Motor Dysfunction Research Articles

Plasma circulating extracellular vesicles indicate dysregulation of synaptic vesicle-associated signaling pathways in SHIV-infected rhesus macaque

Background: Recent studies point out the involvement of circulating extracellular vesicles (crEVs), in regulating neurotransmission via transferring proteins, lipids, and nucleic acids. Recently, we reported that plasma crEV proteins of either simian human immunodeficiency virus (SHIV) infected rhesus macaque or HIV-infected patient indicate a link to neuropathogenesis. Here, we tested the hypothesis that crEV proteins are indicative of dysfunction of synaptic vesicle (SV)-associated signaling pathways of SHIV-infected rhesus macaques. Methods: Plasma crEVs were isolated from SHIV-infected (SHIV-crEVs) and uninfected (CTL-crEVs) rhesus macaque and characterized by the ZetaView analyzer. Proteomic analysis of the isolated crEVs was performed using liquid chromatography/mass spectrometry (LC-MS/MS). Results: Our ZetaView analysis indicated that isolated crEVs were predominantly exosomes (particle size < 150 nm). In the LC-MS/MS study, 5,654 proteins were quantified, with 236 proteins (~ 4%) significantly differentially expressed between SHIV-crEVs and CTL-crEVs. Several SV and SV-signaling pathway associated proteins were quantified by tandem mass tags-based proteomic analysis both in SHIV-crEVs and CTL-crEVs. We observed that synaptogyrin, synaptotagmins, synaptobrevin, synaptosomal-associated proteins, syntaxin, and other SV-associated proteins were abundantly under expressed in SHIV-crEVs than in CTL-crEVs. Ingenuity Pathway Analysis demonstrated that proteins in SHIV-crEVs were involved in the deactivation of synaptogenesis, synaptic long-term protentiation/depression, and glutamate receptor signaling pathways. On the other hand, semaphorin neuronal repulsive signaling pathway and amyloid processing were activated in SHIV-crEVs. Bioinformatic analysis revealed that these proteins in SHIV-crEVs were involved in several CNS-related disorders/diseases such as abnormal morphology of synapses, motor dysfunction and movement disorder, seizure disorder, early/progressive neurological disorder, cognitive impairment, tauopathy, dementia, and Alzheimer’s disease. Conclusions: Our novel findings suggest that plasma crEVs could be an attractive noninvasive technique, which may elucidate the development of neuronal dysfunction and progression of neurological diseases. Funding: AG075988, HL148836, AG063345, AI110158, HL141143, HL168568, and the Louisiana Board of Regents Endowed Chairs for Eminent Scholars program. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex Differences in Alpha Synuclein Gastrointestinal Aggregation

Parkinson’s Disease (PD) is a neurodegenerative disorder with prodromal symptoms often emerging decades before motor issues, including gastrointestinal (GI) symptoms such as constipation and visceral pain. The pathological hallmark of PD is accumulation of misfolded α-synuclein (aSyn) protein in the brain and periphery, including the GI tract. Men have two times the risk of developing PD compared to women. However, disease progression and mortality are higher in women, who also report worse GI symptoms. Gut calcitonin gene related peptide (CGRP) is involved in modulating intestinal contractions and pain, and CGRP receptor antagonists lead to constipation. We hypothesize that sex differences in GI symptoms of PD are the result of sex specific aSyn aggregation and differential enteric CGRP signaling. Intraperitoneal injections of the pesticide rotenone were given to C57BL/6J mice to facilitate aggregation of aSyn. Immunohistochemistry was performed on colon sections using antibodies to aSyn, protein gene product (PGP) 9.5, and CGRP. Quantities of aSyn were analyzed in myenteric PGP9.5+ neuronal fibers. Vehicle treated females had 48% (mean +/- SEM = 0.66 μm2 +/- 0.04) less immunoreactive (ir) enteric aSyn than males (1.3 μm2 +/- 0.13; [F(1,22) = 4.8, p < 0.05). Rotenone treatment increased aSyn-ir by 56% (1.5 μm2 +/- 0.13) in females and 28% (1.08 μm2 +/- 0.14) in males. When interrogated by region, rotenone treatment increased the average precent area of CGRP-ir in the apical crypt (male 9% +/- 0.6; female 10% +/- 0.6) compared to vehicle (male 7% +/- 0.8; female 7% +/- 0.7). This increase was 14% higher in females compared to males (F(1,12) = 5.6, p < 0.05). In males and females, the average percent area of CGRP-ir in the mid-basal crypt region decreased with rotenone treatment (male 4% +/- 0.4; female 2.6% +/- 0.1) compared to vehicle (male 3%+/-0.2, female 1.7%+/-0.06; [F(1,12) = 19.62, p < 0.001). Microbiota have been shown to modulate visceral pain via the release of CGRP, and PD patients have altered microbiotas. The larger increase in CGRP-ir at the apical region of crypts after rotenone treatment in females may contribute to sensitivity to noxious stimuli from the lumen, including microbiota and their metabolites. In addition, decreased mid-basal CGRP-ir and aSyn increases in females after rotenone treatment provide valuable data towards explaining increased GI symptoms seen in PD females. Females are significantly understudied within the context of PD, however, investigating the underlying pathophysiology of GI symptoms while addressing sex as a variable could provide clues to the sex differences seen in clinical outcomes. Since these symptoms often arise years before motor dysfunction and diagnosis, it is critical to determine sex specific mechanisms of aSyn aggregation and influence on enteric neural involvement in prodromal GI symptoms. SCORE MGH ORWH U54-MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electroacupuncture blocked motor dysfunction and gut barrier damage by modulating intestinal NLRP3 inflammasome in MPTP-induced Parkinson's disease mice

Parkinson's disease (PD) is a neurodegenerative disorder commonly accompanied by gut dysfunction. EA has shown anti-inflammatory and neuroprotective effects. Here, we aim to explore whether EA can treat Parkinson's disease by restoring the intestinal barrier and modulating NLRP3 inflammasome. We applied 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a PD mouse model and EA at the GV16, LR3, and ST36 for 12 consecutive days. The open-field test results indicated that EA alleviated depression and behavioral defects, upregulated the expressions of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), and blocked the accumulation of α-synuclein (α-syn) in the midbrain. Moreover, EA blocked the damage to intestinal tissues of PD mice, indicative of suppressed NLRP3 inflammasome activation and increased gut barrier integrity. Notably, the antibiotic-treated mouse experiment validated that the gut microbiota was critical in alleviating PD dyskinesia and intestinal inflammation by EA. In conclusion, this study suggested that EA exhibited a protective effect against MPTP-induced PD by alleviating behavioral defects, reversing the block of motor dysfunction, and improving the gut barrier by modulating intestinal NLRP3 inflammasome. Above all, this study could provide novel insights into the pathogenesis and therapy of PD.

Expanding the clinical phenotype and genetic spectrum of GEMIN5 disorders: Early-infantile developmental and epileptic encephalopathies.

Several biallelic truncating and missense variants of the gem nuclear organelle-associated protein 5 (GEMIN5) gene have been reported to cause neurodevelopmental disorders characterized by cerebellar atrophy, intellectual disability, and motor dysfunction. However, the association between biallelic GEMIN5 variants and early-infantile developmental and epileptic encephalopathies (EIDEEs) has not been reported. This study aimed to expand the phenotypic spectrum of GEMIN5 and explore the correlations between epilepsy and molecular sub-regional locations. We performed whole-exome sequencing in two patients with EIDEE with unexplained etiologies. The damaging effects of variants were predicted using multiple in silico tools and modeling. All reported patients with GEMIN5 pathogenic variants and detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype relationship. Novel biallelic GEMIN5 variants were identified in two unrelated female patients with EIDEE, including a frameshift variant (Hg19, chr5:154284147-154284148delCT: NM_015465: c.2551_c.2552delCT: p.(Leu851fs*30)), a nonsense mutation (Hg19, chr5:154299603-154299603delTinsAGA: NM_015465: c.1523delTinsAGA: p.(Leu508*)), and two missense variants (Hg19, chr5:154282663T>A: NM_015465: c.2705T>A: p.(Leu902Gln) and Hg19, chr5:154281002C>G: NM_015465: c.2911C>G: p.(Gln971Glu)), which were inherited from asymptomatic parents and predicted to be damaging or probably damaging using in silico tools. Except p.Leu508*, all these mutations are located in tetratricopeptide repeat (TPR) domain. Our two female patients presented with seizures less than 1 month after birth, followed by clusters of spasms. Brain magnetic resonance imaging suggests dysgenesis of the corpus callosum and cerebellar hypoplasia. Video electroencephalogram showed suppression-bursts. Through a literature review, we found 5 published papers reporting 48 patients with biallelic variants in GEMIN5. Eight of 48 patients have epilepsy, and 5 patients started before 1 year old, which reminds us of the relevance between GEMIN5 variants and EIDEE. Further analysis of the 49 GEMIN5 variants in those 50 patients demonstrated that variants in TPR-like domain or RBS domain were more likely to be associated with epilepsy. We found novel biallelic variants of GEMIN5 in two individuals with EIDEE and expanded the clinical phenotypes of GEMIN5 variants. It is suggested that the GEMIN5 gene should be added to the EIDEE gene panel to aid in the clinical diagnosis of EIDEE and to help determine patient prognosis.

Food-derived Peptides as Promising Neuroprotective Agents: Mechanism and Therapeutic Potential.

Many food-derived peptides have the potential to improve brain health and slow down neurodegeneration. Peptides are produced by the enzymatic hydrolysis of proteins from different food sources. These peptides have been shown to be involved in antioxidant and anti-inflammatory activity, neuro-transmission modulation, and gene expression regulation. Although few peptides directly affect chromatin remodeling and histone alterations, others indirectly affect the neuroprotection process by interfering with epigenetic changes. Fish-derived peptides have shown neuroprotective properties that reduce oxidative stress and improve motor dysfunction in Parkinson's disease models. Peptides from milk and eggs have been found to have anti-inflammatory properties that reduce inflammation and improve cognitive function in Alzheimer's disease models. These peptides are potential therapeutics for neurodegenerative diseases, but more study is required to assess their efficacy and the underlying neuroprotective benefits. Consequently, this review concentrated on each mechanism of action used by food-derived peptides that have neuroprotective advantages and applications in treating neurodegenerative diseases. This article highlights various pathways, such as inflammatory pathways, major oxidant pathways, apoptotic pathways, neurotransmitter modulation, and gene regulation through which food-derived peptides interact at the cellular level.

Perinatal High Fat Diet Exposure Reduces KCC2 Expression and Alters GABAergic Signaling in the Dorsal Motor Nucleus of the Vagus

Perinatal high fat diet (pHFD) exposure alters the development of vagal neurocircuits controlling gastrointestinal (GI) functions resulting in gastric motor dysfunction. GABAergic synaptic inhibition of vagal efferent motoneurons within the dorsal motor nucleus of the vagus (DMV) is critical in the brain’s ability to modulate gastric motility. This inhibition is maintained by KCC2, a Cl− transporter, who determines intracellular chloride concentration. The current study was designed to test the hypothesis that pHFD reduces KCC2 levels in DMV neurons, subsequently decreasing GABAergic inhibition and delaying gastric emptying rates. Pregnant Sprague-Dawley rats were fed either a control or high fat (14% vs 60% kcal from fat, respectively) diet from embryonic day 13, and offspring were used starting postnatal day 28. In vitro electrophysiological recordings were made from adult DMV neurons in brainstem slices. To assess the GABA-mediated inhibition, cell-attached recordings were made to preserve the internal Cl− concentration, and firing rate was quantified before and after application of bicuculline (BIC; 30μM), a GABAA antagonist. To determine the Cl− reversal potential, perforated patch clamp recordings were performed and the response to picospritz application of the GABAA agonist muscimol (100μM) was measured. KCC2 expression was quantified using pharmacology in the in vitro slice preparation, as well as immunofluorescence in brainstem cross-sections. Gastric emptying rates were quantified using the in vivo13C octanoic acid breath test technique. KCC2 transfection and induced expression in the DMV of pHFD rats was achieved using an adeno-associated viral vector. BIC increased firing rate in control DMV neurons (143.1% of baseline), but failed to increase DMV firing rate in DMV neurons from pHFD rats (96.27% of baseline; p=0.0103 using unpaired t-test). When control DMV neurons were treated with VU0240551 (VU; 10μM), a KCC2 blocker, BIC application led to a decrease in the firing rate (3.118 Hz to 1.606 Hz; p=0.0375 via paired t-test), demonstrating that antagonizing KCC2 attenuates GABAergic inhibition at this synapse. In control DMV neurons, the Cl− reversal potential was calculated to be -64.6mV. There was a depolarizing shift in Cl− reversal potential observed in pHFD neurons (-43.0mV; p=0.0007 using unpaired t-test). Application of VU shifted the chloride reversal from -64.6mV to -57.3mV in control neurons (p=0.0416 using a paired t-test). VU application had a reduced impact on pHFD neurons, shifting the reversal from -46.7mV to -45.0mV (p=0.1689 using a paired t-test), suggesting KCC2 downregulation. In fact, compared to control rats, there was a significant reduction in KCC2 expression in the pHFD DMV (2.237% area fluorescence in pHFD vs. 5.335%; p=0.0147 using unpaired t-test). When KCC2 expression was virally induced in young adult pHFD rats, GABA became inhibitory (163.7% of baseline firing rate after BIC application vs. 93.25% in pHFD + empty vector (EV); p=0.0019 using unpaired t-test), the Cl− reversal potential was normalized (-63.0mV vs. -49.7mV in pHFD + EV; p=0.0012 using an unpaired t-test), and gastric emptying rates were accelerated (58.7min vs 72.1min in pHFD + EV). Taken together, these results suggest that the loss of KCC2 function is a driver of the gastric pathophysiology seen in the pHFD rats, and that normalizing KCC2 levels can rescue the cellular and gastric phenotype. DK 111667. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Effect of Balance-Resistance Training on the Immunity Levels and Physical Fitness of Children With Cerebral Palsy

Background and Aims Cerebral palsy is a non-specific and descriptive term referring to motor dysfunction in early childhood. The disease is non-progressive and is caused by permanent damage to the developing brain. This study aimed to investigate the effect of balance-resistance training on the immunity levels and physical fitness of children with cerebral palsy. Methods The present study was quasi-experimental and employed a pret-est-post-test design with a control group. For this study, 30 children (6-10 years) with cerebral palsy were recruited and divided into two groups (15 in the experimental group and 15 in the control group). The experimental group took part in resistance and balance exercises (resistance exercises for knee flexor muscles, knee extensor, and ankle extensor and free balance exercises in two levels of stable support and appropriate level of support) for 8 weeks, 3 sessions per week and each session lasted for 45 minutes. All dependent variables of the research (immunoglobulin A index, cardiorespiratory endurance, flexibility, muscle strength, muscle endurance, and body composition) were measured in two rounds of pre-test and post-test. To analyze the data, the independent t test, paired t test, 2-way analysis of variance, and Bonferroni test were used at a significance level of 0.05. All statistical analyses were performed using SPSS software, version 24. Results The results showed that combined resistance-balance training has a significant effect on immunity levels (immunoglobulin A), maximum oxygen consumption, flexibility, muscle strength, muscle endurance, and body composition of children with cerebral palsy (P≤0.001). Conclusion Patients with cerebral palsy are recommended to benefit from these exercises and medical treatments. The advantage of such adjuvant methods over medical therapies is that there are no side effects.

An integrated approach to the assessment of balance and functional mobility in individuals with history of severe traumatic brain injury

Individuals who experienced severe Traumatic Brain Injury (sTBI) are often characterized by relevant motor dysfunctions which are likely to negatively affect activities of daily living and quality of life and often persist for years. However, detailed objective information about their magnitude are scarce. The aim of this study was to quantitatively assess the extent of motor deficits in terms of postural control effectiveness under static and dynamic conditions and to investigate the existence of possible correlations between the results of clinical tests and instrumental measures. Postural sway and functional mobility (i.e., instrumented Timed Up and Go test, iTUG) were objectively measured in 18 individuals with sTBI and 18 healthy controls using a pressure plate and a wearable inertial sensor. Additionally, participants with history of sTBI completed the Rivermead Mobility Index (RMI). One-way ANOVA and Spearman's rank correlation analysis were employed to examine differences between the two groups and determine potential correlations between the instrumental tests and clinical scales.The results show that people with sTBI were characterized by larger sway area and longer iTUG walking sub-phase. Significant correlations were also detected between RMI scores and iTUG total duration, as well as the walking phase. Taken together, these findings suggest that, even years after the initial injury, individuals with sTBI appear characterized by impaired postural control and functional mobility, which appears correlated with the RMI score. The integration of instrumental measures with clinical scales in the routine assessment and treatment of individuals with sTBI would result in more comprehensive, objective, and sensitive evaluations, thus improving precision in treatment planning, enabling ongoing progress monitoring, and highlighting the presence of motor deficits even years after the initial injury. Such integration is of importance for enhancing the long-term quality of life for individuals with sTBI.

Non-motor symptoms associated with progressive loss of dopaminergic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse non-motor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the non-motor symptoms of PD in a mouse model of the disease (the TIF-IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the swing speed and step sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent non-motor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

α-Synuclein: A Promising Biomarker for Parkinson's Disease and Related Disorders.

Mutations in the SNCA gene, which encodes α-synuclein (α-syn), play a key role in the development of genetic Parkinson's disease (PD). α-Syn is a major component of Lewy bodies in PD and glial cytoplasmic inclusions in multiple system atrophy (MSA). Rapid eye movement sleep behavior disorder patients often progress to PD, dementia with Lewy bodies, or MSA, which are collectively known as α-synucleinopathies. The loss of dopaminergic neurons with Lewy bodies precedes motor dysfunction in these diseases, but the mechanisms of neurodegeneration due to α-syn aggregation are poorly understood. Monitoring α-syn aggregation in vivo could serve as a diagnostic biomarker and help elucidate pathogenesis, necessitating a simple and accurate detection method. Seed amplification assays (SAAs), such as real-time quaking-induced conversion and protein misfolding cyclic amplification, are used to detect small amounts of abnormally structured α-syn protofibrils, which are central to aggregation. These methods are promising for the early diagnosis of α-synucleinopathy. Differences in α-syn filament structures between α-synucleinopathies, as observed through transmission electron microscopy and cryo-electron microscopy, suggest their role in the pathogenesis of neurodegeneration. SAAs may differentiate between subtypes of α-synucleinopathy and other diseases. Efforts are also being made to identify α-syn from blood using various methods. This review introduces body fluid α-syn biomarkers based on pathogenic α-syn seeds, which are expected to redefine α-synucleinopathy diagnosis and staging, improving clinical research accuracy and facilitating biomarker development.

FNIRS based study of brain network characteristics in children with cerebral palsy during bilateral lower limb movement.

Motor dysfunctions in children with cerebral palsy (CP) are caused by nonprogressive brain damage. Understanding the functional characteristics of the brain is important for rehabilitation. This paper aimed to study the brain networks of children with CP during bilateral lower limb movement using functional near-infrared spectroscopy (fNIRS) and to explore effective fNIRS indices for reflecting functional brain activity. Using fNIRS, cerebral oxygenation signals in the bilateral prefrontal cortex (LPFC/RPFC) and motor cortex (LMC/RMC) were recorded from fifteen children with spastic CP and seventeen children with typical development (CTDs) in the resting state and during bilateral lower limb movement. Functional connectivity matrices based on phase-locking values (PLVs) were calculated using Hilbert transformation, and binary networks were constructed at different sparsity levels. Network metrics such as the clustering coefficient, global efficiency, local efficiency, and transitivity were calculated. Furthermore, the time-varying curves of network metrics during movement were obtained by dividing the time window and using sparse inverse covariance matrices. Finally, conditional Granger causality (GC) was used to explore the causal relationships between different brain regions. Compared to CTDs, the connectivity between RMC-RPFC (p=0.017) and RMC-LMC (p=0.002) in the brain network was decreased in children with CP, and the clustering coefficient (p=0.003), global efficiency (p=0.034), local efficiency (p=0.015), and transitivity (p=0.009) were significantly lower. The standard deviation of the changes in global efficiency of children with CP during motion was also greater than that of CTDs. Using GC, it was found that there was a significant increase in causal strength from the RMC to the RPFC (p=0.04) and from the RMC to the LMC (p=0.042) in children with CP during motion. Additionally, there were significant negative correlations between the PLV of LMC-RMC (p=0.002) and the Gross Motor Function Classification System (GMFCS) and between the GMFCS and the clustering coefficient (p=0.01). During rehabilitation training of the lower limbs, there were significant differences in brain network indices between children with CP and CTDs. The indicators proposed in this paper are effective at evaluating motor function and the real-time impact of rehabilitation training on the brain network and have great potential for application in guiding clinical motor function assessment and planning rehabilitation strategies.

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique

BackgroundSpinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. MethodsSeven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. ResultsThe results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. ConclusionThe study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS/FTD phenotypes.

The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, but its role in disease pathogenesis is unknown. Here, we show alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We find that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also show that one of the arginine-rich DPRs (PR) could directly contribute to glucose metabolism and metabolic stress by inhibiting glucose uptake in neurons. Our findings provide a potential mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and suggest a feedforward loop model with potential opportunities for therapeutic intervention.

Biomimetic Peripheral Nerve Stimulation Promotes the Rat Hindlimb Motion Modulation in Stepping: An Experimental Analysis.

Peripheral nerve stimulation is an effective neuromodulation method in patients with lower extremity movement disorders caused by stroke, spinal cord injury, or other diseases. However, most current studies on rehabilitation using sciatic nerve stimulation focus solely on ankle motor regulation through stimulation of common peroneal and tibial nerves. Using the electrical nerve stimulation method, we here achieved muscle control via different sciatic nerve branches to facilitate the regulation of lower limb movements during stepping and standing. A map of relationships between muscles and nerve segments was established to artificially activate specific nerve fibers with the biomimetic stimulation waveform. Then, characteristic curves depicting the relationship between neural electrical stimulation intensity and joint control were established. Finally, by testing the selected stimulation parameters in anesthetized rats, we confirmed that single-cathode extraneural electrical stimulation could activate combined movements to promote lower limb movements. Thus, this method is effective and reliable for use in treatment for improving and rehabilitating lower limb motor dysfunction.

Summary of best evidence for rehabilitation management of patients with motor dysfunction after stroke.

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. 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. 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. 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.

Daidzein ameliorates nonmotor symptoms of manganese-induced Parkinsonism in zebrafish model: Behavioural and biochemical approach.

Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti-inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn-induced Parkinsonism. Naïve zebrafish were exposed to 2mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ. DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn-induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection. DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn-induced Parkinsonism.

Nervonic acid alleviates MPTP-induced Parkinson's disease via MEK/ERK pathway.

Nervonic acid (NA) is a primary long-chain fatty acid and has been confirmed to have neuroprotective effects in neurologic diseases. Oxidative stress and neuronal damage are the main causes of Parkinson's disease (PD). This study mainly explored whether NA is involved in regulating oxidative stress and apoptosis in MPTP-induced mouse model and MPP-induced cell model. Through behavior tests, we proved that MPTP-induced motor dysfunction in mice was recovered by NA treatment. NA can reduce MPTP-induced neuronal damage, manifested by elevated levels of TH and dopamine, as well as decreased levels of α-syn. In the in vitro model, we observed from CCK8 assay and flow cytometry that the induction of MPP markedly suppressed cell activity and enhanced cell apoptosis, but these functions were all reversed by NA. Furthermore, NA administration reversed the increase in ROS production and MDA levels induced by MPTP or MPP, as well as the decrease in SOD levels, suggesting the antioxidant properties of NA in PD. Meanwhile, we confirmed that NA can regulate oxidative stress and neuronal damage by activating the MEK/ERK pathway. Overall, we concluded that NA could alleviate MPTP-induced PD via MEK/ERK pathway.

Dorsal dentate gyrus mediated enriched environment-induced anxiolytic and antidepressant effects in cortical infarcted mice

Anxiety and depression are the most common mental health disorders worldwide, each affecting around 30% stroke survivors. These complications not only affect the functional recovery and quality of life in stroke patients, but also are distressing for caregivers. However, effective treatments are still lacking. Enriched environment (EE), characterized with novel and multi-dimensional stimulation, has been reported to exert therapeutic effects on physical and cognitive function. In addition, EE also had potential positive effects on emotional disorders after ischemic stroke; however, the underling mechanisms have not been well elucidated. This study aimed to explore the effectiveness of EE on emotional disorders after cerebral ischemia and its underling mechanism. Sensorimotor cortical infarction was induced by photothrombosis with stable infarct location and volume, resulting in motor dysfunction, anxiety and depression-like behaviors in mice, with decreased ALFF and ReHo values and decreased c-fos expression in the infarction area and adjacent regions. Seven days' EE treatment significantly improved motor function of contralateral forelimb and exhibited anxiolytic and antidepressant effects in infarcted mice. Compared to the mice housing in a standard environment, those subjected to acute EE stimulation had significantly increased ALFF and ReHo values in the bilateral somatosensory cortex (S1, S2), dorsal dentate gyrus (dDG), dorsal CA1 of hippocampus (dCA1), lateral habenular nucleus (LHb), periaqueductal gray (PAG), ipsilateral primary motor cortex (M1), retrosplenial cortex (RSC), parietal association cortex (PtA), dorsal CA3 of hippocampus (dCA3), claustrum (Cl), ventral pallidum (VP), amygdala (Amy), and contralateral auditory cortex (Au). Some of, but not all, the ipsilateral brain regions mentioned above showed accompanying increases in c-fos expression with the most significant changes in the dDG. The number of FosB positive cells in the dDG, decreased in infarcted mice, was significantly increased after chronic EE treatment. Chemogenetic activation of dDG neurons reduced anxiety and depressive-like behaviors in infarcted mice, while neuronal inhibition resulted in void of the anxiolytic and antidepressant effects of EE. Altogether, these findings indicated that dDG neurons may mediate EE-triggered anxiolytic and antidepressant effects in cortical infarcted mice.

Transsynaptic degeneration of ventral horn motor neurons exists but plays a minor role in lower motor system dysfunction in acute ischemic rats.

As a leading cause of mortality and long-term disability, acute ischemic stroke can produce far-reaching pathophysiological consequences. Accumulating evidence has demonstrated abnormalities in the lower motor system following stroke, while the existence of Transsynaptic degeneration of contralateral spinal cord ventral horn (VH) neurons is still debated. Using a rat model of acute ischemic stroke, we analyzed spinal cord VH neuron counts contralaterally and ipsilaterally after stroke with immunofluorescence staining. Furthermore, we estimated the overall lower motor unit abnormalities after stroke by simultaneously measuring the modified neurological severity score (mNSS), compound muscle action potential (CMAP) amplitude, repetitive nerve stimulation (RNS), spinal cord VH neuron counts, and the corresponding muscle fiber morphology. The activation status of microglia and extracellular signal-regulated kinase 1/2 (ERK 1/2) in the spinal cord VH was also assessed. At 7 days after stroke, the contralateral CMAP amplitudes declined to a nadir indicating lower motor function damage, and significant muscle disuse atrophy was observed on the same side; meanwhile, the VH neurons remained intact. At 14 days after focal stroke, lower motor function recovered with alleviated muscle disuse atrophy, while transsynaptic degeneration occurred on the contralateral side with elevated activation of ERK 1/2, along with the occurrence of neurogenic muscle atrophy. No apparent decrement of CMAP amplitude was observed with RNS during the whole experimental process. This study offered an overview of changes in the lower motor system in experimental ischemic rats. We demonstrated that transsynaptic degeneration of contralateral VH neurons occurred when lower motor function significantly recovered, which indicated the minor role of transsynaptic degeneration in lower motor dysfunction during the acute and subacute phases of focal ischemic stroke.

Effects of Virtual Reality Therapy Combined With Conventional Rehabilitation on Pain, Kinematic Function, and Disability in Patients With Chronic Neck Pain: Randomized Controlled Trial.

Neck pain is a common condition that leads to neck motor dysfunction and subsequent disability, with a significant global health care burden. As a newly emerging tool, virtual reality (VR) technology has been employed to address pain and reduce disability among patients with neck pain. However, there is still a lack of high-quality studies evaluating the efficacy of VR therapy combined with conventional rehabilitation for patients with chronic neck pain, particularly in terms of kinematic function. This study aims to investigate the effect of VR therapy combined with conventional rehabilitation on pain, kinematic function, and disability in patients with chronic neck pain. We conducted an assessor-blinded, allocation-concealed randomized controlled trial. Sixty-four participants experiencing chronic neck pain were randomly allocated into the experimental group that underwent VR rehabilitation plus conventional rehabilitation or the control group receiving the same amount of conventional rehabilitation alone for 10 sessions over 4 weeks. Pain intensity, disability, kinematic function (cervical range of motion, proprioception, and mean and peak velocity), degree of satisfaction, and relief of symptoms were evaluated at 3 timepoints (baseline, postintervention, and at 3 months follow-up). A 2*3 mixed repeated measures analysis of variance was utilized for analyzing the difference across indicators, with a significant difference level of .05. Both groups demonstrated significant improvements in pain, disability, and kinematic functions (P<.05) at postintervention and at 3-month follow-up. The experimental group showed superior therapeutic outcomes compared to the control group in pain reduction (mean difference from the baseline: 5.50 vs 1.81 at posttreatment; 5.21 vs 1.91 at the 3-month follow-up, respectively; P<.001), disability improvement (mean difference from baseline: 3.04 vs 0.50 at posttreatment; 3.20 vs 0.85 at the 3-month follow-up, respectively; P<.001), and enhanced kinematic functions (P<.05). Moreover, participants in the experimental group reported better satisfaction and relief of symptoms than the control group (P<.05), with better initiative for exercising during the follow-up period. However, there was no between-group difference of improvement in proprioception. No adverse events were reported or observed in our research. The findings of our study support the efficacy of combining VR therapy with conventional rehabilitation in alleviating pain, enhancing kinematic function, and reducing disability of patients with chronic neck pain. Future research should focus on refining the therapeutic protocols and dosages for VR therapy as well as on optimizing its application in clinical settings for improved convenience and effectiveness. Chinese Clinical Trial Registry ChiCTR2000040132; http://www.chictr.org.cn/showproj.aspx?proj=64346.