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Objectives Spinal cord stimulation is a potential therapeutic option for the treatment of Parkinson's disease (PD)-associated symptoms. Repetitive trans-spinal magnetic stimulation (rTSMS) is a non-invasive and safe alternative for stimulation of spinal pathways that has not been studied for therapeutic efficacy in PD. We assessed the benefits of rTSMS on camptocormia, an often treatment-resistant postural abnormality observed in PD patients. Methods We compared rTSMS to sham stimulation in PD patients with camptocormia in a single-centre, randomised, single-blind, crossover, placebo-controlled study. PD patients with camptocormia were administered a single trial of rTSMS (a train of 40 stimuli) or sham treatment followed 1 week later by the alternate treatment. Primary outcome measure was thoracolumbar spine flexion angle in the standing position immediately after the trial. Results Of 320 PD patients examined, 37 had concomitant camptocormia and were randomly assigned to either the rTSMS first group (n=19) or sham first group (n=18). Flexion angle in the standing position decreased by a mean of 10.9° (95% CI 8.1 to 13.65) after rTSMS but remained unchanged after sham stimulation (mean, −0.1°; 95% CI −0.95 to 0.71). The flexion angle while sitting (secondary outcome) decreased by 8.1° (95% CI 5.89 to 10.25) after rTSMS, whereas sham treatment had no significant effect (mean, −0.8°; 95% CI −1.62 to 0.05). Conclusions We found an immediate beneficial effect of rTSMS on camptocormia in PD patients. Although the effect was transient, this successful trial justifies further studies to test if repeated rTSMS treatments can induce longer term improvements in camptocormia associated with PD. Clinical trial registration UMIN Clinical Trials Registry: UMIN000011495.

Regeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined specifically in injured sensory neurons. Using RNA sequencing of dorsal root ganglion, we determined that thoracic SCI elicits a transcriptional response distinct from sciatic nerve injury (SNI). Both SNI and SCI induced upregulation of ATF3 and Jun, yet this response failed to promote growth in sensory neurons after SCI. RNA sequencing of purified sensory neurons one and three days after injury revealed that unlike SNI, the SCI response is not sustained. Both SCI and SNI elicited the expression of ATF3 target genes, with very little overlap between conditions. Pathway analysis of differentially expressed ATF3 target genes revealed that fatty acid biosynthesis and terpenoid backbone synthesis were downregulated after SCI but not SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating palmitic acid, decreased axon growth and regeneration in vitro. These results support the notion that decreased expression of lipid metabolism-related genes after SCI, including fatty acid synthase, may restrict axon regenerative capacity after SCI.

Background The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. Methods Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = ‘Walk unaided’, 2 = ‘With walking aid’ and 3 = ‘Bed-bound’. The margin used to establish non-inferiority was a detrimental change of −0.4 in the mean difference between arms. Results One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30–87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was −0.12 to 0.6. Since −0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2–3 AE compared with six (11%) patients in the SF arm ( p  = 0.093). Conclusion For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. Clinical Trial Registration Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

Chemotherapy-induced peripheral neuropathy (CIPN) and associated neuropathic pain is a debilitating adverse effect of cancer treatment. Current understanding of the mechanisms underpinning CIPN is limited and there are no effective treatment strategies. In this study, we treated male C57BL/6J mice with 4 cycles of either Paclitaxel (PTX) or Oxaliplatin (OXA) over a week and tested pain hypersensitivity and changes in peripheral immune responses and neuroinflammation on days 7 and 13 post 1st injection. We found that both PTX and OXA caused significant mechanical allodynia. In the periphery, PTX and OXA significantly increased circulating CD4+ and CD8+ T-cell populations. OXA caused a significant increase in the percentage of interleukin-4+ lymphocytes in the spleen and significant down-regulation of regulatory T (T-reg) cells in the inguinal lymph nodes. However, conditional depletion of T-reg cells in OXA-treated transgenic DEREG mice had no additional effect on pain sensitivity. Furthermore, there was no leukocyte infiltration into the nervous system of OXA- or PTX-treated mice. In the peripheral nervous system, PTX induced expression of the neuronal injury marker activating transcription factor-3 in IB4+ and NF200+ sensory neurons as well as an increase in the chemokines CCL2 and CCL3 in the lumbar dorsal root ganglion. In the central nervous system, PTX induced significant astrocyte activation in the spinal cord dorsal horn, and both PTX and OXA caused reduction of P2ry12+ homeostatic microglia, with no measurable changes in IBA-1+ microglia/macrophages in the dorsal and ventral horns. We also found that PTX induced up-regulation of several inflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL11, CCL4, CCL3, IL-12p70 and GM-CSF) in the spinal cord. Overall, these findings suggest that PTX and OXA cause distinct pathological changes in the periphery and nervous system, which may contribute to chemotherapy-induced neuropathic pain.

Abstract Dorsal root ganglia, dorsal roots (DR), and dorsal root entry zones (DREZ) are vulnerable to frataxin deficiency in Friedreich ataxia (FA). A previously unrecognized abnormality is the intrusion of astroglial tissue into DR. Segments of formalin-fixed upper lumbar spinal cord of 13 homozygous and 2 compound heterozygous FA patients were sectioned longitudinally to represent DREZ and stained for glial fibrillary acidic protein (GFAP), S100, vimentin, the central nervous system (CNS)-specific myelin protein proteolipid protein, the peripheral nervous system (PNS) myelin proteins PMP-22 and P0, and the Schwann cell proteins laminin, alpha-dystroglycan, and periaxin. Normal DREZ showed short, sharply demarcated, dome-like extensions of CNS tissue into DR. The Schwann cell-related proteins formed tight caps around these domes. In FA, GFAP-, S100-, and vimentin-reactive CNS tissue extended across DREZ and into DR over much longer distances by breaching the CNS-PNS barrier. The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3–IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3–IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SOD G93A mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases. Madaro et al. show that denervation induces accumulation of IL-6–STAT3-activated fibro-adipogenic progenitors without inflammation or muscle regeneration, leading to muscle atrophy and fibrosis.

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-β1–dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K–phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2–PI3K–p-Akt signalling pathway. Hervera et al. show that extracellular vesicles containing NOX2 complexes are released from macrophages and incorporated into injured axons, leading to axonal regeneration through PI3K–p-Akt signalling.

Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus-9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, we evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. We found widespread transgene expression throughout the spinal cord in mice and nonhuman primates when using a 10 times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. We present a detailed analysis of transduction levels throughout the brain, brainstem, and spinal cord of nonhuman primates, providing new guidance for translation toward therapy for a wide range of neurodegenerative disorders.

Intradural spinal cord compression impairs perfusion pressure and is putatively rate-limiting for recovery after traumatic spinal cord injury (tSCI). After cervical tSCI, even minimally improved tissue preservation may help promote neurological recovery. To assess the nature and extent of spinal cord swelling and compression post-acute cervical tSCI, we evaluated several baseline MRI parameters including BASIC score, intramedullary lesion (IML) length, maximal canal compromise (MCC), maximal spinal cord compression (MSCC), extent of cord compression (ECC), maximal swollen anteroposterior diameter adjacent to injury site (Dmax), and maximal cord swelling (MCS) in 169 consecutive patients across 2 centers. In patients with either primarily intradural or combined (MSCC ≤5% or >5%, respectively) cord compression, we examined the predictive value of clinical and imaging admission parameters on American Spinal Injury Association Impairment Scale (AIS) severity and conversion up to 1-year follow-up. 37 (21.9%) patients presented with primarily intradural while 132 (78.1%) had combined cord compression. MSCC, MCS, and Dmax values differed significantly between the two groups (p < 0.0001, < 0.01 and < 0.001, respectively). MSCC was associated with age, MCC and MCS at baseline, while MCS was associated with age, MSCC and Dmax, on multivariable analysis. Logistic regression analysis of areas under receiver operating characteristic curve (AUROC) confirmed ECC (AUC 0.678) and MCS (AUC 0.922) as good and excellent predictors, respectively of AIS-conversion at 1-year for intradural compression participants. Additionally, MCS was significantly more accurate in predicting AIS-conversion in intradural group and the probability of AIS-conversion significantly decreased with each 1% increase in MCS (p = 0.003; OR 0.949), for both compression subtypes. In conclusion, baseline measures of cord swelling predict AIS-conversion likelihood up to 1-year. The deleterious effects of intradural cord compression, either isolated or presenting with extradural compression, may benefit from supplemental decompression strategies in addition to current standard-of-care.

Talking antisense: rescue of SMN2 in motor neurone disease Spinal muscular atrophy (SMA) is a motor neurone disease caused by a mutation in a gene called SMN1 that is necessary for the survival of motor neurons. Humans have a duplicate gene, SMN2 , but that is barely expressed. One promising form of therapy involves increasing SMN2 expression. It has been assumed that it would be necessary to increase the expression of SMN2 in spinal cord motor neurons to achieve a therapeutic effect. Not so. In a mouse model of SMA, subcutaneous, peripheral administration of an antisense oligonucleotide that corrects a splicing defect in SMN2 is shown to provide a much more powerful therapy than direct delivery to the brain. Surprisingly, peripheral rescue is found to be essential for long-term rescue of SMA, and biomarkers suggest that the liver has an important role of the liver in SMA pathogenesis. Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality; it results from loss-of-function mutations in the survival motor neuron 1 ( SMN1 ) gene 1 . Humans have a paralogue, SMN2 , whose exon 7 is predominantly skipped 2 , but the limited amount of functional, full-length SMN protein expressed from SMN2 cannot fully compensate for a lack of SMN1 . SMN is important for the biogenesis of spliceosomal small nuclear ribonucleoprotein particles 3 , but downstream splicing targets involved in pathogenesis remain elusive. There is no effective SMA treatment, but SMN restoration in spinal cord motor neurons is thought to be necessary and sufficient 4 . Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported in severe SMA mouse models and patients 5 , 6 , 7 , 8 , reflecting autonomic dysfunction or direct effects in cardiac tissues. Here we compared systemic versus CNS restoration of SMN in a severe mouse model 9 , 10 . We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection 11 , 12 . Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median lifespan by 25 fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals expression, leading to a pronounced reduction in circulating insulin-like growth factor 1 (IGF1), and ASO-10-27 treatment restored IGF1 to normal levels. These results suggest that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate.