The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes.

Globally, depression is a leading cause of disability and has remained so for decades. Antidepressant medications have suboptimal outcomes and are too frequently associated with side effects, highlighting the need for alternative treatment options. Although primarily known for its robust physical health benefits, exercise is increasingly recognized for its mental health and antidepressant benefits. Empirical evidence indicates that exercise is effective in treating individuals with depression; however, the mechanisms by which exercise exerts anti-depressant effects are not fully understood. Acute bouts of exercise have been shown to transiently modulate circulating levels of serotonin and norepinephrine, brain-derived neurotrophic factor, and a variety of immuno-inflammatory mechanisms in clinical cohorts with depression. However, exercise training has not been demonstrated to consistently modulate such mechanisms, and evidence linking these putative mechanisms and reductions in depression is lacking. The complexity of the biological underpinnings of depression coupled with the intricate molecular cascade induced by exercise are significant obstacles in the attempt to disentangle exercise's effects on depression. Notwithstanding our limited understanding of these effects, clinical evidence uniformly argues for the use of exercise to treat depression. Regrettably, exercise remains underutilized despite being an accessible, low-cost alternative/adjunctive intervention that can simultaneously reduce depression and improve overall health. To address the gaps in our understanding of the clinical and molecular effects of exercise on depression, we propose a model that leverages systems biology and multidisciplinary team science with a large-scale public health investment. Until the science matches the scale of complexity and burden posed by depression, our ability to advance knowledge and treatment will continue to be plagued by fragmented, irreproducible mechanistic findings and no guidelines for standards of care.

Weight Loss and Exercise Effects on Rate of Torque Development and Physical Function in Overweight Older Women.

Exercise training (EX) and weight loss (WL) improve lower extremity physical function (LEPF) in older overweight women; however, effects on rate of torque development (RTD) are unknown. This study aimed to determine the effects of WL + EX or WL alone on RTD, and relatedly LEPF, in overweight older women. Leg strength was assessed using isokinetic dynamometry, and RTD was calculated (RTD200 = RTD at 200 ms, RTDPeak = peak RTD, T2P = time to 1st peak). LEPF was determined via clinical functional tasks. Women (n = 44, 69.1 ± 3.6 years, 30.6 ± 4.3 kg/m2) completed a 6-month trial in EX + WL or WL groups with similar weight loss (-9.8 ± 4.2%, p > .95). EX + WL had greater improvements in (a) most LEPF tasks (p < .001) and (b) RTD200, compared with WL (36% vs. -16%, p = .031); no other RTD parameters differed. Changes in RTD parameters and LEPF were not related (all p > .05). RTD is responsive to EX but is not associated with LEPF in older women.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Evaluating a novel MR-compatible foot pedal device for unipedal and bipedal motion: Test-retest reliability of evoked brain activity.

The purpose of this study was to develop and evaluate a new, open-source MR-compatible device capable of assessing unipedal and bipedal lower extremity movement with minimal head motion and high test-retest reliability. To evaluate the prototype, 20 healthy adults participated in two magnetic resonance imaging (MRI) visits, separated by 2-6 months, in which they performed a visually guided dorsiflexion/plantar flexion task with their left foot, right foot, and alternating feet. Dependent measures included: evoked blood oxygen level-dependent (BOLD) signal in the motor network, head movement associated with dorsiflexion/plantar flexion, the test-retest reliability of these measurements. Left and right unipedal movement led to a significant increase in BOLD signal compared to rest in the medial portion of the right and left primary motor cortex (respectively), and the ipsilateral cerebellum (FWE corrected, p < .001). Average head motion was 0.10 ± 0.02 mm. The test-retest reliability was high for the functional MRI data (intraclass correlation coefficients [ICCs]: >0.75) and the angular displacement of the ankle joint (ICC: 0.842). This bipedal device can robustly isolate activity in the motor network during alternating plantarflexion and dorsiflexion with minimal head movement, while providing high test-retest reliability. Ultimately, these data and open-source building instructions will provide a new, economical tool for investigators interested in evaluating brain function resulting from lower extremity movement.

Using Inferred Mobility Status to Estimate the Time to Major Depressive Disorder Diagnosis Post-Spinal Cord Injury.

OBJECTIVE: Estimate (1) prevalence of major depressive disorder (MDD) diagnosis; (2) risk factors associated with MDD diagnosis; (3) time at which MDD is diagnosed post-spinal cord injury (SCI); and (4) interaction of inferred mobility status (IMS) in a commercially insured population over 3 years. DESIGN: Retrospective longitudinal cohort design. SETTING: A commercial insurance claims database from January 1, 2010 to December 31, 2013. PARTICIPANTS: Individuals with an index cervical or thoracic SCI in 2011 or 2012, without history of MDD ≤30 days pre-SCI (N=1409). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Prevalence of, risk factors associated with, and time to MDD diagnosis post-SCI. A stratified survival analysis using IMS, based upon durable medical equipment (DME) claims, was also completed. RESULTS: Post-SCI, 294 out of 1409 (20.87%) were diagnosed with new-onset MDD. Significant (P<.05) risk factors included: employment, length of index hospitalization, discharge from index hospitalization with healthcare services, rehabilitation services post-SCI, and 2 of 5 IMS comparisons. Median time to MDD was 86 days. Survival analysis demonstrated a significant difference between 6 of 10 IMS comparisons. Regarding new-onset or recurring MDD, 432 out of 1409 (30.66%) were diagnosed post-SCI. Significant risk factors included: female, employment, length of index hospitalization, discharge from index hospitalization with healthcare services, rehabilitation services post-SCI, MDD>30 days pre-SCI, catheter claims, and 2 of 5 IMS comparisons. Median time to MDD was 74 days. Survival analysis demonstrated a significant difference between 4 of 10 IMS comparisons. CONCLUSIONS: Prevalence of MDD post-SCI is greater than the general population. Stratification by IMS illustrated that individuals with greater inferred reliance on DME are at a greater risk for MDD and have shorter time to MDD diagnosis post-SCI.

Assessing the relationship between neighborhood factors and diabetes related health outcomes and self-care behaviors.

BACKGROUND: Studies have shown that community and neighborhood characteristics can impact health outcomes of those with chronic illness, including T2DM. Factors, such as crime, violence, and lack of resources have been shown to be barriers to optimal health outcomes in diabetes. Thus, the objective of this study is to assess the effects of neighborhood factors on diabetes-related health outcomes and self-care behaviors. METHODS: Adult patients (N = 615) with type 2 diabetes mellitus (T2DM) were recruited from an academic medical center and a Veterans Affairs medical center in the southeastern United States. Validated scales and indices were used to assess neighborhood factors and diabetes-related self-care behaviors. The most recent HbA1c, blood pressure, and LDL cholesterol were abstracted from each patients' electronic medical record. RESULTS: In the fully adjusted model, significant associations were between neighborhood aesthetics and diabetes knowledge (ß = 0.141) and general diet (ß = -0.093); neighborhood comparison and diabetes knowledge (ß = 0.452); neighborhood activities and general diet (ß = -0.072), exercise (ß = -0.104), and foot care (ß = -0.114); food insecurity and medication adherence (ß = -0.147), general diet (ß = -0.125), and blood sugar testing (ß = -0.172); and social support and medication adherence (ß = 0.009), foot care (ß = 0.010), and general diet (ß = 0.016). Significant associations were also found between neighborhood violence and LDL Cholesterol (ß = 4.04), walking environment and exercise (ß = -0.040), and social cohesion and HbA1c (ß = -0.086). DISCUSSION: We found that neighborhood violence, aesthetics, walking environment, activities, food insecurity, neighborhood comparison, social cohesion and social support have statistically significant associations with self-care behaviors and outcomes to varying degrees. However, the key neighborhood factors that had independent associations with multiple self-care behaviors and outcomes were food insecurity, neighborhood activities and social support. CONCLUSION: This study suggests that food insecurity, neighborhood activities, aesthetics, and social support may be important targets for interventions in individuals with T2DM.

Acute effects of aerobic exercise on corticomotor plasticity in individuals with and without depression.

BACKGROUND: Although complex in nature, the pathophysiology of depression involves reduced or impaired neuroplastic capabilities. Restoring or enhancing neuroplasticity may serve as a treatment target for developing therapies for depression. Aerobic exercise (AEx) has antidepressant benefits and may enhance neuroplasticity in depression although the latter has yet to be substantiated. Therefore, we sought to examine the acute effect of AEx on neuroplasticity in depression. METHODS: Sixteen individuals with (DEP; 13 female; age = 28.5 ± 7.3; Montgomery-Äsberg Depression Rating Scale [MADRS] = 21.3 ± 5.2) and without depression (HC; 13 female; age 27.2 ± 7.5; MADRS = 0.8 ± 1.2) completed three experimental visits consisting of 15 min of low intensity AEx (LO) at 35% heart rate reserve (HRR), high intensity AEx (HI) at 70% HRR, or sitting (CON). Following AEx, excitatory paired associative stimulation (PAS25ms) was employed to probe neuroplasticity. Motor evoked potentials (MEP) were assessed via transcranial magnetic stimulation before and after PAS25ms to indicate acute changes in neuroplasticity. RESULTS: PAS25ms primed with HI AEx led to significant increases in MEP amplitude compared to LO and CON. HI AEx elicited enhanced PAS25ms-induced neuroplasticity for up to 1-h post-PAS. There were no significant between-group differences. CONCLUSION: HI AEx enhances PAS measured neuroplasticity in individuals with and without depression. HI AEx may have a potent influence on the brain and serve as an effective primer, or adjunct, to therapies that seek to harness neuroplasticity.

Relative handgrip strength as a vitality measure in US stroke survivors.

PURPOSE: Stroke is a leading cause of long-term disability in the US, yet a feasible assessment measure with predictive value for components of the International Classification of Functioning, Disability, and Health (ICF) Core Set for Stroke is lacking. The purpose of the present study was to explore the predictive value of potential assessment measures on factors within each ICF component in stroke survivors. MATERIALS AND METHODS: Demographic, anthropometric, blood-based biomarker, physical functioning, and Global Physical Activity Questionnaire data were collected on stroke survivors in the 2011-2018 NHANES cycles. Potential predictors (handgrip strength relative to weight, age, sex, race, education level, marital status, poverty ratio, stroke chronicity) of physical function, activities of daily living (ADLs), participation in social activities, metabolic syndrome, and meeting physical activity recommendations were evaluated using weighted linear and ordinal logistic regression. RESULTS: Relative handgrip strength was a significant predictor of physical function, difficulty participating in ADLs and social activities, and odds of meeting physical activity recommendations. As relative handgrip strength increased, these factors improved among stroke survivors. CONCLUSIONS: To decrease disability rates and optimize function among stroke survivors, the use of assessment measures like relative handgrip strength that may predict multiple ICF components is warranted.

Handgrip strength relative to weight may be a significant predictor of multiple components of the International Classification of Functioning, Disability, and Health (ICF) Core Set for Stroke, including physical function, difficulty completing activities of daily living, difficulty participating in social activities, and the odds of meeting physical activity recommendations.Environmental and personal factors, such as income and education, may influence outcomes; thus, education and appropriate resources may need to be included as an aspect of stroke rehabilitation.The heterogenous and pervasive effects of chronic stroke highlight the need to identify outcome measures, like relative handgrip strength, that can influence multiple domains of stroke recovery.

Locomotor rehabilitation of individuals with chronic stroke: difference between responders and nonresponders.

OBJECTIVES: To identify the clinical measures associated with improved walking speed after locomotor rehabilitation in individuals poststroke and how those who respond with clinically meaningful changes in walking speed differ from those with smaller speed increases. DESIGN: A single group pre-post intervention study. Participants were stratified on the basis of a walking speed change of greater than (responders) or less than (nonresponders) .16m/s. Paired sample t tests were run to assess changes in each group, and correlations were run between the change in each variable and change in walking speed. SETTING: Outpatient interdisciplinary rehabilitation research center. PARTICIPANTS: Hemiparetic subjects (N=27) (17 left hemiparesis; 19 men; age: 58.74±12.97y; 22.70±16.38mo poststroke). INTERVENTION: A 12-week locomotor intervention incorporating training on a treadmill with body weight support and manual trainers accompanied by training overground walking. MAIN OUTCOME MEASURES: Measures of motor control, balance, functional walking ability, and endurance were collected at pre- and postintervention assessments. RESULTS: Eighteen responders and 9 nonresponders differed by age (responders=63.6y, nonresponders=49.0y, P=.001) and the lower extremity Fugl-Meyer Assessment score (responders=24.7, nonresponders=19.9, P=.003). Responders demonstrated an average improvement of .27m/s in walking speed as well as significant gains in all variables except daily step activity and paretic step ratio. Conversely, nonresponders demonstrated statistically significant improvements only in walking speed and endurance. However, the walking speed increase of .10m/s was not clinically meaningful. Change in walking speed was negatively correlated with changes in motor control in the nonresponder group, implying that walking speed gains may have been accomplished via compensatory mechanisms. CONCLUSIONS: This study is a step toward discerning the underlying factors contributing to improved walking performance.

Feasibility of performing a multi-arm clinical trial examining the novel combination of repetitive transcranial magnetic stimulation and aerobic exercise for post-stroke depression.

BACKGROUND: Post-stroke depression (PSD) occurs in approximately one-third of chronic stroke survivors. Although pharmacotherapy reduces depressive symptoms, side effects are common and stroke survivors have increased likelihood of multimorbidity and subsequent polypharmacy. Thus, alternative non-pharmacological treatments are needed. Combining two non-pharmacological anti-depressant treatments, aerobic exercise (AEx) and repetitive transcranial magnetic stimulation (rTMS), has been demonstrated to be feasible and well-tolerated in chronic stroke survivors. OBJECTIVES: The purpose of this trial was to determine the feasibility of conducting a multi-arm combinatorial trial of rTMS and AEx and to provide an estimate of effect size of rTMS+AEx on PSD symptoms. METHODS: Twenty-four participants were allocated to one of four treatment arms AEx, rTMS, rTMS+AEx, or non-depressed Control receiving AEx. All participants received a total of 24 treatment sessions. Participant adherence was the primary outcome measure for feasibility and within group effect sizes in Patient Health Questionnaire-9 (PHQ-9) score was the primary outcome for preliminary efficacy. RESULTS: Mean adherence rates to the exercise intervention for AEx, rTMS+AEx, and Control subjects were 83%, 98%, and 95%, respectively. Mean adherence rates for rTMS and rTMS+AEx subjects were 97% and 99%, respectively. The rTMS and rTMS+AEx treatment groups demonstrated clinically significant reductions of 10.5 and 6.2 points in PHQ-9 scores, respectively. CONCLUSION: Performing a multi-arm combinatorial trial examining the effect of rTMS+AEx on PSD appears feasible. All treatment arms demonstrated strong adherence to their respective interventions and were well received. rTMS and the combination of AEx with rTMS may be alternative treatments for PSD.

Interhemispheric Asymmetries in Intracortical Facilitation Correlate With Fatigue Severity in Individuals With Poststroke Fatigue.

PURPOSE: Poststroke fatigue (PSF) contributes to increased mortality and reduces participation in rehabilitative therapy. Although PSF's negative influences are well known, there are currently no effective evidence-based treatments for PSF. The lack of treatments is in part because of a dearth of PSF pathophysiological knowledge. Increasing our understanding of PSF's causes may facilitate and aid the development of effective therapies. METHODS: Twenty individuals, >6 months post stroke, participated in this cross-sectional study. Fourteen participants had clinically relevant pathological PSF, based on fatigue severity scale (FSS) scores (total score ≥36). Single-pulse and paired-pulse transcranial magnetic stimulation were used to measure hemispheric asymmetries in resting motor threshold, motor evoked potential amplitude, and intracortical facilitation (ICF). Asymmetry scores were calculated as the ratios between lesioned and nonlesioned hemispheres. The asymmetries were then correlated (Spearman rho) to FSS scores. RESULTS: In individuals with pathological PSF (N = 14, range of total FSS scores 39-63), a strong positive correlation (rs = 0.77, P = 0.001) between FSS scores and ICF asymmetries was calculated. CONCLUSIONS: As the ratio of ICF between the lesioned and nonlesioned hemispheres increased so did self-reported fatigue severity in individuals with clinically relevant pathological PSF. This finding may implicate adaptive/maladaptive plasticity of the glutamatergic system/tone as a contributor to PSF. This finding also suggests that future PSF studies should incorporate measuring facilitatory activity and behavior in addition to the more commonly studied inhibitory mechanisms. Further investigations are required to replicate this finding and identify the causes of ICF asymmetries.

Effect of power training on rate of torque development and spatiotemporal gait parameters post stroke.

BACKGROUND: Maximizing independence and function post-stroke are two common therapy goals. Rate of torque development in lower-extremity muscles was recently reported to be associated with walking speed; however, trainability and subsequent effect on gait is unknown. This study aimed to determine effect of power training on paretic and non-paretic limb torque parameters, spatiotemporal gait parameters, and walking speed in chronic stroke survivors. METHODS: Individuals with chronic stroke (n = 22; 7 females; 62.7 ± 8.8 yrs) completed 24 progressive power-training sessions over 8 weeks with pre and post assessments. Knee extensor strength was assessed via dynamometry with torque parameters measured from maximal voluntary isometric contractions. Gait speed and spatiotemporal gait parameters were assessed via an instrumented gait mat, and a 6-min walk test was performed. FINDINGS: Rate of torque development at 200 ms and peak torque improved 58.6% and 14.1%, respectively, in the quadricep of the paretic limb (p < 0.05); conversely the non-paretic limb was unchanged. On average, self-selected walking speed, fastest-comfortable walking speed, and 6-min walk test improved 21.7%, 21.1%, and 19.5%, respectively (all p < 0.05). Change in torque development at 100 ms in the quadricep of the non-paretic limb was positively associated with improvements in self-selected and fastest-comfortable walking speeds (both r = 0.70, p < 0.05) and 6-min walk (r = 0.78, p < 0.001). INTERPRETATIONS: These findings suggest power training may be an effective intervention for improving torque development in the quadricep of the paretic limb in individuals with chronic stroke. Further research to explore utility and mechanistic aspects of force development for gait function in chronic stroke survivors is warranted.

Combined Aerobic Exercise and Virtual Reality-Based Upper Extremity Rehabilitation Intervention for Chronic Stroke: Feasibility and Preliminary Effects on Physical Function and Quality of Life.

Objectives: To (1) examine the feasibility of combining lower extremity aerobic exercise (AEx) with a virtual reality (VR) upper extremity (UE) rehabilitation intervention and (2) provide an estimate of effect size for the combined intervention on UE function, aerobic capacity, and health-related quality of life. Design: Single-group feasibility trial. Setting: Research laboratory. Participants: Community-dwelling individuals with mild to moderate impairment of the UE at least 6 months post stroke (N=10; male, n=6; female n=4; mean age, 54 years). Intervention: All participants received 18 sessions over a nominal 2-3 sessions per week schedule of a combined AEx and VR-UE rehabilitation intervention. During each session, participants completed 15 minutes of lower extremity AEx followed by playing a VR-UE rehabilitation game for approximately 20 minutes. Main Outcome Measures: Feasibility was evaluated by metrics of adherence, retention, treatment acceptability, data completeness, and adverse events. UE function, aerobic capacity (peak oxygen consumption [Vo2peak]), and quality of life were assessed with the Fugl-Meyer Assessment of Upper Extremity (FMA-UE), expired gas exchange analysis, and Stroke Impact Scale (SIS), respectively. Results: Adherence was 100%, and there were no withdrawals or losses to follow-up to report. Participants completed the intervention in 49±14 days. Cohen's dz effect size calculations indicated the intervention elicited medium effects on FMA-UE (dz =0.50) and SIS memory domain (dz =0.46) and large effects on absolute Vo2peak (dz =1.46), relative Vo2peak (dz =1.21), SIS strength (dz =1.18), and SIS overall recovery domains (dz =0.81). Conclusions: Combining lower extremity AEx and VR-UE rehabilitation appears feasible in the clinical research setting. Fifteen minutes of lower extremity AEx performed at vigorous intensity appears to elicit clinically meaningful benefits in chronic stroke. Further examination of the combination of lower extremity AEx and VR-UE rehabilitation and its effects on physical function and quality of life is warranted.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

Advancing measurement of locomotor rehabilitation outcomes to optimize interventions and differentiate between recovery versus compensation.

Progress in locomotor rehabilitation has created an increasing need to understand the factors that contribute to motor behavior, to determine whether these factors are modifiable, and if so, to determine how best to modify them in a way that promotes improved function. Currently available clinical measures do not have the capacity to distinguish between neuromotor recovery and compensation for impaired underlying body structure/functions. This Special Interest article examines the state of outcomes measurement in physical therapy in regard to locomotor rehabilitation, and suggests approaches that may improve assessment of recovery and clinical decision-making capabilities. We examine historical approaches to measurement of locomotor rehabilitation outcomes, including rating scales, timed movement tasks, and laboratory-based outcome measures, and we discuss the emerging use of portable technology to assess walking in a free-living environment. The ability to accurately measure outcomes of rehabilitation, both in and away from the clinical/laboratory setting, allows assessment of skill acquisition, retention, and long-term carryover in a variety of environments. Accurate measurement allows behavioral changes to be observed, and assessments to be made, regarding an individual's ability to adapt during interventions and to incorporate new skills into real-world behaviors. The result of such an approach to assessment may be that interventions truly translate from clinical/laboratory to real-world environments. Future locomotor measurement tools must be based on a theoretical framework that can guide their use to accurately quantify treatment effects and provide a basis upon which to develop and refine therapeutic interventions.

The relationship between motor pathway damage and flexion-extension patterns of muscle co-excitation during walking.

Background: Mass flexion-extension co-excitation patterns during walking are often seen as a consequence of stroke, but there is limited understanding of the specific contributions of different descending motor pathways toward their control. The corticospinal tract is a major descending motor pathway influencing the production of normal sequential muscle coactivation patterns for skilled movements. However, control of walking is also influenced by non-corticospinal pathways such as the corticoreticulospinal pathway that possibly contribute toward mass flexion-extension co-excitation patterns during walking. The current study sought to investigate the associations between damage to corticospinal (CST) and corticoreticular (CRP) motor pathways following stroke and the presence of mass flexion-extension patterns during walking as evaluated using module analysis. Methods: Seventeen healthy controls and 44 stroke survivors were included in the study. We used non-negative matrix factorization for module analysis of paretic leg electromyographic activity. We typically have observed four modules during walking in healthy individuals. Stroke survivors often have less independently timed modules, for example two-modules presented as mass flexion-extension pattern. We used diffusion tensor imaging-based analysis where streamlines connecting regions of interest between the cortex and brainstem were computed to evaluate CST and CRP integrity. We also used a coarse classification tree analysis to evaluate the relative CST and CRP contribution toward module control. Results: Interhemispheric CST asymmetry was associated with worse lower extremity Fugl-Meyer score (p = 0.023), propulsion symmetry (p = 0.016), and fewer modules (p = 0.028). Interhemispheric CRP asymmetry was associated with worse lower extremity Fugl-Meyer score (p = 0.009), Dynamic gait index (p = 0.035), Six-minute walk test (p = 0.020), Berg balance scale (p = 0.048), self-selected walking speed (p = 0.041), and propulsion symmetry (p = 0.001). The classification tree model reveled that substantial ipsilesional CRP or CST damage leads to a two-module pattern and poor walking ability with a trend toward increased compensatory contralesional CRP based control. Conclusion: Both CST and CRP are involved with control of modules during walking and damage to both may lead to greater reliance on the contralesional CRP, which may contribute to a two-module pattern and be associated with worse walking performance.

A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms.

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research.

A novel modulation strategy to increase stimulation duration in neuromuscular electrical stimulation.

INTRODUCTION: Neuromuscular electrical stimulation (NMES) has been shown to be an effective treatment for muscular dysfunction. Yet, a fundamental barrier to NMES treatments is the rapid onset of muscle fatigue. The purpose of this study is to examine the effect of feedback-based frequency modulation on the closed-loop performance of the quadriceps during repeated dynamic contractions. METHODS: In the first experiment, subjects completed four different frequency modulation NMES protocols utilizing the same amplitude modulation control to compare the successful run times (SRTs). A second experiment was performed to determine the change in muscle response to high- and low-frequency stimulation. RESULTS: Compared with constant-frequency stimulation, results indicate that using an error-driven strategy to vary the stimulation frequency during amplitude modulation increases the number of successful contractions during non-isometric conditions. CONCLUSION: Simultaneous frequency and amplitude modulation increases the SRT during closed-loop NMES control.

Motor unit recruitment during neuromuscular electrical stimulation: a critical appraisal.

Neuromuscular electrical stimulation (NMES) is commonly used in clinical settings to activate skeletal muscle in an effort to mimic voluntary contractions and enhance the rehabilitation of human skeletal muscles. It is also used as a tool in research to assess muscle performance and/or neuromuscular activation levels. However, there are fundamental differences between voluntary- and artificial-activation of motor units that need to be appreciated before NMES protocol design can be most effective. The unique effects of NMES have been attributed to several mechanisms, most notably, a reversal of the voluntary recruitment pattern that is known to occur during voluntary muscle contractions. This review outlines the assertion that electrical stimulation recruits motor units in a nonselective, spatially fixed, and temporally synchronous pattern. Additionally, it synthesizes the evidence that supports the contention that this recruitment pattern contributes to increased muscle fatigue when compared with voluntary actions and provides some commentary on the parameters of electrical stimulation as well as emerging technologies being developed to facilitate NMES implementation. A greater understanding of how electrical stimulation recruits motor units, as well as the benefits and limitations of its use, is highly relevant when using this tool for testing and training in rehabilitation, exercise, and/or research.

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide.

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T1-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes.