Trauma of Peripheral Innervation Impairs Content of Epidermal Langerhans Cells.

Langerhans cells represent the first immune cells that sense the entry of external molecules and microorganisms at the epithelial level in the skin. In this pilot case-study, we evaluated Langerhans cells density and progression of epidermal atrophy in permanent spinal cord injury (SCI) patients suffering with either lower motor neuron lesions (LMNSCI) or upper motor neuron lesions (UMNSCI), both submitted to surface electrical stimulation. Skin biopsies harvested from both legs were analyzed before and after 2 years of home-based Functional Electrical Stimulation for denervated degenerating muscles (DDM) delivered at home (h-bFES) by large anatomically shaped surface electrodes placed on the skin of the anterior thigh in the cases of LMNSCI patients or by neuromuscular electrical stimulation (NMES) for innervated muscles in the cases of UMNSCI persons. Using quantitative histology, we analyzed epidermal thickness and flattening and content of Langerhans cells. Linear regression analyses show that epidermal atrophy worsens with increasing years of LMNSCI and that 2 years of skin electrostimulation reverses skin changes, producing a significant recovery of epidermis thickness, but not changes in Langerhans cells density. In UMNSCI, we did not observe any statistically significant changes of the epidermis and of its content of Langerhans cells, but while the epidermal thickness is similar to that of first year-LMNSCI, the content of Langerhans cells is almost twice, suggesting that the LMNSCI induces an early decrease of immunoprotection that lasts at least 10 years. All together, these are original clinically relevant results suggesting a possible immuno-repression in epidermis of the permanently denervated patients.

Skeletal muscle weakness in older adults home-restricted due to COVID-19 pandemic: a role for full-body in-bed gym and functional electrical stimulation.

Persons suffering with systemic neuromuscular disorders or chronic organ failures, spend less time for daily physical activity, aggravating their mobility impairments. From 2020, patients at risk are also older adults, who, though negative for the SARS-Cov-2 infection, suffer with a fatigue syndrome due to home restriction/quarantine. Besides eventual psycological managements, it could be useful to offer to these patients a rehabilitation workouts easy to learn and to independently repeat at home (Full-Body In-Bed Gym). Inspired by the proven capability to recover skeletal muscle contractility and strength by home-based volitional exercises and functional electrical stimulation (FES), we suggest for this fatigue syndrome a 10-20 min long daily routine of easy and safe physical exercises that may recover from muscle weakness the main 400 skeletal muscles used for every-day activities. Leg muscles could be trained also by an adjunctive neuro-muscular electrical stimulation (NMES) in frail old persons. Many of the exercises could be performed in bed (Full-Body in-Bed Gym), thus hospitalized patients can learn this light training before leaving the hospital. Full-Body in-Bed Gym is, indeed, an extension of well-established cardiovascular-ventilation rehabilitation training performed by patients after heavy surgery. Blood pressure readings, monitored before and after daily routine of Full-Body in-Bed Gym, demonstrate a transient decrease in peripheral resistance due to increased blood flow to major body muscles. Continued regularly, Full-Body in-Bed Gym may help maintaining independence of frail people, including those suffering with the fatigue syndrome related to the restrictions/quarantine imposed to the general population during the COVID-19 pandemic.

Functional Electrical Stimulation (FES) and the Effect on Equine Multifidi Asymmetry.

Asymmetry of the multifidi has been correlated with scoliosis and back pain in humans and has been investigated as a factor in equine back pain as well. The purpose of this study was to determine if FES would affect the symmetry of equine thoracolumbar multifidi when compared to controls. Twelve horses received 24 FES treatments bilaterally over the thoracolumbar region for 8 weeks. Twelve additional control horses received no FES treatments. Ultrasonographic measurements of the cross-sectional area (CSA) of the multifidi of the treatment horses at seven thoracolumbar levels were compared to determine the change in left and right asymmetry post-FES. The same measurements during the same period were also taken in the control group. All measurements were blinded for evaluation. Statistical significance was assessed utilizing two-sided, matched-pairs t-tests, and Welch's (unequal variances) t-test (alpha = 0.05). Multiple comparisons were accounted for using the Sidak correction. A significant improvement in multifidi asymmetry was observed, post-FES, at all seven thoracolumbar levels, with no evidence of asymmetry improvement in the control group. The difference between mean improvements of the treatment and control groups was statistically significant (P < .001). FES significantly improved the symmetry of equine multifidi, and evidence was provided for the effectiveness of FES at each of seven thoracolumbar levels. The improvement in symmetry appeared to result from increases, decreases, and maintenance of the CSA of the left and right multifidi in various combinations. The FES protocol used in this study has the potential to improve spinal function and assist in reducing back pain in horses.

Thirty years of translational research in Mobility Medicine: Collection of abstracts of the 2020 Padua Muscle Days.

More than half a century of skeletal muscle research is continuing at Padua University (Italy) under the auspices of the Interdepartmental Research Centre of Myology (CIR-Myo), the European Journal of Translational Myology (EJTM) and recently also with the support of the A&CM-C Foundation for Translational Myology, Padova, Italy. The Volume 30(1), 2020 of the EJTM opens with the collection of abstracts for the conference "2020 Padua Muscle Days: Mobility Medicine 30 years of Translational Research". This is an international conference that will be held between March 18-21, 2020 in Euganei Hills and Padova in Italy. The abstracts are excellent examples of translational research and of the multidimensional approaches that are needed to classify and manage (in both the acute and chronic phases) diseases of Mobility that span from neurologic, metabolic and traumatic syndromes to the biological process of aging. One of the typical aim of Physical Medicine and Rehabilitation is indeed to reduce pain and increase mobility enough to enable impaired persons to walk freely, garden, and drive again. The excellent contents of this Collection of Abstracts reflect the high scientific caliber of researchers and clinicians who are eager to present their results at the PaduaMuscleDays. A series of EJTM Communications will also add to this preliminary evidence.

Two-years of home based functional electrical stimulation recovers epidermis from atrophy and flattening after years of complete Conus-Cauda Syndrome.

To evaluate progression of skin atrophy during 8 years of complete Conus-Cauda Syndrome and its recovery after 2 years of surface Functional Electrical Stimulation a cohort study was organized and implemented.Functional assessments, tissue biopsies, and follow-up were performed at the Wilhelminenspital, Vienna, Austria; skin histology and immunohistochemistry at the University of Padova, Italy on 13 spinal cord injury persons suffering up to 10 years of complete conus/cauda syndrome. Skin biopsies (n. 52) of both legs were analyzed before and after 2 years of home-based Functional Electrical Stimulation delivered by large anatomically shaped surface electrodes placed on the skin of the anterior thigh. Using quantitative histology we analyzed: 1. Epidermis atrophy by thickness and by area; 2. Skin flattening by computing papillae per mm and Interdigitation Index of dermal-epidermal junctions; 3. Presence of Langerhans cells.Linear regression analyses show that epidermal atrophy and flattening worsen with increasing years post- spinal cord injury and that 2 years of skin electrostimulation by large anatomically shaped electrodes reverses skin changes (pre-functional Electrical Stimulation vs post-functional Electrical Stimulation: thickness 39%, P < .0001; area 41%, P < .0001; papillae n/mm 35%, P < 0.0014; Interdigitation index 11%, P < 0.018), producing a significant recovery to almost normal levels of epidermis thickness and of dermal papillae, with minor changes of Langerhans cells, despite 2 additional years of complete Conus-Cauda Syndrome.In complete Conus-Cauda Syndrome patients, the well documented beneficial effects of 2 years of surface h-b Functional Electrical Stimulation on strength, bulk, and muscle fiber size of thigh muscles are extended to skin, suggesting that electrical stimulation by anatomically shaped electrodes fixed to the skin is also clinically relevant to counteract atrophy and flattening of the stimulated skin. Mechanisms, pros and cons are discussed.

To Reverse Atrophy of Human Muscles in Complete SCI Lower Motor Neuron Denervation by Home-Based Functional Electrical Stimulation.

After spinal cord injury (SCI), patients spend daily several hours in wheelchairs, sitting on their hamstring muscles. SCI causes muscle atrophy and wasting, which is especially severe after complete and permanent damage to lower motor neurons. A European Union (EU)-supported work demonstrates that electrical fields produced by large electrodes and purpose-developed electrical stimulators recover both quadriceps and hamstring muscles, producing a cushioning effect capable of benefitting SCI patients, even in the worst case of complete and long-term lower motor neuron denervation of leg muscles. We reported that 20 out of 25 patients completed a 2-year h-bFES program, which resulted in (1) a 35% increase in cross-sectional area of the quadriceps muscles (P < 0.001), (2) a 75% increase in mean diameter of quadriceps muscle fibers (P < 0.001), and (3) improvement of the ultrastructural organization of contractile machinery and of the Ca2+-handling system. Though not expected, after 2 years during which the 20 subjects performed 5 days per week h-bFES of the atrophic quadriceps muscles, the CT cross-sectional area of the hamstring muscles also augmented, increasing from 26.9+/-8.4 (cm2) to 30.7+/-9.8 (cm2), representing a significant (p ≤ 0.05) 15% increase. Here we show by quantitative muscle color computed tomography (QMC-CT) that h-bFES-induced tissue improvements are present also in the hamstring muscles: a once supposed drawback (lack of specificity of muscle activation by large surface electrodes) is responsible for a major positive clinical effect. Interestingly, 2 years of home-based FES by large surface electrodes reversed also the denervation-induced skin atrophy, increasing epidermis thickness. Finally, we would like to attract attention of the readers to quantitative muscle color computed tomography (QMC-CT), a sensitive quantitative imaging analysis of anatomically defined skeletal muscles introduced by our group to monitor atrophy/degeneration of skeletal muscle tissue. Worldwide acceptance of QMC-CT will provide physicians an improved tool to quantitate skeletal muscle atrophy/degeneration before and during rehabilitation strategies so that therapy for mobility-impaired persons can be better prescribed, evaluated, and altered where needed.

In complete SCI patients, long-term functional electrical stimulation of permanent denervated muscles increases epidermis thickness.

Our studies have shown that atrophic Quadriceps muscles from spinal cord injury patients suffering with permanent denervation-induced atrophy and degeneration of muscle fibers, were almost completely rescued to normal size after two years of home-based functional electrical stimulation (h-bFES). Because we used surface electrodes to stimulate the muscle, we wanted to know how the skin was affected by the treatments. Here, we report preliminary data from histological morphometry of Hematoxylin-Eosin-stained paraffin-embedded skin sections harvested from the legs of three SCI patients before and after two years of h-bFES. Despite the heterogeneity of gender and time from SCI, comparing pre vs post h-bFES in these three SCI patients, the data show that: (1) In one subject skin biopsies from both the right and left leg experienced a statistically significant increase in thickness of the epidermis after two years of H-bFES; (2) In the other two subjects, one leg showed a significant increase in epidermis thickness, while in the other leg there was either small positive or negative non-significant changes in epidermis thickness; and (3) more importantly, comparison of grouped data from the three subjects shows that there was a significant 28% increase in the thickness of the epidermis in response to two years of h-bFES rehabilitation. In conclusion, the three educational cases show a long-term positive modulation of epidermis thickness after two years of h-bFES, thus extending to skin the positive results previously demonstrated in skeletal muscle, specifically, a substantial recovery of muscle mass and contractile function after long-term h-bFES.

Atrophy, ultra-structural disorders, severe atrophy and degeneration of denervated human muscle in SCI and Aging. Implications for their recovery by Functional Electrical Stimulation, updated 2017.

OBJECTIVES: Long-term lower motor neuron denervation of skeletal muscle is known to result in degeneration of muscle with replacement by adipose and fibrotic tissues. However, long-term survival of a subset of skeletal myofibers also occurs. METHODS: We performed transverse and longitudinal studies of patients with spinal cord injury (SCI), patients specifically complete Conus and Cauda Equina Syndrome and also of active and sedentary seniors which included analyses of muscle biopsies from the quadriceps m. RESULTS: Surprisingly, we discovered that human denervated myofibers survive years of denervation after full and irreversible disconnection from their motor neurons. We found that atrophic myofibers could be rescued by home-based Functional Electrical Stimulation (h-bFES), using purpose developed stimulators and electrodes. Although denervated myofibers quickly lose the ability to sustain high-frequency contractions, they respond to very long impulses that are able to allow for re-emergence of tetanic contractions. A description of the early muscle changes in humans are hampered by a paucity of patients suffering complete Conus and Cauda Equina Syndrome, but the cohort enrolled in the EU RISE Project has shown that even five years after SCI, severe atrophic myofibers with a peculiar cluster reorganization of myonuclei are present in human muscles and respond to h-bFES. CONCLUSIONS: Human myofibers survive permanent denervation longer than generally accepted and they respond to h-bFES beyond the stage of simple atrophy. Furthermore, long-term denervation/reinnervation events occur in elderly people and are part of the mechanisms responsible for muscle aging and again h-bFES was beneficial in delaying aging decay.

Recovery from muscle weakness by exercise and FES: lessons from Masters, active or sedentary seniors and SCI patients.

Many factors contribute to the decline of skeletal muscle that occurs as we age. This is a reality that we may combat, but not prevent because it is written into our genome. The series of records from World Master Athletes reveals that skeletal muscle power begins to decline at the age of 30 years and continues, almost linearly, to zero at the age of 110 years. Here we discuss evidence that denervation contributes to the atrophy and slowness of aged muscle. We compared muscle from lifelong active seniors to that of sedentary elderly people and found that the sportsmen have more muscle bulk and slow fiber type groupings, providing evidence that physical activity maintains slow motoneurons which reinnervate muscle fibers. Further, accelerated muscle atrophy/degeneration occurs with irreversible Conus and Cauda Equina syndrome, a spinal cord injury in which the human leg muscles may be permanently disconnected from the nervous system with complete loss of muscle fibers within 5-8 years. We used histological morphometry and Muscle Color Computed Tomography to evaluate muscle from these peculiar persons and reveal that contraction produced by home-based Functional Electrical Stimulation (h-bFES) recovers muscle size and function which is reversed if h-bFES is discontinued. FES also reverses muscle atrophy in sedentary seniors and modulates mitochondria in horse muscles. All together these observations indicate that FES modifies muscle fibers by increasing contractions per day. Thus, FES should be considered in critical care units, rehabilitation centers and nursing facilities when patients are unable or reluctant to exercise.

3D False Color Computed Tomography for Diagnosis and Follow-Up of Permanent Denervated Human Muscles Submitted to Home-Based Functional Electrical Stimulation.

This report outlines the use of a customized false-color 3D computed tomography (CT) protocol for the imaging of the rectus femoris of spinal cord injury (SCI) patients suffering from complete and permanent denervation, as characterized by complete Conus and Cauda Equina syndrome. This muscle imaging method elicits the progression of the syndrome from initial atrophy to eventual degeneration, as well as the extent to which patients' quadriceps could be recovered during four years of home-based functional electrical stimulation (h-b FES). Patients were pre-selected from several European hospitals and functionally tested by, and enrolled in the EU Commission Shared Cost Project RISE (Contract n. QLG5-CT-2001-02191) at the Department of Physical Medicine, Wilhelminenspital, Vienna, Austria. Denervated muscles were electrically stimulated using a custom-designed stimulator, large surface electrodes, and customized progressive stimulation settings. Spiral CT images and specialized computational tools were used to isolate the rectus femoris muscle and produce 3D and 2D reconstructions of the denervated muscles. The cross sections of the muscles were determined by 2D Color CT, while muscle volumes were reconstructed by 3D Color CT. Shape, volume, and density changes were measured over the entirety of each rectus femoris muscle. Changes in tissue composition within the muscle were visualized by associating different colors to specified Hounsfield unit (HU) values for fat, (yellow: [-200; -10]), loose connective tissue or atrophic muscle, (cyan: [-9; 40]), and normal muscle, fascia and tendons included, (red: [41; 200]). The results from this analysis are presented as the average HU values within the rectus femoris muscle reconstruction, as well as the percentage of these tissues with respect to the total muscle volume. Results from this study demonstrate that h-b FES induces a compliance-dependent recovery of muscle volume and size of muscle fibers, as evidenced by the gain and loss in muscle mass. These results highlight the particular utility of this modality in the quantitative longitudinal assessment of the responses of skeletal muscle to long-term denervation and h-b FES recovery.

Muscle, tendons, and bone: structural changes during denervation and FES treatment.

OBJECTIVES: This paper describes a novel approach to determine structural changes in bone, muscle, and tendons using medical imaging, finite element models, and processing techniques to evaluate and quantify: (1) progression of atrophy in permanently lower motor neuron (LMN) denervated human muscles, and tendons; (2) their recovery as induced by functional electrical stimulation (FES); and (3) changes in bone mineral density and bone strength as effect of FES treatment. METHODS: Briefly, we used three-dimensional reconstruction of muscle belly, tendons, and bone images to study the structural changes occurring in these tissues in paralysed subjects after complete lumbar-ischiadic spinal cord injury (SCI). These subjects were recruited through the European project RISE, an endeavour designed to establish a novel clinical rehabilitation method for patients who have permanent and non-recoverable muscle LMN denervation in the lower extremities. This paper describes the use of segmentation techniques to study muscles, tendons, and bone in several states: healthy, LMN denervated-degenerated but not stimulated, and LMN denervated-stimulated. Here, we have used medical images to develop three-dimensional models and advanced imaging, including computational tools to display tissue density. Different tissues are visualized associating proper Hounsfield intervals defined experimentally to fat, connective tissue, and muscle. Finite element techniques are used to calculate Young's modulus on the patella bone and to analyse correlation between muscle contraction and bone strength changes. RESULTS: These analyses show restoration of muscular structures, tendons, and bone after FES as well as decline of the same tissues when treatment is not performed. This study suggests also a correlation between muscle growth due to FES treatment and increase in density and strength in patella bone. CONCLUSION: Segmentation techniques and finite element analysis allow the study of the structural changes of human skeletal muscle, tendons, and bone in SCI patient with LMN injury and to monitor effects and changes in tissue composition due to FES treatment. This work demonstrates improved bone strength in the patella through the FES treatment applied on the quadriceps femur.

Monitoring of muscle and bone recovery in spinal cord injury patients treated with electrical stimulation using three-dimensional imaging and segmentation techniques: methodological assessment.

Muscle tissue composition accounting for the relative content of muscle fibers and intramuscular adipose and loose fibrous tissues can be efficiently analyzed and quantified using images from spiral computed tomography (S-CT) technology and the associated distribution of Hounsfield unit (HU) values. Muscle density distribution, especially when including the whole muscle volume, provides remarkable information on the muscle condition. Different physiological and pathological scenarios can be depicted using the muscle characterization technique based on the HU values and the definition of appropriate intervals and the association of such intervals to different colors. Using this method atrophy, degeneration, and restoration in denervated muscle undergoing electrical stimulation treatments can be clearly displayed and monitored. Moreover, finite element methods are employed to calculate Young's modulus on the patella bone and to analyze correlation between muscle contraction and bone strength changes. The reliability of this tool though depends on S-CT assessment and calibration. To assess imaging quality and the use of HU values to display muscle composition, different S-CT devices are compared using a Quasar body scanner. Density distributions and volumes of various calibration elements such as lung, polyethylene, water equivalent, and trabecular and dense bone are measured with different scanning protocols and at different points of time. The results show that every scanned element undergoes HU variations, which are greater for materials at the extremes of the HU scale, such as dense bone and lung inhale. Moreover, S-CT scanning with low tube voltages (80 KV) produces inaccurate HU values especially in bones. In conclusion, 3-D modeling techniques based on S-CT scanning is a powerful follow-up tool that may provide structural information at the millimeter scale, and thus may drive choice and timing to validate rehabilitation protocols.

Home-based functional electrical stimulation rescues permanently denervated muscles in paraplegic patients with complete lower motor neuron lesion.

BACKGROUND: Spinal cord injury causes muscle wasting and loss of function, which are especially severe after complete and permanent damage to lower motor neurons. In a previous cross-sectional study, long-standing denervated muscles were rescued by home-based functional electrical stimulation (h-bFES) training. OBJECTIVE: To confirm results by a 2-year longitudinal prospective study of 25 patients with complete conus/cauda equina lesions. METHODS: Denervated leg muscles were stimulated by h-bFES using a custom-designed stimulator and large surface electrodes. Muscle mass, force, and structure were determined before and after 2 years of h-bFES using computed tomography, measurements of knee torque during stimulation, and muscle biopsies analyzed by histology and electron microscopy. RESULTS: Twenty of 25 patients completed the 2-year h-bFES program, which resulted in (a) a 35% cross-sectional increase in area of the quadriceps muscle from 28.2 ± 8.1 to 38.1 ± 12.7 cm(2) (P < .001), a 75% increase in mean diameter of muscle fibers from 16.6 ± 14.3 to 29.1 ± 23.3 µm (P < .001), and improvements of the ultrastructural organization of contractile material; and (b) a 1187% increase in force output during electrical stimulation from 0.8 ± 1.3 to 10.3 ± 8.1 N m (P < .001). The recovery of quadriceps force was sufficient to allow 25% of the subjects to perform FES-assisted stand-up exercises. CONCLUSIONS: Home-based FES of denervated muscle is an effective home therapy that results in rescue of muscle mass and tetanic contractility. Important immediate benefits for the patients are the improved cosmetic appearance of lower extremities and the enhanced cushioning effect for seating.

One year of home-based daily FES in complete lower motor neuron paraplegia: recovery of tetanic contractility drives the structural improvements of denervated muscle.

OBJECTIVE: Spinal cord injury (SCI) causes muscle atrophy, which is particularly severe, due to inability to perform tetanic contractions, when lower motor neurons (LMN) are involved. We performed a longitudinal study in 25 Europeans suffering from complete conus cauda syndrome from 0.7 to 8.7 years comparing functional and structural thigh muscle properties before and after 2 years of home-based daily training by functional electrical stimulation (FES). The mid-term results after 1 year and preliminary muscle biopsy observations at project end-point from a subset of subjects are here reported. METHODS: Muscles were electrically stimulated at home by means of large surface electrodes and a custom-designed stimulator. The poor excitability of the LMN denervated muscles was first improved by twitch-contraction training. Then, tetanic contractions against progressively increased loading were elicited. Finally, standing-up exercises were daily performed. The bulk of thigh muscle was estimated by transverse computer tomography (CT) scan and force measurements. Needle biopsies of vastus lateralis were harvested before and after 2 years of FES. RESULTS: The 1 year home-based daily FES training induced: (1) very similar increases in muscle excitability and contractility in right and left legs; (2) feasibility to elicit tetanic contractions by means of train-stimulation with about ten times improvement of muscle force; (3) increase in the 26% of muscle bulk, as shown by CT scan analyses, improving appearance of limbs and muscle cushioning; (4) myofiber size increase (+94%) in a small series of muscle biopsies obtained after 2 years of FES. None of the subjects that performed 1 year home-based daily FES training (20 persons) had worsened their functional class, while 20% (4/20) improved to functional class 4, that is, the ability to stand. DISCUSSION: The European Union (EU) Project Rise shows that 'home-based daily FES training' is a safe and effective therapy that may maintain life-long physical exercise by active muscle contraction (FES is the only option for denervated muscle) as a procedure to recover the early-lost tetanic contractility of denervated muscle, and to counteract muscle atrophy in order to prevent clinical complications.

Walking performance, medical outcomes and patient training in FES of innervated muscles for ambulation by thoracic-level complete paraplegics.

OBJECTIVE: To discuss functional electric stimulation (FES) gait training of upper motoneuron spinal cord injured complete paraplegics considering ambulation performance, physiologic and metabolic responses as well as psychologic outcome, while providing myologic insight into ambulation via FES when training starts many years post-injury. METHODS: Transcutaneous FES using the Parastep stimulation system, gait training methods with and without major emphasis on muscle reinforcement, cardiovascular and respiratory conditioning. Examination of myofiber tissues and correlation of normal muscles histology versus innervated muscles of upper motor neuron and of denervated muscles of lower motor neuron paraplegics. RESULTS: Published works in literature reviewed in this paper report average walking distance of 440 m/walk when major muscle reinforcement and preconditioning cardiovascular and respiratory systems precedes gait training, versus average 115 m/walk when undergoing direct gait training. Medical, metabolic and psychologic outcomes, as reported in several works, point to benefits of FES walking, including 60% increase in blood flow to lower extremities. Myofiber tissues of patients with upper motor neuron paralysis compare well with those of normal tissue even many years post-injury, while adipose tissue substitute muscle fibers in patients with lower motor neuron lesions. DISCUSSION: Transcutaneous FES allows considerably longer walking distances and speed at the end of training when training involves an extensive pre-conditioning program than with direct gait training. Medical and psychologic benefits are observed, especially concerning blood flow to the lower extremities. Myofiber examinations provide myologic understanding of effectiveness of FES many years post-injury.

Muscle biopsies show that FES of denervated muscles reverses human muscle degeneration from permanent spinal motoneuron lesion.

This paper presents biopsy analyses in support of the clinical evidence of muscle recovery induced by a new system of life-long functional-electrical-stimulation (FES) training in permanent spinal-motoneuron-denervated human muscle. Not earlier than 1 year after subjects experienced complete conus cauda lesion, their thigh muscles were electrically stimulated at home for several years with large skin surface electrodes and an expressly designed stimulator that delivered much longer impulses than those presently available for clinical use. The poor excitability of long-term denervated muscles was first improved by several months of twitch-contraction training. Then, the muscles were tetanically stimulated against progressively increased loads. Needle biopsies of vastus lateralis from long-term denervated subjects showed severe myofiber atrophy or lipodystrophy beginning 2 years after spinal cord injury (SCI). Muscle biopsies from a group of 3.6- to 13.5-year denervated subjects, who underwent 2.4 to 9.3 years of FES, show that this progressive training almost reverted long-term muscle atrophy/degeneration.

Electrical stimulation of denervated muscles: first results of a clinical study.

To evaluate the effects of electrical stimulation on denervated muscles in spinal cord injured humans, the EU Project RISE was started in 2001. The aims of this project are: to design and build sufficient stimulators; to develop stimulation protocols by means of mathematical models, animal experiments, and practice in humans with denervated lower limbs; to develop examination methods and devices for evaluation of electrical stimulation training effects; and to acquire basic scientific knowledge on denervated and stimulated denervated muscle. In the clinical study 27 spinal cord injured individuals were included, furthermore 13 pilot patients participated. After a series of initial examinations they underwent an electrical stimulation program for their denervated lower limb muscles. Some of the patients have already follow up examinations. A marked increase of muscle mass and quality was observed, the trophic situation of the denervated lower limbs had improved obviously.

Recovery of long-term denervated human muscles induced by electrical stimulation.

We investigated the restorative potential of intensive electrical stimulation in a patient with long-standing quadriceps denervation. Stimulation started 18 months after injury. After 26 months, the thighs were visibly less wasted. Muscle cross-sectional areas, measured by computerized tomography, increased from 36.0 cm(2) to 57.9 cm(2) (right) and from 36.1 cm(2) to 52.4 cm(2) (left). Knee torque had become sufficient to maintain standing without upper extremity support. Biopsies revealed evidence of both growth and regeneration of myofibers. The results suggest that electrical stimulation may offer a route to the future development of mobility aids in patients with lower motor neuron lesions.

Long-term denervation in humans causes degeneration of both contractile and excitation-contraction coupling apparatus, which is reversible by functional electrical stimulation (FES): a role for myofiber regeneration?

Over the last 30 years there has been considerable interest in the use of functional electrical stimulation (FES) to restore movement to the limbs of paralyzed patients. Spinal cord injury causes a rapid loss in both muscle mass and contractile force. The atrophy is especially severe when the injury involves lower motoneurons because many months after spinal cord injury, atrophy is complicated by fibrosis and fat substitution. In this study we describe the effects of long-term lower motoneuron denervation of human muscle and present the structural results of muscle trained using FES. By means of an antibody for embryonic myosin, we demonstrate that many regenerative events continue to spontaneously occur in human long-term denervated and degenerated muscle (DDM). In addition, using electron microscopy, we describe i) the overall structure of fibers and myofibrils in long-term denervated and degenerated muscle, including the effects of FES, and ii) the structure and localization of calcium release units, or triads; the structures reputed to activate muscle contraction during excitation-contraction coupling (ECC). Both apparatus undergo disarrangement and re-organization following long-term denervation and FES, respectively. The poor excitability of human long-term DDM fibers, which extends to the first periods of FES training, may be explained in terms of the spatial disorder of the ECC apparatus. Its disorganization and re-organization following long-term denervation and FES, respectively, may play a key role in the parallel disarrangement and re-organization of the myofibrils that characterize denervation and FES training. The present structural studies demonstrate that the protocol used during FES training is effective in reverting long-term denervation atrophy and dystrophy. The mean fiber diameter in FES biopsies is 42.2 +/- 14.8 SD (p < 0.0001 vs DDM 14.9 +/- 6.0 SD); the mean percentile of myofiber area of the biopsy is 94.3 +/- 5.7 SD (p < 0.0001 vs DDM 25.7 +/- 23.7 SD); the mean percentile fat area is 2.1 +/- 2.4 SD (p < 0.001 vs DDM 12.8 +/- 12.1 SD); and the mean percentile connective tissue area is 3.6 +/- 4.6 SD (p < 0.001 vs DDM 61.6 +/- 20.1 SD). In DDM biopsies more than 50% of myofibers have diameter smaller than 10 microm, while the FES-trained subjects have more that 50% of myofibers larger than 30 microm. The recovery of muscle mass seems to be the result of both a size increase of the surviving fibers and the regeneration of new myofibers.

A review of the concept of circulatory bioassist focused on the "new" demand dynamic cardiomyoplasty: the renewal of dynamic cardiomyoplasty?

After the initial enthusiasm, the dynamic cardiomyoplasty lost its reputation owing to the poor long-term results, caused by the muscular degeneration subsequent to chronic continuous electrical stimulation of the latissimus dorsi. An activity-rest stimulation protocol that avoids full transformation of the skeletal muscle, maintaining muscular properties over time, has been successfully tried. This "demand" stimulation protocol showed in humans good results improving NYHA class, ejection fraction value, and survival. The discussion about the capability of this and a unique kind of cardiocirculatory bioassist is due to be reopened. In fact, heart transplant, percutaneous circulatory-supporting device, multisites stimulation therapy, and total artificial heart have some drawbacks, one of which is the economic cost. In developing countries the more economic demand dynamic cardiomyoplasty may still play a role.