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Stroke is a leading cause of serious long-term disability in adults and is the second leading cause of death worldwide. Early reperfusion and neuroprotection techniques have been the focus of much effort with the aim of very acute treatment of the stroke. Targeting different mechanisms, pharmacological therapies have the potential to reduce disability in a large fraction of patients who survive the acute stroke. The brain's capacity to reorganize after stroke through plasticity mechanisms can be modulated by pharmacological agents. A number of therapeutic interventions are under study, including small molecules, growth factors, and monoclonal antibodies. Recently it has been shown that the SSRI fluoxetine improved motor deficit in patients with ischaemic stroke and hemiplegia which appeared to be independent of the presence of depression. In this context, it is of major importance to support innovative research in order to promote the emergence of new pharmacological treatments targeting neurological recovery after stroke, as opposed to acute de-occlusion and neuroprotection. This paper is the work of a group of 14 scientists with aim of (1) addressing key areas of the basic and clinical aspects of human brain plasticity after stroke and potential pharmacological targets for recovery, (2) asking questions about the most appropriate characteristics of clinical trials testing drugs in post stroke recovery and (3) proposing recommendations for future clinical trials.

Purpose: To propose a consensus-based definition and framework for motor rehabilitation after stroke., Methods: An expert European working group reviewed the literature, attaining internal consensus after external feedback., Findings: Motor rehabilitation is defined as a process that engages people with stroke to benefit their motor function, activity capacity and performance in daily life. It is necessary for people with residual motor disability whose goal is to enhance their functioning, independence and participation. Motor rehabilitation operates through learning- and use-dependent mechanisms. The trajectory of motor recovery varies across patients and stages of recovery. Early behavioral restitution of motor function depends on spontaneous biological mechanisms. Further improvements in activities of daily living are achieved by compensations. Motor rehabilitation is guided by regular assessment of motor function and activity using consensus-based measures, including patient-reported outcomes. Results are discussed with the patient and their carers to set personal goals. During motor rehabilitation patients learn to optimize and adapt their motor, sensory and cognitive functioning through appropriately dosed repetitive, goal-oriented, progressive, task- and context-specific training. Motor rehabilitation supports people with stroke to maximize health, well-being and quality of life. The framework describes the International Classification of Functioning, Disability and Health in the context of stroke, describes neurobiological mechanisms of behavioral restitution and compensation, and summarizes recommendations for clinical assessment, prediction tools, and motor interventions with strong recommendations from clinical practice guidelines (2016-2022)., Conclusions: This definition and framework may guide clinical educators, inform clinicians on current recommendations and guidelines, and identify gaps in the evidence base., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Atlas-based voxel features have the potential to aid motor outcome prognostication after stroke, but are seldom used in clinically feasible prediction models. This could be because neuroimaging feature development is a non-standardized, complex, multistep process. This is a barrier to entry for researchers and poses issues for reproducibility and validation in a field of research where sample sizes are typically small., Objectives: The primary aim of this review is to describe the methodologies currently used in motor outcome prediction studies using atlas-based voxel neuroimaging features. Another aim is to identify neuroanatomical regions commonly used for motor outcome prediction., Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol was constructed and OVID Medline and Scopus databases were searched for relevant studies. The studies were then screened and details about imaging modality, image acquisition, image normalization, lesion segmentation, region of interest determination, and imaging measures were extracted., Results: Seventeen studies were included and examined. Common limitations were a lack of detailed reporting on image acquisition and the specific brain templates used for normalization and a lack of clear reasoning behind the atlas or imaging measure selection. A wide variety of sensorimotor regions relate to motor outcomes and there is no consensus use of one single sensorimotor atlas for motor outcome prediction., Conclusion: There is an ongoing need to validate imaging predictors and further improve methodological techniques and reporting standards in neuroimaging feature development for motor outcome prediction post-stroke.

The proportional recovery rule (PRR) posits that most stroke survivors can expect to reduce a fixed proportion of their motor impairment. As a statistical model, the PRR explicitly relates change scores to baseline values - an approach that arises in many scientific domains but has the potential to introduce artifacts and flawed conclusions. We describe approaches that can assess associations between baseline and changes from baseline while avoiding artifacts due either to mathematical coupling or to regression to the mean. We also describe methods that can compare different biological models of recovery. Across several real datasets in stroke recovery, we find evidence for non-artifactual associations between baseline and change, and support for the PRR compared to alternative models. We also introduce a statistical perspective that can be used to assess future models. We conclude that the PRR remains a biologically relevant model of stroke recovery., Competing Interests: JG, TK, AG, RK, AL, CS, WB, GK, JK No competing interests declared, (© 2022, Goldsmith et al.)

Background: Motor outcomes after stroke can be predicted using structural and functional biomarkers of the descending corticomotor pathway, typically measured using magnetic resonance imaging and transcranial magnetic stimulation, respectively. However, the precise structural determinants of intact corticomotor function are unknown. Identifying structure-function links in the corticomotor pathway could provide valuable insight into the mechanisms of post-stroke motor impairment. This study used supervised machine learning to classify upper limb motor evoked potential status using MRI metrics obtained early after stroke., Methods: Retrospective data from 91 patients (49 women, age 35-97 years) with moderate to severe upper limb weakness within a week after stroke were included in this study. Support vector machine classifiers were trained using metrics from T1- and diffusion-weighted MRI to classify motor evoked potential status, empirically measured using transcranial magnetic stimulation., Results: Support vector machine classification of motor evoked potential status was 81% accurate, with false positives more common than false negatives. Important structural MRI metrics included diffusion anisotropy asymmetry in the supplementary and pre-supplementary motor tracts, maximum cross-sectional lesion overlap in the sensorimotor tract and ventral premotor tract, and mean diffusivity asymmetry in the posterior limbs of the internal capsule., Interpretations: MRI measures of corticomotor structure are good but imperfect predictors of corticomotor function. Residual corticomotor function after stroke depends on both the extent of cross-sectional macrostructural tract damage and preservation of white-matter microstructural integrity. Analysing the corticomotor pathway using a multivariable MRI approach across multiple tracts may yield more information than univariate biomarker analyses., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Rehabilitation is recognised as a cornerstone of multidisciplinary stroke care. Intensity of therapy is related to functional recovery although there is high variability on the amount of time and techniques applied in therapy sessions. There is a need to better describe stroke rehabilitation protocols to develop a better understanding of current practice increasing the internal validity and generalisation of clinical trial results. The aim of this study is to describe an intensive rehabilitation programme for patients with stroke in an inpatient rehabilitation facility, measuring the amount and type of therapies (physical, occupational and speech therapy) provided and reporting functional outcomes., Methods and Analysis: This will be a prospective observational cohort study of patients with subacute stroke admitted to our inpatient rehabilitation facility during 2 years. A therapy recording tool was developed in order to describe the rehabilitation interventions performed in our unit. This tool was designed using the Delphi method, literature search and collaboration with senior clinicians. Therapists will record the time spent on different activities available in our unit during specific therapy sessions. Afterwards, the total time spent in each activity, and the total rehabilitation time for all activities, will be averaged for all patients. Outcome variables were divided into three different domains: body structure and function outcomes, activity outcomes and participation outcomes and will be assessed at baseline (admission at the rehabilitation unit), at discharge from the rehabilitation unit and at 3 and 6 months after stroke., Ethics and Dissemination: This study was approved by the Medical Research Committee at Hospital del Mar Research Institute (Project ID: 34/C/2017). The results of this study will be presented at national and international congress and submitted for publication in peer-reviewed journals., Trial Registration Number: NCT04191109., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fecal incontinence (FI) substantially impairs quality of life and imparts a major socioeconomic burden. Anal sphincter injury and possibly pudendal nerve damage are considered common causes, however, current clinical methods for evaluating their function remain suboptimal. Electromyography (EMG) and pudendal nerve terminal latencies have been applied with some success, but are not considered standard practice due to uncertain accuracy and clinical value. In this study we developed and applied a novel anorectal high-density (HD) EMG probe in humans and pigs to acquire quantitative electrophysiological metrics of the anorectum. In the human trial we assessed somatic pathways and showed that EMG amplitude was greater for tight voluntary squeezes than light voluntary squeezes (0.03 ± 0.02 mV vs. 0.05 ± 0.03 mV). In a porcine model we applied trans-sacral magnetic stimulation to evoke extrinsically activated involuntary pathways and the resulting motor evoked potentials (MEP) were captured using the HD-EMG probe. The mean MEP amplitude at 50% magnetic stimulation intensity output (MSO) was significantly lower that the MEP amplitude at 85, 95 and 100% MSO (1.52 ± 0.50 mV vs. 3.10 ± 0.60 mV). In conclusion, the use of HD-EMG probe in conjunction with trans-sacral magnetic stimulation, for spatiotemporal mapping of anorectal EMG and MEP activity is anticipated to achieve new insights into FI and could offer improved diagnostic and prognostic biomarkers for anorectal dysfunction.

This study investigated the effects of poi (a weight on the end of a cord which is swung in circular patterns around the body) compared with Tai Chi on physical and cognitive function in healthy older adults. A total of 79 participants (60-86 years) were randomly allocated to the poi or Tai Chi group. Physical and cognitive function was measured 1 month before, immediately before, immediately after, and 1 month after the intervention (two lessons a week, for 4 weeks). Immediately postintervention, both groups improved postural stability, upper limb strength, and simple attention. Tai Chi also improved systolic blood pressure. One-month postintervention, compared with immediately postintervention, both groups improved upper limb strength, upper limb range of motion, and memory. Poi also improved systolic blood pressure. Therefore, poi seems to be as effective as Tai Chi for improving physical and cognitive function in healthy older adults.

The Re-Link Trainer (RLT) is a modified walking frame with a linkage system designed to apply a non-individualized kinematic constraint to normalize gait trajectory of the left limb. The premise behind the RLT is that a user's lower limb is constrained into a physiologically normal gait pattern, ideally generating symmetry across gait cycle parameters and kinematics. This pilot study investigated adaptations in the natural gait pattern of healthy adults when using the RLT compared to normal overground walking. Bilateral lower limb kinematic and electromyography data were collected while participants walked overground at a self-selected speed, followed by walking in the RLT. A series of 2-way analyses of variance examined between-limb and between-condition differences. Peak hip extension and knee flexion were reduced bilaterally when walking in the RLT. Left peak hip extension occurred earlier in the gait cycle when using the RLT, but later for the right limb. Peak hip flexion was significantly increased and occurred earlier for the constrained limb, while peak plantarflexion was significantly reduced. Peak knee flexion and plantarflexion in the right limb occurred later when using the RLT. Significant bilateral reductions in peak electromyography amplitude were evident when walking in the RLT, along with a significant shift in when peak muscle activity was occurring. These findings suggest that the RLT does impose a significant constraint, but generates asymmetries in lower limb kinematics and muscle activity patterns. The large interindividual variation suggests users may utilize differing motor strategies to adapt their gait pattern to the imposed constraint., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Walking function post-stroke is characterized by asymmetries in gait cycle parameters and joint kinematics. The Re-Link Trainer is designed to provide kinematic constraint to the paretic lower limb, to guide a physiologically normal and symmetrical gait pattern. The purpose of this pilot study was to assess the immediate influence of the Re-Link Trainer on measures of gait symmetry in healthy adults. Participants demonstrated a significantly lower cadence and a 62% reduction in walking speed in the Re-Link Trainer compared to normal walking. The step length ratio had a significant increase from 1.0 during normal walking to 2.5 when walking in the Re-Link Trainer. The results from this pilot study suggest in its current iteration the Re-Link Trainer imposes an asymmetrical constraint on lower limb kinematics.

Background: Previous research has shown that measuring the size and content of patients' drawings of their illness can reveal their perceptions and predict recovery. This study aimed to assess the usefulness of analyzing kinematic features of drawings., Methods: A pilot observational study was conducted with 15 patients who had been hospitalized with a stroke 8 to 11 months previously. They were asked to draw a picture of what they thought had happened to their brain and describe the drawing using an electronic inking pen and digitizing tablet. Analysis of kinematic data (time to draw/write, drawing/writing speed, and pen pressure) was conducted using MovAlyzeR® software. Evaluations of physical functioning, quality of life, illness perceptions, and emotional well-being were administered, and correlations with kinematic measures assessed., Results: Stronger pen pressure was associated with perceptions of greater control over the stroke. Faster drawing was correlated with greater worry about a recurrent stroke and the perception that the effects of the stroke would last longer. Needing more time to write was associated with perceptions of fewer consequences of the stroke. No associations between kinematic measures and indicators of stroke severity, physical, or emotional well-being were shown., Conclusions: Kinematic measures of stroke patients' drawings of their brain and comments were associated with illness perceptions and not measures of physical or emotional health status. The addition of kinematic analysis may add further utility to the assessment of patients' drawings of their illness. More studies need to be performed with larger sample sizes and other patient groups.

Tinnitus is the conscious perception of sound with no physical sound source. Some models of tinnitus pathophysiology suggest that networks associated with attention, memory, distress and multisensory experience are involved in tinnitus perception. The aim of this study was to evaluate whether a multisensory attention training paradigm which used audio, visual, and somatosensory stimulation would reduce tinnitus. Eighteen participants with predominantly unilateral chronic tinnitus were randomized between two groups receiving 20 daily sessions of either integration (attempting to reduce salience to tinnitus by binding with multisensory stimuli) or attention diversion (multisensory stimuli opposite side to tinnitus) training. The training resulted in small but statistically significant reductions in Tinnitus Functional Index and Tinnitus Severity Numeric Scale scores and improved attentional abilities. No statistically significant improvements in tinnitus were found between the training groups. This study demonstrated that a short period of multisensory attention training reduced unilateral tinnitus, but directing attention toward or away from the tinnitus side did not differentiate this effect.

Being able to predict an individual's potential for recovery of motor function after stroke may facilitate the use of more effective targeted rehabilitation strategies, and management of patient expectations and goals. This review summarises developments since 2010 of approaches based on clinical, neurophysiological and neuroimaging measures for predicting individual patients' potential for upper limb recovery. Clinical assessments alone have low prognostic accuracy. Transcranial magnetic stimulation can be used to assess the functional integrity of the corticomotor pathway, and has some predictive value but is not superior when used in isolation due to its low negative predictive value. Neuroimaging measures can be used to assess the structural integrity of descending white matter tracts. Recent studies indicate that the integrity of corticospinal and alternate motor tracts in both hemispheres may be useful predictors of motor recovery after stroke. The PREP algorithm is currently the only sequential algorithm that combines clinical, neurophysiological and neuroimaging measures at the sub-acute stage to predict the potential for subsequent recovery of upper limb function. Future research could determine if a similar algorithmic approach may be useful for predicting the recovery of gait after stroke., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Aim: To explore the relationship between motor cortical and descending motor pathway reorganization, lesion type, and upper limb function in youth with unilateral cerebral palsy (CP)., Methods: Twenty participants with unilateral CP (mean age 15 ± 3 years; 11 males) completed a range of upper limb functional measures. Structural MRI, diffusion-weighted, and functional MRI were conducted to determine type and extent of brain lesion, descending white matter integrity, and whole-brain activity during affected hand use. Single pulse transcranial magnetic stimulation (TMS) (n = 12) was used to examine functional integrity of the corticospinal pathway as well as primary motor cortex intracortical and interhemispheric inhibition from motor-evoked potentials and silent periods., Results: Fractional anisotropy measures within the posterior limb of the internal capsule were a predictor of upper limb function (R (2) = 0.41, F = 11.3, p = 0.004). Participants with periventricular lesions tended to have better upper limb function [F(2, 17) = 42.48, p < 0.0001]. Five participants with evidence of cortical reorganization and functional ipsilateral projections to their affected hand had worse upper limb function. Deficits in intracortical and interhemispheric inhibitory mechanisms were found in participants with worse upper limb function (Melbourne Assessment of Unilateral Upper Limb Function: Mann Whitney p = 0.02)., Conclusion: Neuroimaging and TMS can provide useful information related to hand function of individuals with unilateral CP and may have potential to assist as a predictive tool and/or guide rehabilitation.

This third chapter discusses the evidence for the rehabilitation of the most common movement disorders of the upper extremity. The authors also present a framework, building on the computation, anatomy, and physiology (CAP) model, for incorporating some of the principles discussed in the 2 previous chapters by Frey et al and Sathian et al in the practice of rehabilitation and for discussing potentially helpful interventions based on emergent neuroscience principles.

Background: Stroke is a leading cause of disability. The ability to live independently after stroke depends largely on the reduction of motor impairment and the recovery of motor function. Accurate prediction of motor recovery assists rehabilitation planning and supports realistic goal setting by clinicians and patients. Initial impairment is negatively related to degree of recovery, but inter-individual variability makes accurate prediction difficult. Neuroimaging and neurophysiological assessments can be used to measure the extent of stroke damage to the motor system and predict subsequent recovery of function, but these techniques are not yet used routinely., Recent Developments: The use of motor impairment scores and neuroimaging has been refined by two recent studies in which these investigations were used at multiple time points early after stroke. Voluntary finger extension and shoulder abduction within 5 days of stroke predicted subsequent recovery of upper-limb function. Diffusion-weighted imaging within 7 days detected the effects of stroke on caudal motor pathways and was predictive of lasting motor impairment. Thus, investigations done soon after stroke had good prognostic value. The potential prognostic value of cortical activation and neural plasticity has been explored for the first time by two recent studies. Functional MRI detected a pattern of cortical activation at the acute stage that was related to subsequent reduction in motor impairment. Transcranial magnetic stimulation enabled measurement of neural plasticity in the primary motor cortex, which was related to subsequent disability. These studies open interesting new lines of enquiry. WHERE NEXT?: The accuracy of prediction might be increased by taking into account the motor system's capacity for functional reorganisation in response to therapy, in addition to the extent of stroke-related damage. Improved prognostic accuracy could also be gained by combining simple tests of motor impairment with neuroimaging, genotyping, and neurophysiological assessment of neural plasticity. The development of algorithms to guide the sequential combinations of these assessments could also further increase accuracy, in addition to improving rehabilitation planning and outcomes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In this article we reviewed the results obtained with the technique of paired-pulse transcranial magnetic stimulation (TMS) in normal subjects and in patients with movement disorders (Parkinson's disease, dystonia, chorea, Tourette's syndrome, myoclonus, essential tremor, and ataxia). Results on short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and long-interval intracortical inhibition (LICI) are reported and discussed for each type of movement disorder.

Constraints pertaining to interlimb coordination have been studied extensively in the past decades. In this debate, F. Mechsner (2004) has taken a provocative position by putting primary emphasis on perceptual principles that mediate coordinative stability. Whereas the present authors agree that the role of perceptual principles is of critical importance during coordination, they take issue with Mechsner's extreme position and with the evidence forwarded to support a purely perceptual-cognitive approach to bimanual coordination. More specifically, the authors emphasize that current knowledge about brain function argues against a dualism between perception and action, criticize the presented evidence that posture manipulations during coordination provide decisive evidence against motoric and muscular constraints, and report on potential pitfalls associated with the use of visual transformation procedures to support complex coordination patterns.

Using transcranial magnetic stimulation (TMS) over the contralateral motor cortex, motor evoked potentials (MEPs) were recorded from resting abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles of eight subjects while they either rested or produced one of six levels of force with the APB ipsilateral to the TMS. F-waves were recorded from each APB at rest in response to median nerve stimulation while subjects either rested or produced one of two levels of force with their contralateral APB. Contraction of the APB ipsilateral to TMS produced facilitation of the MEPs recorded from resting APB and FDI muscles contralateral to TMS but did not modulate F-wave amplitude. Negligible asymmetries in MEP facilitation were observed between dominant and subdominant hands. These results suggest that facilitation arising from isometric contraction of ipsilateral hand muscles occurs primarily at supraspinal levels, and this occurs symmetrically between dominant and subdominant hemispheres.