Evaluating the Neural Underpinnings of Motivation for Walking Exercise.

OBJECTIVE: Motivation is critically important for rehabilitation, exercise, and motor performance, but its neural basis is poorly understood. Recent correlational research suggests that the dorsomedial prefrontal cortex (dmPFC) may be involved in motivation for walking activity and/or descending motor output. This study experimentally evaluated brain activity changes in periods of additional motivation during walking exercise and tested how these brain activity changes relate to self-reported exercise motivation and walking speed. METHODS: Adults without disability (N = 26; 65% women; 25 [standard deviation = 5] years old) performed a vigorous exercise experiment involving 20 trials of maximal speed overground walking. Half of the trials were randomized to include "extra-motivation" stimuli (lap timer, tracked best lap time, and verbal encouragement). Wearable near-infrared spectroscopy measured oxygenated hemoglobin responses from frontal lobe regions, including the dmPFC, primary sensorimotor, dorsolateral prefrontal, anterior prefrontal, supplementary motor, and dorsal premotor cortices. RESULTS: Compared with standard trials, participants walked faster during extra-motivation trials (2.43 vs 2.67 m/s; P < .0001) and had higher oxygenated hemoglobin responses in all tested brain regions, including dmPFC (+842 vs +1694 µM; P < .0001). Greater dmPFC activity was correlated with more self-determined motivation for exercise between individuals (r = 0.55; P = .004) and faster walking speed between trials (r = 0.18; P = .0002). dmPFC was the only tested brain region that showed both of these associations. CONCLUSION: Simple motivational stimuli during walking exercise seem to upregulate widespread brain regions. Results suggest that dmPFC may be a key brain region linking affective signaling to motor output. IMPACT: These findings provide a potential biologic basis for the benefits of motivational stimuli, elicited with clinically feasible methods during walking exercise. Future clinical studies could build on this information to develop prognostic biomarkers and test novel brain stimulation targets for enhancing exercise motivation (eg, dmPFC).

Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Insufficiencies in sensory systems reweighting is associated with walking impairment severity in chronic stroke: an observational cohort study.

Background: Walking and balance impairment are common sequelae of stroke and significantly impact functional independence, morbidity, and mortality. Adequate postural stability is needed for walking, which requires sufficient integration of sensory information between the visual, somatosensory, and vestibular centers. "Sensory reweighting" describes the normal physiologic response needed to maintain postural stability in the absence of sufficient visual or somatosensory information and is believed to play a critical role in preserving postural stability after stroke. However, the extent to which sensory reweighting successfully maintains postural stability in the chronic stages of stroke and its potential impact on walking function remains understudied. Methods: In this cross-sectional study, fifty-eight community-dwelling ambulatory chronic stroke survivors underwent baseline postural stability testing during quiet stance using the modified Clinical test of Sensory Interaction in Balance (mCTSIB) and assessment of spatiotemporal gait parameters. Results: Seventy-six percent (45/58) of participants showed sufficient sensory reweighting with visual and somatosensory deprivation for maintaining postural stability, albeit with greater postural sway velocity indices than normative data. In contrast, survivors with insufficient reweighting demonstrated markedly slower overground walking speeds, greater spatiotemporal asymmetry, and limited acceleration potential. Conclusion: Adequate sensory system reweighting is essential for chronic stroke survivors' postural stability and walking independence. Greater emphasis should be placed on rehabilitation strategies incorporating multisensory system integration testing and strengthening as part of walking rehabilitation protocols. Given its potential impact on outcomes, walking rehabilitation trials may benefit from incorporating formal postural stability testing in design and group stratification.

Optimal Intensity and Duration of Walking Rehabilitation in Patients With Chronic Stroke: A Randomized Clinical Trial.

Importance: For walking rehabilitation after stroke, training intensity and duration are critical dosing parameters that lack optimization. Objective: To assess the optimal training intensity (vigorous vs moderate) and minimum training duration (4, 8, or 12 weeks) needed to maximize immediate improvement in walking capacity in patients with chronic stroke. Design, Setting, and Participants: This multicenter randomized clinical trial using an intent-to-treat analysis was conducted from January 2019 to April 2022 at rehabilitation and exercise research laboratories. Survivors of a single stroke who were aged 40 to 80 years and had persistent walking limitations 6 months or more after the stroke were enrolled. Interventions: Participants were randomized 1:1 to high-intensity interval training (HIIT) or moderate-intensity aerobic training (MAT), each involving 45 minutes of walking practice 3 times per week for 12 weeks. The HIIT protocol used repeated 30-second bursts of walking at maximum safe speed, alternated with 30- to 60-second rest periods, targeting a mean aerobic intensity above 60% of the heart rate reserve (HRR). The MAT protocol used continuous walking with speed adjusted to maintain an initial target of 40% of the HRR, progressing up to 60% of the HRR as tolerated. Main Outcomes and Measures: The main outcome was 6-minute walk test distance. Outcomes were assessed by blinded raters after 4, 8, and 12 weeks of training. Results: Of 55 participants (mean [SD] age, 63 [10] years; 36 male [65.5%]), 27 were randomized to HIIT and 28 to MAT. The mean (SD) time since stroke was 2.5 (1.3) years, and mean (SD) 6-minute walk test distance at baseline was 239 (132) m. Participants attended 1675 of 1980 planned treatment visits (84.6%) and 197 of 220 planned testing visits (89.5%). No serious adverse events related to study procedures occurred. Groups had similar 6-minute walk test distance changes after 4 weeks (HIIT, 27 m [95% CI, 6-48 m]; MAT, 12 m [95% CI, -9 to 33 m]; mean difference, 15 m [95% CI, -13 to 42 m]; P = .28), but HIIT elicited greater gains after 8 weeks (58 m [95% CI, 39-76 m] vs 29 m [95% CI, 9-48 m]; mean difference, 29 m [95% CI, 5-54 m]; P = .02) and 12 weeks (71 m [95% CI, 49-94 m] vs 27 m [95% CI, 3-50 m]; mean difference, 44 m [95% CI, 14-74 m]; P = .005) of training; HIIT also showed greater improvements than MAT on some secondary measures of gait speed and fatigue. Conclusions and Relevance: These findings show proof of concept that vigorous training intensity is a critical dosing parameter for walking rehabilitation. In patients with chronic stroke, vigorous walking exercise produced significant and meaningful gains in walking capacity with only 4 weeks of training, but at least 12 weeks were needed to maximize immediate gains. Trial Registration: ClinicalTrials.gov Identifier: NCT03760016.

Trends in outpatient rehabilitation use for stroke survivors.

BACKGROUND: Stroke survivors with residual disabling deficits who are medically stable may be recommended for acute rehabilitation or outpatient therapy, depending partly on the severity of their deficits. Here we sought to determine if the location at which patients needing rehabilitation post-stroke has shifted from inpatient to an outpatient setting. METHODS: For analysis, we used our Institutional Review Board-approved Get With The Guidelines®-Stroke Database to study stroke survivors discharged to receive either inpatient or outpatient rehabilitation services between 2014 and 2019. Logistic regression analysis was used to identify clinical factors associated with discharge type. Cochran-Armitage trend analysis was used to assess differences in rehabilitation services used over time. RESULTS: A total of 3293 patients were included. Trend analysis demonstrated a significant increase over time in the proportion of patients needing rehabilitation being discharged home with rehabilitation services (P < 0.0001). In addition, older age was associated with discharge to inpatient rehabilitation (OR = 1.018, 95%CI, 1.011-1.026), as was a higher National Institutes of Health Stroke Scale score (OR = 1.149, 95%CI, 1.130-1.168). CONCLUSIONS: We found that home discharges increased, highlighting outpatient rehabilitation as an expanding healthcare resource for reducing stroke-associated disability in adults.

Serial Backward Locomotor Treadmill Training Improves Bidirectional Walking Performance in Chronic Stroke.

Background and Research Question: Walking impairment remains a major limitation to functional independence after stroke. Yet, comprehensive and effective strategies to improve walking function after stroke are presently limited. Backward Locomotor Treadmill Training (BLTT) is a promising training approach for improving walking function; however, little is known about its mechanism of effect or the relationship between backward walking training and resulting overground forward walking performance. This study aims to determine the effects of serial BLTT on spatial aspects of backward and forward walking in chronic post-stroke individuals with residual walking impairment. Methods: Thirty-nine adults (>6 months post-stroke) underwent 6 days of BLTT (3 × /week) over 2 weeks. Outcome measures included PRE-POST changes in backward and forward walking speeds, paretic and non-paretic step lengths, and single-support center of pressure distances. To determine the association between BLTT and overground walking, correlation analyses comparing training-related changes in these variables were performed. Results: We report an overall improvement in BLTT and overground walking speeds, bilateral step lengths, and single-support center of pressure distances over six training sessions. Further, there were weak positive associations between PRE-POST changes in BLTT speed, BLTT paretic step length, and overground forward walking speed. Conclusion and Significance: Our findings suggest that individuals with chronic post-stroke walking impairment experience improvements in spatial walking measures during BLTT and overground. Therefore, BLTT may be a potential adjunctive training approach for post-stroke walking rehabilitation.

Backward Locomotor Treadmill Training Differentially Improves Walking Performance across Stroke Walking Impairment Levels.

BACKGROUND: Post-stroke walking impairment is a significant cause of chronic disability worldwide and often leads to loss of life roles for survivors and their caregivers. Walking impairment is traditionally classified into mild (>0.8 m/s), moderate (0.41-0.8 m/s), and severe (≤0.4 m/s), and those categorized as "severe" are more likely to be homebound and at greater risk of falls, fractures, and rehospitalization. In addition, there are minimal effective walking rehabilitation strategies currently available for this subgroup. Backward locomotor treadmill training (BLTT) is a novel and promising training approach that has been demonstrated to be safe and feasible across all levels of impairment; however, its benefits across baseline walking impairment levels (severe (≤0.4 m/s) vs. mild-moderate (>0.4 m/s)) have not been examined. METHODS: Thirty-nine adults (>6 months post-stroke) underwent 6 days of BLTT (3×/week) over 2 weeks. Baseline and PRE to POST changes were measured during treadmill training and overground walking. RESULTS: Individuals with baseline severe walking impairment were at a more significant functional disadvantage across all spatiotemporal walking measures at baseline and demonstrated fewer overall gains post-training. However, contrary to our working hypothesis, both groups experienced comparable increases in cadence, bilateral percent single support times, and step lengths. CONCLUSION: BLTT is well tolerated and beneficial across all walking impairment levels, and baseline walking speed (≤0.4 m/s) should serve as a covariate in the design of future walking rehabilitation trials.

Preliminary Outcomes of Combined Treadmill and Overground High-Intensity Interval Training in Ambulatory Chronic Stroke.

PURPOSE: Locomotor high-intensity interval training (HIIT) is a promising intervention for stroke rehabilitation. However, overground translation of treadmill speed gains has been somewhat limited, some important outcomes have not been tested and baseline response predictors are poorly understood. This pilot study aimed to guide future research by assessing preliminary outcomes of combined overground and treadmill HIIT. MATERIALS AND METHODS: Ten participants >6 months post-stroke were assessed before and after a 4-week no-intervention control phase and a 4-week treatment phase involving 12 sessions of overground and treadmill HIIT. RESULTS: Overground and treadmill gait function both improved during the treatment phase relative to the control phase, with overground speed changes averaging 61% of treadmill speed changes (95% CI: 33-89%). Moderate or larger effect sizes were observed for measures of gait performance, balance, fitness, cognition, fatigue, perceived change and brain volume. Participants with baseline comfortable gait speed <0.4 m/s had less absolute improvement in walking capacity but similar proportional and perceived changes. CONCLUSIONS: These findings reinforce the potential of locomotor HIIT research for stroke rehabilitation and provide guidance for more definitive studies. Based on the current results, future locomotor HIIT studies should consider including: (1) both overground and treadmill training; (2) measures of cognition, fatigue and brain volume, to complement typical motor and fitness assessment; and (3) baseline gait speed as a covariate.

Mapping the human corticoreticular pathway with multimodal delineation of the gigantocellular reticular nucleus and high-resolution diffusion tractography.

The corticoreticular pathway (CRP) is a major motor tract that transmits cortical input to the reticular formation motor nuclei and may be an important mediator of motor recovery after central nervous system damage. However, its cortical origins, trajectory and laterality are incompletely understood in humans. This study aimed to map the human CRP and generate an average CRP template in standard MRI space. Following recently established guidelines, we manually delineated the primary reticular formation motor nucleus (gigantocellular reticular nucleus [GRN]) using several group-mean MRI contrasts from the Human Connectome Project (HCP). CRP tractography was then performed with HCP diffusion-weighted MRI data (N = 1065) by selecting diffusion streamlines that reached both the cortex and GRN. Corticospinal tract (CST) tractography was also performed for comparison. Results suggest that the human CRP has widespread origins, which overlap with the CST across most of the motor cortex and include additional exclusive inputs from the medial and anterior prefrontal cortices. The estimated CRP projected through the anterior and posterior limbs of the internal capsule before partially decussating in the midbrain tegmentum and converging bilaterally on the pontomedullary reticular formation. Thus, the CRP trajectory appears to partially overlap the CST, while being more distributed and anteromedial to the CST in the cerebrum before moving posterior to the CST in the brainstem. These findings have important implications for neurophysiologic testing, cortical stimulation and movement recovery after brain lesions. We expect that our GRN and tract maps will also facilitate future CRP research.

Mapping the corticoreticular pathway from cortex-wide anterograde axonal tracing in the mouse.

The corticoreticular pathway (CRP) has been implicated as an important mediator of motor recovery and rehabilitation after central nervous system damage. However, its origins, trajectory and laterality are not well understood. This study mapped the mouse CRP in comparison with the corticospinal tract (CST). We systematically searched the Allen Mouse Brain Connectivity Atlas (© 2011 Allen Institute for Brain Science) for experiments that used anterograde tracer injections into the right isocortex in mice. For each eligible experiment (N = 607), CRP and CST projection strength were quantified by the tracer volume reaching the reticular formation motor nuclei (RFmotor ) and pyramids, respectively. Tracer density in each brain voxel was also correlated with RFmotor versus pyramids projection strength to explore the relative trajectories of the CRP and CST. We found significant CRP projections originating from the primary and secondary motor cortices, anterior cingulate, primary somatosensory cortex, and medial prefrontal cortex. Compared with the CST, the CRP had stronger projections from each region except the primary somatosensory cortex. Ipsilateral projections were stronger than contralateral for both tracts (above the pyramidal decussation), but the CRP projected more bilaterally than the CST. The estimated CRP trajectory was anteromedial to the CST in the internal capsule and dorsal to the CST in the brainstem. Our findings reveal a widespread distribution of CRP origins and confirm strong bilateral CRP projections, theoretically increasing the potential for partial sparing after brain lesions and contralesional compensation after unilateral injury.

Revisiting the bipolar disorder with migraine phenotype: Clinical features and comorbidity.

INTRODUCTION: To evaluate the prevalence and clinical correlates of lifetime migraine among patients with bipolar disorder (BD). METHODS: In a cross-sectional study, we evaluated 721 adults with BD from the Mayo Clinic Bipolar Disorder Biobank and compared clinical correlates of those with and without a lifetime history of migraine. A structured clinical interview (DSM-IV) and a clinician-assessed questionnaire were utilized to establish a BD diagnosis, lifetime history of migraine, and clinical correlates. RESULTS: Two hundred and seven (29%) BD patients had a lifetime history of migraine. BD patients with migraine were younger and more likely to be female as compared to those without migraine (p values <0.01). In a multivariate logistic regression model, younger age (OR=0.98, p<0.01), female sex (OR=2.02, p<0.01), higher shape/weight concern (OR=1.04, p=0.02), greater anxiety disorder comorbidities (OR=1.24, p<0.01), and evening chronotype (OR=1.65, p=0.03) were associated with migraine. In separate regression models for each general medical comorbidity (controlled for age, sex, and site), migraines were significantly associated with fibromyalgia (OR=3.17, p<0.01), psoriasis (OR=2.65, p=0.03), and asthma (OR=2.0, p<0.01). Participants with migraine were receiving ADHD medication (OR=1.53, p=0.05) or compounds associated with weight loss (OR=1.53, p=0.02) at higher rates compared to those without migraine. LIMITATIONS: Study design precludes determination of causality. Migraine subtypes and features were not assessed. CONCLUSIONS: Migraine prevalence is high in BD and is associated with a more severe clinical burden that includes increased comorbidity with pain and inflammatory conditions. Further study of the BD-migraine phenotype may provide insight into common underlying neurobiological mechanisms.

Moderate-intensity exercise versus high-intensity interval training to recover walking post-stroke: protocol for a randomized controlled trial.

BACKGROUND: Stroke results in neurologic impairments and aerobic deconditioning that contribute to limited walking capacity which is a major barrier post-stroke. Current exercise recommendations and stroke rehabilitation guidelines recommend moderate-intensity aerobic training post-stroke. Locomotor high-intensity interval training is a promising new strategy that has shown significantly greater improvements in aerobic fitness and motor performance than moderate-intensity aerobic training in other populations. However, the relative benefits and risks of high-intensity interval training and moderate-intensity aerobic training remain poorly understood following stroke. In this study, we hypothesize that locomotor high-intensity interval training will result in greater improvements in walking capacity than moderate-intensity aerobic training. METHODS: Using a single-blind, 3-site randomized controlled trial, 50 chronic (> 6 months) stroke survivors are randomly assigned to complete 36 locomotor training sessions of either high-intensity interval training or moderate-intensity aerobic training. Main eligibility criteria are age 40-80 years, single stroke for which the participant received treatment (experienced 6 months to 5 years prior to consent), walking speed ≤ 1.0 m/s, able to walk at least 3 min on the treadmill at ≥ 0.13 m/s (0.3 mph), stable cardiovascular condition (American Heart Association class B), and the ability to walk 10 m overground without continuous physical assistance. The primary outcome (walking capacity) and secondary outcomes (self-selected and fast gait speed, aerobic fitness, and fatigue) are assessed prior to initiating training and after 4 weeks, 8 weeks, and 12 weeks of training. DISCUSSION: This study will provide fundamental new knowledge to inform the selection of intensity and duration dosing parameters for gait recovery and optimization of aerobic training interventions in chronic stroke. Data needed to justify and design a subsequent definitive trial will also be obtained. Thus, the results of this study will inform future stroke rehabilitation guidelines on how to optimally improve walking capacity following stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03760016 . Registered on November 30, 2018.

Functional magnetic resonance brain imaging of imagined walking to study locomotor function after stroke.

OBJECTIVE: Imagined walking has yielded insights into normal locomotor control and could improve understanding of neurologic gait dysfunction. This study evaluated brain activation during imagined walking in chronic stroke. METHODS: Ten persons with stroke and 10 matched controls completed a walking test battery and a magnetic resonance imaging session including imagined walking and knee extension tasks. Brain activations were compared between tasks and groups. Associations between activations and composite gait score were also calculated, while controlling for lesion load. RESULTS: Stroke and worse gait score were each associated with lesser overall brain activation during knee extension but greater overall activation during imagined walking. During imagined walking, the stroke group significantly activated the primary motor cortex lower limb region and cerebellar locomotor region. Better walking function was associated with less activation of these regions and greater activation of medial superior frontal gyrus area 9. CONCLUSIONS: Compared with knee extension, imagined walking was less sensitive to stroke-related deficits in brain activation but better at revealing compensatory changes, some of which could be maladaptive. SIGNIFICANCE: The identified associations for imagined walking suggest potential neural mechanisms of locomotor adaptation after stroke, which could be useful for future intervention development and prognostication.

Backward locomotor treadmill training combined with transcutaneous spinal direct current stimulation in stroke: a randomized pilot feasibility and safety study.

Walking impairment impacts nearly 66% of stroke survivors and is a rising cause of morbidity worldwide. Despite conventional post-stroke rehabilitative care, the majority of stroke survivors experience continued limitations in their walking speed, temporospatial dynamics and walking capacity. Hence, novel and comprehensive approaches are needed to improve the trajectory of walking recovery in stroke survivors. Herein, we test the safety, feasibility and preliminary efficacy of two approaches for post-stroke walking recovery: backward locomotor treadmill training and transcutaneous spinal direct current stimulation. In this double-blinded study, 30 chronic stroke survivors (>6 months post-stroke) with mild-severe residual walking impairment underwent six 30-min sessions (three sessions/week) of backward locomotor treadmill training, with concurrent anodal (N = 19) or sham transcutaneous spinal direct current stimulation (N = 11) over the thoracolumbar spine, in a 2:1 stratified randomized fashion. The primary outcomes were: per cent participant completion, safety and tolerability of these two approaches. In addition, we collected data on training-related changes in overground walking speed, cadence, stride length (baseline, daily, 24-h post-intervention, 2 weeks post-intervention) and walking capacity (baseline, 24-h post-intervention, 2 weeks post-intervention), as secondary exploratory aims testing the preliminary efficacy of these interventions. Eighty-seven per cent (N = 26) of randomized participants completed the study protocol. The majority of the study attrition involved participants with severe baseline walking impairment. There were no serious adverse events in either the backward locomotor treadmill training or transcutaneous spinal direct current stimulation approaches. Also, both groups experienced a clinically meaningful improvement in walking speed immediately post-intervention that persisted at the 2-week follow-up. However, in contrast to our working hypothesis, anodal-transcutaneous spinal direct current stimulation did not enhance the degree of improvement in walking speed and capacity, relative to backward locomotor treadmill training + sham, in our sample. Backward locomotor treadmill training and transcutaneous spinal direct current stimulation are safe and feasible approaches for walking recovery in chronic stroke survivors. Definitive efficacy studies are needed to validate our findings on backward locomotor treadmill training-related changes in walking performance. The results raise interesting questions about mechanisms of locomotor learning in stroke, and well-powered transcutaneous spinal direct current stimulation dosing studies are needed to understand better its potential role as a neuromodulatory adjunct for walking rehabilitation.

Transcranial direct current stimulation facilitates response inhibition through dynamic modulation of the fronto-basal ganglia network.

BACKGROUND: Response inhibition refers to the ability to stop an on-going action quickly when it is no longer appropriate. Previous studies showed that transcranial direct current stimulation (tDCS) applied with the anode over the right inferior frontal cortex (rIFC), a critical node of the fronto-basal ganglia inhibitory network, improved response inhibition. However, the tDCS effects on brain activity and network connectivity underlying this behavioral improvement are not known. OBJECTIVE: This study aimed to address the effects of tDCS applied with the anode over the rIFC on brain activity and network functional connectivity underlying the behavioral change in response inhibition. METHODS: Thirty participants performed a stop-signal task in a typical laboratory setting as a baseline during the first study visit (i.e., Session 1). In the second visit (at least 24 h after Session 1), all participants underwent resting-state functional magnetic resonance imaging (rsfMRI) scans before and after 1.5 mA tDCS (Anodal or Sham). Immediately following the post-tDCS rsfMRI, participants performed the same stop-signal task as in Session 1 during an event-related fMRI (efMRI) scan in a 3T scanner. Changes in task performance, i.e., the stop-signal response time (SSRT), a measure of response inhibition efficiency, was determined relative to the participants' own baseline performance in Session 1. RESULTS: Consistent with previous findings, Anodal tDCS facilitated the SSRT. efMRI results showed that Anodal tDCS strengthened the functional connectivity between right pre-supplementary motor area (rPreSMA) and subthalamic nuclei during Stop responses. rsfMRI revealed changes in intrinsic connectivity between rIFC and caudate, and between rIFC, rPreSMA, right inferior parietal cortex (rIPC), and right dorsolateral prefrontal cortex (rDLPFC) after Anodal tDCS. In addition, corresponding to the regions of rsfMRI connectivity change, the efMRI BOLD signal in the rDLPFC and rIPC during Go responses accounted for 74% of the variance in SSRT after anodal tDCS, indicating an effect of tDCS on the Go-Stop process. CONCLUSION: These results indicate that tDCS with the anode over the rIFC facilitates response inhibition by modulating neural activity and functional connectivity in the fronto-basal ganglia as well as rDLPFC and rIPC as an integral part of the response inhibition network.

Plasticity and recovery of function.

The frontal lobe plays a crucial role in human motor behavior. It is one of the last areas of the brain to mature, especially the prefrontal regions. After a brief historical perspective on the perceived dichotomy between the view of the brain as a static organ and that of a plastic, constantly changing structure, we discuss the stability/plasticity dilemma including examples of documented cortical reorganization taking place at multiple spatial and temporal scales. We pose that while plasticity is needed for motor learning, stability of the system is necessary for storage and maintenance of memorized skills. We discuss how this plasticity/stability dilemma is resolved along the life span and after a brain injury. We then examine the main challenges that clinicians have to overcome to promote recovery of function in patients with brain lesions, including attempts to use neurostimulation techniques as adjuvant to training-based customary neurorehabilitation.

Transcutaneous spinal direct current stimulation improves locomotor learning in healthy humans.

BACKGROUND: Ambulation is an essential aspect of daily living and is often impaired after brain and spinal cord injuries. Despite the implementation of standard neurorehabilitative care, locomotor recovery is often incomplete. OBJECTIVE: In this randomized, sham-controlled, double-blind, parallel design study, we aimed to determine if anodal transcutaneous spinal direct current stimulation (anodal tsDCS) could improve training effects on locomotion compared to sham (sham tsDCS) in healthy subjects. METHODS: 43 participants underwent a single backwards locomotion training (BLT) session on a reverse treadmill with concurrent anodal (n = 22) or sham (n = 21) tsDCS. The primary outcome measure was speed gain measured 24 h post-training. We hypothesized that anodal tsDCS + BLT would improve training effects on backward locomotor speed compared to sham tsDCS + BLT. A subset of participants (n = 31) returned for two additional training days of either anodal (n = 16) or sham (n = 15) tsDCS and underwent (n = 29) H-reflex testing immediately before, immediately after, and 30 min post-training over three consecutive days. RESULTS: A single session of anodal tsDCS + BLT elicited greater speed gain at 24 h relative to sham tsDCS + BLT (p = 0.008, two-sample t-test, adjusted for one interim analysis after the initial 12 subjects). Anodal tsDCS + BLT resulted in higher retention of the acquired skill at day 30 relative to sham tsDCS + BLT (p = 0.002) in the absence of significant group differences in online or offline learning over the three training days (p = 0.467 and p = 0.131). BLT resulted in transient down-regulation of H-reflex amplitude (Hmax/Mmax) in both test groups (p < 0.0001). However, the concurrent application of anodal-tsDCS with BLT elicited a longer lasting effect than sham-tsDCS + BLT (p = 0.050). CONCLUSION: tsDCS improved locomotor skill acquisition and retention in healthy subjects and prolonged the physiological exercise-mediated downregulation of excitability of the alpha motoneuron pool. These results suggest that this strategy is worth exploring in neurorehabilitation of locomotor function.

Resting-state functional connectivity of subcortical locomotor centers explains variance in walking capacity.

Walking capacity influences the quality of life and disability in normal aging and neurological disease, but the neural correlates remain unclear and subcortical locomotor regions identified in animals have been more challenging to assess in humans. Here we test whether resting-state functional MRI connectivity (rsFC) of midbrain and cerebellar locomotor regions (MLR and CLR) is associated with walking capacity among healthy adults. Using phenotypic and MRI data from the Nathan Kline Institute Rockland Sample (n =119, age 18-85), the association between walking capacity (6-min walk test distance) and rsFC was calculated from subcortical locomotor regions to 81 other gait-related regions of interest across the brain. Additional analyses assessed the independence and specificity of the results. Walking capacity was associated with higher rsFC between the MLR and superior frontal gyrus adjacent to the anterior cingulate cortex, higher rsFC between the MLR and paravermal cerebellum, and lower rsFC between the CLR and primary motor cortex foot area. These rsFC correlates were more strongly associated with walking capacity than phenotypic variables such as age, and together explained 25% of the variance in walking capacity. Results were specific to locomotor regions compared with the other brain regions. The rsFC of locomotor centers correlates with walking capacity among healthy adults. These locomotion-related biomarkers may prove useful in future work aimed at helping patients with reduced walking capacity.

Lasting deficit in inhibitory control with mild traumatic brain injury.

Being able to focus on a complex task and inhibit unwanted actions or interfering information (i.e., inhibitory control) are essential human cognitive abilities. However, it remains unknown the extent to which mild traumatic brain injury (mTBI) may impact these critical functions. In this study, seventeen patients and age-matched healthy controls (HC) performed a variant of the Stroop task and attention-demanding 4-choice response tasks (4CRT) with identical stimuli but two contexts: one required only routine responses and the other with occasional response conflicts. The results showed that mTBI patients performed equally well as the HC when the 4CRT required only routine responses. However, when the task conditions included occasional response conflicts, mTBI patients with even a single concussion showed a significant slow-down in all responses and higher error rates relative to the HC. Results from event-related functional magnetic resonance imaging (efMRI) revealed altered neural activity in the mTBI patients in the cerebellum-thalamo-cortical and the fronto-basal-ganglia networks regulating inhibitory control. These results suggest that even without apparent difficulties in performing complex attention-demanding but routine tasks, patients with mTBI may experience long-lasting deficits in regulating inhibitory control when situations call for rapid conflict resolutions.

Early Rehabilitation After Stroke: a Narrative Review.

PURPOSE OF REVIEW: Despite current rehabilitative strategies, stroke remains a leading cause of disability in the USA. There is a window of enhanced neuroplasticity early after stroke, during which the brain's dynamic response to injury is heightened and rehabilitation might be particularly effective. This review summarizes the evidence of the existence of this plastic window, and the evidence regarding safety and efficacy of early rehabilitative strategies for several stroke domain-specific deficits. RECENT FINDINGS: Overall, trials of rehabilitation in the first 2 weeks after stroke are scarce. In the realm of very early mobilization, one large and one small trial found potential harm from mobilizing patients within the first 24 h after stroke, and only one small trial found benefit in doing so. For the upper extremity, constraint-induced movement therapy appears to have benefit when started within 2 weeks of stroke. Evidence for non-invasive brain stimulation in the acute period remains scant and inconclusive. For aphasia, the evidence is mixed, but intensive early therapy might be of benefit for patients with severe aphasia. Mirror therapy begun early after stroke shows promise for the alleviation of neglect. Novel approaches to treating dysphagia early after stroke appear promising, but the high rate of spontaneous improvement makes their benefit difficult to gauge. The optimal time to begin rehabilitation after a stroke remains unsettled, though the evidence is mounting that for at least some deficits, initiation of rehabilitative strategies within the first 2 weeks of stroke is beneficial. Commencing intensive therapy in the first 24 h may be harmful.