Comparative Efficacy of High-Intensity Training Versus Conventional Training in Individuals With Chronic Traumatic Brain Injury: A Pilot Randomized Controlled Study.

Numerous studies have evaluated the efficacy of interventions to improve locomotion after acute-onset brain injury, although most focus on patients with stroke, with less attention toward traumatic brain injury (TBI). For example, a number of studies in patients post-stroke have evaluated the effects of high-intensity training (HIT) attempting to maximize stepping practice, while no studies have attempted this intervention in patients with TBI. The purpose of this blinded-assessor randomized trial was to evaluate the effects of HIT focused on stepping practice versus conventional training on walking and secondary outcomes in individuals with TBI. Using a crossover design, ambulatory participants with TBI >6-months duration performed HIT focused on stepping in variable contexts (overground, treadmill, stairs) or conventional training for up to 15 sessions over five weeks, with interventions alternated >4 weeks later. HIT focused on maximizing stepping practice while trying to achieve higher cardiovascular intensities (>70% heart rate reserve), while conventional training focused on impairment-based and functional exercises with no restrictions on intensities achieved. Greater increases in 6-min walk test and peak treadmill speed during graded exercise testing were observed after HIT versus conventional training, with moderate associations between differences in stepping practice and outcomes. Greater gains were also observed in estimates of aerobic capacity and efficiency after HIT, with additional improvements in selected cognitive assessments. The present study suggests that the amount and intensity of stepping practice may be important determinants of improved locomotor outcomes in patients with chronic TBI, with possible secondary benefits on aerobic capacity/efficiency and cognition. Clinical Trial Registration-URL: https://clinicaltrials.gov/; Unique Identifier: NCT04503473.

Identification of a know-do gap: An observational study of the assessment and treatment of dysphagia during inpatient stroke rehabilitation in primary healthcare in Norway.

PURPOSE: Oropharyngeal dysphagia is a common swallowing impairment post-stroke managed by speech language pathologists (SLP). This article aims to demonstrate a local know-do gap assessment for usual dysphagia care for patients undergoing inpatient stroke rehabilitation in primary healthcare in Norway, which included an assessment of the functional level of the patients and characteristics and outcomes of treatment. MATERIALS AND METHODS: In this observational study, we assessed the outcomes and interventions of patients admitted to inpatient rehabilitation following stroke. The patients received usual care from SLPs while the research team administered a dysphagia assessment protocol that included assessment of several swallowing domains including oral intake, swallowing, patient self-reported functional health status and health-related quality of life, and oral health. The treating SLPs documented the treatments provided in a treatment diary. RESULTS: Of 91 patients who consented, 27 were referred for SLP and 14 received treatment. During the median treatment period of 31.5 days (IQR = 8.8-57.0), patients received 7.0 treatment sessions (IQR = 3.8-13.5) of 60 minutes (IQR = 55-60). The patients who received SLP treatment demonstrated no/minor disorders (n = 7) and moderate/severe disorders (n = 7). Dysphagia treatments primarily included oromotor training and advice on bolus modification and were provided without association to dysphagia severity. Patients with moderate/severe swallowing impairments received slightly more SLP sessions over a longer time. CONCLUSIONS: This study identified gaps between current and best practices and opportunities to improve assessment, decision-making, and implement evidence-based practices.

Increasing Activity After Stroke: A Randomized Controlled Trial of High-Intensity Walking and Step Activity Intervention.

BACKGROUND: Physical inactivity in people with chronic stroke profoundly affects daily function and increases recurrent stroke risk and mortality, making physical activity improvements an important target of intervention. We compared the effects of a high-intensity walking intervention (FAST), a step activity monitoring behavioral intervention (SAM), or a combined intervention (FAST+SAM) on physical activity (ie, steps/day). We hypothesized the combined intervention would yield the greatest increase in steps/day. METHODS: This assessor-blinded multisite randomized controlled trial was conducted at 4 university/hospital-based laboratories. Participants were 21 to 85 years old, walking without physical assistance following a single, unilateral noncerebellar stroke of ≥6 months duration, and randomly assigned to FAST, SAM, or FAST+SAM for 12 weeks (2-3 sessions/week). FAST training consisted of walking-related activities at 70% to 80% heart rate reserve, while SAM received daily feedback and goal setting of walking activity (steps/day). Assessors and study statistician were masked to group assignment. The a priori-determined primary outcome and end point was a comparison of the change in steps/day between the 3 intervention groups from pre- to post-intervention. Adverse events were tracked after randomization. All randomized participants were included in the intent-to-treat analysis. RESULTS: Participants were enrolled from July 18, 2016, to November 16, 2021. Of 2385 participants initially screened, 250 participants were randomized (mean [SE] age, 63 [0.80] years; 116 females/134 males), with 89 assigned to FAST, 81 to SAM, and 80 to FAST+SAM. Steps/day significantly increased in both the SAM (mean [SE], 1542 [267; 95% CI, 1014-2069] P<0.001) and FAST+SAM group (1307 [280; 95% CI, 752-1861] P<0.001) but not in the FAST group (406 [238; 95% CI, -63 to 876] P=0.09). There were no deaths or serious study-related adverse events. CONCLUSIONS: Only individuals with chronic stroke who completed a step activity monitoring behavioral intervention with skilled coaching and goal progression demonstrated improvements in physical activity (steps/day). REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02835313.

Increasing activity after stroke: a randomized controlled trial of highintensity walking and step activity intervention.

Background: Physical inactivity in people with chronic stroke profoundly affects daily function and increases recurrent stroke risk and mortality, making physical activity improvements an important target of intervention. We compared the effects of a highintensity walking intervention (FAST), a step activity monitoring behavioral intervention (SAM), or a combined intervention (FAST+SAM) on physical activity (i.e., steps per day). We hypothesized the combined intervention would yield the greatest increase in steps per day. Methods: This assessor-blinded multi-site randomized controlled trial was conducted at four university/hospital-based laboratories. Participants were 21-85 years old, walking without physical assistance following a single, unilateral non-cerebellar stroke of ≥6 months duration, and randomly assigned to FAST, SAM, or FAST+SAM for 12 weeks (2-3 sessions/week). FAST training consisted of walking-related activities for 40 minutes/session at 70-80% heart rate reserve, while SAM received daily feedback and goal-setting of walking activity (steps per day). Assessors and study statistician were masked to group assignment.The a priori-determined primary outcome and primary endpoint was change in steps per day from pre- to post-intervention. Adverse events (AEs) were tracked after randomization. All randomized participants were included in the intent-to-treat analysis.This study is registered at ClinicalTrials.gov, NCT02835313. Findings: Participants were enrolled from July 18, 2016-November 16, 2021. Of 250 randomized participants (mean[SE] age 63[0.80], 116F/134M), 89 were assigned to FAST, 81 to SAM, and 80 to FAST+SAM. Steps per day significantly increased in both the SAM (mean[SE] 1542[267], 95%CI:1014-2069, p<0.001) and FAST+SAM groups (1307[280], 752-1861, p<0.001), but not in the FAST group (406[238], 63-876, p=0.09). There were no deaths or serious study-related AEs and all other minor AEs were similar between groups. Interpretation: Only individuals with chronic stroke who completed a step activity monitoring behavioral intervention with skilled coaching and goal progression demonstrated improvements in physical activity (steps per day).

In vivo genome editing using novel AAV-PHP variants rescues motor function deficits and extends survival in a SOD1-ALS mouse model.

CRISPR-based gene editing technology represents a promising approach to deliver therapies for inherited disorders, including amyotrophic lateral sclerosis (ALS). Toxic gain-of-function superoxide dismutase 1 (SOD1) mutations are responsible for ~20% of familial ALS cases. Thus, current clinical strategies to treat SOD1-ALS are designed to lower SOD1 levels. Here, we utilized AAV-PHP.B variants to deliver CRISPR-Cas9 guide RNAs designed to disrupt the human SOD1 (huSOD1) transgene in SOD1G93A mice. A one-time intracerebroventricular injection of AAV.PHP.B-huSOD1-sgRNA into neonatal H11Cas9 SOD1G93A mice caused robust and sustained mutant huSOD1 protein reduction in the cortex and spinal cord, and restored motor function. Neonatal treatment also reduced spinal motor neuron loss, denervation at neuromuscular junction (NMJ) and muscle atrophy, diminished axonal damage and preserved compound muscle action potential throughout the lifespan of treated mice. SOD1G93A treated mice achieved significant disease-free survival, extending lifespan by more than 110 days. Importantly, a one-time intrathecal or intravenous injection of AAV.PHP.eB-huSOD1-sgRNA in adult H11Cas9 SOD1G93A mice, immediately before symptom onset, also extended lifespan by at least 170 days. We observed substantial protection against disease progression, demonstrating the utility of our CRISPR editing preclinical approach for target evaluation. Our approach uncovered key parameters (e.g., AAV capsid, Cas9 expression) that resulted in improved efficacy compared to similar approaches and can also serve to accelerate drug target validation.

Increasing the Amount and Intensity of Stepping Training During Inpatient Stroke Rehabilitation Improves Locomotor and Non-Locomotor Outcomes.

BACKGROUND: The efficacy of traditional rehabilitation interventions to improve locomotion post-stroke, including providing multiple exercises targeting impairments and activity limitations, is uncertain. Emerging evidence rather suggests attempts to prioritize stepping practice at higher cardiovascular intensities may facilitate greater locomotor outcomes. OBJECTIVE: The present study was designed to evaluate the comparative effectiveness of high-intensity training (HIT) to usual care during inpatient rehabilitation post-stroke. METHODS: Changes in stepping activity and functional outcomes were compared over 9 months during usual-care (n = 131 patients < 2 months post-stroke), during an 18-month transition phase with attempts to implement HIT (n = 317), and over 12 months following HIT implementation (n = 208). The transition phase began with didactic and hands-on education, and continued with meetings, mentoring, and audit and feedback. Fidelity metrics included percentage of sessions prioritizing gait interventions and documenting intensity. Demographics, training measures, and outcomes were compared across phases using linear or logistic regression analysis, Kruskal-Wallis tests, or χ2 analysis. RESULTS: Across all phases, admission scores were similar except for balance (usual-care>HIT; P < .02). Efforts to prioritize stepping and achieve targeted intensities during HIT vs transition or usual-care phases led to increased steps/day (P < .01). During HIT, gains in 10-m walk [HIT median = 0.13 m/s (interquartile range: 0-0.35) vs usual-care = 0.07 m/s (0-0.24), P = .01] and 6-min walk [50 (9.3-116) vs 2.1 (0-56) m, P < .01] were observed, with additional improvements in transfers and stair-climbing. CONCLUSIONS: Greater efforts to prioritize walking and reach higher intensities during HIT led to increased steps/day, resulting in greater gains in locomotor and non-locomotor outcomes.

Gains in Daily Stepping Activity in People With Chronic Stroke After High-Intensity Gait Training in Variable Contexts.

OBJECTIVE: Many physical therapist interventions provided to individuals with chronic stroke can lead to gains in gait speed or endurance (eg, 6-Minute Walk Test [6MWT]), although changes in objective measures of participation are not often observed. The goal of this study was to determine the influence of different walking interventions on daily stepping (steps per day) and the contributions of demographic, training, and clinical measures to these changes. METHODS: In this secondary analysis of a randomized clinical trial, steps per day at baseline and changes in steps per day following 1 of 3 locomotor interventions were evaluated in individuals who were ambulatory and >6 months after stroke. Data were collected on 58 individuals who received ≤30 sessions of high-intensity training (HIT) in variable contexts (eg, tasks and environments; n = 19), HIT focused on forward walking (n = 19), or low-intensity variable training (n = 20). Primary outcomes were steps per day at baseline, at post-training, and at a 3-month follow-up, and secondary outcomes were gait speed, 6MWT, balance, and balance confidence. Correlation and regression analyses identified demographic and clinical variables associated with steps per day. RESULTS: Gains in steps per day were observed across all groups combined, with no between-group differences; post hoc within-group analyses revealed significant gains only following HIT in variable contexts. Both HIT groups showed gains in endurance (6MWT), with increases in balance confidence only following HIT in variable contexts. Changes in steps per day were associated primarily with gains in 6MWT, with additional associations with baseline 6MWT, lower-extremity Fugl-Meyer scores, and changes in balance confidence. CONCLUSION: HIT in variable contexts elicited gains in daily stepping, with changes primarily associated with gains in gait endurance. IMPACT: Providing HIT in variable contexts appears to improve measures of participation (eg, daily stepping) that may be associated with clinical measures of function. Gains in multiple measures of mobility and participation with HIT in variable contexts may improve the efficiency and value of physical therapy services.

Step Monitor Accuracy During PostStroke Physical Therapy and Simulated Activities.

Introduction/Purpose: The amount of stepping activity during rehabilitation post-stroke can predict walking outcomes, although the most accurate methods to evaluate stepping activity are uncertain with conflicting findings on available stepping monitors during walking assessments. Rehabilitation sessions also include non-stepping activities and the ability of activity monitors to differentiate these activities from stepping is unclear. The objective of this study was to examine the accuracy of different activity monitors worn by individuals post-stroke with variable walking speeds during clinical physical therapy (PT) and research interventions focused on walking. Methods: In Part I, 28 participants post-stroke wore a StepWatch, ActiGraph with and without a Low Frequency Extension (LFE) filter, and Fitbit on paretic and non-paretic distal shanks at or above the ankle during clinical PT or research interventions with steps simultaneously hand counted. Mean absolute percent errors were compared between limbs and tasks performed. In Part II, 12 healthy adults completed 8 walking and 9 non-walking tasks observed during clinical PT or research. Data were descriptively analyzed and used to assist interpretation of Part I results. Results: Part I results indicate most devices did not demonstrate an optimal limb configuration during research sessions focused on walking, with larger errors during clinical PT on the non-paretic limb. Using the limb that minimized errors for each device, the StepWatch had smaller errors than the ActiGraph and Fitbit (p<0.01), particularly in those who walked < 0.8 m/s. Conversely, errors from the ActiGraph-LFE demonstrated inconsistent differences in step counts between Fitbit and ActiGraph. Part II results indicate that errors observed during different stepping and non-stepping activities were often device-specific, with non-stepping tasks frequently detected as stepping. Conclusions: The StepWatch and ActiGraph-LFE had smaller errors than the Fitbit or ActiGraph, with greater errors in those walking at slower speeds. Inclusion of non-stepping activities affected step counts and should be considered when measuring stepping activity in individuals post-stroke to predict locomotor outcomes following rehabilitation.

Predicting Discharge Walking Function With High-Intensity Stepping Training During Inpatient Rehabilitation in Nonambulatory Patients Poststroke.

OBJECTIVE: This cohort investigation identified primary predictors of discharge walking function of nonambulatory individuals poststroke with high-intensity training (HIT) during inpatient rehabilitation. DESIGN: Observational cohort investigation. SETTING: Inpatient rehabilitation. PARTICIPANTS: Data were collected from individuals (N=257) <6 months poststroke who required assistance to walk at admission. INTERVENTION: Clinical physical therapy interventions attempted to maximize stepping practice at higher intensities. MAIN OUTCOME MEASURES: Primary outcomes included the discharge level of assistance required during walking (minimal or no assistance) and attainment of specific gait speed thresholds (0.4 and 0.8 m/s) during the 10-m walk test. Independent predictors were demographics, training interventions (including steps/day), baseline Berg Balance Scale (BBS), and paretic leg strength. RESULTS: Participants performed a median (interquartile range) of 1270 (533-2297) steps per day throughout inpatient rehabilitation, with significant differences between those who walked with versus without assistance at discharge. Logistic regressions indicate steps per day was a primary predictor of unassisted walking recovery; removal of steps per day resulted in primary predictors of baseline BBS and strength. Receiver operating characteristic (ROC) analyses indicate significant areas under the curve for BBS and relatively low cutoff scores of 5.5 points at admission to walk without assistance at any speed. ROC analyses performed using 1-week outcomes indicate BBS scores of 5-17 points were needed to achieve locomotor thresholds. CONCLUSION: Stepping activity, BBS, and paretic leg strength were primary predictors of walking outcomes in patients performing HIT, and ROC analyses indicated recovery of independent walking could be achieved in low functioning patients early poststroke.

The Value of High Intensity Locomotor Training Applied to Patients With Acute-Onset Neurologic Injury.

Long-standing research in animal models and humans with stroke or incomplete spinal cord injury (iSCI) indicate that specific physical training variables, such as the specificity and amount of practice, may influence neurologic recovery and locomotor function. More recent data highlight the contributions of exercise intensity, as estimated indirectly by cardiovascular exertion, as potentially more important than previously considered. The effects of exercise intensity are well described in neurologically intact individuals, although confusion regarding the definitions of intensity and safety concerns have limited its implementation during physical rehabilitation of patients with neurologic injury. The purpose of this review is to delineate some of the evidence regarding the effects of exercise intensity during locomotor training in patients with stroke and iSCI. We provide specific definitions of exercise intensity used within the literature, describe methods used to ensure appropriate levels of exertion, and discuss potential adverse events and safety concerns during its application. Further details on the effects of locomotor training intensity on clinical outcomes, and on neuromuscular and cardiovascular function will be addressed as available. Existing literature across multiple studies and meta-analyses reveals that exercise training intensity is likely a major factor that can influence locomotor function after neurologic injury. To extend these findings, we describe previous attempts to implement moderate to high intensity interventions during physical rehabilitation of patients with neurologic injury, including the utility of specific strategies to facilitate implementation, and to navigate potential barriers that may arise during implementation efforts.

Elimination of glutamatergic transmission from Hb9 interneurons does not impact treadmill locomotion.

The spinal cord contains neural circuits that can produce the rhythm and pattern of locomotor activity. It has previously been postulated that a population of glutamatergic neurons, termed Hb9 interneurons, contributes to locomotor rhythmogenesis. These neurons were identified by their expression of the homeobox gene, Hb9, which is also expressed in motor neurons. We developed a mouse line in which Cre recombinase activity is inducible in neurons expressing Hb9. We then used this line to eliminate vesicular glutamate transporter 2 from Hb9 interneurons, and found that there were no deficits in treadmill locomotion. We conclude that glutamatergic neurotransmission by Hb9 interneurons is not required for locomotor behaviour. The role of these neurons in neural circuits remains elusive.

Use of CRISPR/Cas9-mediated disruption of CNS cell type genes to profile transduction of AAV by neonatal intracerebroventricular delivery in mice.

Adeno-associated virus (AAV) transduction efficiency and tropism are conventionally determined by high expression of a fluorescent reporter gene. Emerging data has suggested that such conventional methods may underestimate AAV transduction for cells in which reporter expression from AAV vectors is undetectable. To explore an alternative method that captures AAV transduction in cells in which low expression of a cargo is sufficient for the intended activity, we sought after CRISPR/Cas9-mediated gene disruption. In this study, we use AAV to deliver CRISPR/guide RNA designed to abolish the genes NeuN, GFAP, or MOG expressed specifically in neurons, astrocytes, or oligodendrocytes respectively in the central nervous system (CNS) of mice. Abrogated expression of these cell-type-specific genes can be measured biochemically in CNS subregions and provides quantitative assessment of AAV transduction in these CNS cell types. By using this method, we compared CNS transduction of AAV9, AAV-PHP.B, and AAV-PHP.eB delivered via intracerebroventricular injection (ICV) in neonatal mice. We found both AAV-PHP.B and AAV-PHP.eB resulted in marked disruption of the NeuN gene by CRISPR/Cas9, significantly greater than AAV9 in several brain regions and spinal cord. In contrast, only modest disruption of the GFAP gene and the MOG gene was observed by all three AAV variants. Since the procedure of ICV circumvents the blood-brain barrier, our data suggests that, independent of their ability to cross the blood-brain barrier, AAV-PHP.B variants also exhibit remarkably improved neuronal transduction in the CNS. We anticipate this approach will facilitate profiling of AAV cellular tropism in murine CNS.

Stepwise Regression and Latent Profile Analyses of Locomotor Outcomes Poststroke.

BACKGROUND AND PURPOSE: Previous data suggest patient demographics and clinical presentation are primary predictors of motor recovery poststroke, with minimal contributions of physical interventions. Other studies indicate consistent associations between the amount and intensity of stepping practice with locomotor outcomes. The goal of this study was to determine the relative contributions of these combined variables to locomotor outcomes poststroke across a range of patient demographics and baseline function. METHODS: Data were pooled from 3 separate trials evaluating the efficacy of high-intensity training, low-intensity training, and conventional interventions. Demographics, clinical characteristics, and training activities from 144 participants >1-month poststroke were included in stepwise regression analyses to determine their relative contributions to locomotor outcomes. Subsequent latent profile analyses evaluated differences in classes of participants based on their responses to interventions. RESULTS: Stepwise regressions indicate primary contributions of stepping activity on locomotor outcomes, with additional influences of age, duration poststroke, and baseline function. Latent profile analyses revealed 2 main classes of outcomes, with the largest gains in those who received high-intensity training and achieved the greatest amounts of stepping practice. Regression and latent profile analyses of only high-intensity training participants indicated age, baseline function, and training activities were primary determinants of locomotor gains. Participants with the smallest gains were older (≈60 years), presented with slower gait speeds (<0.40 m/s), and performed 600 to 1000 less steps/session. CONCLUSIONS: Regression and cluster analyses reveal primary contributions of training interventions on mobility outcomes in patients >1-month poststroke. Age, duration poststroke, and baseline impairments were secondary predictors. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02507466 and NCT01789853.

Locomotor Kinematics and Kinetics Following High-Intensity Stepping Training in Variable Contexts Poststroke.

Background and Purpose. Previous studies suggest that individuals poststroke can achieve substantial gains in walking function following high-intensity locomotor training (LT). Recent findings also indicate practice of variable stepping tasks targeting locomotor deficits can mitigate selected impairments underlying reduced walking speeds. The goal of this study was to investigate alterations in locomotor biomechanics following 3 different LT paradigms. Methods. This secondary analysis of a randomized trial recruited individuals 18 to 85 years old and >6 months poststroke. We compared changes in spatiotemporal, joint kinematics, and kinetics following up to 30 sessions of high-intensity (>70% heart rate reserve [HRR]) LT of variable tasks targeting paretic limb and balance impairments (high-variable, HV), high-intensity LT focused only on forward walking (high-forward, HF), or low-intensity LT (<40% HRR) of variable tasks (low-variable, LV). Sagittal spatiotemporal and joint kinematics, and concentric joint powers were compared between groups. Regressions and principal component analyses were conducted to evaluate relative contributions or importance of biomechanical changes to between and within groups. Results. Biomechanical data were available on 50 participants who could walk ≥0.1 m/s on a motorized treadmill. Significant differences in spatiotemporal parameters, kinematic consistency, and kinetics were observed between HV and HF versus LV. Resultant principal component analyses were characterized by paretic powers and kinematic consistency following HV, while HF and LV were characterized by nonparetic powers. Conclusion. High-intensity LT results in greater changes in kinematics and kinetics as compared with lower-intensity interventions. The results may suggest greater paretic-limb contributions with high-intensity variable stepping training that targets specific biomechanical deficits. Clinical Trial Registration. https://clinicaltrials.gov/ Unique Identifier: NCT02507466.

Task-Specific Versus Impairment-Based Training on Locomotor Performance in Individuals With Chronic Spinal Cord Injury: A Randomized Crossover Study.

Background. Many research studies attempting to improve locomotor function following motor incomplete spinal cord injury (iSCI) focus on providing stepping practice. However, observational studies of physical therapy strategies suggest the amount of stepping practice during clinical rehabilitation is limited; rather, many interventions focus on mitigating impairments underlying walking dysfunction. Objective. The purpose of this blinded-assessor randomized trial was to evaluate the effects of task-specific versus impairment-based interventions on walking outcomes in individuals with iSCI. Methods. Using a crossover design, ambulatory participants with iSCI >1-year duration performed either task-specific (upright stepping) or impairment-based training for up to 20 sessions over ≤6 weeks, with interventions alternated after >4 weeks delay. Both strategies focused on achieving higher cardiovascular intensities, with training specificity manipulated by practicing only stepping practice in variable contexts or practicing tasks targeting impairments underlying locomotor dysfunction (strengthening, balance tasks, and recumbent stepping). Results. Significantly greater increases in fastest overground and treadmill walking speeds were observed following task-specific versus impairment-based training, with moderate associations between differences in amount of practice and outcomes. Gains in balance confidence were also observed following task-specific vs impairment-based training, although incidence of falls was also increased with the former protocol. Limited gains were observed with impairment-based training except for peak power during recumbent stepping tests. Conclusion. The present study reinforces work from other patient populations that the specificity of task practice is a critical determinant of locomotor outcomes and suggest impairment-based exercises may not translate to improvements in functional tasks. Clinical Trial Registration URL. https://clinicaltrials.gov/ ; Unique Identifier: NCT02115685.

Amyotrophic Lateral Sclerosis Modifiers in Drosophila Reveal the Phospholipase D Pathway as a Potential Therapeutic Target.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a devastating neurodegenerative disorder lacking effective treatments. ALS pathology is linked to mutations in >20 different genes indicating a complex underlying genetic architecture that is effectively unknown. Here, in an attempt to identify genes and pathways for potential therapeutic intervention and explore the genetic circuitry underlying Drosophila models of ALS, we carry out two independent genome-wide screens for modifiers of degenerative phenotypes associated with the expression of transgenic constructs carrying familial ALS-causing alleles of FUS (hFUSR521C) and TDP-43 (hTDP-43M337V). We uncover a complex array of genes affecting either or both of the two strains, and investigate their activities in additional ALS models. Our studies indicate the pathway that governs phospholipase D activity as a major modifier of ALS-related phenotypes, a notion supported by data we generated in mice and others collected in humans.

Clinical Practice Guideline to Improve Locomotor Function Following Chronic Stroke, Incomplete Spinal Cord Injury, and Brain Injury.

BACKGROUND: Individuals with acute-onset central nervous system (CNS) injury, including stroke, motor incomplete spinal cord injury, or traumatic brain injury, often experience lasting locomotor deficits, as quantified by decreases in gait speed and distance walked over a specific duration (timed distance). The goal of the present clinical practice guideline was to delineate the relative efficacy of various interventions to improve walking speed and timed distance in ambulatory individuals greater than 6 months following these specific diagnoses. METHODS: A systematic review of the literature published between 1995 and 2016 was performed in 4 databases for randomized controlled clinical trials focused on these specific patient populations, at least 6 months postinjury and with specific outcomes of walking speed and timed distance. For all studies, specific parameters of training interventions including frequency, intensity, time, and type were detailed as possible. Recommendations were determined on the basis of the strength of the evidence and the potential harm, risks, or costs of providing a specific training paradigm, particularly when another intervention may be available and can provide greater benefit. RESULTS: Strong evidence indicates that clinicians should offer walking training at moderate to high intensities or virtual reality-based training to ambulatory individuals greater than 6 months following acute-onset CNS injury to improve walking speed or distance. In contrast, weak evidence suggests that strength training, circuit (ie, combined) training or cycling training at moderate to high intensities, and virtual reality-based balance training may improve walking speed and distance in these patient groups. Finally, strong evidence suggests that body weight-supported treadmill training, robotic-assisted training, or sitting/standing balance training without virtual reality should not be performed to improve walking speed or distance in ambulatory individuals greater than 6 months following acute-onset CNS injury to improve walking speed or distance. DISCUSSION: The collective findings suggest that large amounts of task-specific (ie, locomotor) practice may be critical for improvements in walking function, although only at higher cardiovascular intensities or with augmented feedback to increase patient's engagement. Lower-intensity walking interventions or impairment-based training strategies demonstrated equivocal or limited efficacy. LIMITATIONS: As walking speed and distance were primary outcomes, the research participants included in the studies walked without substantial physical assistance. This guideline may not apply to patients with limited ambulatory function, where provision of walking training may require substantial physical assistance. SUMMARY: The guideline suggests that task-specific walking training should be performed to improve walking speed and distance in those with acute-onset CNS injury although only at higher intensities or with augmented feedback. Future studies should clarify the potential utility of specific training parameters that lead to improved walking speed and distance in these populations in both chronic and subacute stages following injury. DISCLAIMER: These recommendations are intended as a guide for clinicians to optimize rehabilitation outcomes for persons with chronic stroke, incomplete spinal cord injury, and traumatic brain injury to improve walking speed and distance.

Etv1 Controls the Establishment of Non-overlapping Motor Innervation of Neighboring Facial Muscles during Development.

The somatotopic motor-neuron projections onto their cognate target muscles are essential for coordinated movement, but how that occurs for facial motor circuits, which have critical roles in respiratory and interactive behaviors, is poorly understood. We report extensive molecular heterogeneity in developing facial motor neurons in the mouse and identify markers of subnuclei and the motor pools innervating specific facial muscles. Facial subnuclei differentiate during migration to the ventral hindbrain, where neurons with progressively later birth dates-and evolutionarily more recent functions-settle in more-lateral positions. One subpopulation marker, ETV1, determines both positional and target muscle identity for neurons of the dorsolateral (DL) subnucleus. In Etv1 mutants, many markers of DL differentiation are lost, and individual motor pools project indifferently to their own and neighboring muscle targets. The resulting aberrant activation patterns are reminiscent of the facial synkinesis observed in humans after facial nerve injury.

Contributions of Stepping Intensity and Variability to Mobility in Individuals Poststroke.

Background and Purpose- The amount of task-specific stepping practice provided during rehabilitation poststroke can influence locomotor recovery and reflects one aspect of exercise dose that can affect the efficacy of specific interventions. Emerging data suggest that markedly increasing the intensity and variability of stepping practice may also be critical, although such strategies are discouraged during traditional rehabilitation. The goal of this study was to determine the individual and combined contributions of intensity and variability of stepping practice to improving walking speed and distance in individuals poststroke. Methods- This phase 2, randomized, blinded assessor clinical trial was performed between May 2015 and November 2018. Individuals between 18 and 85 years old with hemiparesis poststroke of >6 months duration were recruited. Of the 152 individuals screened, 97 were randomly assigned to 1 of 3 training groups, with 90 completing >10 sessions. Interventions consisted of either high-intensity stepping (70%-80% heart rate reserve) of variable, difficult stepping tasks (high variable), high-intensity stepping performing only forward walking (high forward), and low-intensity stepping in variable contexts at 30% to 40% heart rate reserve (low variable). Participants received up to 30 sessions over 2 months, with testing at baseline, post-training, and a 3-month follow-up. Primary outcomes included walking speeds and timed distance, with secondary measures of dynamic balance, transfers, spatiotemporal kinematics, and metabolic measures. Results- All walking gains were significantly greater following either high-intensity group versus low-variable training (all P<0.001) with significant correlations with stepping amount and rate (r=0.48-60; P<0.01). Additional gains in spatiotemporal symmetry were observed with high-intensity training, and balance confidence increased only following high-variable training in individuals with severe impairments. Conclusions- High-intensity stepping training resulted in greater improvements in walking ability and gait symmetry than low-intensity training in individuals with chronic stroke, with potential greater improvements in balance confidence. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02507466.

FGF family members differentially regulate maturation and proliferation of stem cell-derived astrocytes.

The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes - including functional glutamate uptake - could be enhanced by fibroblast growth factor (FGF)1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs - including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others (FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation.