VGLUT3 Deletion Rescues Motor Deficits and Neuronal Loss in the zQ175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lacking Slc17a8 gene (VGLUT3 -/-) with heterozygous zQ175 knock-in mouse model of HD (zQ175:VGLUT3 -/-). Longitudinal assessment of motor and cognitive functions from 6 to 15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and female zQ175 mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum of zQ175 mice of both sexes. Interestingly, the rescue in neuronal survival in zQ175:VGLUT3 -/- mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics.SIGNIFICANCE STATEMENT Dysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies, such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of the Slc17a8 (Vglut3) gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management.

Potential optimized route for mesenchymal stem cell transplantation in a rat model of cerebral palsy.

Cerebral palsy (CP) is a movement and posture disorder that affects over 50 million people worldwide. Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation has emerged as an attractive therapeutic strategy for CP. The administration route appears to be crucial for hUC-MSC to provide adequate neuroprotection. Wistar rats were given hypoxia-ischemia to make the CP model on postnatal day 5. On postnatal day 21, DiR-labeled hUC-MSC were transplanted into the CP rats by intravenous, intrathecal, and lateral ventricle for cell tracking. Uninfused CP rats served as the negative control. The motor behavioral and pathological alteration was analyzed 11, 25, and 39 days after transplantation to assess motor function, immune inflammation, neurotrophy, and endogenous repair. In vivo imaging tracking techniques revealed that intravenous infusion resulted in fewer transplanted cells in the target brain than intrathecal and lateral ventricle infusion (p＜0.05). Three different routes of hUC-MSC infusion improved the motor function of CP rats (p＜0.05). At 11 days post-infusion, intrathecal infusion outperformed intravenous with a significant neurotrophic and oligodendrocyte maturation effect (p＜0.05). Intrathecal infusion equaled lateral ventricle infusion after 25 days. At 39 days post-infusion, lateral ventricle infusion exceeded intravenous and intrathecal infusion with a significant immunosuppressive effect (p＜0.05). Considering the improved effect and less trauma shown early in the intrathecal infusion, repeated intrathecal administration may ultimately lead to the greatest benefit.

Clinical application of repetitive transcranial magnetic stimulation in improving functional impairments post-stroke: review of the current evidence and potential challenges.

In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.

Impact of motor dysfunction on neuropsychiatric symptom profile in patients with autopsy-confirmed Alzheimer's disease.

Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer's Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer's Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Electroacupuncture combined with wet compress formula ameliorates upper limb dysfunction associated with stroke: A retrospective analysis of 126 cases.

OBJECTIVES: Upper limb motor dysfunction (ULMD) is one of the most common complications of ischemic stroke (IS). Electroacupuncture (EA) is a noninvasive procedure that has the potential to manage symptoms associated with IS. To improve the treatment effects of EA, our hospital performed combined treating strategy against ULMD by subjecting IS patients to both EA and external application of wet compress formula (WCF). In the current analysis, the potential improving effects of the combined treatment against ULMD were evaluated. MATERIALS AND METHODS: 126 patients with ULMD induced by IS handled with normal rehabilitation treatment, EA treatment alone, and EA combined with WCF respectively were enrolled in the current analysis. The clinicopathological information and changes in motor function assessment scales, including Visual analogue (VAS), Fugl-Meyer assessment-upper extremity (FMA-UA), and Modified Barthel index (MBI) scales were collected and the difference between different treating strategies was assessed. RESULTS: All the treating strategies improved the values of VAS, FMA-UA, and MBI scales, with combined treating strategy showing the strongest improving effects, and traditional rehabilitation strategy showing the weakest effects. Moreover, the assessment of hand and wrist motor function by FMA-UE also showed that the combined treatment strategy has significantly stronger improving effects against ULMD compared with other strategies. CONCLUSIONS: The current analysis showed that the use of external application of WCF could substantially increase the treating effects of EA on ULMD induced by IS without severe side effects, which could guide the future clinical management of motor dysfunction.

Data-Driven Identification of Stroke through Machine Learning Applied to Complexity Metrics in Multimodal Electromyography and Kinematics.

A stroke represents a significant medical condition characterized by the sudden interruption of blood flow to the brain, leading to cellular damage or death. The impact of stroke on individuals can vary from mild impairments to severe disability. Treatment for stroke often focuses on gait rehabilitation. Notably, assessing muscle activation and kinematics patterns using electromyography (EMG) and stereophotogrammetry, respectively, during walking can provide information regarding pathological gait conditions. The concurrent measurement of EMG and kinematics can help in understanding disfunction in the contribution of specific muscles to different phases of gait. To this aim, complexity metrics (e.g., sample entropy; approximate entropy; spectral entropy) applied to EMG and kinematics have been demonstrated to be effective in identifying abnormal conditions. Moreover, the conditional entropy between EMG and kinematics can identify the relationship between gait data and muscle activation patterns. This study aims to utilize several machine learning classifiers to distinguish individuals with stroke from healthy controls based on kinematics and EMG complexity measures. The cubic support vector machine applied to EMG metrics delivered the best classification results reaching 99.85% of accuracy. This method could assist clinicians in monitoring the recovery of motor impairments for stroke patients.

[Research status of lower limb exoskeleton rehabilitation robot].

Lower limb exoskeleton rehabilitation robots are used to improve or restore the walking and movement ability of people with lower limb movement disorders. However, the required functions for patients differ based on various diseases. For example, patients with weak muscle strength require power assistance, patients with spinal cord injuries require motion compensation, patients with gait abnormalities require gait correction, and patients with strokes require neural rehabilitation. To design a more targeted lower limb exoskeleton rehabilitation robot for different diseases, this article summarised and compared existing lower limb exoskeleton rehabilitation robots according to their main functions and the characteristics and rehabilitation needs of various lower limb movement disorders. The correlations between the functions of existing devices and diseases were summarised to provide certain references for the development of new lower limb exoskeleton rehabilitation robots.

Summary of best evidence for rehabilitation management of patients with motor dysfunction after stroke. / è„‘å’ä¸­è¿åŠ¨åŠŸèƒ½éšœç¢æ‚£è€ åº·å¤ç®¡ç†çš„æœ€ä½³è¯æ®æ€»ç»“.

OBJECTIVES: The rehabilitation work for patients with motor dysfunction after stroke is crucial. However, there is currently a lack of summarized evidence regarding the rehabilitation management of stroke patients in rehabilitation wards, communities, and at home. This study aims to compile relevant evidence on the rehabilitation management of patients with motor dysfunction after stroke, providing a reference for clinical and community health professionals to carry out rehabilitation interventions. METHODS: A systematic search was conducted in BMJ Best Practice, UpToDate, National Guidebook Clearinghouse, American Heart Association/American Stroke Association, Canadian Medical Association, National Institute for Health and Clinical Excellence, United States Department of Veterans Affairs/ Department of Defense, Registered Nurses Association of Ontario, JBI Evidence-Based Healthcare Center Database, The Cochrane Library, PubMed, Web of Science, Embase, CINAHL, CNKI, Wanfang Database, SinoMed, and other databases for all literature on the rehabilitation management of patients with motor dysfunction after stroke. This included clinical decision-making, guidelines, expert consensuses, recommended practices, systematic reviews, and evidence summaries, with the search period spanning from the establishment of each database to October 2023. Two researchers independently evaluated the quality of the literature. RESULTS: A total of twenty-one documents were included, consisting of 11 guidelines, 2 expert consensus, and 8 systematic reviews. Evidence was extracted and integrated from the included literature, summarizing forty-five pieces of evidence across nine areas: rehabilitation management model, rehabilitation institutions, rehabilitation teams, timing of rehabilitation interventions, rehabilitation assessment, rehabilitation programs, rehabilitation duration and frequency, rehabilitation intensity, and rehabilitation support These covered comprehensive rehabilitation management content for stroke patients in the early, subacute, and chronic phases. CONCLUSIONS: The best evidence summarized in this study for the rehabilitation management of patients with motor dysfunction after stroke is comprehensive and of high quality. It provides important guidance for clinical and community healthcare professionals in carrying out rehabilitation interventions. When applying the evidence, it is recommended to consider the current condition of the stroke patient, the extent of motor dysfunction, environmental factors, and the patient's preferences. Then, select the most appropriate rehabilitation plan, and adjust the type and intensity of training according to each patient's specific needs and preferences.

Deletion of equilibrative nucleoside transporter 2 disturbs energy metabolism and exacerbates disease progression in an experimental model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease, characterized by motor dysfunction and abnormal energy metabolism. Equilibrative nucleoside transporter 1 (ENT1) and ENT2 are the major nucleoside transporters in cellular plasma membrane of the brain. Yet, unlike ENT1 whose function has been better investigated in HD, the role of ENT2 in HD remains unclear. The present study aimed to investigate the impacts of ENT2 deletion on HD using a well-characterized mouse model (R6/2). Microarray analysis, quantitative real-time polymerase chain reaction, and immunostaining of ENT2 in postmortem human brain tissues were conducted. R6/2 mice with or without genetic deletion of ENT2 were generated. Motor functions, including rotarod performance and limb-clasping test, were examined at the age of 7 to 12 weeks. Biochemical changes were evaluated by immunofluorescence staining and immunoblotting at the age of 12 to 13 weeks. In regard to energy metabolism, levels of striatal metabolites were determined by liquid chromatography coupled with the fluorescence detector or quadrupole time-of-flight mass spectrometer. Mitochondrial bioenergetics was assessed by the Seahorse assay. The results showed that ENT2 protein was detected in the neurons and astrocytes of human brains and the levels in the postmortem brain tended to be higher in patients with HD. In mice, ENT2 deletion did not alter the phenotype of the non-HD controls. Yet, ENT2 deletion deteriorated motor function and increased the number of aggregated mutant huntingtin in the striatum of R6/2 mice. Notably, disturbed energy metabolism with decreased ATP level and increased AMP/ ATP ratio was observed in R6/2-Ent2-/- mice, compared with R6/2-Ent2+/+ mice, resulting in the activation of AMPK in the late disease stage. Furthermore, ENT2 deletion reduced the NAD+/NADH ratio and impaired mitochondrial respiration in the striatum of R6/2 mice. Taken together, these findings indicate the crucial role of ENT2 in energy homeostasis, in which ENT2 deletion further impairs mitochondrial bioenergetics and deteriorates motor function in R6/2 mice.

The Effect of Cerebellar rTMS on Modulating Motor Dysfunction in Neurological Disorders: a Systematic Review.

The effectiveness of cerebellar repetitive transcranial magnetic stimulation (rTMS) on motor dysfunction in patients with neurological disorders has received increasing attention because of its potential for neuromodulation. However, studies on the neuromodulatory effects, parameters, and safety of rTMS implementation in the cerebellum to alleviate motor dysfunction are limited. This systematic review aimed to evaluate the effectiveness and safety of cerebellar rTMS treatment for motor dysfunction caused by neurological disorders and to review popular stimulation parameters. Five electronic databases-Medline, Web of Science, Scopus, Cochrane Library, and Embase-were searched for relevant research published from inception to July 2022. All randomized controlled trials (RCTs) that reported the effects of cerebellar rTMS combined with behavioral rating scales on motor dysfunction were eligible for enrollment. Additionally, reference lists of the enrolled studies were manually checked. Among 1156 articles screened, 21 RCTs with 666 subjects were included. rTMS conducted on the cerebellum showed an improvement in stroke (spasticity, balance, and gait), cervical dystonia, Parkinson's disease (tremor), cerebellar ataxia, and essential tremor but not in multiple sclerosis. The 8-shaped coil with a diameter of 70 mm was determined as the most common therapeutic choice. None of the studies reported severe adverse events except mild side effects in three. Therefore, rTMS appears to be a promising and safe technique for the treatment of motor dysfunction, targeting the cerebellum to induce motor behavioral improvement. Further rigorous RCTs, including more samples and longer follow-up periods, are required to precisely explore the effective stimulation parameters and possible mechanisms.

Assessing traffic-related air pollution-induced fiber-specific white matter degradation associated with motor performance declines in aged rats.

Fine particulate matter (PM2.5) is thought to exacerbate Parkinson's disease (PD) in the elderly, and early detection of PD progression may prevent further irreversible damage. Therefore, we used diffusion tensor imaging (DTI) for probing microstructural changes after late-life chronic traffic-related PM2.5 exposure. Herein, 1.5-year-old Fischer 344 rats were exposed to clean air (control), high-efficiency particulate air (HEPA)-filtered ambient air (HEPA group), and ambient traffic-related PM2.5 (PM2.5 group, 9.933 ± 1.021 µg/m3) for 3 months. Rotarod test, DTI tractographic analysis, and immunohistochemistry were performed in the end of study period. Aged rats exposed to PM2.5 exhibited motor impairment with decreased fractional anisotropy and tyrosine hydroxylase expression in olfactory and nigrostriatal circuits, indicating disrupted white matter integrity and dopaminergic (DA) neuronal loss. Additionally, increased radial diffusivity and lower expression of myelin basic protein in PM2.5 group suggested ageing progression of demyelination exacerbated by PM2.5 exposure. Significant production of tumor necrosis factor-α was also observed after PM2.5 exposure, revealing potential inflammation of injury to multiple fiber tracts of DA pathways. Microstructural changes demonstrated potential links between PM2.5-induced inflammatory white matter demyelination and behavioral performance, with indication of pre-manifestation of DTI-based biomarkers for early detection of PD progression in the elderly.

Activation of SIRT1 by hyperbaric oxygenation promotes recovery of motor dysfunction in spinal cord injury rats.

BACKGROUND: Hyperbaric oxygenation (HBO) therapy can improve locomotor dysfunction following spinal cord injury (SCI). Emerging evidence has demonstrated that sirtuin1 (SIRT1) exerts protective effects on neurons. However, whether HBO alleviates locomotor dysfunction by regulating SIRT1 is unclear. METHODS: The traumatic SCI animal model was performed on the adult Sprague-Dawley rats. The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay, and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms. RESULTS: We found that series HBO therapy significantly improved locomotor dysfunction and ameliorated the decreased mRNA, protein, and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection of SIRT1 inhibitor EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with the HBO application. CONCLUSION: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of the inflammatory cascade, apoptosis, and autophagy, which contributed to the recovery of motor dysfunction.

Gut Microbiome Dysbiosis as a Potential Risk Factor for Idiopathic Toe-Walking in Children: A Review.

Idiopathic toe walking (ITW) occurs in about 5% of children. Orthopedic treatment of ITW is complicated by the lack of a known etiology. Only half of the conservative and surgical methods of treatment give a stable positive result of normalizing gait. Available data indicate that the disease is heterogeneous and multifactorial. Recently, some children with ITW have been found to have genetic variants of mutations that can lead to the development of toe walking. At the same time, some children show sensorimotor impairment, but these studies are very limited. Sensorimotor dysfunction could potentially arise from an imbalanced production of neurotransmitters that play a crucial role in motor control. Using the data obtained in the studies of several pathologies manifested by the association of sensory-motor dysfunction and intestinal dysbiosis, we attempt to substantiate the notion that malfunction of neurotransmitter production is caused by the imbalance of gut microbiota metabolites as a result of dysbiosis. This review delves into the exciting possibility of a connection between variations in the microbiome and ITW. The purpose of this review is to establish a strong theoretical foundation and highlight the benefits of further exploring the possible connection between alterations in the microbiome and TW for further studies of ITW etiology.

Non-invasive brain stimulation for limb motor function and daily living activity improvement in acute stroke: A meta-analysis.

OBJECTIVE: To evaluate the effect of non-invasive brain stimulation (NIBS) in improving limb motor dysfunction and daily living activity during at the phase of acute stroke. MATERIALS AND METHODS: Randomized controlled trials about the effect of NIBS on hemiparesis in acute stroke were retrieved from databases of China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data, CBM, PubMed, Embase, Cochrane Library, and Web of Science from inception until January 3rd 2022. The quality of the trials was assessed, and the data were extracted according to the Cochrane Handbook for Systematic Reviews of Interventions. A statistical analysis was carried out using Review Manager 5.3 and STATA 14. The effect size was evaluated by using the weighed mean difference (WMD) and a 95% confidence interval (CI). The stability and sensitivity of the results and sources of heterogeneity were also analyzed. RESULTS: 12 studies involving 639 patients were included. Our meta-analysis showed that NIBS could improve the Fugl-Meyer Assessment (weighed mean difference = 3.96, 95% confidence interval = 3.45 to 4.48) and Barthel Index (weighed mean difference = 12.29, 95% confidence interval = 4.93 to 19.66), while reducing the National Institutes of Health Stroke Scale (weighed mean difference = -2.37, 95% confidence interval = -3.43 to -1.31). CONCLUSION: NIBS is effective in improving paretic limb motor function and activities of daily living in patients during at the phase of acute stroke.

Application of intraoperative evoked potential monitoring in patients with anterior cerebral artery aneurysms.

OBJECTIVES: The location of the aneurysm can affect the relationship between changes in intraoperative neurophysiological monitoring indicators and postoperative outcomes. The current study aimed to evaluate the application value of motor evoked potential and somatosensory evoked potential monitoring in anterior cerebral artery aneurysm surgery. METHODS: The data of 219 patients with anterior cerebral artery aneurysms treated via surgical clipping were retrospectively reviewed. The correlation of motor/somatosensory evoked potential monitoring with postoperative motor dysfunction was assessed using false positive rate, false negative rate, sensitivity, and specificity. Binary multivariate logistic regression analysis was applied to identify potential predictors for postoperative motor dysfunction. RESULTS: Motor evoked potential monitoring showed satisfactory effectiveness in predicting postoperative motor dysfunction (Sensitivity, 60.00%; Specificity, 85.43%; False positive rate, 14.57%; False negative rate, 40%). While somatosensory evoked potential did not (Sensitivity, 15.00%; Specificity, 96.98%; False positive rate, 3.02%; False negative rate, 85%). Abnormal motor evoked potential was identified as the only independent predictor for both short-term (odds ratio, 8.893; 95% confidence interval, 2.749-28.773; p<0.001) and long-term postoperative motor dysfunction (odds ratio, 7.877; 95% confidence interval, 2.144-28.945; p=0.002). CONCLUSIONS: During intraoperative neurophysiological monitoring for patients with anterior cerebral artery aneurysms, paying more attention to motor evoked potential changes was a reasonable choice. And somatosensory evoked potential monitoring can serve as an auxiliary reference.

Altered basal ganglia infraslow oscillation and resting functional connectivity in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a painful condition commonly accompanied by movement disturbances and often affects the upper limbs. The basal ganglia motor loop is central to movement, however, non-motor basal ganglia loops are involved in pain, sensory integration, visual processing, cognition, and emotion. Systematic evaluation of each basal ganglia functional loop and its relation to motor and non-motor disturbances in CRPS has not been investigated. We recruited 15 upper limb CRPS and 45 matched healthy control subjects. Using functional magnetic resonance imaging, infraslow oscillations (ISO) and resting-state functional connectivity in motor and non-motor basal ganglia loops were investigated using putamen and caudate seeds. Compared to controls, CRPS subjects displayed increased ISO power in the putamen contralateral to the CRPS affected limb, specifically, in contralateral putamen areas representing the supplementary motor area hand, motor hand, and motor tongue. Furthermore, compared to controls, CRPS subjects displayed increased resting connectivity between these putaminal areas as well as from the caudate body to cortical areas such as the primary motor cortex, supplementary and cingulate motor areas, parietal association areas, and the orbitofrontal cortex. These findings demonstrate changes in basal ganglia loop function in CRPS subjects and may underpin motor disturbances of CRPS.

Elucidation of pathological mechanism caused by human disease mutation in CaMKIIß.

Recently, we have identified CaMKIIα and CaMKIIß mutations in patients with neurodevelopmental disorders by whole exome sequencing study. Most CaMKII mutants have increased phosphorylation of Thr286/287, which induces autonomous activity of CaMKII, using cell culture experiments. In this study, we explored the pathological mechanism of motor dysfunction observed exclusively in a patient with Pro213Leu mutation in CaMKIIß using a mouse model of the human disease. The homozygous CaMKIIß Pro213Leu knockin mice showed age-dependent motor dysfunction and growth failure from 2 weeks after birth. In the cerebellum, the mutation did not alter the mRNA transcript level, but the CaMKIIß protein level was dramatically decreased. Furthermore, in contrast to previous result from cell culture, Thr287 phosphorylation of CaMKIIß was also reduced. CaMKIIß Pro213Leu knockin mice showed similar motor dysfunction as CaMKIIß knockout mice, newly providing evidence for a loss of function rather than a gain of function. Our disease model mouse showed similar phenotypes of the patient, except for epileptic seizures. We clearly demonstrated that the pathological mechanism is a reduction of mutant CaMKIIß in the brain, and the physiological aspects of mutation were greatly different between in vivo and cell culture.

The Essential Role of Epigenetic Modifications in Neurodegenerative Diseases with Dyskinesia.

Epigenetics play an essential role in the occurrence and improvement of many diseases. Evidence shows that epigenetic modifications are crucial to the regulation of gene expression. DNA methylation is closely linked to embryonic development in mammalian. In recent years, epigenetic drugs have shown unexpected therapeutic effects on neurological diseases, leading to the study of the epigenetic mechanism in neurodegenerative diseases. Unlike genetics, epigenetics modify the genome without changing the DNA sequence. Research shows that epigenetics is involved in all aspects of neurodegenerative diseases. The study of epigenetic will provide valuable insights into the molecular mechanism of neurodegenerative diseases, which may lead to new treatments and diagnoses. This article reviews the role of epigenetic modifications neurodegenerative diseases with dyskinesia, and discusses the therapeutic potential of epigenetic drugs in neurodegenerative diseases.

Effectiveness of robot-assisted virtual reality mirror therapy for upper limb motor dysfunction after stroke: study protocol for a single-center randomized controlled clinical trial.

BACKGROUND: Upper limb motor dysfunction is a common sequela of stroke, and its clinical efficacy needs to be improved. This protocol describes a trial to verify the clinical efficacy of robot-assisted virtual reality mirror therapy (RAVRMT) in improving upper limb motor dysfunction in stroke patients, and to explore the central mechanism by using functional magnetic resonance imaging (fMRI). METHODS: This trial will be a single-center, assessor-blinded, randomized controlled clinical study. Thirty-two eligible patients will be randomly divided into 2 groups according to the ratio of 1:1, namely virtual reality mirror therapy (VRMT) group and robot-assisted virtual reality mirror therapy (RAVRMT) group. The interventions will be performed once a day for 4 weeks. Primary outcome is Fugl-Meyer motor function assessment-Upper Extremity (FMA-UE), secondary outcomes are the Montreal Cognitive Assessment (MoCA), activities of daily living (ADL), quality of life (QOL), the pain visual analogue scale (VAS-pain) and fMRI. Adverse events will be recorded, and severe adverse events will be used as criteria to discontinue the intervention. DISCUSSION: Combined application of robot-assisted therapy and virtual reality mirror therapy could theoretically activate mirror neuron system and reward circuits to a greater extent, but further high-quality research is needed. The results of this trial will determine whether RAVRMT could better improve upper limb motor dysfunction after stroke and explore its central mechanism using fMRI. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov (ChiCTR2200061721; 01 July 2022).

Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study.

BACKGROUND: Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer's disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. METHODS: In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months' treatment with PE-A 5% and 6 months' follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. RESULTS: The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. CONCLUSION: Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EUDRACT NUMBER: 2013-004842-40. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02479802.