Direct Muscle Stimulation Research Articles

Skeletal muscle weakness due to deficiency of CuZn-superoxide dismutase is associated with loss of functional innervation

An association between oxidative stress and muscle atrophy and weakness in vivo is supported by elevated oxidative damage and accelerated loss of muscle mass and force with aging in CuZn-superoxide dismutase-deficient (Sod1(-/-)) mice. The purpose was to determine the basis for low specific force (N/cm(2)) of gastrocnemius muscles in Sod1(-/-) mice and establish the extent to which structural and functional changes in muscles of Sod1(-/-) mice resemble those associated with normal aging. We tested the hypothesis that muscle weakness in Sod1(-/-) mice is due to functionally denervated fibers by comparing forces during nerve and direct muscle stimulation. No differences were observed for wild-type mice at any age in the forces generated in response to nerve and muscle stimulation. Nerve- and muscle-stimulated forces were also not different for 4-wk-old Sod1(-/-) mice, whereas, for 8- and 20-mo-old mice, forces during muscle stimulation were 16 and 30% greater, respectively, than those obtained using nerve stimulation. In addition to functional evidence of denervation with aging, fiber number was not different for Sod1(-/-) and wild-type mice at 4 wk, but 50% lower for Sod1(-/-) mice by 20 mo, and denervated motor end plates were prevalent in Sod1(-/-) mice at both 8 and 20 mo and in WT mice by 28 mo. The data suggest ongoing denervation in muscles of Sod1(-/-) mice that results in fiber loss and muscle atrophy. Moreover, the findings support using Sod1(-/-) mice to explore mechanistic links between oxidative stress and the progression of deficits in muscle structure and function.

Functional electrical stimulation of intrinsic laryngeal muscles under varying loads in exercising horses.

Bilateral vocal fold paralysis (BVCP) is a life threatening condition and appears to be a good candidate for therapy using functional electrical stimulation (FES). Developing a working FES system has been technically difficult due to the inaccessible location and small size of the sole arytenoid abductor, the posterior cricoarytenoid (PCA) muscle. A naturally-occurring disease in horses shares many functional and etiological features with BVCP. In this study, the feasibility of FES for equine vocal fold paralysis was explored by testing arytenoid abduction evoked by electrical stimulation of the PCA muscle. Rheobase and chronaxie were determined for innervated PCA muscle. We then tested the hypothesis that direct muscle stimulation can maintain airway patency during strenuous exercise in horses with induced transient conduction block of the laryngeal motor nerve. Six adult horses were instrumented with a single bipolar intra-muscular electrode in the left PCA muscle. Rheobase and chronaxie were within the normal range for innervated muscle at 0.55±0.38 v and 0.38±0.19 ms respectively. Intramuscular stimulation of the PCA muscle significantly improved arytenoid abduction at all levels of exercise intensity and there was no significant difference between the level of abduction achieved with stimulation and control values under moderate loads. The equine larynx may provide a useful model for the study of bilateral fold paralysis.

Muscle ischaemia in patients with orthostatic hypotension assessed by velocity recovery cycles

ObjectivePatients with orthostatic hypotension may experience neck pain radiating to the occipital region of the skull and the shoulders while standing (so-called coat-hanger ache). This study assessed muscle membrane potential...

P5.17 The use of M responses of motor nerve and direct muscle stimulation in neuromuscular diseases other than intensive care related diseases

P5.17 The use of M responses of motor nerve and direct muscle stimulation in neuromuscular diseases other than intensive care related diseases

P11.8 Direct muscle stimulation versus composed motor action potential (CMAP) duration for the diagnosis of critical illness “neuromyopathy”: evaluation of sensitivity and specificity

P11.8 Direct muscle stimulation versus composed motor action potential (CMAP) duration for the diagnosis of critical illness “neuromyopathy”: evaluation of sensitivity and specificity

Velocity recovery cycles of human muscle action potentials: Repeatability and variability

Objective Velocity recovery cycles (VRCs) of human muscle action potentials have been proposed as a new technique for assessing muscle membrane function in myopathies. This study was undertaken to determine the variability and repeatability of VRC measures such as supernormality, to help guide future clinical use of the method. Methods To assess repeatability, VRCs with one and two conditioning stimuli were recorded from brachioradialis muscle by direct muscle stimulation in 20 normal volunteers, and the measurements repeated 1 week later. To further assess variability and dependence on electrode separation, age and sex, recordings from an additional 20 normal volunteers were added. Results There was a high intraclass correlation between repeated recordings of early supernormality, indicating excellent reliability of this VRC measure. However, relative refractory period had a smaller coefficient of repeatability in relation to the changes previously described during ischemia. We found no evidence that any of the excitability measures depended on electrode separation, conduction time or apparent velocity. There were also no significant differences between the recordings from men and women, or between the recordings from older (mean 44.9 y) and younger (26.5 y) subjects. Conclusions VRC measures are sufficiently consistent to be suitable for comparing muscle membrane function both within subjects and between groups. Early supernormality measurements benefit most from within subject comparisons. Significance These normative data sets provide a firm basis for planning clinical studies.

The bronchoconstrictor action of the tetradecapeptide bombesin in the guinea-pig.

Abstract The tetradecapeptide bombesin was found to exert a potent spasmogenic action on the bronchiolar muscle of the anaesthetized guinea-pig. The threshold bronchoconstrictor dose ranged between 50 and 200 ng kg−1. Other spasmogenic substances tested in the same experimental conditions, except physalaemin, were much less effective. Since antagonists of acetylcholine, histamine or 5-hydroxytryptamine did not inhibit the bronchoconstriction it is suggested that bombesin acts either by direct stimulation of the smooth muscle or by the prior release of other, as yet unidentified, spasmogenic substances.

8. High dose, fast absorbed intranasal midazolam as a potential treatment for status epilepticus: A pharmacokinetic–pharmacodynamic study in healthy volunteers using quantitative EEG

(CIM), which has been attributed to chronic muscle membrane depolarisation. The aim of this study was to investigate muscle membrane properties by measuring velocity recovery cycles (VRCs) of muscle action potentials in the early stage of experimental sepsis. VRCs chart the changes in velocity of a muscle action potential in the wake of another, and provide an indirect indication of the afterpotentials following the muscle action potential. Hence, they are strongly dependent on membrane potential. Methods: Twenty-five anesthesized pigs were randomized to either fecal peritonitis (n = 11) or to non-septic controls (n = 14). Multi-fibre responses to direct muscle stimulation through needle electrodes were recorded from the front leg immediately before induction of peritonitis as well as 6, 18 and 24 h thereafter. Latency changes were measured as conditioning stimuli were applied at inter-stimulus intervals of 2–1000 ms. Relative refractory period (RRP) and maximal supernormality (SN) were assessed. Results: In septic animals, RRP was increased by 38% (P < 0.05) and SN was reduced by 22% (P < 0.05) 24 h after induction of peritonitis compared with baseline measurements. The effect of increased RRP and reduced SN in the sepsis group was already apparent 6 h after induction of peritonitis, whereas in the non-septic controls there were no significant differences over time. The changes in SN in the sepsis group were significantly correlated with muscle oxygenation and with serum potassium levels. Conclusion: VRC changes in the sepsis group corresponded to muscle membrane depolarisation, which seems to be an important factor in the pathogenesis of CIM. Muscle membrane depolarisation was most likely caused by muscle hypoperfusion. VRCs provide a practicable mean for monitoring muscle membrane changes and may allow an early diagnosis of CIM.

Identification, Pharmacologic Considerations, and Management of Prostatitis

Background Prostatitis is a collection of signs and symptoms that occur as a result of inflammation or swelling of the prostate gland. There are many different causes for prostatitis, including infection; occasionally no clear etiology for the inflammation is found. Effective treatment often depends on identification of the cause, but a microbiologic organism is not always detectable, especially in cases of chronic prostatitis. Objective The aim of this article was to review identification and treatment options for prostatitis, including pharmacologic and nonpharmacologic interventions. Methods Relevant information was identified through a search of MEDLINE (1966–June 2010), International Pharmaceutical Abstracts (1970–June 2010), and EMBASE (1947–June 2010). Randomized, controlled trials that examined prostate cancer, benign prostatic hypertrophy, or procedures related to the prostate (ie, biopsies) were excluded. Results A working classification system for prostatitis was developed in 1999, but there are few randomized controlled trials that distinguish between the various treatment options. Bacterial prostatitis can be acute or chronic but always requires some degree of antimicrobial therapy. Pharmacologic features of fluoroquinolones make them the preferred agents for most patients. These antibiotics can become trapped in a chronically inflamed prostate due to pH differences between prostatic tissue and serum. Many fluoroquinolones have penetration ratios (prostate level:serum level) of up to 4:1. A study in European men (N = 117) who received levofloxacin 500 mg/d with a diagnosis of chronic bacterial prostatitis demonstrated clinical success rates of 92% (95% CI 84.8%–96.5%), 77.4% (95% CI, 68.2–84.9%), 66.0% (95% CI, 56.2%–75.0%), and 61.9% (95% CI, 51.9%–71.2%) at 5–12 days, 1 month, 3 months, and 6 months after treatment. Additionally, there have been numerous randomized, placebo-controlled trials in patients with chronic prostatitis that have studied α-blockers, steroid inhibitors, anti-inflammatory agents, and bioflavonoids. Treatment responses to α-blockers appear to be greater with longer durations of therapy in α-blocker–naïve patients (National Institutes of Health-Chronic Prostatitis Symptom Index [NIH-CPSI] score reduction of at least 3.6 points after 6 weeks of tamsulosin therapy [ P = 0.04] and up to 14.3 and 9.9 point NIH-CPSI score reductions with 14 weeks of terazosin and 24 weeks of alfuzosin therapy, respectively [ P = 0.01 for both]). Combination therapy with an α-blocker, an anti-inflammatory, and a muscle relaxant does not appear to offer significant advantages over monotherapy (12.7 vs 12.4 point reduction in NIH-CPSI scores) and a stepwise approach to therapy involving antibiotics followed by bioflavonoids and then α-blockers appears to effectively reduce symptoms for up to 1 year in patients with chronic prostatitis (mean NIH-CPSI point reduction of 9.5 points compared with baseline, P < 0.0001). Patients who have had multiple unsuccessful treatment regimens may benefit from direct stimulation of the pelvic muscles through electromagnetic or electroacupuncture therapy. Conclusions Prostatitis can resemble various other medical conditions but proper classification and an understanding of the pharmacologic features and expectations of the medications used to treat it can help identify effective treatment strategies. Fluoroquinolones are the preferred agents for treating bacterial causes of prostatitis and have demonstrated efficacy in some cases of chronic prostatitis when an organism has not been identified. However, the use of agents with anti-inflammatory or antiadrenergic properties may be necessary in combination with or after trying antimicrobial agents.

Muscle membrane dysfunction in critical illness myopathy assessed by velocity recovery cycles

Objective To test the hypothesis that muscle fibers are depolarized in patients with critical illness myopathy by measuring velocity recovery cycles (VRCs) of muscle action potentials. Methods VRCs were recorded from brachioradialis muscle by direct muscle stimulation in 10 patients in intensive care with evidence of critical illness myopathy (CIM). Two sets of recordings were made, mean 3.9 d apart, and compared with those from 10 age-matched controls. Results Muscle supernormality was reduced in the patients by 50% compared with controls ( P < 0.002) and relative refractory period was increased by 59% ( P < 0.01). Supernormality was correlated with plasma potassium levels ( R = −0.753, P < 0.001), and the slope of this relationship was much steeper than previously reported for non-critically ill patients with renal failure ( P < 0.01). Conclusions The abnormal excitability properties indicate that the muscle fibers in CIM were depolarized, and/or that sodium channel inactivation was increased. The heightened sensitivity to potassium is consistent with the hypothesis that an endotoxin reduces sodium channel availability in depolarized muscle fibers. Significance VRCs provide a practicable means to monitor muscle membrane changes in intensive care and to investigate the pathogenesis of CIM.

Comparison of quadriceps inactivation between nerve and muscle stimulation

We evaluated the use of direct muscle stimulation for quantifying quadriceps inactivation at different contraction levels as opposed to conventional twitch interpolation using nerve stimulation. Fourteen healthy volunteers were tested. Paired stimuli were delivered to the femoral nerve or to the quadriceps muscle belly during voluntary contractions ranging from 20% to 100% of maximum, and the amplitude of the superimposed doublet was quantified to investigate inactivation. Superimposed doublet for muscle and nerve stimulation, respectively between the range of 60% to 100% of maximum (e.g., at 100%, muscle stimulation was 14 ± 5 Nm and nerve stimulation was 15 ± 6 Nm). Despite higher current doses, muscle stimulation was associated with less discomfort than nerve stimulation (P < 0.05). Collectively, our data suggest that direct muscle stimulation could be used to assess quadriceps inactivation at maximal and quasi-maximal contraction levels as a valid alternative to motor nerve stimulation.

A Nerve Clamp Electrode Design for Indirect Stimulation of Skeletal Muscle

A nerve clamp electrode was developed to indirectly stimulate skeletal muscle innervated by α motor neurons as an alternative to conventional electrodes. The stimulating electrode device consists of a spring coil-activated nerve clamp mounted inside a 1-mL syringe barrel. Supramaximal pulses were generated by a Grass stimulator and delivered to the nerve segment via the nerve clamp electrode. The salient feature of the electrode is its ability to produce muscle contractions indirectly through stimulation of the attached nerve. Indirect muscle stimulation is critical for studying the paralytic actions of presynaptic-acting toxins such as botulinum neurotoxins (BoNT), a potent inhibitor of acetylcholine (ACh) release from α motor neurons. This device enables stimulation of muscle contraction indirectly as opposed to contraction from direct muscle stimulation. The electrode is able to stimulate indirect muscle contraction when tested on ex vivo preparations from rodent phrenic nerve-hemidiaphragm muscle in similar fashion to conventional electrodes. In addition, the electrode stimulated external intercostal nerve-muscle preparations. This was confirmed after applying BoNT serotype A, a potent inhibitor of ACh release, to induce muscle paralysis. Alternative methods, including suction and bipolar loop electrodes, were unsuccessful in stimulating indirect muscle contraction. Therefore, this novel electrode is useful for physiological assessment of nerve agents and presynaptic actions of toxins that cause muscle paralysis. This electrode is useful for stimulating nerve-muscle preparations for which the length of nerve is a concern.

P14-25 Effects of evoked pain on the muscle action potential obtained by direct muscle stimulation

P14-25 Effects of evoked pain on the muscle action potential obtained by direct muscle stimulation

Differential effect of hyperthermia on nerves and smooth muscle of the mouse ileum

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) gained wide acceptance as the treatment of choice for selected patients with peritoneal surface malignancies. Patients tend to suffer from prolonged ileus following CRS + HIPEC, complicating their recovery. We studied the effects of hyperthermia on the intestine to gain insight into mechanisms of ileus post-HIPEC. Segments of mouse ileum were incubated at 36°C. Electrical field stimulation (EFS) was applied, stimulating nerves, and the resultant muscle contraction was measured. The response was measured at varying temperatures (38-43°C) at exposure times of up to 120 min. We also stimulated the tissues with 10(-6) M carbachol, a muscarinic receptor agonist, which acts directly on smooth muscle. Response to EFS decreased at high temperatures, especially above 41°C. This effect was irreversible for 120 min after decreasing temperature. When stimulating with carbachol, both transient and plateau responses decreased at 43°C (plateau more than transient) but the effect reversed on returning to 36°C. The irreversible decline in responses to nerve stimulation when exposed to high temperatures was not seen with direct muscle stimulation. This indicates that smooth muscle is resilient and that the main effect of hyperthermia is on nerves. These results have significance for HIPEC.

Exploring the mechanisms of intravesical electrical stimulation in the in vitro rat whole bladder after treatment with atropine, α,β-methylATP and tetrodotoxin

In a previous study, we showed that the working mechanism of intravesical electrical stimulation (IVES) is probably mainly nerve mediated. But even after bladder decentralization, IVES can induce detrusor contraction. This study explores the effect of IVES in decentralized bladders and the importance of receptors in the bladder wall for a response on IVES. IVES (10 Hz square wave pulses, 20 msec pulse duration, 6 mA) was used in the bladder of 16 female Sprague-Dawley rats. After repeating IVES after consecutive bilateral bladder nerves section (L6-roots, pelvic nerves, and major pelvic ganglion (MPG)), the bladders were mounted in a tissue bath. IVES was performed in the control (n=16), after administration of tetrodotoxin (TTX) (n=6), after atropine and atropine with α,β-methylATP (n=6), and after α,β-methylATP and α,β-methylATP with atropine (n=4). The IVES-induced pressure rise (ΔP) was recorded. Maximum ΔP (maxΔP) after transection of the MPG was significantly lower than after pelvic nerves transection. Treatment with TTX and with α,β-methylATP plus atropine abolished ΔP. Atropine alone gave an insignificant decrease of maxΔP. Treatment with α,β-methylATP alone reduced maxΔP significantly. IVES can evoke contractions in a decentralized bladder. IVES-induced contractions are not a result of direct muscle stimulation, but are nerve mediated, involving intramural innervation and several parts of the bladder innervation. IVES-evoked contraction can be divided in a, contraction duration determining, cholinergic part and a, contraction strength determining, purinergic part. The peripheral innervation could play a role in IVES treatment in patients with interrupted central reflex pathway.

Calcium/Calmodulin Kinase II-Dependent Acetylcholine Receptor Cycling at the Mammalian Neuromuscular JunctionIn Vivo

At the mammalian skeletal neuromuscular junction, cycling of nicotinic ACh receptors (nAChRs) is critical for the maintenance of a high postsynaptic receptor density. However, the mechanisms that regulate nAChRs recycling in living animals remain unknown. Using in vivo time-lapse imaging, fluorescence recovery after photobleaching, and biochemical pull down assays, we demonstrated that recycling of internalized nAChRs into fully functional and denervated synapses was promoted by both direct muscle stimulation and pharmacologically induced intracellular calcium elevations. Most of internalized nAChRs are recycled directly into synaptic sites. Chelating of intracellular calcium below resting level drastically decreased cycling of nAChRs. Furthermore we found that calcium-dependent AChR recycling is mediated by Ca(2+)/calmodulin-dependent kinase II (CaMKII). Inhibition of CaMKII selectively blocked recycling and caused intracellular accumulation of internalized nAChRs, whereas internalization of surface receptors remained unaffected. Electroporation of CaMKII-GFP isoforms into the sternomastoid muscle showed that muscle-specific CaMKIIβm isoform is highly expressed at the neuromuscular junction (NMJ) and precisely colocalized with nAChRs at crests of synaptic folds while the CaMKIIγ and δ isoforms are poorly expressed in synaptic sites. These results indicate that Ca(2+) along with CaMKII activity are critical for receptor recycling and may provide a mechanism by which the postsynaptic AChR density is maintained at the NMJ in vivo.

Critical illness myopathy is frequent: accompanying neuropathy protracts ICU discharge

ObjectivesNeuromuscular dysfunction in critically ill patients is attributed to either critical illness myopathy (CIM) or critical illness polyneuropathy (CIP) or a combination of both. However, it is unknown whether differential...

Comparative study on the actions of toxin extracts from two different puffer fishes on I(Na) and respiratory N-M transmission in the rat.

We performed a comparative study on the effects of toxin extracts prepared from muscle and liver of two different puffer fishes on voltage dependent sodium current (I(Na)), and compared the results with that of tetrodotoxin (TTX). The amount of toxin contained in the muscle or liver expressed as an amount of equipotent TTX differed in the two species (0.11-57.98 microg TTX/g tissue). In addition, we observed the effects of TTX or toxin extracts on the twitch contraction evoked by direct muscle stimulation of the rat hemidiaphragm or indirect phrenic nerve stimulations, in an attempt to understand the mechanisms involved in the transmission failure in the respiratory muscles, due to the ingestion of TTX bearing puffers, and found that TTX or toxin extracts preferentially affect motor nerve rather than muscle.

Electrophysiological characteristics of motor units and muscle fibers in trained and untrained young male subjects

We hypothesized that the amplitudes of compound muscle action potentials (CMAPs) and interference pattern analysis (IPA) would be larger in trained subjects compared with untrained subjects, possibly due to hypertrophy of muscle fibers and/or increased central drive. Moreover, we hypothesized that the untrained muscle is less excitable compared with the trained muscle. An electromyographic (EMG) needle electrode was used to record the IPA at maximal voluntary effort. The CMAP was obtained by stimulating the musculocutaneous nerve and recording the brachial biceps muscle using surface electrodes. CMAPs were obtained by direct muscle stimulation (DMS) with two stainless-steel subdermal electrodes placed subcutaneously in the distal third of the muscle. Amplitudes of CMAP and IPA were significantly larger in trained subjects compared with untrained subjects. We found no differences between trained and untrained subjects in IPA power spectrum and turns per second or amplitude of the CMAPs obtained by DMS. Muscle fiber hypertrophy and/or altered central drive may account for our results, but there was no indication of changes in muscle fiber excitability.

Neurotrophins improve neuromuscular transmission in rats with myasthenia gravis

Myasthenia gravis is a disease of the neuromuscular junction (NMJ) associated with autoimmune destruction of the motor end‐plate. Inhibitors of acetylcholine (ACh) esterase are commonly used to mitigate symptoms by increasing ACh availability at the NMJ. Brain‐derived neurotrophic factor (BDNF) improves neuromuscular transmission in the rat diaphragm muscle (DIAm) by maintaining ACh release with repeated activation. We hypothesized that BDNF will mitigate the deficit of neuromuscular transmission in a passive transfer model of myasthenia gravis. Female Lewis rats were injected with vehicle, McAb1 (that does not induce myasthenia), and a myasthenogenic McAb3 antibody. Neuromuscular transmission failure (NMTF) was determined in DIAm‐phrenic nerve preparations by comparing the isometric force evoked by phrenic nerve stimulation and that evoked by superimposed direct muscle stimulation. After 2 min of repetitive stimulation, neuromuscular transmission was significantly impaired in myasthenic animals (NMTF: 80%) compared to vehicle and McAb1 animals (NMTF: ~60%). Exogenous BDNF treatment significantly improved neuromuscular transmission in all groups and NMTF in McAb3‐treated rats was no longer different from control or McAb1‐treated animals. We conclude that BDNF improves neuromuscular transmission in adult myasthenic rats.Supported by a Career Development Award from Mayo Clinic.