Pierce Boyne

Introduction: High-intensity locomotor training (HIT) is recommended for improving walking capacity, but treatment responses are variable. Understanding the brain changes underlying responsiveness to training could provide insight into this variability. Emerging evidence suggests upregulation of the contralesional cortico-reticulospinal tract (CRST) may contribute to walking function after stroke. However, it is unclear whether CRST upregulation is supportive or maladaptive, and no studies have examined CRST changes after HIT. This study investigated how CRST and corticospinal tract (CST) strength and laterality reorganize, and their relationship with walking capacity after locomotor HIT. Methods: Ten participants with chronic stroke completed a 4-week no-intervention control phase then 4 weeks of HIT. Diffusion MRI and 6-minute walk distance were obtained at weeks 0, 4, and 8. Analysis tested changes in ipsilesional and contralesional CRST and CST strength and laterality. Associations between changes in tract laterality and walking capacity were examined. Results: During the treatment phase (vs the control phase), there were significantly greater increases in contralesional CRST strength (1.02 SD [95% CI: 0.25, 1.79]), contralesional CRST laterality (4.44 [2.15, 6.72]), and 6-minute walk distance (33 meters [17, 50]). Walking capacity improvements were associated with changes in CRST laterality ( r = 0.77, P = .01), but not CST laterality ( r = −0.01, P = 0.98). Discussion: Following HIT, increases in contralesional CRST strength and laterality were observed. CRST laterality changes were strongly associated with walking improvements, suggesting an association between contralesional CRST changes and training-related improvements. Clinical trial registration: ClinicalTrials.gov Identifier: NCT02858349, https://clinicaltrials.gov/study/NCT02858349?term=NCT02858349&rank=1

Background: Moderate- to high-intensity walking training (M-HIT) is an established intervention for improving walking capacity in chronic stroke. Musculoskeletal (MSK) adverse events commonly occur during M-HIT, yet tools to identify individuals at higher risk are limited. Baseline clinical characteristics may provide insight into susceptibility to training-related MSK adverse events during M-HIT. Thus, this study aimed to develop and internally validate a model for predicting MSK adverse events during a 12-week M-HIT program in chronic stroke using baseline clinical characteristics. Methods: Participants (n=100) from HIT-Stroke Trials 1 and 2 were included. Baseline clinical characteristics included measures of orthopedic history, pre-existing pain, motor function, recent exercise history, demographics and health characteristics, stroke chronicity, and psychological health. Logistic regression models evaluated all possible combinations of baseline characteristics with up to three predictors. Leave-one-out cross-validation was used for internal validation to mitigate overfitting. Predictive performance was quantified using the C-statistic, and the candidate model with the highest cross-validated C-statistic was selected as the final model. Results: MSK adverse events occurred in 32.0% of participants. The optimal three-variable model included prior orthopedic condition (Odds ratio [OR] 3.02 [95% CI 1.14-8.64]), Fugl-Meyer lower extremity motor score (OR 1.14 [95% CI 1.02-1.28]), and self-reported participation in regular walking exercise (OR 0.17 [95% CI 0.05-0.49]) at baseline. This model demonstrated moderate discrimination (cross-validated C-statistic = 0.74; apparent C-statistic = 0.78). Conclusions: Participants reporting at least one pre-existing lower extremity or lumbar spine orthopedic condition and those with better lower-extremity motor function exhibited greater odds of experiencing MSK adverse events during M-HIT, while participants reporting participation in regular walking exercise had lower odds. These findings suggest that baseline clinical characteristics may help identify individuals at elevated risk for MSK adverse events during M-HIT who may warrant closer monitoring or risk-reduction strategies. Future studies are needed for external validation. Clinical Trial Registration: https://ClinicalTrials.gov ; Unique identifiers: NCT03760016 , NCT06268041

Purpose: Evidence suggests the contralesional cortico-reticulospinal tract (cCRST) upregulates after stroke, and that this upregulation correlates with worse motor function, suggesting it may be harmful for walking recovery. However, this relationship may be confounded by the extent of ipsilesional corticospinal tract (CST) and CRST damage, which could cause both greater cCRST upregulation and worse walking function. No previous studies have tested whether this confounding relationship exists, nor whether the amount of damage to the ipsilesional motor tracts is related to the amount of cCRST upregulation. We hypothesized that lower ipsilesional motor tract strength would: (1) be associated with greater cCRST compensation; and (2) explain the negative association between cCRST compensation and worse walking function. Methods: Ten individuals with chronic stroke and ten age- and sex-matched controls completed diffusion MRI, from which quantitative anisotropy was derived to evaluate the strength of the ipsilesional and contralesional CRST and CST. Walking capacity was assessed using 6-minute walk distance (6MWD). Linear regressions were applied to examine relationships among ipsilesional corticomotor tract strength (iCRST and iCST combined), cCRST strength, and 6MWD. Results: Compared with controls, participants with stroke had lower ipsilesional and higher contralesional strength for both motor tracts. Lower ipsilesional tract strength was associated with greater cCRST strength z-score (–0.12 SDs [–0.23, –0.02]). The unadjusted association between greater cCRST strength z-score and lower walking capacity (−72 meters [−136, −9]) was no longer present after adjusting for ipsilesional tract strength (−3 meters [−28, 23]). Conclusions: Greater damage to ipsilesional motor tracts (lower strength) was associated with increased cCRST strength. The extent of ipsilesional tract injury fully explained the negative association between cCRST strength and worse walking capacity. These findings suggest that cCRST upregulation is an adaptive compensation mediated by the extent of ipsilesional tract damage, and unlikely to impede walking recovery.

Background: Current practice guidelines recommend moderate to vigorous intensity locomotor training to improve walking outcomes in chronic stroke. However, these intensities span a wide range, and the lack of specificity may lead to under-dosing or over-dosing of training intensity. Recent evidence indicates that vigorous intensity locomotor training improves walking outcomes significantly more than moderate intensity. Although, previous studies have not been powered to rule out the possibility of meaningful risk increases or negligible benefit with vigorous versus moderate intensity, nor have they been designed to compare sustained effects after training ends. In addition, small subgroup analyses have suggested that individuals with severe walking limitations (speed 6 months) stroke survivors will be allocated to 36 sessions (3 times a week for 12 weeks) of either high intensity interval or moderate intensity continuous locomotor training. Eligible participants have residual walking limitations from stroke and can walk without continuous physical assistance from another person. At least 52 participants will have severe baseline walking speed limitations. Outcomes are assessed at baseline, after 4 weeks, 8 weeks, 12 weeks (POST), and 3 months after completing training. The primary outcome is walking capacity (6-minute walk distance). Secondary outcomes include comfortable and fast gait speed, aerobic capacity, fatigue, balance confidence, quality of life, and motivation for exercise. Statistical analyses will compare outcome changes and adverse events between treatment groups, and will include subgrouping by walking limitation severity. Discussion: This study will provide important new information to guide greater specificity and individualization of locomotor training intensity in chronic stroke. Trial Registration: ClinicalTrials.gov NCT06268041 ; Registration Date: 2024-02-12

People with chronic stroke have significant impairments in their walking capacity. Minimal clinically important differences (MCIDs) can be used to interpret changes in patient outcomes following interventions. There is significant variability in the response to moderate-to-high walking interventions in people with chronic stroke. One reason for this response variability could be the lack of understanding of the threshold exercise dose needed to achieve an MCID. The purpose of this analysis was to determine the threshold of exercise training speed most predictive of a small (≥20 m) or moderate (≥50 m) clinically important difference in 6MWT in people with chronic stroke. Participants with chronic stroke with a walking speed of 0.3-1.0 m/s were randomized into a 12-week (1) fast-walking training or (2) fast-walking training and step-activity monitoring intervention. This analysis included participants (n = 129; age: 63.1 ± 12.5, 46% female) with complete pre- and post-intervention data. Exercise intensity was quantified as average training speed. Receiver operating characteristic curves analyzed whether training speed is predictive of attaining a clinically important difference in the 6MWT. Training speed had poor, non-significant accuracy of predicting a small (AUC [95% CI] = 0.584 [0.475-0.693], p = 0.131) or moderate (AUC [95% CI] = 0.597 [0.498-0.696], p = 0.056) change in 6MWT. The average walking training speed during this high-intensity walking intervention did not accurately predict which people with chronic stroke would attain a small or moderate clinically meaningful change in 6MWT distance.

Current doses and intensities of post-stroke rehabilitation therapy provided as “usual care” are paltry compared to the magnitudes needed to drive large behaviorally-relevant reductions in neurologic impairments. There is convergent evidence indicating that high dose, high intensity rehabilitation is effective for improving outcomes after stroke with large effect sizes compared to usual care. Here we highlight some of this evidence (focusing on studies of upper extremity motor rehabilitation) and then ask the simple question— why are we not delivering high doses and intensities of rehabilitation in clinical practice? We contend that reasons for lack of implementation of high dose, high intensity rehabilitation have to do with questionable conceptual, ideological, and economic assumptions. In addition, there are practical challenges, which we argue can be overcome with technology. Current practice (we refer primarily to the context of US healthcare) in stroke rehabilitation is itself built on very little evidence, indeed considerably less than the cumulative evidence indicating that high dose, high intensity rehabilitation would be more effective. Our hope is that this Perspective will help persuade multiple stake holders (neurologists, physiatrists, therapists, researchers, patients, policy makers, and insurance companies) to advocate for higher doses and intensities of rehabilitation. There is certainly more research to be done on new ways to deliver high-dose, high-intensity neurorehabilitation, as well as zeroing in on its best timing and dosing, and how to best combine it with drugs and physiological stimulation. In the meantime, our view is that a large body of convergent evidence already justifies seeking to incorporate higher doses and intensities of therapy into current clinical practice as the new standard of care.

Background: Defined as a self-selected speed of 0.99) and 90 (p > 0.99) days follow up. Likewise, there were no significant between-group differences in spatiotemporal symmetry and the 3M TUG across time points. Conclusions: While preliminary, this study found that 12 training sessions did not lead to group-level achievement of MCID for walking speed in our cohort and found no significant between-group differences in walking capacity or dynamic postural stability. Future well-powered dosing trials and mechanistically driven studies are needed to optimize and identify predictors of training response.