Matthias Krenn

Long-Term High-Level Exercise Promotes Muscle Reinnervation With Age

The histologic features of aging muscle suggest that denervation contributes to atrophy, that immobility accelerates the process, and that routine exercise may protect against loss of motor units and muscle tissue. Here, we compared muscle biopsies from sedentary and physically active seniors and found that seniors with a long history of high-level recreational activity up to the time of muscle biopsy had 1) lower loss of muscle strength versus young men (32% loss in physically active vs 51% loss in sedentary seniors); 2) fewer small angulated (denervated) myofibers; 3) a higher percentage of fiber-type groups (reinnervated muscle fibers) that were almost exclusive of the slow type; and 4) sparse normal-size muscle fibers coexpressing fast and slow myosin heavy chains, which is not compatible with exercise-driven muscle-type transformation. The biopsies from the old physically active seniors varied from sparse fiber-type groupings to almost fully transformed muscle, suggesting that coexpressing fibers appear to fill gaps. Altogether, the data show that long-term physical activity promotes reinnervation of muscle fibers and suggest that decades of high-level exercise allow the body to adapt to age-related denervation by saving otherwise lost muscle fibers through selective recruitment to slow motor units. These effects on size and structure of myofibers may delay functional decline in late aging.

Electrical Stimulation Counteracts Muscle Decline in Seniors

The loss in muscle mass coupled with a decrease in specific force and shift in fiber composition are hallmarks of aging. Training and regular exercise attenuate the signs of sarcopenia. However, pathologic conditions limit the ability to perform physical exercise. We addressed whether electrical stimulation (ES) is an alternative intervention to improve muscle recovery and defined the molecular mechanism associated with improvement in muscle structure and function. We analyzed, at functional, structural, and molecular level, the effects of ES training on healthy seniors with normal life style, without routine sport activity. ES was able to improve muscle torque and functional performances of seniors and increased the size of fast muscle fibers. At molecular level, ES induced up-regulation of IGF-1 and modulation of MuRF-1, a muscle-specific atrophy-related gene. ES also induced up-regulation of relevant markers of differentiating satellite cells and of extracellular matrix remodeling, which might guarantee shape and mechanical forces of trained skeletal muscle as well as maintenance of satellite cell function, reducing fibrosis. Our data provide evidence that ES is a safe method to counteract muscle decline associated with aging.

Safe neuromuscular electrical stimulator designed for the elderly.

A stimulator for neuromuscular electrical stimulation (NMES) was designed, especially suiting the requirements of elderly people with reduced cognitive abilities and diminished fine motor skills. The aging of skeletal muscle is characterized by a progressive decline in muscle mass, force, and condition. Muscle training with NMES reduces the degradation process. The discussed system is intended for evoked muscle training of the anterior and posterior thigh. The core of the stimulator is based on a microcontroller with two modular output stages. The system has two charge-balanced biphasic voltage-controlled stimulation channels. Additionally, the evoked myoelectric signal (M-wave) and the myokinematic signal (surface acceleration) are measured. A central controller unit allows using the stimulator as a stand-alone device. To set up the training sequences and to evaluate the compliance data, a personal computer is connected to the stimulator via a universal serial bus. To help elderly people handle the stimulator by themselves, the user interface is kept very simple. For safety reasons, the electrode impedance is monitored during stimulation. A comprehensive compliance management with included measurements of muscle activity and stimulation intensity enables a scientific use of the stimulator in clinical trials.

Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals

The level of sustainable excitability within lumbar spinal cord circuitries is one of the factors determining the functional outcome of locomotor therapy after motor-incomplete spinal cord injury. Here, we present initial data using noninvasive transcutaneous lumbar spinal cord stimulation (tSCS) to modulate this central state of excitability during voluntary treadmill stepping in three motor-incomplete spinal cord-injured individuals. Stimulation was applied at 30 Hz with an intensity that generated tingling sensations in the lower limb dermatomes, yet without producing muscle reflex activity. This stimulation changed muscle activation, gait kinematics, and the amount of manual assistance required from the therapists to maintain stepping with some interindividual differences. The effect on motor outputs during treadmill-stepping was essentially augmentative and step-phase dependent despite the invariant tonic stimulation. The most consistent modification was found in the gait kinematics, with the hip flexion during swing increased by 11.3° ± 5.6° across all subjects. This preliminary work suggests that tSCS provides for a background increase in activation of the lumbar spinal locomotor circuitry that has partially lost its descending drive. Voluntary inputs and step-related feedback build upon the stimulation-induced increased state of excitability in the generation of locomotor activity. Thus, tSCS essentially works as an electrical neuroprosthesis augmenting remaining motor control.

Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics.

Age‐related sarcopenia is characterized by a progressive loss of muscle mass with decline in specific force, having dramatic consequences on mobility and quality of life in seniors. The etiology of sarcopenia is multifactorial and underlying mechanisms are currently not fully elucidated. Physical exercise is known to have beneficial effects on muscle trophism and force production. Alterations of mitochondrial Ca2+ homeostasis regulated by mitochondrial calcium uniporter (MCU) have been recently shown to affect muscle trophism in vivo in mice. To understand the relevance of MCU‐dependent mitochondrial Ca2+ uptake in aging and to investigate the effect of physical exercise on MCU expression and mitochondria dynamics, we analyzed skeletal muscle biopsies from 70‐year‐old subjects 9 weeks trained with either neuromuscular electrical stimulation (ES) or leg press. Here, we demonstrate that improved muscle function and structure induced by both trainings are linked to increased protein levels of MCU. Ultrastructural analyses by electron microscopy showed remodeling of mitochondrial apparatus in ES‐trained muscles that is consistent with an adaptation to physical exercise, a response likely mediated by an increased expression of mitochondrial fusion protein OPA1. Altogether these results indicate that the ES‐dependent physiological effects on skeletal muscle size and force are associated with changes in mitochondrial‐related proteins involved in Ca2+ homeostasis and mitochondrial shape. These original findings in aging human skeletal muscle confirm the data obtained in mice and propose MCU and mitochondria‐related proteins as potential pharmacological targets to counteract age‐related muscle loss.

Dynamic Impedance Model of the Skin-Electrode Interface for Transcutaneous Electrical Stimulation

Transcutaneous electrical stimulation can depolarize nerve or muscle cells applying impulses through electrodes attached on the skin. For these applications, the electrode-skin impedance is an important factor which influences effectiveness. Various models describe the interface using constant or current-depending resistive-capacitive equivalent circuit. Here, we develop a dynamic impedance model valid for a wide range stimulation intensities. The model considers electroporation and charge-dependent effects to describe the impedance variation, which allows to describe high-charge pulses. The parameters were adjusted based on rectangular, biphasic stimulation pulses generated by a stimulator, providing optionally current or voltage-controlled impulses, and applied through electrodes of different sizes. Both control methods deliver a different electrical field to the tissue, which is constant throughout the impulse duration for current-controlled mode or have a very current peak for voltage-controlled. The results show a predominant dependence in the current intensity in the case of both stimulation techniques that allows to keep a simple model. A verification simulation using the proposed dynamic model shows coefficient of determination of around 0.99 in both stimulation types. The presented method for fitting electrode-skin impedance can be simple extended to other stimulation waveforms and electrode configuration. Therefore, it can be embedded in optimization algorithms for designing electrical stimulation applications even for pulses with high charges and high current spikes.

Selectivity of transcutaneous stimulation of lumbar posterior roots at different spinal levels in humans

Posterior root-muscle (PRM) reflexes can be elic- ited by epidural as well as recently also transcutaneous elec- trical stimulation of the lumbar spinal cord. We tested the se- lectivity of transcutaneous spinal cord stimulation by eliciting PRM reflexes and recording the compound muscle action po- tentials of the thigh and shank. The stimulation set-up con- sisted of an electrode array with 7 levels centered at the spinal level of T12. With the variation of the stimulation level a defi- nite change in the recruitment of PRM reflexes was observed. Even though the distribution of the generated electrical field with transcutaneous electrodes is unfocused in relation to the target structures, a selective stimulation is possible.

Multi-Electrode Array for Transcutaneous Lumbar Posterior Root Stimulation

Interest in transcutaneous electrical stimulation of the lumbosacral spinal cord is increasing in human electrophysiological and clinical studies. The stimulation effects on lower limb muscles depend on the depolarization of segmentally organized posterior root afferents and, thus, the rostro-caudal stimulation site. In previous studies, selective stimulation was achieved by varying the positions of single self-adhesive electrodes over the thoracolumbar spine. Here, we developed a multi-electrode surface array consisting of 3 × 8 electrode pads and tested its stimulation-site specificity. The array was placed longitudinally over the spine covering the T10-L2 vertebrae. Two different hydrogel layer configurations were utilized: a single layer adhered to all electrode pads of the array and a configuration comprised of eight separate strips attached to the three transverse electrode pads of each level. Voltage measurements demonstrated that an effectively focused field distribution along the longitudinal extent of the array was not accomplished when using the single continuous hydrogel layer, and segmental selective stimulation of the posterior root afferents was not possible. The separate strips produced a focused electric field distribution at the rostro-caudal level of the electrode pads selected for stimulation. This configuration allowed for the preferential elicitation of posterior root-muscle reflexes in either the L2-L4 innervated quadriceps or the L5-S2 innervated triceps surae muscle groups. Such multi-electrode array for transcutaneous spinal cord stimulation shall allow for improved control of stimulation conditions in electrophysiological studies and time-dependent and site-specific stimulation patterns for neuromodulation applications.

Body Position Influences Which Neural Structures Are Recruited by Lumbar Transcutaneous Spinal Cord Stimulation

Transcutaneous stimulation of the human lumbosacral spinal cord is used to evoke spinal reflexes and to neuromodulate altered sensorimotor function following spinal cord injury. Both applications require the reliable stimulation of afferent posterior root fibers. Yet under certain circumstances, efferent anterior root fibers can be co-activated. We hypothesized that body position influences the preferential stimulation of sensory or motor fibers. Stimulus-triggered responses to transcutaneous spinal cord stimulation were recorded using surface-electromyography from quadriceps, hamstrings, tibialis anterior, and triceps surae muscles in 10 individuals with intact nervous systems in the supine, standing and prone positions. Single and paired (30-ms inter-stimulus intervals) biphasic stimulation pulses were applied through surface electrodes placed on the skin between the T11 and T12 inter-spinous processes referenced to electrodes on the abdomen. The paired stimulation was applied to evaluate the origin of the evoked electromyographic response; trans-synaptic responses would be suppressed whereas direct efferent responses would almost retain their amplitude. We found that responses to the second stimulus were decreased to 14%±5% of the amplitude of the response to the initial pulse in the supine position across muscles, to 30%±5% in the standing, and to only 80%±5% in the prone position. Response thresholds were lowest during standing and highest in the prone position and response amplitudes were largest in the supine and smallest in the prone position. The responses obtained in the supine and standing positions likely resulted from selective stimulation of sensory fibers while concomitant motor-fiber stimulation occurred in the prone position. We assume that changes of root-fiber paths within the generated electric field when in the prone position increase the stimulation thresholds of posterior above those of anterior root fibers. Thus, we recommend conducting spinal reflex or neuromodulation studies with subjects lying supine or in an upright position, as in standing or stepping.

Epidural and transcutaneous spinal electrical stimulation for restoration of movement after incomplete and complete spinal cord injury

PURPOSE OF REVIEW The Purpose of this review is to outline and explain the therapeutic use of electrical spinal cord stimulation (SCS) for modification of spinal motor output. Central functional stimulation provides afferent input to posterior root neurons and is applied to improve volitional movements, posture and their endurance, control spasticity, and improve bladder function or perfusion in the lower limbs. Clinical accomplishments strongly depend on each individuals physiological state and specific methodical adaptation to that physiological state. RECENT FINDINGS Effectiveness of this neuromodulory technique for changing motor control after spinal cord injury (SCI) continues to be explored along with the underlying mechanisms of its effect in people with complete and incomplete spinal cord injuries. There are extensive studies of tonic and rhythmical activity elicited from the lumbar cord as well as data demonstrating augmentation of residual volitional activity. Recent studies have focused on verifying if and how SCS can modify features of neurocontrol in ambulatory spinal cord patients. SUMMARY In this review, we emphasize recent publications of research revealing that SCS can substitute for the reduced brain drive for control of excitability in people with SCI. Artificially replacing diminished or lost brain control over the spinal cord has limitations. A fundamental requirement for successful SCS application is analysis of each individuals residual postinjury neural function. This will allow a better understanding of the physiological interactions between SCS and spinal cord motor control below injury and provide criteria for its application. Finally, the publication of both successful and failed applications of SCS will be crucial for gaining future progress.