Treatment of spinal muscular atrophy

Abstract

A method for treating spinal muscular atrophy in a subject is disclosed herein. A particular method comprises applying a therapeutically effective dose of electrical stimulation to sensory neurons innervating a body region of the subject with motor impairment due to spinal muscular atrophy, wherein the application of electrical stimulation, in conjunction with the administration of SMA therapy, treats the motor impairment due to 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 / 461,545, filed Apr. 24, 2023; U.S. Provisional Application No. 63 / 510,880, filed Jun. 28, 2023; U.S. Provisional Application No. 63 / 609,235, filed Dec. 12, 2023; and U.S. Provisional Application No. 63 / 550,939, filed Feb. 7, 2024, 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. The present disclosure also relates to methods of treating SMA in a subject by electrical stimulation of the spinal cord in combination with SMA therapy.

Background Art

[0003] Background SMA is a neurodegenerative disease caused by genetic mutations in the Surviving Motor Neuron 1 (SMN1) gene (Lefebvre et al., 1995. Cell 80(1):155-165). In SMA patients, affected motor neurons (MNs, also called "motor neurons") have a reduced ability to produce sustained firing, degrade over time, and can lead to MN death. Surprisingly, despite the ubiquitous expression of the SMN1 gene in all MNs, not all muscles are affected. SMA particularly affects the lower extremities 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, in the later stages of the disease, to MN death (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 advanced stages 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 not by the death of the MNs, but by the dysfunction of a certain percentage of them. Therefore, MN dysfunction and MN death in SMA patients are two independent processes.

[0004] The SMN gene is 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 or telomere copy deletions of the gene (SMN1) on both chromosomes, leading to loss of SMN1 gene function. However, patients retain a centromere copy of the gene (SMN2), and the copy number of the SMN2 gene in SMA patients is generally inversely correlated with disease severity; that is, patients with less severe SMA have a higher SMN2 copy number. 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, the majority of transcripts produced from SMN2 lack exon 7 (47 SMN2), encoding a cleaved SMN protein that is dysfunctional and rapidly degraded.

[0005] SMN proteins are thought to play a role in RNA processing and metabolism, and their function in mediating the assembly of a specific class of RNA-protein complexes called snRNPs is well-characterized. While SMNs may have other functions in MNs, their role in preventing selective denaturation of MNs is not yet fully 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 SMN1 inactivation, some of which are known, while others are still undefined. In some cases, if the SMN1 gene test is not feasible or shows no abnormality, other tests such as electromyography (EMG) or muscle biopsy may be indicated.

[0007] Several mouse models of SMA have been developed. In particular, the SMN delta-exon 7 (Δ7 SMN) model (Le et al., Hum. Mol. Genet., 2005, 14:845) possesses both the SMN2 gene and several copies of Δ7 SMN2 cDNA, and reproduces many of the phenotypic features of type 1 SMA. The Δ7 SMN model can be used for both SMN2 expression studies and assessment 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 with reduced levels of both SMN2 full-length (FL SMN2) mRNA and SMN protein. The C / C allele mouse phenotype possesses 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 can be used for SMN2 expression studies.

[0008] The severity of SMA ranges from respiratory failure in the neonatal period (types 1-2) to mild muscle weakness observed in adulthood (type 4). Infant SMA is the most severe form of this neurodegenerative disorder. Symptoms include muscle weakness, weak muscle tone, weak cry, flaccidity or tendency to fall, difficulty sucking or swallowing, accumulation of secretions in the lungs or pharynx, difficulty feeding, and increased susceptibility to respiratory infections. Legs tend to be weaker than arms, and developmental goals such as lifting the head or sitting up are not achieved. Generally, the earlier symptoms appear, the shorter the life expectancy. Symptoms appear soon after deterioration of MN cells. Severe forms of the disease are fatal, and there are no known treatments for all forms. The course of SMA is directly related to the rate of MN cell deterioration and the resulting severity of muscle weakness. Infants with severe forms of SMA frequently die from respiratory illnesses due to weakened muscles that support breathing. Children with milder SMA tend to survive considerably longer, but may require extensive medical support, especially if they are on the more severe side of the spectrum. The clinical spectrum of SMA disorders is divided into the following five groups: Type 0 SMA (intrauterine SMA) is the most severe form of the disease and begins before birth. Typically, the first symptom of type 0 SMA is decreased fetal movement, which can first be observed between 30 and 36 weeks of gestation. After birth, these newborns are barely mobile and have difficulty swallowing and breathing. Type 1 SMA (infant SMA or Werdnig-Hoffmann disease) presents with symptoms between 0 and 6 months of age. This form of SMA is also very severe. Patients never achieve the ability to sit up and usually die within the first two years without mechanical ventilation. The age of onset for type 2 SMA (intermediate SMA) is 7 to 18 months. Patients achieve the ability to sit without support, but are unable to stand or walk on their own. The prognosis for this group largely depends on the degree of respiratory complications. Type 3 SMA (juvenile SMA or Kugelberg-Welander disease) is generally diagnosed at 18 months of age. Individuals with type 3 SMA may be able to walk independently at some point during the course of the disease, but often become wheelchair-bound during their youth or adulthood. • Type 4 SMA (adult-onset SMA). Muscle weakness usually begins in late adolescence, in the tongue, hands, or feet, and then progresses to other areas of the body. The course of adult SMA is much slower and has little to no impact on life expectancy.

[0009] SMA differs from other types of motor disorders, such as those caused by spinal cord injury or stroke, in that non-functional neuropathy (MN) is the underlying cause of the SMA-related impairment. MNs in spinal cord injury or stroke patients lack the underlying cellular pathophysiology. Therefore, if the MNs in these patients receive appropriate excitatory input, they are expected to produce a response. In contrast to MNs in spinal cord injury or stroke patients, MNs in SMA patients, which have cellular pathophysiology as a result of a genetic mutation in the SMN1 gene, do not respond to excitatory input because the MNs themselves are dysfunctional or dead. Therefore, SCS aimed at increasing excitatory input to spinal cord MNs is not expected to produce the same effects in SMA patients as observed in spinal cord injury, stroke, and other conditions treated with SCS such as pain, where the MNs are still functional.

[0010] Conventional methods for treating motor disorders, such as exercise or physiotherapy, may not be effective in treating SMA alone because neither exercise nor physiotherapy can increase the firing rate of muscle neurons (MNs) to mobilize muscle cells. Reduced MN firing rate in SMA patients hinders the full involvement of muscle cells and leads to decreased sensory input from the central nervous system. Therefore, therapeutic methods that improve MN firing and function, thereby mobilizing more muscle cells, are needed to improve the quality of life for SMA patients. Nerve repair agents are available, such as onasemnogene abeparvovec (Zolgensma®), a gene therapy based on an IV-administered adeno-associated virus vector that delivers a copy of the SMN1 gene; nusinersen (Spinraza®), an intrathecal antisense oligonucleotide (ASO) therapy targeting the SMN2 gene; and risdiplam (Evrysdi®), an oral SMN2 splicing modifier that delays or prevents MN death caused by SMA. Onasemnogene abeparvovec, nusinersen, and risdiplam are gene therapies designed to treat SMA by increasing the production of SMN protein. As provided herein, SMA is caused by a deletion or mutation in the SMN1 gene, resulting in selective degeneration of SMN-deficient MN. Human subjects retain several copies of the SMN2 gene, but the small amount of functional SMN protein expressed from SMN2 does not fully compensate for the loss of SMN that would have been expressed from the SMN1 gene.

[0011] Onasemnogen abeparvovec is a nerve repair agent, more specifically a gene therapy, and more specifically, a recombinant autocomplementary AAV9 containing a transgene encoding human survival motor neuron (SMN) protein under the control of a cytomegalovirus enhancer / chicken-β-actin hybrid promoter. Intravenous administration of onasemnogen abeparvovec results in cytotransduction and expression of the SMN protein.

[0012] Nusinersen is a nerve repair agent, more specifically a gene therapy, and more specifically an antisense therapy that alters the SMN2 preRNA splicing process by inhibiting splicing factors. In particular, nusinersen binds to a specific sequence of intron downstream of exon 7 of the SMN2 transcript. This promotes the incorporation of exon 7 into mRNA, thereby enhancing full-length SMA protein levels.

[0013] Risdiplam is a nerve repair agent, more specifically a gene therapy, and more specifically a small molecule splicing modulator that increases the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 minigene and the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 minigene. The minigene replicates the alternative splicing reaction of exon 7 of SMN2 and SMN1, resulting in the skipping of exon 7 in most SMN2 and SMN1 transcripts.

[0014] These nerve repair agents and / or gene therapies alone are not always fully effective in all patients and are not particularly effective in restoring motor function. Therefore, new therapies that target motor impairment in SMA patients and improve the effectiveness of current treatments are needed to improve the quality of life for these patients. [Overview of the Initiative]

[0015] overview This specification provides embodiments of a method for treating a target SMA. The method comprises applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a target body region affected by motor impairment due to the SMA, wherein the electrical stimulation is applied using one or more electrodes controlled by a nerve stimulator, and the application of electrical stimulation treats the motor impairment due to the target SMA. In some embodiments, the treatment of the SMA includes treatment with neuromuscular stimulation combined with a nerve repair agent. In some embodiments, the nerve repair agent is a gene therapy, such as onasemnogene abeparvovec, nusinersen, or risdiplam.

[0016] 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

[0017] [Figure 1A] Shows various models of SCS enhancement of MN output according to some embodiments. [Figure 1B] Shows various models of SCS enhancement of MN output according to some embodiments. [Figure 1C] Shows various models of SCS enhancement of MN output according to some embodiments. [Figure 1D] Shows various models of SCS enhancement of MN output according to some embodiments. [Figure 1E] Shows various models of SCS enhancement of MN output according to some embodiments. [Figure 1F] Shows various models of SCS enhancement of MN output according to some embodiments. [Figure 1G] Shows various models of SCS enhancement of MN output according to some embodiments.

[0018] [Figure 2A] Shows a graph explaining the force enhancement during simulated voluntary brain input according to some embodiments. [Figure 2B] Shows a graph explaining the force enhancement during simulated voluntary brain input according to some embodiments. [Figure 2C] Shows a graph explaining the force enhancement during simulated voluntary brain input according to some embodiments.

[0019] [Figure 3A] Shows an SMA-affected neuron model with various ion channels in which the delayed rectifier potassium channel (K-dr) is blocked, according to some embodiments.

[0020] [Figure 3B] We present MN models with various ion channels, including a specific delayed-rectification potassium channel (Kv2.1), according to several embodiments.

[0021] [Figure 4A] The following are various HUMAC® Norm configurations for testing the maximum torque at different joints in SMA patients receiving SCS stimulation of sensory neurons innervating the lower limbs, according to several embodiments. [Figure 4B] The following are various HUMAC® Norm configurations for testing the maximum torque at different joints in SMA patients receiving SCS stimulation of sensory neurons innervating the lower limbs, according to several embodiments. [Figure 4C] The following are various HUMAC® Norm configurations for testing the maximum torque at different joints in SMA patients receiving SCS stimulation of sensory neurons innervating the lower limbs, according to several embodiments.

[0022] [Figure 5A] The following are examples of isokinetic machines (e.g., HUMAC® Norm isokinetic machines) configured to test hip flexion and knee extension, respectively, in patients with SMA, according to several embodiments. [Figure 5B] The following are examples of isokinetic machines (e.g., HUMAC® Norm isokinetic machines) configured to test hip flexion and knee extension, respectively, in patients with SMA, according to several embodiments.

[0023] [Figure 6] This section shows a comparison of the intraoperative and postoperative positions of electrodes in SMA patients according to several embodiments.

[0024] [Figure 7A] The following shows various torque measurements over time in two SMA patients according to several embodiments. [Figure 7B]The following shows various torque measurements over time in two SMA patients according to several embodiments. [Figure 7C] The following shows various torque measurements over time in two SMA patients according to several embodiments. [Figure 7D] The following shows various torque measurements over time in two SMA patients according to several embodiments. [Figure 7E] The following shows various torque measurements over time in two SMA patients according to several embodiments.

[0025] [Figure 8A] Several embodiments demonstrate that spinal cord stimulation increases maximum hip flexion during movement in patients with SMA. [Figure 8B] Several embodiments demonstrate that spinal cord stimulation increases maximum hip flexion during movement in patients with SMA.

[0026] [Figure 9A] Several embodiments demonstrate that spinal cord stimulation of a target only temporarily disrupts balance in patients with SMA. [Figure 9B] Several embodiments demonstrate that spinal cord stimulation of a target only temporarily disrupts balance in patients with SMA.

[0027] [Figure 10] Several embodiments demonstrate that SCS reliably increases the maximum velocity in SMA patients.

[0028] [Figure 11A] The effects of completing a study on SCS in hip flexion in SMA patients, according to several embodiments, are shown. [Figure 11B] The effects of completing a study on SCS in hip flexion in SMA patients, according to several embodiments, are shown.

[0029] [Figure 12A]This study demonstrates the improvement in right knee extension in two SMA patients according to several embodiments. [Figure 12B] This study demonstrates the improvement in right knee extension in two SMA patients according to several embodiments. [Figure 12C] This study demonstrates the improvement in right knee extension in two SMA patients according to several embodiments. [Figure 12D] This study demonstrates the improvement in right knee extension in two SMA patients according to several embodiments. [Figure 12E] This study demonstrates the improvement in right knee extension in two SMA patients according to several embodiments. [Figure 12F] This study demonstrates the improvement in right knee extension in two SMA patients according to several embodiments.

[0030] [Figure 13A] Several embodiments demonstrate the improvement in left knee extension in patients with SMA. [Figure 13B] Several embodiments demonstrate the improvement in left knee extension in patients with SMA. [Figure 13C] Several embodiments demonstrate the improvement in left knee extension in patients with SMA.

[0031] [Figure 14A] Several embodiments demonstrate improvements in the completion of studies on right hip flexion in patients with SMA. [Figure 14B] Several embodiments demonstrate improvements in the completion of studies on right hip flexion in patients with SMA. [Figure 14C] Several embodiments demonstrate improvements in the completion of studies on right hip flexion in patients with SMA.

[0032] [Figure 15A] This describes an improvement in the end of a study in left hip flexion in a first SMA patient according to several embodiments. [Figure 15B]This describes an improvement in the end of a study in left hip flexion in a first SMA patient according to several embodiments. [Figure 15C] This describes an improvement in the end of a study in left hip flexion in a first SMA patient according to several embodiments.

[0033] [Figure 15D] This describes the improvement in the completion of a study on right hip extension in a second SMA patient, according to several embodiments. [Figure 15E] This describes the improvement in the completion of a study on right hip extension in a second SMA patient, according to several embodiments. [Figure 15F] This describes the improvement in the completion of a study on right hip extension in a second SMA patient, according to several embodiments.

[0034] [Figure 16] This paper presents, in several embodiments, manual muscle testing scores in SMA patients, as well as sessions with and without stimulation.

[0035] [Figure 17A] This shows the distance traveled by two SMA patients during a 6-minute walking test across different sessions comparing stimulation off versus stimulation on, according to several embodiments. [Figure 17B] This shows the distance traveled by two SMA patients during a 6-minute walking test across different sessions comparing stimulation off versus stimulation on, according to several embodiments. [Figure 17C] This shows the distance traveled by two SMA patients during a 6-minute walking test across different sessions comparing stimulation off versus stimulation on, according to several embodiments.

[0036] [Figure 18A] The Hammersmith Functional Motor Scale Expanded and Revised Hammersmith Scale scores in two SMA patients, according to several embodiments, are shown. [Figure 18B] The Hammersmith Functional Motor Scale Expanded and Revised Hammersmith Scale scores in two SMA patients, according to several embodiments, are shown. [Figure 18C] The Hammersmith Functional Motor Scale Expanded and Revised Hammersmith Scale scores in two SMA patients, according to several embodiments, are shown.

[0037] [Figure 19A] The results of principal component analysis (PCA) in two SMA patients, according to several embodiments, are shown below. [Figure 19B] The results of principal component analysis (PCA) in two SMA patients, according to several embodiments, are shown below. [Figure 19C] The results of principal component analysis (PCA) in two SMA patients, according to several embodiments, are shown below. [Figure 19D] The results of principal component analysis (PCA) in two SMA patients, according to several embodiments, are shown below.

[0038] [Figure 20A] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20B] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20C] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20D] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20E]Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20F] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20G] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on. [Figure 20H] Several embodiments demonstrate short-term improvements in several gait quality variables in two SMA patients when comparing stimulation off versus stimulation on.

[0039] [Figure 21A] The effects of the end of the study on the gait patterns of two SMA patients in a 6-minute walk test, according to several embodiments, are shown. [Figure 21B] The effects of the end of the study on the gait patterns of two SMA patients in a 6-minute walk test, according to several embodiments, are shown. [Figure 21C] The effects of the end of the study on the gait patterns of two SMA patients in a 6-minute walk test, according to several embodiments, are shown. [Figure 21D] The effects of the end of the study on the gait patterns of two SMA patients in a 6-minute walk test, according to several embodiments, are shown.

[0040] [Figure 22A] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22B] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22C] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22D]This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22E] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22F] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22G] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments. [Figure 22H] This study demonstrates the improvement in several gait quality variables in two SMA patients according to several embodiments.

[0041] [Figure 23A] This figure shows the results of neural activation in a first patient during an active task, according to several embodiments. [Figure 23B] This figure shows the results of neural activation in a first patient during an active task, according to several embodiments.

[0042] [Figure 24A] This figure shows the results of neural activation in a second patient during an active task, according to some embodiments. [Figure 24B] This figure shows the results of neural activation in a second patient during an active task, according to some embodiments.

[0043] [Figure 25A] This figure shows the results of neural activation in a first patient during a passive task, according to some embodiments. [Figure 25B] This figure shows the results of neural activation in a first patient during a passive task, according to some embodiments.

[0044] [Figure 26A] The MN firing rates during maximum spontaneous contractions in SMA patients at different time points during and after the study, according to several embodiments, are shown. [Figure 26B] The MN firing rates during maximum spontaneous contractions in SMA patients at different time points during and after the study, according to several embodiments, are shown.

[0045] [Figure 27A] Several embodiments demonstrate improvements in the conclusion of studies on torque measurement in SMA patients. [Figure 27B] Several embodiments demonstrate improvements in the conclusion of studies on torque measurement in SMA patients.

[0046] [Figure 28A] This shows a short-term increase in torque measurements in SMA patients when comparing stimulation off versus stimulation on, according to several embodiments. [Figure 28B] This shows a short-term increase in torque measurements in SMA patients when comparing stimulation off versus stimulation on, according to several embodiments.

[0047] [Figure 29A] The following shows the changes at the end of a study of MN input resistance in SMA patients according to several embodiments. [Figure 29B] The following shows the changes at the end of a study of MN input resistance in SMA patients according to several embodiments. [Figure 29C] The following shows the changes at the end of a study of MN input resistance in SMA patients according to several embodiments.

[0048] [Figure 30A] The long-term changes in torque measurements of two SMA patients compared with SMA treatment (Figures 30B and 30C) versus no SMA treatment (Figure 30A) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 30B]The long-term changes in torque measurements of two SMA patients compared with SMA treatment (Figures 30B and 30C) versus no SMA treatment (Figure 30A) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 30C] The long-term changes in torque measurements of two SMA patients compared with SMA treatment (Figures 30B and 30C) versus no SMA treatment (Figure 30A) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®).

[0049] [Figure 31A] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31B] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31C] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31D] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31E]The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31F] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31G] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®). [Figure 31H] The long-term changes in several gait quality variables when comparing two SMA patients with SMA treatment (Figures 31E-31H) versus no SMA treatment (Figures 31A-31D) according to several embodiments are shown. The administered SMA therapy was nusinersen (Spinraza®).

[0050] [Figure 32] A table showing the optimal current values ​​and lead configurations for various SMA patients is provided.

[0051] [Figure 33] A table of discomfort scores for each SCS stimulation configuration, as provided by various SMA patients, is shown.

[0052] [Figure 34] Web plots are used to show the percentage increase in absolute torque at all assessed joints over the course of the study for two SMA patients, compared to pre-study assessments during isometric tasks.

[0053] [Figure 35] This shows the torque generated by the first SMA patient during maximum isometric contraction for various movements.

[0054] [Figure 36] This shows the torque generated by a third SMA patient during maximum isometric contraction for various movements.

[0055] [Figure 37A] This paper shows the joint angles with and without SCS at various time points in three different SMA patients, as well as the gait cycle profiles of range of motion. [Figure 37B] This paper shows the joint angles with and without SCS at various time points in three different SMA patients, as well as the gait cycle profiles of range of motion.

[0056] [Figure 38] The table shows hip and knee joint range of motion (ROM) for three SMA subjects before versus after the study, and with or without SCS. The before-to-post comparison is at week 4 compared to baseline (or week 3 for SMA01).

[0057] [Figure 39] This paper presents a z-score analysis related to performing spinal fMRI during activity in various SMA patients.

[0058] [Figure 40] Using web plots, we show the percentage change in the inter-peak amplitude of MEP in various SMA patients after the procedure (or at 4 weeks for SMA01) compared to pre-implantation during resting TMS for all participants and all muscles at 100% TMS pulse intensity.

[0059] [Figure 41] The TMS recruitment curves for the second SMA patient are shown before implantation, at week 3 of the study, and after explantation.

[0060] [Figure 42]The TMS recruitment curves for SMA03 are shown before implantation, at week 3 of the study, and after explantation.

[0061] [Figure 43A] The bar graphs show the number of units, innervation area, and peak firing rate of single MN discharges from surface EMG signals during isometric maximal voluntary contraction in three SMA patients as part of isometric knee extension movement. [Figure 43B] The bar graphs show the number of units, innervation area, and peak firing rate of single MN discharges from surface EMG signals during isometric maximal voluntary contraction in three SMA patients as part of isometric knee extension movement. [Figure 43C] The bar graphs show the number of units, innervation area, and peak firing rate of single MN discharges from surface EMG signals during isometric maximal voluntary contraction in three SMA patients as part of isometric knee extension movement.

[0062] [Figure 44] This chart shows the long-term changes in isometric maximum torque measurements generated by left and right hip flexion in SMA patients SMA01 and SMA02. Negative numbers indicate sessions before implantation, numbers without (-) or (+) indicate sessions during the study (with implantation), and numbers with (+) indicate sessions after explantation.

[0063] [Figure 45] The table shows fatigue values ​​for three SMA patients before, during, and after the study, measured in relation to speed on the final lap of a 6MWT compared to the first lap.

[0064] [Figure 46] The graph shows the lap-by-lap speed for three SMA patients in a 6MWT (6-minute walk test).

[0065] [Figure 47]The table shows the distance traveled by three SMA patients during a 6MWT with SCS off in different sessions, specifically comparing pre-implantation distance, end-of-study distance, and follow-up distance. The numbers in parentheses represent the change in vapserin.

[0066] [Figure 48] The graph shows the improvement in the 6MWT for three SMA patients, plotted against each patient's HFMSE score at the start of the study. The value "38" refers to the initial HFMSE score for SMA02; "49" for SMA03; and "60" for SMA01.

[0067] [Figure 49A] Various plots of step height, step length, and walking speed are shown to provide an overview of the changes in gait in three SMA patients during the course of the study. [Figure 49B] Various plots of step height, step length, and walking speed are shown to provide an overview of the changes in gait in three SMA patients during the course of the study. [Figure 49C] Various plots of step height, step length, and walking speed are shown to provide an overview of the changes in gait in three SMA patients during the course of the study.

[0068] [Figure 50] The TMS recruitment curves for the first SMA patient before implantation and at the end of the study are shown.

[0069] [Figure 51A] This is a trace of the single-unit motor neuron firing rate during maximal voluntary contraction of the right knee of SMA03 under isometric conditions, before and after the study. [Figure 51B] This is a trace of the single-unit motor neuron firing rate during maximal voluntary contraction of the right knee of SMA03 under isoangular conditions with stimulus on versus stimulus off.

[0070] [Figure 52A]For each of the three patients, we present a quantitative analysis of the mean peak firing rate across all isoangular conditions, both before and after the procedure. [Figure 52B] For each of the three patients, we present a quantification of the mean peak firing rate across all isoangular conditions for stimulus on versus stimulus off. [Modes for carrying out the invention]

[0071] Detailed explanation I. Introduction Methods for treating subjects with SMA are provided herein. As will be discussed in detail herein, motor impairment due to SMA in a subject is treated by applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject with SMA-related motor impairment via one or more electrodes controlled by a neurostimulator. Though not bound by theory, the application of electrical stimulation to sensory neurons is thought to directly mobilize monosynaptic and polysynaptic excitation pathways in the spinal cord, which in turn increases the membrane potential and firing rate probability of spinal MNs innervating a body region of the subject with SMA-related motor impairment. This mobilization of pathways may increase neuronal plasticity and allow the subject to recover motor function. Furthermore, in some embodiments, applying a therapeutically effective amount of electrical stimulation to a subject over time (e.g., at least 2 hours / day for a period of at least 6 months, or at least 1 hour / day for a period of at least 1 month) may result in ion channel remodeling on the MN membrane, a sustained increase in the firing rate probability of spinal MNs, and improvement of motor impairment, even without stimulation. In some embodiments, treatment of SMA includes treatment with neuromuscular stimulation combined with a nerve repair agent. In some embodiments, the nerve repair agent is a gene therapy, such as onasemnogene abeparvovec, nusinersen, or risdipram. In some embodiments, the agent is risdipram.

[0072] Therefore, in one embodiment, therapeutic electrical stimulation may be applied to a subject by implanted or percutaneous placement of electrodes under the control of an implanted or external nerve stimulator. Both the electrodes and the nerve stimulator comprise a system that delivers SCS to a subject to improve motor impairments resulting from SMA, such as muscle weakness, muscle control, and / or speech disorders. This system may be used in combination with other SMA therapies, such as targeted exercise rehabilitation, to improve patient outcomes.

[0073] The application of SCS to SMA patients yielded unexpected results, given the unique pathophysiology of SMA. As mentioned earlier, SMA differs from other types of motor disorders, such as those caused by spinal cord injury or stroke, in that a non-functioning MN is the underlying cause of the SMA-related impairment. Therefore, SCS, which aims to increase excitatory input to the spinal cord MN, is not expected to produce the same effects in SMA patients as is observed in other conditions treated with SCS, such as spinal cord injury, stroke, and pain, where the MN is still functioning.

[0074] However, as discussed below, both significant immediate and long-term effects of SCS have been observed in SMA patients treated in accordance with this disclosure. Unexpectedly, the magnitude of the immediate effect of SCS in SMA patients is at least more dramatic than that observed in patients with stroke and spinal cord injury. As will be described in detail below, the magnitude of the end-of-study effects observed after just four weeks of treatment relating to this disclosure is even more remarkable (e.g., MN excitability, MN firing rate, torque generated at different leg joints, EMG signal, maximal voluntary contraction during knee extension and / or hip flexion, hip flexion during movement, balance, transition from sitting to standing, maximum running speed, range of motion, muscle strength (manual muscle testing), gait (6-minute walk test), motor capacity (Hammersmith Functional Motor Scale Expanded test and Revised Hammersmith Scale test), and measurements related to leg circumference). Specifically, the improvement in muscle strength is so large that it cannot be attributed solely to exercise. For example, in one experiment, left hip flexion more than doubled in SMA patients even though subjects did not perform any hip strength training other than walking during the study. The participants' exercise levels did not change from their pre-study levels. These changes are also reflected in the improvements observed in clinical outcome tests such as manual muscle testing, the Revised Hammersmith Scale (RHS) test, and the 6-minute walk test. Furthermore, the data did not indicate a plateau, suggesting that longer use of the SCS may lead to even greater improvements in SMA patients.

[0075] Over a 50+ day period after the removal of SCS, the long-term effects of SCS varied among SMA patients. Patients treated with SCS rather than SMA therapies such as nerve repair agents to increase SMN protein production (e.g., onasemnogene abeparvovec, nusinersen, or risdipram) experienced a gradual decline in certain motor metrics (e.g., measurements related to torque generated at different leg joints, locomotion, and gait). Conversely, patients treated with SMA therapy in conjunction with SCS did not experience a decline in these locomotion metrics. Neither group of patients experienced a decline in some clinical outcome metrics (e.g., RHS test), and one group of SMA patients treated with SMA therapy experienced an increase in RHS metrics despite not being treated with SCS within 50+ days. In summary, the data suggest that SMA patients treated with SMA therapy in conjunction with SCS may experience longer-term benefits from SCS than patients treated with SCS alone. In some embodiments, the SMA therapy used in combination with SCS is onasemnogene abeparvovec, nusinersen, or risdipram. In some embodiments, the SMA therapy is nusinersen or risdipram. In further embodiments, the SMA therapy is risdipram.

[0076] By applying SCS according to some embodiments of this disclosure, the activity of the same sensory afferent fibers (e.g., Ia) affected by SMA can be artificially increased. This may have immediate effects (stimulus on vs. stimulation off during the study) and long-term effects (stimulus off before the study vs. stimulation off after the study) in patients with SMA. Although not bound by any particular theory, SCS can immediately increase excitatory input to MNs, and therefore their firing rate. This may immediately improve motor impairment. In the long term, the artificial increase in sensory afferent activity may enhance the affected sensory synapses, reverse maladaptive changes in MN ion channels, and thereby improve MN dysfunction that results in measurable changes in motor function. Thus, SCS can address motor deficits resulting from reduced presynaptic activity of sensory afferent fibers.

[0077] In some embodiments, SCS may be combined with pharmaceutical interventions designed to halt disease progression, such as drug therapy to increase SMN protein production. In embodiments, the drug therapy includes onasemnogene abeparvovec, nusinersen, or risdipram. In some embodiments, the drug therapy is nusinersen or risdipram. In further embodiments, the drug therapy is risdipram. II.Acronyms CST corticospinal tract DRG (Dorsal Root Ganglion) EMG (Electromyography) Test MN: motor neuron SCS (Spinal Cord Stimulation) SMA (Spinal Muscular Atrophy) SMN1 Survival Motor Neuron 1 TMS (Transcranial Magnetic Stimulation)

[0078] III. Overview of Terminology Unless otherwise specified, technical terms are used in accordance with their conventional usage. As used herein, the term “comprises” means “includes.” Many methods and materials similar or equivalent to those described herein may be used, but specific suitable methods and materials are described below. To facilitate consideration of various embodiments, the following definitions of terms are provided.

[0079] Approximately: As used herein, the term “approximately” refers to an approximation of a qualitative or quantitative measurement. Whether a measurement is qualitative or quantitative should be clear from the context. With respect to quantitative measurements, “approximately” refers to ±5% of a baseline value. For example, “approximately” 100mA refers to a range of 95mA to 105mA.

[0080] Posterior aneurysms: Small branches of sensory neuron roots that emerge from the posterior spinal cord and migrate to the dorsal root ganglia.

[0081] Posterolateral spinal cord: The region on the outer surface of the spinal cord located between the dorsal midline and the point where the posterior roots enter the main spinal cord.

[0082] Electrical stimulation: The selective application of various types of electrical currents to a target location within an object (e.g., a specific region of the dorsolateral spinal cord) through one or more electrodes.

[0083] Electrodes: Conductors through which electric current can pass. Electrodes may be collectors and / or emitters of current. In some embodiments, electrodes are solid and comprise a conductive metal as a conductive layer. Non-limiting examples of conductive metals include noble metals or heat-resistant metals and alloys such as stainless steel, tungsten, platinum, iridium, tantalum, titanium, titanium nitride, and niobium. Electrodes may be interconnected or wired independently.

[0084] End-of-study effect: A medium-term effect induced by SCS. Also known as the "post-study effect." As used herein, "end-of-study" may refer to the effect measured around the time the SCS electrodes were removed, within approximately one week before or after the end of the 4-week study.

[0085] Immediate effect: An immediate (e.g., same-day) effect induced by SCS. Also known as a “supplementary effect.” To measure the immediate / supplementary effect of SCS, the experiment is repeated with and without SCS at short intervals. As used herein, “immediate” may refer to the effect measured during a 4-week study with respect to the use of SCS.

[0086] Implantation: For example, surgical techniques are used to fully or partially place an electrode, or a device containing an electrode, within a subject. A device is partially implanted when a portion of the device reaches or extends outside the subject. Implantable electrodes and devices can be implanted epidurally in the spinal cord, such as on the posterior lateral surface of the spinal cord. Electrodes or devices can be implanted for a variety of durations, such as short-term (e.g., one or two days or less) or long-term or long-lasting (e.g., one month, six months, one year or more), as daily assistive devices.

[0087] Long-term effects: Long-term effects (e.g., over a period of several months) induced by SCS. Also known as “therapeutic effects.” Where used herein, “long-term” may refer to effects measured 50 days after electrode removal. Long-term effects of SCS can be identified based on changes that occur over time in the intrinsic motor capacity of the SCS subject. These changes indicate the disease-modifying effects of SCS, are measured when SCS is off, and thereby reflect true changes in motor control.

[0088] Motor impairment: Partial or total loss of function in body parts, such as the legs, feet, arms, hands, fingers, neck, and torso (e.g., respiratory muscles). Specific motor impairments include loss of muscle strength, partial paralysis (incomplete paralysis), loss of dexterity (such as finger movements), and uncontrolled muscle tone. Patients may present with multiple motor impairments as comorbidities of SMA.

[0089] Motor threshold: The minimum thalamic stimulation intensity at which a given amplitude of motor output can be produced from resting muscle (RMT) or during muscle contraction (AMT).

[0090] Nerve stimulator: A current or voltage-controlled electrical stimulator. A nerve stimulator controls the delivery of an electrical pulse or 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, pulse width, and on-time and off-time. The controlled electrical pulse is delivered via one or more electrodes (e.g., leadless electrodes, or electrodes located at the ends of leads, thin insulated wires) configured to apply the electrical stimulation to the target tissue of the subject. A nerve stimulator may have at least one multi-contact lead. A nerve stimulator may be used to apply a series of electrical pulse stimuli (e.g., charge equilibrium pulses) via at least one electrode, for example, but not limited to, low-frequency pulse train patterns, frequency-sequenced pulse burst train patterns (e.g., different sequences of modulated electrical stimulation are generated at different burst frequencies), and phase train patterns (e.g., stimulation control parameters change over the course of feedback from the subject's movement).

[0091] Perceptual threshold: The minimum electrical stimulation intensity required for a conscious person to notice a specific sensation caused by electrical stimulation.

[0092] Sensory neurons: Also known as afferent neurons, sensory neurons are nerve cells in the peripheral nervous system that convert stimuli from the environment into internal electrical impulses and transmit these impulses to the central nervous system.

[0093] SMA therapy: nerve repair agents, drug therapies, and / or gene therapies (e.g., onasemnogene abeparvovec, nusinersen, or risdipram) to increase SMN protein production. SMA therapy may be administered to a subject before, during, and / or after administering a stimulus to the subject. In some specific embodiments, SMA therapy is nusinersen, or risdipram, or more specifically, risdipram.

[0094] 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.

[0095] Subjects: A category including living multicellular vertebrate organisms, non-human primates, rats, mice, guinea pigs, cats, dogs, cattle, horses, and other human and non-human mammals. Therefore, the term "subjects" includes both human and veterinary subjects. The term "biomarker" may be used interchangeably with the term "marker" in this specification.

[0096] Therapeutic effective dose: The amount of compound or treatment (or both) sufficient to produce a beneficial or therapeutic effect on a subject or a given proportion of subjects. The therapeutic effective dose of a particular compound or treatment can be determined in many different ways, such as by assaying for reduction of disease or symptoms (e.g., motor impairment caused by SMA). Therapeutic compounds and treatments may be administered in a single application or in several applications (e.g., chronically over an appropriate period of time). However, the effective dose may depend on the source of application, the subject being treated, the severity and type of symptoms being treated, and the mode of treatment.

[0097] Percutaneous placement: For example, placing electrodes, or devices containing electrodes, on or near the skin surface of a target using non-invasive techniques. Electrodes may be attached to the skin surface of a target to apply electrical stimulation, for example, under the control of an external nerve stimulator. Electrodes or devices can be placed percutaneously for various periods, such as short-term (e.g., one or two days or less) or long-term (e.g., one month, six months, one year or more), as daily auxiliary devices.

[0098] Treatment / Cure: With respect to a disease or symptom (e.g., SMA), any of the terms include one or more of the following: (1) preventing the disease or symptom, e.g., preventing the development of the clinical symptoms of the disease or symptom in a person who may be exposed to or predisposed to the disease or symptom but has not yet experienced or shown any symptoms of the disease or symptom; (2) inhibiting the disease or symptom, e.g., stopping the development of the disease or symptom or its clinical symptoms; and (3) reducing the disease or symptom, e.g., causing regression of the disease or symptom or its clinical symptoms.

[0099] More specifically, treating or managing SMA results in at least one of the following beneficial effects: reduced muscle strength loss, increased muscle strength, reduced muscle atrophy, reduced loss of motor function, reduced contractures, increased muscle mass (MN), reduced loss of MN, SMN deficiency, protection from MN degeneration, increased motor function, increased lung function, reduced loss of lung function, and / or increased quality of life.

[0100] More specifically, treating or managing SMA means the functional ability or retention of the ability of a human infant or toddler to perform certain movements such as sitting without assistance, or the functional ability or retention of the ability of a human infant, toddler, child or adult to perform certain movements such as standing up without assistance, walking without assistance, running without assistance, breathing without assistance, turning over in sleep without assistance, or swallowing without assistance.

[0101] IV. Stimulation of sensory neurons to treat SMA Methods for treating subjects (e.g., human subjects) with SMA are provided herein. These methods may be used to treat (i.e., prevent, improve, suppress, and / or alleviate) motor impairments caused by SMA in subjects. The methods include applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of a subject with motor impairments caused by SMA. The electrical stimulation may be applied using one or more electrodes controlled, for example, by a nerve stimulator.

[0102] In one embodiment, applying electrical stimulation to sensory neurons increases the firing probability of spinal cord MNs innervating body regions of a subject with motor impairment due to SMA. While not theoretically bound, it is thought that applying electrical stimulation to sensory neurons may directly recruit monosynaptic and polysynaptic excitation pathways in the spinal cord, which may indirectly increase the membrane potential and firing probability of spinal cord MNs innervating body regions of a subject with motor impairment due to SMA. This recruitment of pathways may increase neuronal plasticity and enable the subject to recover motor function.

[0103] Any suitable subject with or at risk of motor impairment due to SMA can be treated by the method provided herein. Motor impairment may be located in the limbs of the upper or lower body, including above or below the elbow, above or below the knee, or the entire arm or leg. Subjects may have any of SMA types 1-4, such as type 1, type 2, type 3, or type 4. In some embodiments, subjects with SMA are selected for treatment. The method can be initiated at any point after the onset of motor impairment in the subject, or before detectable motor impairment in SMA patients at risk of motor impairment.

[0104] By applying a therapeutically effective dose of electrical stimulation to a subject with SMA, at least one motor impairment caused by the SMA in the subject is treated. For example, the application of a therapeutically effective dose of electrical stimulation may result in a reduction in muscle strength loss, an increase in muscle strength, a reduction in muscle atrophy, a reduction in motor function loss, an increase in motor function, an increase in lung function, and / or a reduction in lung function loss.

[0105] In some embodiments, the motor impairment includes a reduction in control of a limb (such as an arm or leg), and the methods provided herein increase control of the limb in question 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 appropriate assessment metric such as balance or strength metrics (e.g., sensory tissue tests).

[0106] In some embodiments, the motor impairment includes a decrease in postural balance and stability, and the methods provided herein increase the postural balance and stability of the subject 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 appropriate assessment metric such as balance or strength metrics (e.g., sensory tissue tests).

[0107] In some embodiments, the motor impairment includes a reduction in leg torque, and the methods provided herein increase the target 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.

[0108] One or more electrodes may be positioned at any suitable location for applying electrical stimulation to the target sensory neurons. In some embodiments, one or more electrodes are positioned to deliver electrical stimulation to one or more sensory neurons innervating a body region with motor impairment.

[0109] A spinal cord stimulation (SCS) system may comprise a nerve stimulator and one or more spinal cord leads equipped with multiple electrodes or contacts. The contacts of the SCS system can target specific muscles. For example, a contact located near spinal cord segment L2 may target the hip flexor muscles, while a contact located near spinal cord segment S1 may target the gluteal and ankle extensor muscles. Therefore, the location of the contacts or electrodes can be selected to selectively target specific nerves innervating the affected muscles in SMA. For example, if a human subject has significant deficits in the knee extensor and hip flexor muscles, the stimulation system can be positioned to selectively target these muscles. Furthermore, it may be advantageous or desirable to avoid stimulating specific nerves to avoid adverse events. For example, one or more electrodes encompassing multiple nerves, including those innervating muscles that are not affected or have only a very low level of motor impairment, can be implanted. Stimulating muscles that are not affected or have only a low level of motor impairment can be unpleasant or harmful. Therefore, in some embodiments, the number of sensory neurons stimulated is less than the number encompassed by the electrode implant. In other words, one or more electrodes are implanted in an object that spans multiple sensory neurons, but not all of those sensory neurons are stimulated.

[0110] In some embodiments, the placement of SCS can be optimized and fine-tuned by stimulating various contact points in a SMA patient, measuring electrical activity such as electromyographic (EMG) signals generated by muscles (e.g., agonist and antagonist muscles of each joint), and evaluating the measurements. In one example, during surgery, electrode placement is determined by stimulating each contact point and recording EMG signals from muscles ranging from the trunk to the ankle. Stimulation of a particular contact point may begin at a low frequency (e.g., about 1 Hz), and the amplitude of the stimulation is gradually increased until electrical activity associated with muscle activity in response to the stimulation is recorded. Based on the recorded electrical activity, specific muscles targeted by a particular contact point can be identified, and thus the stimulated contact point can be identified as a suitable location 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 location of the muscle. For example, rostral contact points may generate their first waveforms in the hip flexor muscles, while caudal contact points may generate their first waveforms in the calf muscles. The stimulation may be repeated until a location is identified where the electrodes are activated, for example, from the hip muscles that make the most rostral contact to the calf muscles that make the most caudal contact. In other words, the lead positions can be fixed when the multiple contacts of the SCS system completely cover the leg muscles (e.g., from the hip to the ankle) for the purpose of performing SCS. In some embodiments, the identified locations can be used in a second SMA patient exhibiting similar symptoms without performing the above test on the second SMA patient. In some embodiments, the above test is performed during surgery to implant the electrodes.

[0111] In some embodiments, the body region of the subject with motor impairment is selected from the hip, hip, leg, ankle, and foot. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of the T11-S1 nerve roots. For example, one or more electrodes may be implanted in the sensory nerve or DRG, or they may be implanted epidurally on the posterior aneurysm or posterolateral surface of the spinal cord for one or more sensory neurons of the T11-S1 nerve roots. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of the L1-T11 nerve roots. In some embodiments, electrical stimulation is applied to fewer neurons than those covered by the positioning of one or more electrodes. Therefore, for example, in some embodiments, electrical stimulation is applied to the T11-S1 nerve root or a subset thereof, such as the T12-S1, L1-S1, L2-S1, L3-S1, L4-S1, L5-S1, T11-L5, T12-L5, L1-L5, L2-L5, L3-L5, L4-L5, T11-L4, T12-L4, L1-L4, L2-L4, L3-L4, T11-L3, T12-L3, L1-L3, L2-L3, T11-L2, T12-L2, L1-L2, T11-L1, or T12-L1 nerve roots. In some embodiments, electrical stimulation is applied to the L1-S2 nerve roots or a subset thereof, such as L1-S1, L1-L5, L1-L4, L1-L3, L2-S2, L3-S2, L4-S2, L5-S2, L2-S1, L2-L5, or L2-L4 nerve roots. In certain embodiments, electrical stimulation is applied to the L1-S2 nerve roots. In some embodiments, two or more nerve roots selected from the group consisting of T11, T12, L1, L2, L3, L4, L5, and S1 are stimulated independently. In some embodiments, three or more nerve roots selected from the group consisting of T11, T12, L1, L2, L3, L4, L5, and S1 are stimulated independently. In some embodiments, four or more nerve roots selected from the group consisting of T11, T12, L1, L2, L3, L4, L5, and S1 are stimulated independently. In some embodiments, the subjects are also given SMA therapy such as onasemnogene abeparvovec, nusinersen, or risdiplam.In some embodiments, the SMA therapy is nusinersen or risdiplam. In further embodiments, the SMA therapy is risdiplam.

[0112] In some embodiments, the body region of the subject with motor impairment is selected from the upper arm, shoulder, arm, hand, and respiratory muscles (such as intercostal muscles or diaphragm). In some embodiments, the muscles are selected from the deltoid, biceps, triceps, and wrist extensor flexors of the arm. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of the C3-T2 nerve root. For example, one or more electrodes may be implanted in the sensory nerve or DRG, or they may be implanted epidurally on the posterior aneurysm or posterolateral surface of the spinal cord for one or more sensory neurons of the C3-T2 nerve root.

[0113] In some embodiments, the body region of the subject with motor impairment is selected from the upper arm, shoulder, arm, hand, and respiratory muscles (such as intercostal muscles or diaphragm). In some embodiments, the muscles are selected from the deltoid, biceps, triceps, and wrist extensor flexors of the arm. In certain embodiments, the respiratory muscles (such as intercostal muscles or diaphragm) are not specifically stimulated. In such embodiments, one or more electrodes are implanted in the epidural space of the C4-T1 vertebrae to apply electrical stimulation to one or more sensory neurons present in that space. In some embodiments, the electrical stimulation is applied to the C4-T1 nerve root or a subset thereof, such as the C4-C8, C4-C7, C4-C6, C4-C5, C5-T1, C5-C6, or C6-T1 nerve roots. In some embodiments, two or more nerve roots are independently selected from the group consisting of C4, C5, C6, C7, C8, and T1. In some embodiments, three or more nerve roots are independently selected from the group consisting of C4, C5, C6, C7, C8, and T1. In some embodiments, the subject is also subjected to SMA therapy such as onasemnogene abeparvovec, nusinersen, or risdipram. In some embodiments, the SMA therapy is nusinersen or risdipram. In further embodiments, the SMA therapy is risdipram.

[0114] In some embodiments, the body region of the subject with motor impairment is selected from the chest, chest wall, abdomen, upper back, and mid-back. In such embodiments, one or more electrodes are positioned to apply electrical stimulation to sensory neurons, such as sensory neurons of the T3-T10 nerve roots. For example, one or more electrodes for sensory neurons of the T3-T10 nerve roots may be implanted in the sensory nerve or DRG, or implanted epidurally on the posterior aneurysm or posterolateral surface of the spinal cord. In some embodiments, electrical stimulation is applied to the T3-T10 nerve roots or a subset thereof, such as T3-T9, T3-T8, T3-T7, T3-T6, T3-T5, T3-T4, T4-T10, T4-T9, T4-T8, T4-T7, T4-T6, T4-T5, T5-T10, T5-T9, T5-T8, T5-T7, T5-T6, T6-T10, T6-T9, T6-T8, T6-T7, T7-T10, T7-T9, T7-T8, T8-T10, T8-T9, or T9-T10 nerve roots. In some embodiments, two or more nerve roots selected from the group consisting of T3, T4, T5, T6, T7, T8, T9, and T10 are stimulated independently. In some embodiments, three or more nerve roots selected from the group consisting of T3, T4, T5, T6, T7, T8, T9, and T10 are stimulated independently. In some embodiments, four or more nerve roots selected from the group consisting of T3, T4, T5, T6, T7, T8, T9, and T10 are stimulated independently. In some embodiments, the subject is also subjected to SMA therapy such as onasemnogene abeparvovec, nusinersen, or risdiplam. In some embodiments, the SMA therapy is nusinersen or risdiplam. In further embodiments, the SMA therapy is risdiplam.

[0115] In some embodiments, the body region of the subject with motor impairment is selected from the trunk, back, and upper limbs. This may include, for example, the chest, chest wall, abdomen, upper back, mid-back, upper arm, shoulder, arm, and hand. In some embodiments, the muscles are selected from the deltoid, biceps, triceps, and wrist extensor flexors of the arm. In certain embodiments, one or more electrodes are implanted in the epidural space of the vertebrae from C4 to T1 to apply electrical stimulation to one or more sensory neurons present in that space. For example, in some embodiments, one or more C5-T1 nerve roots such as C5-C6, C5-C7, C5-C8, C6-T1, C6-C7, C6-C8, C7-T1, or C7-C8, C8-T1 are stimulated. In some embodiments, C5-T2 nerve roots such as C5-T2, C6-T2, C7-T2, C8-T2, or T1-T2 are stimulated. In some embodiments, two or more nerve roots are independently selected from the group consisting of C4, C5, C6, C7, C8, T1, and T2. In some embodiments, two or more nerve roots are independently selected from the group consisting of C5, C6, C7, C8, T1, and T2. In some embodiments, two or more nerve roots are independently selected from the group consisting of C5, C6, C7, C8, and T1. In some embodiments, for each electrode, the stimulation amplitude is 0.2 to 10 mA. The stimulation frequency is between 0.1 and 500 Hz, and the pulse width is 100 to 400 μs. In some embodiments, the subject is also subjected to SMA therapy such as onasemnogen abeparvovec, nusinersen, or risdiplam. In some embodiments, the SMA therapy is nusinersen or risdiplam. In further embodiments, the SMA therapy is risdiplam.

[0116] In some embodiments, the placement of electrodes during surgery can be adjusted to account for postoperative electrode movement. Such postoperative movement is variable and may be difficult to avoid with non-permanent implants. For example, electrodes may move caudally and shift medially. Therefore, based on the predicted postoperative movement of the electrodes, the electrodes may be implanted in a position adjusted during surgery so that the electrodes move to a predetermined optimal position postoperatively. Further details regarding devices and surgical procedures that can be used to acquire chronic electromyography (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.

[0117] Any suitable stimulation pattern may be used to treat the motor impairment of the subject. In some embodiments, the electrical stimulation includes an electrical pulse defined by parameters including, but not limited to, amplitude, pulse width, and pulse frequency. Such an electrical pulse may include a charge equilibrium pulse, such as a cathode first two-phase pulse or a single-phase charge equilibrium pulse. In these and further embodiments, the electrical stimulation may be a continuous electrical stimulation or a periodic stimulation.

[0118] The stimulation parameters of the SCS can be configured according to the techniques and values / ranges described herein. In one example, the electrical stimulation can be configured to include 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 / 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. In some embodiments, for each electrode, the stimulation amplitude is 0.2 to 10 mA, the stimulation frequency is between 0.1 and 500 Hz, and the pulse width is 100 to 400 μs.

[0119] In certain examples, the electrical stimulation includes electrical pulses having amplitudes of approximately 10 μA to 50 mA, such as approximately 10 μA to 10 mA, approximately 10 μA to approximately 1 mA, approximately 10 μA to approximately 100 μA, or approximately 100 μA to approximately 1 mA.

[0120] In certain cases, electrical stimulation lasts approximately 40 μs to 2 ms, for example, 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, 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 Includes electrical pulses having pulse widths of s~1.5ms, 600μs~1.5ms, 700μs~1.5ms, 800μs~1.5ms, 800μs~1.5ms, 900μs~1.5ms, 1ms~1.5ms, 1.5ms~2ms, 80μs~1ms, 100μs~1ms, 200μs~1ms, 300μs~1ms, 400μs~1ms, 500μs~1ms, 600μs~1ms, 700μs~1ms, 800μs~1ms, 800μs~1ms, and 900μs~1ms.

[0121] In certain cases, electrical stimulation includes pulse frequencies ranging from approximately 10 Hz to approximately 2000 Hz, for example, 20 Hz to 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.

[0122] In some embodiments, the electrical stimulation includes an electrical pulse having an amplitude of 10 μA to about 50 mA, a pulse width of about 40 μs to about 2 ms, and a pulse frequency of about 10 Hz to about 2000 Hz. In some embodiments, the electrical stimulation includes an electrical pulse having an amplitude of 10 μA to about 10 mA, a pulse width of about 40 μs to about 2 ms, and a pulse frequency of about 10 Hz to about 1000 Hz. In some embodiments, the electrical stimulation includes an electrical pulse having an amplitude of 100 μA to about 10 mA, a pulse width of about 40 μs to about 500 μs, and a pulse frequency of about 10 Hz to about 1000 Hz.

[0123] In some embodiments, bipolar and / or tripolar stimulation may be used. In some embodiments, the spinal cord is stimulated using bipolar stimulation at the two rostral contacts of the right lead, for example, to target the muscles of the right leg. In some examples, the electrical stimulation includes an electrical pulse having an amplitude of about 2 mA, a pulse width of about 400 μs, and a pulse frequency of about 40 Hz.

[0124] In some embodiments, tripolar stimulation is used, for example, to target the muscles of the left leg. In some examples, the electrical stimulation includes an electrical pulse having an amplitude of approximately 3.7 mA, a pulse width of approximately 400 μs, and a pulse frequency of approximately 40 Hz.

[0125] In some embodiments, the electrical stimulation includes an electrical pulse 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 includes an electrical pulse 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 include an electrical pulse 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.

[0126] Electrical stimulation may be applied to the subject for any appropriate time necessary to achieve a positive functional benefit for the patient. In some embodiments, the electrical stimulation includes a series of 2 to 5 pulses separated by pulse intervals of approximately 3 ms to approximately 10 ms, and this series of pulses is repeated at a frequency of approximately 10 Hz to approximately 100 Hz. In some embodiments, the electrical stimulation is applied for at least 1 hour / day over a period of at least 1 month. In some embodiments, the electrical stimulation is applied for at least 2 hours / day over a period of at least 6 months.

[0127] In certain embodiments, the stimulus is applied below the motor threshold and / or the perceptual threshold of the target. For example, the stimulus may be applied below both the motor threshold and the perceptual threshold, below the motor threshold but above the perceptual threshold, or below the perceptual threshold but above the motor threshold.

[0128] The SCS system can be configured to provide an electrospinal stimulation protocol that enables control of the degree of muscle extension and flexion of its limbs, e.g., each leg during movement, as well as gait kinematics and gait performance in real time, within a few days. In some embodiments, the subject may be monitored and tested to establish the parameters of the electrical stimulation based on the subject's motor abnormalities and motor impairments, for example, by monitoring one or more motor outputs that give a measure of the degree of motor impairment and the subject's response to stimulation. In some embodiments, electrical stimulation via 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 impairment, e.g., a forelimb task (e.g., reaching, grasping, pinching with opposing thumbs, gripping, fine motor work with precise finger movements) or a lower limb task (e.g., walking, jumping, leg extension).

[0129] Once configured, the stimulation bursts are delivered across specific spinal cord locations at precise timings that replicate the natural spatiotemporal activation of the moving MN. These protocols can also be readily adapted, as described below, to safely implant the system near the spinal cord and to provide an SCS including real-time motion feedback and a closed-loop controller. In some embodiments, the parameters of the electrical stimulation controlled by the neurostimulator are adjusted according to changes in one or more motor outputs monitored while the subject is performing a specific task, for example, to improve motor output and thereby treat a motor impairment of the subject. In certain embodiments, the adjusted neurostimulator is part of a daily auxiliary device for treating the subject over a long period. In certain embodiments, once the subject is released from clinical practice, the operation of the device and / or neurostimulator may be at least partially under the subject's control. In these and further embodiments, the subject is taught how to use the device and / or neurostimulator. In some non-limiting embodiments, this treatment may increase the input to the membrane of spinal cord MNs by direct recruitment of sensory afferent nerves from electrical pulses, or induce ion channel remodeling on the MN membrane to increase the firing rate probability of spinal cord MNs and / or improve motor impairment caused by SMA, including when electrical stimulation is no longer applied to the patient. Accordingly, this disclosure includes a method for increasing the firing rate of motor neurons impaired by SMA.

[0130] Stimulation of sensory afferent nerves using implanted electrodes is an advanced neurosurgical procedure involving the implantation of one or more electrodes that deliver electrical stimulation under the control of an external or implanted nerve stimulator unit. Implantation of electrodes and / or nerve stimulators in cases where the nerve stimulator is not external is typically performed by a clinical team including a neurologist, neurosurgeon, neurophysiologist, and other specialists trained in the assessment, treatment, and care of neurological symptoms. Typically, precise placement of at least one electrode within the patient's sensory afferent nerve region (such as the posterior-lateral surface of the spinal cord), following selection of an appropriate subject and determination of the target area of ​​the subject to be stimulated, is performed in an operating room setting, typically utilizing spinal imaging techniques. After administration of local anesthesia, the subject receiving electrode implantation experiences little to no discomfort and may remain awake during the implantation procedure to allow communication with the surgical team.

[0131] Some embodiments of this specification use an implant comprising one or more electrodes and / or nerve stimulators embedded in a target (e.g., completely or partially). Further embodiments of this specification use an implant comprising one or more magnets or optical fibers and / or nerve stimulators embedded in a target.

[0132] Numerous types and styles of implants (e.g., implants including one or more electrodes for providing electrical stimulation) are available and known to those skilled in the art. Any implant for specific stimulation of sensory neurons in a subject may be used in particular embodiments. In some embodiments, two or more electrodes, such as an array of electrodes, are implanted. Additional embodiments provide devices that may include one or more electrodes. Non-limiting examples include arrays of electrodes, through-microarrays (e.g., Utah and Michigan microarrays), microwire electrodes and arrays, nerve cuffs, and paddle arrays.

[0133] In some embodiments, one or more electrodes are implanted in the posterior root of one or more sensory neurons innervating the body region of the subject with motor impairment. In some embodiments, one or more electrodes are implanted in the posterolateral surface of the spinal cord adjacent to the posterior root of one or more sensory neurons innervating the body region of the subject with motor impairment. In some embodiments, one or more electrodes are implanted in the posterior root ganglion of one or more sensory neurons innervating the body region of the subject with motor impairment. In some embodiments, one or more electrodes are housed in a cuff surrounding or at least partially surrounding a peripheral nerve containing sensory neurons innervating the body region of the subject with motor impairment due to SMA. In further embodiments, one or more electrodes penetrate a peripheral nerve or posterior root ganglion containing sensory neurons innervating the body region of the subject with motor impairment due to SMA.

[0134] In some embodiments, epidural electrical stimulation (EES) targeting the posterior root filaments using an array of paddle electrodes is utilized in the manner disclosed, for example, as described by Rowald et al. 2022, Nat. Medicine, 28:260-271 and Wagner et al. 2018, Nature, 563:65-71, respectively, which are incorporated herein by reference. Additional non-limiting examples of paddle arrays and their uses are provided, for example, in U.S. Patent Application Publication No. 2009 / 0351221 and U.S. Patent Application Publication No. 2019 / 0366077, respectively, which are incorporated herein by reference.

[0135] In some embodiments, a circuit is embedded that connects a nerve stimulator to one or more electrodes. In certain embodiments, the circuit is either fully embedded (typically in a subcutaneous pocket within the subject's body) or partially embedded in the subject. The operable connection of the nerve stimulator to the electrodes may be by one or more leads, but any operable connection capable of transmitting stimulation signals from the circuit to the electrodes may be used in certain embodiments.

[0136] Electrical stimulation can be applied to a target using any suitable control system in conjunction with electrodes. Non-limiting examples of controllable nerve stimulation systems are provided in U.S. Patent Publication No. 2020 / 0254260, U.S. Patent Publication No. 2020 / 0360693, U.S. Patent Publication No. 2020 / 0360697, U.S. Patent Publication No. 2020 / 0152078, U.S. Patent No. 10,252,065, U.S. Patent No. 10,799,702, U.S. Patent Publication No. 2021 / 0016093, and U.S. Patent Publication No. 2020 / 0391030, each of which is incorporated herein by reference. Furthermore, non-limiting examples of closed-loop neural stimulation systems are provided in U.S. Patent Nos. 10,265,525, 10,279,167, 10,279,177, 10,391,309, 10,751,539, 10,981,004, and U.S. Patent Application Publication No. 2020 / 0147382, each of which is incorporated herein by reference.

[0137] Postoperative control of selective electrical stimulation by implanted electrodes is, in some embodiments, performed by a nerve stimulator that may be external or implanted subcutaneously (e.g., in the chest or abdomen of the subject). In some embodiments, the disclosed method is influenced by the use of an implantable nerve stimulator 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 a nerve stimulator comprise a daily assistive device to improve muscle weakness in the affected limb of the subject.

[0138] Following implantation, surgery, and recovery from connection of electrode leads to a nerve stimulator, the subject may be monitored and tested, for example, by monitoring one or more motor outputs that provide measures of the degree of motor impairment and the subject's response to stimulation, in order to establish parameters for electrical stimulation based on the subject's motor impairment. In some embodiments, electrical stimulation from implanted electrodes is delivered to the subject's sensory neurons while the subject performs voluntary activities or tasks affected by the subject's motor impairment, such as forelimb tasks (e.g., reaching, grasping, pinching with opposing thumbs, gripping, fine motor work involving precise finger movements) or lower limb tasks (e.g., walking, jumping, leg extension).

[0139] In some embodiments, a transcutaneous electrical stimulation system is used to apply electrical stimulation to the target sensory neuron. 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 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 10,000 Hz.

[0140] As described herein, the subjects may also be administered SMA therapy in conjunction with SCS. In some embodiments, the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdipram.

[0141] In some embodiments, subjects are administered onasemnogen abeparvovec. Onasemnogen abeparvovec, also known as ZOLGENSMA®, is approved only as a single-dose intravenous administration. Therefore, if subjects are administered SMA therapy in combination with the SCS described herein, and the SMA therapy is onasemnogen abeparvovec, a single dose of onasemnogen abeparvovec may be administered to the subject within 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months prior to the initiation of the SCS. For example, in some embodiments, onasemnogen abeparvovec was administered at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 24 months prior to the initiation of the SCS. In some embodiments, subjects were administered onasemnogen abeparvovec more than 24 months prior to the initiation of SCS, for example, more than 2, 3, 4, 5, or 6 years prior to the initiation of SCS. In this case, the initiation of SCS is the application of electrical stimulation and must also be performed, but does not constitute the initiation of SCS. Furthermore, in some embodiments, initiating SCS includes the initiation or first instance of electrical stimulation after implantation (e.g., stimulation that may occur during implantation to position the electrodes or to map their stimulation to nerve roots and / or muscle groups). In some embodiments, initiating SCS includes the initiation or first instance of electrical stimulation after implantation, according to a stimulation protocol administered or supervised by a physician. References to SCS in these embodiments may also be described as applying electrical stimulation to sensory neurons.

[0142] In some embodiments, subjects are administered nusinersen. Nusinersen, also known as SPINRAZA®, is approved for intrathecal administration in the United States according to a recommended administration schedule. It is initiated with four loading doses of 12 mg (5 mL) per dose, the first three of which are 14 days apart, followed by a fourth loading dose 30 days after the third loading dose, and then maintenance doses every four months thereafter. Therefore, if subjects are administered nusinersen in conjunction with SCS, the initiation of SCS can occur at any point during the nusinersen administration schedule. Thus, in some embodiments, SCS is initiated between the first and second nusinersen loading doses, between the second and third nusinersen loading doses, between the third and fourth nusinersen loading doses, or after the fourth loading dose. If the SCS is initiated after the fourth loading dose of nusinersen, the SCS may be initiated at any point in time, i.e., after the fourth loading dose but before the first maintenance dose, or during any subsequent maintenance dose. In this case, the initiation of the SCS is the application of electrical stimulation and must also involve the implantation of one or more electrodes, but does not constitute the initiation of the SCS. Furthermore, in some embodiments, initiating the SCS includes the initiation or first instance of electrical stimulation after implantation (e.g., not including stimulation that may occur during implantation to position the electrodes or map their stimulation to nerve roots and / or muscle groups). In some embodiments, initiating the SCS includes the initiation or first instance of electrical stimulation after implantation, according to a stimulation protocol administered or supervised by a physician. In some specific embodiments, subjects administered with nusinersen using the SCS described herein have already completed four loading doses and are within a maintenance dose schedule when the SCS is initiated. In some embodiments, subjects received their first dose of nusinersen (e.g., the first loading dose) at least 58 days before initiating the SCS.In some embodiments, subjects received their first dose of nusinersen (e.g., the first loading dose) at least 58 days, at least 3 months, at least 4 months, at least 6 months, at least 9 months, at least 12 months, at least 16 months, or at least 18 months prior to the initiation of the SCS. In some embodiments, subjects have received nusinersen therapy for at least 58 days, at least 3 months, at least 4 months, at least 6 months, at least 9 months, at least 12 months, at least 16 months, or at least 18 months at the time of the initiation of the SCS. In further embodiments, subjects had received nusinersen therapy for at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years or more prior to the initiation of the SCS. In some embodiments, at the time of initiation of the SCS, subjects are on a maintenance dosing schedule of nusinersen. The reference to the SCS in these embodiments can also be described as applying electrical stimulation to sensory neurons.

[0143] In further embodiments, subjects are administered risdiplam. Risdiplam, also known as EVRYSDI®, is approved for once-daily oral administration as follows: 0.15 mg / kg body weight once daily for patients under 2 months of age; 0.2 mg / kg body weight once daily for patients between 2 months and under 2 years of age; 0.25 mg / kg body weight once daily for patients under 20 kg of body weight for patients 2 years and older; and 5 mg once daily for patients 2 years and older weighing over 20 kg. Therefore, when subjects are administered risdiplam in conjunction with SCS, the initiation of SCS occurs after the subjects have started risdiplam administration. In some embodiments, subjects started risdiplam administration within 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months prior to the initiation of SCS. In some embodiments, subjects have received risdiplam therapy for more than one, two, three, four, five, or six years prior to the initiation of SCS. In this case, the initiation of SCS is the application of electrical stimulation and must also involve the implantation of one or more electrodes, but does not constitute the initiation of SCS. Furthermore, in some embodiments, initiating SCS includes the initiation or first instance of electrical stimulation after implantation (e.g., not including stimulation that may occur during implantation to position the electrodes or map their stimulation to nerve roots and / or muscle groups). In some embodiments, initiating SCS includes the initiation or first instance of electrical stimulation after implantation, according to a stimulation protocol administered or supervised by a physician. References to SCS in these embodiments may also be described as applying electrical stimulation to sensory neurons.

[0144] In certain embodiments, the methods disclosed herein can be used in combination with protocolized physical rehabilitation exercises to improve long-term outcomes. [Examples]

[0145] The following embodiments are provided to illustrate specific features of a particular embodiment, but the claims should not be limited to the illustrated features.

[0146] Example 1 Biophysical models of spinal cord stimulation for treating SMA This embodiment provides a biophysical model illustrating the efficacy of sensory neuron stimulation therapy for SMA patients, as well as a stimulation protocol for treating SMA patients (such as type 3 and type 4 SMA patients) using stimulation of the posterolateral surface of the spinal cord.

[0147] The application of SCS to SMA patients yielded unexpected results, given the unique pathophysiology of SMA. While SMA patients generally possess intact corticospinal tracts, unlike patients with spinal cord injury or stroke, many, if not all, of the MNs in SMA patients are non-functional or dead, rendering them functionally inactive, especially in the advanced stages of the disease. Therefore, SCS, which aims to increase excitatory input to the spinal MNs, is not expected to have any effect on SMA patients, since their MNs are already non-functional or dead. Of course, the application of SCS to treat SMA is not expected to produce the effects observed in other conditions treated with SCS, such as spinal cord injury, stroke, and pain, where the MNs are still functional.

[0148] However, surprisingly, both significant immediate effects and study-termination effects of SCS have been unexpectedly observed in SMA patients treated in accordance with this disclosure, as discussed below. While experiments using SMA mouse models have shown a decrease in presynaptic activity from sensory afferent fibers, this disclosure demonstrates that a therapeutically effective dose of SCS, appropriately applied to the posterolateral surface of the spinal cord, can increase the excitability of MNs via remaining excitatory connections and produce long-term potentiation of affected synapses, which can contribute to the reversal of electrical changes in SMA-affected MNs, by artificially increasing activity in sensory afferent fibers via SCS. Furthermore, therapeutically effective doses of SCS may also enhance the firing rate of SMA-unaffected MNs, resulting in a more robust effect.

[0149] Network model of spinal cord circuits Healthy Neuron Model Figure 1A shows a network model diagram in which MNs receive excitatory input from the corticospinal tract and spinal cord stimulation (SCS), e.g., 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 from the corticospinal tract (CST, N=110) and the spinal cord tract (SCS) (N=60) via the recruitment of sensory afferent fibers (see Capogrosso et al., 2013. J Neuroscience. 33(49):19326-40; Gerasimenko et al., 2006. J Neuroscience Methods 157(2):253-63; Hofstoetter et al., 2015. J Neurophysiology 114(1):400-410; Rattay et al., 2000. Spinal Cord 38(8):473-89). The difference between the two excitatory sources is that the SCS has its own frequency and amplitude, while the CST is modeled as a population of Poisson neurons. To investigate motor recovery during SCS, the forces generated by the MN pool were 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 the MN, SCS is controlled by the experimenter. Therefore, to improve voluntary movement, SCS should enhance MN firing rate only when CST is activated.

[0150] SMA neuron model Figure 3A shows a SMA-affected neuron model with various ion channels in which the delayed-rectifying potassium channel (K-dr) is blocked. For healthy neuron models, the established method for describing the dynamics of membrane potential as a function of different ion channels is the Hodgkin-Huxley model. In this model, the membrane potential (V) is described by: TIFF2026514929000001.tif15170

[0151] 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, which generally depends on the membrane potential and ion concentration. The following prior 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) includes, as shown in Figure 3A, ion channels such as delayed-rectifying 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 performed in a neuronal stimulation environment designed to model individual neurons and networks of neurons, referred to herein as neurons (Hines and Carnevale. 1997. Neural Computation 9(6):1179-1209).

[0152] Figure 3B shows an MN model with various ion channels, including a specific delayed-rectifying potassium channel (Kv2.1). While not bound by any particular theory, the loss of sensory afferent input induced by SMA (e.g., Ia) can cause the Kv2.1 channel of the MN to become dysfunctional, with an increased refractory period (e.g., a slower firing rate) and / or increased input resistance. Furthermore, the deficiency of MN function may be restored by increasing sensory afferent input to the SMA-affected MN (e.g., via SCS), which reduces the input resistance of the MN. Moreover, SCS can immediately increase sensory afferent input, thereby increasing the firing rate of the SMA-affected MN. Over time, SCS can rescue MN function by changing the Kv2.1 channel of the MN back to its healthy functional state.

[0153] SCS increases the excitability of the MN without causing involuntary movements. Figures 1B to 1G show various models of SCS enhancement of MN output. In all panels from Figure 1D to 1G, the "amplitude" unit represents the percentage of sensory afferent fibers recruited by the SCS. Figure 1B plots the membrane potential (mV) of an MN stimulated at a frequency of 69 Hz and an amplitude that recruits 30% of sensory afferent fibers. The parameters shown in Figure 1B correspond to the point labeled "1" in Figure 1D. The black dashed line shows the resting potential of the MN membrane potential, and the gray dashed line shows the MN spike threshold. With appropriate parameters, the SCS can increase the excitability of the MN without generating an action potential. Figure 1C plots the membrane potential (mV) of an MN stimulated at a frequency of 69 Hz and an amplitude that recruits 80% of sensory afferent fibers. The parameters shown in Figure 1C correspond to the point labeled "2" in Figure 1D. Figure 1D, showing gradient plots, plots MN firing rate as a function of SCS parameters without input from the corticospinal tract (CST), indicating that the SCS alone generates involuntary movements (MN firing rate > 8 Hz). Larger spikes / s are indicated by darker shading in Figures 1D–1F, respectively, on a scale of 0–30 spikes / s. Figure 1E, showing gradient plots, plots MN firing rate as a function of SCS parameters with input from the CST. Figure 1F, showing gradient plots, plots MN firing rate for combinations of SCS parameters that produce only voluntary movements normalized by the MN firing rate without SCS. Figure 1G, showing gradient plots, plots how the SCS enhances the forces 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. Therefore, these figures show that the MN firing rate is up to 2.2 times higher with SCS than without SCS.

[0154] To study the effect of continuous SCS on MN firing rate, a series of stimulation parameters were investigated. In general, MN firing rate increased as a function of both SCS frequency and amplitude, as shown in Figure 1D. However, a maximum was identified at 25 Hz, which is associated with 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 MN firing rate beyond the minimum firing rate, generating movement (>8 Hz), as shown in Figures 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 generated movement without the involvement of CST (i.e., involuntary movement) was discarded. However, as shown in Figures 1B and 1D, SCS was also able to increase MN excitability (i.e., depolarize the membrane potential) without producing involuntary movements (i.e., MN firing rate < 8 Hz). This increase in MN excitability represents a mechanism that enhances CST input.

[0155] SCS enhances spinal cord input and increases the rate of MN firing. Healthy Neuron Model Having demonstrated that SCS can increase MN excitability in a healthy model, we evaluated whether SCS can also enhance CST input to activate MN and generate force. To perform this evaluation, we fixed the input from the CST and generated a relatively low firing rate (9.3 Hz) in the MN. The MN firing rate was calculated while systematically varying the SCS parameters (frequency and amplitude). Within the range of these parameters, as shown in Figures 1E and 1F, SCS enhanced the input from the CST and increased the firing rate of the MN without generating involuntary movement. As shown in Figure 1G, the enhanced firing rate of the MN with SCS generated up to 2.2 times stronger force than the firing rate generated by the same CST input without SCS.

[0156] Figures 2A and 2C show graphs illustrating force enhancement during simulated voluntary brain input. Figure 2A plots the following network activity parameters: SCS amplitude, corticospinal tract (CST) firing rate (Hz), MN firing rate (Hz), and force normalized by the applied average force. In the network activity shown 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 movement domain. The parameters shown in Figure 2B correspond to the point labeled "3" in Figure 1E. The MN firing rate, and therefore force, is enhanced compared to when SCS is off. Figure 2C plots the network activity with SCS applied to the involuntary movement domain. The parameters shown in Figure 2C correspond to the point labeled "4" in Figure 1E. The MN firing rate is high in both stages, regardless of whether or not there is input from the CST.

[0157] To further understand the enhancement of CST input induced by SCS, we modeled an oscillatory force task in which CST input periodically reaches the MN, as shown in Figures 2A-2C. We evaluated the difference between voluntary and involuntary movement domains. In the voluntary movement domain, SCS increased the excitability of the MN, resulting in a higher firing rate than observed without SCS. However, as shown in Figures 2A and 2B, SCS did not increase the firing rate of the MN during periods without CST input. In the involuntary movement domain, as shown in Figure 2C, SCS increased the firing rate throughout the entire trial, even during periods without input from the CST. In summary, these results indicate that, in a biophysical model of a healthy spinal cord, it is possible to enhance input from the CST to increase the firing rate of the MN and thus generate stronger forces.

[0158] SMA neuron model A series of experiments using SMA mouse models have shown that SMA-affected synaptic neurons (MNs) possess dysfunctional electrical properties (Mentis et al., 2011. Neuron 69(3):453-67; Fletcher et al., 2017. Nat Neuroscience 20(7):905-16), resulting from reduced synaptic activity due to blockage of sensory afferent fibers and delayed rectifying 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 reduces the excitability of MNs, as shown in Figure 3A. Therefore, to model SMA-affected MNs, synaptic weight (i.e., synaptic strength) is reduced from the conductance of sensory afferent fibers and delayed rectifying potassium channels, as shown in Figure 3A. This neuronal model can be validated by reproducing the electrical characteristics of the following three dysfunctions in MN affected by SMA. (1) High input resistance: In neuron simulation environments designed to model individual neurons and networks of neurons, it is easy to inject current directly into the MN and calculate the input resistance as the gradient of the voltage-current function. Blocking potassium channels reduces the outflow of potassium ions, thereby increasing the input resistance. (2) Reduced rheobase: As in (1), current is injected into the MN, and it is possible to calculate the minimum input current from there to generate an action potential. Similarly, reducing potassium ion efflux causes the membrane potential to depolarize more quickly, reducing the injection current required to induce an action potential. (3) Low firing rate induced by a current higher than the current required to induce repetitive firing: When an artificial current exceeding the threshold for repeating the firing rate in an MN test affected by SMA is injected, it is tested whether blocking potassium channels is sufficient to reduce the firing rate. After the action potential, potassium channels open and repolarize the membrane potential. Blocking them causes the repolarization phase to be slower than in a healthy MN, reducing the output firing rate (Fletcher et al., 2017. Nat Neuroscience 20(7):905-16).

[0159] Example 2 Spinal stimulation for treating SMA This embodiment describes a specific method that can be used to treat a patient's SMA by applying a therapeutically effective amount of electrical stimulation to the posterolateral surface of the spinal cord, including sensory neurons that innervate areas of the body of a patient with motor impairment due to SMA. A specific method and protocol are provided, but as those skilled in the art will see, modifications can be made without substantially affecting the treatment. Three SMA patients were identified and participated in this spinal cord stimulation trial. One patient (described in more detail below as "SMA01") was also not receiving SMA therapy while participating in this SCS trial. Two patients (described in more detail below as SMA02 and SMA03) were receiving the SMA therapy nusinersen while participating in this SCS trial.

[0160] Three human patients with type 3 SMA exhibiting quantifiable leg motor impairment were selected for treatment. Patient 1 (hereinafter referred to as "SMA01") was a 22-year-old male with an initial Hammersmith Functional Motor Scale Expanded (HFMSE) motor function score of 60 (out of 66) and had not received SMA therapy. Patient 2 (hereinafter referred to as "SMA02") was a 55-year-old male with lower motor function than SMA01 (reflected by an HFMSE score of 38 out of 66) and had received SMA therapy (nusinersen). Patient 3 (hereinafter referred to as "SMA03") was a 30-year-old male with motor function between SMA01 and SMA02 (reflected by an HFMSE score of 49 out of 66) and had also received SMA therapy (nusinersen). Percutaneous bilateral linear spinal leads were implanted near the lumbar spinal cord of all three patients for up to 29 days (4 weeks).

[0161] To quantify the immediate motor improvement brought about by SCS, the maximum torque generated at different joints, such as the hip, knee, and ankle, during isometric exercise was measured. The HUMAC® Norm system was used for these measurements. This system allows the patient to be positioned at different locations and the maximum torque at such joints can be evaluated (Figures 4A-4C). Figure 4A shows hip extension, Figure 4B shows knee extension, and Figure 4C shows ankle extension.

[0162] During evaluation, patients underwent progressive contractions from rest to maximum intensity, receiving real-time torque visual feedback. The same assay was repeated to systematically investigate different SCS parameters, including no SCS, to determine the parameters most effective in reducing the patient's motor impairment. As an example, electrical stimulation can be applied with electrical pulses having amplitudes of approximately 10 μA to 50 mA, widths of approximately 40 μs to 2 ms, and frequencies of approximately 10 Hz to 2000 Hz. Furthermore, surface electromyography (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.

[0163] This embodiment aims to measure the immediate, end-of-study, and long-term effects of SCS on SMA, including various clinical outcomes. First, this embodiment measures the immediate effect of SCS on SMA by turning the stimulation on and off in the same session and measuring the effect of SCS that is present only during stimulation and disappears when the stimulation is turned off. As used herein, “immediate” refers to the effect measured during a 4-week study and relates to the use of SCS. Next, this embodiment measures the long-term effect of SCS on SMA by comparing the performance of patients without stimulation across different sessions. As used herein, “end-of-study” refers to the effect measured around the time the SCS electrodes were removed, within approximately one week before and after the end of the 4-week study. Third, the embodiment measures the long-term effect of SCS on SMA by tracking patients after the end of the study, several weeks after the stimulation was removed. In particular, as used herein, “long-term” refers to the effect measured 50+ days after electrode removal and relates to changes in motor capacity over time without continuous application of SCS. Both immediate and long-term effects of SCS on SMA patients were observed. Contrary to what is expected in patients with SMA, the magnitude of the immediate effect was similar to that observed in patients with stroke and spinal cord injury. In subjects with spinal cord injury and / or stroke, the immediate effect outweighed the long-term effect of SCS. Conversely, in subjects with SMA, the long-term effect outweighed the immediate effect of SCS. Furthermore, the magnitude of the long-term effect observed over a trial of only four weeks was unexpected for patients with non-functional MN who experienced muscle strength improvements exceeding what is expected to be achieved in patients with normal SMA. These muscle strength improvements are too high to be attributed solely to exercise. For example, left hip flexion more than doubled in SMA01, even though the patient did not perform any hip strength training other than walking during the study. The exercise level of SMA01 did not change from the exercise level before the study.These changes were reflected in improvements in clinical outcome tests such as manual muscle testing, the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Hammersmith Scale (RHS), and the 6-minute walk test in SMA01 and SMA02. Furthermore, the data did not indicate a plateau, suggesting that longer use of the SCS could lead to even greater improvements. SMA02 was older and had more severe motor impairment than SMA01, so the improvement in muscle strength in this individual was smaller than that of SMA01, but consistent with that. However, improvements in walking at the end of the study and immediate improvements were more pronounced in SMA02 than in SMA01, who had only mild gait impairment.

[0164] Furthermore, for SMA01, SCS treatment increased leg joint torque (up to +180%) and MN firing rate over a 4-week period, demonstrating that SCS improved MN function without reporting side effects. These results suggest that SCS can potentially enhance the quality of life for patients with severe and mild SMA by improving muscle strength and gait. Improvements of this magnitude within such a short timeframe observed in SMA patients are unexpected. The observed improvement in muscle strength of this magnitude, and improvement within such a short timeframe, may indicate a disease-modifying effect. While not bound by any particular theory, the improved strength may be due to rescued MN function in response to increased afferent input provided by SCS targeting the patient's hip flexors and knee extensors. This conclusion was supported by analysis of spinal reflexes and single MN firing rates obtained from HD-EMG recordings. In addition, fMRI analysis shows increased activity in the spinal circuit pre-implantation compared to post-explantation. This increase may indicate that stimulation rescued MN function by artificially increasing afferent input.

[0165] Initial configuration and optimization Before implanting electrodes, the patient's initial performance can be measured. The HUMAC® Norm system can be used for these measurements. This system allows for the evaluation of maximum torque at different joints by positioning the patient in different locations. Figures 5A and 5B show isokinetic machines (e.g., the HUMAC® Norm isokinetic machine) configured to test human hip flexion and knee extension, respectively. Specifically, the maximum torque generated by the patient during extension and / or flexion at the knee, hip, and ankle joints can be measured.

[0166] Bilateral linear SCS leads were implanted in the epidural space from the T11 to the L1 vertebra. To target the muscles of the right leg, in one example, the spinal cord was stimulated using bipolar stimulation of the two most rostral contacts of the right lead. The SCS parameters in this example were 2 mA, 40 Hz, and a pulse width of 400 μs. To target the muscles of the left leg, in one example, tripolar stimulation was used. The SCS parameters in this example were 3.7 mA, 40 Hz, and a pulse width of 400 μs.

[0167] Figure 32 shows a table of optimal current values ​​and lead configurations for SMA01, SMA02, and SMA03. Electrode names are coded from 1 to 8, followed by a letter indicating whether they are left or right electrodes. For example, 1L indicates the furthest rostral contact in the left array. 7R indicates the second-to-last caudal contact in the right lead. When indicating configurations, the first contact is the cathode, and the contact after "pair" is the anode. For example, 1L pair 1R 5L means that 1L is selected as the cathode, but both 1R and 5L are selected as anodes.

[0168] Therapeutic SCS treatment administered via implanted leads did not cause significant discomfort or pain in the subjects. While SCS produced stabbing sensations and other types of sensory phenomena, the stimulation intensity required to improve motor function remained within the range of non-painful sensations. As shown in Figure 33, SMA01, SMA02, and SMA03 were asked to provide a score from 1 to 10 for each stimulation setting (higher numbers indicate greater discomfort). In the optimal configuration, the maximum discomfort rating provided by any of the subjects was 2 out of 10. In the suboptimal configuration, the maximum discomfort rating provided was 5 out of 10.

[0169] SCS can be applied to target muscles affected by SMA. In this example, SMA01 is found to have significant deficits in the knee extensor and hip flexor muscles, consistent with his type 3 diagnosis. Furthermore, SMA01 has slightly more deficits in the left leg. Therefore, the stimulator could be programmed to selectively target these muscles. In this example, the entire experiment was conducted over 4 weeks and a total of 19 sessions. The experiment was performed daily, 5 days a week, until the day electrodes were explanted. Each session lasted 4 hours with approximately 2-3 hours of task execution time, and the estimated dose of stimulation was active for 2 hours per day during these sessions.

[0170] The placement of the SCS could be optimized and fine-tuned by stimulating various contact points, measuring the electrical activity generated by the muscles (e.g., agonist and antagonist muscles of each joint), and evaluating the measurements. Maximum torque and EMG activity were then measured to determine the therapeutically effective amount of electrical stimulation using appropriate SCS parameters. In this example, during the procedure, electrode placement was determined by stimulating each contact and recording EMG signals from muscles ranging from the trunk to the ankle. Stimulation was repeated until a position was identified where the electrodes activated the hip muscles at the most rostral contact and the calf muscles at the most caudal contact.

[0171] These implants can be used to configure electrospinal cord stimulation (ESS) treatments that allow control over the degree of extension and flexion of each leg during movement. This protocol, utilizing real-time processing of gait kinesiology and gait performance, can be configured within days. Once configured, stimulation bursts are delivered across specific spinal cord locations at precise timings that replicate the natural spatiotemporal activation of the midline muscle 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.

[0172] The placement of electrodes during surgery can be adjusted to account for postoperative electrode movement. Such postoperative movement is variable and may be difficult to avoid with non-permanent implants. For example, electrodes may move caudally and shift medially. Figure 6 shows a comparison of the intraoperative (black) and postoperative (white) electrode positions in a subject. In this particular example, the change in position did not interfere with stimulation of the correct muscle groups. Based on the predicted postoperative movement of the electrodes, the electrodes may be implanted in a position adjusted during surgery so that the electrodes move to a predetermined optimal position postoperatively. Further details regarding instruments and surgical procedures that can be used to obtain long-term 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.

[0173] Observed immediate effects The immediate effects of SCS were measured in terms of maximal voluntary contraction, hip flexion during movement, balance, transition from sitting to standing, maximum speed, and walking on the ground. Each measurement is described below. Please understand that different metrics may be used depending on the patient's target muscles and symptoms.

[0174] Maximum Voluntary Contraction: To assess maximum voluntary contraction, SMA01 is asked to produce maximum voluntary isometric contraction (MVC) during knee extension for 5 seconds with and without SCS. After several repetitions of knee extension, SMA01 will show clear signs of fatigue. At that point, the immediate effect of SCS on the patient's maximum voluntary contraction (MVC) during fatigued knee extension was tested. Figures 7A–7C show various torque measurements over time. Figure 7A shows a single trace of torque generated by SMA01 with and without stimulation (see element 702) during maximum voluntary contraction repetitions. In Figure 7B, each dot corresponds to the average torque generated during a single trial with and without stimulation. In Figure 7C, each dot corresponds to the maximum torque generated during a single trial with and without stimulation. In Figures 7B and 7C, the square markers represent the average over repetitions, and the error bars correspond to the standard error of the mean. As shown in the figure, MVC during SCS stimulation was significantly higher on days 12 and 27.

[0175] Similarly, SMA02 was asked to produce MVC during 2 seconds of knee extension with and without SCS. Because SMA02 can only produce very small forces, the increase in intensity is not statistically significant between stimulation on or off, or between different stimulation parameters, as shown in Figures 7D and 7E. Figures 7D and 7E show the torque measurements obtained during knee extension in SMA02 at baseline and at two different stimulation contacts, 1L and 4L. As shown, the mean torque was higher at 1L than at baseline, but not at contact 4L. The overall peak torque was higher at both 1L and 4L. The figures show that the contact configuration affects torque output.

[0176] To obtain more data on the role of SCS in immediately increasing muscle strength (measured by the torque generated by MVC), SMA03 was asked to produce MVC during knee flexion with and without SCS. Figures 28A–28B show various torque measurements across trials on different days. Each dot corresponds to the average / maximum torque generated during a single trial, the square markers represent the average between trials on the same day, and the error bars correspond to the standard error of the mean. Before implantation of contact (e.g., days -9, -4, and -3), baseline values ​​of knee flexion ability of SMA03 without SCS were measured. After implantation (e.g., on days 6 and 7), knee flexion torque generated by SMA03 with and without stimulation was measured. Figure 28A shows the average torque generated during trials with and without stimulation. When stimulation was applied, the average torque generated was greater than when the stimulation was off. Similarly, Figure 28B, which shows the maximum torque generated during the stimulated and unstimulated tests, indicates that the maximum torque is greater with stimulation on than with stimulation off. In both figures, the torque with stimulation is greater than the baseline torque before implantation and the torque without stimulation. These figures demonstrate that applying stimulation via the SCS immediately increases muscle strength beyond the normal capacity of the unstimulated patient.

[0177] Hip Flexion During Movement: SMA01 patients were asked to produce maximum hip flexion by raising their knees as high as possible while their weight was supported by the treadmill. The stimulation was switched on and off every 20 seconds while the patients walked. SMA01 patients did not receive visual feedback on their legs during the task. Tracking markers were placed on the ankle, toes, and metatarsals of each foot to measure changes in stride length. A machine learning model (e.g., a deep neural network) could be trained to track the markers. Figures 8A and 8B show that spinal stimulation increases maximum hip flexion during movement. Specifically, Figure 8A shows the traces of the ankle marker during movement with and without stimulation (see element 802). In Figure 8B, the dots represent the height of each step, calculated as the difference between the smallest and largest values ​​for each trace in Figure 8A. The square markers represent the average of the steps, and the error bars correspond to the standard error of the average. As shown in Figures 8A and 8B, the SCS immediately increases the maximum hip flexion of the SMA01 during movement, which leads to a higher step height.

[0178] Balance: SMA01 was asked to walk from heel to toe while looking straight at a beam that narrowed with distance, without receiving visual feedback from their own feet. In the first session, SMA01 worsened with stimulation and consistently covered less distance. The patient reported that the stimulation disrupted their balance as precise control of their legs became more difficult.

[0179] However, when SMA01's balance was retested during the second session (one week after the first session) and the third session (one week after the second session), it was found that the patient had learned to control the stimulation and improved their balance so that the on and off of the stimulation produced similar distances. Figures 9A and 9B show that spinal cord stimulation only temporarily disrupted the patient's balance. In Figure 9A, each dot represents the walking distance of SMA01 in narrowed beam tests with and without stimulation (see element 902). The squares represent the mean, and the error bars represent the standard error of the mean over the iterations. Figure 9B is a photograph of SMA01 walking on a narrowing bean.

[0180] Transition from sitting to standing: SMA01 was asked to stand from a position with one knee on the ground and the opposite foot planted on the ground. Different knee heights were tested until the maximum height at which the patient could not stand was identified. Then, stimuli were applied. SMA01 was consistently able to reach a standing position with the right knee on the ground.

[0181] The patient was also asked to stand up from a seated position on a box 46 cm above the ground. Without stimulation, SMA01 was able to perform a corrected standing position while excessively spreading its legs. The patient was then instructed to try to bring its feet closer together until it reached a distance between them to which it could no longer stand. Stimulation was then applied to the patient with its feet in the same position, i.e., separated to the distance from which it could no longer stand, and SMA01 was able to consistently stand from such a position.

[0182] Maximum Speed: SMA01 was asked to run on a treadmill, and the speed was gradually increased every 30 seconds until the patient reported reaching their maximum speed. Figure 10 shows that SCS (see element 1004) reliably increased the patient's maximum speed compared to when SCS was not applied (see element 1002).

[0183] Ground Walking: SMA01 and SMA02 were asked to walk back at a self-selected speed with and without stimulation. Using the Vicon® system, the position and orientation of reflective markers attached to specific anatomical landmarks were recorded, and joint angles, velocities, and accelerations were reconstructed from there. Principal component analysis (PCA) was performed to evaluate the kinematic variables that accounted for the majority of the variance between the SCS-enabled and SMA02 tests. For SMA01, the variable that could account for the majority of the variance was related to the velocity of knee flexion / extension during the swing phase, showing that the stimulation resulted in faster knee flexion movement, as shown in Figure 19B. The stimulation was found to increase walking speed and decrease stride length, as shown in Figures 20C and 20D.

[0184] PCA analysis of SMA01 shows that stimulation reduces knee joint rotation during the swing phase, indicating a decrease in compensatory strategies during gait. The knee did not rotate outward much during the stimulation-on trajectory, which may also indicate a decrease in compensatory strategies during gait. Figures 19A and 19B show the PCA results for SMA01. Figure 19A shows the principal component (PC) space composed of the first three PCs. The separation between the stimulation-on and stimulation-off trials is clear along the direction of the third PC. Overall, the stimulation-on trials have lower third PC values ​​than the PC-off trials. Figure 19B shows gait features that correlate more strongly with the third PC. Figures 19C and 19D show similar PCA results for SMA02. Figures 20A–20D show short-term improvements in several gait quality variables for SMA01. These figures show that, on both his left and right sides, the step length increased (Figure 20A), the step height increased (Figure 20B), and the duration of his steps decreased with the stimulus (Figure 20C). Figure 20D shows that the stimulus improved, i.e., decreased, the duration of steps in SMA01. Figures 20E–20H show short-term improvements in several gait quality variables of SMA02, similar to the gait quality variables of SMA01 when the stimulus was on.

[0185] PCA analysis of SMA02 shows that the stimulus improved various gait patterns.

[0186] 1) The stimulation increased the range of hip abduction / adduction and knee flexion / extension (as shown in Figure 19D), as well as the maximum hip flexion angle (as shown in Figures 21C and 21D). As a result, SMA02 was able to take longer and higher steps than without stimulation (as shown in Figures 20E and 20F).

[0187] 2) The stimulation also increased the maximum ankle dorsiflexion angle during the stance phase (as shown in Figure 19D) and improved foot clearance and toe lift (as shown in Figures 21C and 21D).

[0188] Furthermore, the method of this disclosure was found to mitigate compensatory strategies in individuals with SMA. For example, individuals with SMA tend to compensate for weak quadriceps during the swing phase by flexing the soles of their feet to increase hip flexion. Both SMA01 and SMA02 reduced this compensatory strategy upon stimulation, showing decreased plantar flexion and increased hip flexion. Thus, the results indicate that SCS has the potential to bring about biomechanical changes that immediately alleviate gait disturbances during walking on the ground.

[0189] Observed effects of ending the study In this example, the effects of SCS at the end of the study were measured in terms of hip flexion during movement, maximal voluntary contraction, walking on the ground, and functional magnetic resonance imaging of the spine. Measurements were taken immediately before or after (i.e., within one week of) the removal of the patient's electrodes and show the effects of SCS at the end of the 4-week experiment. Each measurement is described below. Please note that different metrics may be used depending on the patient's target muscles and symptoms. During the 4-week experiment, no serious adverse events (e.g., falls) associated with SCS were observed. Injuries during falls were avoided by predetermined risk mitigation strategies for the experiment, such as the use of straps, harnesses, and / or the presence of a physical therapist during physical activity.

[0190] Hip flexion during movement: SMA01 was asked to walk on a treadmill while lifting his knees as high as possible during week 4. Figures 11A and 11B show the long-term effects of SCS on hip flexion over the 4-week experiment. Figure 11A shows the traces of ankle markers during movement, comparing the traces from week 1 without stimulation (see element 1102) with the traces from week 4 without stimulation (see element 1104). In Figure 11B, the dots represent the height of each step, calculated as the difference between the smallest and largest values ​​for each trace in Figure 11A. The squares represent the mean and standard error of the mean over the steps. Comparing week 1 and week 4, a significant increase in maximum hip flexion during movement was observed in SMA01 even without stimulation, demonstrating the long-term effects of the SCS intervention. While not bound by any particular theory, the application of electrical stimulation to patients over time may result in ion channel remodeling on the MN membrane and a sustained increase in the firing rate probability of spinal cord MNs, which may improve motor function even without stimulation.

[0191] Maximum Voluntary Contraction: At the start of each session using an isokinetic machine, the maximum volatility (MVC) of SMA01 and SMA02 was measured as torque (Nm) during knee extension and / or hip flexion without stimulation. The patient's MVC during knee extension was approximately 20 Nm, while the MVC of healthy young adults exceeded 100 Nm. SMA01 was asked to generate maximum torque in each of these joints for 6 repetitions of 5 seconds each. To prevent premature fatigue, SMA02 was asked to generate maximum torque in each of these joints for 6 repetitions of 2 seconds each. Knee extension was tested twice a week, and hip flexion was tested before implantation, at week 1, week 3, and after explantation. In general, a significant increase in MVC was observed for all exercises starting from week 2.

[0192] Regarding right knee extension, from the 18th day until the end of the experiment, when SCS was turned off, a consistent increase in maximum torque and average torque was observed. The final increase from before implantation until the end of the study was +43.5%. Figures 12A - 12C show the improvement at the end of the study of right knee extension in SMA01. Figure 12A shows the torque traces for 6 repetitions in each session. In Figures 12B - 12C, each dot is the average torque for each 5 - second repetition. The squares are the mean, average, and standard error of the mean torque over the repetitions. As shown, the effect appears to be linear and there is no evidence of reaching a plateau by the 4th week. From the 18th day until the end of the experiment, when SCS was turned off, SMA01 experienced a consistent increase in maximum and average right knee extension torque. The final increase from before implantation until the end of the study was +43.5% for SMA01.

[0193] The MVC of SMA02 during knee extension was less than 1 Nm, while the MVC of SMA01 was over 20 Nm and that of healthy young adults was over 100 Nm. Thus, the knee extension of SMA02 was more restricted than that of SMA01. Figures 12D - 12F show the improvement at the end of the study of right knee extension in SMA02. The increase in average torque from before implantation until the end of the study was +33.3% for SMA02 (as shown in Figure 12E). However, no significant difference was observed in the peak torque of this subject (as shown in Figure 12F).

[0194] A consistent increase in left knee extension of SMA01 was similarly observed from the 18th day until the end of the 4 - week experiment, despite it being the more impaired leg of SMA01. The results of left knee extension during the 4 - week SCS experiment were almost identical to those of right knee extension in that no increase was observed until the 18th day and then a sustained increase was observed. The final increase from the 5th day of the test until the end of the study was +65.1%. Figures 13A - 13C show the improvement at the end of the study of left knee extension. Figure 13A shows the torque traces for 6 repetitions in each session. In Figures 13B - 13C, each dot is the average torque for each 5 - second repetition. The squares are the mean, average, and standard error of the mean torque over the repetitions.

[0195] The timing of improvement in the flexion of the left and right hip joints of SMA01 was consistent with the results of knee joint extension, and increases in both were observed from the 18th day until the end of the 4-week experiment on hip joint flexion. The final increase from before implantation to after explantation was +65.1% on the right side and +179.7% on the left side of SMA01. Figures 14A - 14C show the improvement at the end of the study on right hip joint flexion. Figure 14A shows the torque traces of 6 repetitions in each session. In Figures 14B - 14C, each dot is the average torque for each 5-second repetition. The squares are the mean, mean, and standard error of the average of the average torque over the repetitions. Figures 15A - 15C show the improvement at the end of the study on left hip joint flexion of SMA01. Figure 15A shows the torque traces of 6 repetitions in each session. In Figures 15B - 15C, each dot is the average torque for each 5-second repetition. The squares are the mean, mean, and standard error of the average of the average torque over the repetitions.

[0196] The right hip joint extension of SMA02 increased by +21.7% from before implantation to after explantation. Figures 15D - 15F show the improvement at the end of the study on right hip joint extension of SMA02. Figure 15D shows the torque traces of 6 repetitions in each session. In Figures 15E - 15F, each dot is the average torque for each 5-second repetition. The squares are the mean, mean, and standard error of the average of the average torque over the repetitions.

[0197] As a result of these improvements in hip joint flexion and knee joint extension, the overall range of motion of the patient became much higher than before after the end of the experiment. The improvement in the range of motion of the patient was most prominent in hip joint flexion and whole body movement. Without being bound by any specific 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 that innervate the body regions of patients with movement disorders caused by SMA. This mobilization of the pathway may increase neural plasticity and enable the patient to improve motor function.

[0198] To obtain more data on the role of SCS in increasing muscle strength (measured by torque generated by MVC) over the course of the study, SMA03 was asked to produce multiple MVCs during knee flexion over the four weeks of the study. Figures 27A–27B, which expand on the dataset in Figures 28A–28B, show various torque measurements of SMA03 over trials on different days. Each dot corresponds to the mean / maximum torque generated during a single trial, the square markers represent the mean between trials on the same day, and the error bars correspond to the standard error of the mean. Compared to the baseline values ​​of SMA03's knee flexion ability (e.g., values ​​on days -9, -4, and -3) before implantation, the patient's MVC values ​​showed a significant upward trend throughout the course of the study (e.g., from day 6 to day 26). In addition, knee flexion torque was measured with and without stimulation during the study. When stimulation was applied (represented by bright dots for "stimulation on"), the torque generated was greater than when stimulation was off (represented by dark dots for "stimulation off"). Figure 27A shows the average torque generated, which increased throughout the study. Similarly, Figure 27B shows the maximum torque, which increased throughout the study. In both figures, the torque measured at the end of the study (e.g., day 26), with and without stimulation, was significantly greater than the baseline torque before implantation. These figures indicate that applying stimulation via SCS resulted in a gradual increase in muscle strength beyond the patient's normal capacity throughout the study. Even without aggressive application of SCS at the end of the study, muscle strength in SMA03 was greater compared to the baseline value at the start of the study.

[0199] Figure 34 shows the percentage increase in absolute torque at all joints over the course of the SMA01 and SMA03 studies, using web plots. (The raw data used to create Figure 2 can be found in the “Supplementary Data” section corresponding to Figures 35 and 36.) Comparing pre- and post-study results, a clear improvement in hip flexor and extensor was present in both participants. At the 6-week follow-up appointment after the end of the study, hip torque had increased slightly, while other torques had returned to pre-study levels. No SCS was administered when collecting either of these results.

[0200] Despite significant differences in disease severity, both groups exhibited similar results, with substantial increases in isoangular torque observed primarily in the hip joint, resulting in a high change of +200%. The magnitude of these improvements in such a short period suggests changes at the spinal cord muscle network (MN) level, particularly in the efficiency of muscle recruitment. This is especially true for hip muscles that did not receive weekly strength training. Hip torque was assessed only three times: before, during, and after the study, with minimal strength training. Conversely, knee muscles were tested multiple times per week, thereby providing effective knee strength training. Therefore, while the increase in hip function cannot be explained by strength training, it shows the best improvement from SCS treatment. These findings correlate with the phenotype of the Delta7 muse model described by the Mentis lab study (Mentis et al., 2011. Neuron 69(3):453-67), which shows that hip muscles are significantly more affected by SMA than ankle muscles. However, other studies, whether for treating SMA or other conditions, have not demonstrated such a magnitude of improvement (+200%) in leg muscle strength after four weeks. Since it is not possible to "train" participants to double their muscle strength in four weeks, strength training alone cannot explain these improvements.

[0201] Range of Motion (ROM): The ROM of the hip and knee joints during ground movement for SMA01, SMA02, and SMA03 was calculated after the study. ROM is defined here as (maximum angle - minimum angle). This calculation specifically refers to the angle during the swing. Figures 37A–37B provide gait cycle profiles of joint angles and ROM for hip and knee movement in SMA01, SMA02, and SMA03 at different weeks with SCS turned off. Figure 38 presents some of the data from Figures 37A–37B as a table of hip and knee joint ROM for all three subjects before vs. after the study and with SCS on vs. off. As shown in the table, none of the participants showed improvement beyond 20% when comparing SCS on vs. SCS off. However, when comparing pre- and post-study results, SMA02 and SMA03 showed improvement of over 50% over time. SMA01 underwent less improvement, which is due to the fact that SMA01 had the least advanced disease progression among the subjects and was within the normal biomechanical limits of range of motion during movement.

[0202] Hip joint improvement was more pronounced in SMA02 and SMA03. In particular, SMA02 also showed substantial improvement in knee ROM. This may be due to the fact that the severe disease progression and limited ROM in SMA02 allowed for the greatest room for improvement. Overall, ROM significantly improved in all subjects and all joints compared to pre-study versus post-study.

[0203] Ground Walking: Changes in the walking patterns of SMA01 and SMA02 during a 6-minute walk test, in which subjects walked as fast as possible for 6 minutes, were analyzed over 4 weeks. Following the same approach as the PCA experiment described in the "Observed Immediate Effects" section above, data from week 2 and after explantation were compared for SMA01, and data from before implantation and after explantation were compared for SMA02. Figures 21A–21D show the effect of the end of the study on the 6-minute walk test walking patterns of SMA01 and SMA02 over the weeks. Figures 21A and 21C show the 3D space defined by the principal components (PCs) of SMA01 and SMA02, respectively. Figures 21B and 21D show histogram plots reporting the mean values ​​of the variables that contribute most to the PCs of SMA01 and SMA02, respectively. As shown in Figures 21A and 21C, for both subjects, the walking patterns of different weeks are clearly separable along the direction of the maximum variation (PC1), indicating that the stimulus resulted in a change in walking pattern. As shown in Figures 21B and 21D, for both subjects, the features explaining the variance were primarily related to joint velocity. For this reason, we analyzed temporal and spatial gait variables that could indicate faster and more efficient gait. Figures 22A–22D show the end-of-study improvements in several gait quality variables for SMA01. These figures show that for both the left and right sides of SMA01, step length increased (Figure 22A), step height increased (Figure 22B), and step duration decreased with the duration of the study (Figure 22C). Figure 22D shows that step duration improved, i.e., decreased, for SMA01 over the duration of this study. Figures 22E–22H show the end-of-study improvements in several gait quality variables for SMA02, similar to those for SMA01. Results for both subjects, as shown in Figures 22A–22H, consistently show that as an effect of the end-of-study stimulus, stride length, step length, and gait speed increased for each subject, while stride length decreased. In summary, these results indicate that the stimulation interventions described herein were able to reduce gait impairments in people living with SMA over a period of just four weeks.

[0204] Functional Magnetic Resonance Imaging (fMRI) of the Spinal Cord: fMRI of the spinal cord waaas was performed to evaluate whether functional reorganization of lumbar spine activity results from the use of SCS termination studies. While not bound by any particular theory, improvements in the termination of studies from SCS can reverse maladaptive changes in MN ion channels and improve MN dysfunction, and thus be reflected in the hemodynamic signals measured during fMRI. The lumbar spine of SMA01 was scanned twice before implantation and once after implantation with a scan centered on the cone. Similarly, the lumbar spine of SMA02 was scanned twice before implantation and twice after implantation. Acquisition of fMRI of the spinal cord focused on inducing MN activation and recruiting proprioceptive afferent nerves from specific leg muscles. This was achieved by performing task-based functional scans that measured responses to active or passive tasks. Neuronal activation was then compared across spinal cord segments to find active voxels and quantify the number of voxels that exceeded the statistical significance threshold considered active. Responses to both active and passive tasks showed an increase in the number of active voxels and z-score voxel values ​​at the anatomically relevant vertebral level, indicating a stronger neuronal activation signal at the end of the spinal cord study compared to pre-study. The active task of the task-based functional scan involved subjects performing right leg extension at a fixed velocity when prompted on screen. This directly activates the MN in response to the induction of controlled movement. Three runs were taken between each session, as shown in Figures 23 and 24. Figures 23A and 23B show the results of neuronal activation of SMA01 during the active task. Figure 23A shows a bar graph representing the mean z-score of the fixed-effect mean run for each session during the active task. Black error bars represent SEM, and asterisks represent significance (p<0.001). Figure 23B shows a histogram representing the number of active voxels at different z-score values ​​for each session. Z-scores are thresholded at Z>2. As shown in Figure 23B, the number and / or firing rate of MNs increased after implantation, which is represented by an increase in the number of active voxels and their z-scores. Figures 24A–24B show the results of neural activation of SMA02 during an active task.The results shown in Figure 24A are comparable to those in Figure 23A. Figure 24B shows a histogram representing the number of active voxels at different z-score values ​​for each session. The z-score is thresholded at Z > 2.5. Although the data in Figure 24B are not statistically significant, they follow the same trend as the SMA01 results, as shown in Figure 23A. In particular, the terminals of the z-score distribution are consistently larger after explantation than before implantation.

[0205] Figure 39 shows the results of spinal fMRI during active tasks (i.e., voluntary leg movements) in SMA01, SMA02, and SMA03. The z-score is a statistical value used to determine whether or not voxels were activated. Based on the z-score, the activation of spinal segments L1-S1, which are targeted for SCS treatment, is calculated. An increase in the number of activated voxels was observed in all subjects, indicating that the subjects' spinal circuits were neurologically more active after 4 weeks of SCS treatment than at pre-study levels. Detailed fMRI methodology is presented in the "Supplementary Data" section.

[0206] The passive task of the task-based functional scan involved limb mobilization by a physical therapist. When a limb, such as the right leg, was recruited, the muscle spindle was recruited by stretching the implanted muscle. The physical therapist extended the right knee joint at a constant speed, prompting by voice cues. Three runs were taken between each session, as shown in Figure 25. Figures 25A and 25B show the results of neural activation of SMA01 during the passive task. Figure 25A shows a bar graph representing the mean z-score of the fixed-effect mean run for each session during the passive task. Figure 25B shows a histogram representing the number of activated voxels at different z-score values ​​for each session. The Z-score is thresholded at Z > 2.5. As shown in Figure 25B, the number and / or firing rate of MNs increased after implantation, which is represented by the increase in the number of activated voxels and their z-scores. This may be due to increased post-implantation recruitment of proprioceptive afferent nerves. In addition to functional T2 sequences, anatomical images and physiological signals (heart rate, respiratory rate) were acquired during each run. The data were analyzed using a generalized linear model.

[0207] Observed long-term effects In this embodiment, the long-term effects of SCS were measured with respect to MN resistance / recruitment, MN firing rate, maximal voluntary contraction, and ground walking. Measurements were taken several weeks after the patient's electrodes were removed (e.g., 50+ days later) and show the changes in the patient's motor capacity after several weeks without SCS application. Each measurement is described below. It should be understood that different metrics may be used depending on the patient's target muscles and symptoms.

[0208] Four weeks of SCS treatment combined with walking and strength training substantially and robustly improves strength, fatigue, and motor capacity in all subjects. The magnitude of the long-term effects of SCS treatment surpassed all other known treatments for SMA. These changes correlated with electrophysiological and imaging signatures of changes occurring in the spinal cord, particularly in spinal MNs, indicating that spinal MNs showed reduced hyperexcitability and higher firing rates after SCS treatment. This suggests that SCS treatment is a disease-modifying intervention that alters the neuronal properties of motor neurons affected by SMA, thereby improving motor capacity. In general, the overall changes, both functional and electrophysiological, are inversely proportional to disease progression (i.e., the effect is greater in SMA01 where disease progression is not progressing, and smaller in SMA02 where disease progression is progressing). These findings suggest that SCS treatment should be administered to SMA patients as early as possible to maximize its effectiveness.

[0209] Patients treated with SMA therapy (SMA02 and SMA03, both treated with nusinersen) did not show substantially better results than patients not treated with SMA therapy (SMA01) throughout the 4-week trial period. However, the efficacy of SMA therapy became apparent during long-term follow-up of the trial. Patients not treated with SMA therapy tended to show a long-term decline in the beneficial effects of SCS. Conversely, the two patients who received SMA therapy during SCS surprisingly showed long-term stability in the beneficial effects of SCS. These findings indicate better long-term efficacy of SCS treatment with SMA therapy compared to SCS without concurrent SMA therapy.

[0210] MN resistance / recruitment: The recruitment resistance of MNs affected by SMA is abnormally high compared to healthy MNs, resulting in hyperexcitability of SMA-affected MNs. This hyperexcitability makes SMA-affected MNs abnormally easy to recruit. Treating SMA-affected MNs with SCS can reduce their recruitment resistance, allowing them to function more similarly to healthy MNs.

[0211] Transcranial magnetic stimulation (TMS) is a method of generating action potentials in the MN (muscle motor evoked potentials (MEPs)) by stimulating the corticospinal tract, i.e., the brain structure that connects the human motor cortex to the human spinal cord MN. This pathway is independent of the spinal cord structure stimulated by SCS, thereby providing a method to independently assess the excitability of the spinal cord MN by checking the intensity of the evoked MEPs with TMS pulses. Figure 40 shows the percentage change in MEP peak-to-peak amplitude for SMA01, SMA02, and SMA03 using a web plot. The thick heptagonal line represents no change. Compared to pre-study values, all participants showed a substantial decrease in MEP peak-to-peak amplitude. The change was inversely proportional to disease progression, with SMA01 showing the largest change. The data indicate that spinal cord MNs in all subjects exhibit reduced excitability in response to SCS treatment. This supports the hypothesis that the changes observed in clinical scores, mobility, and / or intensity are caused by the effects of SCS at the MN level. (Figures 41 and 42 show how inter-peak MEP changes with pulse intensity for various targets.)

[0212] As shown in Figures 29A-29C, which display data from SMA02, the MN was more difficult to recruit after the study than before for pulses of the same intensity, and therefore the input resistance of the MN was greater after the study. This means that, overall, the MN function was closer to that of a healthy MN after SCS treatment in combination with SMA therapy. As shown in Figure 29A, the TMS-induced motor-induced potential (MEP) of the rectus femoris, represented by the inter-peak amplitude readings for various TMS pulse intensities, differed between pre- and post-study measurements. The post-study amplitude readings were significantly lower than the pre-study amplitude readings, especially at stronger TMS pulse intensities (85%+). As shown in Figures 29B and 29C, which display the response amplitude over time for TMS pulses at 90% and 95% intensity, respectively, the post-study readings have smaller inter-peak amplitudes than the pre-study readings. As shown in Figures 29A-29C, the change in MN input resistance before and after the study is similar to the change observed in SMA01 (not shown).

[0213] MN Firing Count / Rate: Figures 43A–43C show single MN discharges from surface EMG signals of knee extensor and flexor muscles during isometric maximal voluntary contraction of SMA01, SMA02, and SMA03, respectively. Based on high-density EMG data, the number of MN units observed, their peak firing rates, and their (i.e., how much muscle is activated by one MN) were calculated. Across data from all three subjects, no clear trend in the number of MN units was detected over the study period. This may be due, at least in part, to the fact that surface EMG is not a reliable measure of true motor neuron numbers, as the number of units detected depends on electrode placement as well as other nutritional factors. Regarding peak firing rates, higher peak firings were observed in all three subjects at the end of the 4-week study. Higher firing rates indicate the ability of MN units to increase intensity as needed, correlate with torque changes, and show changes at the MN level. Innervation area is calculated by observing the size of the electrical signature of each unit on the high-density electrode patch. Using this scale, a general mean increase in the size of detected muscle neurons (MNs) was observed over the course of the 4-week study. This correlated with the increase in muscle strength observed in the subjects. In short, at the end of the SCS treatment study, MNs showed a faster firing rate, and their innervation areas on the muscles were larger.

[0214] Figures 26A and 26B show the MN firing rates during maximal spontaneous contraction of SMA01 at different time points during and after the study, according to several embodiments. Figure 26A, which plots the firing rates of two MNs (unit 1 and unit 2) aligned with maximal knee extension torque over time, shows how the maximum firing rate is determined. Figure 26B shows the changes in MN firing rates during and after the study. Throughout the course of the SCS treatment study, i.e., from week 2 to week 3 of the 4-week experiment, the firing rate increased from less than 60 peaks / second to more than 64 peaks / second. Immediately after the end of the study, i.e., immediately after the SCS electrode was explanted, the firing rate remained at approximately 64 peaks / second, indicating that the benefit of SCS treatment (i.e., increased MN firing rate) still exists within this time frame. However, in long-term follow-up, i.e., several weeks after explantation, the firing rate decreased to approximately 60 peaks / second, indicating that the benefit of SCS treatment decreased over time as the stimulation was removed. Therefore, as shown in Figure 26B, the improvement in immediate and study-end firing rates associated with SCS treatment in SMA01 underwent a long-term decline. This long-term decline is thought to be because SMA01 was not receiving SMA treatment concurrently with SCS treatment.

[0215] Maximum Voluntary Contraction: Figures 30A–30C show the long-term changes in torque measurements for SMA01 and SMA02. Dots correspond to the maximum torque generated during a single test, and square markers represent the average for the entire test on the same day. Figure 30A shows the maximum left hip flexion torque measurements for SMA01 at different time points before the experiment (-9 days), during the experiment (5 and 18 days), and after the experiment (+3 days and +52 days). As shown, the MVC of SMA01 significantly increased over the course of the experiment (-9 to 18 days), but decreased over the long term (+3 days to +52 days after explantation). Here again, as shown in Figures 7A-7E, 12A-12C, 13A-13C, 14A-14C, and 15A-15C, the immediate and end-of-study torque increase associated with SCS treatment in SMA01 was followed by a long-term decrease, which is thought to be because SMA01 was not receiving SMA treatment at the same time as receiving SCS.

[0216] In contrast to SMA01, SMA02 experienced muscle strength improvement even after the SCS treatment ended. Figure 30B shows the maximum left hip flexion torque measurements of SMA02 at different time points before the experiment (-6 days) and after the experiment (+5 days and +55 days). As shown, the left hip MVC of SMA02 significantly increased over the course of the experiment (-6 days to +5 days), but also significantly increased over the long term (from +5 days to +55 days after explant). Even after the SCS treatment ended, the patient experienced muscle strength improvement. However, this is different from Figure 30C, which shows the maximum right hip flexion torque measurements of SMA02 at different time points throughout the experiment. As shown, the right hip MVC of SMA02 decreased over the long term, even though the left hip MVC increased over the same time frame. Overall, these figures suggest that when combined with SMA therapy, the beneficial effects of SCS may begin to be maintained in some muscles over the long term.

[0217] Figure 44 shows the long-term changes in the isometric maximum torque measurements generated by the left and right hip flexions of SMA01 and SMA03. The dots correspond to the maximum torque generated during a single test, and the square markers represent the average of all tests on the same day. As shown in the figure, when SCS was applied at the beginning of the study, SCS had a significant immediate effect in some situations (e.g., for SMA01, +18% in the right hip on day 5 with SCS vs. without SCS; for SMA03, +>20% in the left hip on day 10 with SCS vs. without SCS), but there was little to no immediate effect in other situations (e.g., for SMA01, the left hip on day 19; for SMA01, the right hip on day 19; for SMA02, the left hip on days 16 and 26; and for SMA02, the right hip on days 10 and 25). Therefore, the immediate effect of SCS was only seen at the beginning of the study and was not bilateral. After the study ended, both subjects maintained the improvement in torque generation even without SCS.

[0218] Ground Walking: Figures 31A–31H show long-term changes in several walking quality variables for SMA01 and SMA02. Figures 31A–31D show that for SMA01, step length (Figure 31A) and step duration (Figure 31C) remained nearly constant over the long term, while step height (Figure 31B) and walking speed (Figure 31D) significantly decreased between the end-of-study measurement (within one week of explantation) and the long-term measurement (50+ days after explantation). These results suggest that the long-term effect of SCS alone (without concurrent SMA therapy) may decrease over time, potentially leading to a deterioration in the patient's walking quality. Conversely, Figures 31E–31H show that for SMA02, step length (Figure 31E), step height (Figure 31F), step duration (Figure 31G), and walking speed (Figure 31H) did not significantly decrease between the end-of-study measurement and the long-term measurement. These results indicate that when SCS is combined with SMA therapy, the long-term effects of SCS can be preserved over time, and the patient's walking quality can be maintained at the study's end level even several weeks after the SCS electrodes are removed.

[0219] Fatigue: Fatigue was quantified using a 6-meter walking test. For SMA02 and SMA03, fatigue was quantified using the ratio of the walking speed on the last lap to the walking speed on the first lap. For SMA01, which was able to complete multiple laps, the ratio was calculated using the average of the first three laps and the last three laps.

[0220] Figure 45 shows a table of fatigue values ​​for SMA01, SMA02, and SMA03 before, during, and after the study. The calculated fatigue values ​​represent the decrease in performance due to fatigue. For example, a value of 0.46 (shown by SMA02 at the start of the study) means that the speed on the last lap was only 46% of the speed at the start of the test, indicating considerable fatigue. Overall, SMA01's fatigue did not change significantly throughout the study. The fatigue value was close to 100%, indicating that SMA01 was not particularly fatigued in the 6MWT. Conversely, both SMA02 and SMA03 experienced considerable fatigue at around 40-50 at the start of the study (at enrollment). Throughout the course of the study, SMA02's fatigue value increased significantly and remained elevated for several weeks after the follow-up. In SMA03, fatigue increased significantly during the study but then decreased to the pre-study value. However, fatigue calculations are estimates for quantifying fatigue and do not represent the overall picture of the benefits of SCS treatment. For example, Figure 46 shows the lap-by-lap speeds for the 6MWT, demonstrating a clear improvement in lap-by-lap speeds for all subjects.

[0221] Clinical outcome trial Clinical outcome studies were conducted, including manual muscle testing, a 6-minute walk test, and leg circumference tests. Immediate effects, end-of-study effects, and long-term effects were observed throughout the clinical outcome studies, as discussed below.

[0222] Manual Muscle Testing: Manual muscle testing (MMT) is a commonly accepted method for assessing muscle strength. It involves individually measuring the strength of each muscle and then summing the individual strength measurements to report a total score. MMT was performed on SMA01 both before implantation and at 14 and 28 days post-implantation. MMT showed a consistent immediate effect with stimulation. Specifically, both the knee extensor / flexor and hip extensor / flexor muscles showed improved scores with stimulation, as shown in Figure 16, which includes manual muscle testing scores for SMA patients with and without stimulation sessions and by muscle, and is shown in the spreadsheet.

[0223] 6-Minute Walk Test: The 6-minute walk test (6MWT) was performed for SMA01, SMA02, and SMA03 before implantation, at 14 days with and without stimulation, after electrode explantation, and for 50 days after explantation. No significant immediate effect from stimulation was observed, but a large improvement from the effect of stimulation on total distance traveled was observed for all subjects at the end of the 4-week experiment, as shown in Figures 17A-17C and the table shown in Figure 47. Therefore, the effect of ending the stimulation study included an increase in total distance traveled for both types of subjects. However, the long-term effects of SCS differed among SMA01, SMA02, and SMA03. In the long-term measurement (50+ days after explantation), as shown in Figure 17B, the total distance traveled by SMA01 decreased compared to the result at the end of his study. Conversely, as shown in Figure 17C, the total distance traveled by SMA02 during the long-term measurement increased slightly compared to the result at the end of his study. As shown in Figure 47, the total distance SMA03 traveled during long-term measurements was lower than the measurement at the end of the study, but still higher than the initial measurement. In summary, this may indicate that when SCS is linked to SMA therapy, as in SMA02 and SMA03, the long-term effects of SCS can be maintained to some extent over time, and the increase in patients' walking distance may suggest that SCS can be maintained to some extent even after the SCS electrode has been removed for several weeks, rather than decreasing over time, as in patients not linked to SMA therapy, such as SMA01.

[0224] Figure 17A shows the distance SMA01 traveled during the 6MWT across different sessions, comparing stimulus-off versus stimulus-on during the study (day 14). Zooming in on this dataset, Figure 17B shows the distance SMA01 traveled during the 6MWT across different sessions, specifically comparing the distance before implantation, the distance at the end of the study, and the distance at follow-up. Similarly, Figure 17C shows the distance SMA02 traveled during the 6MWT across different sessions. Figure 47 displays the same distances as in Figures 17A–17C, along with additional distance information for SMA03.

[0225] Existing literature has investigated the effects of physical exercise on the 6MWT in adults with a walkable SMA. (Montes, J. et al., A randomized, controlled clinical trial of exercise in patients with spinal muscular atrophy: methods and baseline characteristics. J. Neuromuscul. Dis. 1, 151-161 (2014); Bartels, B., Montes, J., van der Pol, WL & de Groot, JF Physical exercise training for type 3 spinal muscular atrophy. Cochrane Database Syst. Rev. (2019).) This study found that after 6 months of physical exercise, participants improved by an average of only 9m in the 6MWT. In this experiment, by incorporating SCS in addition to physical exercise, at least a twofold improvement was achieved for each subject, regardless of the severity of their SMA, in a much shorter period (4 weeks). As shown in Figure 48, the improvement in the 6MWT was proportional to each subject's HFMSE at enrollment, but all were above 20m. Coincidentally, SMA02, who participated in both the exercise-only clinical trial and the 4-week experiment including SCS, achieved 0m in the 6MWT after 6 months of participation in the exercise-only clinical trial, in contrast to 20m in the 4-week experiment including SCS.

[0226] Clinical scales, Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Hammersmith Scale (RHS): The HFMSE and RHS tests are validated means for assessing motor function in children and adults with SMA type 2 and 3. HFMSE and RHS test results were measured pre-implantation, on the date of explantation (end of study), and at long-term follow-up after explantation. The HFMSE test for SMA01 (without SMA therapy) showed a small but relevant long-term effect, with an increase in the total score, achieving a final HFMSE score of 61. Improvement in HFMSE can generally be very difficult for patients to achieve. Therefore, even small changes (1-2 points in this case) indicate improvement, as shown in the tables in Figures 18A and 18B, which include HFMSE scores for SMA01. Similarly, the RHS test for SMA01 shows a pre-implantation RHS score of 64 and an explantation RHS score of 65 (a 1-point increase), as shown in the table in Figure 18B. The increase in HFMSE and RHS scores remained consistent even 52 days after explantation, indicating a small but relevant long-term effect associated with the 4-week experiment.

[0227] Figure 18C shows the HFMSE and RHS test scores for SMA02 (with SMA therapy), which show similar long-term trends. The end-of-study scores for SMA02 increased by several points compared to the pre-implantation score, and this increase remained at 55 days post-explantation, demonstrating a reasonable long-term effect associated with the 4-week experiment. The score increase for SMA02 was greater than that for SMA01, although the baseline motor impairment in SMA02 was more severe than that in SMA01. In summary, these figures suggest that in both cases, patients may experience small but sustained improvements in motor capacity, which do not necessarily decline over the long term.

[0228] Leg circumference: On day 18 after implantation, the circumference of the left and right legs of the SMA01 was measured from 15.24 cm above the patella on each side. The left and right leg circumferences of the SMA01 were measured at 43.5 cm and 46 cm, respectively. Five days after the completion of the 4-week experiment and explantation, the left and right leg circumferences at the end of the patient's study were measured at 44 cm and 45 cm, respectively. These small differences may be considered insignificant.

[0229] Supplementary data Figures 49A–49C present an overview of the changes in gait in SMA01, SMA02, and SMA02, respectively, over the course of a 4-week experiment. The subjects' abilities between the SCS-enabled and SMA02-disabled trials are illustrated for different weeks throughout the experiment. Ability was measured with respect to gait quality variables, specifically step height, step length, and gait speed, all calculated using full 3D limb kinematics. All subjects underwent a significant increase in all gait quality variables between the initial and final measurements. The increase in gait quality variables demonstrates a substantial improvement in the subjects' gait quality and indicates that each patient, regardless of SMA severity, underwent gait improvement when treated with SCS. For each assessment, the immediate effect of SCS-on compared to SCS-off changed the subjects' ability only slightly; rather, the greatest change was observed between the initial and final measurements, demonstrating that SCS leads to long-term improvements in gait quality.

[0230] Figure 35 shows the torque generated by SMA01 during maximum isometric contraction for various movements. Each dot represents a single representation of the maximum spontaneous contraction for each day of the study. The dots are grouped vertically based on when the study was performed (e.g., pre-implantation / week 1, post-study / week 4, and / or post-study / week 6).

[0231] Figure 36 shows the torque generated by SMA03 during maximal isometric contraction for various movements. Each dot represents a single representation of the maximal spontaneous contraction for each day of the study. The dots are grouped vertically based on when the study was performed (e.g., pre-implantation / week 1, post-study / week 4, and / or post-study / week 6).

[0232] Figure 50 shows the TMS recruitment curves for SMA01 before implantation and at the end of the study (week 4). Each data point represents the inter-peak value of MEP for different stimulation intensities, plotted along the x-axis.

[0233] Figure 41 shows the TMS recruitment curves for SMA02 before implantation, at week 3 of the study, and after explantation. Each data point represents the inter-peak value of MEP for different stimulation intensities, plotted along the x-axis.

[0234] Figure 42 shows the TMS recruitment curves for SMA03 before implantation, at week 3 of the study, and after explantation. Each data point represents the inter-peak value of MEP for different stimulation intensities, plotted along the x-axis.

[0235] fMRI data acquisition: Participants were comfortably mounted to the scanner (Siemens Prisma 3 Tesla) in a supine position. A spinal coil was used. Participants were instructed to relax, remain still, and breathe normally. All three participants underwent separate experimental records for at least three days, including active limb recruitment to stretch specific muscle groups. Functional acquisition was performed using a gradient echo-echoplanar sequence with ZOOMit field imaging, with a repetition time (TR) of 2.5 s, echo duration (TE) of 34 ms, a field of view of 48 × 144 mm, a flip angle of 80°, a planar resolution of 1.0 mm × 1.0 mm, and a slice thickness of 3 mm. 32 axial slices per volume were acquired. The lower slice was placed at the end of the conus spinal cord, located around the T12 / L1 vertebra. Manual shimming adjustments focused on the spinal cord were performed to adjust for magnetic field uniformity. Physiological data (respiratory and cardiac signals) are acquired directly using MRI-compatible photoplethysmography and a respiratory belt (for SMA02 and SMA03). For registration and normalization purposes, T2-weighted high-resolution anatomical images (sequence space with resolution of 0.4 mm × 0.4 mm × 0.8 mm, TR=1.5 s, TE=135 ms) were acquired.

[0236] Spinal fMRI and preprocessing: Lumbosacral spinal fMRI was performed to visualize the activation of neuronal processes innervating specific muscles. The fMRI preprocessing, processing, and analysis pipeline was based on recent cervical and lumbar spinal fMRI studies. (Rowald, A., Komi, S., Demesmaeker, R. et al., Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. Nat Med 28, 260-271 (2022); Kinany, N, et al., Dynamic functional connectivity of resting-state spinal cord fMRI reveals fine-grained intrinsic architecture. Neuron 2020; 108(3): 424-435 e4; Kinany, N., Pirondini, E., Martuzzi, R., Mattera, L., Micera, S., Van de Ville, D., 2019. Functional imaging of rostrocaudal spinal activity during upper limb motor tasks. Neuroimage 200, 590-600.) The pipeline was adjusted to image the lumbar spinal cord. The protocol included three runs for active leg mobilization. Each run consisted of a 16-second active block, during which participants extended their knees at a rate of 0.5 Hz. Each run consisted of nine active blocks and lasted a total of six minutes.

[0237] fMRI preprocessing was performed using the FMRIB software library (FSL) v5.0.15 and the spinal cord toolbox (SCT) v5.0. Motion correction was performed using the SCT toolbox. The spinal cord midline was automatically detected using the mean functional image. A cylindrical mask (30 mm in diameter) along the midline was generated to exclude regions moving independently of the spinal cord, and slice-by-slice readjustment was performed relative to the mean functional image. All runs corresponding to the same session in the scanner were aligned to the first run of the session using three-dimensional rigid body readjustment (spline interpolation and least-squares cost function). All images were examined to ensure that any artifacts with insufficient signal were trimmed. Motion scrubbing was also performed using FSL tools to identify outlier volumes using the DVARS (root mean square of the difference in intensity between 26 continuous volumes) metric in the spinal cord with a box plot cutoff (75th percentile + 1.5 times the interquartile range). Both cerebrospinal fluid and spinal cord were automatically segmented using SCT from the mean functional image (with manual correction as needed). Using FSL's physiological noise modeling tool, noise regressors were constructed on acquired cardiac and respiratory signals using a RETROICOR procedure-based approach. Physiological signals were modeled using low and higher-order Fourier expansions, yielding 32 noise regressors (10% of the most variable cerebrospinal fluid voxels), including additional cerebrospinal fluid (CSF) regressors. These 33 physiological noise regressors (PNM and CSF) were combined with motion correction parameters (i.e., regressors for every two slices for motion in x and y) and motion outliers, and regressed from fMRI time series using FSL's fMRI Expert Analysis Tool (FEAT). The resulting residuals were then processed on a 2×2×6mm matrix. 3Spatially smoothed was performed using a 3D Gaussian kernel with full width at half maximum (FWHM). To maintain anatomical consistency, smoothing was performed along the midline of the spinal cord. Finally, acquisition timing corresponding to the task design was submitted to a specific first-level generalized linear model. A second-level fixed-effects analysis (control level) was performed by combining three runs. Where possible, multiple comparison corrections were performed (Z>1.5, p<0.05), otherwise, possible maps were not corrected (Z>1.5, p<0.05). Next, pre-implant or post-implant maps were averaged.

[0238] High-resolution structural MRI was used to identify the L1–S2 vertebral segments. The L1 posterior root was identified from its entrance region of the spinal canal (directly below the L1 vertebra) to the spinal cord innervating region that delineates the L1 vertebral segment. The more caudal segments (L2–S2) were identified by tracing the posterior root along the rostral caudal axis. The window of analysis was concentrated between the single vertebral level and the root level involved in leg extension movement.

[0239] Further consideration of subjects SMA01, SMA02, and SMA03 Over the several weeks the subjects were tested, a remarkable change was observed in the maximum force generated by patients, with a clear and sudden increase even without stimulation from week to week. When investigating changes in torque over time, surprisingly large increases were seen in almost all leg muscles, particularly the hip flexors and extensors in all participants, as well as in the knee flexors and flexors. These changes began to appear from week 2 and recovered significantly from week 3. When assessing movement in all joints, the changes appeared to be concentrated in the hip muscles, which were directly targeted in the stimulation protocol, were the most vulnerable to SMA, and were less trained in training that focused on the knee. Importantly, these improvements far exceeded the magnitude of the auxiliary effect and resulted in considerable exercise benefits over time. For example, with the auxiliary effect built upon the newly acquired force, SMA03 was able to stand up from a hinged movement on a desk by week 4, a task that participants were unable to perform without SCS before the start of the study. In summary, when SCS was turned on, a measurable boost to intensity was found, and these effects were found to be comparable to the large, sudden changes in intensity that occur over four weeks without stimulation.

[0240] Improvements in fatigue and gait were also observed. Despite significant differences in initial deficits among participants, all three showed significant improvement over four weeks in gait variables, including step height, step length, and gait speed. Importantly, when the SCS was turned on, further improvements in step height, step length, and gait speed were observed, determining a visible change in gait pattern even within the same session. SMA02 experienced particularly significant improvement in gait quality—they had severe muscle degeneration and were unable to flex their knees at all before the test, but after treatment their gait completely changed, and they were able to fully flex their knees. The changes in the kinematic image, along with an immediate increase in EMG power when the SCS was turned on, as well as an increase in the modulation of EMG activity over time, signaled that the kinematic movement was triggered by changes in muscle activation. Using a standardized 6MWT, we assessed improvements in fatigue and, surprisingly, all three participants were found to have improved by more than 20m in the 6MWT in just four weeks (compared to a minimally significant clinical difference of 14m). Furthermore, while improvements were observed in both the 6MWT and fatigue, previous reports have indicated no correlation between these two factors. This demonstrates an inherent change in exercise syndrome among the participants in this study as a result of SCS.

[0241] The magnitude and speed of the observed improvements in force and motor control suggested that these could be caused by neurally driven changes rather than muscle mass. To assess this, high-density electromyography (HDEMG) was used during maximal voluntary contractions to extract single motor unit discharges. It was found that when SCS was activated, motor units increased their overall firing rate. Comparing pre- and post-study motor neuron firing rates, unit firing dynamics were fairly consistent between units pre-study when generating isometric forces. However, after the study, new units emerged that appeared to behave significantly differently. These units showed significantly higher firing rate bursts at the onset of force, correlated with higher experimentally obtained peak values ​​(Figure 51A). The distribution of firing rates at this peak differed significantly from any other unit recorded pre-study, and these units were labeled "rescue units" as they demonstrated significantly higher firing capacity. These rescue units with significantly similar behavior were observed in all three participants. Figures 51A and 51B present traces of single-unit motor neuron firing rates during maximal voluntary contraction under isometric conditions. Rescued motor neurons are defined as those whose mean peak firing rate over repetitions (n=6) was above the 99.7th percentile of the mean peak firing rate during the pre-study session. Raster plots show spike times for two exemplary motor neurons. Figure 51A shows pre- and post-examples, and Figure 51B shows stimulus-on versus stimulus-off. Figures 52A and 52B present quantifications of mean peak firing rates across all isometric conditions for pre-versus-post (Figure 52A) and stimulus-on versus stimulus-off (Figure 52B) for each of the three patients.

[0242] Further details of the clinical trial can be found at Clinicaltrials.gov Identifier NCT05430113, “Spinal Cord Stimulation in Spinal Muscular Atrophy (SCSinSMA)” at https: / / clinicaltrials.gov / ct2 / show / NCT05430113.

[0243] Example 3 Spinal stimulation for treating upper limb muscle dysfunction in patients with SMA In this study, patients with SMA were recruited and their cervical spinal cord was stimulated using SCS.

[0244] Prior to electrode implantation, each subject will undergo a detailed medical history and physical examination, as well as detailed musculoskeletal and neurological examinations. The Physical Activity Disability Survey (PADS) and the Revised Hammersmith Function Scale (RHS) will be administered, and the subject's ability to stand independently for at least 3 seconds will also be assessed. Preoperative high-resolution MRI will be performed, and the resulting images will include high-resolution T1-weighted images, high-resolution T2-weighted images, and diffusion tensor imaging (DTI). The same brain images will be acquired at the end of the study to demonstrate possible structural changes in fiber bundles that may correlate with brain plasticity and motor recovery. Spinal functional magnetic resonance imaging will also be obtained at rest and during muscle contraction, and the same images will be acquired at the end of the study to demonstrate possible changes in brain and spinal cord functional connectivity that may correlate with plasticity and motor recovery.

[0245] To perform SCS, in steps 2-4, an ocular polarity Medtronic lead is temporarily implanted in the epidural space of the C4-T1 vertebrae in each patient. This portion of the vertebrae contains nerve roots that innervate the muscles of the trunk, back, and upper limbs. The device is passed percutaneously through the skin, secured in place with tape, and left outside for up to 29 days. During SCS testing, the lead is connected to an external stimulator. Examples of external stimulators that can be used include the Natus Medical Protektor32, Digitimer DS8, or the external wireless stimulator of Medtronic's Intellis system.

[0246] Following implantation, each subject participates in a series of electrophysiological stimulation tests. Stimulation parameters are modified but remain within the following ranges: pulse amplitude 0.2–10 mA; pulse frequency 0.1 Hz–500 Hz; pulse width 100–400 μs. EMG responses and joint movement patterns are recorded in response to stimulation training, and subjects are asked to respond to a standard set of psychophysical questions to assess the level of possible discomfort and to provide any additional comments. Patients also participate in various motor task assessments to measure the effect of the SCS on upper limb function, including the deltoid, biceps, triceps, and wrist extensor muscles of the arm flexors.

[0247] KINARM System: Since the SCS recruits proprioceptive afferent nerves to the dorsal root, it is important to assess each subject's ability to consciously and unconsciously process proprioceptive feedback. Each subject's active proprioceptive ability is assessed by performing arm movement assessments with the KINARM system (Kinarm, Kingston, Ontario, Canada) at baseline, day 29, and during follow-up visits. KINARM is a system intended for human research used to assess motor ability in stroke subjects. Participants sit in a chair with their arms supported against gravity. Participants are asked to actively perform isotonic elbow extension and flexion, e.g., movements, against constant opposing forces at 0%, 10%, 20%, and 30% of maximum voluntary surface electromyography (EMG). Surface EMG from the biceps muscles is recorded. Throughout the experiment, the participant's arms and hands are shielded from vision by a protective screen integrated into the KINARM system. Each patient's ability to assess limb position and joint movement is evaluated.

[0248] HUMAC NORM by CSMi: Each patient is evaluated using the HUMAC NORM clinical isokinetic testing system by CSMi to quantify the range of motion of the arm joint and the joint torque generated with and without SCS. This data can be captured at baseline, during the 29-day implantation period, and at follow-up visits.

[0249] Handbike: The effects of SCS are also evaluated using a handbike. Periodically, patients are asked to use a handbike whenever possible. During these trials, the SCS is provided to verify its effect on exercise task performance. Subjects use the handbike at their preferred speed and resistance while receiving the SCS or in a controlled trial without stimulation. Parameters evaluated include torque asymmetry between arms, time, distance, and speed. This evaluation may be performed pre-implantation (baseline), during implantation, and at follow-up stages after the implant is removed to assess the effect of the SCS on upper limb function.

[0250] Three-dimensional reaching / simulated activities of daily living (ADL) task: Upper limb function is also assessed through the performance of a three-dimensional reaching / simulated activities of daily living (ADL) task. The patient is asked to reach for custom-made objects and grasp them. Each object facilitates a specific type of grasping. For example, a large sphere facilitates full-force grasping, a cylinder facilitates cylindrical grasping, while a flat-shaped object facilitates precise pinch grasping with the index finger and thumb. The objects may be placed in space by a tactile robot capable of measuring grasping force and interaction force.

[0251] Primary outcomes related to muscle strength will be assessed pre-study, week 2, week 4, and post-study follow-up (at least 4 weeks after completion). SCS leads will be removed within 29 days of device placement.

[0252] Enumerated embodiments This disclosure should be read in connection with the preceding paragraph and is further described by the following numbered embodiments, which are not limiting to this disclosure. The features, options, and preferences described above also apply to the following embodiments.

[0253] 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 the subject with motor impairment due to SMA, wherein the electrical stimulation is applied using one or more electrodes controlled by a nerve stimulator, and the application of electrical stimulation treats the motor impairment due to SMA in the subject.

[0254] Embodiment 2. The method according to Embodiment 1, wherein applying electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of the subject with motor impairment due to SMA.

[0255] Embodiment 3. The method according to Embodiment 1 or Embodiment 2, wherein the stimulus is applied below the motor threshold so as not to directly induce movement and / or muscle activity in the target body region associated with motor impairment due to SMA.

[0256] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein 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.

[0257] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein 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.

[0258] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the electrical stimulation comprises 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.

[0259] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the electrical stimulation comprises a series of 2 to 5 pulses of stimulation separated by pulse intervals of approximately 3 ms to approximately 10 ms, and the series of pulses is repeated at a frequency of approximately 10 Hz to approximately 100 Hz.

[0260] Embodiment 8. The method according to Embodiment 7, wherein the stimulation pattern is a series of three pulses separated by an interpulse interval of about 5 ms, the series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the pulse width is about 200 μs.

[0261] Embodiment 9. The method according to any one of Embodiments 4 to 8, wherein the pulse is a cathode first two-phase pulse or a single-phase charge equilibrium pulse.

[0262] Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein electrical stimulation is applied for at least 2 hours / day over a period of at least 6 months.

[0263] Embodiment 11. The method according to any one of Embodiments 1 to 9, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

[0264] Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein one or more electrodes are included in an array of independently controllable electrodes that are implanted in a target.

[0265] Embodiment 13. The method according to Embodiment 12, wherein the electrode array is a multi-electrode paddle array.

[0266] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein one or more electrodes are implanted epidurally in the target spinal cord.

[0267] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein one or more electrodes are implanted in the posterior root of one or more sensory neurons that innervate a body region affected by a motor impairment of the subject.

[0268] 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 root of one or more sensory neurons that innervate a body region with motor impairment of the subject.

[0269] Embodiment 17. The method according to any one of Embodiments 1 to 13, wherein one or more electrodes are embedded in the dorsal root ganglia of one or more sensory neurons that innervate a body region affected by a motor impairment.

[0270] Embodiment 18. The method according to any one of Embodiments 1 to 12, wherein one or more electrodes are housed in a cuff surrounding peripheral nerves, including sensory neurons that innervate a body region of a subject with motor impairment due to SMA.

[0271] 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 that innervate a body region of the subject with motor impairment due to SMA.

[0272] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein the target body region is selected from at least one of the following: the waist, hip, leg, ankle, and foot, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and span one or more of the T11-S1 nerve roots.

[0273] Embodiment 21. The method according to any one of Embodiments 1 to 20, wherein the target body area 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 span one or more of the C3-T2 nerve roots.

[0274] Embodiment 22. The method according to any one of Embodiments 1 to 21, wherein the target body region 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 span one or more of the T3 to T10 nerve roots.

[0275] Embodiment 23. The method according to any one of Embodiments 1 to 22, wherein the nerve stimulator is an external or implanted pulse generator.

[0276] Embodiment 24. The method according to any one of Embodiments 1 to 23, further comprising implanting a nerve stimulator.

[0277] Embodiment 25. The method according to any one of Embodiments 1 to 24, further comprising selecting a subject with SMA for treatment.

[0278] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

[0279] Embodiment 27. The method according to any one of Embodiments 1 to 26, wherein the location of one or more electrodes is selected based on the body region of the subject with motor impairment due to SMA.

[0280] Embodiment 28. The method of Embodiment 27, wherein the positions of one or more electrodes are determined by stimulating a plurality of contact points in the subject to target at least one muscle in a body region of the subject with motor impairment due to SMA, measuring the electrical activity associated with the muscle in response to the stimulation, and identifying one or more of the contact points in the plurality of contact points as the positions of electrodes based on the electrical activity.

[0281] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein at least one of one or more electrodes is placed transcutaneously.

[0282] Embodiment 30. The method according to any one of Embodiments 1 to 29, wherein at least one of one or more electrodes is embedded.

[0283] Embodiment 31. A method for stimulating one or more motor neurons impaired by SMA, comprising applying electrical stimulation to at least one motor neuron, wherein the motor neuron innervates a body region of a subject with motor impairment due to SMA.

[0284] Embodiment 32. A method for treating spinal muscular atrophy (SMA) of a subject, comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a subject body region affected by motor impairment due to SMA.

[0285] Embodiment 33. A method for increasing the firing rate of motor neurons impaired by SMA in a subject, comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the subject to increase the firing rate of the motor neurons of the subject.

[0286] Embodiment 34. The method according to Embodiment 33, wherein the subject is the firing rate of a first motor neuron before the application of a therapeutically effective amount of electrical stimulation, and the firing rate of a second motor neuron after the application.

[0287] Embodiment 35. The method according to Embodiment 33 or Embodiment 34, wherein 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.

[0288] Embodiment 36. The method according to any one of Embodiments 33 to 35, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

[0289] Embodiment 37. The method according to any one of embodiments 33 to 36, wherein the firing rate of a target motor neuron is calculated based on the electrical signals generated by the motor neuron while varying the parameters of the electrical stimulation.

[0290] Embodiment 38. The method according to any one of Embodiments 33 to 37, wherein increasing the firing rate of motor neurons impaired by SMA increases the joint torque and muscle strength of the target.

[0291] Embodiment 39. A method for increasing the excitability of motor neurons impaired by a target SMA to sensory afferent input, comprising applying a therapeutically effective amount of electrical stimulation to sensory neurons innervating a body region of the target to increase the excitability of the target motor neurons.

[0292] Embodiment 40. The method according to Embodiment 39, wherein the subject has a first motor neuron excitability before the application of a therapeutically effective amount of electrical stimulation and a second motor neuron excitability after the application.

[0293] Embodiment 41. The method according to Embodiment 39 or Embodiment 40, wherein 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.

[0294] Embodiment 42. The method according to any one of Embodiments 39 to 41, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

[0295] Embodiment 43. The method according to any one of Embodiments 39 to 42, wherein the excitability of the motor neuron in question is calculated based on the electrical signals generated by the motor neuron while varying the parameters of the electrical stimulation.

[0296] Embodiment 44. The method according to any one of Embodiments 39 to 43, wherein increasing the excitability of motor neurons impaired by SMA increases the joint torque and muscle strength of the target.

[0297] 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 the treatment of a target SMA, wherein the electrical stimulation is applied using one or more electrodes controlled by a nerve stimulator, and the application of the electrical stimulation is a therapeutically effective amount of electrical stimulation to treat the motor impairment due to the target SMA.

[0298] Embodiment 46. Electrical stimulation for use according to Embodiment 45, wherein the application of electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of the subject with motor impairment due to SMA.

[0299] Embodiment 47. Electrical stimulation for use as described in Embodiment 45 or Embodiment 46, wherein the stimulation is applied below the motor threshold so as not to directly induce movement and / or muscle activity in the body region of the subject with motor impairment due to SMA.

[0300] Embodiment 48. Electrical stimulation for use according to Embodiments 45 to 47, comprising 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.

[0301] Embodiment 49. Electrical stimulation for use according to Embodiments 45 to 48, wherein 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.

[0302] Embodiment 50. Electrical stimulation for use according to Embodiments 45 to 49, wherein the electrical stimulation comprises 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.

[0303] Embodiment 51. Electrical stimulation for use according to any one of Embodiments 1 to 50, comprising a series of 2 to 5 pulse stimulation patterns separated by pulse intervals of about 3 ms to about 10 ms, the series of pulses being repeated at a frequency of about 10 Hz to about 100 Hz.

[0304] Embodiment 52. The stimulation pattern is a series of three pulses separated by an interpulse interval of about 5 ms, the series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the pulse width is about 200 μs, the electrical stimulation for use as described in Embodiment 51.

[0305] Embodiment 53. Electrical stimulation for use according to any one of Embodiments 48 to 52, wherein the pulse is a cathode first two-phase pulse or a single-phase charge equilibrium pulse.

[0306] Embodiment 54. Electrical stimulation for use according to any one of Embodiments 1 to 53, wherein the electrical stimulation is applied for at least 2 hours / day over a period of at least 6 months.

[0307] Embodiment 55. Electrical stimulation for use according to any one of Embodiments 45 to 53, wherein the electrical stimulation is applied for at least one hour / day over a period of at least one month.

[0308] Embodiment 56. Electrical stimulation for use according to any one of Embodiments 1 to 55, wherein one or more electrodes are included in an array of independently controllable electrodes implanted in a subject.

[0309] Embodiment 57. Electrical stimulation for use according to Embodiment 56, wherein the electrode array is a multi-electrode paddle array.

[0310] Embodiment 58. Electrical stimulation for use according to any one of Embodiments 1 to 57, wherein one or more electrodes are implanted epidurally in the spinal cord of the subject.

[0311] Embodiment 59. Electrical stimulation for use according to any one of Embodiments 45 to 58, wherein one or more electrodes are implanted in the posterior root of one or more sensory neurons that innervate a body region with motor impairment in question.

[0312] Embodiment 60. Electrical stimulation for use according to any one of Embodiments 45 to 58, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord adjacent to the dorsal root of one or more sensory neurons innervating a body region with motor impairment of the subject.

[0313] Embodiment 61. Electrical stimulation for use according to any one of Embodiments 45 to 57, wherein one or more electrodes are embedded in the dorsal root ganglia of one or more sensory neurons innervating a body region with motor impairment in question.

[0314] Embodiment 62. Electrical stimulation for use according to any one of Embodiments 45 to 56, wherein one or more electrodes are housed in a cuff surrounding peripheral nerves, including sensory neurons that innervate a body region of a subject with motor impairment due to SMA.

[0315] Embodiment 63. Electrical stimulation for use according to any one of Embodiments 45 to 56, wherein one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons that innervate a body region of a subject with motor impairment due to SMA.

[0316] Embodiment 64. The target body area is selected from at least one of the lumbar region, hip joint, leg, ankle, and foot, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and extend across one or more of the T11-S1 nerve roots, for electrical stimulation for use according to any one of Embodiments 1 to 63.

[0317] Embodiment 65. The target body area 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 span one or more of the C3-T2 nerve roots, wherein the electrical stimulation for use is as described in any one of Embodiments 1 to 64.

[0318] Embodiment 66. The target body region 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 span one or more of the T3-T10 nerve roots, wherein the electrical stimulation for use is as described in any one of Embodiments 1 to 65.

[0319] Embodiment 67. Electrical stimulation for use according to any one of Embodiments 1 to 66, wherein the nerve stimulator is an external or implanted pulse generator.

[0320] Embodiment 68. Electrical stimulation for use according to any one of Embodiments 1 to 67, wherein a nerve stimulator is implanted in the subject.

[0321] Embodiment 69. Electrical stimulation for use according to any one of Embodiments 1 to 68, wherein a subject with SMA is selected for treatment.

[0322] Embodiment 70. Electrical stimulation for use according to any one of Embodiments 1 to 69, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

[0323] Embodiment 71. Electrical stimulation for use according to any one of Embodiments 1 to 70, wherein the position of one or more electrodes is selected based on the body region of the subject with motor impairment due to SMA.

[0324] Embodiment 72. Electrical stimulation for use according to Embodiment 71, wherein the positions of one or more electrodes are determined by stimulating a plurality of contact points in the subject to target at least one muscle in a body region of the subject with motor impairment due to SMA, measuring the electrical activity associated with the muscle in response to the stimulation, and identifying one or more contact points in the plurality of contact points as the positions of electrodes based on the electrical activity.

[0325] Embodiment 73. Electrical stimulation for use according to any one of Embodiments 1 to 72, wherein at least one of one or more electrodes is placed transcutaneously.

[0326] Embodiment 74. Electrical stimulation for use according to any one of Embodiments 1 to 73, wherein at least one of one or more electrodes is implanted.

[0327] Embodiment 75. Use of one or more electrodes controlled by a nerve stimulator in the manufacture of a pharmaceutical for treating a target SMA, wherein the one or more electrodes controlled by the nerve stimulator are configured to apply a therapeutically effective amount of electrical stimulation to sensory neurons innervating a target body region with motor impairment due to the SMA.

[0328] Embodiment 76. The use described in Embodiment 75, wherein electrical stimulation is applied to increase the firing rate probability of spinal motor neurons innervating the body region of the subject with motor impairment due to SMA.

[0329] Embodiment 77. The use described in Embodiment 75 or Embodiment 76, wherein the stimulus is applied below the motor threshold so as not to directly induce movement and / or muscle activity in the body region of the subject with motor impairment due to SMA.

[0330] Embodiment 78. The use according to Embodiments 75 to 77, wherein 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.

[0331] Embodiment 79. The use according to Embodiments 75 to 78, wherein 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.

[0332] Embodiment 80. The use according to Embodiments 75 to 79, wherein the electrical stimulation comprises 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.

[0333] Embodiment 81. The use according to any one of Embodiments 75 to 80, wherein 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.

[0334] Embodiment 82. The stimulation pattern is a series of three pulses separated by an interpulse interval of approximately 5 ms, the series of pulses is repeated at a frequency of approximately 30 to approximately 100 Hz, and the pulse width is approximately 200 μs, as described in Embodiment 81.

[0335] Embodiment 83. Use according to any one of embodiments 78 to 82, wherein the pulse is a cathode first two-phase pulse or a single-phase charge equilibrium pulse.

[0336] Embodiment 84. The use according to any one of Embodiments 75 to 83, wherein the electrical stimulation is applied for at least 2 hours / day over a period of at least 6 months.

[0337] Embodiment 85. The use according to any one of Embodiments 75 to 83, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

[0338] Embodiment 86. The use according to any one of Embodiments 75 to 85, wherein one or more electrodes are included in an array of independently controllable electrodes that are implanted in the subject.

[0339] Embodiment 87. The use of Embodiment 86, wherein the electrode array is a multi-electrode paddle array.

[0340] Embodiment 88. The use according to any one of Embodiments 75 to 87, wherein one or more electrodes are implanted epidurally in the target spinal cord.

[0341] Embodiment 89. The use according to any one of Embodiments 75 to 88, wherein one or more electrodes are implanted in the posterior root of one or more sensory neurons that innervate the body region affected by the motor impairment in question.

[0342] Embodiment 90. The use according to any one of Embodiments 75 to 88, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord adjacent to the dorsal root of one or more sensory neurons that innervate the body region with motor impairment in question.

[0343] Embodiment 91. The use according to any one of Embodiments 75 to 87, wherein one or more electrodes are embedded in the dorsal root ganglia of one or more sensory neurons that innervate the body region affected by the motor impairment in question.

[0344] Embodiment 92. The use according to any one of Embodiments 75 to 86, wherein one or more electrodes are housed in a cuff surrounding peripheral nerves, including sensory neurons that innervate a body region of a subject with motor impairment due to SMA.

[0345] Embodiment 93. The use according to any one of Embodiments 75 to 86, wherein one or more electrodes penetrate a peripheral nerve or dorsal root ganglion containing sensory neurons that innervate a body region of the subject with motor impairment due to SMA.

[0346] Embodiment 94. The body region to be used is selected from at least one of the following: the waist, hip, leg, ankle, and foot, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and span one or more of the T11-S1 nerve roots, as described in any one of Embodiments 75 to 93.

[0347] Embodiment 95. The body area to be used 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 span one or more of the C3-T2 nerve roots, as described in any one of Embodiments 75 to 94.

[0348] Embodiment 96. The body region to be used 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 span one or more of the T3-T10 nerve roots, as described in any one of Embodiments 75 to 95.

[0349] Embodiment 97. The use according to any one of Embodiments 75 to 96, wherein the nerve stimulator is an external or implanted pulse generator.

[0350] Embodiment 98. The use according to any one of Embodiments 75 to 97, wherein the nerve stimulator is implanted in the subject.

[0351] Embodiment 99. The use according to any one of Embodiments 75 to 98, wherein a subject with SMA is selected for treatment.

[0352] Embodiment 100. Use according to any one of Embodiments 75 to 99, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

[0353] Embodiment 101. The use according to 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 motor impairment due to SMA.

[0354] Embodiment 102. The use of 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 in a body region of the subject with motor impairment due to SMA, measuring the electrical activity associated with the muscle in response to the stimulation, and identifying one or more contact points among the plurality of contact points as the position of electrodes based on the electrical activity.

[0355] Embodiment 103. The use according to any one of embodiments 75 to 102, wherein at least one of one or more electrodes is placed transcutaneously.

[0356] Embodiment 104. The use according to any one of embodiments 75 to 103, wherein at least one of one or more electrodes is embedded.

[0357] Embodiment 105. Use of one or more electrodes controlled by a nerve stimulator in the manufacture of a pharmaceutical for treating SMA in a subject, wherein electrical stimulation is applied to sensory neurons innervating a body area of ​​the subject with motor impairment due to SMA, using one or more electrodes controlled by a nerve stimulator.

[0358] Embodiment 106. The use described in Embodiment 105, wherein applying electrical stimulation increases the firing rate probability of spinal motor neurons innervating a body region of the subject with motor impairment due to SMA.

[0359] Embodiment 107. The use described in Embodiment 105 or Embodiment 106, wherein the stimulus is applied below the motor threshold so as not to directly induce movement and / or muscle activity in the body region of the subject with motor impairment due to SMA.

[0360] Embodiment 108. The use according to Embodiments 105 to 107, wherein 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.

[0361] Embodiment 109. The use according to Embodiments 105 to 108, wherein 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.

[0362] Embodiment 110. The use according to Embodiments 105 to 109, wherein 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.

[0363] Embodiment 111. The use according to any one of Embodiments 105 to 110, wherein 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.

[0364] Embodiment 112. The stimulation pattern is a series of three pulses separated by an interpulse interval of about 5 ms, the series of pulses is repeated at a frequency of about 30 to about 100 Hz, and the pulse width is about 200 μs, as described in Embodiment 111.

[0365] Embodiment 113. Use according to any one of Embodiments 108 to 112, wherein the pulse is a cathode first two-phase pulse or a single-phase charge equilibrium pulse.

[0366] Embodiment 114. The use according to any one of Embodiments 105 to 113, wherein the electrical stimulation is applied for at least 2 hours / day over a period of at least 6 months.

[0367] Embodiment 115. The use according to any one of Embodiments 105 to 113, wherein the electrical stimulation is applied for at least one hour / day over a period of at least one month.

[0368] Embodiment 116. The use according to any one of Embodiments 105 to 115, wherein one or more electrodes are included in an array of independently controllable electrodes that are implanted in the target.

[0369] Embodiment 117. The use according to Embodiment 116, wherein the electrode array is a multi-electrode paddle array.

[0370] Embodiment 118. The use according to any one of Embodiments 105 to 117, wherein one or more electrodes are implanted epidurally in the spinal cord of the subject.

[0371] Embodiment 119. The use according to any one of Embodiments 105 to 118, wherein one or more electrodes are implanted in the posterior root of one or more sensory neurons that innervate the body region affected by the motor impairment in question.

[0372] Embodiment 120. The 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 root of one or more sensory neurons that innervate the body region with motor impairment in question.

[0373] Embodiment 121. The use according to any one of Embodiments 105 to 117, wherein one or more electrodes are embedded in the dorsal root ganglia of one or more sensory neurons that innervate a body region affected by the motor impairment in question.

[0374] Embodiment 122. The use according to any one of Embodiments 105 to 116, wherein one or more electrodes are housed in a cuff surrounding peripheral nerves, including sensory neurons that innervate a body region of the subject with motor impairment due to SMA.

[0375] Embodiment 123. The 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 that innervate a body region of the subject with motor impairment due to SMA.

[0376] Embodiment 124. The body region to be used is selected from at least one of the following: the waist, hip, leg, ankle, and foot, and one or more electrodes are implanted on the posterolateral surface of the spinal cord and span one or more of the T11-S1 nerve roots, as described in any one of Embodiments 105 to 123.

[0377] Embodiment 125. The body area to be used 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 span one or more of the C3-T2 nerve roots, as described in any one of Embodiments 105 to 124.

[0378] Embodiment 126. The body region to be used 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 span one or more of the T3-T10 nerve roots, as described in any one of Embodiments 105 to 125.

[0379] Embodiment 127. The use according to any one of Embodiments 105 to 126, wherein the nerve stimulator is an external or implanted pulse generator.

[0380] Embodiment 128. The use according to any one of Embodiments 105 to 127, wherein the nerve stimulator is implanted in the subject.

[0381] Embodiment 129. The use according to any one of Embodiments 105 to 128, wherein a subject with SMA is selected for treatment.

[0382] Embodiment 130. Use according to any one of Embodiments 105 to 129, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

[0383] Embodiment 131. The use according to any one of Embodiments 105 to 130, wherein the location of one or more electrodes is selected based on the body region of the subject with motor impairment due to SMA.

[0384] Embodiment 132. The use of Embodiment 131, wherein the position of one or more electrodes is determined by stimulating multiple contact points in the subject to target at least one muscle in a body region of the subject with motor impairment due to SMA, measuring the electrical activity associated with the muscle in response to the stimulation, and identifying one or more contact points among the multiple contact points as the position of electrodes based on the electrical activity.

[0385] Embodiment 133. The use according to any one of embodiments 105 to 132, wherein at least one of one or more electrodes is placed transcutaneously.

[0386] Embodiment 134. The use according to any one of embodiments 105 to 133, wherein at least one of one or more electrodes is embedded.

[0387] Embodiment 135. The method according to any one of Embodiments 1 to 44, wherein the subject is receiving SMA therapy in addition to electrical stimulation.

[0388] Embodiment 136. The method according to Embodiment 135, wherein the SMA therapy is selected from the group consisting of a vector-based gene therapy for delivering a copy of the SMN1 gene, an antisense oligonucleotide (ASO) therapy targeting the SMN2 gene, or a small molecule SMN2-splicing modifier.

[0389] Embodiment 137. The method according to Embodiment 135 or 136, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdiplam.

[0390] Embodiment 138. The method according to any one of Embodiments 135 to 137, wherein the subject was administered onasemnogen abeparvovec within six years prior to the first application of electrical stimulation.

[0391] Embodiment 139. The method according to any one of Embodiments 135 to 137, wherein the subject was administered onasemnogene abeparvovec at least 18 months prior to the first application of electrical stimulation.

[0392] Embodiment 140. The method according to any one of Embodiments 135 to 137, wherein the subject is administered nusinersen according to a maintenance dosing schedule during electrical stimulation.

[0393] Embodiment 141. The method according to any one of Embodiments 135 to 137 or 140, wherein the subject was first administered nusinersen at least 6 months prior to the first application of electrical stimulation.

[0394] Embodiment 142. The method according to any one of Embodiments 135 to 137, wherein the subject is administered risdiplam.

[0395] Embodiment 143. The method according to any one of Embodiments 135 to 137 or 142, wherein the subject initiated administration of risdiplam within 18 months prior to the first application of electrical stimulation.

[0396] Embodiment 144. The method according to any one of Embodiments 135 to 137 or 142, wherein the subject has been administered risdiplam for at least one year prior to the first application of electrical stimulation.

[0397] Embodiment 145. Electrical stimulation for use according to any one of Embodiments 45 to 74, wherein the subject is receiving SMA therapy in conjunction with electrical stimulation.

[0398] Embodiment 146. Electrical stimulation for use according to Embodiment 145, wherein the SMA therapy is selected from the group consisting of gene therapy based on a vector that delivers a copy of the SMN1 gene, antisense oligonucleotide (ASO) therapy targeting the SMN2 gene, or small molecule SMN2-splicing modifiers.

[0399] Embodiment 147. Electrical stimulation for use according to Embodiment 145 or 146, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdipram.

[0400] Embodiment 148. Electrical stimulation for use according to any one of Embodiments 145 to 147, wherein the subject was administered onasemnogene abeparvovec within six years prior to the first application of electrical stimulation.

[0401] Embodiment 149. Electrical stimulation for use according to any one of Embodiments 145 to 147, wherein the subject was administered onasemnogene abeparvovec at least 18 months prior to the first application of electrical stimulation.

[0402] Embodiment 150. Electrical stimulation for use according to any one of Embodiments 145 to 147, wherein the subject is being administered nusinersen according to a maintenance dosing schedule at the time of electrical stimulation.

[0403] Embodiment 151. Electrical stimulation for use according to any one of Embodiments 145 to 147 or 150, wherein the subject was first administered nusinersen at least 6 months prior to the first application of electrical stimulation.

[0404] Embodiment 152. Electrical stimulation for use according to any one of Embodiments 145 to 147, wherein the subject is administered risdiplam.

[0405] Embodiment 153. Electrical stimulation for use according to any one of Embodiments 145 to 147 or 152, wherein the subject initiated administration of risdiplam within 18 months prior to the application of the first electrical stimulation.

[0406] Embodiment 154. Electrical stimulation for use according to any one of Embodiments 145 to 147 or 152, wherein the subject has been administered risdiplam for at least one year prior to the first application of electrical stimulation.

[0407] Embodiment 155. The use according to any one of Embodiments 75 to 134, wherein the subject is receiving SMA therapy in conjunction with electrical stimulation.

[0408] Embodiment 156. The use according to Embodiment 155, wherein the SMA therapy is selected from the group consisting of a vector-based gene therapy for delivering a copy of the SMN1 gene, an antisense oligonucleotide (ASO) therapy targeting the SMN2 gene, or a small molecule SMN2-splicing modifier.

[0409] Embodiment 157. The method according to Embodiment 155 or 156, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdiplam.

[0410] Embodiment 158. The use according to any one of Embodiments 155 to 157, wherein the subject was administered onasemnogen abeparvovec within six years prior to the first application of electrical stimulation.

[0411] Embodiment 159. The use according to any one of Embodiments 155 to 157, wherein the subject was administered onasemnogene abeparvovec at least 18 months prior to the first application of electrical stimulation.

[0412] Embodiment 160. The use according to any one of Embodiments 155 to 157, wherein the subject is administered nusinersen according to a maintenance dosing schedule during electrical stimulation.

[0413] Embodiment 161. The use according to any one of Embodiments 155 to 157 or 160, wherein the subject was first administered nusinersen at least six months prior to the first application of electrical stimulation.

[0414] Embodiment 162. The use according to any one of Embodiments 155 to 157, wherein the subject is administered risdiplam.

[0415] Embodiment 163. The use according to any one of Embodiments 155 to 157 or 162, wherein the subject initiated administration of risdiplam within 18 months prior to the first application of electrical stimulation.

[0416] Embodiment 164. The use according to any one of Embodiments 155 to 157 or 162, wherein the subject has been administered risdiplam for at least one year prior to the first application of electrical stimulation.

[0417] Embodiment 165. The method according to any one of Embodiments 1 to 44 or 135 to 144, wherein the subject has a type 1 SMA.

[0418] Embodiment 166. The method according to any one of Embodiments 1 to 44 or 135 to 144, wherein the subject has a type 2 SMA.

[0419] Embodiment 167. The method according to any one of Embodiments 1 to 44 or 135 to 144, wherein the subject has a type 3 SMA.

[0420] Embodiment 168. The method according to any one of Embodiments 1 to 44 or 135 to 144, wherein the subject has a type 4 SMA.

[0421] Embodiment 169. Electrical stimulation for use according to any one of Embodiments 45 to 74 or 145 to 154, wherein the subject has a type 1 SMA.

[0422] Embodiment 170. Electrical stimulation for use according to any one of Embodiments 45 to 74 or 145 to 154, wherein the subject has a type 2 SMA.

[0423] Embodiment 171. Electrical stimulation for use according to any one of Embodiments 45 to 74 or 145 to 154, wherein the subject has a type 3 SMA.

[0424] Embodiment 172. Electrical stimulation for use according to any one of Embodiments 45 to 74 or 145 to 154, wherein the subject has a type 4 SMA.

[0425] Embodiment 173. Use according to any one of Embodiments 75 to 134 or 155 to 164, wherein the subject has a type 1 SMA.

[0426] Embodiment 174. Use according to any one of Embodiments 75 to 134 or 155 to 164, wherein the subject has a type 2 SMA.

[0427] Embodiment 175. Use according to any one of Embodiments 75 to 134 or 155 to 164, wherein the subject has a Type 3 SMA.

[0428] Embodiment 176. Use according to any one of Embodiments 75 to 134 or 155 to 164, wherein the subject has a Type 4 SMA.

[0429] Embodiment 177. A method for treating spinal muscular atrophy (SMA),

[0430] This includes applying a therapeutically effective amount of electrical stimulation to one or more sensory neurons innervating a body region of a subject with motor impairment due to SMA,

[0431] The method involves the patient receiving SMA therapy in conjunction with electrical stimulation.

[0432] Embodiment 178. A method for stimulating one or more motor neurons impaired by SMA, wherein the method is

[0433] The procedure includes applying electrical stimulation to at least one motor neuron, the motor neuron innervating a body region of the subject with motor impairment due to SMA,

[0434] The method involves the patient receiving SMA therapy in conjunction with electrical stimulation.

[0435] Embodiment 179. A method for increasing the firing rate of one or more motor neurons impaired by SMA in a subject,

[0436] Applying electrical stimulation to one or more sensory neurons that innervate a target area of ​​the body.

[0437] The subjects received SMA therapy in addition to electrical stimulation.

[0438] A method comprising thereby increasing the firing rate of one or more motor neurons impaired by SMA in a subject.

[0439] Embodiment 180. The method according to any one of Embodiments 177 to 179, wherein the SMA therapy is selected from the group consisting of a gene therapy based on a vector that delivers a copy of the SMN1 gene, an antisense oligonucleotide (ASO) therapy that targets the SMN2 gene, or a small molecule SMN2-splicing modifier.

[0440] Embodiment 181. The method according to any one of Embodiments 177 to 180, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdiplam.

[0441] Embodiment 182. The method according to any one of Embodiments 177 to 181, wherein the body region of interest is selected from at least one of the waist, hip, leg, ankle, and foot.

[0442] Embodiment 183. The method according to any one of Embodiments 177 to 182, wherein one or more electrodes are implanted on the posterolateral surface of the spinal cord, spanning one or more T11-S1 nerve roots, and electrical stimulation is provided by one or more of the electrodes.

[0443] Embodiment 184. The method according to any one of Embodiments 177 to 180, wherein the body region of interest is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles.

[0444] Embodiment 185. The method according to any one of Embodiments 177 to 180 or 184, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord, spanning one or more C3-T2 nerve roots, and electrical stimulation is provided by one or more of the electrodes.

[0445] Embodiment 186. The method according to any one of Embodiments 177 to 180, wherein the body region of interest is selected from at least one of the chest, chest wall, abdomen, upper back, and mid-back.

[0446] Embodiment 187. The method according to any one of Embodiments 177 to 180 or 186, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord, spanning one or more T3-T10 nerve roots, and electrical stimulation is provided by one or more of the electrodes.

[0447] Embodiment 188. The method according to any one of Embodiments 177 to 187, for increasing the probability of firing of spinal motor neurons innervating a body region of a subject with motor impairment due to SMA.

[0448] Embodiment 189. The method according to any one of Embodiments 177 to 188, wherein joint torque and muscle force of a target within the body region are increased.

[0449] Embodiment 190. The method according to any one of Embodiments 177 to 189, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

[0450] Embodiment 191. The method according to any one of Embodiments 177 to 190, wherein the stimulus is applied below the motor threshold so as not to directly induce movement and / or muscle activity in the body region of the subject with motor impairment due to SMA.

[0451] Embodiment 192. The method according to any one of Embodiments 177 to 191, wherein 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.

[0452] Embodiment 193. The method according to any one of claims 177 to 192, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

[0453] Embodiment 194. The method according to any one of Embodiments 177 to 193, wherein the subject has a type 1 SMA.

[0454] Embodiment 195. The method according to any one of Embodiments 177 to 194, wherein the subject has a type 2 SMA.

[0455] Embodiment 196. The method according to any one of Embodiments 177 to 194, wherein the subject has a type 3 SMA.

[0456] Embodiment 197. The method according to any one of Embodiments 177 to 194, wherein the subject has a type 4 SMA.

[0457] Embodiment 198. The method according to any one of Embodiments 177 to 197, wherein the SMA therapy is nusinersen.

[0458] Embodiment 199. The method according to any one of Embodiments 177 to 198, wherein the SMA therapy is risdiplam.

[0459] Embodiment 200. Electrical stimulation for use in the treatment of spinal muscular atrophy (SMA) of a subject, wherein a therapeutically effective amount of electrical stimulation is applied to one or more sensory neurons innervating a body region of the subject having motor impairment due to SMA, and the subject is receiving SMA therapy in conjunction with the electrical stimulation.

[0460] Embodiment 201. Electrical stimulation for use in stimulating one or more motor neurons impaired by SMA, wherein the electrical stimulation is applied to at least one motor neuron, the motor neuron innervates a body region of a subject having a motor impairment due to SMA, and the subject is receiving SMA therapy in conjunction with the electrical stimulation.

[0461] Embodiment 202. Electrical stimulation for use in increasing the firing rate of one or more motor neurons impaired by SMA in a subject, wherein the electrical stimulation is applied to one or more sensory neurons innervating a body region of the subject, and the subject receives SMA therapy in conjunction with the electrical stimulation, thereby increasing the firing rate of the subject's motor neurons.

[0462] Embodiment 203. Electrical stimulation for use according to any one of Embodiments 200 to 202, wherein the SMA therapy is selected from the group consisting of a vector-based gene therapy for delivering a copy of the SMN1 gene, an antisense oligonucleotide (ASO) therapy targeting the SMN2 gene, or a small molecule SMN2-splicing modifier.

[0463] Embodiment 204. Electrical stimulation for use according to any one of Embodiments 200 to 203, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdipram.

[0464] Embodiment 205. Electrical stimulation for use according to any one of Embodiments 200 to 204, wherein the target body area is selected from at least one of the waist, hip, leg, ankle, and foot.

[0465] Embodiment 206. Electrical stimulation for use according to any one of Embodiments 200 to 205, wherein the electrical stimulation is provided by one or more electrodes implanted in the posterolateral surface of the spinal cord and spanning one or more of the T11-S1 nerve roots.

[0466] Embodiment 207. Electrical stimulation for use according to any one of Embodiments 200 to 204, wherein the target body area is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles.

[0467] Embodiment 208. Electrical stimulation for use according to any one of Embodiments 200 to 204 or 207, wherein the electrical stimulation is provided by one or more electrodes implanted in the posterolateral surface of the spinal cord and spanning one or more of the C3-T2 nerve roots.

[0468] Embodiment 209. Electrical stimulation for use according to any one of Embodiments 200 to 204, wherein the target body region is selected from at least one of the chest, chest wall, abdomen, upper back, and mid-back.

[0469] Embodiment 210. Electrical stimulation for use according to any one of Embodiments 200 to 204 or 209, wherein the electrical stimulation is provided by one or more electrodes implanted in the posterolateral surface of the spinal cord and spanning one or more of the T3 to T10 nerve roots.

[0470] Embodiment 211. Electrical stimulation for use according to any one of Embodiments 200 to 210, for increasing the firing rate probability of spinal motor neurons innervating a body region of a subject with motor impairment due to SMA.

[0471] Embodiment 212. Electrical stimulation for use according to any one of Embodiments 200 to 211, which increases joint torque and muscle strength of a target within a body region.

[0472] Embodiment 213. Electrical stimulation for use according to any one of Embodiments 200 to 212, wherein the electrical stimulation is applied for at least one hour / day over a period of at least one month.

[0473] Embodiment 214. Electrical stimulation for use according to any one of Embodiments 200 to 213, wherein the stimulation is applied below the motor threshold so as not to directly induce movement and / or muscle activity in the body region of the subject with motor impairment due to SMA.

[0474] Embodiment 215. Electrical stimulation for use according to any one of Embodiments 200 to 214, comprising 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.

[0475] Embodiment 216. Electrical stimulation for use according to any one of Embodiments 200 to 215, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

[0476] Embodiment 217. Electrical stimulation for use according to any one of Embodiments 200 to 216, wherein the subject has a type 1 SMA.

[0477] Embodiment 218. Electrical stimulation for use according to any one of Embodiments 200 to 216, wherein the subject has a type 2 SMA.

[0478] Embodiment 219. Electrical stimulation for use according to any one of Embodiments 200 to 216, wherein the subject has a type 3 SMA.

[0479] Embodiment 220. Electrical stimulation for use according to any one of Embodiments 200 to 216, wherein the subject has a type 4 SMA.

[0480] Embodiment 221. Electrical stimulation for use according to any one of Embodiments 200 to 220, wherein the SMA therapy is nusinersen.

[0481] Embodiment 222. Electrical stimulation for use according to any one of Embodiments 200 to 220, wherein the SMA therapy is risdiplam.

[0482] Embodiment 223. An electrode assembly comprising one or more electrodes configured to provide electrical stimulation for use according to any one of Embodiments 200 to 222.

[0483] Embodiment 224. The electrode assembly according to Embodiment 223, wherein one or more electrodes comprise a multi-electrode paddle array.

[0484] Embodiment 224. The electrode assembly according to Embodiment 222 or 223, further comprising a nerve stimulator that controls one or more electrodes.

[0485] Embodiment 225. One or more electrodes are implanted epidurally in the spinal cord of the subject, comprising any one electrode assembly according to Embodiments 222 to 224.

[0486] Embodiment 226. The electrode assembly according to any one of claims 222 to 225, wherein one or more electrodes are embedded in the posterior root of one or more sensory neurons that innervate a body region affected by a motor impairment.

[0487] The above description is provided for illustrative purposes and with reference to specific examples. However, the above illustrative discussion is not intended to be exhaustive or to limit the invention to the exact form disclosed. Many modifications and variations are possible in light of the above teachings. The examples have been selected and described to best illustrate the principles of the art and their practical applications. Therefore, other persons skilled in the art will be able to best utilize the art and various examples with various modifications suitable for the specific use intended.

[0488] It is clear that the exact details of the described methods or compositions may be altered 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 spirit are described in the claims.

Claims

1. A method for treating spinal muscular atrophy (SMA), This includes applying a therapeutically effective amount of electrical stimulation to one or more sensory neurons that innervate the body region of the subject having motor impairment due to SMA, A method wherein the subject receives SMA therapy in combination with the electrical stimulation.

2. A method for stimulating one or more motor neurons damaged by SMA, wherein the method is The application includes applying electrical stimulation to at least one of the motor neurons, wherein the motor neuron innervates a body region of the subject affected by motor impairment due to SMA. A method wherein the subject receives SMA therapy in combination with the electrical stimulation.

3. A method for increasing the firing rate of one or more motor neurons impaired by SMA in a subject, Applying electrical stimulation to one or more sensory neurons that innervate the aforementioned body region, The subject receives SMA therapy in addition to the electrical stimulation. A method comprising thereby increasing the firing rate of one or more motor neurons impaired by SMA in the subject.

4. The method according to any one of claims 1 to 3, wherein the SMA therapy is selected from the group consisting of a gene therapy based on a vector for delivering a copy of the SMN1 gene, an antisense oligonucleotide (ASO) therapy targeting the SMN2 gene, or a small molecule SMN2-splicing modifier.

5. The method according to any one of claims 1 to 4, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdipram.

6. The method according to any one of claims 1 to 5, wherein the body region of the target is selected from at least one of the waist, hip, leg, ankle, and foot.

7. The method according to any one of claims 1 to 6, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord and span one or more T11-S1 nerve roots, and the electrical stimulation is provided by one or more of the one or more electrodes.

8. The method according to any one of claims 1 to 5, wherein the body region of the target is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles.

9. The method according to any one of claims 1 to 5 or 8, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord and span one or more C3-T2 nerve roots, and the electrical stimulation is provided by one or more of the one or more electrodes.

10. The method according to any one of claims 1 to 5, wherein the body region of the target is selected from at least one of the chest, chest wall, abdomen, upper back, and mid-back.

11. The method according to any one of claims 1 to 5 or 10, wherein one or more electrodes are implanted in the posterolateral surface of the spinal cord and span one or more T3 to T10 nerve roots, and the electrical stimulation is provided by one or more of the one or more electrodes.

12. The method according to any one of claims 1 to 11, for increasing the probability of firing rate of spinal motor neurons innervating the body region of the subject that is affected by the motor impairment caused by the SMA.

13. The method according to any one of claims 1 to 12, wherein the joint torque and muscle strength of the target within the body region are increased.

14. The method according to any one of claims 1 to 13, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

15. The method according to any one of claims 1 to 14, wherein the stimulus is applied below a motor threshold such that the stimulus does not directly induce movement and / or muscle activity in the body region of the subject accompanied by motor impairment due to SMA.

16. The method according to any one of claims 1 to 14, wherein 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.

17. The method according to any one of claims 1 to 16, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

18. The method according to any one of claims 1 to 17, wherein the subject has a type 1 SMA.

19. The method according to any one of claims 1 to 17, wherein the subject has a type 2 SMA.

20. The method according to any one of claims 1 to 17, wherein the subject has a type 3 SMA.

21. The method according to any one of claims 1 to 17, wherein the subject has a type 4 SMA.

22. The method according to any one of claims 1 to 21, wherein the SMA therapy is nusinersen.

23. The method according to any one of claims 1 to 21, wherein the SMA therapy is risdiplam.

24. Electrical stimulation for use in the treatment of spinal muscular atrophy (SMA) of a subject, wherein a therapeutically effective amount of the electrical stimulation is applied to one or more sensory neurons innervating a body region of the subject having motor impairment due to SMA, and the subject is receiving SMA therapy in conjunction with the electrical stimulation.

25. Electrical stimulation for use in stimulating one or more motor neurons impaired by SMA, wherein the electrical stimulation is applied to at least one of the motor neurons, the motor neuron innervates a body region of a subject having a motor impairment due to SMA, and the subject is receiving SMA therapy in conjunction with the electrical stimulation.

26. Electrical stimulation for use in increasing the firing rate of one or more motor neurons impaired by SMA in a subject, wherein the electrical stimulation is applied to one or more sensory neurons innervating a body region of the subject, and the subject receives SMA therapy in conjunction with the electrical stimulation, thereby increasing the firing rate of the motor neurons in the subject.

27. Electrical stimulation for use according to any one of claims 24 to 26, wherein the SMA therapy is selected from the group consisting of gene therapy based on a vector that delivers a copy of the SMN1 gene, antisense oligonucleotide (ASO) therapy targeting the SMN2 gene, or small molecule SMN2-splicing modifiers.

28. Electrical stimulation for use according to any one of claims 24 to 27, wherein the SMA therapy is onasemnogene abeparvovec, nusinersen, or risdipram.

29. Electrical stimulation for use according to any one of claims 24 to 28, wherein the target body region is selected from at least one of the waist, hip, leg, ankle, and foot.

30. The electrical stimulation for use according to any one of claims 24 to 29, wherein the electrical stimulation is provided by one or more electrodes implanted in the posterolateral surface of the spinal cord and spanning one or more of the T11 to S1 nerve roots.

31. Electrical stimulation for use according to any one of claims 24 to 28, wherein the body region of the target is selected from at least one of the upper arm, shoulder, arm, hand, and respiratory muscles.

32. The electrical stimulation for use according to any one of claims 24 to 28 or 31, wherein the electrical stimulation is provided by one or more electrodes implanted in the posterolateral surface of the spinal cord and spanning one or more of the C3 to T2 nerve roots.

33. Electrical stimulation for use according to any one of claims 24 to 28, wherein the body region of the target is selected from at least one of the chest, chest wall, abdomen, upper back, and mid-back.

34. The electrical stimulation for use according to any one of claims 24 to 28 or 33, wherein the electrical stimulation is provided by one or more electrodes implanted in the posterolateral surface of the spinal cord and spanning one or more of the T3 to T10 nerve roots.

35. Electrical stimulation for use according to any one of claims 24 to 34, for increasing the firing rate probability of spinal motor neurons innervating the body region of the subject affected by the motor impairment caused by the SMA.

36. Electrical stimulation for use according to any one of claims 24 to 35, wherein the joint torque and muscle strength of the target within the body region are increased.

37. The electrical stimulation for use according to any one of claims 24 to 36, wherein the electrical stimulation is applied for at least one hour per day over a period of at least one month.

38. Electrical stimulation for use according to any one of claims 24 to 37, 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 that is associated with motor impairment due to the SMA.

39. The electrical stimulation for use according to any one of claims 24 to 38, wherein 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.

40. Electrical stimulation for use according to any one of claims 24 to 39, wherein the motor impairment includes partial or complete paralysis, loss of dexterity, loss of muscle strength, and / or uncontrolled muscle tone.

41. Electrical stimulation for use according to any one of claims 24 to 40, wherein the subject has a type 1 SMA.

42. Electrical stimulation for use according to any one of claims 24 to 40, wherein the subject has a type 2 SMA.

43. Electrical stimulation for use according to any one of claims 24 to 40, wherein the subject has a type 3 SMA.

44. Electrical stimulation for use according to any one of claims 24 to 40, wherein the subject has a type 4 SMA.

45. Electrical stimulation for use according to any one of claims 24 to 44, wherein the SMA therapy is nusinersen.

46. Electrical stimulation for use according to any one of claims 24 to 44, wherein the SMA therapy is risdiplam.

47. An electrode assembly comprising one or more electrodes configured to provide the electrical stimulation for use according to any one of claims 24 to 46.

48. The electrode assembly according to claim 47, wherein one or more electrodes comprise a multi-electrode paddle array.

49. The electrode assembly according to claim 47 or 48, further comprising a nerve stimulator that controls one or more electrodes.

50. The electrode assembly according to any one of claims 47 to 49, wherein one or more electrodes are implanted epidurally in the target spinal cord.

51. The electrode assembly according to any one of claims 47 to 50, wherein the one or more electrodes are embedded in the posterior root of the one or more sensory neurons that innervate the body region of the target subject to the motor impairment.

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