Treatment of Spinal Muscular Atrophy

Abstract

A method for treating spinal muscular atrophy in a subject is disclosed herein. The particular method includes applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with a movement disorder resulting from spinal muscular atrophy, and the application of the electrical stimulation treats the movement disorder resulting from spinal muscular atrophy in the subject.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 352,599, filed Jun. 15, 2022, and U.S. Provisional Application No. 63 / 450,901, filed Mar. 8, 2023, the entire contents of which are incorporated herein by reference.

[0002] Field The present disclosure relates to methods of treating spinal muscular atrophy (SMA) in a subject by stimulating sensory afferent nerves in the subject.

Background Art

[0003] Background Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by genetic mutations in the survival motor neuron 1 (SMN1) gene (Lefebvre et al., 1995. Cell 80(1):155-165). Motor neurons (MNs) affected in SMA patients have a reduced ability to generate sustained firing and degenerate over time, which can lead to MN death. Surprisingly, although the SMN1 gene is ubiquitously expressed in all MNs, not all muscles are affected. SMA particularly affects the lower limbs and, in more severe cases, respiratory function. Experiments in mouse models have shown that insufficient expression of the SMN protein initially leads to dysfunction and MN death in the later stages 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 non-functional or dead in SMA patients, especially when the patient is in the progressive 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), suggesting that muscle weakness is caused by dysfunction of a percentage of MNs rather than their death. Thus, MN dysfunction and their death in SMA patients are two independent processes.

[0004] The SMN gene has been mapped to a complex region on chromosome 5q by linkage analysis. In humans, this region contains an inverted duplication of approximately 500,000 base pairs (kb), resulting in two nearly identical copies of the SMN gene. SMA is caused by inactivating mutations of the gene (SMN1) on both chromosomes or deletion of the telomeric copy, leading to loss of SMN1 gene function. However, patients retain the centromeric copy of the gene (SMN2), and the copy number of the SMN2 gene in SMA patients generally correlates inversely with disease severity. That is, patients with less severe SMA have more SMN2 copies. Nevertheless, SMN2 cannot fully compensate for the loss of SMN1 function due to alternative splicing of exon 7 caused by a translationally silent C-to-T mutation in exon 7. As a result, most of the transcripts produced from SMN2 lack exon 7 (47 SMN2), encode a truncated SMN protein with dysfunction and rapid degradation.

[0005] The SMN protein is thought to play a role in RNA processing and metabolism, and its function in mediating the assembly of a specific class of RNA-protein complexes called snRNPs is well characterized. SMN may have other functions in MN, but its role in preventing selective degeneration of MN is not well established.

[0006] In most cases, SMA is diagnosed based on clinical symptoms and the presence of at least one copy of the SMN1 gene test. However, in about 5% of cases, SMA is caused by mutations in genes other than the inactivation of SMN1, some of which are known and others are not yet defined. In some cases, other tests such as electromyogram (EMG) or muscle biopsy may be indicated when the SMN1 gene test is not feasible or shows no abnormality.

[0007] Several SMA mouse models have been developed. In particular, the SMN delta exon 7 (Δ7SMN) model (Le et al., Hum. Mol. Genet., 2005, 14:845) carries both the SMN2 gene and several copies of Δ7SMN2 cDNA and recapitulates many of the phenotypic features of type 1 SMA. The Δ7SMN model can be used for both SMN2 expression studies and evaluation of motor function and survival. 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 the levels of both SMN2 full-length (FL SMN2) mRNA and SMN protein are reduced. The C / C allele mouse phenotype has the SMN2 gene and a hybrid mSMN1-SMN2 gene that undergoes alternative splicing, but does not show obvious muscle weakness. The C / C allele mouse model is used for SMN2 expression studies.

[0008] The severity of SMA ranges from neonatal respiratory failure (types 1-2) to mild muscle weakness (type 4) recognized in adulthood. Infantile SMA is the most severe form of this neurodegenerative disorder. Symptoms include muscle weakness, poor muscle tone, weak cry, floppiness or tendency to fall, difficulty sucking or swallowing, accumulation of secretions in the lungs or pharynx, difficulty nursing, and increased susceptibility to respiratory infections. The legs tend to be weaker than the arms, and milestones such as holding the head up or sitting cannot be reached. Generally, the earlier the symptoms appear, the shorter the lifespan. Symptoms appear soon after MN cells deteriorate. The severe forms of the disease are lethal, and there is no known cure for all forms. The course of SMA is directly related to the rate of MN cell deterioration and the severity of the resulting muscle weakness. Infants with severe SMA may die of respiratory disease due to reduced strength of the muscles assisting breathing. Children with milder SMA survive much longer, but may require extensive medical support, especially on the severe end of the spectrum. The clinical spectrum of SMA disorders is divided into the following five groups.

[0009] · Type 0 SMA (intrauterine SMA) is the most severe form of the disease and begins prenatally. Typically, the first symptoms of type 0 SMA are decreased fetal movement, which can first be observed at 30 - 36 weeks of gestation. After birth, these neonates can hardly move and have difficulty swallowing and breathing. · Type 1 SMA (infantile SMA or Werdnig - Hoffmann disease) presents symptoms between 0 - 6 months. This form of SMA is also very severe. Patients do not achieve the ability to sit and usually die within the first 2 years without artificial respiration. · The onset age of type 2 SMA (intermediate SMA) is between 7 - 18 months. Patients achieve the ability to sit unsupported but cannot stand or walk alone. The prognosis of this group depends greatly on the degree of respiratory complications. · Type 3 SMA (juvenile SMA or Kugelberg - Welander disease) is generally diagnosed after 18 months. Individuals with type 3 SMA can walk alone at some point during the course of the disease but often become wheelchair - bound during adolescence or adulthood. · Type 4 SMA (adult - onset SMA). Muscle weakness usually begins in the tongue, hands, or feet in late adolescence and then progresses to other areas of the body. The course of adult SMA is much slower and has little or no impact on life expectancy.

[0010] SMA differs from other types of motor disorders, such as those caused by spinal cord injury or stroke, in that non - functional MNs are the root cause of the impairment in SMA. The MNs of spinal cord injury or stroke patients do not have the underlying cellular pathophysiology. Thus, if the MNs of these patients receive appropriate excitatory input, they are expected to produce a response. In contrast to the MNs of spinal cord injury or stroke patients, the MNs of SMA patients, which have cellular pathophysiology as a result of genetic mutations in the SMN1 gene, do not respond to excitatory input because the MNs themselves are dysfunctional or dead. Therefore, spinal cord stimulation (SCS) aimed at increasing excitatory input to spinal MNs is not expected to produce the same effects in SMA patients as those observed in other conditions treated with SCS, such as spinal cord injury, stroke, and pain, where the MNs are still functional.

[0011] Conventional methods for treating movement disorders such as exercise or physical therapy may not be effective in treating SMA alone because neither exercise nor physical therapy can increase the firing rate of MNs to recruit muscle cells. The decreased firing rate of MNs in SMA patients prevents complete involvement of muscle cells and causes a decrease in sensory input from the central nervous system. Therefore, a treatment method to improve the firing and function of MNs and thereby recruit more muscle cells is needed to improve the quality of life of SMA patients. New gene therapies have been shown to prevent the need for permanent respiratory support and death in neonatal patients (types 1-2). However, these gene therapies have not been able to help type 3-4 patients with severe mobility impairments in adulthood. Furthermore, type 1-2 patients treated with gene therapy also develop severe mobility impairments. Additionally, other SMA therapies such as neuroprotective agents may not be completely effective in all patients. Therefore, a new treatment that targets the movement disorders in SMA patients and improves the effectiveness of current treatments is needed to improve the quality of life of these patients.

Summary of the Invention

[0012] Summary This specification provides embodiments 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 a subject with a movement disorder resulting from SMA, the electrical stimulation being applied using one or more electrodes controlled by a nerve stimulation device, and the application of the electrical stimulation treating the movement disorder resulting from SMA in the subject.

[0013] The above and other objects, features, and advantages of the embodiments will become more apparent from the following detailed description taken in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0014] This patent or application file contains at least one drawing created in color. Copies containing color drawings of this patent or patent application publication will be provided by the Patent Office upon request and payment of the required fees.

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Mode for Carrying Out the Invention

[0016] Detailed Description I. Introduction A method for treating a subject with SMA is provided herein. As discussed in detail herein, a therapeutically effective amount of electrical stimulation is applied to sensory neurons innervating a body region of a subject with a movement disorder due to SMA via one or more electrodes controlled by a nerve stimulation device, thereby treating the movement disorder in the subject due to SMA. Without being bound by theory, application of electrical stimulation to sensory neurons directly recruits monosynaptic and polysynaptic excitatory pathways in the spinal cord, which in turn is thought to increase the membrane potential and firing rate probability of spinal MNs innervating the body region of a subject with a movement disorder due to SMA. This recruitment of pathways may increase neural plasticity and enable the subject to recover motor function. Further, in some embodiments, applying a therapeutically effective amount of electrical stimulation to the subject over time (e.g., at least 2 hours per day over a period of at least 6 months, or at least 1 hour per day over a period of at least 1 month) can result in ion channel remodeling on the MN membrane, a sustained increase in the firing rate probability of spinal MNs, and improvement of the movement disorder even in the absence of stimulation.

[0017] Thus, in one embodiment, the therapeutic electrical stimulation can be applied to the subject by an implanted or percutaneous placement of the electrodes under the control of an implanted or external nerve stimulation device. The electrodes and the nerve stimulation device together comprise a system for delivering SCS to the subject to improve movement disorders due to SMA, such as muscle weakness, muscle control, and / or dysarthria. This system can be used in combination with other SMA therapies, such as targeted motor rehabilitation, to improve patient outcomes.

[0018] The application of SCS to SMA patients has yielded unexpected results considering the unique pathophysiology of SMA. As described above, SMA differs from other types of motor disorders, such as those caused by spinal cord injury or stroke, in that non-functional MNs are the root cause of the disorders resulting from SMA. Therefore, SCS, which aims to increase excitatory input to spinal MNs, is not expected to produce the same effects in SMA patients as those observed in other conditions treated with SCS, such as spinal cord injury, stroke, and pain, where the MNs are still functional.

[0019] However, as discussed below, both significant immediate and long-term effects of SCS have been observed in SMA patients treated in accordance with the present disclosure. Unexpectedly, the magnitude of the immediate effect of SCS in SMA patients is at least as dramatic as that observed in patients with stroke and spinal cord injury. As will be described in detail below, the magnitude of the long-term effects observed after only 4 weeks of treatment according to the present disclosure is even more remarkable (e.g., 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 movement, balance, transition from sitting to standing, maximum walking speed, range of motion, muscle strength (manual muscle test), walking (6-minute walk test), motor ability (Hammersmith Functional Motor Scale Expanded test and Revised Hammersmith Scale test), and measurements related to leg circumference). Specifically, the improvement in muscle strength is of a magnitude that could not be attributed solely to exercise. For example, in one experiment, the left hip flexion of SMA subjects more than doubled even though the subjects did not perform hip strength training other than walking during the study. The subjects' exercise levels did not change from their pre-test exercise levels. These changes are also reflected in the improvements observed in clinical outcome tests such as the manual muscle test, Revised Hammersmith Scale (RHS) test, and 6-minute walk test. Furthermore, the data do not indicate that a plateau has been reached, suggesting that longer use of SCS may result in even greater improvements in SMA patients.

[0020] By performing SCS according to some embodiments of the present disclosure, the activity of the same sensory afferent fibers (e.g., Ia) affected by SMA can be artificially increased. This can have an immediate effect (stimulus ON during the test vs. stimulus OFF) and a long-term effect (stimulus OFF before the test vs. stimulus OFF after the test) on SMA patients. Without being bound by any particular theory, SCS can immediately increase the excitatory input to MNs and thus their firing rate. Thereby, the movement disorder can be immediately improved. Long-term, the artificial increase in sensory afferent activity can enhance the affected sensory synapses, reverse the maladaptive changes in MN ion channels, and thereby improve the MN dysfunction that results in a measurable change in motor function. Thus, SCS can address the motor deficits caused by the decrease in presynaptic activity of sensory afferent fibers. In some embodiments, SCS can be combined with a pharmaceutical intervention designed to halt disease progression.

[0021] II. Acronyms: CST corticospinal tract DRG dorsal root ganglion EMG electromyogram MN motoneuron or motor neuron SCS spinal cord stimulation SMA spinal muscular atrophy SMN1 survival motor neuron 1

[0022] III. Overview of Terms Unless otherwise specified, technical terms are used according to their conventional usage. As used herein, the term "comprises" means "includes". Many methods and materials similar or equivalent to those described herein can be used, but specific suitable methods and materials are described below. For ease of consideration of various embodiments, the following explanations of terms are provided.

[0023] About: As used herein, the term "about" refers to an approximation of a qualitative or quantitative measurement. Whether the measurement is qualitative or quantitative should be apparent from the context. With respect to quantitative measurements, "about" refers to ±5% of the reference value. For example, "about" 100 mA refers to 95 mA to 105 mA.

[0024] Dorsal rootlet: A small branch of the root of a sensory neuron that emerges from the posterior spinal cord and travels to the dorsal root ganglion.

[0025] Posterolateral spinal cord: The area on the outer surface of the spinal cord located between the dorsal midline and the entry point of the dorsal rootlets into the spinal cord.

[0026] Electrical stimulation: Passing various types of current through one or more electrodes selectively to a target location (e.g., a specific area of the dorsolateral spinal cord) within a subject.

[0027] Electrode: A conductor through which current can pass. The electrode may be a current collector and / or emitter. In some embodiments, the electrode is solid and comprises a conductive metal as a conductive layer. Non-limiting examples of conductive metals include noble 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.

[0028] Implantation: For example, using surgical techniques to completely or partially place an electrode or a device containing an electrode within a subject. The device is partially implanted when part of the device reaches or extends outside the subject. Implantable electrodes and devices can be implanted epidurally to the spinal cord, such as on the posterolateral surface of the spinal cord. The electrode or device can be implanted for various periods, such as short-term (e.g., 1 day or less than 2 days) like a daily assistive device, or long-term or long-duration (e.g., 1 month, 6 months, 1 year or more).

[0029] Motor disorder: Partial or total loss of function of a body part, e.g., leg, foot, arm, hand, finger, neck, and functional parts of the torso (e.g., respiratory muscles). Specific motor disorders include loss of muscle strength, partial paralysis (paresis), loss of dexterity (such as finger movement), and uncontrollable muscle tension. The subject may exhibit multiple motor disorders as a complication of SMA.

[0030] Motor threshold: The minimum thalamic stimulation intensity capable of generating a motor output of a given amplitude during rest muscle (RMT) or muscle contraction (AMT).

[0031] Nerve stimulation device: A current or voltage-controlled electrical stimulation device. The nerve stimulation device controls the delivery of an electrical pulse or a pattern of electrical pulses having defined parameters such as, for example, but not limited to, pulse frequency, duration, amplitude, phase symmetry, duty cycle, pulse current, width of the pulse, and on-time and off-time. The controlled electrical pulses are delivered via one or more electrodes (e.g., leadless electrodes, or electrodes located at the end of a lead, thin insulated wire) configured to apply the electrical stimulation to the target tissue of the subject. The nerve stimulation device may comprise at least one multi-contact lead. The nerve stimulation device may be utilized to apply a series of electrical pulse stimulations (e.g., charge-balanced pulses) via at least one electrode, such as, for example, but not limited to, a low-frequency pulse train pattern, a frequency-sequenced pulse burst train pattern (e.g., different sequences of modulated electrical stimulation are generated at different burst frequencies), and a phase train pattern (e.g., the stimulation control parameters vary over the course of a feedback process from the movement of the subject).

[0032] Perceptual threshold: The minimum electrical stimulation intensity required for a conscious human to notice a specific sensation caused by an electrical stimulation.

[0033] Sensory neuron: Also known as an afferent neuron, a sensory neuron is a nerve cell within the peripheral nervous system that converts a stimulus from the neuron's environment into an internal electrical impulse and serves to transmit the impulse to the central nervous system.

[0034] Spinal muscular atrophy (SMA): The disease is typically caused by inactivating mutations or deletions in the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function.

[0035] Subject: A category that includes living multicellular vertebrate organisms, including humans and non-human mammals such as non-human primates, rats, mice, guinea pigs, cats, dogs, cows, horses, etc. Thus, the term "subject" includes both human subjects and veterinary subjects.

[0036] 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 proportion of subjects. The therapeutically effective amount of a particular compound or treatment can be determined in many different ways, such as by assaying for a reduction in a disease or symptom (such as a movement disorder resulting from SMA). The therapeutic compound and treatment can be administered in a single application or in several applications (e.g., chronically over an appropriate period). However, the effective amount can depend on the source being applied, the subject being treated, the severity and type of the symptom being treated, and the mode of administration.

[0037] Transcutaneous placement: Placing, for example, an electrode or a device containing an electrode on or near the skin surface of a subject using non-invasive techniques. The electrode may be attached to the skin surface of the subject for applying electrical stimulation, for example, under the control of an external nerve stimulation device. The electrode or device can be placed transcutaneously for various periods, such as short-term (e.g., one day or less than two days) or long-term or long durations (e.g., one month, six months, one year or more), like a daily assistive device.

[0038] Treatment / Treating: With respect to a disease or condition (e.g., SMA), either term includes one or more of the following: (1) preventing a disease or condition, e.g., not causing the clinical symptoms of a disease or condition in a subject who may be exposed to or is predisposed to the disease or condition but who has not yet experienced or manifested the symptoms of the disease or condition; (2) inhibiting a disease or condition, e.g., stopping the development of the disease or condition or its clinical symptoms; and (3) alleviating a disease or condition, e.g., causing regression of the disease or condition or its clinical symptoms.

[0039] More specifically, treating SMA or treatment of SMA exhibits 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, protection from degeneration of SMN-deficient MNs, increase in motor function, increase in lung function, reduction in loss of lung function, and / or increase in quality of life.

[0040] Even more specifically, treating SMA or treatment of SMA refers to the maintenance of the functional ability or capabilities for a human infant or human toddler to perform certain movements such as sitting without assistance, or for a human infant, human toddler, human child or human adult to perform certain movements such as standing up without assistance, walking without assistance, running without assistance, breathing without assistance, rolling over during sleep without assistance, or swallowing without assistance.

[0041] IV. Stimulation of Sensory Neurons for Treating SMA Methods are provided herein for treating a subject (e.g., a human subject) with SMA. The methods can be utilized to treat (i.e., prevent, ameliorate, inhibit, and / or alleviate) movement disorders resulting from SMA in a subject. The method includes applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with a movement disorder resulting from SMA. The electrical stimulation may be applied, for example, using one or more electrodes controlled by a nerve stimulation device.

[0042] In one embodiment, applying electrical stimulation to a sensory neuron increases the firing rate probability of spinal MNs innervating a body region of a subject with a movement disorder due to SMA. Without being bound by theory, applying electrical stimulation to a sensory neuron may directly recruit monosynaptic and polysynaptic excitatory pathways in the spinal cord, which is thought to indirectly increase the membrane potential and firing rate probability of spinal MNs innervating a body region of a subject with a movement disorder due to SMA. This recruitment of the pathway may increase neural plasticity and enable the subject to recover motor function.

[0043] Any suitable subject with or at risk of a movement disorder due to SMA can be treated by the methods provided herein. The movement disorder can be in the upper or lower extremities of the upper or lower body, including above or below the elbow or knee, or the entire arm or leg. The subject can have any of SMA types 1-4, 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 the movement disorder in the subject or before a detectable movement disorder in an SMA patient at risk of the movement disorder.

[0044] By applying a therapeutically effective amount of electrical stimulation to a subject with SMA, at least one movement disorder due to SMA in the subject is treated. For example, applying a therapeutically effective amount of electrical stimulation can result in a decrease in loss of muscle strength, an increase in muscle strength, a decrease in muscle atrophy, a decrease in loss of motor function, an increase in motor function, an increase in lung function, and / or a decrease in loss of lung function.

[0045] In some embodiments, the movement disorder includes a decrease in the control of the limbs (such as the arms or legs), and the methods provided herein increase the control of the subject's limbs by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) compared to before treatment, as measured by any suitable evaluation metric such as a balance or intensity metric (e.g., a sensory organization test).

[0046] In some embodiments, the movement disorder includes a decrease in postural balance and stability, and the methods provided herein increase the subject's postural balance and stability by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) compared to before treatment, as measured by any suitable evaluation metric such as a balance or intensity metric (e.g., a sensory organization test).

[0047] In some embodiments, the movement disorder includes a decrease in leg torque, and the methods provided herein increase the subject's leg torque by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) compared to before treatment, as measured using the HUMAC® Norm system.

[0048] One or more electrodes may be placed at any suitable location for applying electrical stimulation to the sensory neurons of the subject. In some embodiments, one or more electrodes are positioned to deliver electrical stimulation to one or more sensory neurons innervating the body region of the subject with the movement disorder.

[0049] A spinal cord stimulation (SCS) system may comprise a nerve stimulation device and one or more spinal cord leads having a plurality of electrodes or contacts. The contacts of the SCS system can target specific muscles. For example, contacts located near spinal segment L2 can target hip flexor muscles, while contacts located near spinal segment S1 can target gluteal and ankle extensor muscles. Thus, the position of the contacts or electrodes can be selected to selectively target specific nerves innervating the muscles affected in SMA. For example, if a subject has significant deficits in knee extensor and hip flexor muscles, the stimulation system can be positioned to selectively target these muscles.

[0050] In some embodiments, the location for delivering SCS can be optimized and fine-tuned by stimulating various contact points on the SMA patient, measuring the electrical activity such as electromyogram (EMG) signals generated by muscles (e.g., agonist and antagonist muscles of each joint), and evaluating the measurements. In one example, during surgery, the position of the electrodes is determined by stimulating each contact point and recording the EMG signals of muscles in the range from the trunk to the ankle. Stimulation of a particular contact can start at a low frequency (e.g., about 1 Hz) and the amplitude of the stimulation can be gradually increased until the electrical activity associated with the muscle activity in response to the stimulation is recorded. Based on the recorded electrical activity, the particular muscle targeted by a particular contact can be identified, and thus the stimulated contact point can be identified as a position suitable for the electrode. The peak-to-peak amplitude of the EMG waveform generated due to the stimulation can be used to identify the response in the target muscle, thereby determining the correct position of the muscle. For example, the rostral contacts can generate their first waveform in the hip flexor muscles, while the caudal contacts can generate their first waveform in the gastrocnemius muscles. The stimulation may be repeated, for example, from the hip joint muscle that contacts most rostrally to the gastrocnemius muscle that contacts most caudally until the position where the electrode is activated is identified. In other words, if the multiple contacts of the SCS system completely cover the leg muscles (e.g., from the hip joint to the ankle) for the purpose of delivering SCS, the position of the lead can be fixed. In some embodiments, the identified position can be used in a second SMA patient presenting similar symptoms without performing the above test on the second SMA patient. In some embodiments, the above test is performed during the surgery for implanting the electrodes.

[0051] In some embodiments, the body region of a subject with movement disorders is selected from the lower back, hip joint, leg, ankle, and foot. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons such as the sensory neurons of the T11-S1 nerve roots. For example, one or more electrodes may be implanted in the sensory nerve or DRG, or may be implanted epidurally in the dorsal root or posterolateral surface of the spinal cord for one or more sensory neurons of the T11-S1 nerve roots.

[0052] In some embodiments, the body region of the subject with movement disorder 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 the sensory neurons of the C3-T2 nerve roots. For example, one or more electrodes may be implanted in the sensory nerve or DRG, or may be implanted epidurally in the dorsal rootlets or the posterolateral surface of the spinal cord for one or more sensory neurons of the C3-T2 nerve roots.

[0053] In some embodiments, the body region of the subject with movement disorder is selected from the chest, chest wall, abdomen, upper back, and middle back. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons such as the sensory neurons of the T3-T10 nerve roots. For example, one or more electrodes may be implanted in the sensory nerve or DRG for the sensory neurons of the T3-T10 nerve roots, or may be implanted epidurally in the dorsal rootlets or the posterolateral surface of the spinal cord.

[0054] In some embodiments, the placement of the electrodes during surgery can be adjusted in consideration of the movement of the electrodes after surgery. Such postoperative movement is variable and may be difficult to avoid with non-permanent implants. For example, the electrodes can move caudally and shift medially. Thus, based on the predicted postoperative movement of the electrodes, the electrodes can be implanted at an adjusted position during surgery such that the electrodes move to a predetermined optimal position after surgery. Further details regarding the devices and surgical procedures that can be used to obtain chronic electromyogram (EMG) recordings from leg muscles and to implant a targeted spinal cord stimulation system can be found in Capogrosso et al., 2018. Nature Protocols 13.2031-2061, which is incorporated herein by reference.

[0055] Any suitable stimulation pattern may be used to treat the motor disorder of the subject. In some embodiments, the electrical stimulation includes electrical pulses defined by parameters including, for example, but not limited to, amplitude, pulse width, and pulse frequency. Such electrical pulses may include charge-balanced pulses such as cathodal first biphasic pulses or single-phase charge-balanced pulses. In these and further embodiments, the electrical stimulation may be continuous electrical stimulation or periodic stimulation.

[0056] The stimulation parameters of SCS can be configured according to 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 of about 40 μs to 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.

[0057] In certain examples, the electrical stimulation includes electrical pulses having an amplitude of about 10 μA to about 50 mA, such as about 10 μA to 10 mA, about 10 μA to about 1 mA, about 10 μA to about 100 μA, or about 100 μA to about 1 mA.

[0058] In certain examples, the electrical stimulation includes electrical pulses having a pulse width of from about 40 μs to about 2 ms, such as 40 μs to 2 ms, 100 μs to 2 ms, 200 μs to 2 ms, 300 μs to 2 ms, 400 μs to 2 ms, 500 μs to 2 ms, 600 μs to 2 ms, 700 μs to 2 ms, 800 μs to 2 ms, 800 μs to 2 ms, 900 μs to 2 ms, 1 ms to 2 ms, 1.5 ms to 2 ms, 80 μs to 1.5 ms, 100 μs to 1.5 ms, 200 μs to 1.5 ms, 300 μs to 1.5 ms, 400 μs to 1.5 ms, 500 μs to 1.5 ms, 600 μs to 1.5 ms, 700 μs to 1.5 ms, 800 μs to 1.5 ms, 800 μs to 1.5 ms, 900 μs to 1.5 ms, 1 ms to 1.5 ms, 1.5 ms to 2 ms, 80 μs to 1 ms, 100 μs to 1 ms, 200 μs to 1 ms, 300 μs to 1 ms, 400 μs to 1 ms, 500 μs to 1 ms, 600 μs to 1 ms, 700 μs to 1 ms, 800 μs to 1 ms, 800 μs to 1 ms, and 900 μs to 1 ms.

[0059] In certain examples, the electrical stimulation includes pulse frequencies of from about 10 Hz to about 2000 Hz, such as between 20 Hz and 100 Hz, 20 Hz to 90 Hz, 20 Hz to 80 Hz, 20 Hz to 70 Hz, 20 Hz to 60 Hz, 20 Hz to 50 Hz, 20 Hz to 40 Hz, and 20 Hz to 30 Hz.

[0060] In some embodiments, the electrical stimulation includes electrical pulses having an amplitude of 10 μA to about 50 mA, a pulse width of from about 40 μs to about 2 ms, and a pulse frequency of from about 10 Hz to about 2000 Hz. In some embodiments, the electrical stimulation includes electrical pulses having an amplitude of 10 μA to about 10 mA, a pulse width of from about 40 μs to about 2 ms, and a pulse frequency of from about 10 Hz to about 1000 Hz. In some embodiments, the electrical stimulation includes electrical pulses having an amplitude of 100 μA to about 10 mA, a pulse width of from about 40 μs to about 500 μs, and a pulse frequency of from about 10 Hz to about 1000 Hz.

[0061] In some embodiments, bipolar stimulation and / or tripolar stimulation may be used. In some embodiments, for example, to target the muscles of the right leg, spinal cord stimulation is performed using bipolar stimulation of the two most rostral contacts of the right lead. In some examples, 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.

[0062] In some embodiments, for example, to target the muscles of the left leg, tripolar stimulation is used. In some examples, the electrical stimulation comprises 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.

[0063] In some embodiments, the electrical stimulation comprises electrical pulses having an amplitude of less than about 10 mA, a pulse width of about 80 μs to about 2 ms, and a pulse frequency of about 20 Hz to about 100 Hz. In some examples, the electrical stimulation comprises electrical pulses having an amplitude of 0.5 mA to 5 mA, a pulse width of 80 μs to 200 μs, and a pulse frequency of 20 Hz to 80 Hz. For example, the electrical stimulation may comprise electrical pulses having an amplitude of about 1.5 to about 3.5 mA, a pulse width of about 100 μs to about 200 μs, and a pulse frequency of about 40 Hz to about 80 Hz.

[0064] The electrical stimulation can be applied to the subject over any suitable time necessary to achieve a positive functional benefit for the patient. In some embodiments, the electrical stimulation comprises a stimulation pattern of 2 to 5 pulses separated by a pulse interval of about 3 ms to about 10 ms, and this series of pulses 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 per day over a period of at least 1 month. In some embodiments, the electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months.

[0065] In certain embodiments, the stimulus is applied below the motor threshold of the subject and / or below the sensory threshold of the subject. For example, the stimulus may be applied below the motor threshold and below the sensory threshold, below the motor threshold but above the sensory threshold, or below the sensory threshold but above the motor threshold.

[0066] The SCS system can be configured to provide an electrical spinal cord stimulation protocol within a few days that enables control of the subject's limbs, e.g., each leg during movement, and the degree of muscle stretch and flexion during real-time processing of gait kinematics and gait performance. In some embodiments, the subject may be monitored and tested to establish the parameters of the electrical stimulation based on the subject's movement abnormalities and motor disorders, e.g., by monitoring one or more motor outputs that provide measurements of the degree of motor disorder and the subject's response to the stimulus. In some embodiments, the electrical stimulation by the electrodes is delivered to the subject's sensory neurons while the subject is performing a voluntary activity or task affected by the subject's motor disorder, e.g., an upper limb task (e.g., reaching, grasping, pinching with an opposable thumb, gripping, fine motor work involving precise finger movements) or a lower limb task (e.g., walking, jumping, leg extension).

[0067] Once configured, the stimulation bursts are delivered over specific spinal cord locations at precise timings that reproduce the natural spatio-temporal activation of the moving MNs. These protocols can also be readily adapted to safely implant the system near the spinal cord and to provide SCS including real-time motion feedback and closed-loop controllers, as described below. In some embodiments, the parameters of the electrical stimulation controlled by the nerve stimulation device are adjusted according to changes in one or more motion outputs that are monitored while the subject is performing a specific task, for example, to improve the motor output and thereby treat the subject's motor disorder. In certain embodiments, the adjusted nerve stimulation device is part of a daily assistive device for treating the subject over a long period of time. In certain embodiments, when the subject is released from the clinical site, the operation of the device and / or the nerve stimulation device 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 nerve stimulation device. In some non-limiting embodiments, this treatment can increase the input on the membrane of the spinal cord MNs by direct recruitment of the sensory afferent nerves from the electrical pulses, or result in ion channel remodeling on the MN membrane, increasing the firing rate probability of the spinal cord MNs, and / or improving the motor disorder caused by the SMA, including when the electrical stimulation is no longer applied to the patient. Accordingly, the present disclosure includes a method of increasing the firing rate of motor neurons impaired by SMA.

[0068] The stimulation of sensory afferent nerves using implanted electrodes is an advanced neurosurgical procedure that involves the implantation of one or more electrodes to deliver electrical stimulation under the control of an externalized or implanted nerve stimulation device unit. The implantation of electrodes and / or nerve stimulation devices in examples where the nerve stimulation device is not external typically occurs by a clinical team that includes a neurologist, neurosurgeon, neurophysiologist, and other specialists trained in the evaluation, treatment, and care of neurological conditions. Typically, following the selection of an appropriate subject and determination of the target area of the subject to be stimulated, the precise placement of at least one electrode within the area of the subject's sensory afferent nerve (such as the posterolateral aspect of the spinal cord) is typically performed in an operating room environment using spinal imaging techniques. After administration of local anesthesia, the subject undergoing electrode implantation experiences little discomfort and can remain awake during the implantation procedure to enable communication with the surgical team.

[0069] Some embodiments of this specification use implants that include one or more electrodes and / or nerve stimulation devices implanted (e.g., fully or partially implanted) in a subject. Further embodiments of this specification use implants that include one or more magnets or optical fibers, and / or nerve stimulation devices implanted in a subject.

[0070] Numerous types and styles of implants (e.g., implants that include one or more electrodes for providing electrical stimulation) are available and known to those skilled in the art. Any implant for the specific stimulation of sensory neurons in a subject can be utilized in a particular embodiment. In some embodiments, two or more electrodes, such as an array of electrodes, are implanted. In additional embodiments, devices that can include one or more electrodes are provided. Non-limiting examples include arrays of electrodes, penetrating microarrays (e.g., the Utah and Michigan microarrays), micro-wire electrodes and arrays, nerve cuffs, and paddle arrays.

[0071] In some embodiments, one or more electrodes are implanted into the dorsal roots of one or more sensory neurons innervating a body region of a subject with a movement disorder. In some embodiments, one or more electrodes are implanted into the posterolateral surface of the spinal cord adjacent to the dorsal roots of one or more sensory neurons innervating a body region of a subject with a movement disorder. In some embodiments, one or more electrodes are implanted into the dorsal root ganglia of one or more sensory neurons innervating a body region of a subject with a movement disorder. In some embodiments, one or more electrodes are housed in a cuff that surrounds or at least partially surrounds a peripheral nerve containing sensory neurons innervating a body region of a subject with a movement disorder due to SMA. In a further embodiment, one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons innervating a body region of a subject with a movement disorder due to SMA.

[0072] In some embodiments, epidural electrical stimulation (EES) targeting the dorsal roots using an array of paddle electrodes is utilized in the disclosed method, as described, for example, in Rowald et al., Nat. Med., 28:260 - 271, 2022 and Wagner et al., Nature, 563:65 - 71, 2018, each of which is incorporated herein by reference. Additional non - limiting examples of paddle arrays and their use are provided, for example, in U.S. Patent Application Publication No. 2009 / 0351221 and U.S. Patent Application Publication No. 2019 / 0366077, each of which is incorporated herein by reference.

[0073] In some embodiments, a circuit connecting a nerve stimulation device to one or more electrodes is implanted. 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 to the electrodes of the nerve stimulation device can be by one or more leads, although any operable connection capable of transmitting a stimulation signal from the circuit to the electrodes may be used in certain embodiments.

[0074] Any suitable control system can be used with the electrodes to apply electrical stimulation to a subject. Non-limiting examples of controllable nerve stimulation systems are provided in U.S. Patent Application Publication No. 2020 / 0254260, U.S. Patent Application Publication No. 2020 / 0360693, U.S. Patent Application Publication No. 2020 / 0360697, U.S. Patent Application Publication No. 2020 / 0152078, U.S. Patent No. 10,252,065, U.S. Patent No. 10,799,702, U.S. Patent Application Publication No. 2021 / 0016093, and U.S. Patent Application Publication No. 2020 / 0391030, each of which is incorporated herein by reference. Further, non-limiting examples of closed-loop nerve stimulation systems are provided in U.S. Patent No. 10,265,525, U.S. Patent No. 10,279,167, U.S. Patent No. 10,279,177, U.S. Patent No. 10,391,309, U.S. Patent No. 10,751,539, U.S. Patent No. 10,981,004, and U.S. Patent Application Publication No. 2020 / 0147382, each of which is incorporated herein by reference.

[0075] Post-operative control of selective electrical stimulation by implanted electrodes is, in some embodiments, performed by a nerve stimulation device that can be external or implanted, for example, subcutaneously (e.g., in the chest or abdomen of the subject). In some embodiments, the disclosed method is affected by the use of an implantable nerve stimulation device that controls stimulation (e.g., electrical stimulation via one or more implanted electrodes) according to predetermined parameters or parameters determined by feedback in a closed-loop system. In certain embodiments, one or more electrodes and the nerve stimulation device comprise a daily assistive device that improves muscle strength reduction in the affected limb of the subject.

[0076] After implantation, surgery, and recovery from the connection of the electrode lead to the nerve stimulation device, in order to establish the parameters of electrical stimulation based on the subject's movement disorder and movement disorder, the subject may be monitored and tested, for example, by monitoring one or more motor outputs that provide measurements of the degree of movement disorder and the subject's response to the stimulation. In some embodiments, the electrical stimulation by the implanted electrodes is delivered to the subject's sensory neurons while the subject is performing a voluntary activity or task affected by the subject's movement disorder, such as a forelimb task (e.g., reaching, grasping, pinching with the opposable thumb, gripping, fine motor tasks involving precise finger movements) or a lower limb task (e.g., walking, jumping, leg extension).

[0077] In some embodiments, a transcutaneous electrical stimulation system is used to apply electrical stimulation to the subject's sensory neurons. Non-limiting examples of transcutaneous stimulation systems are provided in U.S. Patent No. 10,806,927, which is incorporated herein by reference. In such transcutaneous embodiments, the electrical stimulation may include electrical pulses having an amplitude of about 10 μA to about 100 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 10,000 Hz.

[0078] In certain embodiments, the methods disclosed herein can be used in combination with protocolized physical rehabilitation exercises to improve long-term outcomes.

Examples

[0079] The following examples are provided to illustrate specific features of certain embodiments, but the claims should not be limited to the features exemplified.

[0080] Example 1 Biophysical Model of Spinal Cord Stimulation for Treating SMA This example provides a biophysical model demonstrating the effectiveness of sensory neuron stimulation therapy for SMA patients and a stimulation protocol for treating SMA patients (such as type 3 and type 4 SMA patients) using stimulation of the posterolateral surface of the spinal cord.

[0081] The application of SCS to SMA patients has yielded results that are unexpected considering the unique pathophysiology of SMA. SMA patients generally have intact corticospinal tracts, but unlike patients with spinal cord injury or stroke, especially when SMA patients are in the progressive stage of the disease, many, if not all, MNs in SMA patients are non-functional or dead and functionally inactivated. Therefore, SCS, which aims to increase excitatory input to spinal MNs, is not expected to 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 for treating SMA will yield the effects observed in other conditions treated with SCS, such as spinal cord injury, stroke, and pain, where MNs are still functional.

[0082] However, surprisingly, as discussed below, both significant immediate and long-term effects of SCS have been unexpectedly observed in SMA patients treated in accordance with the present disclosure. Experiments using the SMA mouse model have shown a decrease in presynaptic activity from sensory afferent fibers, but the present disclosure demonstrates that a therapeutically effective amount of SCS appropriately applied, such as to the posterolateral surface of the spinal cord, can increase the excitability of MNs through the remaining excitatory connections and produce long-term potentiation of synapses that contribute to the reversal of the electrical changes in SMA-affected MNs by artificially increasing the activity in sensory afferent fibers via SCS. Furthermore, a therapeutically effective amount of SCS can also enhance the firing rate of non-SMA-affected MNs, resulting in a more robust effect.

[0083] Network model of the spinal cord circuit Healthy neuron model Figure 1A shows a network model diagram in which MN receives excitatory input from the corticospinal tract and spinal cord stimulation (SCS, such as dorsolateral SCS) through the recruitment of sensory afferent fibers. As shown in Figure 1A, a biophysical model was constructed using a population of healthy MNs (N = 169 modified Hodgkin-Huxley neurons, McIntyre et al., 2002. J Neurophysiology 88(4):1592-1604). Each MN receives excitatory input (N = 60) from the corticospinal tract (CST, N = 110) and SCS through the recruitment of sensory afferent fibers (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 excitatory sources is that SCS has its own frequency and amplitude, while CST was modeled as a population of Poisson neurons. To investigate the recovery of movement during SCS, the force generated by the MN pool was quantified in arbitrary units (Fuglevand et al., 1993. J Neurophysiology, 70(6):2470-2488). In contrast to CST, which represents voluntary input from the brain to MN, SCS is controlled by the experimenter. Therefore, to improve voluntary movement, SCS should enhance the MN firing rate only when CST is active.

[0084] SMA neuron model Figure 3A shows an SMA-affected neuron model with various ion channels in which the delayed rectifier potassium channel (K-dr) is blocked. For a healthy neuron model, the method established to describe the dynamics of the membrane potential as a function of different ion channels is the Hodgkin-Huxley model. In this model, the membrane potential (V) is described as follows. TIFF2025520450000002.tif12170

[0085] Here, C is the membrane capacitance, I is the current artificially injected into the neuron, and g is the conductance x of the ion channel x that generally depends on the membrane potential and ion concentration. Following 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), as shown in FIG. 3A, the following ion channels are included, namely, delayed rectifier sodium (Na) and potassium (K - dr), N - like calcium (Ca - N), L - like calcium (Ca - L), and calcium - dependent potassium (K(Ca)). The model is implemented in a neuron - stimulation environment designed to model individual neurons and networks of neurons, which are referred to herein as neurons (Hines and Carnevale, 1997. Neural Computation 9(6):1179 - 1209).

[0086] FIG. 3B shows an MN model having various ion channels including a specific delayed - rectifier potassium channel (Kv2.1). Without being bound by any particular theory, the loss of sensory afferent input (e.g., Ia) induced by the SMA may change the Kv2.1 channels of the MNs to a dysfunctional state with an increase in the refractory period (e.g., slower firing rate) and / or an increase in the input resistance. Further, the deficit in MN function may be restored by increasing the sensory afferent input to the SMA - affected MNs (e.g., via SCS), which decreases the input resistance of the MNs. Additionally, SCS can immediately increase the sensory afferent input, thereby increasing the firing rate of the SMA - affected MNs. Over time, SCS can rescue MN function by changing the Kv2.1 channels of the MNs to their healthy functional state.

[0087] Spinal cord stimulation increases the excitability of MNs without causing involuntary movements Figures 1B to 1G show various models of SCS enhancement of MN output. In all panels of Figures 1D to 1G, the unit of "amplitude" is the percentage of sensory afferent fibers recruited by SCS. Figure 1B plots the membrane potential (mV) of MNs stimulated at a frequency of 69 Hz and an amplitude that recruited 30% of the sensory afferent fibers. The parameters shown in Figure 1B correspond to the point marked "1" in Figure 1D. The black dashed line indicates the resting potential of the MN membrane, and the gray dashed line indicates the MN spike threshold. For appropriate parameters, SCS can increase the excitability of MNs without generating action potentials. Figure 1C plots the membrane potential (mV) of MNs stimulated at a frequency of 69 Hz and an amplitude that recruited 80% of the sensory afferent fibers. The parameters shown in Figure 1C correspond to the point marked "2" in Figure 1D. Figure 1D, which shows a gradient plot, plots the MN firing rate as a function of SCS parameters without input from the corticospinal tract (CST), indicating that SCS alone can generate involuntary movements (MN firing rate > 8 Hz). Higher spikes / second are indicated by darker shading in each of Figures 1D to 1F on a scale of 0 to 30 spikes / second. Figure 1E, which shows a gradient plot, plots the MN firing rate as a function of SCS parameters with input from the CST. Figure 1F, which shows a gradient plot, plots the MN firing rate for combinations of SCS parameters that generate only voluntary movements normalized by the MN firing rate without SCS. Figure 1G, which shows a gradient plot, plots how SCS enhances the force generated by the MN population. The "arbitrary unit" scale in Figures 1F and 1G represents how many times the firing rate with SCS is compared to the firing rate without SCS. The upper end of the "arbitrary unit" scale is 2.2 times. Thus, these figures indicate that the MN firing rate is up to 2.2 times greater with SCS than without SCS.

[0088] To study the effect of continuous SCS on MN firing rate, a series of stimulation parameters were investigated. In general, the firing rate of MNs increased as a function of both SCS frequency and amplitude, as shown in Fig. 1D. However, a maximum value was identified at 25 Hz, which is related to the time constant of the modified Hodgkin-Huxley neuron model (McIntyre et al., 2002. J Neurophysiology 88(4):1592 - 1604). SCS was able to increase the firing rate of MNs above the minimum firing rate and produce movement (>8 Hz), as shown in Figs. 1C and 1D (Monster and Chan, 1977. J Neurophysiology 40(6):1432 - 43). For the recovery of voluntary movement, any combination of SCS parameters that produced movement without the involvement of the CST (i.e., involuntary movement) was discarded. However, SCS was also able to increase MN excitability (i.e., depolarize the membrane potential) without producing involuntary movement (i.e., MN firing rate <8 Hz), as shown in Figs. 1B and 1D. This increase in MN excitability represents a mechanism to enhance CST input.

[0089] SCS enhances supraspinal input and increases MN firing rate Healthy neuron model Since it was shown that SCS could increase MN excitability in the healthy model, it was evaluated whether SCS could also enhance CST input to activate MNs and generate force. To perform this evaluation, the input from the CST was fixed to produce a relatively low firing rate (9.3 Hz) in the MNs. The MN firing rate was calculated while systematically varying the SCS parameters (frequency and amplitude). Within the range of these parameters, as shown in Figs. 1E and 1F, SCS enhanced the input from the CST and increased the firing rate of MNs without producing involuntary movement. As shown in Fig. 1G, the enhanced firing rate of MNs with SCS generated a force up to 2.2 times stronger than the firing rate generated by the same CST input without SCS.

[0090] Figures 2A-2C show graphs explaining the force enhancement during simulated voluntary brain input. Figure 2A plots the following network activity parameters, namely, SCS amplitude, firing rate (Hz) of the corticospinal tract (CST), MN firing rate (Hz), and force normalized by the applied average force. In the case of the network activity in Figure 2A, no SCS stimulation is applied and a 22 Hz CST input is applied. Figure 2B plots the network activity with SCS applied to the voluntary motor area. Note that the parameters shown in Figure 2B correspond to the point marked "3" in Figure 1E. The MN firing rate, and thus the force, is enhanced relative to SCS off. Figure 2C plots the network activity with SCS applied to the involuntary motor area. Note that the parameters shown in Figure 2C correspond to the point marked "4" in Figure 1E. The MN firing rate is high at both stages regardless of the presence or absence of input from the CST.

[0091] To further understand the enhancement of CST input brought about by SCS, as shown in Figures 2A-2C, a vibratory force task in which CST input periodically reaches the MNs was modeled. The difference between the voluntary and involuntary motor areas was evaluated. In the voluntary motor area, SCS increased the excitability of the MNs, resulting in a higher firing rate than that observed without SCS. However, as shown in Figures 2A and 2B, SCS did not increase the MN firing rate during the periods when there was no CST input. In the involuntary motor area, as shown in Figure 2C, SCS increased the firing rate throughout the trial even during the periods when there was no input from the CST. Overall, these results indicate that in a biophysical model of a healthy spinal cord, it is possible to enhance the input from the CST to increase the MN firing rate and thus generate a stronger force.

[0092] SMA neuron model A series of experiments using the SMA mouse model showed 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) due to a decrease in synaptic activity resulting from the block of sensory afferent fibers and 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 decreases the excitability of MNs, as shown in Fig. 3A. Thus, to model MNs affected by SMA, synaptic weight (i.e., synaptic strength) decreases from the conductance of sensory afferent fibers and delayed rectifier potassium channels, as shown in Fig. 3A. This neuron model can be validated by reproducing the following three dysfunctional electrical properties of MNs affected by SMA. (1) High input resistance: In a neuron simulation environment designed to model individual neurons and neuron networks, it is easy to directly inject current 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. (2) Reduced rheobase: As in (1), it is possible to inject current into the MN and calculate the minimum input current from it to generate an action potential. Similarly, reducing the outflow of potassium ions causes the membrane potential to depolarize faster and decreases the injection current required to induce an action potential. (3) Low firing rates induced by currents higher than those necessary to induce repetitive firing: To test whether blockage of potassium channels is sufficient to reduce the firing rate, an artificial current exceeding the threshold for repeating the firing rate of the MN test affected by SMA is injected. Potassium channels open after an action potential and repolarize the membrane potential. Due to their blockage, the repolarization phase is slower than in healthy MNs, reducing the output firing rate (Fletcher et al., 2017. Nat Neuroscience 20(7):905-16).

[0093] Example 2 Spinal cord stimulation for treating SMA This example describes a specific method that can be used to treat a subject's SMA by applying a therapeutically effective amount of electrical stimulation to the posterolateral surface of the spinal cord containing sensory neurons innervating a body region of the subject with a movement disorder due to SMA. Specific methods and protocols are provided, but as will be appreciated by those skilled in the art, variations can be made without substantially affecting the treatment.

[0094] A 22-year-old human patient with type 3 or 4 SMA who exhibits a quantifiable movement disorder of the legs but can independently stand is selected for treatment. Percutaneous bilateral linear spinal cord leads are implanted near the lumbar spinal cord of the patient for up to 29 days.

[0095] To quantify the immediate movement improvement brought about by SCS, the maximum torque generated at different joints such as the hip, knee, and ankle joints during isometric exercise is measured. For these measurements, the HUMAC® Norm system is used. In this system, the patient can be placed in different positions to evaluate the maximum torque of such joints (Figures 4A - 4C). Figure 4A shows hip joint extension, Figure 4B shows knee joint extension, and Figure 4C shows ankle joint extension.

[0096] During the evaluation, the patient undergoes a progressive contraction from rest to maximum intensity, where they receive real-time torque visual feedback. The same assay is repeated to systematically investigate different SCS parameters, including without SCS, to determine the most effective parameters for reducing the patient's motor impairment. As an example, electrical stimulation of an electrical pulse having an amplitude of about 10 μA to about 50 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz can be applied. Additionally, surface electromyogram (EMG) activity 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.

[0097] This example aims to measure the short-term and long-term effects of SCS on the SMA. First, in this example, the immediate effect of SCS on the SMA is measured by turning the stimulation on and off within the same session and measuring the effect of SCS that only exists during stimulation and disappears when the stimulation is turned off. Next, this example measures the long-term effect of SCS on the SMA by comparing the performance of the patient without stimulation across different sessions. Also, various clinical outcome tests are conducted.

[0098] Both immediate and long-term effects of SCS were observed in SMA patients. In contrast to what was expected in patients with SMA, the magnitude of the immediate effect was similar to that observed in patients with stroke and spinal cord injury. Furthermore, the magnitude of the long-term effect observed over a mere four-week trial was unexpected for patients with non-functional MNs who experienced muscle strength improvements beyond what was expected to be achieved by patients with normal SMA. These muscle strength improvements were too high to be attributed to exercise alone. For example, the patient's left hip flexion more than doubled, yet the patient did not perform hip strength training other than walking during the study. The patient's exercise level did not change from the pre-study exercise level. These changes were reflected in improvements in clinical outcome tests such as manual muscle testing, Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Hammersmith Scale (RHS), and the six-minute walk test in the patient. Furthermore, the data did not show that a plateau had been reached, indicating that longer use of SCS may result in further significant improvements.

[0099] Over four weeks, SCS treatment increased the patient's ankle joint torque (maximum +180%) and MN firing rate, indicating that SCS improved MN function without reporting side effects. These results indicate that SCS can potentially enhance the quality of life of severe and mild SMA patients by improving muscle strength and walking. Such improvement of this magnitude within such a short time frame observed in SMA patients was unexpected. The observed improvement in muscle strength of this magnitude, and the improvement within such a short time frame, may indicate a disease-modifying effect. Without being bound by any particular theory, the improved strength may be brought about by the rescued MN function in response to the increased afferent input provided by SCS targeting the patient's hip flexors and knee extensors. This conclusion was supported by analyzing spinal cord reflexes and single MN firing rates obtained from HD-EMG recordings.

[0100] Initial Configuration and Optimization Before implanting the electrodes, the initial performance of the patient can be measured. For these measurements, the HUMAC® Norm system can be used. In this system, the patient can be placed in different positions to evaluate the maximum torque of different joints. FIGS. 5A and 5B show an isokinetic machine (e.g., a HUMAC® Norm isokinetic machine) configured to test hip flexion and knee extension of a human patient, respectively. In particular, the maximum torque generated by the patient during extension and / or flexion at the knee, hip, and ankle joints can be measured.

[0101] Both bilateral straight SCS leads are implanted into the epidural space from T11 to L1 vertebrae. To target the muscles of the right leg, in one example, the spinal cord is stimulated using bipolar stimulation of the two most rostral contacts of the right lead. The SCS parameters in this example are a pulse width of 2 mA, 40 Hz, and 400 μs. To target the muscles of the left leg, in one example, tripolar stimulation is used. The SCS parameters in this example are a pulse width of 3.7 mA, 40 Hz, and 400 μs.

[0102] SCS can be performed to target the muscles affected by SMA. In this example, it is found that SMA-afflicted patients have significant deficits in knee extensors and hip flexors, consistent with their type 3 diagnosis. Further, the patient has slightly more deficits in the left leg. Thus, the stimulation device can be programmed to selectively target these muscles. In this example, all experiments are conducted over 4 weeks and a total of 19 sessions. The experiments are performed daily, 5 days a week, until the day the electrodes are explanted. Each session lasts 4 hours with a task execution time of about 2 - 3 hours, and the estimated dose of stimulation is active for 2 hours a day during these sessions.

[0103] The positions for applying SCS can be optimized and fine-tuned by stimulating various contact points, measuring the electrical activity generated by muscles (e.g., the agonist and antagonist muscles of each joint), and evaluating the measured values. Then, the maximum torque and EMG activity are measured to determine a therapeutically effective amount of electrical stimulation using appropriate SCS parameters. In this example, during surgery, the electrode positions are determined by stimulating each contact and recording the EMG signals of muscles in the range from the trunk to the ankle. Stimulation is repeated until the position where the most rostral contact activates the hip joint muscles and the most caudal contact activates the calf muscles is identified.

[0104] These implants can be used to constitute an electrical spinal cord stimulation treatment that enables control of the degree of extension and flexion of each leg during movement. This protocol can be configured within a few days using real-time processing of gait kinematics and gait performance. Once configured, the stimulation bursts are delivered over specific spinal cord positions at the exact timing that reproduces the natural spatiotemporal activation of MNs during movement. These protocols can also be easily adapted to safely implant the system near the spinal cord and to conduct experiments involving real-time motion feedback and closed-loop controllers, as described below.

[0105] In some embodiments, the intraoperative electrode placement can be adjusted in consideration of postoperative electrode movement. Such postoperative movement can be variable and difficult to avoid with non-permanent implants. For example, the electrodes can move caudally and shift medially. Figure 6 shows a comparison of the intraoperative electrode position (black) and the postoperative position (white). In this particular example, the change in position does not interfere with the stimulation of the correct muscle group. In some embodiments, based on the predicted postoperative movement of the electrodes, the electrodes can be implanted at an adjusted position during surgery such that the electrodes move to a predetermined optimal position postoperatively. Further details regarding the devices and surgical procedures that can be used to acquire chronic EMG recordings from leg muscles and implant a targeted spinal cord stimulation system can be found in Capogrosso et al., 2018. Nature Protocols 13.2031-2061, which is incorporated herein by reference.

[0106] Observed immediate effects In this example, the immediate effects of SCS are measured with respect to maximal voluntary contraction, hip flexion during movement, balance, transition from sitting to standing, and maximal speed. It should be understood that different metrics can be used depending on the patient's target muscle and symptoms.

[0107] Maximum Voluntary Contraction: To evaluate maximum voluntary contraction, the patient is asked to produce a maximum voluntary isometric contraction (MVC) during 5 seconds of knee extension with and without SCS. After repeating knee extension several times, the patient will show signs of obvious fatigue. At that point, the immediate effect of SCS on the patient's maximum voluntary contraction (MVC) during fatigued knee extension is tested. FIGS. 7A-7C show various torque measurements over time. FIG. 7A shows a single trace of the torque generated by the patient with (see element 704) and without (see element 702) stimulation during maximum voluntary contraction repetitions. In FIG. 7B, each dot corresponds to the average torque generated during one trial with and without stimulation. In FIG. 7C, each dot corresponds to the maximum torque generated during one trial with and without stimulation. In FIGS. 7B and 7C, the square markers represent the average over the repetitions, and the error bars correspond to the standard error of the mean. As shown, the MVC during SCS stimulation is significantly higher on days 12 and 27.

[0108] Hip Flexion During Movement: The patient is asked to produce maximum hip flexion by raising the knee as high as possible while the body weight is supported by the treadmill. During the patient's walking, the stimulation period is repeated on and off every 20 seconds. The patient does not receive visual feedback of the leg during the task. To measure the change in stride width, tracking markers are placed on the ankle joint, toe, and midfoot bone of each foot. A machine learning model (e.g., a deep neural network) can be trained to track the markers. FIGS. 8A-8B show that spinal cord stimulation increases maximum hip flexion during movement. Specifically, FIG. 8A shows the traces of the ankle joint markers during movement without (see element 802) and with (see element 804) stimulation. In FIG. 8B, the dots represent the height of each step calculated as the difference between the small and large values of each trace in FIG. 8A. The square markers represent the average over the entire step, and the error bars correspond to the standard error of the mean. As shown in FIGS. 8A-8B, SCS immediately increases the maximum hip flexion of the patient during movement, which leads to a higher step height.

[0109] Balance: The patient is asked to walk from heel to toe while looking straight at a beam that narrows with distance without receiving visual feedback of their feet. In the first session, the patient deteriorates with stimulation and consistently moves a shorter distance. The patient reports that the stimulation is disrupting their balance as precise control of the leg is becoming more difficult.

[0110] However, when the patient's balance is retested during the second session (one week after the first session) and the third session (one week after the second session), it is found that the patient has learned to control the stimulation and has improved their balance such that the on and off of the stimulation produces similar distances. Figures 9A - 9B show that spinal cord stimulation for the patient only temporarily disrupts balance. In Figure 9A, each dot is the patient's walking distance in a 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 over the repetitions. Figure 9B is a photograph of the patient walking on a narrowing beam.

[0111] Transfer from sitting to standing: The patient is asked to stand from a position where one knee is on the ground and the opposite foot is planted on the ground. Different knee heights are tested until the maximum height at which the patient cannot stand is determined. Then, the stimulation is applied. The patient can consistently reach a standing position with the right knee on the ground.

[0112] The patient is also asked to stand from a sitting position on a box that is 46 cm in size from the ground. Without stimulation, the patient can perform a corrected standing position while spreading their legs too wide. Then, the patient is instructed to try to bring their feet closer together until they reach the separation distance between the feet at which they can no longer stand. Then, the stimulation is applied to the patient with the feet in the same position, i.e., separated by the distance at which the patient could not stand, and the patient can consistently stand from such a position.

[0113] Maximum speed: The patient is asked to run on a treadmill, and the speed is gradually increased every 30 seconds until the patient reports reaching the maximum speed. Figure 10 shows that SCS (refer to element 1004) reliably increases the patient's maximum speed compared to the case where SCS is not applied (refer to element 1002).

[0114] Observed long-term effects In this example, the long-term effects of SCS are measured with respect to hip flexion during movement and maximum voluntary contraction. It should be understood that different metrics can be used depending on the patient's target muscle and symptoms.

[0115] Hip flexion during movement: The patient is asked to walk on a treadmill while raising the knee as high as possible at the 4th week. Figures 11A - 11B show the long-term effects of SCS on hip flexion over a 4-week experiment. Figure 11A shows the traces of the ankle joint markers during movement, comparing the trace from the 1st week without stimulation (refer to element 1102) with the trace from the 4th week without stimulation (refer to element 1104). In Figure 11B, the dots are the height of each step calculated as the difference between the small and large values of each trace in Figure 11A. The squares are the mean average and standard error across the steps. Comparing the 1st week and the 4th week, a significant increase in the patient's maximum hip flexion during movement is observed even without stimulation, indicating the long-term effects of SCS intervention. Without being bound by any particular theory, the application of electrical stimulation to the patient over time can result in ion channel remodeling on the MN membrane and a sustained increase in the firing rate probability of spinal MNs, which can improve motor function even in the absence of stimulation.

[0116] Maximum Voluntary Contraction: At the start of each session using an isokinetic machine, the patient's MVC is measured as the torque (Nm) during knee joint extension and / or hip joint flexion without stimulation. The patient's MVC during knee extension is approximately 20 Nm, while that of healthy young adults exceeds 100 Nm. The patient is asked to generate maximum torque at these joints in six repetitions of 5 seconds each. Knee joint extension is tested twice a week, and hip joint flexion is tested before implantation, at week 1, week 3, and after explantation. Generally, a significant increase in MVC is observed for all exercises starting from week 2.

[0117] Regarding right knee extension, from day 18 until the end of the experiment, when SCS is turned off, a consistent increase in maximum and average torque is observed. The final increase from before implantation until the end of the study is +43.5%. Figures 12A - 12C show the long - term improvement of the patient's right knee extension. Figure 12A shows the torque traces of six repetitions in each session. In Figures 12B - 12C, each dot is the average torque for each 5 - second repetition. The squares are the mean and standard error of the average torque across repetitions. 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 SCS is turned off, the patient experiences a consistent increase in maximum and average right knee extension torque. The final increase from before implantation until the end of the study is +43.5% for the patient.

[0118] A consistent increase in the patient's left knee extension is similarly observed from day 18 until the end of the 4 - week experiment, despite the patient's more impaired leg. The results of left knee extension during the 4 - week SCS experiment are almost identical to those of right knee extension in that no increase is observed until day 18, after which a sustained increase is observed. The final increase from day 5 of the test until the end of the test is +65.1%. Figures 13A - 13C show the long - term improvement of left knee extension. Figure 13A shows the torque traces of six repetitions in each session. In Figures 13B - 13C, each dot is the average torque for each 5 - second repetition. The squares are the mean and standard error of the average torque across repetitions.

[0119] The timing of improvement in the patient's bilateral hip flexion was consistent with the results of knee extension, and both increases were observed from the 18th day until the end of the 4-week experiment of hip flexion. The final increase from before implantation to after explantation was +65.1% on the patient's right side and +179.7% on the left side. FIGS. 14A-14C show the long-term improvement of the right hip flexion. FIG. 14A shows the torque traces of 6 repetitions in each session. In FIGS. 14B-14C, each dot is the average torque for each 5-second repetition. The squares are the mean and standard error of the average torque over the repetitions. FIGS. 15A-15C show the long-term improvement of the patient's left hip flexion. FIG. 15A shows the torque traces of 6 repetitions in each session. In FIGS. 15B-15C, each dot is the average torque for each 5-second repetition. The squares are the mean and standard error of the average torque over the repetitions.

[0120] As a result of these improvements in hip flexion and knee extension, the patient's overall range of motion becomes much higher than before after the end of the experiment. The improvement in the patient's range of motion is most prominent in hip flexion and whole-body movement. Without being bound by any particular theory, the application of electrical stimulation to sensory neurons may directly mobilize 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 regions of patients with movement disorders due to SMA. This mobilization of the pathway may increase neural plasticity and enable the patient to improve motor function.

[0121] Clinical Outcome Tests Clinical outcome tests including manual muscle strength tests, 6-minute walk tests, and limb circumference tests were conducted, and immediate and long-term effects were observed throughout the clinical outcome tests as described below.

[0122] Manual Muscle Testing: Manual Muscle Testing (MMT) is a commonly accepted method for evaluating muscle strength. It measures the strength of each muscle individually and then sums them to report a total score. MMT is performed on patients both before implantation and on days 14 and 28 after implantation. MMT shows a consistent immediate effect from the stimulation. Specifically, both the knee extensors / flexors and the hip extensors / flexors show improved scores from the stimulation, as shown in the spreadsheet presented in Figure 16, which includes the MMT scores of SMA patients for sessions with and without stimulation and for the muscles.

[0123] Six-Minute Walk Test: The six-minute walk test is performed on patients before implantation, on day 14 regardless of the presence or absence of stimulation, and after explantation of the electrodes. No significant immediate effect from the stimulation is observed, but a large improvement from the long-term effect of the stimulation in the total distance traveled is observed for the patients, as shown in the table presented in Figure 17. Figure 17 shows the distance traveled by the patients during the six-minute walk test over different sessions comparing stimulation off to stimulation on.

[0124] Clinical scales, Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Hammersmith Scale (RHS): The HFMSE and RHS tests are validated instruments for assessing the motor abilities of children and adults with SMA types 2 and 3. The results of the HFMSE and RHS tests are measured at pre-implantation, the date of explant, and during follow-up after explant. The patient's HFMSE test shows small but relevant long-term effects along with an increase in the total score, achieving a final HFMSE score of 61. Improvement in the HFMSE can generally be very difficult for patients to achieve. Thus, as shown in the tables presented in FIGS. 18A and 18B, which include the patient's HFMSE scores, even small changes (in this case, 1 to 2 points) indicate improvement. Similarly, as shown in the table presented in FIG. 18B, the patient's RHS test shows a pre-implant RHS score of 64 and an explant RHS score of 65 (a 1-point increase). The increase in the RHS score is consistent even 52 days after explant, indicating small but relevant long-term effects related to the 4-week experiment.

[0125] Leg circumference: On the 18th day after implantation, the circumference of the patient's left and right legs is measured from 15.24 cm above the left and right patellae, respectively. The patient's left and right leg circumferences are measured as 43.5 cm and 46 cm, respectively. Five days after the end of the 4-week experiment and explant, the patient's left and right leg circumferences are measured as 44 cm and 45 cm, respectively. These small differences may be considered negligible.

[0126] Further details of the clinical trial can be found at Clinicaltrials.gov Identifier NCT05430113, “Spinal Cord Stimulation in Spinal Muscular Atrophy (SCSinSMA),” available at https: / / clinicaltrials.gov / ct2 / show / NCT05430113.

[0127] This disclosure should be read in relation to the previous paragraph and is further illustrated by the following numbered embodiments which do not limit the disclosure. The above features, options, and preferences also apply to the following embodiments.

[0128] Embodiment 1. A method for treating spinal muscular atrophy (SMA) in a subject, comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with a movement disorder caused by SMA, the electrical stimulation being applied using one or more electrodes controlled by a nerve stimulation device, and the application of the electrical stimulation treating the movement disorder caused by SMA in the subject.

[0129] Embodiment 2. The method of Embodiment 1, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of a subject with a movement disorder caused by SMA.

[0130] Embodiment 3. The method of Embodiment 1 or Embodiment 2, wherein the stimulation is applied below the motor threshold such that the stimulation does not directly induce movement and / or muscle activity in the body region of the subject with a movement disorder caused by SMA.

[0131] 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 of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0132] 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 of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0133] 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 of about 40 μs to about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0134] Embodiment 7. The electrical stimulation includes a stimulation pattern of 2 to 5 pulses separated by a pulse interval of about 3 ms to about 10 ms, and the series of pulses is repeated at a frequency of about 10 Hz to about 100 Hz, according to any one of the methods of Embodiments 1 to 6.

[0135] Embodiment 8. The stimulation pattern is a series of 3 pulses separated by a pulse interval of about 5 ms, the series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the width of the pulse is about 200 μs, according to the method of Embodiment 7.

[0136] Embodiment 9. The pulse is a cathodal first biphasic pulse or a monophasic charge-balanced pulse, according to any one of the methods of Embodiments 4 to 8.

[0137] Embodiment 10. The electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months, according to any one of the methods of Embodiments 1 to 9.

[0138] Embodiment 11. The electrical stimulation is applied for at least 1 hour per day over a period of at least 1 month, according to any one of the methods of Embodiments 1 to 9.

[0139] Embodiment 12. One or more electrodes are included within an array of independently controllable electrodes implanted in the subject, according to any one of the methods of Embodiments 1 to 11.

[0140] Embodiment 13. The array of electrodes is a multi-electrode paddle array, according to the method of Embodiment 12.

[0141] Embodiment 14. One or more electrodes are implanted epidurally in the spinal cord of the subject, according to any one of the methods of Embodiments 1 to 13.

[0142] Embodiment 15. One or more electrodes are implanted into the dorsal roots of one or more sensory neurons innervating a body region of the subject with motor impairment, according to any one of the methods of Embodiments 1 to 14.

[0143] Embodiment 16. The method according to any one of Embodiments 1 to 14, wherein one or more electrodes are implanted on the posterolateral surface of the spinal cord adjacent to the dorsal roots of one or more sensory neurons innervating a body region of the subject with motor impairment.

[0144] Embodiment 17. The method according to any one of Embodiments 1 to 13, wherein one or more electrodes are implanted in the dorsal root ganglia of one or more sensory neurons innervating a body region of the subject with motor impairment.

[0145] Embodiment 18. The method according to any one of Embodiments 1 to 12, wherein one or more electrodes are housed in a cuff surrounding a peripheral nerve containing sensory neurons innervating a body region of the subject with motor impairment caused by SMA.

[0146] Embodiment 19. The method according to any one of Embodiments 1 to 12, wherein one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons innervating a body region of the subject with motor impairment caused by SMA.

[0147] Embodiment 20. The body region of the subject is selected from at least one of the waist, hip joint, leg, ankle, and foot, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T11-S1 nerve roots. The method according to any one of Embodiments 1 to 19.

[0148] Embodiment 21. The body region of the subject is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the C3-T2 nerve roots. The method according to any one of Embodiments 1 to 20.

[0149] Embodiment 22. The body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back, and middle back, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T3-T10 nerve roots. The method according to any one of Embodiments 1 to 21.

[0150] Embodiment 23. The method according to any one of Embodiments 1 to 22, wherein the nerve stimulation device is an external or implanted pulse generator.

[0151] Embodiment 24. The method according to any one of Embodiments 1 to 23, further comprising implanting a nerve stimulation device into a subject.

[0152] Embodiment 25. The method according to any one of Embodiments 1 to 24, further comprising selecting a subject with an SMA for treatment.

[0153] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein the movement disorder includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrollable muscle tension.

[0154] Embodiment 27. The method according to any one of Embodiments 1 to 26, wherein the position of the one or more electrodes is selected based on the body region of a subject with a movement disorder caused by the SMA.

[0155] Embodiment 28. The method according to Embodiment 27, wherein the position of the one or more electrodes is determined by stimulating a plurality of contact points in a subject to target at least one muscle within the body region of the subject with a movement disorder caused by the SMA, measuring the 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.

[0156] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein at least one of the one or more electrodes is disposed transcutaneously.

[0157] Embodiment 30. The method according to any one of Embodiments 1 to 29, wherein at least one of the one or more electrodes is implanted.

[0158] Embodiment 31. A method of stimulating one or more motor neurons damaged by SMA, comprising applying electrical stimulation to at least one of the motor neurons, wherein the motor neurons innervate a body region of a subject with a movement disorder caused by SMA.

[0159] Embodiment 32. A method for treating spinal muscular atrophy (SMA) in a subject, comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons that innervate a body region of the subject with a movement disorder caused by SMA.

[0160] Embodiment 33. A method of increasing the firing rate of motor neurons damaged by SMA in a subject, comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons that innervate a body region of the subject to increase the firing rate of the subject's motor neurons.

[0161] Embodiment 34. The method of Embodiment 33, wherein the subject has a firing rate of a first motor neuron before application of a therapeutically effective amount of electrical stimulation and a firing rate of a second motor neuron after application.

[0162] 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 of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0163] Embodiment 36. The method according to any one of Embodiments 33 to 35, wherein the electrical stimulation is applied for at least 1 hour per day over a period of at least 1 month.

[0164] Embodiment 37. The method according to any one of Embodiments 33 to 36, wherein the firing rate of the subject's motor neurons is calculated based on an electrical signal generated by the motor neurons while varying the parameters of the electrical stimulation.

[0165] Embodiment 38. Increasing the firing rate of motor neurons impaired by SMA is one method from Embodiments 33 to 37 that increases the joint torque and muscle strength of a subject.

[0166] Embodiment 39. A method for increasing the excitability of motor neurons impaired by SMA in a subject in response 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.

[0167] Embodiment 40. The method of Embodiment 39, wherein the subject has a first motor neuron excitability before application of a therapeutically effective amount of electrical stimulation and a second motor neuron excitability after application.

[0168] 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 of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0169] Embodiment 42. The method of any one of Embodiments 39 to 41, wherein the electrical stimulation is applied for at least 1 hour per day over a period of at least 1 month.

[0170] Embodiment 43. The method of any one of Embodiments 39 to 42, wherein the excitability of the subject's motor neurons is calculated based on electrical signals generated by the motor neurons while varying the parameters of the electrical stimulation.

[0171] Embodiment 44. Increasing the excitability of motor neurons impaired by SMA is one method from Embodiments 39 to 43 that increases the joint torque and muscle strength of a subject.

[0172] Embodiment 45. A therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with motor impairment due to SMA for treating the subject's SMA, wherein the electrical stimulation is adapted to be applied using one or more electrodes controlled by a nerve stimulation device, and the application of the electrical stimulation treats the motor impairment caused by the subject's SMA.

[0173] Embodiment 46. The electrical stimulation for use according to Embodiment 45, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of a subject with motor impairment due to SMA.

[0174] Embodiment 47. The electrical stimulation for use according to Embodiment 45 or Embodiment 46, wherein the stimulation is applied below the motor threshold so that the stimulation does not directly induce movement and / or muscle activity in the body region of a subject with motor impairment due to SMA.

[0175] Embodiment 48. The electrical stimulation for use according to any one of Embodiments 45 to 47, wherein the electrical stimulation includes electrical pulses having an amplitude of about 10 μA to about 100 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0176] Embodiment 49. The electrical stimulation for use according to any one of Embodiments 45 to 48, wherein the electrical stimulation includes electrical pulses having an amplitude of about 10 μA to about 10 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0177] Embodiment 50. The electrical stimulation for use according to any one of Embodiments 45 to 49, wherein the electrical stimulation includes electrical pulses having an amplitude of about 100 μA to about 10 mA, a width of about 40 μs to about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0178] Embodiment 51. The electrical stimulation includes a stimulation pattern of 2 to 5 pulses separated by a pulse interval of about 3 ms to about 10 ms, and the series of pulses is repeated at a frequency of about 10 Hz to about 100 Hz. The electrical stimulation is for use in any one of Embodiments 45 to 50.

[0179] Embodiment 52. The stimulation pattern is a series of 3 pulses separated by a pulse interval of about 5 ms. The series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the width of the pulse is about 200 μs. The electrical stimulation is for use in Embodiment 51.

[0180] Embodiment 53. The pulse is a cathodal first biphasic pulse or a monophasic charge balanced pulse. The electrical stimulation is for use in any one of Embodiments 48 to 52.

[0181] Embodiment 54. The electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months. The electrical stimulation is for use in any one of Embodiments 45 to 53.

[0182] Embodiment 55. The electrical stimulation is applied for at least 1 hour per day over a period of at least 1 month. The electrical stimulation is for use in any one of Embodiments 45 to 53.

[0183] Embodiment 56. One or more electrodes are included within an array of independently controllable electrodes implanted in a subject. The electrical stimulation is for use in any one of Embodiments 45 to 55.

[0184] Embodiment 57. The array of electrodes is a multi-electrode paddle array. The electrical stimulation is for use in Embodiment 56.

[0185] Embodiment 58. One or more electrodes are implanted epidurally in the spinal cord of a subject. The electrical stimulation is for use in any one of Embodiments 45 to 57.

[0186] Embodiment 59. Electrical stimulation for use in any one of Embodiments 45 to 58, wherein one or more electrodes are implanted into the dorsal roots of one or more sensory neurons innervating a body region of a subject with movement disorder.

[0187] Embodiment 60. Electrical stimulation for use in any one of Embodiments 45 to 58, wherein one or more electrodes are implanted into the posterolateral surface of the spinal cord adjacent to the dorsal roots of one or more sensory neurons innervating a body region of a subject with movement disorder.

[0188] Embodiment 61. Electrical stimulation for use in any one of Embodiments 45 to 57, wherein one or more electrodes are implanted into the dorsal root ganglia of one or more sensory neurons innervating a body region of a subject with movement disorder.

[0189] Embodiment 62. Electrical stimulation for use in any one of Embodiments 45 to 56, wherein one or more electrodes are housed in a cuff surrounding a peripheral nerve containing sensory neurons innervating a body region of a subject with movement disorder caused by SMA.

[0190] Embodiment 63. Electrical stimulation for use in any one of Embodiments 45 to 56, wherein one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons innervating a body region of a subject with movement disorder caused by SMA.

[0191] Embodiment 64. The body region of the subject is selected from at least one of the waist, hip joint, leg, ankle, and foot, and one or more electrodes are implanted into the posterolateral surface of the spinal cord and extend to one or more of the T11 - S1 nerve roots, for use in any one of Embodiments 45 to 63.

[0192] Embodiment 65. The body region of the subject is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles, and one or more electrodes are implanted into the posterolateral surface of the spinal cord and extend to one or more of the C3 - T2 nerve roots, for use in any one of Embodiments 45 to 64.

[0193] Embodiment 66. The body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back, and middle back, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T3-T10 nerve roots, for use in any one of Embodiments 45 to 65 for electrical stimulation.

[0194] Embodiment 67. The nerve stimulation device is an external or implanted pulse generator, for use in any one of Embodiments 45 to 66 for electrical stimulation.

[0195] Embodiment 68. The nerve stimulation device is implanted in the subject, for use in any one of Embodiments 45 to 67 for electrical stimulation.

[0196] Embodiment 69. A subject with SMA is selected for treatment, for use in any one of Embodiments 45 to 68 for electrical stimulation.

[0197] Embodiment 70. The movement disorder includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrollable muscle tension, for use in any one of Embodiments 45 to 69 for electrical stimulation.

[0198] Embodiment 71. The position of one or more electrodes is selected based on the body region of the subject with a movement disorder caused by SMA, for use in any one of Embodiments 45 to 70 for electrical stimulation.

[0199] Embodiment 72. The position of 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 with a movement disorder caused by SMA, measuring the electrical activity associated with the muscle in response to the stimulation, and identifying one or more of the contact points at the plurality of contact points as the position of the electrode based on the electrical activity, for use in Embodiment 71 for electrical stimulation.

[0200] Electrical stimulation for use in any one of Embodiments 45 to 72, wherein at least one of the one or more electrodes is disposed transcutaneously.

[0201] Electrical stimulation for use in any one of Embodiments 45 to 73, wherein at least one of the one or more electrodes is implanted.

[0202] Use of one or more electrodes controlled by a nerve stimulation device in the manufacture of a medicament for treating the SMA of a subject, wherein the one or more electrodes controlled by the nerve stimulation device are configured to apply a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with a movement disorder resulting from SMA.

[0203] The use according to Embodiment 75, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of a subject with a movement disorder resulting from SMA.

[0204] The use according to Embodiment 75 or Embodiment 76, wherein the stimulation is applied below a movement threshold so that the stimulation does not directly induce movement and / or muscle activity in a body region of a subject with a movement disorder resulting from SMA.

[0205] The use according to any one of Embodiments 75 to 77, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 100 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0206] The use according to any one of Embodiments 75 to 78, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0207] Embodiment 80. The electrical stimulation is any one use from Embodiments 75 to 79, including electrical pulses having an amplitude of about 100 μA to about 10 mA, a width of about 40 μs to about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0208] Embodiment 81. The electrical stimulation is any one use from Embodiments 75 to 80, including a stimulation pattern of 2 to 5 pulses separated by a pulse interval of about 3 ms to about 10 ms, and the series of pulses is repeated at a frequency of about 10 Hz to about 100 Hz.

[0209] Embodiment 82. The stimulation pattern is a series of 3 pulses separated by a pulse interval of about 5 ms, the series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the width of the pulses is about 200 μs. This is the use of Embodiment 81.

[0210] Embodiment 83. The use of any one from Embodiments 78 to 82, where the pulse is a cathodic first biphasic pulse or a monopolar charge balanced pulse.

[0211] Embodiment 84. The electrical stimulation is any one use from Embodiments 75 to 83, applied for at least 2 hours per day over a period of at least 6 months.

[0212] Embodiment 85. The electrical stimulation is any one use from Embodiments 75 to 83, applied for at least 1 hour per day over a period of at least 1 month.

[0213] Embodiment 86. The use of any one from Embodiments 75 to 85, where one or more electrodes are included within an independently controllable electrode array implanted in the subject.

[0214] Embodiment 87. The use of Embodiment 86, where the electrode array is a multi-electrode paddle array.

[0215] Embodiment 88. The use of any one from Embodiments 75 to 87, where one or more electrodes are implanted epidurally in the spinal cord of the subject.

[0216] Embodiment 89. Use of any one of Embodiments 75 to 88, wherein one or more electrodes are implanted into the dorsal roots of one or more sensory neurons innervating a body region of a subject with movement disorder.

[0217] Embodiment 90. Use of any one of Embodiments 75 to 88, wherein one or more electrodes are implanted into the posterolateral surface of the spinal cord adjacent to the dorsal roots of one or more sensory neurons innervating a body region of a subject with movement disorder.

[0218] Embodiment 91. Use of any one of Embodiments 75 to 87, wherein one or more electrodes are implanted into the dorsal root ganglia of one or more sensory neurons innervating a body region of a subject with movement disorder.

[0219] Embodiment 92. Use of any one of Embodiments 75 to 86, wherein one or more electrodes are housed in a cuff surrounding a peripheral nerve containing sensory neurons innervating a body region of a subject with movement disorder caused by SMA.

[0220] Embodiment 93. Use of any one of Embodiments 75 to 86, wherein one or more electrodes penetrate a peripheral nerve or a dorsal root ganglion containing sensory neurons innervating a body region of a subject with movement disorder caused by SMA.

[0221] Embodiment 94. The body region of the subject is selected from at least one of the waist, hip joint, leg, ankle, and foot, and one or more electrodes are implanted into the posterolateral surface of the spinal cord and extend to one or more of the T11 - S1 nerve roots. Use of any one of Embodiments 75 to 93.

[0222] Embodiment 95. The body region of the subject is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles, and one or more electrodes are implanted into the posterolateral surface of the spinal cord and extend to one or more of the C3 - T2 nerve roots. Use of any one of Embodiments 75 to 94.

[0223] Embodiment 96. The body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back, and middle back, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T3-T10 nerve roots, for use in any one of Embodiments 75 to 95.

[0224] Embodiment 97. For use in any one of Embodiments 75 to 96, wherein the nerve stimulation device is an external or implanted pulse generator.

[0225] Embodiment 98. For use in any one of Embodiments 75 to 97, wherein the nerve stimulation device is implanted in the subject.

[0226] Embodiment 99. For use in any one of Embodiments 75 to 98, wherein a subject with SMA is selected for treatment.

[0227] Embodiment 100. For use in any one of Embodiments 75 to 99, wherein the movement disorder includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrollable muscle tone.

[0228] Embodiment 101. For use in any one of Embodiments 75 to 100, wherein the position of one or more electrodes is selected based on the body region of the subject with a movement disorder caused by SMA.

[0229] Embodiment 102. For use in Embodiment 101, wherein the position of 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 with a movement disorder caused by SMA, measuring the 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.

[0230] Embodiment 103. For use in any one of Embodiments 75 to 102, wherein at least one of the one or more electrodes is placed percutaneously.

[0231] Use of any one of Embodiments 75 to 103, wherein at least one of the one or more electrodes is implanted.

[0232] Embodiment 105. Use of one or more electrodes controlled by a nerve stimulation device in the manufacture of a medicament for treating SMA in a subject, wherein the electrical stimulation is applied to sensory neurons innervating a body region of a subject with a movement disorder caused by SMA using one or more electrodes controlled by the nerve stimulation device.

[0233] Embodiment 106. The use according to Embodiment 105, wherein applying the electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of a subject with a movement disorder caused by SMA.

[0234] Embodiment 107. The use according to Embodiment 105 or Embodiment 106, wherein the stimulation is applied below the motor threshold so that the stimulation does not directly induce movement and / or muscle activity in the body region of a subject with a movement disorder caused by SMA.

[0235] Embodiment 108. The use according to any one of Embodiments 105 to 107, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz.

[0236] Embodiment 109. The use according to any one of Embodiments 105 to 108, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 10 μA to about 10 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 1000 Hz.

[0237] Embodiment 110. The use according to any one of Embodiments 105 to 109, wherein the electrical stimulation comprises electrical pulses having an amplitude of about 100 μA to about 10 mA, a width of about 40 μs to about 500 μs, and a frequency of about 10 Hz to about 1000 Hz.

[0238] Embodiment 111. The electrical stimulation includes a stimulation pattern of 2 to 5 pulses separated by a pulse interval of about 3 ms to about 10 ms, and the series of pulses is repeated at a frequency of about 10 Hz to about 100 Hz, for use according to any one of Embodiments 105 to 110.

[0239] Embodiment 112. The stimulation pattern is a series of 3 pulses separated by a pulse interval of about 5 ms, the series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the width of the pulses is about 200 μs, for use according to Embodiment 111.

[0240] Embodiment 113. The pulses are cathodal first biphasic pulses or monopolar charge balanced pulses, for use according to any one of Embodiments 108 to 112.

[0241] Embodiment 114. The electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months, for use according to any one of Embodiments 105 to 113.

[0242] Embodiment 115. The electrical stimulation is applied for at least 1 hour per day over a period of at least 1 month, for use according to any one of Embodiments 105 to 113.

[0243] Embodiment 116. One or more electrodes are included within an array of independently controllable electrodes implanted in a subject, for use according to any one of Embodiments 105 to 115.

[0244] Embodiment 117. The array of electrodes is a multi-electrode paddle array, for use according to Embodiment 116.

[0245] Embodiment 118. One or more electrodes are implanted epidurally in the spinal cord of a subject, for use according to any one of Embodiments 105 to 117.

[0246] Embodiment 119. One or more electrodes are implanted in the dorsal roots of one or more sensory neurons innervating a body region of a subject with motor impairment, for use according to any one of Embodiments 105 to 118.

[0247] Embodiment 120. Use according to any one of Embodiments 105 to 118, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord adjacent to the dorsal roots of one or more sensory neurons innervating a body region of the subject with movement disorder.

[0248] Embodiment 121. Use according to any one of Embodiments 105 to 117, wherein one or more electrodes are implanted in the dorsal root ganglion of one or more sensory neurons innervating a body region of the subject with movement disorder.

[0249] Embodiment 122. Use according to any one of Embodiments 105 to 116, wherein one or more electrodes are housed in a cuff surrounding a peripheral nerve containing sensory neurons innervating a body region of the subject with movement disorder caused by SMA.

[0250] Embodiment 123. Use according to any one of Embodiments 105 to 116, wherein one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons innervating a body region of the subject with movement disorder caused by SMA.

[0251] Embodiment 124. The body region of the subject is selected from at least one of the waist, hip joint, leg, ankle, and foot, and one or more electrodes are implanted in the posterolateral surface of the spinal cord and extend to one or more of the T11-S1 nerve roots. Use according to any one of Embodiments 105 to 123.

[0252] Embodiment 125. The body region of the subject is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles, and one or more electrodes are implanted in the posterolateral surface of the spinal cord and extend to one or more of the C3-T2 nerve roots. Use according to any one of Embodiments 105 to 124.

[0253] Embodiment 126. The body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back, and middle back, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T3-T10 nerve roots, for use in any one of Embodiments 105 to 125.

[0254] Embodiment 127. For use in any one of Embodiments 105 to 126, where the nerve stimulation device is an external or implanted pulse generator.

[0255] Embodiment 128. For use in any one of Embodiments 105 to 127, where the nerve stimulation device is implanted in the subject.

[0256] Embodiment 129. For use in any one of Embodiments 105 to 128, where a subject with SMA is selected for treatment.

[0257] Embodiment 130. For use in any one of Embodiments 105 to 129, where the movement disorder includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrollable muscle tension.

[0258] Embodiment 131. For use in any one of Embodiments 105 to 130, where the position of one or more electrodes is selected based on the body region of a subject with a movement disorder caused by SMA.

[0259] Embodiment 132. For use in Embodiment 131, where the position of 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 a subject with a movement disorder caused by SMA, measuring the electrical activity associated with the muscle in response to the stimulation, and identifying one or more of the contact points among the plurality of contact points as the position of the electrode based on the electrical activity.

[0260] Embodiment 133. For use in any one of Embodiments 105 to 132, where at least one of the one or more electrodes is placed transcutaneously.

[0261] Use of any one of Embodiments 105 to 133, in which at least one of the one or more electrodes is embedded.

[0262] The foregoing description has been presented for purposes of illustration and is described with reference to specific examples. However, the foregoing exemplary discussion is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teachings. The examples were chosen and described in order to best explain the principles of the technology and their practical application, thereby enabling others skilled in the art to best utilize the technology with various modifications as are suited to the particular use contemplated.

[0263] It is apparent that the exact details of the methods or compositions described may be changed or modified without departing from the spirit of the described embodiments. All such modifications and variations that fall within the scope of the following claims and the scope of the spirit are claimed.

Claims

1. A kit for treating spinal muscular atrophy (SMA) in a subject, comprising one or more electrodes controlled by a nerve stimulator, A kit comprising: applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with motor impairment due to SMA, wherein the electrical stimulation is applied using one or more electrodes, and the application of the electrical stimulation treats the motor impairment in the subject caused by SMA.

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

3. The kit according to claim 1 or 2, wherein the stimulus is applied below a motor threshold so as not to directly induce movement and / or muscle activity in the body region of the subject accompanied by the motor impairment caused by SMA.

4. (i) The electrical stimulation comprises an electrical pulse having an amplitude of about 10 μA to about 100 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 2000 Hz; (ii) The electrical stimulation comprises an electrical pulse having an amplitude of about 10 μA to about 10 mA, a width of about 40 μs to about 2 ms, and a frequency of about 10 Hz to about 1000 Hz; (iii) The electrical stimulation includes an electrical pulse having an amplitude of about 100 μA to about 10 mA, a width of about 40 μs to about 500 μs, and a frequency of about 10 Hz to about 1000 Hz; and / or (iv) The electrical stimulation comprises a series of 2 to 5 pulses separated by pulse intervals of about 3 ms to about 10 ms, and the series of pulses is repeated at a frequency of about 10 Hz to about 100 Hz. The kit according to claim 1 or 2.

5. The kit according to claim 4, wherein the pulse is a cathode first two-phase pulse or a single-phase charge equilibrium pulse.

6. The kit according to claim 1 or 2, wherein the electrical stimulation is applied for at least 2 hours per day over a period of at least 6 months.

7. The kit according to claim 1 or 2, wherein the one or more electrodes are included in an array of independently controllable electrodes that are implanted in the subject.

8. The kit according to claim 7, wherein the electrode array is a multi-electrode paddle array.

9. (i) The one or more electrodes are implanted epidurally in the spinal cord of the subject; (ii) The one or more electrodes are implanted in the posterior root of the one or more sensory neurons that innervate the body region of the subject that is affected by the motor impairment; (iii) The one or more electrodes are implanted in the posterolateral surface of the spinal cord adjacent to the dorsal root of the one or more sensory neurons that innervate the body region of the subject with the motor impairment; (iv) The one or more electrodes are embedded in the dorsal root ganglia of the one or more sensory neurons that innervate the body region of the subject that is affected by the motor impairment; (v) The one or more electrodes are housed in a cuff that surrounds peripheral nerves including the sensory neurons that innervate the body region of the subject with motor impairment due to SMA; and / or (vi) The one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing the sensory neurons that innervate the body region of the subject with the motor impairment caused by SMA, The kit according to claim 1 or 2.

10. (i) The body region of the subject is selected from at least one of the hip, hip, leg, ankle, and foot, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T11-S1 nerve roots; (ii) The body region of the subject is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the C3-T2 nerve roots; and / or (iii) The body region of the subject is selected from at least one of the chest, chest wall, abdomen, upper back, and mid-back, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend to one or more of the T3-T10 nerve roots. The kit according to claim 1 or 2.

11. The kit according to claim 1 or 2, wherein the nerve stimulator is an external or embedded pulse generator.

12. The kit according to claim 1 or 2, wherein the nerve stimulator is implanted in the subject and / or a subject with SMA is selected for treatment.

13. The kit according to claim 1 or 2, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

14. The kit according to claim 1 or 2, wherein the positions of the one or more electrodes are selected based on the body region of the subject having the motor impairment caused by SMA.

15. The position of the one or more electrodes is Multiple contact points in the subject are stimulated to target at least one muscle within the body region of the subject who has the motor impairment caused by SMA, The electrical activity associated with the muscle is measured in response to the stimulus, and Based on the aforementioned electrical activity, one or more contact points among the plurality of contact points are identified as the position of the electrode. The kit according to claim 14, determined by the following:

16. The kit according to claim 1 or 2, wherein at least one of the one or more electrodes is placed percutaneously and / or at least one of the one or more electrodes is implanted.

17. A kit for stimulating one or more motor neurons impaired by SMA, wherein electrical stimulation is applied to at least one of the motor neurons, and the motor neurons innervate a body region of a subject with motor impairment due to SMA.

18. A kit for treating SMA in a subject, wherein a therapeutically effective amount of electrical stimulation is applied to sensory neurons innervating a body region of the subject with motor impairment due to SMA.

19. A kit for increasing the firing rate of motor neurons impaired by SMA in a subject, wherein a therapeutically effective amount of electrical stimulation is applied to sensory neurons innervating a body region of the subject, thereby increasing the firing rate of the motor neurons of the subject.

20. A kit for increasing the excitability of motor neurons impaired by SMA in a subject to sensory afferent input, wherein a therapeutically effective amount of electrical stimulation is applied to sensory neurons innervating a body region of the subject, thereby increasing the excitability of the subject's motor neurons.

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