Testosterone replacement therapy in combination with neuromuscular stimulation

Abstract

A method is provided for treating musculoskeletal atrophy in a patient suffering from a neurological or neuromuscular disease or disorder by combining testosterone replacement therapy with neuromuscular electrical stimulation of multiple muscle populations and optionally physical activity.

Description

[0001] This application is a divisional application of the following application: Application date: June 22, 2017; Application number: 201780051748.6; Invention name “Combination of testosterone replacement therapy and neuromuscular stimulation”. Technical Field

[0002] The present invention relates generally to the field of musculoskeletal rehabilitation following traumatic and non-traumatic spinal cord injury, stroke and brain injury. In one embodiment, a method of treating musculoskeletal atrophy in a patient suffering from a neurological disease or disorder is provided by combining testosterone replacement therapy with neuromuscular electrical stimulation of multiple muscle groups.

[0003] All documents cited or relied upon below are expressly incorporated herein by reference. Background Art

[0004] There are over 1.2 million men in the United States with spinal cord injury ("SCI"), and 10,000 new cases are reported each year. It should be understood that serum testosterone levels in men decrease after stress, including after acute SCI, and it can be speculated that serum testosterone levels remain low for varying periods of time, perhaps up to one or two years, after the acute event. Risks associated with testosterone deficiency have been reported, including sarcopenia, bone loss, increased cardiovascular disease, and adverse psychological / mood changes. As many as 41% of men aged 18 to 58 with SCI may have low testosterone levels associated with immobilization, which is associated with disuse atrophy of muscle and bone loss.

[0005] Muscle atrophy, changes in muscle molecular phenotype and increased intramuscular fat after SCI lead to serious adverse musculoskeletal changes and cardiovascular dysfunction. The deterioration of cardiovascular health significantly limits the performance of daily living activities ("ADL"), may be prone to metabolic syndrome, and is expected to increase morbidity and mortality. In addition, bone and muscle loss often lead to other direct secondary complications, such as increased risk of fractures during transfer, bending or slight falls. These "fragile" fractures may often occur without trauma or pain and cannot be diagnosed immediately. In addition, atrophy and weakness of the musculoskeletal system may limit the possibility of standing or walking. Time after injury and injury level are good predictors of osteoporosis and muscle loss severity.

[0006] Understanding the neural and physiological mechanisms of the human spinal cord is essential for developing effective systemic rehabilitation strategies for patients with neurological injuries. Ultimately, our aim is to provide innovative rehabilitation strategies that promote better functional recovery and improved long-term health for SCI patients. While improvements in the neuromuscular and skeletal systems are prerequisites to prepare the body for potential healing, there are significant additional health benefits in terms of better metabolic function and improved cardiovascular health.

[0007] To date, clinical interventions after SCI have not prevented musculoskeletal deterioration. Therefore, improved strategies to protect musculoskeletal function are urgently needed. Summary of the invention

[0008] The present invention relates to a method for treating musculoskeletal atrophy in patients with neurological diseases or disorders by combining testosterone replacement therapy with neuromuscular electrical stimulation ("NMES") of multiple muscle groups. In one embodiment, testosterone is applied to the patient and NMES is subsequently administered. In another embodiment, NMES is characterized by having a wide pulse width and a high frequency. Such wide pulse width, high frequency NMES is referred to herein as "WPHF-NMES". The WPHF-NMES method involves placing surface electrodes on a subject for stimulating multiple muscle groups; and administering: a) multiple intervention sessions, each of the multiple intervention sessions comprising a WPHF-NMES combination to a muscle group, and b) a specific physical activity regimen according to a protocol. DETAILED DESCRIPTION

[0009] It should be understood that the description of the present invention has been simplified to illustrate relevant elements to clearly understand the present invention, while for clarity, eliminating many other elements present in typical systems and devices. Those of ordinary skill in the art will recognize that other elements and / or steps are desired and / or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they are not conducive to a better understanding of the present invention, the discussion of such elements and steps is not provided herein. The disclosure herein relates to all such changes and modifications of such elements and methods known to those skilled in the art. In addition, the embodiments identified and illustrated herein are only for exemplary purposes and are not meant to be exclusive or to be limited to their descriptions of the present invention.

[0010] As used herein, "TRT" refers to testosterone replacement therapy. "ST" refers to dynamic standing training (defined below). NMES uses electric pulses to trigger muscle contraction. In one embodiment of the present invention, NMES is used for neurorehabilitation of patients suffering from, especially SCI. NMES produces contraction by depolarizing the axons under the stimulating electrodes, which are placed on the skin above the muscle belly or peripheral nerve trunk. Traditionally, NMES is delivered using a relatively narrow pulse width of about 0.05ms to 0.4ms and a low frequency of about 20Hz to 40Hz). This traditional type of NMES is conducive to the activation of motor axons, and therefore mainly produces contraction by peripheral pathways that do not involve the central nervous system ("CNS"). Therefore, traditional NMES supplements motor units in a non-physiological manner with a random supplementary order of motor unit types, and all motor units discharge synchronously.

[0011] The inventors believe that when testosterone replacement therapy is combined with NMES of multiple muscle groups and optional physical activities (such as standing), musculoskeletal atrophy can be treated in patients with neurological diseases or disorders. Muscle atrophy below the level of lesions is associated with the loss of muscle activation after SCI. Muscle loss, especially in larger muscles, may lead to energy imbalance (input and output) due to reduced metabolic rate and increased fat storage. If energy imbalance is not controlled, obesity and other chronic diseases may result. As expected, due to increased muscle mass loss in the case of higher lesions, lesion levels are associated with basal metabolic rate. Lack of peripheral sympathetic nervous system response after injury can also lead to reduced metabolic rate. It is reported that due to reduced muscle mass and reduced sympathetic nervous system activity, the resting metabolic rate of individuals with SCI is 14-27% lower than that of healthy individuals.

[0012] Many studies have reported that fat mass increases significantly after SCI, which is related to the time after injury, age at the time of injury, injury level and integrity. Early studies examined the intramuscular fat and cross-sectional area and muscle cross-sectional area ("CSA") of individuals with complete and incomplete SCI in movement at 6 weeks and 3 months after injury, and compared these with the height and weight of healthy controls matched for age. At 6 weeks, individuals with SCI showed that intramuscular fat increased 3 times compared to controls, and at 6 months, intramuscular fat increased 26% compared to 6 weeks. These findings are relevant, especially considering that compared with subcutaneous fat, intramuscular fat is a better predictor of insulin resistance in non-disabled, obese diabetic and non-diabetic patients. Compared with controls, the higher prevalence of insulin resistance in SCI has been fully confirmed, and it has been speculated that intramuscular fat explains the main cause of glucose intolerance observed in chronic SCI patients.

[0013] Muscle Dysfunction and Testosterone

[0014] Muscle loss is associated with a decline in the secretion of the androgen testosterone, which is necessary for the maintenance of lean body mass and strength. Decreased testosterone levels have also been associated with SCI, suggesting that individuals with SCI are susceptible to age-related changes in body composition. Hypogonadism afflicts approximately 30% of men aged 40 to 79 years, and its prevalence increases with age, as do healthy controls.

[0015] Changes in muscle atrophy, metabolic factors, and fat mass

[0016] Muscle atrophy below the level of the lesion is associated with loss of muscle activation after SCI. In previous studies, other investigators evaluated CSA within the first 6 months after injury. They found that muscle CSA was 18-46% lower in SCI than in control subjects. The reported muscle CSA losses were: 24% for the gastrocnemius, 12% for the soleus, 16% for the quadriceps, 14% for the hamstrings, and 16% for the adductor group. In a previous longitudinal study using dual-energy X-ray absorptiometry ("DXA"), other investigators reported a 15% loss of lean body mass after the first year of lower extremity injury, but initial measurements were obtained approximately 5 weeks after the acute injury. 10 The inventors of the present invention have collected preliminary data on lean tissue in over 100 individuals with SCI (both non-ambulatory and ambulatory) that show a sustained loss of leg lean tissue mass over time, particularly in non-ambulatory individuals.

[0017] Muscle loss, particularly in larger muscles, can lead to an energy imbalance (input versus output) due to reduced metabolic rate and increased fat storage. If the energy imbalance is not controlled, it can lead to obesity and other chronic diseases. As expected, the level of lesion correlated with basal metabolic rate due to increased muscle mass loss in the presence of higher lesions. The lack of a peripheral sympathetic nervous system response following injury can also lead to a reduced metabolic rate. It has been reported that individuals with SCI have a resting metabolic rate that is 14-27% lower than healthy individuals due to reduced muscle mass and reduced sympathetic nervous system activity.

[0018] Many previous studies have reported that fat mass increases significantly after SCI, which is related to the time after injury, age at injury, injury level and completeness. Recent studies have examined intramuscular fat CSA and muscle CSA in individuals with complete and incomplete SCI with movement at 6 weeks and 3 months after injury, and compared these with the height and weight of age-matched healthy controls. At 6 weeks, individuals with SCI showed a 3-fold increase in intramuscular fat compared to controls, while at 6 months, intramuscular fat increased by 26% compared to 6 weeks. These findings are relevant, especially considering that intramuscular fat is a better predictor of insulin resistance in non-disabled, obese diabetic and non-diabetic patients compared to subcutaneous fat. The higher prevalence of insulin resistance in SCI compared to controls has been well documented, and it has been speculated that intramuscular fat explains the main cause of glucose intolerance observed in chronic SCI patients.

[0019] Muscle loss is associated with a decline in the secretion of the androgen testosterone, which is necessary for the maintenance of lean body mass and strength. Decreased testosterone levels have also been associated with SCI, suggesting that individuals with SCI are susceptible to age-related changes in body composition. Hypogonadism affects approximately 30% of men aged 40 to 79 years as healthy controls age, and its prevalence increases with age.

[0020] Bone adaptation after SCI

[0021] Within the first few months of injury, paralysis results in skeletal unloading and rapid linear bone loss, particularly in the lower extremities. Some studies using DXA or peripheral quantitative computed tomography ("pQCT") have reported that 50% of bone loss will occur within 2 years after SCI. Studies have also shown that bone mineral density ("BMD") can continue to decline for more than 7 years after injury, suggesting that there is no plateau in bone loss.

[0022] Bone structure after SCI

[0023] Bone structural changes are an additional consequence of bone loss accompanying SCI. Magnetic resonance imaging ("MRI") studies have shown that in patients with chronic SCI, a decrease in bone volume and an increase in trabecular spacing will result. In a cross-sectional study evaluating long-term changes in bone metabolism and BMD as well as fracture incidence after SCI, bone loss was reported to vary in different compartments. The researchers concluded that in sites with a high proportion of trabecular bone, bone loss follows a long curve with a gradual decrease from 1 to 3 years after injury, but in cortical bone sites (such as the tibial diaphysis), bone loss continues even more than 10 years after injury and the rate of bone loss is higher than in other areas. The loss of trabecular bone in the tibia within 2 years after SCI ranged from 0.4% to 80%, and cortical bone changes ranged from an increase of 1.7% to a decrease of 33%.

[0024] Bone metabolism after SCI

[0025] Comparison between different markers of bone metabolism may be very valuable to understand the course of immobilization-related events and the effects of any intervention in the SCI population. As previously reported by other researchers, serum ionized calcium increased above the upper limit of normal, and serum parathyroid hormone was suppressed. Markers of bone resorption [total pyridinoline, deoxypyridinoline (free and total), and N-telopeptide] showed a significant increase (up to 10 times the upper limit of normal) after acute immobilization, with the highest values ​​between weeks 10 and 16. Pyridinoline increased more from baseline in tetraplegic patients compared with those in paraplegic patients. Markers of bone formation (total alkaline phosphatase and osteocalcin) showed no significant increase, and the markers remained within the normal range.

[0026] Effects of testosterone on bones

[0027] Testosterone is a bone anabolic metabolite. Androgen receptors are present in all three types of bone cells: osteoblasts, osteoclasts, and osteocytes. Androgens can promote osteoblast proliferation and differentiation, inhibit osteoclast recruitment and bone resorption activity, or affect osteoblast-osteoclast signaling, suggesting a role for androgen receptors in regulating bone remodeling. In men with idiopathic osteoporosis, decreased testosterone levels are associated with a decrease in BMD; TRT increases BMD in the vertebrae. As expected, a recent study of those with acute SCI noted that the observed bone resorption was not associated with endocrine abnormalities, possibly due to the overwhelming effects of immobilization itself. However, decreased total testosterone and free androgen index levels may be exacerbating factors in the occurrence of acute bone loss. In a rat model of bone loss due to hindlimb weight loss, administration of testosterone or nandrolone prevented most of the immobilization-related decrease in BMD. Recently, researchers tested whether nandrolone could protect against bone loss in male rats that underwent sciatic nerve axotomy and were treated with nandrolone or vehicle for 28 days after 28 days. Denervation resulted in a 7% and 12% decrease in BMD in the femur and tibia, respectively.

[0028] Risk of fracture after SCI

[0029] Low-energy fractures following commonly performed ADLs, such as transfers or bed rotations, may pose serious health risks to individuals with SCI. Subsequent complications following fractures, including altered healing, pressure sores, infections, and myelitis, increase the common morbidity of these individuals. In addition, due to the loss of sensation below the level of injury and impaired pain perception, SCI patients may not be aware of the fracture, and therefore, inadvertently delay seeking medical care, potentially leading to complications that prevent or interfere with fracture treatment. Common fracture sites are located around the knee joint, the distal femur, and the proximal tibia. Because individuals with tetraplegia have a higher risk of fractures or bone injuries, fracture rates also increase with increasing levels of injury.

[0030] Individuals with SCI not only lose motor and / or sensory function, but also experience dramatic muscle and bone loss. Exercise training is an activity-based intervention that engages the neuromuscular system below the level of the lesion to enable standing and walking, enhances EMG activity, and shows modest improvements in muscle without any loss in bone density.

[0031] Combined NMES, TRT and Physical Activity Embodiments of the Invention

[0032] TRT has been shown to provide reasonable, effective and cost-effective intervention to partially offset these adverse body composition, metabolism and functional sequelae of those chronic SCI patients' relative hypogonadism. In addition, it has been shown that testosterone alone increases muscle mass, muscle strength and bone in males with androgen deficiency and old men with low testosterone levels. The inventor believes that, according to the present invention, TRT combined with NMES will further obtain benefits to the favorable benefits of those SCI patients along with the increase of physical activity (such as standing training). In this type of embodiment of the present invention, the compression load model produced during the combination of standing retraining and multi-muscle NMES will be multi-directional and will increase muscle strength and the power applied to hip, femur and tibia.

[0033] Standing training, specifically dynamic standing training, provides sensory feedback associated with standing and bilateral weight bearing, leading to bilateral muscle activation via a central pathway through the spinal cord. Dynamic standing training is accomplished by, for example, the participant standing in a dynamic standing frame or suspended on a safety belt by an overhead cable (e.g., a body weight support BWS) on a treadmill. When dynamic standing training requires, other devices that assist balance can be used. The dynamic standing training protocol of this embodiment of the present invention is intended to restore stable control during normal standing and involves repeatedly performing a series of dynamic movements while standing. Therapists or other trainers provide manual assistance using specific techniques as needed, which will promote the required movement patterns to facilitate the completion of tasks. Therefore, according to this embodiment of the present invention, the standing retraining component provides physiologically relevant multi-muscle activation through a central pathway, dynamic gravity relative loading of the legs, and additional task-specific muscle activation.

[0034] The inventors believe that the standing training model using TRT will increase muscle mass and strength more than standing alone. The combination of multi-muscle NMES and TRT during standing training will further increase muscle strength compared to either group alone, resulting in a synergistic response increase in benefit that will exceed the threshold required to significantly increase bone repair. This novel three-combination synergistic approach of TRT, NMES, and standing training is believed to increase muscle mass and strength to a greater extent than using either alone or only two of these interventions.

[0035] WPHF-NMES Embodiments of the present invention

[0036] The method of the present invention helps to regulate the electrophysiological properties of the central nervous system ("CNS") circuit during a specific task. These can be achieved by activating the CNS circuit through a combination of intentional supraspinal signals from the participant, afferent signals induced by NMES, and sensory feedback provided by proprioceptors activated during the task. Together, these signals drive the plasticity of the nervous system to restore specific motor functions. Moreover, activating the CNS circuit consistently by the method of the present invention provides more muscle torque generation and leads to improved secondary consequences of paralysis, such as cardiovascular and respiratory complications and muscle and bone loss.

[0037] As described in the applicant's U.S. patent application serial number 14 / 994,613, entitled "Neuromuscular Stimulation System and Method" filed on January 13, 2016, it was found that the torque generation of muscles was significantly greater using WPHF-NMES, the entire contents of which are incorporated herein by reference. The inventors of the patent application have demonstrated the restoration of arm and hand function in chronic SCI patients treated with WPHF-NMES. In addition, using the methods and systems described in the patent application, the ability to actively move the legs and trunk has been observed in individuals with upper and motor neuron injuries, as well as improved trunk stability, posture, standing and walking abilities.

[0038] The inventors of the above-referenced patent application unexpectedly discovered additional efficacy when delivering WPHF-NMES stimulation in a manner that produces contractions via pathways through the central nervous system using surface electrodes. When contractions are produced using the method described in the patent application, motor neurons are synaptically recruited, thereby reducing fatigue during voluntary contractions (ordered recruitment, asynchronous discharge). Surprisingly, prior to the method described in the patent application, several methods had been developed to synaptically recruit motor units via electrically induced sensory plethora during NMES.

[0039] The inventors of the above-referenced patent applications have also discovered that WPHF-NMES, which has a wider pulse duration (e.g., at least about 1 ms) and a higher frequency (e.g., about 100 Hz) than conventionally used, produces contractions via pathways across the CNS. Thus, the WPHF-NMES parameters disclosed herein are designed to increase electrically evoked sensory volleys to engage CNS circuits that control movement and produce contractions that are more fatigue-resistant, better reduce muscle and bone atrophy, and improve voluntary muscle control than contractions produced using conventional NMES.

[0040] During an exemplary WPHF-NMES session according to the present invention, contractions were formed via two pathways. Part of the contraction was caused by the known peripheral pathway due to the activation of motor axons below the stimulating electrode. However, additional torque was formed by the activation of sensory axons, which recruited motor units via pathways that passed through the CNS and returned to the muscle. This occurred even when the stimulation intensity was adjusted to account for different pulse durations (and therefore, overall stimulation charge) and to ensure that the stimulation recruited a similar number of motor axons (i.e., similarly sized M waves).

[0041] The inventors of the above-referenced patent application further discovered that WPHF-NMES produces additional contractions because a relatively larger sensory burst is sent to the CNS than during conventional NMES. Two reasons explain this. First, sensory axons have lower basic current intensities and longer intensity-duration constants than motor axons due to differences in the complementarity of ion channels on the two types of axons. In this way, when a given number of motor axons are stimulated (i.e., M waves of similar size), the wider pulses supplement a larger proportion of sensory axons, resulting in a greater reflex contribution to contraction and greater torque. Second, the relatively high stimulation frequency (e.g., about 100 Hz) sends more pulses to the CNS in a given period of time than occurs during conventional NMES.

[0042] In addition, the inventors of the above-referenced patent application found that when a multi-muscle WPHF-NMES session was combined with physical activity (such as, for example, dynamic standing), the BMD of the hip and knee increased. The load force during dynamic standing with multi-muscle WPHF-NMES can be, for example, about 0.7 body weight per limb. The combination of a multi-muscle WPHF-NMES session with physical activity (such as, for example, dynamic standing intervention) can also increase muscle strength and muscle volume.

[0043] Physiologically, the enhanced synaptic drive produced by WPHF-NMES engages the CNS circuit that controls movement. In this way, WPHF-NMES synaptically supplements motor neurons in a more physiologically relevant way than traditional NMES. WPHF-NMES supplements motor units according to the size principle of Henneman, and many motor units discharge asynchronously with each other. Because fatigue-resistant motor units are supplemented first and lower motor unit discharges are required to produce contractions at functionally relevant amplitudes, the supplementation of motor units in these two aspects reduces the fatigue of voluntary contractions. In addition, WPHF-NMES increases the excitability of the pathway that mediates the voluntary command from the brain to the muscle. NMES delivered at about 100Hz but not 50Hz or 200Hz increases the excitability of the corticospinal pathway. This effect of WPHF-NMES on the excitatory CNS circuit that mediates voluntary commands may be partially responsible for the improvement of voluntary control observed using this method.

[0044] Representative Embodiments of the Invention

[0045] In one embodiment of the present invention, a method of treating musculoskeletal deterioration during treatment or recovery of a subject suffering from a neurological or neuromuscular injury, disease or condition is provided. The method comprises the steps of applying testosterone to the subject; placing surface electrodes on the subject for stimulating a plurality of muscle groups; and administering a plurality of intervention sessions, each of the plurality of intervention sessions comprising neuromuscular electrical stimulation of the muscle group.

[0046] The method may further comprise a specific physical activity regimen in combination with the neuromuscular electrical stimulation. More than one specific physical activity may be administered. The physical activity may be, but is not limited to, standing, sitting, sit-to-stand transition, walking, weight bearing, flexing a body part, or stretching a body part, or a combination thereof. Standing may be dynamic standing or standing suspended in a harness.

[0047] The testosterone applied to the subject can be in the form of a gel or a patch. When in the form of a gel or a patch, the testosterone gel concentration is a concentration of 1.62%, which can be dispensed by a pump. In a contemplated embodiment of the present invention, after a baseline test period, TRT will begin in the treatment group by applying 40.5 mg of testosterone gel from a pump every day. A suitable testosterone gel for this purpose is from AbbVie Inc, North Chicago, IL. When transdermal testosterone is applied, it will be absorbed and eliminated (therefore, daily application) in the process of one day. In order to ensure appropriate dosage, the dosage will be titrated based on the morning serum testosterone concentration before administration of a single blood draw at baseline, 2 weeks, 1 month and 3 months time point. Therefore, it will be necessary to follow up the participant to determine the correct replacement dose of TRT, and therefore adjust the dosage, for example, testosterone gel is in the range of about 40.5mg to 81mg. If serum testosterone level is not within the normal physiological range at 2 weeks time point, dosage will be increased to 81mg with an increment of 20.25mg.

[0048] Alternative testosterone patches and gels useful in the methods of the present invention include, for example, Patches; and gel.

[0049] During each intervention session, the neuromuscular electrical stimulation of the present invention may have a current amplitude of, for example, no more than 140 mA. In addition, the neuromuscular electrical stimulation during each intervention session may have a pulse width of about 50 to 3000 μs; and preferably, for example, a pulse width of 50 to 500 μs. The frequency may be, for example, in the range of about 10 to 100 Hz.

[0050] In one embodiment, the neuromuscular electrical stimulation during each intervention session may be WPHF-NMES. The wide pulse width may be 0.5 to 3 milliseconds. And the high frequency may be 50 to 150 Hz.

[0051] In one embodiment, the wide pulse width used in a WPHF-NMES session is, for example, about 0.5 to 3 milliseconds. In certain embodiments of the invention, the wide pulse width can be, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 and 3.0 milliseconds or a combination thereof.

[0052] The frequencies used in a WPHF-NMES session are, for example, in the range of about 50 to 150 Hz. In some embodiments, the high frequency can be, for example, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 147, 148, 149, and 150 Hz, or a combination thereof.

[0053] A WPHF-NMES session produces contractions at least in part via pathways through the subject's central nervous system. A single session of WPHF-NMES may include, for example, an initial increase in frequency from a low frequency to a high frequency, and then maintained at this high frequency to produce muscle contractions suitable for a particular physical activity. In another embodiment, a WPHF-NMES session may further include one or more rest periods. In one embodiment, the low frequency is less than about 5 Hz. In another embodiment, the low frequency may be direct current (DC).

[0054] In another embodiment of the invention, a certain number of intervention sessions are administered until a target level of recovery is reached. The target level depends on many clinical factors, such as, for example, the type of injury that caused the paralysis, the extent of the injury, the age of the subject, and other physiological parameters. For example, the neuromuscular injury, disease, or condition that caused the paralysis can be a traumatic and / or non-traumatic spinal cord injury, a stroke, or a brain injury.

[0055] As mentioned above, the WPHF-NMES intervention can be combined with a physical activity regimen common in the field of neurorehabilitation. In one embodiment, more than one specific physical activity is administered. The physical activity can be, but is not limited to, standing, sitting, sit-to-stand transition, walking, weight bearing, flexing a body part, or stretching a body part, or a combination thereof. In one embodiment, standing can be dynamic standing or standing suspended in a safety belt, optionally on a treadmill.

[0056] The methods of the present invention may also include, for example, applying a loading force to the subject during the intervention session. Examples of loading forces include a compressive force parallel to the long axis of the bone.

[0057] The inventors unexpectedly discovered that during a voluntary or electrically induced contraction of a subject, recovery comprises an increase in the force generated by the muscle or a decrease in contraction fatigue. Thus, in one embodiment of the invention, the method results in a decrease in muscle or bone atrophy in the subject, and an increase in voluntary control of skeletal muscle during a motor task.

[0058] Example

[0059] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that examples are provided to illustrate certain embodiments and are therefore not intended to limit the scope of the present disclosure. It should be further understood that various other embodiments, modifications and equivalents may be conceived by those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0060] Example 1

[0061] Administration of testosterone replacement therapy (TRT) gel pump

[0062] After the baseline test period, TRT will be started in the treatment group by applying 40.5mg testosterone gel (Androgel, AbbVie Inc, North Chicago, IL, USA) from the pump every day. When transdermal testosterone is applied, it will be absorbed and eliminated in the course of a day (therefore, daily application). In order to ensure the appropriate dose, the dose will be titrated based on the morning serum testosterone concentration before administration of a single blood draw at baseline, 2 weeks, 1 month and 3 months time points. Therefore, it will be necessary to follow up the participants to determine the correct replacement dose of TRT, and therefore adjust the dose (e.g., 40.5mg to 81mg of gel): (i.e. 2 pump pressures vs. 3-4 pump pressures). Therefore, if the serum T level is not within the normal physiological range at the 2-week time point, the dose will be increased to 81mg in increments of 20.25mg (1 pump pressure). (4 pump pressures).

[0063] Prior to using the pump for the first time, the subject will be instructed to prime the pump by pushing the pump down slowly all the way three times. Any gel released during priming should be completely flushed down the drain to avoid accidental exposure to others. After priming, the pump is ready for use.

[0064] To apply the gel, subjects should ensure that their upper arms and shoulders are clean, dry, and free of broken skin. They should squeeze the pump firmly to dispense the gel into their palms or directly onto the application site (upper arms and shoulders). Subjects rub the gel onto their upper arms and shoulders, which are areas that are normally covered by a shirt. After applying the gel, subjects should immediately wash their hands with soap and water.

[0065] Subjects were to wait until the gel was completely dry on the skin before putting on a shirt to cover the application area. Application of the gel should be done at the same time each morning. To prevent T-gel skin irritation, subjects were instructed to use a topical corticosteroid (e.g., triamcinolone) cream on the application site if skin irritation occurred.

[0066] Table 1 summarizes the daily dose, number of pumps, and method of application of testosterone gel:

[0067] Table 1

[0068]

[0069]

[0070] Example 2

[0071] Stand-up training alone: ​​Stand-up training (placebo or testosterone)

[0072] All individuals randomized to standing training (with or without ES or testosterone) will perform manual assisted training using a body weight support ("BWS") and will undergo a standing assessment. During the assessment, participants will be placed on a treadmill in an upright position and suspended in a harness by overhead cables. A trainer located behind the participant will help stabilize the pelvis and trunk by applying an anterior force at the pelvis and / or a posterior force at the shoulder, ensuring that the trunk and pelvis are not flexed or hyperextended. The trainer will assist in maintaining dynamic knee extension to promote extensor activity of the weight-bearing limb by applying a posteriorly directed gentle pressure on the patellar tendon. The trainer will also promote slight knee flexion and extension to promote dynamic weight-bearing to enhance neuromuscular activation. All trainers are careful to provide manual assistance only when needed.

[0073] The participant will stop and rest whenever they feel the need during the training session. During the assessment, the BWS will be reduced until the trainer's assistance is insufficient to maintain proper motor function or ensure the patient's safety. The number of BWS and the level of assistance provided by each trainer for each body segment will be recorded. The BWS level at which the participant is able to independently support a good standing position will also be recorded. Medial-lateral and anterior-posterior shifts will also be performed on the treadmill. Standing time on the treadmill and on the ground will be recorded daily as part of the training session.

[0074] BWS will be given when the subject is unable to maintain body weight while performing limb movements. During standing with moderate assistance from the trainer, the level of BWS will be adjusted to maximize load without bending the knee joint. Manual assistance will be given when the subject (with BWS) is unable to perform standing movements relative to the lower limbs and trunk. Assistance will be given during standing to help knee extension if necessary. Assistance will also be given to maintain the pelvis in a stable position and to maintain the trunk in an extended position.

[0075] Each subject will be encouraged to hold their arms relaxed at their sides. To initiate standing, participants will be encouraged to load evenly between the legs, limiting pelvic motion (anterior / posterior or lateral). The leg trainer will assist in knee extension by repeatedly pushing on the patellar tendon to promote knee extension, and the medial hamstrings (behind the knee) to prevent hyperextension. The overall goal is to obtain stable control during standing (and limb control) that is similar to normal standing, as well as repetitive practice movements. This will be determined by adjusting and ultimately minimizing BWS and minimizing manual assistance.

[0076] Circuit training of BWS will be determined for 60 minutes of training [15 minutes assisted 100% full load, 10 minutes increasing BWS to stand unassisted, 10 minutes assisted full body weight load, increasing BWS to stand unassisted, 15 minutes assisted full load]. The duration of the standing retraining session will be a maximum of 1 hour or determined by the subject's fatigue. Blood pressure will be continuously measured. To help maintain the participant's blood pressure ("BP"), arm exercises will be used while standing.

[0077] If BP drops below the limit recommended by the examining physician, or the participant complains of dizziness, mild headache, or any autonomic nervous system oscillations (nausea, vomiting): the participant will rest in a sitting position (feet elevated). After a 5-minute rest, the participant will once again start standing and have blood pressure monitored. The participant will have three opportunities to complete a 60-minute training session. The duration of the training and blood pressure will be recorded for further analysis. If the participant cannot tolerate the 60-minute training, he or she will end the training and the training time will be recorded for future analysis. Before each training session, BP will be assessed (3 consecutive blood pressure measurements within 5 mmHg, 1 minute apart). Once blood pressure is stable, the participant will start training.

[0078] Example 3

[0079] Standing training and ES: Standing training and ES (placebo or testosterone)

[0080] The RT300 functional electrical stimulator, available from Restorative Therapies Inc., Baltimore, MD. USA, is a 6-channel stimulator that can be expanded to 16 channels using wireless single-channel stimulators. Each stimulation channel is independently adjustable, including, for example, amplitude 0 to 140 mA; pulse width 50 to 500 μs; frequency from 10 to 100 Hz. In research mode, pulse width can reach 3,000 μs. Stimulation is controlled by a Windows CE-based controller with a 7-inch color touch-sensitive display. Optional I / O ports can be configured to provide additional control triggering and timing functions to support research applications. The software included with the RT300 will allow clinicians to generate arbitrary patterns and complex stimulation sequences for other applications. For our stimulation protocol, we will stimulate all muscles of the lower extremity, including the rectus femoris, biceps femoris, gastrocnemius, tibialis anterior, and gluteus maximus bilaterally.

[0081] Electrical stimulation will be applied via bifurcated leads and self-adhesive reusable surface electrodes. Electrodes will be applied to the motor points (both legs) of the following muscles: gluteus maximus (GL), rectus femoris (RF), biceps femoris (BF), gastrocnemius (GC), and tibialis anterior (TA) of both legs. Two electrodes will be used for each muscle. Electrical stimulation will be induced using an RT300 portable stimulator with 10 sets of electrodes for stimulation. In one stimulation protocol, symmetrical biphasic pulses are applied at 35 Hz for 300 μs, delivered over a 1000 ohm load, in a duty cycle of 11 seconds on and 60 seconds off, with overlap during each contraction between the upper and lower legs. Thus, the GC and TA muscles will first contract for 4 seconds. Next, the BF and RF will contract for 7 seconds, while the other muscle tissues are still stimulated (11 seconds in total). This will be followed by a 60-second rest (no stimulation).

[0082] The timing and phasing of this contraction is chosen to induce the muscle groups to alternately contract and relax in an overlapping manner. Since the intravenous pump requires maximal FES-induced contraction to be effective, the subjects will be acclimated to FES before training to find the maximal tolerable stimulation level for each muscle and applied during training. The stimulation will start at the minimum contraction threshold level and will reach maximum contraction within 2 seconds. EMG information can be collected during this time to measure muscle response.

[0083] BP and heart rate will be monitored during the whole session. If BP drops below the limit recommended by the examining physician or clinician, or the participant complains of dizziness, mild headache or any autonomic nervous system oscillation (nausea, vomiting), the participant will rest. After resting for 5 minutes, the participant will restart ES again and continue to monitor BP. The participant will have three opportunities to complete a 60-minute training session. The duration and blood pressure of the training will be recorded for further analysis. The participant will be asked to complete 60 minutes of FES-induced muscle contraction. If the participant cannot tolerate 60 minutes of training (pulse per second = 3 or 4), she / he will end the training and will record the training time for future analysis. Before each training, BP will be evaluated (3 consecutive blood pressure measurements, within 5mmHg, 1 minute apart). Once blood pressure is stable, the participant will start training. BP is continuously collected throughout the training process.

[0084] When the participant sits down and before he stands completely, the electrical stimulation will start. During the standing treatment and before and after the session, BP and heart rate will be monitored. If BP drops below the limit recommended by the examining physician, or the participant complains of dizziness, mild headache or any autonomic nervous system oscillation (nausea, vomiting), the standing treatment will be stopped and the participant will be walked to a suitable position or brought to a sitting position. The same procedures described for the other 2 groups will be followed to adapt the individual to ES and standing.

[0085] Example 4

[0086] Standing training with TRT and ES induced beneficial changes in muscle mass compared with other combinations of these interventions

[0087] Test 1 will measure muscle volume in the thigh. The percentage change in muscle volume of the bilateral thighs from pre-intervention to post-intervention will be compared by fitting a linear mixed effects model to the muscle volume data. The use of a mixed effects model is necessitated by the repeated measures nature of the data - at each visit, each participant will be measured on the left and right sides. The random effect of the model will be the intercept term, assuming that each patient is randomized. The mixed effects model will have the change in muscle volume as the dependent variable, and the treatment group as a four-level fixed factor as the main independent variable. Side (left or right), study site, previous baclofen use, and time after SCI (parameterized as a two-level factor, indicating 0.5-1 years after SCI and greater than 1-2 years after SCI) will be included as control factors, but the side, site, and time after SCI comparison terms are not the main focus. Linear contrasts will be applied to the model to compare the ST+ES+TRT group with the remaining three treatment groups (ST, ST+ES, ST+TRT) separately. We fixed ST+ES+TRT as the control group during the multiple comparison process, eliminating the need to correct for multiple comparisons.

[0088] Mixed effects models allow for the inclusion of additional covariates in the model if warranted and sample size permits - factors such as age and weight should be considered. These covariates will be control variables rather than comparisons of interest. It is expected that those subjects in the Stand+TRT+ES group will show greater increases in muscle volume than Stand+TRT, Stand+ES, and Stand alone. As a secondary analysis, the same mixed effects model as above should be employed, but with treatment parameterized as two two-level factors (use of TRT, use of ES) rather than as a single 4-level factor, allowing for testing of interactions between TRT and ES. Additional analyses will include more general mixed effects models that include measurements taken at the 3-month follow-up. From these models, we will be able to generate an interval estimate that not only estimates the effect of treatment across the 4 study groups, but also any post-training effects. Absolute values ​​rather than percentage changes will also be considered as primary outcomes, as shown in the Statistical Contingencies section below.

[0089] Test 2: Quadriceps muscle torque, muscle cross-sectional area will be assessed. Other ancillary measures include BMD of the hip and proximal tibia and distal femur as well as markers of bone formation and resorption, 3D volumetric measurements of cortical and trabecular bone of the lower extremity. MRI of the lower extremity (from above the iliopsoas origin to the Achilles tendon insertion) will provide an accurate assessment of the physiological cross-sectional area (PCSA) and volume of individual muscles. Muscle physiological quadriceps muscle torque will be calculated.

[0090] The BMD of hip, distal femur and proximal tibia will be measured.Except BMD, the three-dimensional volume measurement of lower limb cortex and trabecular bone will also be determined.The measurement of the biochemical markers of bone conversion (resorption / formation) will be carried out.The marker for resorption is the urine cross-linked N-terminal peptide of type I collagen (NTx), such as Osteomark, Ostex International, Inc., Seattle, WA, and serum osteocalcin will be analyzed as the marker formed, such as Diagnostic Systems Laboratories, Inc., Webster, TX, Texas.

[0091] These tests indicate a comparison of the ST+ES+TRT group with the remaining three treatment groups. Therefore, the analysis should be a linear mixed-effects model with a 4-level factor for the fixed effect term and a single, patient-specific random effect for each group of repeated measures (right and left leg). The treatment groups should be compared identically - a linear contrast comparing the ST+ES+TRT group with the remaining three groups. Study site, time since SCI, and previous baclofen use should be included as control variables, and additional covariates (age, weight, etc.) should be included in these models if warranted and sample size permits. Additional analyses should include reparameterizing the fixed effects into two two-level factors (corresponding to ES and TRT) and including measurements taken at follow-up, as for the primary outcome.

[0092] Example 5

[0093] Testosterone replacement therapy combined with WPHF-NMES

[0094] As in the above examples, testosterone can be applied to the subject. Surface electrodes are placed on muscles or nerves of the lower and / or upper limbs and trunk (legs, trunk, arms and hands). Stimulation is delivered in a frequency modulated mode using pulses with a duration equal to or greater than 1 ms and a frequency of at least 100 Hz. WPHF-NMES is designed to produce contractions by activating motor and sensory axons, which activate the spinal cord and other circuits in the central nervous system that control movement.

[0095] The temporal parameters of stimulation are synchronized with the specific motor task targeted for recovery. As described below, WPHF-NMES is combined with training in specific tasks of daily living to improve motor function to a level representative of pre-injury or normal activity with limited use of compensatory movements.

[0096] Dynamic Standing Retraining and WPHF-NMES Combination

[0097] Dynamic standing includes, for example, dynamic weight bearing to increase activation of standing muscles while enhancing activation of the spinal cord and other circuits in the central nervous system that control movement. Major muscle groups of the legs and trunk are stimulated simultaneously using surface electrodes placed on muscles or nerves of the lower limbs and trunk. Stimulation is delivered in a frequency modulated mode using pulses with a duration equal to or greater than 1 ms and a frequency of at least 100 Hz. WPHF-NMES is designed to produce contractions by activating motor and sensory axons, which activate the spinal cord and other circuits in the central nervous system that control movement. Muscles stimulated include the triceps brachii, tibialis anterior, quadriceps femoris, hamstrings, gluteus maximus, and erector spinae.

[0098] Participants stand in a dynamic standing frame or on a treadmill while suspended in a harness by overhead cables (e.g., body weight supports). Other devices to assist balance are used when needed. The dynamic standing protocol is designed to restore stable control during normal standing and involves repetitive practice of a range of dynamic movements while standing. A therapist or other trainer provides manual assistance as needed using specific techniques that will facilitate the required movement patterns to facilitate completion of the task.

[0099] Sit-to-Stand Combination with WPHE-NMES

[0100] The goal was to achieve a transition from sitting to standing with motor function in the trunk, pelvis, and legs as close to pre-injury levels as possible. WPHF-NMES was used to stimulate the major muscles of the legs, pelvis, and trunk in a timed sequence to facilitate sitting to standing. Stimulation was delivered in a frequency-modulated mode using pulses of duration equal to or greater than 1 ms and a frequency of at least 100 Hz. Muscles stimulated included the triceps brachii, tibialis anterior, quadriceps femoris, hamstrings, gluteus maximus, and erector spinae.

[0101] Seated Trunk Stretch with WPHF-NMES Combination

[0102] The major muscle groups of the trunk were stimulated in a continuous temporal pattern for trunk extension while sitting. Stimulation was delivered in a frequency modulated pattern using pulses of duration equal to or greater than 1 ms and a frequency of at least 100 Hz. WPHF-NMES was administered to produce contractions by activating motor and sensory axons, which activated the spinal cord and other circuits in the central nervous system that control movement. The major muscle groups of the trunk were stimulated simultaneously using surface electrodes placed over the motor points of the trunk muscles. The stimulated muscles included the abdomen, upper and lower erector spinae, and trapezius.

[0103] Overhead press combined with WPHF-NMES

[0104] Each arm and trunk muscle was stimulated in a sequential pattern appropriate to the overhead press movement. Surface electrodes were placed on the muscles or nerves of the trunk and arms. Stimulation was delivered in a frequency-modulated pattern using pulses of duration equal to or greater than 1 ms and a frequency of at least 100 Hz. WPHF-NMES is designed to produce contractions by activating motor and sensory axons, which activate the spinal cord and other circuits in the central nervous system that control movement.

[0105] The present invention is further described by the following numbered paragraphs:

[0106] 1. A method for treating musculoskeletal deterioration during treatment or recovery of a subject suffering from a neurological or neuromuscular injury, disease or condition, the method comprising the steps of:

[0107] a) administering testosterone to the subject;

[0108] b) placing surface electrodes on the subject for stimulating a plurality of muscle groups; and

[0109] c) administering a plurality of intervention sessions, each of the plurality of intervention sessions comprising neuromuscular electrical stimulation of the muscle group.

[0110] 2. According to the method of paragraph 1, the method further comprises a specific physical activity program combined with the neuromuscular electrical stimulation.

[0111] 3. A method according to paragraph 1, wherein the testosterone is in the form of a gel or a patch.

[0112] 4. The method according to paragraph 1, wherein the concentration of testosterone is 1.62%.

[0113] 5. The method according to paragraph 1, wherein the testosterone is administered in a dose of 40.5 to 81 mg per day.

[0114] 6. The method of paragraph 1, wherein the neuromuscular electrical stimulation has an amplitude of no greater than 140 mA during each intervention session.

[0115] 7. A method according to paragraph 1, wherein the neuromuscular electrical stimulation has a pulse width of 50 μs to 3000 μs during each intervention session.

[0116] 8. The method according to paragraph 1, wherein the neuromuscular electrical stimulation during each intervention session has a pulse width of 50 μs to 500 μs.

[0117] 9. A method according to paragraph 1, wherein the neuromuscular electrical stimulation has a frequency of 10 to 100 Hz during each intervention session.

[0118] 10. The method according to paragraph 1, wherein the neuromuscular electrical stimulation during each intervention session is wide pulse width, high frequency neuromuscular electrical stimulation (WPHF-NMES).

[0119] 11. The method according to paragraph 10, wherein the wide pulse width is 0.5 to 3 milliseconds.

[0120] 12. The method according to paragraph 10, wherein the high frequency is 50 to 150 Hz.

[0121] 13. The method according to paragraph 10, wherein the WPHF-NMES produces contraction at least in part via a pathway through the central nervous system of the subject.

[0122] 14. The method of paragraph 10, wherein a single session of WPHF-NMES comprises an initial increase in frequency from a low frequency of 50 to 150 Hz to a high frequency, maintained at the high frequency to produce muscle contractions appropriate for a specific physical activity.

[0123] 15. A method according to paragraph 14, wherein the low frequency is less than 5 Hz.

[0124] 16. A method according to paragraph 15, wherein the low frequency is DC.

[0125] 17. The method of paragraph 1, wherein a certain number of intervention sessions are administered until the target level of recovery is achieved.

[0126] 18. The method according to paragraph 1, wherein the neuromuscular injury, disease or condition causing paralysis is traumatic and / or non-traumatic spinal cord injury, stroke or brain injury.

[0127] 19. A method according to paragraph 2, wherein more than one specific physical activity is administered.

[0128] 20. The method according to paragraph 2, wherein the physical activity is standing, sitting, sit-to-stand transition, walking, weight bearing, flexing a body part or stretching a body part or a combination thereof.

[0129] 21. The method according to paragraph 20, wherein the standing is dynamic standing or standing suspended in a safety harness.

[0130] 22. The method of paragraph 1, further comprising the step of applying a load force to the subject during the intervention session.

[0131] 23. The method according to paragraph 1, wherein the subject is a human.

[0132] 24. The method according to paragraph 23, wherein the human is quadriplegic, paraplegic or hemiplegic.

[0133] It will be appreciated that the present invention is not limited to the particular embodiments of the invention described above, as variations may be made thereto and still fall within the scope of the appended claims.

Claims

1. A combination of testosterone and an electrical stimulator for treating musculoskeletal deterioration during treatment or recovery of a subject suffering from a neurological or neuromuscular injury, disease or condition, the electrical stimulator comprising a controller and a plurality of surface electrodes, wherein the electrical stimulator is capable of stimulating a plurality of muscle groups, and wherein the testosterone and the surface electrodes are used to be applied to the subject, and wherein the controller is used to control the electrical stimulator to administer a plurality of intervention sessions, each of the plurality of intervention sessions comprising neuromuscular electrical stimulation of the muscle group.

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