Severe Motor Deficits Research Articles

Diminished sense of agency inhibits paretic upper-limb use in patients with post-stroke motor deficits

Post-stroke motor deficits often disrupt the voluntary control of body movements, leading to abnormal feelings. Among these, alterations in the sense of agency (SoA), the feeling of controlling one’s movement, are notable because SoA facilitates actions. However, whether patients with more severe motor deficits experience poorer SoA and SoA’s clinical impact on motor activity remain unclear. To address these questions, this longitudinal study quantified SoA in 156 post-stroke patients through factor analyses with multiple question items to differentiate SoA from potentially confounding discomfort. Structural equation modeling revealed that SoA decreased significantly with upper-limb motor deficit severity and that reduced SoA correlated significantly with decreased paretic upper-limb use. Notably, this effect persisted after controlling for motor deficit severity, suggesting a direct clinical impact of SoA on motor activity. Further, improvements in SoA were significantly associated with increased upper-limb use in patients with moderate or severe motor deficits, emphasizing the role of SoA in maintaining or increasing paretic upper-limb activity. These findings highlight the importance of rehabilitation treatments that consider patients’ subjective experiences, particularly agency attribution.

A 14-year longitudinal study of neurofilament light chain dynamics in premanifest and transitional Huntington's disease.

Growing evidence supports the value of neurofilament light (NfL) as a prognostic biomarker in premanifest Huntington's disease (HD). To date, however, there has been no longitudinal study exceeding 3years examining either its serial dynamics or predictive power in HD. We aimed to conduct the first such study. Serum NfL was sampled using ultrasensitive immunoassay at four timepoints across a 14-year period in a cohort of HD gene carriers (n = 21) and controls (n = 14). Gene carriers were premanifest at baseline. Clinical features of HD were evaluated by Unified Huntington's Disease Rating Scale (UHDRS TMS), Montreal Cognitive Assessment (MoCA), Trail A/B task, Symbol Digit Modalities Task and semantic/phonemic fluency tasks. 14/21 HD gene carriers converted to prodromal or manifest disease by the final timepoint ("converters"). At baseline and each subsequent timepoint, NfL levels were higher in converters than in non-converters and controls (p = < 0.001-0.03, ηp2 = 0.25-0.66). The estimated rate of change in NfL was higher in converters than in non-converters (p = 0.03) and controls (p = 0.001). Baseline NfL was able to discriminate converters from non-converters (area under curve = 1.000, p = 0.003). A higher rate of change in NfL was predictive of more severe motor (UHDRS-TMS p = 0.007, β = 0.711, R2 = 0.468) and cognitive deficits (MoCA p = 0.007, β = -0.798, R2 = 0.604; Trail B, p = 0.007, β = 0.772, R2 = 0.567; phonemic fluency p = 0.035, β = -0.632, R2 = 0.345). Our data suggest that (1) NfL longitudinal dynamics in premanifest/transitional HD are non-constant; rising faster in those closer to disease onset, and (2) NfL can identify individuals at risk of conversion to manifest disease and predict clinical trajectory, > 10years from disease onset.

B-301 Deciphering Neuropathy features in the Context of Nitrous Oxide abuse: An Integrated Analysis of Electrophysiology and Metabolism

Abstract Background Nitrous oxide (N2O), used medically for its analgesic and anxiolytic properties, has emerged as a common recreational substance, leading to a rise in chronic toxicity cases. N2O abuse induces peripheral neurological damage with a spectrum of clinical presentations, ranging from mild sensory disturbances to severe motor deficits. Neurological complications from N2O include axonal and demyelinating neuropathies, leading to diagnostic and prognostic challenges. The pathophysiology of N2O toxicity is linked to functional inactivation of vitamin B12, resulting in biochemical and electrophysiological alterations. This study aims to enhance understanding of N2O pathophysiology by examining metabolic changes in consumers with axonal and demyelinating patterns. Methods This study included 35 patients with recent N2O abuse (last declarative consumption within the past week) who were treated at Lille University Hospital between March 2020 and April 2023 and underwent electromyography. The collected clinical features encompassed sensory symptoms, motor weakness, gait abnormalities and deep tendon reflexes. Patients were classified based on clinical phenotypes, distinguishing between length-dependent and non-length dependent, sensory or sensory-motor involvement and their peripheral neuropathy disability (PND) score (ranging from I to IV). Neurophysiological data analysis followed the criteria of Hadden et al. to identify patients with demyelinating criteria, while those lacking demyelinating criteria were categorized as “axonal” in the neuropathy group. Simultaneously, biochemical evaluations of serum vitamin B12 and B9 by CLIA methods (Roche), along with plasma homocysteine by LC/MS/MS and CLIA methods (Snibe), methylmalonic acid (MMA), and methionine by LC/MS/MS, were systematically performed for all patients. Results 40% of the selected patients exhibited demyelination criteria. The demyelinated group showed a significantly higher disability PND score compared to the axonal group (3.0 and 2.2, respectively; p-value = 0.028). Elevated levels of homocysteine and methylmalonic acid were found in all patients. Interestingly, plasma concentrations of homocysteine were significantly higher in the group of patient with axonal outcomes compared to the demyelinating group (90 µM and 114 µM; p-value = 0.04), suggesting an involvement of homocysteine in the type of lesion related to N2O abuse. Conclusions This study highlights the diverse electrophysiological manifestations of N2O-induced neuropathy and highlight the potential role of metabolic parameters as biomarkers to understand the pathophysiology. Indeed, lower hyperhomocysteinemia levels were observed in demyelinating patterns, highlighting a potentially biochemical difference between the groups: plasma homocysteine could also be used as a marker of neurological severity. The homocysteine assay used in these conditions must enable the patient to be managed rapidly: it would therefore be preferable to use rapid methods such as immunoanalysis. On the other hand, plasma methylmalonic acid did not differ between groups, which also suggests that other mechanisms have yet to be identified in the pathophysiology of N2O abuse.

Differential susceptibility of human motor neurons to infection with Usutu and West Nile virus

West Nile virus (WNV) and Usutu virus (USUV) are closely related flaviviruses with differing capacities to cause neurological disease in humans. WNV is thought to use a transneural route of neuroinvasion along motor neurons and causes severe motor deficits. The potential for use of transneural routes of neuroinvasion by USUV has not been investigated experimentally, and evidence from the few clinical case reports of USUV-associated neuroinvasive disease is lacking. We hypothesised that, compared with WNV, USUV is less able to infect motor neurons, and therefore determined the susceptibility of human induced pluripotent stem cell (iPSC)-derived spinal cord motor neurons to infection. Both viruses could grow to high titres in iPSC-derived neural cultures. However, USUV could not productively infect motor neurons due to restriction by the antiviral response, which was not induced upon WNV infection. Inhibition of the antiviral response allowed for widespread infection and transportation of USUV along motor neurons within a compartmented culture system. These results show a stark difference in the ability of these two viruses to evade initiation of intrinsic antiviral immunity. Our data suggests that USUV cannot infect motor neurons in healthy individuals but in case of immunodeficiency may pose a risk for motor-related neurological disease and transneural invasion.

Innovative Strategies in 3D Bioprinting for Spinal Cord Injury Repair.

Spinal cord injury (SCI) is a catastrophic condition that disrupts neurons within the spinal cord, leading to severe motor and sensory deficits. While current treatments can alleviate pain, they do not promote neural regeneration or functional recovery. Three-dimensional (3D) bioprinting offers promising solutions for SCI repair by enabling the creation of complex neural tissue constructs. This review provides a comprehensive overview of 3D bioprinting techniques, bioinks, and stem cell applications in SCI repair. Additionally, it highlights recent advancements in 3D bioprinted scaffolds, including the integration of conductive materials, the incorporation of bioactive molecules like neurotrophic factors, drugs, and exosomes, and the design of innovative structures such as multi-channel and axial scaffolds. These innovative strategies in 3D bioprinting can offer a comprehensive approach to optimizing the spinal cord microenvironment, advancing SCI repair. This review highlights a comprehensive understanding of the current state of 3D bioprinting in SCI repair, offering insights into future directions in the field of regenerative medicine.

Redox Homeostasis, Gut Microbiota, and Epigenetics in Neurodegenerative Diseases: A Systematic Review.

Neurodegenerative diseases encompass a spectrum of disorders marked by the progressive degeneration of the structure and function of the nervous system. These conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS), often lead to severe cognitive and motor deficits. A critical component of neurodegenerative disease pathologies is the imbalance between pro-oxidant and antioxidant mechanisms, culminating in oxidative stress. The brain's high oxygen consumption and lipid-rich environment make it particularly vulnerable to oxidative damage. Pro-oxidants such as reactive nitrogen species (RNS) and reactive oxygen species (ROS) are continuously generated during normal metabolism, counteracted by enzymatic and non-enzymatic antioxidant defenses. In neurodegenerative diseases, this balance is disrupted, leading to neuronal damage. This systematic review explores the roles of oxidative stress, gut microbiota, and epigenetic modifications in neurodegenerative diseases, aiming to elucidate the interplay between these factors and identify potential therapeutic strategies. We conducted a comprehensive search of articles published in 2024 across major databases, focusing on studies examining the relationships between redox homeostasis, gut microbiota, and epigenetic changes in neurodegeneration. A total of 161 studies were included, comprising clinical trials, observational studies, and experimental research. Our findings reveal that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, with gut microbiota composition and epigenetic modifications significantly influencing redox balance. Specific bacterial taxa and epigenetic markers were identified as potential modulators of oxidative stress, suggesting novel avenues for therapeutic intervention. Moreover, recent evidence from human and animal studies supports the emerging concept of targeting redox homeostasis through microbiota and epigenetic therapies. Future research should focus on validating these targets in clinical settings and exploring the potential for personalized medicine strategies based on individual microbiota and epigenetic profiles.

Differential encoding of mammalian proprioception by voltage-gated sodium channels.

Animals that require purposeful movement for survival are endowed with mechanosensory neurons called proprioceptors that provide essential sensory feedback from muscles and joints to spinal cord circuits, which modulates motor output. Despite the essential nature of proprioceptive signaling in daily life, the mechanisms governing proprioceptor activity are poorly understood. Here, we have identified distinct and nonredundant roles for two voltage-gated sodium channels (NaVs), NaV1.1 and NaV1.6, in mammalian proprioception. Deletion of NaV1.6 in somatosensory neurons (NaV1.6cKO mice) causes severe motor deficits accompanied by complete loss of proprioceptive transmission, which contrasts with our previous findings using similar mouse models to target NaV1.1 (NaV1.1cKO). In NaV1.6cKO animals, loss of proprioceptive feedback caused non-cell-autonomous impairments in proprioceptor end-organs and skeletal muscle that were absent in NaV1.1cKO mice. We attribute the differential contribution of NaV1.1 and NaV1.6 in proprioceptor function to distinct cellular localization patterns. Collectively, these data provide the first evidence that NaV subtypes uniquely shape neurotransmission within a somatosensory modality.

User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study

ObjectiveRobotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device.MethodsA prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4–6; range 0–12 points). User expectations before provision (expectation group, n = 85) and user experiences after provision (experience group, n = 14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed.ResultsIn the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0–9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n = 85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n = 14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n = 10), and 28.6% (n = 4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was + 57 demonstrating strong patient satisfaction.ConclusionsInitiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.

Regeneration and Plasticity Induced by Epidural Stimulation in a Rodent Model of Spinal Cord Injury.

Traumatic spinal cord injury is a major cause of disability for which there are currently no fully effective treatments. Recent studies using epidural electrical stimulation have shown significant advances in motor rehabilitation, even when applied during chronic phases of the disease. The present study aimed to investigate the effectiveness of epidural electric stimulation in the motor recovery of rats with spinal cord injury. Furthermore, we aimed to elucidate the neurophysiological mechanisms underlying motor recovery. First, we improved upon the impact spinal cord injury model to cause severe and permanent motor deficits lasting up to 2 months. Next, we developed and tested an implantable epidural spinal cord stimulator device for rats containing an electrode and an implantable generator. Finally, we evaluated the efficacy of epidural electrical stimulation on motor recovery after spinal cord injury in Wistar rats. A total of 60 animals were divided into the following groups: (i) severe injury with epidural electrical stimulation (injury + stim, n = 15), (ii) severe injury without stimulation (group injury, n = 15), (iii) sham implantation without battery (sham, n = 15), and (iv) a control group, without surgical intervention (control, n = 15). All animals underwent weekly evaluations using the Basso, Beattie, Bresnahan (BBB) locomotor rating scale index, inclined plane, and OpenField test starting one week before the lesion and continuing for eight weeks. After this period, the animals were sacrificed and their spinal cords were explanted and prepared for histological analysis (hematoxylin-eosin) and immunohistochemistry for NeuN, β-III-tubulin, synaptophysin, and Caspase 3. Finally, NeuN-positive neuronal nuclei were quantified through stereology; fluorescence signal intensities for β-tubulin, synaptophyin, and Caspase 3 were quantified using an epifluorescence microscope. The injury + stim group showed significant improvement on the BBB scale compared with the injured group after the 5th week (p < 0.05). Stereological analysis showed a significantly higher average count of neural cells in the injury + stim group in relation to the injury group (1783 ± 2 vs. 897 ± 3, p < 0.001). Additionally, fluorescence signal intensity for synaptophysin was significantly higher in the injury + stim group in relation to the injury group (1294 ± 46 vs. 1198 ± 23, p < 0.01); no statistically significant difference was found in β-III-tubulin signal intensity. Finally, Caspase 3 signal intensity was significantly lower in the stim group (727 ± 123) compared with the injury group (1225 ± 87 p < 0.05), approaching levels observed in the sham and control groups. Our data suggest a regenerative and protective effect of epidural electrical stimulation in rats subjected to impact-induced traumatic spinal cord injury.

Effectiveness of a Virtual Reality rehabilitation in stroke patients with sensory-motor and proprioception upper limb deficit: A study protocol.

Stroke is the second leading cause of death in Europe. In the case of stroke survival (almost 70%), only 25% of patients recover completely, while the remaining 75% will undergo a rehabilitation phase that varying from months to years. The primary outcomes of a stroke involve motor impairment in the upper limbs, resulting in a partial or complete inability to move the limb on the right or left side, depending on the affected hemisphere. Furthermore, the motor deficit distorts the proprioception of the body and the embodiment ability of the injured limb. This could be rehabilitated through the paradigm of body illusion that modulates the motor rehabilitation. The present protocol aims to investigate the effectiveness of a Virtual Reality system for sensorimotor and proprioception upper limb deficit compared to a traditional upper limb rehabilitation program. This study has a randomized and controlled design with control and experimental groups, and 4 measurement times: pre-intervention, immediately after the intervention, and two follow-ups (at 6 and 12 months). The inclusion criteria are: (a) Being 18 to 85 years old, both males and females; (b) Suffering from ischemic or haemorrhagic stroke; (c) The stroke event must have occurred from two to eighteen months before recruitment; (d) Patients must have moderate to severe upper limb motor deficit, and the alteration of sensorimotor and proprioception abilities of the injury upper limb; (e) Patients must understand and sign the written consent for enrolment. The rehabilitation last four weeks with three sessions per week at Bellaria Hospital of Bologna (Italy). The VR protocol uses two types of technology: immersive and non-immersive, and the control group follow the traditional rehabilitation program.

Acute calcitriol treatment mitigates vitamin D deficiency-associated mortality after intracerebral haemorrhage

ObjectiveVitamin D deficiency (VDD) is emerging as a predictor of poor prognosis in various neurological conditions, where clinical outcomes are often worse in stroke patients with VDD. This study aimed to provide experimental evidence on whether and how pre-existing VDD would affect survival and neurofunctional outcomes in intracerebral haemorrhage (ICH), and to evaluate whether acute vitamin D (VD) supplementation would improve post-stroke outcomes. MethodsExperimental ICH models were induced in mice with and without VDD. Haematoma size was measured using T2*-weighted MRI and haemoglobin concentration. Post-ICH mortality, neurofunctional outcomes and the extent of blood–brain barrier (BBB) leakage were assessed to identify their correlations with VD status. Therapeutic benefits of acute VD administration were also evaluated. ResultsMice with VDD exhibited significantly higher acute mortality rates and more severe motor deficits than mice without VDD post-ICH. Marked haematoma expansion and increased Evans blue extravasation were observed in VDD mice, suggesting that VDD was associated outcomes with increased BBB disruption. Acute treatment with a loading dose of VD (calcitriol) significantly improved outcomes in VDD mice. ConclusionThis study provides novel insights into the pathophysiological mechanisms at play in ICH concomitant with VDD and a scientific rationale for acute treatment with VD.

Age-Related Effects of Inhalational Anesthetics in B4galnt1-Null and Cuprizone-Treated Mice: Clinically Relevant Insights into Demyelinating Diseases.

Anesthetics are essential agents that are frequently used in clinical practice to induce a reversible loss of consciousness and sensation by depressing the central nervous system. The inhalational anesthetics isoflurane and sevoflurane are preferred due to their rapid induction and recovery times and ease of administration. Despite their widespread use, the exact molecular mechanisms by which these anesthetics induce anesthesia are not yet fully understood. In this study, the age-dependent effects of inhalational anesthetics on two demyelination models were investigated: congenital (B4galnt1-null) and chemically induced (cuprizone). Various motor and cognitive tests were used to determine sensitivity to isoflurane and sevoflurane anesthesia. B4galnt1-null mice, which exhibit severe motor deficits due to defects in ganglioside synthesis, showed significant impairments in motor coordination and balance in all motor tests, which were exacerbated by both anesthetics. Cuprizone-treated mice, which mimic the demyelination in B4galnt1-null mice, also showed altered, age-dependent sensitivity to anesthesia. The study showed that older mice exhibited more pronounced deficits, with B4galnt1-null mice showing the greatest susceptibility to sevoflurane. These differential responses to anesthetics suggest that age and underlying myelin pathology significantly influence anesthetic effects.

Spinal hydatid disease: A case report

Introduction: The parasitic tapeworm Echinococcus granulosus causes cystic echinococcosis, also known as hydatidosis. It is a serious medical condition that can show up in a lot of different ways. Although spinal involvement occurs in about 45% of bone echinococcosis cases, it represents only 0.5–4% of all echinococcosis cases. The disease can spread to the spine through hematogenous dissemination, direct invasion, or cerebrospinal fluid seeding from ruptured cysts. While the liver and lungs are the most commonly affected organs, spinal involvement can lead to severe complications, including radiculopathy, motor deficits, and paraparesis. Imaging, such as computed tomography (CT) and (MRI), typically makes the diagnosis by revealing cystic and osteolytic lesions. Case Report: The patient is a 51-year-old male from the Kakheti region (a region in Georgia) who presented with progressive generalized weakness, nausea, vomiting, and lumbar pain. He had a history of spinal echinococcosis, diagnosed 15 years ago, but was unable to complete antiprotozoal treatment due to intolerance to albendazole. Over the years, his condition deteriorated, leading to lower paraplegia and urinary incontinence, necessitating a suprapubic cystostomy. Imaging revealed extensive septated cystic lesions in Th4-S1, which spread to the ribs and subcutaneous tissues. Despite neurosurgical intervention to reduce the cyst burden, the infestation persisted. Multiple hospitalizations were required for complications, such as urinary tract infections and pneumonia. Joint supervision managed the patient’s condition, but he continued to experience spherocyte discharge from numerous fistulas. Conclusion: This case underscores the severe and chronic nature of spinal echinococcal infection, particularly when complete antiprotozoal treatment is not feasible. The patient did not experience severe neurological complications despite the extensive disease burden and the development of multiple vertebral-cutaneous fistulas, possibly due to the continuous drainage of spherocytes. This unusual clinical course highlights the importance of comprehensive management and the potential impact of innovative approaches on managing complex parasitic infections.

Progression of Scoliosis after Skeletal Maturity in Patients with Cerebral Palsy: A Systematic Review.

Background: The progression of scoliosis has been observed in skeletally mature patients with cerebral palsy (CP). The aims of this systematic review were to determine the incidence of curve progression of untreated scoliosis after skeletal maturity, to estimate the average annual increase and to identify factors that influence the progression. Methods: A systematic literature search was performed in PubMed, Embase and the Cochrane Library for original research articles published between 1968 and May 2024 with a retrospective, prospective or cross-sectional design, investigating CP patients that were followed up beyond the age of 15 years. The search was limited to articles in English, French, German and Dutch. Articles were excluded if the study population concerned neuromuscular diseases other than CP. After an assessment of the methodological quality of each study, estimates of annual curve progression and the effect of the investigated risk factors for progression were recorded systematically and synthetized. Results: Fifteen studies met the inclusion criteria, resulting in a total sample size of 2569 participants. The study populations of the included original research articles were small and heterogeneous in terms of patient age and the type and severity of CP. Curve progression after skeletal maturity occurred in all included studies. A greater curve magnitude at the end of adolescence and a severe motor deficit (an inability to walk or GMFCS IV-V) were identified as significant risk factors for the progression of scoliosis after skeletal maturity. If at least one of these risk factors was present, scoliotic curves progressed after skeletal maturity in up to 74% of patients, with an average annual increase of 1.4 to 3.5 degrees per year. No significant association was found between curve progression and the physiologic type of CP, the type of scoliotic curve, previous hip surgery, positioning and gravity, weight and length, sex, epilepsy, or pelvic obliquity. Findings on the effect of hip instability were inconsistent: a positive correlation was found with the progression of scoliosis overall, but not after skeletal maturity in particular. A significant selection bias should be considered in the calculation of average annual curve progression, as patients that received interventions to halt curve progression were excluded from follow-up. Conclusions: The identification of risk factors in patients with CP and scoliosis can aid in predicting curve progression and managing follow-ups in clinical practice. Based on the findings in this review a radiographic follow-up once every 3 years is recommended for skeletally mature CP patients with at least one risk factor, and once every 5 years if no risk factors are present.

A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes

ATPase, class 1, type 8 A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings born from a consanguineous, first-cousin union from Sudan presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.

Local neuronal sleep after stroke: The role of cortical bistability in brain reorganization

BackgroundAcute cerebral ischemia triggers a number of cellular mechanisms not only leading to excitotoxic cell death but also to enhanced neuroplasticity, facilitating neuronal reorganization and functional recovery. ObjectiveTransferring these cellular mechanisms to neurophysiological correlates adaptable to patients is crucial to promote recovery post-stroke. The combination of TMS and EEG constitutes a promising readout of neuronal network activity in stroke patients. MethodsWe used the combination of TMS and EEG to investigate the development of local signal processing and global network alterations in 40 stroke patients with motor deficits alongside neural reorganization from the acute to the chronic phase. ResultsWe show that the TMS-EEG response reflects information about reorganization and signal alterations associated with persistent motor deficits throughout the entire post-stroke period. In the early post-stroke phase and in a subgroup of patients with severe motor deficits, TMS applied to the lesioned motor cortex evoked a sleep-like slow wave response associated with a cortical off-period, a manifestation of cortical bistability, as well as a rapid disruption of the TMS-induced formation of causal network effects. Mechanistically, these phenomena were linked to lesions affecting ascending activating brainstem fibers. Of note, slow waves invariably vanished in the chronic phase, but were highly indicative of a poor functional outcome. ConclusionIn summary, we found evidence that transient effects of sleep-like slow waves and cortical bistability within ipsilesional M1 resulting in excessive inhibition may interfere with functional reorganization, leading to a less favorable functional outcome post-stroke, pointing to a new therapeutic target to improve recovery of function.

Lumbar Disc Herniation—the Significance of Symptom Duration for the Indication for Surgery.

Lumbar disc surgery is among the more common spinal procedures. In this paper, we report the current treatment recommendations for patients with symptomatic disc herniation. This review is based on pertinent publications retrieved by a selective literature search in PubMed using the terms [timing] AND [lumbar disc herniation], supplemented by other relevant articles and guidelines. Symptoms resolve in 60% to 80% of patients with herniated discs in 6-12 weeks, and in 80% to 90% over the long term (≥ 1 year). According to the guidelines, 6-12 weeks of conservative treatment are recommended in the absence of significant neu - rologic deficits. Early surgery is indicated in case of worsening pain or new onset of neurologic deficits. Lumbar disc herniation associated bladder or bowel dysfunction (cauda equina syndrome) is considered an absolute surgical emergency that requires immediate decompression (within 24 to 48 hours). Patients with severe motor deficits (MRC ≤ 3/5) benefit from early intervention and should be offered surgery within three days, if possible, for the best chance of recovery. The degree of weakness and the duration of symptoms have been identified as risk factors for incomplete recovery. Early surgery can be considered in patients with mild paresis (MRC 4/5) in case of functional impairment (e.g., quadriceps paresis). Longer symptom duration and lower motor scores are associated with worse outcome and a lower chance of neurologic recovery. The recovery rate for motor deficits ranges from 33% to 75%, depending on the timing and modality of treatment as well as the motor score.

Clinical outcome after surgical management of spontaneous spinal epidural hematoma

PurposeSpontaneous spinal epidural hematoma (SSEH) is a rare pathology characterized by a hemorrhage in the spinal epidural space without prior surgical or interventional procedure. Recent literature reported contradictory findings regarding the clinical, radiological and surgical factors determining the outcome, hence the objective of this retrospective analysis was to re-assess these outcome-determining factors.MethodsPatients surgically treated for SSEH at our institution from 2010 – 2022 were screened and retrospectively assessed regarding management including the time-to-treatment, the pre-and post-treatment clinical status, the radiological findings as well as other patient-specific parameters. The outcome was assessed using the modified McCormick Scale. Statistical analyses included binary logistic regression and Fisher’s exact test.ResultsIn total, 26 patients (17 men [65%], 9 women [35%], median age 70 years [interquartile range 26.5]) were included for analysis. The SSEHs were located cervically in 31%, cervicothoracically in 42% and thoracically in 27%. Twenty-four patients (92%) improved after surgery. Fifteen patients (58%) had a postoperative modified McCormick Scale grade of I (no residual symptoms) and 8 patients (31%) had a grade of II (mild symptoms). Only 3 (12%) patients remained with a modified McCormick Scale grade of IV or V (severe motor deficits / paraplegic). Neither time-to-treatment, craniocaudal hematoma expansion, axial hematoma occupation of the spinal canal, anticoagulation or antiplatelet drugs, nor the preoperative clinical status were significantly associated with the patients’ outcomes.ConclusionEarly surgical evacuation of SSEH generally leads to favorable clinical outcomes. Surgical hematoma evacuation should be indicated in all patients with symptomatic SSEH.

Macrophage GIT1 promotes oligodendrocyte precursor cell differentiation and remyelination after spinal cord injury.

Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.

Replication and reliability of Parkinson's disease clinical subtypes

BackgroundWe recently identified three distinct Parkinson's disease subtypes: “motor only” (predominant motor deficits with intact cognition and psychiatric function); “psychiatric & motor” (prominent psychiatric symptoms and moderate motor deficits); “cognitive & motor” (cognitive and motor deficits). ObjectiveWe used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes. MethodsWe tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification. ResultsFirst, LCA supported the three-class solution – Motor Only, Psychiatric & Motor, and Cognitive & Motor– in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively. ConclusionsThese results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups.