50% MVC for 2 min. Contractions were immediately followed by 6 min of post-exercise schemia (PEI); 6 min of recovery separated contractions. Cross-correlation analysis was performed between the negative-going sympathetic spikes of the raw neurogram and the ECG. MSNA increased as contraction intensity increased, reaching mean values (± SD) of 207 ± 210 spikes/min at 10% MVC (P = 0.04), 270 ± 189 spikes/min at 20% MVC (P < 0.01), 538 ± 329 spikes/min at 30% MVC (P < 0.01), 816 ± 551 spikes/min at 40% MVC (P < 0.01), and 1,097 ± 782 spikes/min at 50% MVC (P < 0.01). Mean arterial pressure also increased in an intensity-dependent manner from 76 ± 3 mmHg at rest to 90 ± 6 mmHg (P < 0.01) during contractions of 50% MVC. At all contraction intensities, blood pressure remained elevated during PEI, but MSNA returned to pre-contraction levels, indicating that the metaboreflex does not contribute to the increase in MSNA to contracting muscle even at these high contraction intensitie

Microstructural changes in the trigeminal nerve of patients with episodic migraine assessed using magnetic resonance imaging

Background: There is histological evidence of microstructural changes in the zygomaticotemporal branch of the trigeminal nerve in migraineurs. This raises the possibility that altered trigeminal nerve properties contribute to migraine pathophysiology. Whilst it is not possible to explore the anatomy of small trigeminal nerve branches it is possible to explore the anatomy of the trigeminal root entry zone using magnetic resonance imaging in humans. The aim of this investigation is to assess the microstructure of the trigeminal nerve in vivo to determine if nerve alterations occur in individuals with episodic migraine. Methods: In 39 migraineurs and 39 matched controls, T1-weighted anatomical images were used to calculate the volume (mm3) and maximal cross-sectional area of the trigeminal nerve root entry zone; diffusion tensor images were used to calculate fractional anisotropy, mean diffusion, axial diffusion and radial diffusion. Results: There were significant differences between the left and right nerve of controls and migraineurs with respect to volume and not cross-sectional area. Migraineurs displayed reduced axial diffusion in the right nerve compared to the left nerve, and reduced fractional anisotropy in the left nerve compared to left controls. Furthermore, although there were no differences in mean diffusion or radial diffusion, regional analysis of the nerve revealed significantly greater radial diffusion in the middle and rostral portion of the left trigeminal nerve in migraineurs compared with controls. Conclusions: Migraine pathophysiology is associated with microstructural abnormalities within the trigeminal nerve that are consistent with histological evidence of altered myelin and/or organization. These peripheral nerve changes may provide further insight into migraine pathophysiology and enable a greater understanding for targeted treatments of pain alleviation

Altered cardiac structure and function is related to seizure frequency in a rat model of chronic acquired temporal lobe epilepsy

Objective: This study aimed to prospectively examine cardiac structure and function in the kainic acid-induced post-status epilepticus (post-KA SE) model of chronic acquired temporal lobe epilepsy (TLE), specifically to examine for changes between the pre-epileptic, early epileptogenesis and the chronic epilepsy stages. We also aimed to examine whether any changes related to the seizure frequency in individual animals. Methods: Four hours of SE was induced in 9 male Wistar rats at 10 weeks of age, with 8 saline treated matched control rats. Echocardiography was performed prior to the induction of SE, two- and 10-weeks post-SE. Two weeks of continuous video-EEG and simultaneous ECG recordings were acquired for two weeks from 11 weeks post-KA SE. The video-EEG recordings were analyzed blindly to quantify the number and severity of spontaneous seizures, and the ECG recordings analyzed for measures of heart rate variability (HRV). PicroSirius red histology was performed to assess cardiac fibrosis, and intracellular Ca2+ levels and cell contractility were measured by microfluorimetry. Results: All 9 post-KA SE rats were demonstrated to have spontaneous recurrent seizures on the two-week video-EEG recording acquired from 11 weeks SE (seizure frequency ranging from 0.3 to 10.6 seizures/day with the seizure durations from 11 to 62 s), and none of the 8 control rats. Left ventricular wall thickness was thinner, left ventricular internal dimension was shorter, and ejection fraction was significantly decreased in chronically epileptic rats, and was negatively correlated to seizure frequency in individual rats. Diastolic dysfunction was evident in chronically epileptic rats by a decrease in mitral valve deceleration time and an increase in E/E` ratio. Measures of HRV were reduced in the chronically epileptic rats, indicating abnormalities of cardiac autonomic function. Cardiac fibrosis was significantly increased in epileptic rats, positively correlated to seizure frequency, and negatively correlated to ejection fraction. The cardiac fibrosis was not a consequence of direct effect of KA toxicity, as it was not seen in the 6/10 rats from separate cohort that received similar doses of KA but did not go into SE. Cardiomyocyte length, width, volume, and rate of cell lengthening and shortening were significantly reduced in epileptic rats. Significance: The results from this study demonstrate that chronic epilepsy in the post-KA SE rat model of TLE is associated with a progressive deterioration in cardiac structure and function, with a restrictive cardiomyopathy associated with myocardial fibrosis. Positive correlations between seizure frequency and the severity of the cardiac changes were identified. These results provide new insights into the pathophysiology of cardiac disease in chronic epilepsy, and may have relevance for the heterogeneous mechanisms that place these people at risk of sudden unexplained death

Discharge rates and discharge variability of muscle spindle afferents in human chronic spinal cord injury

The aim of this study was to test the hypothesis that the firing rates and discharge variability of human muscle spindles are not affected by spinal cord injury. Tungsten microelectrodes were inserted into muscle fascicles of the peroneal nerve in six individuals with complete paralysis of the lower limbs following spinal cord injury: 12 afferents were spontaneously active at rest and 7 were recruited during passive muscle stretch. For comparison, recordings were made from 17 spontaneously active and 9 stretch-recruited afferents in 12 intact subjects. Firing rates for the spontaneously active muscle spindles were not significantly different between the spinal (9.8 +/- 1.6 HZ) and intact (10.2 +/- 1.3 HZ) subjects; the same was true for the stretch-recruited afferents - static firing rates, measured over the final 1 s of a ramp-and-hold stretch, were not different between the spinal and intact groups (13.1 +/- 3.1% vs 10.0 +/- 2.5 HZ). There were also no differences in discharge variability between the spinal and intact subjects, either for the spontaneously active spindles (8.1 +/- 2.0% vs 5.7 +/- 0.9%) or for the stretch-activated spindles, calculated over the final 1 s of static stretch (19.7 +/- 5.6% vs 17.0 +/- 1.9%). In addition, the responses to stretch imposed manually by the experimenter provided no evidence for an increase in the dynamic response to stretch in the patients. The static stretch sensitivity of human muscle spindles is not affected by chronic spinal cord injury, suggesting that there is no difference in static (and possibly dynamic) fusimotor drive to paralyzed muscles in chronic spinal cord injury. This study provides no evidence for an increase in fusimotor drive as a mechanism for the spasticity associated with chronic spinal injury, though further studies using controlled stretch would be required before it can be concluded that dynamic fusimotor drive is “normal” in these patients

Sympathetic microneurography

The sympathetic nervous system plays important roles in the beat-to-beat control of blood pressure, the control of blood flow through various organs and the maintenance of core temperature through thermoregulatory processes. The development of microneurography, in which nerve activity can be recorded directly from intraneural microelectrodes inserted percutaneously into a peripheral nerve in awake human subjects, has provided a wealth of information on the control of sympathetic outflow to muscle and skin. Although not intended to be diagnostic, recordings of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) in different disease states have increased our understanding of the operation of the sympathetic nervous system. And while quantification of sympathetic nerve activity is still largely limited to measures of burst frequency (bursts/minute) and burst incidence (bursts/100 heart beats), the development of single-unit recordings of MSNA and SSNA have provided more detailed information on how the sympathetic nervous system grades its output. This chapter reviews the development of sympathetic microneurography and its application in health and disease

The roles of mechanoreceptors in muscle and skin in human proprioception

The somatosensory nervous system is subserved by specialised mechanoreceptors in muscles, joints and skin. We now know that joint receptors primarily act as limit detectors of joint rotation, and that both cutaneous afferents and muscle spindle afferents can encode joint movements. Moreover, studies in individuals lacking muscle spindles emphasise the importance of these receptors in sensorimotor control, but also point to the redundancy in the system that allows cutaneous afferents to take over

Obstructive sleep apnoea and hypertension : the role of the central nervous system

Purpose of review Obstructive sleep apnoea (OSA) is associated with both nocturnal and daytime hypertensions which increase cardiovascular morbidity and mortality. It is thought that the repeated episodes of hypoxia and hypercapnia during nocturnal airway obstructions that characterise OSA result in increased sympathetic drive that persists during wakefulness. Although the underlying mechanisms responsible for this hypertension remain to be elucidated, several neural and humoral mechanisms have been proposed and recent evidence suggesting changes in the central nervous system may play a significant role. The purpose of this review is to explore recent evidence of central changes associated with elevated sympathetic drive in individuals with OSA. Recent findings Recent human brain imaging investigations and, in particular, combined microneurography recording of resting sympathetic activity with high-resolution functional magnetic resonance imaging have provided some important insights into changes in brain function and anatomy associated with resting sympathetic activity. Functional and anatomical changes occur in OSA, including in regions of the brainstem circuitry known to be responsible for setting resting sympathetic activity. Furthermore, these changes are reversed following continuous positive airway treatment in concert with reductions in resting sympathetic drive. Summary These resent findings suggest that the central changes may contribute significantly to the hypertension associated with OSA

Multiple firing of single muscle vasoconstrictor neurons during cardiac dysrhythmias in human heart failure

Single vasoconstrictor nerve fibers in humans normally fire only once but have the capacity to fire as many as eight times, per cardiac interval. Our laboratory recently demonstrated that the mean firing frequency of individual vasoconstrictor fibers is more than doubled in the sympathoexcitation associated with congestive heart failure (Macefield VG, Rundqvist B, Sverrisdottir YB, Wallin BG, and Elam M. Circulation 100: 1708-1713, 1999). However, the propensity to fire only once per cardiac interval was retained. In the present retrospective study, we tested the hypothesis that vasoconstrictor fibers fire more than once per cardiac interval in response to transient sympathoexcitatory stimuli, providing one mechanism for further increase of an already augmented sympathetic discharge. Six patients with congestive heart failure (New York Heart Association functional class II-IV; left ventricular ejection range 13-37%, average 22%) were studied at rest and during premature ectopic heartbeats. Analyzed for a total of 60 premature beats, the average firing probability of 10 vasoconstrictor fibers increased from 61 to 80% in the prolonged cardiac interval (i.e., reduced diastolic pressure) after premature beats. The incidence of multiple within-burst firing increased markedly, with two spikes being more common than one. Our results illustrate two different mechanisms (increases in firing probability and multiple within-burst firing), and indirectly indicate a third mechanism (recruitment of previously silent fibers), for acute sympathoexcitatory responses

Susceptibility to motion sickness is not increased following spinal cord injury

BACKGROUND: There are two leading theories on the origin of motion sickness. One, the sensory conflict theory, states that sensory information provided by one sensory channel does not match the expected input from another channel; commonly, these two inputs originate in the vestibular system and the eyes. The second theory - the postural instability theory - states that motion sickness comes about not through sensory conflict, but through an inability to control one's posture. OBJECTIVE: Given that people with a motor-complete spinal cord injury cannot control their muscles below the level of the spinal lesion, we predicted that susceptibility to motion sickness would be higher in individuals who have suffered a spinal cord injury. METHODS: Twenty-one people living with chronic spinal cord injury (9 quadriplegics, 12 paraplegics) completed the Motion Sickness Susceptibility Questionnaire (MSSQ), via an online survey, to compare susceptibility to motion sickness before and after injury. RESULTS: Spinal cord injury, regardless of level, did not produce an increase in susceptibility to motion sickness. CONCLUSION: We have tested the general validity of the postural-instability theory by assessing susceptibility to motion sickness in individuals with spinal cord injury. Despite the loss of postural control, there was no increase in motion sickness susceptibility