Alpha-motoneurons Research Articles

Optogenetic methods to stimulate gamma motor neuron axons ex vivo.

It is challenging to stimulate gamma motor neurons, which are important regulators of muscle spindle afferent function, without also recruiting alpha motor neurons. Here, we test the feasibility of stimulating gamma motor neuron axons using optogenetics in two transgenic mouse lines. We used an ex vivo muscle-nerve preparation in adult mice to monitor muscle spindle afferent firing, which should increase in response to gamma motor neuron-induced lengthening of the sensory region of the muscle spindle. A force transducer measured alpha motor neuron-mediated twitch contractions. Blue LED light (470nm; 1-5mW) was delivered via a light guide to the sciatic nerve. We confirmed that the more slowly conducting gamma motor neurons were recruited first in mice expressing channelrhodopsin 2 in choline acetyltransferase-positive motor neurons, whereas alpha motor neurons required higher optical intensities, enabling co-activation of alpha and gamma motor neurons depending on light intensity. However, this approach cannot isolate gamma motor neuron activity completely. Cre-dependent channelrhodopsin 2 optoactivation using the putative gamma motor neuron marker neuronal PAS domain protein 1 (Npas1) also increased muscle spindle afferent firing rates and caused only small twitch contractions. This provides functional validation that Npas1 is present primarily in gamma motor neurons and can be used to manipulate gamma motor neurons independently. We propose optogenetic stimulation as a promising tool to manipulate gamma motor neuron activity.

Comprehensive copy number analysis of spinal muscular atrophy among the Iranian population

Copy number variations in the SMN1 gene on chromosome 5 are the primary cause of Spinal Muscular Atrophy (SMA) disease, characterized by muscle weakness and degeneration due to impaired alpha motor neurons in the spinal cord. To obtain a comprehensive molecular understanding of the SMA, including carriers, silent carriers, and patients in the Iranian population, we analyzed data from 5224 individuals referred to Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran, between 2006 and 2023 using MLPA and quantitative RT-PCR methods. The carrier frequency of SMA was estimated to be 5.55%. Furthermore, 3.06% of SMA parents (n = 24) had two copies of the SMN1 gene. Among 725 patients, those with an earlier onset of SMA were more likely to have two copies of the SMN2 gene (46.45%) and no copies of the NAIP gene (49.36%). Among the 654 fetal samples screened for SMA, 22.33% were found to be affected, while 3.46% of their parents tested normal. These findings are valuable for genetic counseling, carrier screening, and prenatal diagnosis of SMA in Iran. Furthermore, they underscore the importance of CNV analysis of SMN1, SMN2, and NAIP genes for accurate diagnosis and prognosis of SMA.

Качество жизни у детей со спинальной мышечной атрофией: обзор литературы

INTRODUCTION. Quality of life is a comprehensive characteristic of the standard of living, consisting of objective and subjective living conditions of the population. Specialized questionnaires are used to assess the quality of life in adults and children. In particular, the general PedsQL questionnaire and its specialized modules are used to assess the quality of life of children with various diseases. AIM. To evaluate the use of questionnaires in patients with various diseases, such as cardiovascular pathology, gastrointestinal diseases, neuromuscular diseases, etc. One of the severe neuromuscular diseases is spinal muscular atrophy, characterized by progressive symptoms of flaccid paralysis and muscle atrophy due to degeneration of α-motor neurons of the anterior horns of the spinal cord. This disease most often manifests itself in childhood or infancy and significantly worsens the quality of life of young patients. In the world, PedsQL 3.0 Neuromuscular Module is used to assess the quality of life of children with spinal muscular atrophy, to determine the level of their physical, psychosocial and material well-being. This questionnaire has proven itself to be the most convenient not only for parents, but also for children. CONCLUSION. Different questionnaires are used for different groups of diseases, but all questionnaires have a common denominator in the form of an assessment of physical and psychosocial well-being indicators.

Pain in Spinal Muscular Atrophy Type 2 and Type 3 Patients

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons. It is a multisystemic disease affecting non-neuronal systems and quality of life. We aimed to investigate the prevalence and characteristics of pain in children with spinal muscular atrophy. In this single-center study, by using visual analog scales, 13 patients diagnosed with SMA type 2 and type 3 accompanied by their parents filled out a questionnaire involving questions about the presence of chronic pain, pain frequency, duration, location, and intensity, causes of pain, and coping methods. All patients reported that they experienced chronic pain. Patients with type 3 experienced pain more frequently than those with type 2—multiple times each month. The terms "minutes," "mild," and "intermittent" were most commonly used to describe the length, intensity, and course of the pain in both groups. The mean pain intensity according to Visual Analogue Scale were 35.526.3 mm in type 2 and 25.110.2 mm in type 3. The localization of pain was primarily concentrated in the back and lower extremities. The most common causes of pain were stretching exercises during physical therapy and posture disorder. The most common methods of coping with pain were distraction strategy and massage. Pain is a common problem in children with SMA. Management of the pain might increase the life quality of SMA patients. A multidisciplinary approach must be considered in the treatment of these children.

Electrophysiological evidence of dry needling efficacy on spasticity in poststroke patients: A randomized control trial

Abstract: CONTEXT: Therapists use dry needling (DN) to treat myofascial trigger points and various pain conditions. Need for study: A gap analysis showed that more information about how DN works on spastic muscles through alpha motor neurofiring and what role it plays in clinical and functional outcomes. Currently, the objective evidence for the usefulness of DN in neurological diseases is required. AIMS: The purpose of this research was to examine how DN affects spasticity in stroke patients using the H reflex and a Modified Tardieu Scale (MTS). SETTINGS AND DESIGN: We conducted a randomized controlled trial. We randomly assigned 81 stroke survivors to one of two groups: one group underwent six sessions of DN over the muscles with conventional treatment, whereas the other group received conventional care. We assessed spasticity using the H reflex and the MTS. We analyzed all outcome measures before, after, and 2 weeks later names as H1, H2, H3 and T1, T2, and T2 receptivity. RESULTS: After the intervention, people who received DN had improvement in spasticity. H3-H1 is statistically significant (P = 0.42) in the experimental group against the control group. T3-T1 and T2-T3 are statistically significant (P = 0.00) in the experimental group compared to the control group. CONCLUSIONS: The DN is effective for lowering spastic muscle tone and local muscle stiffness. This could be because DN diminishes the nodular zone of spastic muscle and reduces the firing of alpha motor neurons. These findings are very promising in terms of lowering spasticity.

Neuromuscular junction dysfunction in Lafora disease.

Lafora disease (LD), a fatal neurodegenerative disorder, is caused by mutations in the EPM2A gene encoding laforin phosphatase or NHLRC1 gene encoding malin ubiquitin ligase. LD symptoms include epileptic seizures, ataxia, dementia and cognitive decline. Studies on LD have primarily concentrated on the pathophysiology in the brain. A few studies have reported motor symptoms, muscle weakness and muscle atrophy. Intriguingly, skeletal muscles are known to accumulate Lafora polyglucosan bodies. Using laforin-deficient mice, an established model for LD, we demonstrate that LD pathology correlated with structural and functional impairments in the neuromuscular junction (NMJ). Specifically, we found impairment in NMJ transmission, which coincided with altered expression of NMJ-associated genes and reduced motor endplate area, fragmented junctions and loss of fully innervated junctions at the NMJ. We also observed a reduction in alpha-motor neurons in the lumbar spinal cord, with significant presynaptic morphological alterations. Disorganised myofibrillar patterns, slight z-line streaming and muscle atrophy were also evident in LD animals. In summary, our study offers insight into the neuropathic and myopathic alterations leading to motor deficits in LD.

Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.

Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates, but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation was unchanged in spinal cords from Slc31a1+/- mice but highly upregulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.

Effect of Dry Needling Plus Static Stretching on Plantar Flexors Spasticity in Chronic Stroke Patients.

Stroke is a leading cause of disability worldwide and is often accompanied by complications such as spasticity. Static stretching (SS) is a common physiotherapy intervention for reducing spasticity, whereas dry needling (DN) is a novel approach. However, the combined effects of DN and SS on spasticity have not been thoroughly investigated. Given the pivotal effect of spasticity on daily activities, mitigating spasticity can significantly contribute to restoring patient independence. This study will explore the impact of DN plus SS on spasticity, alpha motor neuron excitability, overall function, and quality of life in patients with chronic stroke. A double-blind, randomized, sham-controlled trial will be conducted in patients with post-stroke spasticity in the plantar flexor muscles. Twentyeight participants will be randomly assigned to either an intervention or control group. The intervention group will receive DN (60s × 3 days/week; 1 week) plus SS (20 min × 5 days/ week; 1 week). The control group will undergo sham DN (60s × 3 days/week; 1 week) and SS (20 min × 5 days/week; 1 week). DN plus SS or sham DN plus SS. Both groups will be assessed at baseline, immediately post-treatment, and after 1 week of follow-up. Outcome measures will include the Modified Modified Ashworth Scale, H-reflex latency, Hmax/Mmax ratio, active and passive ankle dorsiflexion range of motion, timed up and go test, and the EuroQol questionnaire. Results from this randomized, sham-controlled study will provide evidence for the effectiveness of DN in combination with SS for spasticity. The additional impact of DN in conjunction with SS, a widely used method for reducing muscle tone, remains unclear and warrants investigation. This study, with a high level of evidence, aims to address this knowledge gap.

The functional state of the respiratory system of the patients with proximal spinal muscular atrophy 5q (SMA 5q): from the natural history of the disease to the era of pathogenetic therapy. Problems and expectations

Proximal spinal muscular atrophy 5q is an autosomal recessive neuromuscular disease. This disorder is characterized by progressive symptoms of flaccid paralysis and muscular atrophy due to degeneration of α-motor neurons in the anterior horns of the spinal cord. The disease is caused by the lack of a fully functional SMN protein due to homozygous deletion of exon 7 in the SMN1 gene. For a long time, spinal muscular atrophy was the leading genetic cause of infant mortality. With the introduction of modern pathogenetic treatment methods that modify the disease, the duration and quality of life of patients increases, and a “blurring of boundaries” between types of spinal muscular atrophy and the formation of new phenotypes happens. In this regard, approaches to patient management, including approaches to the assessment and correction of respiratory disorders, are changing. The review of the available medical literature was conducted. The clinical studies on spinal muscular atrophy in the natural course of the disease and with the use of pathogenetic drugs were analyzed, as well as the data on the state of the respiratory system of the patients.

A computational study of how an α- to γ-motoneurone collateral can mitigate velocity-dependent stretch reflexes during voluntary movement

The primary motor cortex does not uniquely or directly produce alpha motoneurone (α-MN) drive to muscles during voluntary movement. Rather, α-MN drive emerges from the synthesis and competition among excitatory and inhibitory inputs from multiple descending tracts, spinal interneurons, sensory inputs, and proprioceptive afferents. One such fundamental input is velocity-dependent stretch reflexes in lengthening muscles, which should be inhibited to enable voluntary movement. It remains an open question, however, the extent to which unmodulated stretch reflexes disrupt voluntary movement, and whether and how they are inhibited in limbs with numerous multiarticular muscles. We used a computational model of a Rhesus Macaque arm to simulate movements with feedforward α-MN commands only, and with added velocity-dependent stretch reflex feedback. We found that velocity-dependent stretch reflex caused movement-specific, typically large and variable disruptions to arm movements. These disruptions were greatly reduced when modulating velocity-dependent stretch reflex feedback (i) as per the commonly proposed (but yet to be clarified) idealized alpha-gamma (α-γ) coactivation or (ii) an alternative α-MN collateral projection to homonymous γ-MNs. We conclude that such α-MN collaterals are a physiologically tenable propriospinal circuit in the mammalian fusimotor system. These collaterals could still collaborate with α-γ coactivation, and the few skeletofusimotor fibers (β-MNs) in mammals, to create a flexible fusimotor ecosystem to enable voluntary movement. By locally and automatically regulating the highly nonlinear neuro-musculo-skeletal mechanics of the limb, these collaterals could be a critical low-level enabler of learning, adaptation, and performance via higher-level brainstem, cerebellar, and cortical mechanisms.

Phagocytosis of aggrecan-positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP-9 in TDP-43Q331K ALS model mice

Perineuronal nets (PNNs) are extracellular matrix structures that surround excitable neurons and their proximal dendrites. PNNs play an important role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can act as a trigger for neuronal death, and this has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We therefore characterised PNNs around alpha motor neurons and the possible contributing cellular factors in the mutant TDP-43Q331K transgenic mouse, a slow onset ALS mouse model. PNNs around alpha motor neurons showed significant loss at mid-stage disease in TDP-43Q331K mice compared to wild type strain control mice. PNN loss coincided with an increased expression of matrix metallopeptidase-9 (MMP-9), an endopeptidase known to cleave PNNs, within the ventral horn. During mid-stage disease, increased numbers of microglia and astrocytes expressing MMP-9 were present in the ventral horn of TDP-43Q331K mice. In addition, TDP-43Q331K mice showed increased levels of aggrecan, a PNN component, in the ventral horn by microglia and astrocytes during this period. Elevated aggrecan levels within glia were accompanied by an increase in fractalkine expression, a chemotaxic protein responsible for the recruitment of microglia, in alpha motor neurons of onset and mid-stage TDP-43Q331K mice. Following PNN loss, alpha motor neurons in mid-stage TDP-43Q331K mice showed increased 3-nitrotyrosine expression, an indicator of protein oxidation. Together, our observations along with previous PNN research provide suggests a possible model whereby microglia and astrocytes expressing MMP-9 degrade PNNs surrounding alpha motor neurons in the TDP-43Q331K mouse. This loss of nets may expose alpha-motor neurons to oxidative damage leading to degeneration of the alpha motor neurons in the TDP-43Q331K ALS mouse model.

AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.MethodsWe used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.ResultsSOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.ConclusionsAAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.

A Five-Year Review of Newborn Screening for Spinal Muscular Atrophy in the State of Utah: Lessons Learned.

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3-4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Neural Filtering of Physiological Tremor Oscillations to Spinal Motor Neurons Mediates Short-Term Acquisition of a Skill Learning Task.

The acquisition of a motor skill involves adaptations of spinal and supraspinal pathways to alpha motoneurons. In this study, we estimated the shared synaptic contributions of these pathways to understand the neural mechanisms underlying the short-term acquisition of a new force-matching task. High-density surface electromyography (HDsEMG) was acquired from the first dorsal interosseous (FDI; 7 males and 6 females) and tibialis anterior (TA; 7 males and 4 females) during 15 trials of an isometric force-matching task. For two selected trials (pre- and post-skill acquisition), we decomposed the HDsEMG into motor unit spike trains, tracked motor units between trials, and calculated the mean discharge rate and the coefficient of variation of interspike interval (COVISI). We also quantified the post/pre ratio of motor units' coherence within delta, alpha, and beta bands. Force-matching improvements were accompanied by increased mean discharge rate and decreased COVISI for both muscles. Moreover, the area under the curve within alpha band decreased by ∼22% (TA) and ∼13% (FDI), with no delta or beta bands changes. These reductions correlated significantly with increased coupling between force/neural drive and target oscillations. These results suggest that short-term force-matching skill acquisition is mediated by attenuation of physiological tremor oscillations in the shared synaptic inputs. Supported by simulations, a plausible mechanism for alpha band reductions may involve spinal interneuron phase-cancelling descending oscillations. Therefore, during skill learning, the central nervous system acts as a matched filter, adjusting synaptic weights of shared inputs to suppress neural components unrelated to the specific task.

An alpha- to gamma-motoneurone collateral can mitigate velocity-dependent stretch reflexes during voluntary movement: A computational study.

The primary motor cortex does not uniquely or directly produce alpha motoneurone (α-MN) drive to muscles during voluntary movement. Rather, α-MN drive emerges from the synthesis and competition among excitatory and inhibitory inputs from multiple descending tracts, spinal interneurons, sensory inputs, and proprioceptive afferents. One such fundamental input is velocity-dependent stretch reflexes in lengthening muscles, which should be inhibited to enable voluntary movement. It remains an open question, however, the extent to which unmodulated stretch reflexes disrupt voluntary movement, and whether and how they are inhibited in limbs with numerous multi-articular muscles. We used a computational model of a Rhesus Macaque arm to simulate movements with feedforward α-MN commands only, and with added velocity-dependent stretch reflex feedback. We found that velocity-dependent stretch reflex caused movement-specific, typically large and variable disruptions to arm movements. These disruptions were greatly reduced when modulating velocity-dependent stretch reflex feedback (i) as per the commonly proposed (but yet to be clarified) idealized alpha-gamma (α-γ) co-activation or (ii) an alternative α-MN collateral projection to homonymous γ-MNs. We conclude that such α-MN collaterals are a physiologically tenable, but previously unrecognized, propriospinal circuit in the mammalian fusimotor system. These collaterals could still collaborate with α-γ co-activation, and the few skeletofusimotor fibers (β-MNs) in mammals, to create a flexible fusimotor ecosystem to enable voluntary movement. By locally and automatically regulating the highly nonlinear neuro-musculo-skeletal mechanics of the limb, these collaterals could be a critical low-level enabler of learning, adaptation, and performance via higher-level brainstem, cerebellar and cortical mechanisms.

Muscle contractile properties directly influence shared synaptic inputs to spinal motor neurons.

Alpha band oscillations in shared synaptic inputs to the alpha motor neuron pool can be considered an involuntary source of noise that hinders precise voluntary force production. This study investigated the impact of changing muscle length on the shared synaptic oscillations to spinal motor neurons, particularly in the physiological tremor band. Fourteen healthy individuals performed low-level dorsiflexion contractions at ankle joint angles of 90° and 130°, while high-density surface electromyography (HDsEMG) was recorded from the tibialis anterior (TA). We decomposed the HDsEMG into motor units spike trains and calculated the motor units' coherence within the delta (1-5Hz), alpha (5-15Hz), and beta (15-35Hz) bands. Additionally, force steadiness and force spectral power within the tremor band were quantified. Results showed no significant differences in force steadiness between 90° and 130°. In contrast, alpha band oscillations in both synaptic inputs and force output decreased as the length of the TA was moved from shorter (90°) to longer (130°), with no changes in delta and beta bands. In a second set of experiments (10 participants), evoked twitches were recorded with the ankle joint at 90° and 130°, revealing longer twitch durations in the longer TA muscle length condition compared to the shorter. These experimental results, supported by a simple computational simulation, suggest that increasing muscle length enhances the muscle's low-pass filtering properties, influencing the oscillations generated by the Ia afferent feedback loop. Therefore, this study provides valuable insights into the interplay between muscle biomechanics and neural oscillations. KEY POINTS: We investigated whether changes in muscle length, achieved by changing joint position, could influence common synaptic oscillations to spinal motor neurons, particularly in the tremor band (5-15Hz). Our results demonstrate that changing muscle length from shorter to longer induces reductions in the magnitude of alpha band oscillations in common synaptic inputs. Importantly, these reductions were reflected in the oscillations of muscle force output within the alpha band. Longer twitch durations were observed in the longer muscle length condition compared to the shorter, suggesting that increasing muscle length enhances the muscle's low-pass filtering properties. Changes in the peripheral contractile properties of motor units due to changes in muscle length significantly influence the transmission of shared synaptic inputs into muscle force output. These findings prove the interplay between muscle mechanics and neural adaptations.

Non-Invasive Spinal Cord Stimulation for Motor Rehabilitation of Patients with Spinal Muscular Atrophy Treated with Orphan Drugs.

Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in this study. The median duration of drug treatment was over 20 months. The application of tSCS was performed during physical therapy for 20-40 min per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, and forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both type 2 and 3 SMA participants. The magnitude of functional changes was not associated with participant age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation on SMA.

Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1G93A ALS mouse model.

Perineuronal nets (PNNs) are an extracellular matrix structure that encases excitable neurons. PNNs play a role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can trigger neuronal death, which has been implicated in amyotrophic lateral sclerosis (ALS). We investigated the spatio-temporal timeline of PNN breakdown and the contributing cellular factors in the SOD1G93A strain, a fast-onset ALS mouse model. This was conducted at the presymptomatic (P30), onset (P70), mid-stage (P130), and end-stage disease (P150) using immunofluorescent microscopy, as this characterisation has not been conducted in the SOD1G93A strain. We observed a significant breakdown of PNNs around α-motor neurons in the ventral horn of onset and mid-stage disease SOD1G93A mice compared with wild-type controls. This was observed with increased numbers of microglia expressing matrix metallopeptidase-9 (MMP-9), an endopeptidase that degrades PNNs. Microglia also engulfed PNN components in the SOD1G93A mouse. Further increases in microglia and astrocyte number, MMP-9 expression, and engulfment of PNN components by glia were observed in mid-stage SOD1G93A mice. This was observed with increased expression of fractalkine, a signal for microglia engulfment, within α-motor neurons of SOD1G93A mice. Following PNN breakdown, α-motor neurons of onset and mid-stage SOD1G93A mice showed increased expression of 3-nitrotyrosine, a marker for protein oxidation, which could render them vulnerable to death. Our observations suggest that increased numbers of MMP-9 expressing glia and their subsequent engulfment of PNNs around α-motor neurons render these neurons sensitive to oxidative damage and eventual death in the SOD1G93A ALS model mouse.

Molecular, Morphological and Electrophysiological Differences between Alpha and Gamma Motoneurons with Special Reference to the Trigeminal Motor Nucleus of Rat.

The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of γMNs have remained unknown, while those of αMNs have been clarified in detail. Because of the larger size of αMNs compared to γMNs, blindly or even visually recorded MNs were mostly αMNs, as demonstrated with molecular markers recently. Subsequently, the research on αMNs has made great progress in classifying their subtypes based on the molecular markers and electrophysiological membrane properties, whereas only a few studies demonstrated the electrophysiological membrane properties of γMNs. In this review article, we provide an overview of the recent advances in research on the classification of αMNs and γMNs based on molecular markers and electrophysiological membrane properties, and discuss their functional implication and significance in motor control.

Natural History of Mandibular Function in Spinal Muscular Atrophy Types 2 and 3.

Hereditary proximal spinal muscular atrophy (SMA) is characterized by abnormal alpha motor neuron function in brainstem and spinal cord. Bulbar dysfunction, including limited mouth opening, is present in the majority of patients with SMA but it is unknown if and how these problems change during disease course. In this prospective, observational, longitudinal natural history study we aimed to study bulbar dysfunction in patients with SMA types 2 and 3. We included 44 patients with SMA types 2 and 3 (mean age was 33.6 (95% CI 28.4;38.9) and re-examined them after on average 4 years. None were treated with SMN-modulating treatments before or during the course of this study. Longitudinal assessments included a questionnaire on mandibular and bulbar function, the Mandibular Function Impairment Questionnaire (MFIQ), and a clinical examination of masticatory performance, maximum voluntary bite force, and mandibular movements including the active maximal mouth opening. We found significant higher MFIQ scores and a significant decrease of all mandibular movements in patients with SMA type 2 (p < 0.001), but not in SMA type 3. Masticatory performance and maximum voluntary bite force did not change significantly. Mean reduction of active maximal mouth opening at follow-up was 3.5 mm in SMA type 2 (95% CI: 2.3; 4.7, p < 0.001). SMA type 2 was an independent predictor for a more severe reduction of the mouth opening (β= -2.0 mm (95% CI: -3.8; -0.1, p = 0.043)). Bulbar functions such as mandibular mobility and active maximum mouth opening decrease significantly over the course of four years in patients with SMA type 2.