Treatment of spinal muscular atrophy

Abstract

Disclosed herein are methods for treating spinal muscular atrophy in a subject. Particular methods include applying a therapeutically effective amount of an electrical stimulation to sensory neurons innervating a body region of the subject having a motor injury caused by spinal muscular dystrophy, wherein the application of the electrical stimulation treats the motor injury caused by spinal muscular dystrophy in the subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 352,599, filed on June 15, 2022, and U.S. Provisional Application No. 63 / 450,901, filed on March 8, 2023, the entire contents of which are hereby incorporated by reference into this document. Technical Field

[0003] The present disclosure relates to methods of treating spinal muscular atrophy (SMA) in a subject by stimulating sensory afferents in the subject. Background Art

[0004] SMA is a neurodegenerative disease caused by a genetic mutation in the survival motor neuron 1 (SMN1) gene (Lefebvre et al., 1995. Cell 80(1):155-165). The affected motor neurons (MNs) in SMA patients have a poor ability to generate sustained excitation and may degenerate over time, leading to MN death. Obviously, although the SMN1 gene is commonly expressed in all MNs, not all muscles are affected. SMA particularly affects the lower limbs and, in more severe cases, also affects respiratory function. Experiments in mouse models have shown that insufficient expression of SMN protein first causes dysfunction and causes MN death in the late stage of the disease (Le et al., 2005. Human Molecular Genetics 14(6):845–57; Avila et al., 2007. J Clinical Investigation. 117(3):659-671). In other words, many (if not all) MNs are nonfunctional or dead in SMA patients, especially when SMA patients are in the late stage of the disease. Furthermore, even in those muscles affected by SMA, not all neurons are dysfunctional (Fletcher et al., 2017. Nat Neuroscience 20(7):905–16; Mentis et al., 2011. Neuron 69(3):453-67), indicating that muscle weakness is caused by a certain percentage of MN dysfunction rather than their death. Therefore, MN dysfunction and its death in SMA patients are two independent processes.

[0005] The SMN gene has been mapped to a complex region in chromosome 5q by linkage analysis. In humans, this region contains an inverted repeat of approximately 500,000 base pairs (kb), resulting in two nearly identical copies of the SMN gene. SMA is caused by an inactivating mutation or deletion of the telomeric copy of the gene (SMN1) in both chromosomes, resulting in loss of SMN1 gene function. However, patients retain a centromeric copy of the gene (SMN2), and the copy number of the SMN2 gene in SMA patients is generally negatively correlated with disease severity; that is, patients with less severe SMA have more copies of SMN2. However, due to alternative splicing of exon 7 caused by a translationally silent C to T mutation in exon 7, SMN2 cannot fully compensate for the loss of SMN1 function. Therefore, most transcripts produced by SMN2 lack exon 7 (47SMN2) and encode a truncated SMN protein that is functionally impaired and rapidly degraded.

[0006] The SMN protein is thought to play a role in RNA processing and metabolism, with a well-characterized function in mediating the assembly of a specific class of RNA-protein complexes, called snRNPs. SMN may have other functions in MNs, but its role in preventing the selective degeneration of MNs has not been clearly established.

[0007] In most cases, SMA is diagnosed based on clinical symptoms and by the presence of at least one copy of the SMN1 gene test. However, in approximately 5% of cases, SMA is caused by a mutation in a gene other than SMN1 inactivation, some of which is known but others are not. In some cases, when SMN1 gene testing is not feasible or does not show any abnormalities, other tests, such as electromyography (EMG) or muscle biopsy, may be indicated.

[0008] Several SMA mouse models have been developed. In particular, the SMNΔ exon 7 (Δ7SMN) model (Le et al., Hum. Mol. Genet., 2005, 14: 845) carries several copies of the SMN2 gene and Δ7SMN2 cDNA at the same time, and summarizes many phenotypic characteristics of type 1 SMA. The Δ7SMN model can be used for SMN2 expression studies as well as motor function and survival assessments. The C / C allele mouse model (Jackson Laboratory strain #008714, The Jackson Laboratory, Bar Harbor, ME) provides a less severe SMA disease model in which mice have both SMN2 full-length (FL SMN2) mRNA and SMN protein with reduced levels. The C / C allele mouse phenotype has an SMN2 gene and a heterozygous mSMN1-SMN2 gene that undergoes alternative splicing, but without obvious muscle weakness. The C / C allele mouse model is used for SMN2 expression studies.

[0009] SMA severity ranges from respiratory failure in the neonatal period (type 1 to 2) to mild muscle weakness (type 4) that occurs in adulthood. Infant SMA is the most severe form of this neurodegenerative disease. Symptoms include muscle weakness, poor muscle tone, weak cry, limb weakness or easy to fall to the ground, difficulty sucking or swallowing, accumulation of secretions in the lungs or throat, difficulty eating, and increased susceptibility to respiratory infections. The legs are often weaker than the arms, and developmental milestones such as lifting the head or sitting up cannot be reached. In general, the earlier the symptoms appear, the shorter the life span. As MN cells deteriorate, symptoms appear soon after. The severe form of the disease is fatal, and there is no known cure for all forms. The course of SMA is directly related to the rate at which MN cells deteriorate and the resulting weakness severity. Due to the weakness of the muscles that support breathing, infants with severe forms of SMA often die of respiratory diseases. Children with milder forms of SMA live much longer, but they may need extensive medical support, especially those children at the more severe end of the range. The clinical spectrum of SMA disease has been divided into the following five groups:

[0010] Type 0 SMA (in utero SMA) is the most severe form of the disease and begins before birth. Typically, the first symptom of type 0 SMA is decreased fetal movement, which can be first observed between 30 and 36 weeks of pregnancy. After birth, these newborns move very little and have difficulty swallowing and breathing.

[0011] Type 1 SMA (infantile SMA or Werdnig-Hoffmann disease) presents with symptoms between 0 and 6 months of age. This form of SMA is also very severe. Patients are unable to acquire the ability to sit and usually die within the first 2 years without ventilatory support.

[0012] Type 2 SMA (intermediate SMA) has an age of onset between 7 and 18 months. Patients gain the ability to sit without support but are unable to stand or walk without assistance. Prognosis in this group depends largely on the degree of respiratory involvement.

[0013] Type 3 SMA (juvenile SMA or Kugelberg-Welander disease) is usually diagnosed after 18 months of age. Individuals with Type 3 SMA are able to walk independently at some point during the course of their disease, but often become wheelchair-bound during adolescence or adulthood.

[0014] Type 4 SMA (adult-onset SMA). Weakness usually begins in the tongue, hands, or feet during late adolescence and then spreads to other parts of the body. Adult-onset SMA progresses much more slowly and has little or no effect on life expectancy.

[0015] SMA is different from other types of motor injuries, such as those caused by spinal cord injury or stroke, because non-functional MN is the root cause of the damage caused by SMA. MNs in patients with spinal cord injury or stroke do not have underlying cellular pathophysiology. Therefore, if the MNs of these patients receive appropriate excitatory inputs, they are expected to respond. Compared with MNs in patients with spinal cord injury or stroke, MNs in SMA patients with cellular pathophysiology due to genetic mutations in the SMN1 gene do not respond to excitatory inputs because the MNs themselves are dysfunctional or dead. Therefore, it is expected that SCS, which is intended to increase the excitatory input to spinal MNs, will not produce effects similar to those observed in other conditions treated with SCS (such as spinal cord injury, stroke and pain, in which MNs still produce function) in SMA patients.

[0016] Traditional methods of treating motor impairment alone (such as exercise or physical therapy) may not be effective in treating SMA because neither exercise nor physical therapy can increase the excitation rate of MN recruiting muscle cells. The reduced excitation rate of MN in patients with SMA prevents the full involvement of muscle cells and leads to a reduction in sensory input from the central nervous system. Therefore, there is a need for a treatment method that improves MN excitation and function and thereby recruits more muscle cells to improve the quality of life of patients with SMA. It has been demonstrated that new gene therapies can prevent the necessity of permanent respiratory support and the death of neonatal patients (types 1 to 2). However, these gene therapies cannot help type 3 to 4 patients with severe motor deficits in adulthood. In addition, type 1 to 2 patients treated with gene therapy also have severe motor deficits. Additionally, other SMA therapies such as neuroprotectants may not be completely effective in all patients. Therefore, new therapies that target motor impairment in SMA patients and improve the effectiveness of current therapies are needed to improve the quality of life of these patients. Summary of the invention

[0017] Provided herein is an embodiment of a method for treating SMA in a subject. The method includes applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject having motor impairment due to SMA, wherein the electrical stimulation is applied using one or more electrodes controlled by a neurostimulator, and wherein the application of the electrical stimulation treats the motor impairment due to SMA in the subject.

[0018] The foregoing and other objects, features and advantages of the embodiments will become more apparent from the following detailed description made with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with one or more color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0020] Figures 1A to 1G Various models of SCS enhancement for MN output according to some embodiments are shown.

[0021] FIG. 2A to FIG. 2C A graph depicting force enhancement during simulated autonomous brain input is shown in accordance with some embodiments.

[0022] Figure 3A A model of a neuron affected by SMA with various ion channels is shown, wherein the delayed rectifier potassium channel (K-dr) is blocked, according to some embodiments.

[0023] Figure 3B Shown is a MN model with various ion channels including a specific delayed rectifier potassium channel (Kv2.1) according to some embodiments.

[0024] FIG. 4A to FIG. 4C Various Norm configuration to test the maximum torque in different joints in SMA patients receiving SCS stimulation of sensory neurons innervating the lower limb.

[0025] FIG. 5A to FIG. 5B An isokinetic machine (e.g., Norm isokinetic machine).

[0026] Figure 6 A comparison between the position of electrodes during surgery and after surgery in an SMA patient is shown according to some embodiments.

[0027] 7A to 7C Various torque measurements over time are shown for an SMA patient in accordance with some embodiments.

[0028] FIG. 8A to FIG. 8B Spinal cord stimulation according to some embodiments is shown to increase maximum hip flexion during movement in SMA patients.

[0029] FIG. 9A to FIG. 9B It is shown that spinal cord stimulation of a subject according to some embodiments only temporarily disrupts the balance of an SMA patient.

[0030] Fig.10 It is shown that SCS according to some embodiments robustly increases maximum velocity in SMA patients.

[0031] FIG. 11A to FIG. 11B The long-term effect of SCS on hip flexion in SMA patients according to some embodiments is shown.

[0032] FIG. 12A to FIG. 12CLong-term improvement in right knee extension for an SMA patient is shown in accordance with some embodiments.

[0033] FIG. 13A to FIG. 13C Long-term improvement in left knee extension for an SMA patient is shown according to some embodiments.

[0034] FIG. 14A to FIG. 14C Long-term improvement in right hip flexion for an SMA patient is shown in accordance with some embodiments.

[0035] FIG. 15A to FIG. 15C Long-term improvement in left hip flexion for an SMA patient is shown in accordance with some embodiments.

[0036] Fig.16 Shown is manual muscle testing scoring by muscle and session for an SMA patient with and without stimulation, according to some embodiments.

[0037] Fig.17 Shown is the distance traveled by an SMA patient during a six minute walk test across different sessions, comparing stimulation off to stimulation on, according to some embodiments.

[0038] Fig.18A The Hammersmith Functional Motor Scale-Extended score for SMA patients is shown in accordance with some embodiments.

[0039] Fig.18B The Hammersmith Functional Motor Scale-Extended score and the Revised Hammersmith Scale score for SMA patients are shown according to some embodiments. DETAILED DESCRIPTION

[0040] I. Introduction

[0041] Provided herein is a method for treating a subject with SMA.As discussed in detail herein, the electrical stimulation of a therapeutically effective amount is applied to the sensory neurons of the body area of ​​the subject with the motor impairment caused by SMA via one or more electrodes controlled by a neurostimulator to treat the motor impairment caused by SMA of the subject.Without being bound by theory, it is believed that electrical stimulation is applied to sensory neurons to directly recruit monosynaptic and polysynaptic excitatory pathways in the spinal cord, which in turn increases the membrane potential and the excitation rate probability of the spinal cord MN of the body area of ​​the subject with the motor impairment caused by SMA.This pathway recruitment can increase neuroplasticity, thereby allowing the subject to recover motor function.In addition, in some embodiments, over time (e.g., for at least 2 hours / day during a period of at least 6 months, or for at least 1 hour / day during a period of at least 1 month), the electrical stimulation of a therapeutically effective amount is applied to the subject and can cause the ion channel remodeling on the MN membrane and the continuous increase of the excitation rate probability of the spinal cord MN and the improved motor impairment, even in the absence of stimulation.

[0042] Thus, in an embodiment, therapeutic electrical stimulation may be administered to a subject by implantation or percutaneous placement of electrodes under the control of an implanted or external neurostimulator. The electrodes and neurostimulator together constitute a system for providing SCS to a subject to improve motor impairments (such as, for example, muscle weakness, muscle control, and / or speech deficits) caused by SMA. The system may be used in conjunction with other SMA therapies (such as targeted motor rehabilitation) to improve patient outcomes.

[0043] Given the unique pathophysiology of SMA, the application of SCS to SMA patients has produced unexpected results. As discussed above, SMA is different from other types of motor injuries, such as those caused by spinal cord injury or stroke, because non-functional MNs are the root cause of the injuries caused by SMA. Therefore, it is expected that SCS aimed at increasing excitatory input to spinal MNs will not produce effects in SMA patients similar to those observed in other conditions treated with SCS (such as spinal cord injury, stroke, and pain, in which MNs still produce function).

[0044] However, as discussed below, significant immediate and long-term effects of SCS have been observed in SMA patients treated according to the present disclosure. Unexpectedly, the magnitude of the immediate effects of SCS in SMA patients is at least as significant as those observed in patients with stroke and spinal cord injury. Even more significant is the magnitude of the long-term effects observed after only 4 weeks of treatment according to the present disclosure, as discussed in detail below (e.g., measures associated with: MN excitability, MN firing rate, torque generated at different leg joints, EMG signals, maximum voluntary contraction during knee extension and / or hip flexion, hip flexion during exercise, balance, sit-to-stand transitions, maximum running speed, range of motion, muscle strength (manual muscle testing), gait (6-minute walk test), motor ability (Hammersmith Functional Motor Scale Extension and Revised Hammersmith Scale Test), and leg circumference). In particular, the magnitude of the improvement in muscle strength is so large that the improvement cannot be attributed solely to exercise. For example, in one experiment, left hip flexion in SMA subjects more than doubled, even though the subjects did not perform any hip strength training during the study period in addition to walking. The subjects' exercise levels were unchanged relative to their exercise levels before the study. These changes were also reflected in the improvements observed in clinical outcome tests such as manual muscle testing, the revised Hammersmith scale (RHS) test, and the 6-minute walk test. In addition, the data did not indicate that a plateau had been reached, suggesting that longer use of SCS may produce even greater improvements in SMA patients.

[0045] The administration of SCS according to some embodiments of the present disclosure can artificially increase the activity of the same sensory afferent fibers (e.g., Ia) affected by SMA. This may have immediate (stimulation on and stimulation off during the study) and long-term (stimulation off before the study and stimulation off after the study) effects on SMA patients. Without being bound by any particular theory, SCS can instantly increase the excitatory input to MN and thus increase its excitation rate. This can produce an immediate improvement in motor defects. In the long run, the artificial increase in sensory afferent activity can strengthen the affected sensory synapses, and it can restore the maladaptive changes in MN ion channels, thereby improving MN dysfunction, which will produce measurable changes in motor function. Therefore, SCS can address motor defects caused by a reduction in presynaptic activity of sensory afferent fibers. In some embodiments, SCS can be combined with drug interventions designed to prevent disease progression.

[0046] II. Abbreviations

[0047] CST Corticospinal Tract

[0048] DRG Dorsal root ganglion

[0049] EMG Electromyography

[0050] MN motoneuron or motor neuron

[0051] SCS Spinal Cord Stimulation

[0052] SMA Spinal Muscular Atrophy

[0053] SMN1 survival motor neuron 1

[0054] III. Summary of Terminology

[0055] Unless otherwise indicated, technical terms are used in accordance with conventional usage. As used herein, the term "comprising" means "including". Although many methods and materials similar or equivalent to those described herein can be used, specific suitable methods and materials are described below. In order to facilitate viewing of various embodiments, the following terminology is provided:

[0056] About: As used herein, the term "about" refers to an approximation of a qualitative or quantitative measurement. Whether a measurement is qualitative or quantitative should be clear from its context. With respect to quantitative measurements, "about" refers to plus or minus 5% of a reference value. For example, "about" 100 mA means 95 mA to 105 mA.

[0057] Dorsal Roots: Small branches of the roots of sensory neurons that emerge from the back of the spinal cord and travel to the dorsal root ganglia.

[0058] Dorsolateral spinal cord: The area on the outer surface of the spinal cord between the dorsal midline and the point of entry of the dorsal rootlets into the aorta.

[0059] Electrical stimulation: Various types of electrical current are selectively delivered through one or more electrodes to a target location in a subject (eg, a specific area of ​​the dorsolateral spinal cord).

[0060] Electrode: An electrical conductor through which an electric current can pass. An electrode can also be a collector and / or emitter of the electric current. In some embodiments, the electrode is solid and comprises a conductive metal as a conductive layer. Non-limiting examples of conductive metals include precious or refractory metals and alloys such as stainless steel, tungsten, platinum, iridium, tantalum, titanium, titanium nitride, and niobium. The electrodes can be interconnected or wired independently.

[0061] Implantation: For example, placing an electrode or a device containing an electrode completely or partially within a subject using surgical techniques. A device is partially implanted when a portion of the device reaches the subject or extends outside the subject. Implantable electrodes and devices can be implanted epidurally at the spinal cord, such as at the dorsolateral aspect of the spinal cord. The electrodes or devices can be implanted for different durations, such as for a short duration (e.g., one or two days or less) or for a long or extended duration (e.g., one month, six months, one year or more), as in a daily assist device.

[0062] Motor impairment: Partial or complete loss of function of a body part, such as the legs, feet, arms, hands, fingers, neck, and trunk (e.g., respiratory muscles). Specific motor impairments include loss of muscle strength, partial paralysis (incomplete paralysis), loss of dexterity (such as finger movement), and uncontrollable muscle tone. Subjects may exhibit a variety of motor impairments as a comorbidity of SMA.

[0063] Motor threshold: The minimum thalamic stimulation intensity that can produce a motor output of a given amplitude from a muscle at rest (RMT) or during muscle contraction (AMT).

[0064] Neurostimulator: A current or voltage controlled electrical stimulation device. A neurostimulator controls the delivery of electrical pulses or patterns of electrical pulses with defined parameters such as, but not limited to, pulse frequency, duration, amplitude, phase symmetry, duty cycle, pulse current, pulse width, and on and off times. The controlled electrical pulses are delivered via one or more electrodes (e.g., leadless electrodes or electrodes at the end of a lead (thin insulated wire)) configured to apply electrical stimulation to a target tissue of a subject. A neurostimulator may include at least one multi-contact lead. A neurostimulator may be used to apply a series of electrical pulse stimulations (e.g., charge-balanced pulses) via at least one electrode; such as, but not limited to, low frequency pulse train modes, frequency sequence pulse burst train modes (e.g., where different modulated electrical stimulation sequences are generated at different burst frequencies), and phase train modes (e.g., where stimulation control parameters are varied in the course of feedback from the subject's movement).

[0065] Perception threshold: The minimum intensity of an electrical stimulus required for a conscious person to be aware of a specific sensation caused by the stimulus.

[0066] Sensory Neurons: Sensory neurons, also known as afferent neurons, are nerve cells within the peripheral nervous system that are responsible for converting stimuli from the neuron's environment into internal electrical impulses and transmitting the impulses to the central nervous system.

[0067] Spinal muscular atrophy (SMA): A disease usually caused by an inactivating mutation or deletion of the SMN1 gene on both chromosomes (resulting in a loss of SMN1 gene function).

[0068] Subject: A living multicellular vertebrate organism, a class that includes humans and non-human mammals, including non-human primates, rats, mice, guinea pigs, cats, dogs, cows, horses, etc. Thus, the term "subject" includes both human subjects and veterinary subjects.

[0069] Therapeutically effective amount: An amount of a compound or treatment (or both) sufficient to provide a beneficial or therapeutic effect to a subject or a given percentage of subjects. The therapeutically effective amount of a particular compound or treatment can be determined in many different ways, such as an assay for reduction of a disease or condition, such as motor impairment due to SMA. Therapeutic compounds and treatments can be administered in a single application or multiple applications (e.g., chronic applications over an appropriate period of time). However, the effective amount may depend on the source of application, the subject being treated, the severity and type of condition being treated, and the mode of administration.

[0070] Transcutaneous placement: Placing an electrode or a device containing an electrode on or near the surface of a subject's skin, for example using non-invasive techniques. The electrodes can be applied to the surface of a subject's skin to apply electrical stimulation, for example, under the control of an external neurostimulator. The electrodes or devices can be placed transcutaneously for varying durations, such as for a short duration (e.g., one or two days or less) or for a long or extended duration (e.g., one month, six months, one year or longer), as in a daily assist device.

[0071] Treat / treat: With respect to a disease or condition (e.g., SMA), any of the terms include one or more of the following: (1) preventing the disease or condition, e.g., so that clinical symptoms of the disease or condition do not appear in a subject who may be exposed to or susceptible to the disease or condition but does not yet experience or display symptoms of the disease or condition; (2) inhibiting the disease or condition, e.g., preventing the disease or condition or its clinical symptoms from appearing; and (3) ameliorating the disease or condition, e.g., causing regression of the disease or condition or its clinical symptoms.

[0072] More specifically, treatment or therapy of SMA means at least one or more of the following beneficial effects: reduction in loss of muscle strength, increase in muscle strength, reduction in muscle atrophy, reduction in loss of motor function, reduction in contractures, increase in MNs, reduction in loss of MNs, prevention of degeneration of SMN-deficient MNs, increase in motor function, increase in lung function, reduction in loss of lung function, and / or improvement in quality of life.

[0073] More specifically, management or treatment of SMA refers to the ability or maintenance of functional ability for a human infant or human toddler to perform certain movements such as sitting up independently, or for a human infant, human toddler, human child or human adult to perform certain movements such as standing independently, walking independently, running independently, breathing independently, turning independently during sleep, or swallowing independently.

[0074] IV. Stimulating sensory neurons to treat SMA

[0075] Provided herein are methods for treating subjects (e.g., human subjects) with SMA. The methods can be used to treat (i.e., prevent, improve, inhibit and / or alleviate) motor impairment caused by SMA in a subject. The methods include applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with motor impairment caused by SMA. The electrical stimulation can be applied, for example, with one or more electrodes controlled by a neurostimulator.

[0076] In an embodiment, applying electrical stimulation to sensory neurons increases the firing rate probability of spinal cord MNs innervating a body region of a subject having motor impairment caused by SMA. Without being bound by theory, it is believed that applying electrical stimulation to sensory neurons can directly recruit monosynaptic and polysynaptic excitatory pathways in the spinal cord, which can directly increase the membrane potential and firing rate probability of spinal cord MNs innervating a body region of a subject having motor impairment caused by SMA. This pathway recruitment can increase neuroplasticity, thereby allowing the subject to recover motor function.

[0077] Any suitable subject with or at risk of motor impairment due to SMA can be treated with the methods provided herein. The motor impairment can be in a limb of the upper or lower body, such as above or below the elbow, or above or below the knee, or include the entire arm or leg. The subject may have any one of SMA types 1 to 4, such as type 1, type 2, type 3, or type 4. In some embodiments, a subject with SMA is selected for treatment. The method can be initiated at any time after the onset of a motor impairment in a subject, or even before a detectable motor impairment in an SMA patient at risk of a motor impairment.

[0078] Applying a therapeutically effective amount of electrical stimulation to a subject with SMA treats at least one motor impairment in the subject caused by SMA. For example, application of a therapeutically effective amount of electrical stimulation can result in a reduction in loss of muscle strength, an increase in muscle strength, a reduction in muscle atrophy, a reduction in loss of motor function, an increase in motor function, an increase in lung function, and / or a reduction in loss of lung function.

[0079] In some embodiments, the motor impairment comprises decreased control of a limb, such as an arm or leg, and the methods provided herein improve the subject's control of the limb by at least 20% (such as at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) relative to before treatment, as measured by any appropriate assessment metric, such as a balance or strength metric (e.g., sensory tissue testing).

[0080] In some embodiments, the motor impairment comprises decreased postural balance and stability, and the methods provided herein improve the subject's postural balance and stability by at least 20% (such as at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) relative to before treatment as measured by any appropriate assessment metric, such as a balance or strength metric (e.g., sensory tissue testing).

[0081] In some embodiments, the motor impairment comprises a decrease in leg torque, and the methods provided herein increase the subject's leg torque by at least 20% (such as at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) relative to before treatment, such as using What the Norm system measures.

[0082] The one or more electrodes may be placed in any suitable location to apply electrical stimulation to sensory neurons in a subject. In some embodiments, the one or more electrodes are positioned to deliver electrical stimulation to one or more sensory neurons innervating a body region of the subject having motor impairment.

[0083] A spinal cord stimulation (SCS) system can include a neurostimulator and one or more spinal leads containing multiple electrodes or contacts. The contacts of the SCS system can target specific muscles. For example, contacts located near spinal segment L2 can target the hip flexors, while contacts located near spinal segment S1 can target the gluteal muscles and ankle extensors. Therefore, the location of the contacts or electrodes can be selected to selectively target specific nerves that innervate the muscles affected by SMA. For example, if a human subject has significant deficits in the knee extensors and hip flexors, the stimulation system can be positioned to selectively target these muscles.

[0084] In some embodiments, the location for applying SCS can be optimized and fine-tuned by stimulating various contact points in SMA patients, measuring the electrical activity generated by muscles (e.g., agonist and antagonist muscles of each joint), such as electromyography (EMG) signals, and evaluating the measurements. In one example, during surgery, the electrode position is determined by stimulating each contact point and recording the EMG signals of muscles ranging from the trunk down to the ankle. The stimulation of a specific contact point can start at a low frequency (e.g., about 1 Hz) and gradually increase the amplitude of the stimulation until electrical activity associated with muscle activity in response to the stimulation is recorded. Based on the recorded electrical activity, the specific muscle targeted by the specific contact point can be identified, and therefore, the stimulated contact point can be identified as a suitable location for the electrode. The peak-to-peak amplitude of the EMG waveform generated by the stimulation can be used to identify the response in the targeted muscle, and thus determine the correct position of the muscle. For example, the head side contact point can generate its first waveform in the hip flexor muscle, and the tail side contact point can generate its first waveform in the calf muscle. Stimulation can be repeated until the location for the electrode to activate is identified, for example, from the gluteal muscle with the most cephalad contact to the calf muscle with the most caudal contact. In other words, once the multiple contacts of the SCS system provide complete coverage of the leg muscles (e.g., from the hip to the ankle) for administering SCS, the lead position can be fixed. In some embodiments, the identified location can be used for a second SMA patient presenting with similar symptoms without performing the above test on the second SMA patient. In some embodiments, the above test is performed during surgery to implant the electrodes.

[0085] In some embodiments, the body area of ​​the subject suffering from the motor injury is selected from the lower back, buttocks, legs, ankles and feet. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of the T11 to S1 nerve roots. For example, one or more electrodes can be implanted at the sensory nerve or DRG, or epidurally implanted at the dorsal root or dorsolateral aspect of the spinal cord for sensory neurons of one or more of the T11 to S1 nerve roots.

[0086] In some embodiments, the body area of ​​the subject suffering from the motor injury is selected from the upper arm, shoulder, arm, hand, and respiratory muscles (such as intercostal muscles or diaphragm). In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of C3 to T2 nerve roots. For example, one or more electrodes can be implanted at a sensory nerve or DRG, or epidurally implanted at a dorsal root or dorsolateral aspect of the spinal cord for sensory neurons of one or more of the C3 to T2 nerve roots.

[0087] In some embodiments, the body area of ​​the subject suffering from the motor injury is selected from the chest, chest wall, abdomen, upper back and mid-back. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of the T3 to T10 nerve roots. For example, one or more electrodes can be implanted at the sensory nerve or DRG, or epidurally implanted at the dorsal root or dorsolateral aspect of the spinal cord for sensory neurons of the T3 to T10 nerve roots.

[0088] In some embodiments, the placement of electrodes during surgery can be adjusted to account for postoperative electrode movement. This postoperative movement may be variable and difficult to avoid with non-permanent implants. For example, the electrode may move caudally and offset medially. Therefore, based on the predicted postoperative movement of the electrode, the electrode can be implanted in an adjusted position during surgery so that after surgery, the electrode will move to a predefined optimal position. More detailed information about devices and surgical procedures that can be used to obtain chronic electromyographic (EMG) recordings from leg muscles and implant targeted spinal cord stimulation systems can be found in Capogrosso et al., 2018. Nature Protocols 13.2031-2061, which is incorporated herein by reference.

[0089] Any suitable stimulation pattern can be used to treat a subject's motor impairment. In some embodiments, the electrical stimulation comprises electrical pulses defined by parameters including, for example, but not limited to, amplitude, pulse width, and pulse frequency. Such electrical pulses may comprise charge-balanced pulses, such as cathode-preferred biphasic or monophasic charge-balanced pulses. In these and further embodiments, the electrical stimulation may be continuous electrical stimulation or periodic stimulation.

[0090] The stimulation parameters of the SCS can be configured in accordance with the techniques and values / ranges described herein. In one example, the electrical stimulation can be configured to include electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and / or a frequency of about 10 Hz to about 2000 Hz. In one example, the electrical stimulation can be configured to have a preferred frequency of about 40 Hz.

[0091] In particular examples, electrical stimulation includes electrical pulses having an amplitude of about 10 μA to about 50 mA, such as about 10 μA to about 10 mA, about 10 μA to about 1 mA, about 10 μA to about 100 μA, or about 100 μA to about 1 mA.

[0092] In a particular example, the electrical stimulation comprises electrical pulses having a pulse width between about 40 μs and about 2 ms, for example, between 40 μs and 2 ms, between 100 μs and 2 ms, between 200 μs and 2 ms, between 300 μs and 2 ms, between 400 μs and 2 ms, between 500 μs and 2 ms, between 600 μs and 2 ms, between 700 μs and 2 ms, between 800 μs and 2 ms, between 800 μs and 2 ms, between 900 μs and 2 ms, between 1 ms and 2 ms, between 1.5 ms and 2 ms, between 80 μs and 1.5 ms, between 100 μs and 1.5 ms, between 200 μs and 1.5 ms, between 300 μs and 1.5 ms, between 400 μs and 2 ms, between 500 μs and 2 ms, between 600 μs and 2 ms, between 700 μs and 2 ms, between 800 μs and 2 ms, between 800 μs and 2 ms, between 900 μs and 2 ms, between 1 ms and 2 ms, between 1.5 ms and 2 ms, between 80 μs and 1.5 ms, between 1 1ms, between 100μs and 1ms, between 200μs and 1ms, between 300μs and 1ms, between 400μs and 1ms, between 500μs and 1ms, between 600μs and 1ms, between 700μs and 1ms, between 800μs and 1ms, between 800μs and 1ms, between 800μs and 1ms, between 900μs and 1.5ms, between 1ms and 1.5ms, between 1.5ms and 2ms, between 80μs and 1ms, between 100μs and 1ms, between 200μs and 1ms, between 300μs and 1ms, between 400μs and 1ms, between 500μs and 1ms, between 600μs and 1ms, between 700μs and 1ms, between 800μs and 1ms, between 800μs and 1ms, between 800μs and 1ms, and between 900μs and 1ms.

[0093] In particular instances, the electrical stimulation includes a pulse frequency between about 10 Hz and about 2000 Hz, for example, between 20 Hz and 100 Hz, between 20 Hz and 90 Hz, between 20 Hz and 80 Hz, between 20 Hz and 70 Hz, between 20 Hz and 60 Hz, between 20 Hz and 50 Hz, between 20 Hz and 40 Hz, and between 20 Hz and 30 Hz.

[0094] In some embodiments, the electrical stimulation comprises electrical pulses having an amplitude of 10 μA to about 50 mA, a pulse width between about 40 μs and about 2 ms, and a pulse frequency between about 10 Hz and about 2000 Hz. In some embodiments, the electrical stimulation comprises electrical pulses having an amplitude of 10 μA to about 10 mA, a pulse width between about 40 μs and about 2 ms, and a pulse frequency between about 10 Hz and about 1000 Hz. In some embodiments, the electrical stimulation comprises electrical pulses having an amplitude of 100 μA to about 10 mA, a pulse width between about 40 μs and about 500 microseconds, and a pulse frequency between about 10 Hz and about 1000 Hz.

[0095] In some embodiments, bipolar and / or tripolar stimulation may be used. In some embodiments, for example, to target the right leg muscles, the spinal cord is stimulated using bipolar stimulation of the two most cephalad contacts of the right lead. In some instances, the electrical stimulation comprises electrical pulses having an amplitude of about 2 mA, a pulse width of about 400 μs, and a pulse frequency of about 40 Hz.

[0096] In some embodiments, for example, to target the left leg muscles, tripolar stimulation is used. In some examples, the electrical stimulation includes electrical pulses having an amplitude of about 3.7 mA, a pulse width of about 400 μs, and a pulse frequency of about 40 Hz.

[0097] In some embodiments, the electrical stimulation comprises electrical pulses having an amplitude of less than about 10 mA, a pulse width between about 80 μs and about 2 ms, and a pulse frequency between about 20 Hz and about 100 Hz. In some instances, the electrical stimulation comprises electrical pulses having an amplitude between 0.5 mA and 5 mA, a pulse width between 80 μs and 200 μs, and a pulse frequency between 20 Hz and 80 Hz. For example, the electrical stimulation may comprise electrical pulses having an amplitude between about 1.5 and about 3.5 mA, a pulse width between about 100 μs and about 200 μs, and a pulse frequency between about 40 Hz and about 80 Hz.

[0098] Electrical stimulation can be applied to the subject for any suitable amount of time required to achieve a positive functional benefit to the patient. In some embodiments, the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz. In some embodiments, the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month. In some embodiments, the electrical stimulation is applied for at least 2 hours / day for a period of at least 6 months.

[0099] In certain embodiments, stimulation is applied at or below the subject's motor threshold and / or at or below the subject's perception threshold. For example, stimulation may be applied below the motor threshold and below the perception threshold, below the motor threshold but at or above the perception threshold, or below the perception threshold but at or above the motor threshold.

[0100] The SCS system can be configured within a few days to provide an electrical spinal cord stimulation regimen that allows control of the extension and flexion degree of muscles during movement of a limb (e.g., each leg during movement and real-time processing of gait kinematics and motor performance). In some embodiments, the subject can be monitored and tested to establish parameters for electrical stimulation based on the subject's motor disorders and motor impairments, for example, by monitoring one or more motor outputs that provide measurements of the degree of motor impairment and the subject's response to stimulation. In some embodiments, electrical stimulation via electrodes is delivered to sensory neurons in the subject while the subject performs an autonomous activity or task affected by the subject's motor impairment; the autonomous activity or task, for example, a forelimb task (e.g., reaching, grasping, picking up with opposite thumbs, clenching, and fine motor tasks involving precise finger movements) or a lower limb task (e.g., walking, jumping, leg extension).

[0101] Once configured, the stimulation burst is delivered to a specific spinal cord position with the precise timing of the natural spatiotemporal activation of the MN during the reproduction movement. These schemes can also be easily adapted to the safe implantation of the system near the spinal cord, and provide SCS involving real-time mobile feedback and closed-loop controllers, as discussed below. In some embodiments, the parameters of the electrical stimulation controlled by the neurostimulator are adjusted according to the changes in one or more motor outputs monitored when the subject performs a specific task, for example, in order to improve the motor output, thereby treating the subject's motor impairment. In a specific embodiment, the regulated neurostimulator is part of a daily auxiliary device to treat the subject over an extended period of time. In a specific embodiment, once the subject is released from the clinical environment, the operation of the device and / or the neurostimulator can be at least partially under the control of the subject. In these and further embodiments, the subject is taught how to use the device and / or the neurostimulator. In some non-limiting embodiments, this treatment can increase the input on the membrane of the spinal cord MN by directly recruiting sensory inputs from electrical pulses, and or can cause ion channel remodeling on the MN membrane to increase the probability of the excitation rate of the spinal cord MN and / or improve the motor impairment caused by SMA, including when the electrical stimulation is no longer applied to the patient. Thus, the present disclosure includes methods of increasing the firing rate of motor neurons damaged by SMA.

[0102] Stimulation of sensory afferents using implanted electrodes is an advanced neurosurgical procedure that involves the implantation of one or more electrodes that deliver electrical stimulation under the control of an external or implanted neurostimulator unit. In instances where the neurostimulator is not external, the implantation of electrodes and / or neurostimulators is typically performed by a clinical team that includes neurologists, neurosurgeons, neurophysiologists, and other experts trained in the assessment, treatment, and care of neurological disorders. Typically, after the selection of a suitable subject and determination of the target area of ​​the subject to be stimulated, precise placement of at least one electrode in the area of ​​the patient's sensory afferents (such as the dorsolateral aspect of the spinal cord) is performed in an operating room environment, typically using spinal cord imaging techniques. Following the administration of local anesthesia, the subject receiving the electrode implant will experience little discomfort and may remain awake during the implantation surgery to enable communication with the surgical team.

[0103] Some embodiments herein employ an implant comprising one or more electrodes and / or a neural stimulator implanted (e.g., fully or partially) in a subject. Further embodiments herein employ an implant comprising one or more magnets or optical fibers and / or a neural stimulator implanted in a subject.

[0104] Many types and styles of implants (e.g., implants comprising one or more electrodes for providing electrical stimulation) are available and known to those skilled in the art. Any implant for specific stimulation of sensory neurons in a subject may be used in a particular embodiment. In some embodiments, more than one electrode is implanted, such as an electrode array. In other embodiments, a device that may include one or more electrodes is provided. Non-limiting examples include electrode arrays, penetrating microarrays (e.g., Utah and Michigan microarrays), microwire electrodes and arrays, neural cuffs, and paddle arrays.

[0105] In some embodiments, one or more electrodes are implanted at a dorsal root of one or more sensory neurons that innervate a body area of ​​a subject having motor impairment. In some embodiments, one or more electrodes are implanted at a dorsolateral aspect of the spinal cord adjacent to a dorsal root of one or more sensory neurons that innervate a body area of ​​a subject having motor impairment. In some embodiments, one or more electrodes are implanted at a dorsal root ganglion of one or more sensory neurons that innervate a body area of ​​a subject having motor impairment. In some embodiments, one or more electrodes are contained in a cuff that surrounds or at least partially surrounds a peripheral nerve that innervates sensory neurons in a body area of ​​a subject having motor impairment due to SMA. In further embodiments, one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons that innervate a body area of ​​a subject having motor impairment due to SMA.

[0106] In some embodiments, epidural electrical stimulation (EES) targeting dorsal rootlets using a paddle electrode array is utilized in the disclosed methods, for example, as described in Rowald et al., 2022, Nat. Medicine, 28: 260-271 and Wagner et al., 2018, Nature, 563: 65-71, each of which is incorporated herein by reference. Other non-limiting examples of paddle arrays and their uses are provided in, for example, US2009 / 0351221, US2019 / 0366077, each of which is incorporated herein by reference.

[0107] In some embodiments, an implanted circuit connects the neurostimulator to one or more electrodes. In certain embodiments, the circuit is fully implanted (typically in a subcutaneous pocket within the subject's body), or partially implanted in the subject. The operable connection of the neurostimulator to the electrodes may be made via one or more leads, but any operable connection capable of transmitting stimulation signals from the circuit to the electrodes may be used in certain embodiments.

[0108] Any suitable control system can be used with the electrodes to apply electrical stimulation to the subject. Non-limiting examples of controllable neural stimulation systems are provided in US2020 / 0254260, US2020 / 0360693, US2020 / 0360697, US2020 / 0152078, US10,252,065, US10,799,702, US2021 / 0016093, and US2020 / 0391030, each of which is incorporated herein by reference. In addition, non-limiting examples of closed-loop neural stimulation systems are provided in US10,265,525, US10,279,167, US10,279,177, US10,391,309, US10,751,539, US10,981,004, and US2020 / 0147382, each of which is incorporated herein by reference.

[0109] Postoperative control of selective electrical stimulation by implanted electrodes is provided in some embodiments by a neurostimulator that can be external or implanted, for example, subcutaneously (e.g., in the chest or abdomen of the subject). In some embodiments, the disclosed methods are affected by the use of an implanted neurostimulator that controls stimulation (e.g., electrical stimulation via one or more implanted electrodes) in accordance with predetermined parameters or parameters determined by feedback in a closed-loop system. In specific embodiments, one or more electrodes and the neurostimulator comprise a daily assistive device that improves muscle weakness in the affected limb of the subject.

[0110] After recovery from implantation, surgery, and connection of electrode leads to a neurostimulator, the subject can be monitored and tested to establish parameters for electrical stimulation based on the subject's motor disorders and motor impairments, for example, by monitoring one or more motor outputs that provide a measure of the degree of motor impairment and the subject's response to stimulation. In some embodiments, electrical stimulation via implanted electrodes is delivered to sensory neurons in the subject while the subject performs an autonomous activity or task affected by the subject's motor impairment; for example, forelimb tasks (e.g., reaching, grasping, picking up with opposite thumbs, clenching, and fine motor tasks involving precise finger movements) or lower limb tasks (e.g., walking, jumping, leg extension).

[0111] In some embodiments, a transcutaneous electrical stimulation system is used to apply electrical stimulation to sensory neurons in a subject. Non-limiting examples of transcutaneous stimulation systems are provided in US 10,806,927, which is incorporated herein by reference. In one such transcutaneous embodiment, the electrical stimulation may include electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 10000 Hz.

[0112] In certain embodiments, the methods disclosed herein can be used in conjunction with regimented physical rehabilitation exercises to improve long-term outcomes.

[0113] Examples

[0114] The following examples are provided to illustrate specific features of certain embodiments, but the scope of the claims should not be limited to those features exemplified.

[0115] Example 1

[0116] Biophysical Model of Spinal Cord Stimulation for SMA

[0117] This example provides a biophysical model that illustrates the effectiveness of sensory neuron stimulation therapy for SMA patients, as well as a stimulation protocol for treating SMA patients (such as Type 3 and Type 4 SMA patients) with stimulation of the dorsolateral aspect of the spinal cord.

[0118] In view of the unique pathophysiology of SMA, the application of SCS to SMA patients has produced results that are unexpected results. Although the corticospinal tracts of SMA patients are usually intact, unlike patients with spinal cord injury or stroke, in SMA patients, many, if not all, MNs are non-functional or dead, especially in the case of SMA patients in the late stage of the disease, which makes them functionally inert. Therefore, it is expected that SCS aimed at increasing the excitatory input to the spinal MNs will not have any effect on SMA patients because the MNs in SMA patients are already non-functional or dead. Of course, it is not expected that the application of SCS to treat SMA will produce the effects observed in other conditions treated with SCS (such as spinal cord injury, stroke, and pain) when the MNs are still functioning.

[0119] Surprisingly, however, as discussed below, significant immediate and long-term effects of SCS were unexpectedly observed in SMA patients treated according to the present disclosure. Although experiments with SMA mouse models have shown a reduction in presynaptic activity from sensory afferent fibers, the present disclosure demonstrates that by artificially increasing activity at sensory afferent fibers through SCS, such as a therapeutically effective amount of SCS appropriately applied at the dorsolateral aspect of the spinal cord can increase the excitability of MNs through the remaining excitatory connections, and can produce a long-term potentiation of the affected synapses that can help reverse the electrical changes of MNs affected by SMA. In addition, a therapeutically effective amount of SCS can also enhance the firing rate of MNs not affected by SMA, resulting in a more powerful effect.

[0120] Network models of spinal cord circuits

[0121] Healthy neuron model

[0122] Figure 1A A network model diagram is shown in which MNs receive excitatory input from the corticospinal tract and spinal cord stimulation (SCS) (such as dorsolateral SCS) through the recruitment of sensory afferent fibers. Figure 1A As shown, the biophysical model was established with a healthy MN population (N = 169 modified Hodgkin-Huxley neurons, McIntyre et al., 2002. J Neurophysiology 88 (4): 1592-1604). Each MN receives excitatory input from the corticospinal tract (CST, N = 110) and SCS through the recruitment of sensory afferent fibers (N = 60) (see Capogrosso et al., 2013. J Neuroscience. 33 (49): 19326-40; Gerasimenko et al., 2006. J Neuroscience Methods 157 (2): 253-63; Hofstoetter et al., 2015. J Neurophysiology 114 (1): 400-410; Rattay et al., 2000. Spinal Cord 38 (8): 473-89). The difference between the two sources of excitability is that the CST is modeled as a Poisson neuron population, while the SCS has its own frequency and amplitude. In order to study the recovery of movement during SCS, the force generated by the MN pool is quantified in arbitrary units (Fuglevand et al., 1993. J Neurophysiology, 70 (6): 2470-2488). In contrast to the CST, which represents the autonomous input from the brain to the MN, the SCS is controlled by the experimenter. Therefore, in order to improve autonomous movement, SCS should only enhance the MN excitation rate when the CST is active.

[0123] SMA neuron model

[0124] Figure 3A A neuron model affected by SMA with various ion channels is shown, in which the delayed rectifier potassium channel (K-dr) is blocked. For a healthy neuron model, the established method for describing the membrane potential dynamics as a function of different ion channels is the Hodgkin-Huxley model. In this model, the membrane potential (V) is described as:

[0125]

[0126] Where C is the membrane capacity, I is the current artificially injected into the neuron, and g is the conductivity x of the ion channel x, which generally depends on the membrane potential and the ion concentration. According to previous literature (Booth et al., 1997, J Neurophysiology 78(6):3371–85; McIntyre et al., 2002. J Neurophysiology 88(4):1592–1604; Moraud et al., 2016. Neuron 89(4):814-28), the following ion channels are included: delayed rectifier sodium (Na) and potassium (K-dr), N-like calcium (Ca-N), L-like calcium (Ca-L), and calcium-dependent potassium (K(Ca)), such as Figure 3A The model was implemented in a neuronal stimulation environment designed for modeling individual neurons and neural networks referred to herein as NEURON (Hines and Carnevale. 1997. Neural Computation 9(6): 1179–1209).

[0127] Figure 3B A MN model with various ion channels including a specific delayed rectifier potassium channel (Kv2.1) is shown. Without being bound by any particular theory, the loss of SMA-induced sensory afferent input (e.g., Ia) can change the Kv2.1 channel of the MN to a dysfunctional state with an increased refractory period (e.g., a slower firing rate) and / or an increased input resistance. Additionally, defects in MN function can be restored by increasing (e.g., via SCS) the sensory afferent input into the MN affected by SMA, which reduces the input resistance of the MN. In addition, SCS can instantly increase sensory afferent input, thereby increasing the firing rate of the MN affected by SMA. Over time, SCS can rescue MN function by changing the Kv2.1 channel of the MN to its healthy functional state.

[0128] Spinal cord stimulation increases MN excitability without producing involuntary movements

[0129] Figures 1B to 1G Various models of SCS enhancement of MN output are shown. Figure 1D to Figure 1G In all figures, the unit of “amplitude” is the percentage of sensory afferent fibers recruited by SCS. Figure 1B The membrane potential (mV) of a MN stimulated with a frequency of 69 Hz and an amplitude that recruited 30% of the sensory afferent fibers is plotted. Figure 1B The parameters shown in correspond to Figure 1DThe black dashed line shows the resting potential of the MN membrane potential, while the gray dashed line shows the MN spike threshold. For appropriate parameters, SCS can increase the excitability of MNs without generating action potentials. Figure 1C The membrane potential (mV) of a MN stimulated with a frequency of 69 Hz and an amplitude that recruited 80% of the sensory afferent fibers is plotted. Figure 1C The parameters shown in correspond to Figure 1D The point marked as "2" in the figure shows the gradient map. Figure 1D MN firing rate is plotted as a function of SCS parameters in the absence of input from the corticospinal tract (CST), indicating that SCS itself produces involuntary movements (MN firing rate > 8 Hz). In the range of 0 to 30 spikes / second, Figures 1D to 1F The darker shades in each of the 2D and 2D graphs show larger spikes per second. Figure 1E MN firing rate is plotted as a function of SCS parameters with input from the CST. Figure 1F MN firing rates are plotted for SCS parameter combinations that generate only voluntary movements normalized by MN firing rates in the absence of SCS. Figure 1G Depicted is how SCS enhances the force generated by a population of MNs. Figure 1F and Figure 1G The "arbitrary units" scale indicates how many times the firing rate in the presence of SCS is greater than the firing rate in the absence of SCS. The upper limit of the "arbitrary units" scale is 2.2 times. Therefore, these numbers indicate that the firing rate in the presence of SCS is at most 2.2 times greater than the firing rate in the absence of SCS.

[0130] To investigate the effect of continuous SCS on MN firing rate, a range of stimulation parameters were explored. In general, MN firing rate increased with changes in both SCS frequency and amplitude, e.g. Figure 1D However, a local maximum at 25 Hz was determined, which is consistent with the modified Hodgkin-Huxley neuron model (McIntyre et al., 2002. J Neurophysiology 88(4):1592–1604). SCS can increase the firing rate of MNs above the minimum firing rate (>8 Hz) required to produce movement (Monster and Chan. 1977. J Neurophysiology 40(6):1432–43), as shown in Figure 2. Figure 1C and Figure 1DAny combination of SCS parameters that generated movement without CST engagement (i.e., involuntary movement) was discarded to restore voluntary movement. However, SCS was also able to increase MN excitability (i.e., depolarize membrane potential) without generating involuntary movement (i.e., MN firing rate <8 Hz), as shown in Figure 1B and Figure 1D This increase in MN excitability suggests a mechanism that enhances CST input. SCSs enhance supraspinal inputs, thereby increasing MN firing rate.

[0131] Healthy neuron model

[0132] Given that SCS has been shown to increase MN excitability in a healthy model, it was assessed whether SCS could also enhance CST input to activate MNs and generate force. To perform this assessment, input from the CST was fixed to generate a relatively low firing rate (9.3 Hz) in the MN. MN firing rates were calculated while systematically varying SCS parameters (frequency and amplitude). For a range of these parameters, SCS enhanced input from the CST to increase the firing rate of the MN without generating involuntary movements, such as Figure 1E and 1F The enhanced firing rate of MNs in the presence of SCS produces forces that are up to 2.2 times greater than the firing rate generated by the same CST input in the absence of SCS, as shown in Figure 1G .

[0133] FIG. 2A to FIG. 2C Shown are graphs depicting force enhancement during simulated autonomous brain input. Figure 2A The following network activity parameters are plotted: SCS amplitude, corticospinal tract (CST) firing rate in Hz, MN firing rate in Hz, and force normalized by the mean force applied. Figure 2A Network activity without SCS stimulation and with 22 Hz CST input. Figure 2B Plotted are network activity in the presence of SCS applied in the voluntary motor area. Figure 2B The parameters shown in correspond to Figure 1E The point marked "3" in Figure 3. Closure relative to SCS enhances MN firing rate, and therefore force. Figure 2C Plotted are network activity in the presence of SCS applied in the involuntary motor region. Figure 2C The parameters shown in correspond to Figure 1E The point marked as “4” in the graph. MN firing rate is high in both phases: with and without input from the CST.

[0134] To further understand the enhancement of CST input driven by SCS, a vibration-force task was modeled in which CST input reaches the MN in a periodic manner, as FIG. 2A to FIG. 2CDifferences between voluntary and involuntary motor areas were assessed. In voluntary motor areas, SCS increased MN excitability, resulting in firing rates higher than those observed in the absence of SCS. However, SCS did not increase MN firing rates during periods without CST input, as Figure 2A and Figure 2B In involuntary motor areas, SCS increases firing rate throughout the trial and during periods without input from CST, as shown in Figure 2C Together, these results suggest that, in a biophysical model of the healthy spinal cord, input from the CST can be enhanced to generate enhanced MN firing rates, and therefore greater force.

[0135] SMA neuron model

[0136] A series of experiments using SMA mouse models have shown that MNs affected by SMA have dysfunctional electrical properties (Mentis et al., 2011. Neuron 69(3):453–67; Fletcher et al., 2017. Nat Neuroscience 20(7):905-16), which is due to the reduction of synaptic activity from sensory afferent fibers and the blockade of delayed rectifier potassium channels (Fletcher et al., 2017. Nat Neuroscience 20(7):905–16; Simon et al., J Neuroscience. 41(2):376-389, 2021). Downregulation of K-dr channels, such as Figure 3A Thus, to model MNs affected by SMA, the synaptic weights (i.e., the strength of the synapses) are reduced in the sensory afferent fibers and the conductance of the delayed rectifier potassium channels, as shown in Figure 3A This neuronal model can be validated by reproducing the following three dysfunctional electrical properties of SMA-affected MNs:

[0137] (1) High input resistance: Within the NEURON simulation environment designed to model individual neurons and neural networks, it is easy to inject current directly into the MN and calculate the input resistance as the slope of the voltage-current function. Blockade of potassium channels reduces the outflow of potassium ions, thereby increasing the input resistance.

[0138] (2) Reduced base strength: As in (1), current is injected into the MN from which the minimum input current can be calculated to generate an action potential. Similarly, reducing the outflow of potassium ions depolarizes the membrane potential more quickly, thereby reducing the injected current required to trigger an action potential.

[0139] (3) Low firing rate induced by currents above the current required to induce repetitive firing: Injecting an artificial current above the threshold for the repetitive firing rate of SMA-affected MNs was used to test whether blockade of potassium channels is sufficient to reduce the firing rate. After the action potential, potassium channels open, allowing the membrane potential to repolarize. In the case of their blockade, the repolarization phase will be slower than in healthy MNs, thereby reducing the output firing rate (Fletcher et al., 2017. Nat Neuroscience 20(7):905–16).

[0140] Example 2

[0141] Spinal cord stimulation for the treatment of SMA

[0142] This example describes a specific method that can treat SMA in a subject by applying a therapeutically effective amount of electrical stimulation to the dorsolateral aspect of the spinal cord, which contains sensory neurons that innervate a body region of the subject having motor impairment due to SMA. Although specific methods and protocols are provided, those skilled in the art will appreciate that variations can be made without significantly affecting the treatment.

[0143] A 22-year-old human patient with SMA type 3 or 4 who exhibited quantifiable motor deficits in the legs but was able to stand independently was selected for treatment. Percutaneous bilateral linear spinal leads were implanted near the patient's mid-lumbar spinal cord for a period of up to 29 days.

[0144] To quantify the immediate movement improvements driven by SCS, the maximum moments generated at different joints (such as the hip, knee, and ankle) during isometric exercises were measured. The Norm system is used to perform these measurements. With this system, the patient can be placed in different positions to assess the maximum moments of such joints ( FIG. 4A to FIG. 4C ). Figure 4A Shows hip stretch, Figure 4B The knee is shown extended, and Figure 4C Ankle extension is shown.

[0145] During the assessment, the patient performs progressive contractions from rest to maximum intensity, during which the patient receives real-time torque visual feedback. The same determination is repeated to systematically explore different SCS parameters, including in the absence of SCS, to determine the most effective parameters for reducing motor impairment in patients. For example, electrical stimulation of electrical pulses can be applied, the electrical pulses having an amplitude of about 10 μA to about 50 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz. Additionally, surface electromyography (EMG) activity recordings can be used to record the electrical activity generated by the agonist and antagonist muscles of each joint. Applying appropriate SCS parameters to provide a therapeutically effective amount of electrical stimulation is expected to increase maximum torque and EMG activity.

[0146] This example aims to measure the short-term and long-term effects of SCS on SMA. First, this example measures the immediate effects of SCS on SMA by turning stimulation on and off in the same session and measuring the effects of SCS that are only present during stimulation and disappear when stimulation is turned off. Second, this example measures the long-term effects of SCS on SMA by comparing how patients perform without stimulation over different sessions. In addition, various clinical outcome tests are also performed.

[0147] SCS was observed to have both immediate and long-term effects on SMA patients. Contrary to what was expected in patients affected by SMA, the magnitude of the immediate effect was similar to that observed in patients with stroke and spinal cord injury. In addition, the magnitude of the long-term effect observed in only a 4-week trial was unexpected for patients with MN-free function, who experienced improvements in muscle strength that were expected to be achieved by normal patients affected by SMA. These improvements in muscle strength were too high to be attributed solely to exercise. For example, the patient's left hip flexion increased more than double, but the patient did not perform any hip strength training except walking during the study. The patient's motor level did not change relative to his motor level before the study. These changes were reflected in the improvement of clinical outcome tests, such as manual muscle testing, Hammersmith Functional Movement Scale Extension (HFMSE), revised Hammersmith Scale (RHS), and a 6-minute walk test for patients. In addition, the data did not show that a plateau had been reached, indicating that longer use of SCS may produce even greater improvements.

[0148] Over a 4-week course of treatment, SCS therapy increased leg joint torque (up to +180%) and MN firing rates in patients, indicating that SCS was improving MN function, while reporting no side effects. These results suggest that SCS can potentially improve the quality of life of patients with severe and mild SMA by improving muscle strength and gait. It was unexpected to observe such improvements of this magnitude in patients with SMA in such a short time frame. The observation of muscle strength improvements of this magnitude in such a short time may indicate a disease-modifying effect. Without being bound by any particular theory, the magnitude of the improvement may be driven by rescued MN function in response to increased afferent input driven by SCS, which targets hip flexor and knee extensor afferents in patients. Spinal reflexes and single MN firing rates obtained using HD-EMG recordings were analyzed to confirm this conclusion.

[0149] Initial configuration and optimization

[0150] Before the electrodes are implanted, the patient's initial performance can be measured. These measurements are made using the Norm system, which allows the patient to be placed in different positions to assess the maximum moments at different joints. Figure 5A and Figure 5B An isokinetic machine (e.g., Norm isokinetic machine). In particular, the maximum moments generated by the patient during extension and / or flexion at the knee, hip and ankle can be measured.

[0151] Bilateral linear SCS leads were implanted in the epidural space of the T11 to L1 vertebrae. To target the right leg muscles, in one instance, bipolar stimulation of the two most cephalad contacts of the right lead was used to stimulate the spinal cord. The SCS parameters in this instance were 2 mA, 40 Hz, and 400 μs pulse width. In one instance, to target the left leg muscles, tripolar stimulation was used. The SCS parameters in this instance were 3.7 mA, 40 Hz, and 400 μs pulse width.

[0152] SCS can be applied to target muscles affected by SMA. In this example, it was found that the patient affected by SMA had significant deficits in the knee extensors and hip flexors, which is consistent with his type 3 diagnosis. In addition, the patient had slightly more deficits in the left leg. Therefore, the stimulator can be programmed to selectively target these muscles. In this example, all experiments were conducted over a 4-week course and a total of 19 sessions. The experiments were conducted every day, 5 days a week, until the date when the electrodes were removed. Each session lasted 4 hours, with approximately 2 to 3 hours of task time, during which it was estimated that 2 hours of stimulation dose was active per day.

[0153] The location for applying SCS can be optimized and fine-tuned by stimulating various contact points, measuring the electrical activity generated by the muscles (e.g., agonist and antagonist muscles of each joint), and evaluating the measurements. The maximum torque and EMG activity are then measured using appropriate SCS parameters to determine the therapeutically effective amount of electrical stimulation. In this example, during surgery, the location of the electrodes is determined by stimulating each contact and recording the EMG signals of the muscles ranging from the trunk down to the ankle. The stimulation is repeated until the location where the electrodes activate the gluteal muscles with the most cranial contact and the calf muscles with the most caudal contact is identified.

[0154] These implants can be used to configure a spinal cord stimulation procedure that achieves control of the degree of extension and flexion of each leg during movement. The protocol uses real-time processing of gait kinematics and motor performance and can be configured in a few days. Once configured, stimulation bursts are delivered to specific spinal cord locations with precise timing that reproduces the natural spatiotemporal activation of MNs during movement. These protocols can also be easily adapted for safe implantation of systems near the spinal cord and for experiments involving real-time movement feedback and closed-loop controllers, as discussed below.

[0155] In some embodiments, the placement of electrodes during surgery can be adjusted to account for postoperative electrode movement. Such postoperative movement can be variable and difficult to avoid with a non-permanent implant. For example, the electrodes may move caudally and offset medially. Figure 6 A comparison between the position of the electrodes during surgery (in black) and the position of the electrodes after surgery (in white) is shown. In this particular example, the change in position does not prevent stimulation of the correct muscle group. In some embodiments, based on the predicted postoperative movement of the electrodes, the electrodes can be implanted in adjusted positions during surgery so that after surgery, the electrodes will move to a predefined optimal position. More detailed information about the equipment and surgical procedures that can be used to obtain long-term EMG recordings from leg muscles and implant targeted spinal cord stimulation systems can be found in Capogrosso et al., 2018. Nature Protocols 13. 2031-2061, which is incorporated herein by reference.

[0156] Immediate effects observed

[0157] In this example, the immediate effect of SCS is measured in terms of maximum voluntary contraction, hip flexion during exercise, balance, transition from sit to stand, and maximum speed. Each measurement is discussed below. It should be understood that different metrics can be used depending on the patient's targeted muscles and condition.

[0158] Maximum Voluntary Contraction: To assess maximum voluntary contraction, patients were asked to perform their maximum voluntary isometric contraction (MVC) during knee extension for 5 seconds with and without SCS. After multiple repetitions of knee extension, patients showed significant signs of fatigue. At that time, the immediate effect of SCS on the patient's maximum voluntary contraction (MVC) during fatiguing knee extension was tested. 7A to 7C Various torque measurements are shown over time. Fig. 7A A single trace is shown of the torque produced by the patient during a maximum voluntary contraction repetition with stimulation (see element 704) and without stimulation (see element 702). Figure 7B In , each point corresponds to the average torque produced during a single trial with and without stimulation. Figure 7C In , each point corresponds to the maximum torque produced during a single trial with and without stimulation. Figure 7B and Figure 7C In the figure, square marks represent the mean between replicates, and error bars correspond to the standard error of the mean. As shown, MVC during SCS stimulation was significantly higher at days 12 and 27.

[0159] Hip flexion during exercise: Patients are asked to perform maximal hip flexion by raising their knees as high as possible while their body weight is supported by the treadmill. As the patient walks, the stimulation period alternates on and off every 20 seconds. During the task, patients are not given visual feedback of their legs. To measure changes in step height, tracking markers are placed on the ankle, toes, and metatarsals on each foot. A machine learning model (e.g., a deep neural network) can be trained to track the markers. FIG. 8A to FIG. 8B Spinal cord stimulation was shown to increase maximum hip flexion during exercise. Specifically, Fig. 8A Traces of ankle markers during exercise are shown without stimulation (see element 802) and with stimulation (see element 804). Figure 8B The dots represent the calculations Fig. 8A The height of each step is the difference between the higher and lower values ​​of each trace in . The square markers represent the step-by-step average, and the error bars correspond to the standard error of the mean. FIG. 8A to FIG. 8B As shown, SCS provides patients with an immediate increase in maximal hip flexion during exercise, which translates into a higher step height.

[0160] Balance: Patients were asked to perform heel-to-toe walking while looking straight ahead at a beam of light that narrowed with distance, while receiving no visual feedback of their feet. In the first session, patients got worse with the stimulation on and continued to walk shorter distances. Patients reported that the stimulation disturbed their balance because precise control of their legs became more difficult.

[0161] However, when the patient's balance was retested during the second session (one week after the first session) and the third session (one week after the second session), it was found that the patient had learned to control the stimulation and improved his balance so that similar distances were produced with the stimulation turned on and turned off. FIG. 9A to FIG. 9B It was shown that spinal cord stimulation in patients only temporarily disrupted balance. Fig.9A In , each point is the distance a patient walked in the narrowed beam test without stimulation (see element 902) and with stimulation (see element 904). The squares represent the mean, and the error bars represent the standard error of the mean across replicates. Fig. 9B Picture of a patient walking on a narrowed beam.

[0162] Sit-to-Stand Transition: Ask the patient to stand with one knee on the ground and the other foot on the floor. Test different knee heights until the maximum height at which the patient cannot stand is determined. Then apply the stimulus. The patient is always able to reach a standing position with the right knee on the floor.

[0163] The patient was also asked to stand from a sitting position on a box measuring 46 cm from the ground. Without stimulation, the patient was able to compensate for standing with his legs exaggeratedly spread. The patient was then instructed to continue trying to stand, bringing his feet together until the separation distance between his feet reached a distance at which he could no longer stand. Stimulation was then applied to the patient with his feet in the same position (i.e., separated at a distance at which he could not stand), and the patient was able to stand in this position throughout.

[0164] Maximum speed: Patients were asked to run on a treadmill with the speed gradually increasing every 30 seconds until they reported reaching their maximum speed. Fig.10 It is shown that SCS (see element 1004) robustly increases the patient's maximum velocity relative to when SCS is not applied (see element 1002).

[0165] Observed long-term effects

[0166] In this example, the long-term effects of SCS are measured in terms of hip flexion and maximum voluntary contraction during exercise. Each measurement is discussed below. It should be understood that different metrics can be used depending on the targeted muscles and condition of the patient.

[0167] Hip flexion during exercise: At week 4, patients were asked to walk on a treadmill while raising their knees as high as possible. FIG. 11A to FIG. 11B Shown is the long-term effect of SCS on hip flexion over a four-week trial. Fig.11A Traces of ankle markers during exercise are shown, comparing traces from week 1 without stimulation (see element 1102) and traces from week 4 without stimulation (see element 1104). Fig. 11B The point is calculated as Fig.11A The height of each step is the difference between the higher and lower values ​​of each trace. Squares are the step-by-step mean and the standard error of the mean. By comparing Week 1 to Week 4, a significant increase in the patient's maximum hip flexion during exercise was observed even in the absence of stimulation, indicating a long-term effect of the SCS intervention. Without being bound by any particular theory, the application of electrical stimulation to the patient over time may cause ion channel remodeling on the MN membrane and a sustained increase in the firing rate probability of the spinal MNs, which may improve motor function even in the absence of stimulation.

[0168] Maximum Voluntary Contraction: At the beginning of each session using the isokinetic machine, the patient's MVC was measured as the torque in Newton meters (Nm) during knee extension and / or hip flexion without stimulation. The patient's MVC during knee extension was approximately 20 Nm, while the MVC of healthy young adults is above 100 Nm. The patient was asked to produce his maximum torque in these joints, repeated 6 times, 5 seconds each. Knee extension was tested twice a week, and hip flexion was tested before implantation, at week 1, week 3, and after removal. In general, starting from week 2, a significant increase in MVC was observed for all movements.

[0169] In right knee extension, a sustained increase in maximum and mean torque was observed when the SCS was off from the beginning to the end of the experiment on day 18. The final increase from pre-implantation to the end of the study was +43.5%. FIG. 12A to FIG. 12C Long-term improvement in the patient's right knee extension is shown. Fig. 12A The moment traces for the 6 repetitions in each session are shown. FIG. 12B to FIG. 12C In the graph, each point is the average torque for each 5 second repetition. The square is the mean of the average torque between repetitions and the standard error of the mean. As shown, the effect appears to be linear, and there is no evidence of reaching a plateau by week 4. From day 18 until the end of the experiment, when the SCS was turned off, the patient experienced a continuous increase in maximum and average right knee extension torque. For the patient, the final increase from pre-implantation to the end of the study was +43.5%.

[0170] From Day 18 to the end of the four-week experiment, a similar continued increase in the patient's left knee extension was observed, even though this was the patient's more severely impaired leg. The left knee extension results during the four weeks of the SCS experiment were generally consistent with the right knee extension results, as no increase was observed before Day 18, and continued increases were observed thereafter. The final increase from Day 5 to the end of the study was +65.1%. FIG. 13A to FIG. 13C Long-term improvement in left knee extension is shown. Fig.13A The moment traces for the 6 repetitions in each session are shown. FIG. 13B to FIG. 13CIn the graph, each dot is the average torque for each 5-second repetition. The square is the mean of the average torque between repetitions and the standard error of the mean.

[0171] The timing of improvement in the patient's left and right hip flexion was consistent with the results for knee extension, with increases in both observed from day 18 to the end of the four-week trial for hip flexion. For the patient, the final increase from pre-implantation to post-explantation was +65.1% on the right side and +179.7% on the left side. FIG. 14A to FIG. 14C Long-term improvement in right hip flexion is shown. Fig.14A The moment traces for the 6 repetitions in each session are shown. FIG. 14B to FIG. 14C In the graph, each dot is the average torque for each 5-second repetition. The square is the mean of the average torque between repetitions and the standard error of the mean. FIG. 15A to FIG. 15C Long-term improvement in left hip flexion is shown for the patient. Fig.15A The moment traces for the 6 repetitions in each session are shown. FIG. 15B to FIG. 15C In the graph, each dot is the average torque for each 5-second repetition. The square is the mean of the average torque between repetitions and the standard error of the mean.

[0172] Due to these improvements in hip flexion and knee extension, the patient's overall range of motion after the end of the experiment was much higher than before. The patient's improvement in range of motion was most pronounced in hip flexion and whole body movement. Without being bound by any particular theory, the application of electrical stimulation to sensory neurons can directly recruit monosynaptic and polysynaptic excitatory pathways in the spinal cord, which in turn increases the membrane potential and firing rate probability of spinal MNs innervating the body area of ​​the patient with motor impairment caused by SMA. This pathway recruitment can increase neural plasticity, thereby enabling patients to improve motor function.

[0173] Clinical Outcome Tests

[0174] Clinical outcome tests, including manual muscle testing, 6-minute walk test, and leg circumference measurement, were performed and observed for immediate and long-term effects as discussed below.

[0175] Manual muscle testing: Manual muscle testing (MMT) is a commonly accepted method for assessing muscle strength. It measures the strength of each muscle individually, and then adds the strengths together to report a total score. Patients were given the MMT prior to implantation and at days 14 and 28 after implantation. The MMT showed consistent immediate effects from stimulation. Specifically, the knee extensors / flexors and hip extensors / flexors both showed improved scores with stimulation, such as Fig.16 Shown is a spreadsheet containing manual muscle testing scores by muscle and session for SMA patients with and without stimulation.

[0176] 6-Minute Walk Test: The 6-minute walk test was performed on patients before implantation, with and without stimulation, and on day 14 after electrode removal. No significant immediate effects from stimulation were observed, but for patients, a substantial improvement in the long-term effects of stimulation was observed in total distance traveled, as shown in Table 1. Fig.17 . Fig.17 Shown are the distances traveled by patients during a six minute walk test across different sessions, comparing stimulation off versus stimulation on.

[0177] Clinical scales, the Hammersmith Functional Motor Scale-Extended (HFMSE) and the Revised Hammersmith Scale (RHS): The HFMSE and RHS tests are validated tools to assess motor ability in children and adults with Type 2 and Type 3 SMA. Results of the HFMSE and RHS tests were measured prior to implantation, during the explantation period, and at post-explantation follow-up. The HFMSE test on the patients showed a small but relevant long-term effect, with an increase in the total score, achieving a final HFMSE score of 61. Improvements in the HFMSE are often difficult to achieve for patients. Therefore, even small changes (in this case 1 to 2 points) indicate that there is improvement, such as Fig.18A and Fig.18B As shown in the table shown in , it contains the HFMSE scores of the patients. Fig.18B As shown in the table shown, RHS testing for the patient showed a pre-implantation RHS score of 64 and an explantation RHS score of 65 (an increase of 1 point). The increase in RHS score remained consistent for 52 days after explantation, indicating a small but relevant long-term effect associated with the four-week experiment.

[0178] Leg circumference: On the 18th day after implantation, the patient's left and right leg circumferences were measured 15.24 cm above the left and right kneecaps, respectively. The patient's left and right leg circumferences were measured to be 43.5 and 46 cm, respectively. On the 5th day after the end of the four-week experiment and removal, the patient's left and right leg circumferences were measured to be 44 and 45 cm, respectively. These small differences may be considered insignificant.

[0179] More details of the clinical trial can be found under the Clinicaltrials.gov identifier NCT05430113, “Spinal Cord Stimulation in Spinal Muscular Atrophy (SCSinSMA)”, available at: https: / / clinicaltrials.gov / ct2 / show / NCT05430113.

[0180] The present disclosure will now be further described by the following numbered examples, which are to be read in conjunction with the previous paragraphs and do not limit the present disclosure.The features, options and preferences described above also apply to the following examples.

[0181] Example 1. A method for treating spinal muscular atrophy (SMA) in a subject, the method comprising: applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment caused by SMA, wherein the electrical stimulation is applied using one or more electrodes controlled by a neurostimulator, and wherein the application of the electrical stimulation treats the subject's motor impairment caused by SMA.

[0182] Embodiment 2. The method of embodiment 1, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment caused by SMA.

[0183] Embodiment 3. A method according to Embodiment 1 or Embodiment 2, wherein the stimulation is applied at or below the motor threshold so that the stimulation does not directly cause movement and / or muscle activity of the body area of ​​the subject having the motor impairment caused by SMA.

[0184] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0185] Embodiment 5. The method of any one of embodiments 1 to 4, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0186] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0187] Embodiment 7. A method according to any of the preceding embodiments, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

[0188] Embodiment 8. The method of embodiment 7, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

[0189] Embodiment 9. The method of any one of embodiments 4 to 8, wherein the pulse is a cathode-preferential biphasic or monophasic charge-balanced pulse.

[0190] Embodiment 10. The method according to any one of the preceding embodiments, wherein the electrical stimulation is applied for at least 2 hours / day for a period of at least 6 months.

[0191] Embodiment 11. The method of any one of embodiments 1 to 9, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

[0192] Embodiment 12. A method according to any of the preceding embodiments, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

[0193] Embodiment 13. The method of embodiment 12, wherein the electrode array is a multi-electrode paddle array.

[0194] Embodiment 14. A method according to any of the preceding embodiments, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

[0195] Embodiment 15. The method of any one of Embodiments 1 to 14, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body region of the subject having the motor injury.

[0196] Embodiment 16. A method according to any one of embodiments 1 to 14, wherein the one or more electrodes are implanted in a dorsolateral location of the spinal cord adjacent to the dorsal roots of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

[0197] Embodiment 17. The method of any one of Embodiments 1 to 13, wherein the one or more electrodes are implanted at the dorsal root ganglion of the one or more sensory neurons innervating the body region of the subject having the motor injury.

[0198] Embodiment 18. A method according to any one of Embodiments 1 to 12, wherein the one or more electrodes are contained in a cuff surrounding a peripheral nerve containing the sensory neurons that innervate the body area of ​​the subject having the motor impairment caused by SMA.

[0199] Embodiment 19. The method of any one of Embodiments 1 to 12, wherein the one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing the sensory neurons innervating the body area of ​​the subject having the motor impairment caused by SMA.

[0200] Embodiment 20. A method according to any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

[0201] Embodiment 21. A method according to any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the C3-T2 nerve roots.

[0202] Embodiment 22. A method according to any of the preceding embodiments, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T3-T10 nerve roots.

[0203] Embodiment 23. A method according to any of the preceding embodiments, wherein the neurostimulator is an external or implanted pulse generator.

[0204] Embodiment 24. The method according to any of the preceding embodiments, further comprising implanting the neurostimulator in the subject.

[0205] Embodiment 25. The method according to any one of the preceding embodiments, further comprising selecting the subject suffering from SMA for treatment.

[0206] Embodiment 26. The method of any preceding embodiment, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrollable muscle tone.

[0207] Embodiment 27. The method of any preceding embodiment, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

[0208] Example 28. A method according to Example 27, wherein the position of the one or more electrodes is determined by: stimulating multiple contact points in the subject to target at least one muscle in the body area of ​​the subject having the motor injury caused by SMA; measuring electrical activity associated with the muscle in response to the stimulation; and identifying one or more of the multiple contact points as the position of the electrode based on the electrical activity.

[0209] Embodiment 29. The method of any preceding embodiment, wherein at least one of the one or more electrodes is placed percutaneously.

[0210] Embodiment 30. A method according to any of the preceding embodiments, wherein at least one of the one or more electrodes is implanted.

[0211] Embodiment 31. A method of stimulating one or more motor neurons damaged by SMA, the method comprising applying electrical stimulation to at least one of the motor neurons, wherein the motor neuron innervates a body region of a subject having motor impairment due to SMA.

[0212] Embodiment 32. A method for treating spinal muscular atrophy (SMA) in a subject, the method comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment due to SMA.

[0213] Embodiment 33. A method of increasing the firing rate of motor neurons damaged by SMA in a subject, the method comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject to increase the firing rate of motor neurons in the subject.

[0214] Embodiment 34. The method of Embodiment 33, wherein said subject has a first motor neuron firing rate prior to said application of said therapeutically effective amount of said electrical stimulation and a second motor neuron firing rate after said application.

[0215] Embodiment 35. The method of Embodiment 33 or Embodiment 34, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0216] Embodiment 36. The method of any one of Embodiments 33 to 35, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

[0217] Embodiment 37. A method according to any one of embodiments 33 to 36, wherein the motor neuron firing rate of the subject is calculated based on the electrical signals generated by the motor neurons when the parameters of the electrical stimulation are changed.

[0218] Embodiment 38. The method of any one of embodiments 33 to 37, wherein increasing the firing rate of motor neurons damaged by SMA increases joint torque and muscle strength of the subject.

[0219] Embodiment 39. A method of increasing the excitability of motor neurons damaged by SMA in a subject to sensory afferent input, the method comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject to increase the excitability of the subject's motor neurons.

[0220] Embodiment 40. The method of Embodiment 39, wherein said subject has a first motor neuron excitability prior to said application of said therapeutically effective amount of said electrical stimulation and a second motor neuron excitability after said application.

[0221] Embodiment 41. The method of Embodiment 39 or Embodiment 40, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0222] Embodiment 42. The method of any one of Embodiments 39 to 41, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

[0223] Embodiment 43. A method according to any one of embodiments 39 to 42, wherein the excitability of the motor neurons of the subject is calculated based on electrical signals generated by the motor neurons when parameters of the electrical stimulation are changed.

[0224] Embodiment 44. The method of any one of embodiments 39 to 43, wherein increasing the excitability of motor neurons damaged by SMA increases joint torque and muscle strength of the subject.

[0225] Embodiment 45. A therapeutically effective amount of electrical stimulation of sensory neurons innervating an area of ​​the body of a subject having motor impairment due to SMA, for treating SMA in the subject, wherein the electrical stimulation is applied using one or more electrodes controlled by a neurostimulator, and wherein applying the electrical stimulation treats the motor impairment due to SMA in the subject.

[0226] Embodiment 46. Electrical stimulation for use according to embodiment 45, wherein application of said electrical stimulation increases the firing rate probability of spinal motor neurons innervating said body region of said subject having said motor impairment due to SMA.

[0227] Example 47. Electrical stimulation for use according to Example 45 or Example 46, wherein the stimulation is applied at or below the motor threshold so that the stimulation does not directly cause movement and / or muscle activity in the body area of ​​the subject having the motor impairment caused by SMA.

[0228] Embodiment 48. The electrical stimulation for use according to embodiments 45 to 47, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0229] Embodiment 49. The electrical stimulation for use according to embodiments 45 to 48, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0230] Embodiment 50. The electrical stimulation for use according to embodiments 45 to 49, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0231] Embodiment 51. The electrical stimulation used according to any of the preceding embodiments, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

[0232] Embodiment 52. Electrical stimulation for use according to embodiment 51, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

[0233] Embodiment 53. Electrical stimulation for use according to any one of embodiments 48 to 52, wherein the pulses are cathodically preferentially biphasic or monophasic charge balanced pulses.

[0234] Embodiment 54. Electrical stimulation for use according to any one of the preceding embodiments, wherein said electrical stimulation is applied for at least 2 hours / day for a period of at least 6 months.

[0235] Embodiment 55. Electrical stimulation for use according to any one of embodiments 45 to 53, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

[0236] Embodiment 56. Electrical stimulation for use according to any of the preceding embodiments, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

[0237] Embodiment 57. The electrical stimulation for use according to embodiment 56, wherein the electrode array is a multi-electrode paddle array.

[0238] Embodiment 58. Electrical stimulation for use as in any preceding embodiment, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

[0239] Embodiment 59. Electrical stimulation for use according to any one of Embodiments 45 to 58, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

[0240] Embodiment 60. Electrical stimulation for use as described in any one of Embodiments 45 to 58, wherein the one or more electrodes are implanted in a dorsolateral location of the spinal cord adjacent to the dorsal roots of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

[0241] Embodiment 61. Electrical stimulation for use according to any one of Embodiments 45 to 57, wherein the one or more electrodes are implanted at the dorsal root ganglion of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

[0242] Embodiment 62. Electrical stimulation for use according to any one of Embodiments 45 to 56, wherein the one or more electrodes are contained in a cuff surrounding a peripheral nerve containing the sensory neurons that innervate the body area of ​​the subject having the motor impairment caused by SMA.

[0243] Embodiment 63. Electrical stimulation for use according to any one of Embodiments 45 to 56, wherein the one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing the sensory neurons innervating the body area of ​​the subject having the motor impairment due to SMA.

[0244] Embodiment 64. Electrical stimulation for use as described in any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

[0245] Embodiment 65. Electrical stimulation for use as described in any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the C3-T2 nerve roots.

[0246] Embodiment 66. Electrical stimulation for use as described in any of the preceding embodiments, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T3-T10 nerve roots.

[0247] Embodiment 67. Electrical stimulation for use according to any of the preceding embodiments, wherein the neurostimulator is an external or implanted pulse generator.

[0248] Embodiment 68. Electrical stimulation for use according to any of the preceding embodiments, wherein the neurostimulator is implanted in the subject.

[0249] Embodiment 69. Electrical stimulation for use according to any one of the preceding embodiments, wherein the subject suffering from SMA is selected for treatment.

[0250] Embodiment 70. Electrical stimulation for use according to any one of the preceding embodiments, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

[0251] Embodiment 71. Electrical stimulation for use as in any preceding embodiment, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

[0252] Example 72. Electrical stimulation for use as described in Example 71, wherein the position of the one or more electrodes is determined by: stimulating multiple contact points in the subject to target at least one muscle in the body area of ​​the subject having the motor injury caused by SMA; measuring electrical activity associated with the muscle in response to the stimulation; and identifying one or more of the multiple contact points as the position of the electrode based on the electrical activity.

[0253] Embodiment 73. Electrical stimulation for use as described in any of the preceding embodiments, wherein at least one of the one or more electrodes is placed transcutaneously.

[0254] Embodiment 74. Electrical stimulation for use as described in any of the preceding embodiments, wherein at least one of the one or more electrodes is implanted.

[0255] Example 75. Use of one or more electrodes controlled by a neurostimulator in the manufacture of a medicament for treating SMA in a subject, wherein the one or more electrodes controlled by the neurostimulator are configured to apply a therapeutically effective amount of electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment caused by SMA.

[0256] Embodiment 76. The use according to Embodiment 75, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment caused by SMA.

[0257] Embodiment 77. The use according to Embodiment 75 or Embodiment 76, wherein the stimulation is applied at or below the motor threshold such that the stimulation does not directly cause movement and / or muscle activity of the body area of ​​the subject having the motor impairment caused by SMA.

[0258] Embodiment 78. The use according to embodiments 75 to 77, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0259] Embodiment 79. The use according to embodiments 75 to 78, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0260] Embodiment 80. The use according to embodiments 75 to 79, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0261] Embodiment 81. The use according to any of the preceding embodiments, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

[0262] Embodiment 82. The use according to Embodiment 81, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

[0263] Embodiment 83. The use according to any one of embodiments 78 to 82, wherein the pulse is a cathodically preferential biphasic or monophasic charge balanced pulse.

[0264] Embodiment 84. The use according to any one of the preceding embodiments, wherein the electrical stimulation is applied for at least 2 hours / day for a period of at least 6 months.

[0265] Embodiment 85. The use according to any one of Embodiments 75 to 83, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

[0266] Embodiment 86. The use according to any of the preceding embodiments, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

[0267] Embodiment 87. The use according to Embodiment 86, wherein the electrode array is a multi-electrode paddle array.

[0268] Embodiment 88. The use according to any of the preceding embodiments, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

[0269] Embodiment 89. The use of any one of Embodiments 75 to 88, wherein said one or more electrodes are implanted at the dorsal rootlets of said one or more sensory neurons innervating said body region of said subject having said motor injury.

[0270] Embodiment 90. The use of any one of Embodiments 75 to 88, wherein said one or more electrodes are implanted in a dorsolateral location of said spinal cord adjacent to the dorsal roots of said one or more sensory neurons innervating said body region of said subject having said motor injury.

[0271] Embodiment 91. The use of any one of Embodiments 75 to 87, wherein said one or more electrodes are implanted at the dorsal root ganglion of said one or more sensory neurons innervating said body region of said subject having said motor injury.

[0272] Embodiment 92. The use of any one of Embodiments 75 to 86, wherein said one or more electrodes are contained in a cuff surrounding a peripheral nerve containing said sensory neurons innervating said body area of ​​said subject having said motor impairment due to SMA.

[0273] Embodiment 93. The use of any one of Embodiments 75 to 86, wherein said one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing said sensory neurons innervating said body area of ​​said subject having said motor impairment due to SMA.

[0274] Embodiment 94. The use according to any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

[0275] Embodiment 95. The use according to any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the C3-T2 nerve roots.

[0276] Embodiment 96. The use according to any of the preceding embodiments, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T3-T10 nerve roots.

[0277] Embodiment 97. The use according to any of the preceding embodiments, wherein the neurostimulator is an external or implanted pulse generator.

[0278] Embodiment 98. The use according to any of the preceding embodiments, wherein the neurostimulator is implanted in the subject.

[0279] Embodiment 99. The use according to any one of the preceding embodiments, wherein the subject suffering from SMA is selected for treatment.

[0280] Embodiment 100. The use according to any one of the preceding embodiments, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

[0281] Embodiment 101. The use according to any of the preceding embodiments, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

[0282] Embodiment 102. The use according to Embodiment 101, wherein the position of the one or more electrodes is determined by: stimulating a plurality of contact points in the subject to target at least one muscle in the body region of the subject having the motor injury caused by SMA; measuring electrical activity associated with the muscle in response to the stimulation; and identifying one or more of the plurality of contact points as the position of the electrode based on the electrical activity.

[0283] Embodiment 103 The use according to any one of the preceding embodiments, wherein at least one of the one or more electrodes is placed transcutaneously.

[0284] Embodiment 104. The use according to any of the preceding embodiments, wherein at least one of the one or more electrodes is implanted.

[0285] Embodiment 105. Use of one or more electrodes controlled by a neurostimulator in the manufacture of a medicament for treating SMA in a subject, wherein the one or more electrodes controlled by the neurostimulator are to be used to apply electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment caused by SMA.

[0286] Embodiment 106. The use according to Embodiment 105, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment caused by SMA.

[0287] Embodiment 107. The use according to Embodiment 105 or Embodiment 106, wherein the stimulation is applied at or below the motor threshold such that the stimulation does not directly cause movement and / or muscle activity of the body area of ​​the subject having the motor impairment caused by SMA.

[0288] Embodiment 108. The use according to embodiments 105 to 107, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0289] Embodiment 109. The use according to embodiments 105 to 108, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0290] Embodiment 110. The use according to embodiments 105 to 109, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0291] Embodiment 111. The use according to any of the preceding embodiments, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

[0292] Embodiment 112. The use according to Embodiment 111, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

[0293] Embodiment 113. The use according to any one of embodiments 108 to 112, wherein the pulse is a cathodically preferential biphasic or monophasic charge balanced pulse.

[0294] Embodiment 114. The use according to any one of the preceding embodiments, wherein the electrical stimulation is applied for at least 2 hours / day for a period of at least 6 months.

[0295] Embodiment 115. The use according to any one of Embodiments 105 to 113, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

[0296] Embodiment 116. The use according to any of the preceding embodiments, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

[0297] Embodiment 117. The use according to Embodiment 116, wherein the electrode array is a multi-electrode paddle array.

[0298] Embodiment 118. The use according to any of the preceding embodiments, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

[0299] Embodiment 119. The use according to any one of Embodiments 105 to 118, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

[0300] Embodiment 120. The use according to any one of Embodiments 105 to 118, wherein said one or more electrodes are implanted in a dorsolateral location of said spinal cord adjacent to the dorsal roots of said one or more sensory neurons innervating said body region of said subject having said motor injury.

[0301] Embodiment 121. The use according to any one of Embodiments 105 to 117, wherein said one or more electrodes are implanted at the dorsal root ganglion of said one or more sensory neurons innervating said body area of ​​said subject having said motor injury.

[0302] Embodiment 122. The use of any one of Embodiments 105 to 116, wherein said one or more electrodes are contained in a cuff surrounding a peripheral nerve containing said sensory neurons innervating said body area of ​​said subject having said motor impairment due to SMA.

[0303] Embodiment 123. The use of any one of Embodiments 105 to 116, wherein said one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing said sensory neurons innervating said body area of ​​said subject having said motor impairment due to SMA.

[0304] Embodiment 124. The use according to any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

[0305] Embodiment 125. The use according to any of the preceding embodiments, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the C3-T2 nerve roots.

[0306] Embodiment 126. The use according to any of the preceding embodiments, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T3-T10 nerve roots.

[0307] Embodiment 127. The use according to any of the preceding embodiments, wherein the neurostimulator is an external or implanted pulse generator.

[0308] Embodiment 128. The use according to any of the preceding embodiments, wherein the neurostimulator is implanted in the subject.

[0309] Embodiment 129. The use according to any one of the preceding embodiments, wherein the subject suffering from SMA is selected for treatment.

[0310] Embodiment 130 The use according to any one of the preceding embodiments, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

[0311] Embodiment 131. The use according to any of the preceding embodiments, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

[0312] Embodiment 132. The use according to Embodiment 131, wherein the position of the one or more electrodes is determined by: stimulating a plurality of contact points in the subject to target at least one muscle in the body region of the subject having the motor injury caused by SMA; measuring electrical activity associated with the muscle in response to the stimulation; and identifying one or more of the plurality of contact points as the position of the electrode based on the electrical activity.

[0313] Embodiment 133 The use according to any one of the preceding embodiments, wherein at least one of the one or more electrodes is placed transcutaneously.

[0314] Embodiment 134. The use according to any of the preceding embodiments, wherein at least one of the one or more electrodes is implanted.

[0315] The preceding description for purposes of illustration has been described with reference to specific examples. However, the illustrative discussion above is not intended to be exhaustive or to limit the invention to the precise form disclosed. In view of the above teachings, many modifications and variations are possible. Examples are selected and described in order to best illustrate the principles of these techniques and their practical applications. This enables those skilled in the art to best utilize these techniques and various examples with various modifications suitable for the specific purposes contemplated.

[0316] It will be apparent that the precise details of the methods or compositions described may be changed or modified without departing from the spirit of the described embodiments. Protection is sought for all such modifications and variations that come within the scope and spirit of the following claims.

Claims

1. A method for treating spinal muscular atrophy (SMA) in a subject, the method comprising: A therapeutically effective amount of electrical stimulation is applied to sensory neurons innervating an area of ​​the subject's body having a motor impairment due to SMA, wherein the electrical stimulation is applied using one or more electrodes controlled by a neurostimulator, and wherein application of the electrical stimulation treats the subject's motor impairment due to SMA.

2. The method of claim 1, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment caused by SMA.

3. A method according to claim 1 or claim 2, wherein the stimulation is applied at or below the motor threshold so that the stimulation does not directly induce movement and / or muscle activity of the body area of ​​the subject having the motor impairment caused by SMA.

4. The method of any one of claims 1 to 3, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

5. The method of any one of claims 1 to 4, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

6. The method of any one of claims 1 to 5, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

7. A method according to any of the preceding claims, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

8. The method of claim 7, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

9. The method of any one of claims 4 to 8, wherein the pulse is a cathode-preferential biphasic or monophasic charge-balanced pulse.

10. The method according to any one of the preceding claims, wherein the electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months.

11. The method according to any one of claims 1 to 9, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

12. The method of any of the preceding claims, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

13. The method of claim 12, wherein the electrode array is a multi-electrode paddle array.

14. The method of any of the preceding claims, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

15. The method of any one of claims 1 to 14, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

16. The method of any one of claims 1 to 14, wherein the one or more electrodes are implanted in a dorsolateral location of the spinal cord adjacent to the dorsal roots of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

17. The method of any one of claims 1 to 13, wherein the one or more electrodes are implanted at the dorsal root ganglia of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

18. The method of any one of claims 1 to 12, wherein the one or more electrodes are contained in a cuff surrounding a peripheral nerve containing the sensory neurons that innervate the body area of ​​the subject having the motor impairment due to SMA.

19. The method of any one of claims 1 to 12, wherein the one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing the sensory neurons innervating the body area of ​​the subject having the motor impairment due to SMA.

20. The method of any one of the preceding claims, wherein the body region of the subject is selected from at least one of the lower back, buttocks, legs, ankles, and feet; and The one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

21. A method according to any of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the C3-T2 nerve roots.

22. A method according to any of the preceding claims, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the T3-T10 nerve roots.

23. The method of any of the preceding claims, wherein the neurostimulator is an external or implanted pulse generator.

24. The method of any of the preceding claims, further comprising implanting the neurostimulator in the subject.

25. The method of any one of the preceding claims, further comprising selecting the subject having SMA for treatment.

26. The method of any one of the preceding claims, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

27. The method of any of the preceding claims, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

28. The method of claim 27, wherein the position of the one or more electrodes is determined by: stimulating a plurality of contact points in the subject to target at least one muscle within the body region of the subject having the motor impairment due to SMA; measuring electrical activity associated with the muscle in response to the stimulation; and One or more contact points of the plurality of contact points are identified as locations of the electrodes based on the electrical activity.

29. The method of any of the preceding claims, wherein at least one of the one or more electrodes is placed percutaneously.

30. The method of any of the preceding claims, wherein at least one of the one or more electrodes is implanted.

31. A method of stimulating one or more motor neurons damaged by SMA, the method comprising applying electrical stimulation to at least one of the motor neurons, wherein the motor neuron innervates a body region of a subject having motor impairment due to SMA.

32. A method for treating SMA in a subject, the method comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment due to SMA.

33. A method of increasing the firing rate of motor neurons damaged by SMA in a subject, the method comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject to increase the firing rate of motor neurons in the subject.

34. The method of claim 33, wherein the subject has a first motor neuron firing rate prior to the application of the therapeutically effective amount of the electrical stimulation and a second motor neuron firing rate after the application.

35. The method of claim 33 or claim 34, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width of between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

36. The method of any one of claims 33 to 35, wherein the electrical stimulation is applied for at least 1 hour per day for a period of at least 1 month.

37. The method of any one of claims 33 to 36, wherein the motor neuron firing rate of the subject is calculated based on electrical signals generated by the motor neurons when parameters of the electrical stimulation are varied.

38. The method of any one of claims 33 to 37, wherein increasing the firing rate of motor neurons damaged by SMA increases joint torque and muscle strength in the subject.

39. A method of increasing the excitability of motor neurons damaged by SMA in a subject to sensory afferent input, the method comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject to increase the excitability of the subject's motor neurons.

40. The method of claim 39, wherein the subject has a first motor neuron excitability prior to the application of the therapeutically effective amount of the electrical stimulation and a second motor neuron excitability after the application.

41. The method of claim 39 or claim 40, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width of between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

42. The method of any one of claims 39 to 41, wherein the electrical stimulation is applied for at least 1 hour per day for a period of at least 1 month.

43. The method of any one of claims 39 to 42, wherein the motor neuron excitability of the subject is calculated based on electrical signals generated by the motor neurons when parameters of the electrical stimulation are varied.

44. The method of any one of claims 39 to 43, wherein increasing the excitability of motor neurons damaged by SMA increases joint torque and muscle strength in the subject.

45. A therapeutically effective amount of electrical stimulation of sensory neurons innervating an area of ​​a subject's body having motor impairment due to SMA, for treating SMA in the subject, wherein the electrical stimulation is applied using one or more electrodes controlled by a neurostimulator, and wherein application of the electrical stimulation treats the motor impairment due to SMA in the subject.

46. ​​Electrical stimulation for use according to claim 45, wherein application of the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment due to SMA.

47. Electrical stimulation for use according to claim 45 or claim 46, wherein the stimulation is applied at or below motor threshold so that the stimulation does not directly induce movement and / or muscle activity in the body area of ​​the subject having the motor impairment caused by SMA.

48. Electrical stimulation for use according to claims 45 to 47, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width of between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

49. Electrical stimulation for use according to claims 45 to 48, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width of between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

50. Electrical stimulation for use according to claims 45 to 49, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width of between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

51. An electrical stimulation for use according to any of the preceding claims, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

52. Electrical stimulation for use according to claim 51, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

53. Electrical stimulation for use according to any one of claims 48 to 52, wherein the pulses are cathodically preferentially biphasic or monophasic charge balanced pulses.

54. Electrical stimulation for use according to any preceding claim, wherein the electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months.

55. Electrical stimulation for use according to any one of claims 45 to 53, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

56. Electrical stimulation for use according to any preceding claim, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

57. Electrical stimulation for use according to claim 56, wherein the electrode array is a multi-electrode paddle array.

58. Electrical stimulation for use according to any preceding claim, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

59. Electrical stimulation for use according to any one of claims 45 to 58, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

60. Electrical stimulation for use according to any one of claims 45 to 58, wherein the one or more electrodes are implanted in a dorsolateral location of the spinal cord adjacent to the dorsal roots of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

61. Electrical stimulation for use according to any one of claims 45 to 57, wherein the one or more electrodes are implanted at the dorsal root ganglia of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

62. Electrical stimulation for use according to any one of claims 45 to 56, wherein the one or more electrodes are contained in a cuff surrounding a peripheral nerve containing the sensory neurons innervating the body area of ​​the subject having the motor impairment due to SMA.

63. Electrical stimulation for use according to any one of claims 45 to 56, wherein the one or more electrodes penetrate peripheral nerves or dorsal root ganglia containing the sensory neurons innervating the body area of ​​the subject having the motor impairment due to SMA.

64. Electrical stimulation for use according to any of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the T11-S1 nerve roots.

65. Electrical stimulation for use according to any of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the C3-T2 nerve roots.

66. Electrical stimulation for use according to any of the preceding claims, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the T3-T10 nerve roots.

67. Electrical stimulation for use according to any preceding claim, wherein the neurostimulator is an external or implanted pulse generator.

68. Electrical stimulation for use according to any preceding claim, wherein the neurostimulator is implanted in the subject.

69. Electrical stimulation for use according to any preceding claim, wherein the subject suffering from SMA is selected for treatment.

70. Electrical stimulation for use according to any preceding claim, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

71. Electrical stimulation for use according to any preceding claim, wherein the location of the one or more electrodes is selected based on the body area of ​​the subject having the motor impairment due to SMA.

72. The electro-stimulation for use according to claim 71, wherein the position of the one or more electrodes is determined by: stimulating a plurality of contact points in the subject to target at least one muscle within the body region of the subject having the motor impairment due to SMA; measuring electrical activity associated with the muscle in response to the stimulation; and One or more contact points of the plurality of contact points are identified as locations of the electrodes based on the electrical activity.

73. Electrical stimulation for use according to any preceding claim, wherein at least one of the one or more electrodes is placed transcutaneously.

74. Electrical stimulation for use according to any preceding claim, wherein at least one of the one or more electrodes is implanted.

75. Use of one or more electrodes controlled by a neurostimulator in the manufacture of a medicament for treating SMA in a subject, wherein the one or more electrodes controlled by the neurostimulator are configured to apply a therapeutically effective amount of electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment caused by SMA.

76. The use of claim 75, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment due to SMA.

77. The use of claim 75 or claim 76, wherein the stimulation is applied at or below the motor threshold such that the stimulation does not directly induce movement and / or muscle activity in the body area of ​​the subject having the motor impairment due to SMA.

78. The use according to claims 75 to 77, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

79. The use according to claims 75 to 78, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

80. The use according to claims 75 to 79, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

81. The use according to any of the preceding claims, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

82. The use according to claim 81, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

83. The use according to any one of claims 78 to 82, wherein the pulse is a cathodically preferential biphasic or monophasic charge balanced pulse.

84. The use according to any one of the preceding claims, wherein the electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months.

85. The use according to any one of claims 75 to 83, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

86. Use according to any of the preceding claims, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

87. The use according to claim 86, wherein the electrode array is a multi-electrode paddle array.

88. The use of any of the preceding claims, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

89. The use of any one of claims 75 to 88, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

90. The use of any one of claims 75 to 88, wherein the one or more electrodes are implanted in a dorsolateral location of the spinal cord adjacent to the dorsal roots of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

91. The use of any one of claims 75 to 87, wherein the one or more electrodes are implanted at the dorsal root ganglion of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

92. The use of any one of claims 75 to 86, wherein the one or more electrodes are contained in a cuff surrounding a peripheral nerve containing the sensory neurons that innervate the body area of ​​the subject having the motor impairment due to SMA.

93. The use of any one of claims 75 to 86, wherein the one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing the sensory neurons innervating the body area of ​​the subject having the motor impairment due to SMA.

94. The use according to any one of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and The one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

95. The use according to any of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the C3-T2 nerve roots.

96. The use according to any of the preceding claims, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the T3-T10 nerve roots.

97. Use according to any of the preceding claims, wherein the neurostimulator is an external or implanted pulse generator.

98. The use according to any of the preceding claims, wherein the neurostimulator is implanted in the subject.

99. The use according to any one of the preceding claims, wherein the subject suffering from SMA is selected for treatment.

100. The use according to any one of the preceding claims, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

101. The use of any of the preceding claims, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

102. The use according to claim 101, wherein the position of the one or more electrodes is determined by: stimulating a plurality of contact points in the subject to target at least one muscle within the body region of the subject having the motor impairment due to SMA; measuring electrical activity associated with the muscle in response to the stimulation; and One or more contact points of the plurality of contact points are identified as locations of the electrodes based on the electrical activity.

103. The use according to any of the preceding claims, wherein at least one of the one or more electrodes is placed percutaneously.

104. The use according to any of the preceding claims, wherein at least one of the one or more electrodes is implanted.

105. Use of one or more electrodes controlled by a neurostimulator in the manufacture of a medicament for treating SMA in a subject, wherein the one or more electrodes controlled by the neurostimulator are to be used to apply electrical stimulation to sensory neurons innervating an area of ​​the subject's body having motor impairment caused by SMA.

106. The use of claim 105, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating the body region of the subject having the motor impairment due to SMA.

107. The use of claim 105 or claim 106, wherein the stimulation is applied at or below the motor threshold such that the stimulation does not directly induce movement and / or muscle activity in the body area of ​​the subject having the motor impairment due to SMA.

108. The use according to claims 105 to 107, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

109. The use according to claims 105 to 108, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width between about 40 μs and about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

110. The use according to claims 105 to 109, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width between about 40 μs and about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

111. The use according to any of the preceding claims, wherein the electrical stimulation comprises a stimulation pattern of a series of 2 to 5 pulses separated by an inter-pulse interval of about 3 ms to about 10 ms, and wherein the series is repeated at a frequency of about 10 Hz to about 100 Hz.

112. The use according to claim 111, wherein the stimulation pattern is a series of 3 pulses separated by an inter-pulse interval of about 5 ms, wherein the series is repeated at a frequency of about 30 to about 100 Hz, and wherein the pulse width is about 200 μs.

113. The use according to any one of claims 108 to 112, wherein the pulse is a cathodically preferential biphasic or monophasic charge balanced pulse.

114. The use according to any one of the preceding claims, wherein the electrical stimulation is applied for at least 2 hours per day for a period of at least 6 months.

115. The use according to any one of claims 105 to 113, wherein the electrical stimulation is applied for at least 1 hour / day for a period of at least 1 month.

116. The use according to any of the preceding claims, wherein the one or more electrodes are contained within an array of independently controllable electrodes implanted in the subject.

117. The use according to claim 116, wherein the electrode array is a multi-electrode paddle array.

118. The use according to any of the preceding claims, wherein the one or more electrodes are implanted epidurally at the spinal cord of the subject.

119. The use of any one of claims 105 to 118, wherein the one or more electrodes are implanted at the dorsal rootlets of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

120. The use of any one of claims 105 to 118, wherein the one or more electrodes are implanted in a dorsolateral location of the spinal cord adjacent to the dorsal roots of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

121. The use of any one of claims 105 to 117, wherein the one or more electrodes are implanted at the dorsal root ganglion of the one or more sensory neurons innervating the body area of ​​the subject having the motor injury.

122. The use of any one of claims 105 to 116, wherein the one or more electrodes are contained in a cuff surrounding a peripheral nerve containing the sensory neurons that innervate the body area of ​​the subject having the motor impairment due to SMA.

123. The use of any one of claims 105 to 116, wherein the one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing the sensory neurons innervating the body area of ​​the subject having the motor impairment due to SMA.

124. The use according to any one of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the lower back, buttocks, legs, ankles and feet; and The one or more electrodes are implanted at the dorsolateral location of the spinal cord and span one or more of the T11-S1 nerve roots.

125. The use according to any of the preceding claims, wherein the body area of ​​the subject is selected from at least one of the upper arm, shoulder, arm, hand and respiratory muscles; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the C3-T2 nerve roots.

126. The use according to any of the preceding claims, wherein the body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back and mid-back; and the one or more electrodes are implanted at the dorsolateral aspect of the spinal cord and span one or more of the T3-T10 nerve roots.

127. The use according to any of the preceding claims, wherein the neurostimulator is an external or implanted pulse generator.

128. The use according to any of the preceding claims, wherein the neurostimulator is implanted in the subject.

129. The use according to any one of the preceding claims, wherein the subject suffering from SMA is selected for treatment.

130. The use according to any one of the preceding claims, wherein the motor impairment comprises partial or complete paralysis, loss of dexterity, loss of muscle strength and / or uncontrollable muscle tone.

131. The use of any of the preceding claims, wherein the location of the one or more electrodes is selected based on the body region of the subject having the motor impairment due to SMA.

132. The use according to claim 131, wherein the position of the one or more electrodes is determined by: stimulating a plurality of contact points in the subject to target at least one muscle within the body region of the subject having the motor impairment due to SMA; measuring electrical activity associated with the muscle in response to the stimulation; and One or more contact points of the plurality of contact points are identified as locations of the electrodes based on the electrical activity.

133. The use according to any of the preceding claims, wherein at least one of the one or more electrodes is placed percutaneously.

134. Use according to any of the preceding claims, wherein at least one of the one or more electrodes is implanted.

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