Muscle & Nerve

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. Results: The registry included 470 participants (51% male). Genetic confirmation was obtained for 76% (n=356), the remainder were included based on clinical and anamnestic data. Clinical assessment forms and patient-reported questionnaires were analyzed for 310 and 142 patients, respectively. D4Z4 repeat unit (RU) distribution showed patterns consistent with European cohorts, with a predominance of patients with 3 RUs. A moderate inverse correlation was found between RUs number and clinical severity scales. Periscapular weakness was the most common onset manifestation (46.8%), followed by facial weakness (31.6%) which was often unnoticed by patients. The mean age in the Russian cohort was 37.8 years (range 0-97), indicating a younger cohort compared to international data. A delta-adjusted cluster analysis (n=215) identified three distinct trajectories: a classic phenotype with onset before age 14 and early involvement of various muscle groups (n=177), and two clusters characterized by either facial or periscapular onset with slow progression. Conclusion: The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a predominance of patients with 3 D4Z4 repeats and a younger demographic profile compared to international data. Cluster analysis identified three heterogeneous disease trajectories, offering a framework for improved patient stratification.

BackgroundDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which encodes dystrophin in skeletal muscle cells. Although the role of dystrophin as a structural protein is well known, the cellular processes underlying myofiber degeneration are still not fully understood. Despite advances from studies in murine models, these models do not fully replicate the human pathology. MethodsWe investigated sarcolemmal integrity, membrane repair capacity, and annexin protein expression in DMD patient muscle biopsies and human skeletal muscle cell lines using immunohistochemistry, both shear stress-based and laser irradiation injury assays, western blotting, and live-cell imaging of GFP-tagged annexins. ResultsWe identified defective membrane repair in DMD skeletal muscle cells, independent of increased membrane fragility, by evaluating resealing capacity in control and DMD derived-patient cell lines using both a shear stress assay (N = l2, p < 0.000l) and a laser irradiation assay (N = 3, p < 0.000l). Analyses performed on human DMD muscle biopsies (N = l0) further confirmed this defect, demonstrating massive intracellular IgG uptake (p < 0.000l) together with altered annexin expression profiles. While mechanical stress induces the upregulation of annexin A5 (ANXA5, p < 0.0l) and A6 (ANXA6, p < 0.05) in healthy skeletal muscle cells - suggesting an adaptive response to membrane damage, given the annexin familys central role in membrane repair - we observed dysregulated expression patterns of these proteins in DMD cells. Notably, ANXAl (p < 0.05) and ANXA2 (p < 0.0l) were not only significantly overexpressed but also aberrantly localized to the extracellular space, a putative consequence of defective membrane repair. Since extracellular ANXA2 has been associated with adipocyte accumulation in the muscle tissue of patients with dysferlinopathy, a similar pathological mechanism may be at play in DMD. ConclusionsOur findings propose that ANXA2 contributes to muscle degeneration in DMD and highlight it as a potential therapeutic target to prevent adipogenesis and muscle loss.

Background and objectivesA pathogenic GGC repeat expansion in the zinc finger homeobox 3 (ZFHX3) gene, encoding a pure polyglycine tract, is the cause of spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci contribute to the risk of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease involving the progressive loss of motor neurons. There is increasing awareness of the role of short tandem repeat (STR) motif composition and configuration in disease pathogenicity. Given the genetic pleiotropy between ALS and SCA, this study aimed to evaluate whether ZFHX3 GGC expansions were associated with ALS and to characterise repeat motif composition. MethodsExpansionHunter v5 was used to genotype ZFHX3 GGC repeat sizes in short-read whole genome sequencing data from people with ALS and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer v2. Repeat motif configurations of Australian ALS cases were manually derived from REViewer images. Receiver operating characteristic (ROC) curve analysis and Youdens J statistic were performed to find a candidate repeat size threshold for association testing using Fishers exact test. ResultsAnalysis of 5,785 people with ALS and 7,982 healthy controls found no association between ZFHX3 GGC repeat expansions and disease risk. However, more than 30 unique repeat motif compositions were identified across 802 people with ALS. Of these, seven distinct configurations coded a pure polyglycine tract which, when expanded, is canonical to SCA4. DiscussionAlthough no association was observed between ZFHX3 GGC repeat expansions and ALS, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Unique motif compositions were identified both within and between repeat sizes, including the presence of pure polyglycine repeats in ALS. Consideration of repeat motif composition and configuration, in addition to repeat allele length, may be important for assessing neurodegenerative disease risk.

Introduction Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Onasemnogene abeparvovec is a U.S. FDA-approved single-dose gene therapy for SMA. Both its intravenous formulation (Zolgensma, approximately USD 2.13 million per patient) and intrathecal formulation (Itvisma, around USD 2.59 million per patient) are prohibitively expensive, substantially limiting accessibility in low- and middle-income countries (LMICs). We conducted a clinical study of vesemnogene lantuparvovec, an alternative to onasemnogene abeparvovec developed for use in LMIC settings. Methods Sixteen patients with SMA, including 8 with type 1 SMA and 8 with type 2 SMA, received a single intrathecal administration of vesemnogene lantuparvovec. Eleven patients were treated with a low dose (1.5 * 10^14 vg) and five with a high dose (3.0 * 10^14 vg). The primary endpoints were safety and efficacy, assessed by changes from baseline in developmental gross motor milestones according to the World Health Organization criteria. Overall survival was primarily evaluated in type 1 SMA patients. This trial was registered with ClinicalTrials.gov NCT06288230. Results As of the March 2026 cutoff date, 15 of 16 treated patients had completed at least 12 months of follow-up after treatment, while the remaining one type 1 SMA patient died of disease progression at month 6 post-treatment. At 12 months post-treatment, among the surviving 7 patient with type 1 SMA, the median age was 21.6 months (range, 16.1 to 32.3 months). Among the 16 treated patients, the median age at diagnosis was 4.4 months (range, 0.0 to 18.0 months), and the median age at dosing was 10.7 months (range, 2.8 to 22.5 months). All patients experienced at least one AE. Thirty-one AESIs were reported in 13 patients, including hepatotoxicity, thrombocypenia-related events and cardiac events. No patient required prolonged prednisolone prophylaxis. SAEs, including pneumonia, lower respiratory tract infection, upper respiratory tract infection, and haemorrhagic diarrhoea, occurred in 5 of 8 (63%) patients with type 1 SMA and 2 of 8 (25%) patients with type 2 SMA. Two patients with type 1 SMA required invasive ventilation, and one of whom subsequently died. At 12 months post-treatment, 11 of 16 treated patients (69%) gained at least one new WHO motor milestone versus baseline, including 3 type 1 and 8 type 2 SMA patients; one type 2 patient gained six WHO motor milestones and achieved independent walking. Conclusions In patients younger than 24 months of age with type 1 or type 2 SMA, a single intrathecal dose of vesemnogene lantuparvovec was safe and generally well tolerated and was associated with improvements in developmental gross motor milestones compared with outcomes observed among referred but untreated patients. Additional studies are required to further evaluate the long-term safety and efficacy of this gene therapy.

Dystonia treatment evaluation in cerebral palsy (CP) is limited by the lack of clinician-assessed scales linking dystonia severity to functional impact. We asked 7 pediatric movement disorder specialists to review videos of 27 children with CP while performing an upper extremity task and while walking. Experts rated arm and leg dystonia severity using the Global Dystonia Severity Rating Scale (GDRS) and task-specific functional impact on a five-point scale adapted from the Dyskinetic Cerebral Palsy Functional Impact Scale. Arm GDRS scores correlated with functional impact on the upper extremity task (linear regression R2=0.48, p=0.0005). Leg GDRS scores correlated with gait impact (R2=0.43, p=0.001). A four-point increase in total GDRS corresponded to a one-point worsening in combined functional impact. By demonstrating how expert-rated limb dystonia severity correlates with task-specific functional impact in children with CP, these results could help clinically identify functionally-meaningful differences in dystonia severity.

BackgroundCancer cachexia (CC) is characterized by skeletal muscle atrophy and reduced strength, partly linked to dysfunction of muscle stem cells (MuSCs) and alterations in their niche. Although exercise may mitigate muscle loss, its effects in CC remain debated and its feasibility is often limited in advanced patients. Neuromuscular electrical stimulation (NMES) offers a promising alternative, by promoting MuSC proliferation and fusion, increasing muscle size and macrophage content in healthy muscle. This study investigated whether NMES, initiated at tumor onset, could improve MuSC regulation and its niche while limiting muscle atrophy and weakness in a tumor-bearing mouse model. MethodsTen-week-old male BALB/c mice were subcutaneously injected with C26 tumor cells or PBS. Tumor-bearing mice were divided into NMES-treated (C26 NMES) and non-stimulated controls (C26). NMES consisted of six sessions (two series of three consecutive daily sessions separated by one rest day), starting seven days post-inoculation when tumors became visible. Each session was delivered at a submaximal intensity corresponding to 15% of maximal strength. Muscle mass, myofiber size, strength and cellular composition were assessed. ResultsMuscle mass was decreased by 13% in C26 mice as compared to PBS controls, while C26 NMES mice showed a [~]7% improvement over C26 mice. Mean myofiber size decreased similarly in both tumor-bearing groups as compared to PBS controls (-12-14%). However, NMES reduced the proportion of small myofibers (400-600 {micro}m{superscript 2}) as compared to C26 mice. Maximal torque loss was less severe in C26 NMES mice (-28%) than in C26 mice (-34%). As compared with PBS mice, C26 mice exhibited increased MuSC proliferation (+97%) but reduced differentiation (-61%), as indicated by fewer myogenin-positive cells. NMES normalized MuSC proliferation, restored myogenin-positive cell number, and enhanced MuSC fusion, reflected by an increased number of PCM1-positive myonuclei (+8-11%). NMES also modulated inflammation, reducing neutrophils (-42%) and increasing macrophages (+35%), through the proliferation of CD169-positive resident macrophages (+106%). In vitro, macrophages exposed to C26 muscle extracts showed elevated pro-inflammatory markers (COX2 and TNF-; +21% and +16%) as compared to PBS controls. This effect was abolished with extracts from C26 NMES muscles. Additionally, C26 extracts reduced the expression of anti-inflammatory markers by macrophages (CD206 and IL-10; -23%), whereas NMES restored their levels to those of controls. ConclusionNMES-induced mild contractile activity is an effective stimulus for preserving muscle strength and mass, improving MuSC regulation, and modulating muscle inflammation in a mouse model of CC.

ObjectivesEpidural spinal cord stimulation (SCS) is an emerging therapy for motor rehabilitation following spinal cord injury (SCI) and other motor disorders. Conventionally, SCS leads are placed along the dorsal spinal cord (SCSD), where stimulation activates large diameter afferent fibers, which indirectly activate motoneurons through reflex pathways. This leads to broad activation of flexor and extensor muscles and limited fine-tuned control of motor output. Targeting the ventral spinal cord (SCSV) may enable more direct activation of motoneuron pools, potentially improving the specificity of muscle activation; however, there is currently no established method to place leads ventrally. To address this, we evaluated the feasibility of four modified percutaneous implantation techniques to target the ventrolateral thoracolumbar spinal cord. Materials and methodsPercutaneous SCSV implantation was performed in three human cadaver torso specimens under fluoroscopic guidance. The following approaches were evaluated: sacral hiatus, transforaminal, interlaminar contralateral, and interlaminar ipsilateral. The leads in the latter 3 approaches were inserted between L1 and L5. Eighteen implants were attempted, with nine leads retained for analysis. Lead and electrode position were assessed using computed tomography (CT) with three-dimensional reconstruction, along with anatomical dissection to verify lead and electrode placement within the epidural space. ResultsSuccessful ventral epidural lead placement was achieved using all four implantation approaches. The sacral hiatus (16/16 electrodes) and transforaminal (8/8 electrodes) approaches resulted in exclusively ventrolateral placement. The interlaminar contralateral approach led to 27/32 electrodes positioned ventrolaterally and 5/32 dorsally. The interlaminar ipsilateral implantation approach led to 14/32 electrodes positioned ventrolaterally and 18/32 positioned ventromedially. ConclusionsThese findings demonstrate that ventral epidural SCS lead placement can be achieved using modified percutaneous implant techniques. The four approaches outlined here provide a clinically feasible pathway to SCSV and establishes a foundation for future clinical studies investigating SCSV for motor rehabilitation following SCI.

EMG-based muscle force predictions are often inaccurate following active muscle stretch or shortening because of residual force enhancement (rFE) or depression (rFD), respectively, which can alter the neural drive to a muscle. However, the extent of neural drive modulation due to rFE or rFD remains unknown, making it difficult to correct EMG-based force predictions. Therefore, seventeen participants performed dorsiflexion contractions at 20 and 40% of maximum voluntary torque (MVT) in three conditions: stretch-hold, shortening-hold, and fixed-end reference (REF) conditions. The ankle dorsiflexion torques and angles were matched using dynamometry to the REF condition over a 10-s steady state following a 1-s 25{degrees} stretch or shortening, during which we recorded and decomposed tibialis anterior individual motor unit action potentials from high-density surface EMG recordings to gain insights into neural drive. Normalized EMG amplitudes were 2% lower following stretch and 1 or 3% higher following shortening relative to REF at 20 versus 40% MVT (p[&le;].008), respectively. Discharge rates (DRs) from 19 matched motor units per person on average obtained via DEMUSE and MUedit were similar (p=.871). Following stretch and shortening, DRs were [~]1 Hz lower (p[&le;].004) and 0 (p=.966) to 1 Hz higher relative to REF (p=.003), respectively. More unique motor units were also detected following shortening versus REF and in REF versus following stretch. These findings indicate that to account for rFE or rFD, neural drive is respectively decreased or increased via reduced or additional motor unit recruitment and DR modulation, with a contraction-intensity specific discharge rate modulation following active shortening.

Background: Spinal cord injury (SCI) is associated with widespread reorganisation of cortical sensorimotor circuits. Persistent complications such as spasticity and neuropathic pain suggest that homeostatic plasticity, which normally helps stabilise and constrain activity-dependent changes in sensorimotor circuits, may be disrupted after SCI. Homeostatic plasticity can be probed using repeated blocks of transcranial direct current stimulation (tDCS); in healthy individuals, two closely spaced excitatory blocks typically leads to an inhibitory response, reflected as a reduction in corticomotor excitability. Objective: To determine whether individuals with SCI show reduced homeostatic suppression of corticospinal excitability in response to repeated anodal tDCS, compared with healthy controls. Methods: Twenty adults with thoracic or below SCI and 20 healthy controls completed three counterbalanced sessions. Each session comprised two 10-minute blocks of 2 mA tDCS separated by 5 minutes, with the second block always being anodal tDCS over left primary motor cortex. The first block was either anodal, cathodal, or sham tDCS, yielding 3 condition types: anodal-anodal, cathodal-anodal, and sham-anodal. To assess corticomotor excitability, transcranial magnetic stimulation-evoked motor evoked potentials (MEPs) were elicited at baseline, after priming, and every 5 minutes for 60 minutes after the second block. The primary outcome was percent change in MEP amplitude from baseline. Results: In the anodal-anodal condition, the SCI group showed greater facilitation than controls over 0-30 minutes (estimate = 83.09, 95% CI 49.75 to 116.43, p < 0.001), suggestive of a weaker homeostatic response. The cathodal-anodal condition led to a significant overall facilitatory effect with no between-group difference, while the sham-anodal condition showed no change in MEP amplitude relative to baseline. Within the SCI group, exploratory subgroup analysis suggests that those with neuropathic pain and a traumatic injury showed greater facilitation in the anodal-anodal condition than those without these features, indicative of a weaker homeostatic response. Conclusions: SCI is associated with impairment in the homeostatic regulation of corticomotor excitability following repeated excitatory brain stimulation. Disrupted plasticity stabilisation may be relevant to persistent symptoms such as neuropathic pain.

Mitochondrial diseases are a diverse group of inherited neuromuscular disorders leading to progressive disability and early mortality. Mitochondrial myopathy is a common feature of mitochondrial disorders, affecting most patients. Assessment of disease progression and treatment efficacy in mitochondrial disease trials has often relied on muscle biopsies, however, these are increasingly considered unfavourable by patients. Imaging biomarkers of disease could reduce the patient burden, enabling non-invasive longitudinal monitoring of molecular information. Photoacoustic imaging combines the molecular sensitivity of light absorption with the deep tissue imaging capabilities of ultrasound, enabling a safe and fast imaging technique. Tuning the wavelength of light allows for the detection of molecular constituents such as oxy- and deoxy-haemoglobin, lipids, and water. These signatures may reflect underlying pathophysiological alterations and serve as valuable indicators of disease state and progression. We conducted an exploratory study of a photoacoustic imaging dataset in patients with mitochondrial myopathy due to the m.3243A>G mt-tRNALeu mutation and compared to healthy volunteers. We generated photoacoustic measurements at wavelengths in the near infrared, comparing absolute values and ratios derived in the bicep muscle. Confounding factors such as skin colour and sex were considered, and we ensured that these parameters were matched in healthy volunteers and patients. We identified significant differences between patients and controls, revealing changes in ratios between water and total haemoglobin, lipid and total haemoglobin, and lipid and water content. This study highlights the promise of photoacoustic imaging as a novel imaging biomarker in mitochondrial myopathies, paving the way for larger scale studies.

Ankle clonus is a sustained, involuntary, rhythmic muscle contraction frequently observed in humans with spinal cord injury (SCI). Although its pathophysiology remains incompletely understood, converging evidence suggests a role for brainstem systems in its generation. Following SCI, brainstem neuromodulatory inputs partially compensate for the loss of descending motor pathways by regulating motoneuron excitability during involuntary contractions, suggesting their involvement in the generation of clonus. To test this hypothesis, motoneuron excitability in response to Ia synaptic input was quantified using the soleus H reflex and maximal motor response (H/M ratio), and brainstem involvement was probed using the long lasting component of the cutaneous reflex (LLR) in the tibialis anterior and soleus muscles, as well as the StartReact response-an involuntary release of a movement triggered by a startling stimulus thought to engage the reticulospinal tract. We studied individuals with chronic SCI, both with and without ankle clonus, using standardized clinical tests across two days. Participants with clonus showed elevated H/M ratios, indicating increased motoneuron excitability, whereas those without clonus exhibited lower values than controls. Additionally, individuals with clonus exhibited longer LLR duration and greater LLR magnitude in both muscles, along with shorter reaction times to startle stimuli, consistent with enhanced monoaminergic and reticulospinal contributions. Notably, LLR duration was positively correlated with both StartReact response and H/M ratio. Together, these findings support a role for descending brainstem systems-particularly monoaminergic and reticulospinal pathways-in the maintenance of clonus in chronic SCI.

BackgroundThe X-linked muscle wasting disorder Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal disease caused by loss of function mutations in the dystrophin (DMD) gene. Upregulation of utrophin (UTRN), an embryonic homologue of dystrophin, has been proposed as a therapeutic option that could ameliorate disease. We previously generated a bioluminescent screen for utrophin-upregulating compounds using a mouse reporter of endogenous utrophin expression and discovered that inhibition of ERK1/2 and EZH2, increases utrophin expression in myoblasts. MethodologyHere we extend this analysis to show that treatment of human myoblasts with the ERK1/2 inhibitor LY3214996 and the EZH2 inhibitor GSK503, increases UTRN expression in primary and immortalised myoblasts derived from healthy volunteers and DMD patients. ResultsShort-term (24 hours) inhibition of ERK1/2 and EZH2 resulted in increased expression of utrophin in proliferating myoblasts. Surprisingly, in patient-derived samples, but not healthy controls, increased UTRN expression was sustained following drug removal and in vitro differentiation. Furthermore, dystrophin deficient myoblasts have altered expression of myogenic transcription factors MYOD1 and MYOG and proliferation marker Ki67, signalling an altered regenerative capacity of these cells, while ERK1/2 inhibition, alone or combined with EZH2i, reversed this transcriptional signature. ConclusionsTreatment with ERK1/2 and EZH2 inhibitors could offer a therapeutic option for DMD by increasing UTRN and MYOD1 expression. We propose that this may compensate for DMD loss and help restore productive muscle differentiation and regeneration.

Proprioception and reflexive control of muscle tone depend on the activity of muscle spindles, specialized sensory receptors embedded deep within skeletal muscle that detect changes in muscle length. Their location and complex three-dimensional architecture have historically limited morphological analysis to techniques such as silver-impregnation, muscle teasing, or serial sectioning followed by volumetric reconstruction. Here, we describe a workflow for three-dimensional, in situ visualization of muscle spindles in the rabbit tenuissimus muscle, a preparation uniquely enriched in spindles and well suited for whole-mount imaging. The protocol combines fluorescent labeling of spindle sensory and motor innervation, including intrafusal {gamma} neuromuscular junctions labeled with -bungarotoxin, with immunolabeling and solvent-based optical clearing. Optically cleared tenuissimus muscles were compatible with both whole-mount confocal and light-sheet microscopy, enabling volumetric imaging of complete spindle structures and detailed visualization of Ia annulospiral endings at the spindle equator. This approach provides access to spindle morphology and connectivity at multiple spatial scales while avoiding physical sectioning and reconstruction. By enabling reproducible three-dimensional imaging of intact muscle spindles, this workflow offers a practical platform for studying spindle structure and plasticity in health and disease.

BackgroundSystemic sclerosis (SSc) is a severe autoimmune disease characterised by progressive fibrosis driven by fibroblast activation. Primary cilia, key hubs for profibrotic signalling, are markedly shortened in SSc fibroblasts, but the mechanisms underlying this phenotype remain unclear. This study aimed to define the signalling pathways responsible for primary cilia shortening and fibroblast activation in SSc. MethodsPrimary dermal fibroblasts from SSc patients and healthy controls were analysed for cilia incidence and length by immunofluorescence, profibrotic marker expression by qPCR, and contractility using gel contraction assays. Cells were treated with TGF{beta}1 and pharmacological inhibitors targeting AURKA, HDAC6, ROCK2, and Smad3 signalling. CAV1-silenced fibroblasts were used as an in vitro model of SSc. ResultsMaintenance of the constitutively short primary cilia phenotype in SSc fibroblasts did not require active TGF{beta} signalling. However, TGF{beta}1 induced reversible cilia shortening in healthy fibroblasts and further shortened cilia in SSc fibroblasts to a similar final length, mediated by Rho/ROCK2 rather than canonical Smad3-dependent signalling. Constitutive cilia shortening in SSc was driven by aberrant AURKA activity upstream of HDAC6, promoting ciliary disassembly. Pharmacological inhibition of AURKA or HDAC6 selectively elongated cilia in SSc fibroblasts, reduced profibrotic marker expression, and abrogated fibroblast contractility. CAV1-silenced fibroblasts similarly exhibited constitutive cilia shortening that was reversed by AURKA inhibition without affecting healthy cells. ConclusionsAberrant activation of the AURKA/HDAC6 axis maintains short primary cilia and promotes fibroblast activation in SSc. These findings reveal a mechanistic link between cilia morphology and fibrosis and identify AURKA as a potential therapeutic target for SSc-associated tissue remodelling.

BackgroundAs therapeutic options emerge for hereditary spastic paraplegias (HSP), clinical trials require outcome measures that reflect disease aspects most important to patients. Patient priorities in HSP remain poorly defined. This study aimed to develop a regulatory-compliant framework of patient-prioritised health domains to evaluate treatment response in clinical trials. MethodsPatient-reported data on health impacts were collected via two multinational, multilingual online surveys conducted sequentially, including 616 and 504 patients across the clinical and genetic spectrum of HSP. Using a staged approach, we examined prevalence, relevance, and severity, focusing on health impacts that were (i) common (ii) sensitive to disease progression, (iii) highly relevant to patients, and (iv) showed strong severity-relevance correlation. Patient representatives contributed centrally to study design and prioritisation. FindingsOur patient-focused analysis yielded five highly prevalent and relevant core health domains: mobility, lower body function, autonomic dysregulation, pain, and psychosocial aspects. Ambulation and lower body function ranked highest across all disease stages. Among non-motor impacts, reduced ability to work, bladder incontinence, and fatigue were most relevant. In mild disease stages, reduced walking distance, reduced walking speed, and the urgency to empty the bladder were the most frequent and most relevant health impact. InterpretationThis work provides the most comprehensive patient-reported and disease stage specific profiling of HSP health impacts to date. It lays the necessary groundwork for developing patient-focused outcome tools capable of capturing treatment effects in future trials.

Introduction: Adults with spinal cord injury (SCI) often experience reduced or lost sensation and movement, impairing the ability of the brain to locate paralyzed body parts, which, in turn, compromises sensorimotor recovery. This disruption of the internal body map of the brain, or mental body representations (MBR), also contributes to neuropathic pain in about 69% of adults with SCI. Medications for neuropathic pain are often ineffective and can cause adverse reactions. Our previous pilot clinical trial showed that Cognitive Multisensory Rehabilitation (CMR), a physical therapy that restores MBR, produced significant, lasting reductions in neuropathic pain, improved sensorimotor function, and enhanced brain function. Building on these results, we examined whether 8 weeks of CMR or adaptive fitness (1) improved sensorimotor function and reduced pain; (2) greater brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Sixteen participants (52+/-8 years old, 13+/-10 years post-SCI) were randomized to 8 weeks of CMR or adaptive fitness (45 min, 3x/week). Ten participants had neuropathic pain of 3/10 or greater. Pain and sensorimotor function were assessed at baseline, post-intervention, and 3-month follow-up using the Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS). Functional MRI included resting-state and 4 tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR, participants improved on AIS with large effect sizes (touch: d=1.54; pinprick: d=1.83; lower limb motor function: d=1.32), while adaptive fitness had small/moderate effects (touch: d=0.49; pinprick: d=0.53; lower limb motor function: d=0.74). CMR also showed larger effect sizes for NRS (core: d=2.19; upper limb: d=0.69; lower limb: d=0.74) than fitness (core: d=0.73; upper limb: d=0.34; lower limb: d=0.00). Benefits persisted at follow-up. Highest neuropathic pain intensity reduced post-CMR and at 3-month follow-up (d=0.48; d=0.63). Pain increased slightly after fitness (n=6; d=-0.19; d=-0.41). CMR increased brain connectivity and activation during the leg imagery task. Increased activation during whole-body imagery was greater after CMR than fitness. Discussion: These preliminary results support the potential of CMR to improve function and reduce neuropathic pain in adults with SCI, warranting larger confirmatory trials. Clinicaltrial.gov: NCT05167032

BackgroundPeri-synaptic astrocyte processes (PAPs) play a fundamental role in synapse formation and function. Central afferent synapse loss and astrocyte dysfunction greatly impede sensory-motor circuitry in spinal muscular atrophy (SMA) disease progression, however mechanisms underpinning tripartite synapse dysfunction remains to be fully elucidated. The aims of this study were to further define PAP and motor neuron synaptic defects in human SMA disease pathology and implement a therapeutic intervention strategy to improve motor neuron function. MethodsWe derived astrocyte monocultures and motor neuron astrocyte co-cultures from healthy and SMA patient induced pluripotent stem cell (iPSC) lines to assess intrinsic astrocyte filopodia defects and phenotypes occurring at the synapse-PAP interface, respectively, using cell surface capture mass spectrometry proteomics, confocal and super resolution microscopy, synaptogliosome isolation, and electrophysiology. ResultsSMA astrocytes demonstrated intrinsic filopodia actin defects featuring low abundance of actin-associated cell surface N-glycoproteins, and decreased filopodia density and CDC42-GTP levels after actin remodeling stimulation. This phenotype is likely driven by the significant reduction of CD44 and phosphorylated ezrin, radixin and moesin ERM proteins (pERM) within SMA astrocyte filopodia. The dual combination of SMN1 gene therapy and forskolin treatment, an adenylyl cyclase activator leading to increased cyclic adenosine monophosphate (cAMP) levels and actin signaling pathway stimulation, led to extensive branching and increased filopodia density of SMA astrocytes during actin remodeling. SMA patient-derived motor neuron and astrocyte co-cultures, particularly samples derived from male patient iPSC lines, demonstrated a significant decrease in synapse number, actin-associated pre-synaptic neurotransmitter release protein, synapsin I (SYN1), and PAP-associated expression of pERM and glutamate transporter, EAAT1. Our astrocyte-targeted SMN1 augmentation and forskolin treatment paradigm restored SYN1 protein levels within the SMA synaptogliosome, resulting in significant increases in motor neuron synapse formation and function, but did not fully restore PAP-associated proteins levels at the synapse. ConclusionsSMA astrocytes demonstrate intrinsic actin-associated defects within filopodia, which correlates with decreased pERM levels at tripartite motor neuron synapses. We also define a SMN- and cAMP-targeted treatment paradigm that significantly increases pre-synaptic neurotransmitter release protein levels to improved SMA motor neuron synapse formation and function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/714618v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1257ab8org.highwire.dtl.DTLVardef@19c0010org.highwire.dtl.DTLVardef@c84552org.highwire.dtl.DTLVardef@3f1e62_HPS_FORMAT_FIGEXP M_FIG C_FIG

Background and Objectives Patients with peripheral neuropathies (PN) commonly exhibit balance impairment. In clinical practice, balance is typically assessed using the Rombergs test and ataxia scales, which rely on examiner interpretation, while objective biomarkers for quantifying balance remain lacking. Wearable sensors are valuable tools for objectively quantifying gait abnormalities in PN patients and may capture clinically meaningful changes over time. By integrating these parameters, artificial intelligence (AI) can assist in generating a digital score that enables easy, objective, and reproducible monitoring of patients postural balance. This study aims to generate and assess an AI-generated digital Rombergs test to quantify balance impairments in a cohort of PN patients. Methods PN patients were assessed in a longitudinal study using a wearable system composed of inertial sensors placed on the trunk and plantar pressure sensors integrated in insoles. Patients performed the Rombergs test under both eyes-open and eyes-closed conditions and were classified according to ataxia severity (mild, moderate, or severe) following the score obtained in item 1 of MICARS and SARA scales. Results We included 97 patients with PN (including autoimmune and hereditary polyneuropathies), and 117 healthy controls (HC). Significant differences in trunk sway and center of pressure (COP) were observed between groups, particularly with eyes closed. Using wearable sensor parameters, we developed an AI digital Rombergs test, which correlated with clinician-rated Rombergs test performance and distinguished patients with and without ataxia (AUC=0.632) and across different PN pathologies. Longitudinally, digital Rombergs test and iRODS showed concordant trajectories. Also, changes [&ge;]25% in the score were associated with clinical changes in ataxia severity measured by an increase in MICARS-SARA score (+1.42 points), whereas improvement was associated with a decrease (-0.20 points) in the scale. Discussion This study demonstrates that wearable sensors are useful to detect and quantify balance impairment. The AI-generated Rombergs test is an objective and reproducible tool for postural balance assessment, with robust discriminatory performance across clinical ataxia severity in PN. Scores longitudinal changes aligned with clinical severity, supporting its potential for monitoring disease progression and treatment response. Its strong association with balance measures reinforces its role as a quantitative biomarker of postural control in ataxia patients.

Objective: To systematically evaluate the efficacy and safety of Deep Brain Stimulation (DBS) for the management of disabling tremor in patients with Multiple Sclerosis (MS) by synthesizing data from available clinical studies. Methods: This systematic review and meta analysis followed PRISMA 2020 guidelines and was registered with PROSPERO (CRD420261347426). A comprehensive search of PubMed, Scopus, Web of Science, and Embase was performed from database inception until December 2025 with no time or language limitation. A pre-post meta analysis design was used to estimate the pooled effect size using the Standardized Mean Change (SMC) between baseline and follow up tremor severity. Because most included studies were single arm cohorts and clinical heterogeneity was anticipated, a random effects model using the Restricted Maximum Likelihood (REML) estimator with the Hartung-Knapp adjustment was applied. Safety outcomes including hardware complications and postoperative infections were pooled using random effects meta analysis of proportions. Results: Thirteen studies including 131 patients met the eligibility criteria. Eight studies with adequate outcome data were included in the pooled efficacy analysis. DBS was associated with a significant reduction in tremor severity with an overall pooled SMC of 1.42 (95% CI 1.07 to 1.77). Statistical heterogeneity was minimal (I2 = 0.0%, p = 0.6300), although this finding should be interpreted cautiously given the limited number of studies and clinical variability in surgical targets, most commonly the ventral intermediate nucleus (VIM), and follow up duration ranging from months to more than 20 years. The pooled incidence of postoperative infection was approximately 7% with substantial heterogeneity across studies (I2 = 74.1%). The most frequently reported adverse events were stimulation related effects such as dysarthria and disequilibrium, which were generally reversible after adjustment of stimulation parameters. Overall methodological quality of included studies was predominantly moderate. Conclusion: Deep brain stimulation may provide meaningful tremor reduction in selected patients with disabling and medication refractory MS tremor, with a large pooled treatment effect (SMC = 1.42). Although complications such as postoperative infection (approximately 7%) and transient stimulation related adverse effects can occur, these events appear manageable in most cases. However, the current evidence base remains limited by small sample sizes, heterogeneous study designs, and variability in surgical targets and outcome reporting. Larger prospective studies with standardized tremor outcome measures and consistent reporting of safety outcomes are needed to better define the long term efficacy and optimal clinical role of DBS in patients with MS related tremor.

Abstract Objectives: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. Material and Methods: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n =433) and validation cohort (Bonn, n =185). Results: In both cohorts TnT demonstrated a robust correlation with rD50-defined phases across all aggressiveness subgroups (p<0.001). There was no consistent pattern regarding sNfL and the rD50 phases. sNfL concentrations demonstrated a significant and inverse correlation with D50 applied for all disease aggressiveness subgroups (p<0.001). Correlations of TnT levels with D50 disease aggressiveness groups were generally less strong and inconsistent between the two cohorts. In the discovery cohort only low aggressiveness subgroups correlated significantly (p<0.001), intermediate aggressiveness subgroups showed only a weak correlation (p<0.05) with TnT levels. High disease aggressiveness subgroups showed no significant correlation with TnT. Conclusion: In application of the D50 disease progression model, TnT was strongly associated with disease accumulation (rD50) across all disease phases, independent of disease aggressiveness (D50), whereas sNfL robustly reflected disease aggressiveness but not overall disease burden. These complementary biomarker profiles highlight the value of an integrated approach for refined disease stratification in ALS. Combining TnT and sNfL may enhance clinical decision-making, improve monitoring of disease progression and treatment response, and support optimized clinical trial design.