Translingual neurostimulation combined with physical therapy to improve walking and balance in multiple sclerosis (NeuroMSTraLS): Study protocol for a randomized controlled trial.

INTRODUCTION: Physical rehabilitation restores lost function and promotes brain plasticity in people with Multiple Sclerosis (MS). Research groups worldwide are testing the therapeutic effects of combining non-invasive neuromodulation with physical therapy (PT) to further improve functional outcomes in neurological disorders but with mixed results. Whether such devices enhance function is not clear. We present the rationale and study design for a randomized controlled trial evaluating if there is additional benefit to the synergistic pairing of translingual neurostimulation (TLNS) with PT to improve walking and balance in MS. METHODS AND ANALYSIS: A parallel group [PT + TLNS or PT + Sham], quadruple-blinded, randomized controlled trial. Participants (N = 52) with gait and balance deficits due to relapsing-remitting or progressive MS, who are between 18 and 70 years of age, will be recruited through patient registries in Newfoundland & Labrador and Saskatchewan, Canada. All participants will receive 14 weeks of PT while wearing either a TLNS or sham device. Dynamic Gait Index is the primary outcome. Secondary outcomes include fast walking speed, subjective ratings of fatigue, MS impact, and quality of life. Outcomes are assessed at baseline (Pre), after 14 weeks of therapy (Post), and 26 weeks (Follow Up). We employ multiple methods to ensure treatment fidelity including activity and device use monitoring. Primary and secondary outcomes will be analyzed using linear mixed-effect models. We will control for baseline score and site to test the effects of Time (Post vs. Follow-Up), Group and the Group x Time interaction as fixed effects. A random intercept of participant will account for the repeated measures in the Time variable. Participants must complete the Post testing to be included in the analysis. ETHICS AND DISSEMINATION: The Human Research Ethics Boards in Newfoundland & Labrador (HREB#2021.085) & Saskatchewan (HREB Bio 2578) approved the protocol. Dissemination avenues include peer-reviewed journals, conferences and patient-oriented communications.

Fitness Shifts the Balance of BDNF and IL-6 from Inflammation to Repair among People with Progressive Multiple Sclerosis.

Physical sedentarism is linked to elevated levels of circulating cytokines, whereas exercise upregulates growth-promoting proteins such as brain-derived neurotrophic factor (BDNF). The shift towards a 'repair' phenotype could protect against neurodegeneration, especially in diseases such as multiple sclerosis (MS). We investigated whether having higher fitness or participating in an acute bout of maximal exercise would shift the balance of BDNF and interleukin-6 (IL-6) in serum samples of people with progressive MS (n = 14), compared to matched controls (n = 8). Participants performed a maximal graded exercise test on a recumbent stepper, and blood samples were collected at rest and after the test. We assessed walking speed, fatigue, and maximal oxygen consumption (V·O2max). People with MS achieved about 50% lower V·O2max (p = 0.003) than controls. At rest, there were no differences in BDNF between MS and controls; however, IL-6 was significantly higher in MS. Higher V·O2max was associated with a shift in BDNF/IL-6 ratio from inflammation to repair (R = 0.7, p = 0.001) when considering both groups together. In the MS group, greater ability to upregulate BDNF was associated with faster walking speed and lower vitality. We present evidence that higher fitness indicates a shift in the balance of blood biomarkers towards a repair phenotype in progressive MS.

Under-treated depression negatively impacts lifestyle behaviors, participation and health-related quality of life among older people with multiple sclerosis.

PURPOSE: To what extent depression may negatively impact successful aging with multiple sclerosis (MS) is not known. We examined the impact of depression/depressive symptoms on lifestyle choices (diet, exercise, smoking and alcohol), participation and health-related quality of life (HRQoL) among older people living with MS (n = 742). METHODS: Based on self-reported depression diagnosis and scores on the Hospital Anxiety and Depression Scale, we divided the sample into four groups: 1. No depression diagnosis and low symptoms (n = 412), 2. Diagnosed with depression and low symptoms (n = 103), 3. Diagnosed with depression and high symptoms (n = 87), and 4. No depression diagnosis and high symptoms (n = 140). We used regression modelling to predict outcomes, controlling for age, MS disease duration, type of MS at initial diagnosis and disability. RESULTS: A high proportion (44.5%) reported either being diagnosed with depression, having high levels of symptoms or both. Only 12.1% reported that they were prescribed anti-depressants and 13.6% utilized psychosocial services. Compared to those with depression who had low symptoms, respondents who had high depressive symptoms (n = 227) were more likely to be non-exercisers (OR 1.85, 95%CI 1.02-3.34, p = 0.042), consume a poor diet (OR 2.12, 95%CI 1.27-3.52, p = 0.004), have the lowest levels of participation (OR 3.36, 95%CI 1.74-6.49, p = 0.0003) and report the poorest HRQoL (OR 1.95, 95%CI 1.17-3.26, p = 0.011). Men and people experiencing higher levels of disability and fatigue were at greater risk of having high symptoms and being undiagnosed. CONCLUSION: Undiagnosed and under-treated depression is common among older people living with MS and adversely impacts health choices.

Factors Associated With Prolonged Length of Stay and Failed Lower Limb Prosthetic Fitting During Inpatient Rehabilitation.

OBJECTIVE: To identify variables associated with rehabilitation length of stay (LOS) and prosthetic fitting success for people with lower limb amputation (LLA). DESIGN: Retrospective analysis of clinically collected cohort. SETTING: Canadian inpatient rehabilitation hospital. PARTICIPANTS: Consecutive individuals with LLA (N=103) admitted for prosthetic fitting (mean age, 65.3±10.6y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Independent variables included the Lower Limb Amputee Measurement Scale (LLAMS), which is a 31-question tool to predict LOS with items in medical, cognitive, social, physical, activities of daily living, and other subsections; admission FIM; age; sex; level of amputation (below- or above-knee); and time from surgery to admission. LOS was measured as days from admission to discharge. Successful prosthetic fitting was defined as the ability to use a prosthesis on discharge. RESULTS: The mean LOS was 63.6 ± 33.3 days, and 21.4% of patients failed prosthetic fitting. Higher LLAMS, lower FIM, and above-knee amputation were significantly associated with longer LOS (P<.001, R 2=0.36). Age, sex, and time from surgery were not significantly associated with LOS or prosthetic fitting. Higher LLAMS was significantly associated with unsuccessful prosthetic fitting (P=.032). Of the 31 items in the LLAMS, 5 were associated with prolonged LOS and 5 were associated with failed prosthetic fitting (P<.10). CONCLUSIONS: The LLAMS, level of amputation, and admission FIM can be used to predict LOS in lower limb amputees admitted for prosthetic fitting. The LLAMS was weak in identifying patients who failed prosthetic fitting. Future research should consider shortening the LLAMS.

Prolonged cortical silent period is related to poor fitness and fatigue, but not tumor necrosis factor, in Multiple Sclerosis.

OBJECTIVE: Poor fitness among people with Multiple Sclerosis (MS) aggravates disease symptoms. Whether low fitness levels accompany brain functioning changes is unknown. METHODS: MS patients (n = 82) completed a graded maximal exercise test, blood was drawn, and transcranial magnetic stimulation determined resting and active motor thresholds, motor evoked potential latency, and cortical silent period (CSP). RESULTS: Sixty-two percent of participants had fitness levels ranked below 10th percentile. Fitness was not associated with disability measured using the Expanded Disability Status Scale (EDSS). Regression analyses revealed that, cardiorespiratory fitness, when controlling for disease demographics, contributed 23.7% (p < 0.001) to the model explaining variance in CSP. Regression analysis using cardiorespiratory fitness and CSP as predictors showed that CSP alone explained 19.9% of variance in subjective fatigue (p = 0.002). Tumor necrosis factor was not associated with any variable. CONCLUSION: Low fitness was associated with longer CSP in MS. Longer CSP was, in turn, related to greater MS fatigue. SIGNIFICANCE: MS patients had extremely low levels of cardiorespiratory fitness. Poor fitness predicted longer CSP, a marker of greater intracortical inhibition, which was linked to MS fatigue. Future research should examine whether aerobic training could shorten CSP and potentially lessen inhibition of cortical networks.

Over-the-counter anti-oxidant therapies for use in multiple sclerosis: A systematic review.

BACKGROUND: Anti-oxidant compounds that are found in over-the-counter (OTC) supplements and foods are gaining interest as treatments for multiple sclerosis (MS). They are widely used by patients, sometimes without a clear evidence base. OBJECTIVE: We conducted a systematic review of animal and clinical research to determine the evidence for the benefits of OTC anti-oxidants in MS. METHODS: Using predefined criteria, we searched key databases. Two authors scrutinized all studies against inclusion/exclusion criteria, assessed study risk-of-bias and extracted results. RESULTS: Of the 3507 titles, 145 met criteria and included compounds, α(alpha)-lipoic acid (ALA), anti-oxidant vitamins, Ginkgo biloba, quercetin, resveratrol and epigallocatechin-3-gallate (ECGC). The strongest evidence to support OTC anti-oxidants was for compounds EGCG and ALA in animal models; both consistently showed anti-inflammatory/anti-oxidant effects and reduced neurological impairment. Only vitamin E, Ginkgo biloba and ALA were examined for efficacy in pilot clinical trials with either conflicting evidence or evidence of no benefit. CONCLUSION: OTC anti-oxidants EGCG and ALA show the most consistent benefit, however only in preclinical studies. There is no evidence that they alter MS relapses or progression. Future work should focus on testing more of these therapies for clinical efficacy before recommending them to MS patients.

The Canadian survey of health, lifestyle and ageing with multiple sclerosis: methodology and initial results.

OBJECTIVE: People with multiple sclerosis (MS) are living longer so strategies to enhance long-term health are garnering more interest. We aimed to create a profile of ageing with MS in Canada by recruiting 1250 (5% of the Canadian population above 55 years with MS) participants and focusing data collection on health and lifestyle factors, disability, participation and quality of life to determine factors associated with healthy ageing. DESIGN: National multicentre postal survey. SETTING: Recruitment from Canadian MS clinics, MS Society of Canada chapters and newspaper advertisements. PARTICIPANTS: People aged 55 years or older with MS symptoms more than 20 years. OUTCOME MEASURES: Validated outcome measures and custom-designed questions examining MS disease characteristics, living situation, disability, comorbid conditions, fatigue, health behaviours, mental health, social support, impact of MS and others. RESULTS: Of the 921 surveys, 743 were returned (80.7% response rate). Participants (mean age 64.6±6.2 years) reported living with MS symptoms for an average of 32.9±9.5 years and 28.6% were either wheelchair users or bedridden. There was only 5.4% missing data and 709 respondents provided optional qualitative information. According to data derived from the 2012 Canadian Community Health Survey of Canadians above 55 years of age, older people with MS from this survey sample are about eight times less likely to be employed full-time. Older people with MS were less likely to engage in regular physical activity (26.7%) compared with typical older Canadians (45.2%). However, they were more likely to abstain from alcohol and smoking. CONCLUSIONS: Despite barriers to participation, we were able to recruit and gather detailed responses (with good data quality) from a large proportion of older Canadians with MS. The data suggest that this sample of older people with MS is less likely to be employed, are less active and more disabled than other older Canadians.

Exercise is brain food: the effects of physical activity on cognitive function.

This commentary reviews selected biomedical and clinical research examining the relationship between physical exercise and cognitive function especially in youth with disability. Youth with physical disability may not benefit from the effects of exercise on cardiovascular fitness and brain health since they are less active than their non-disabled peers. In animal models, physical activity enhances memory and learning, promotes neurogenesis and protects the nervous system from injury and neurodegenerative disease. Neurotrophins, endogenous proteins that support brain plasticity likely mediate the beneficial effects of exercise on the brain. In clinical studies, exercise increases brain volume in areas implicated in executive processing, improves cognition in children with cerebral palsy and enhances phonemic skill in school children with reading difficulty. Studies examining the intensity of exercise required to optimize neurotrophins suggest that moderation is important. Sustained increases in neurotrophin levels occur with prolonged low intensity exercise, while higher intensity exercise, in a rat model of brain injury, elevates the stress hormone, corticosterone. Clearly, moderate physical activity is important for youth whose brains are highly plastic and perhaps even more critical for young people with physical disability.

A qualitative and quantitative analysis of skilled forelimb reaching impairment following intracerebral hemorrhage in rats.

The Montoya staircase test is commonly used to measure skilled forelimb reaching ability in a number of brain injury and disease models, but little has been done to characterize the precise nature of the impairments observed after stroke. The present study used slow motion video-recording to analyze staircase reaching performance both qualitatively and quantitatively, and to precisely determine the components of fine forelimb motor function that are disturbed in the collagenase model of hemorrhagic stroke. Male Sprague-Dawley rats were trained to reach for pellets in the staircase task, and subjected to either striatal hemorrhage induced by microinjections of bacterial collagenase or sham surgery. Reaching performance was recorded and examined before surgery, and 2 and 4 weeks later. Impaired animals made fewer attempts and retrieved less pellets than did shams, especially from the lower steps. Interestingly, impaired animals were less able to retrieve a pellet even when the forepaw made contact with it. Detailed qualitative analysis determined that significant disturbances were most prominent in components of skilled reaching that involved fine manipulation of the distal muscles, especially the wrist and digits. While some components of the reaching impairment were found to partially recover at 4 weeks post-surgery, the impairments in these distal motor movements persisted and there was no significant improvement in overall success. These results suggest that the collagenase model of intracerebral hemorrhage produces a functional impairment that most severely affects fine control of the distal forelimb and paw.