The test-retest reliability of non-navigated transcranial magnetic stimulation (TMS) measures of corticospinal pathway excitability early after stroke.

PURPOSE: Motor evoked potential (MEP) characteristics are potential biomarkers of whether rehabilitation interventions drive motor recovery after stroke. The test-retest reliability of Transcranial Magnetic Stimulation (TMS) measurements in sub-acute stroke remains unclear. This study aims to determine the test-retest reliability of upper limb MEP measures elicited by non-neuronavigated transcranial magnetic stimulation in sub-acute-stroke. METHODS: In two identical data collection sessions, 1-3 days apart, TMS measures assessed: motor threshold (MT), amplitude, latency (MEP-L), silent period (SP), recruitment curve slope in the biceps brachii (BB), extensor carpi radialis (ECR), and abductor pollicis brevis (APB) muscles of paretic and non-paretic upper limbs. Test-retest reliability was calculated using the intra-class correlation coefficient (ICC) and 95% confidence intervals (CI). Acceptable reliability was set at a lower 95% CI of 0.70 or above. The limits of agreement (LOA) and smallest detectable change (SDC) were calculated. RESULTS: 30 participants with sub-acute stroke were included (av 36 days post stroke) reliability was variable between poor to good for the different MEP characteristics. The SDC values differed across muscles and MEP characteristics in both paretic and less paretic limbs. CONCLUSIONS: The present findings indicate there is limited evidence for acceptable test-retest reliability of non-navigated TMS outcomes when using the appropriate 95% CI for ICC, SDC and LOA values. CLINICAL TRIAL REGISTRATION: Current Controlled Trials: ISCRT 19090862, http://www.controlled-trials.com.

This study identified that Non-navigated Transcranial Magnetic Stimulation (TMS) demonstrates low reliability of TMS measures in upper limb with variation between muscles and measures in sub-acute strokeWhen using non-navigated TMS to explore corticospinal pathway excitability the individual target muscle and TMS measure should be taken into considerationNon-navigated TMS may be more useful in exploring group differences rather than individual differences in corticospinal pathway excitabilityNon-navigated TMS could provide a means of measuring recovery in clinical practice and could inform the development of more effective interventions but this needs further development before it can be used as a clinical recovery biomarker.

Neurophysiological changes accompanying reduction in upper limb motor impairments in response to exercise-based virtual rehabilitation after stroke: systematic review.

BACKGROUND: Virtual reality-augmented therapist-delivered exercise-based training has promise for enhancing upper limb motor recovery after stroke. However, the neurophysiological mechanisms are unclear. OBJECTIVE: To find if neurophysiological changes are correlated with or accompany a reduction in motor impairment in response to virtual reality-aided exercise-based training. DATA SOURCES: Databases searched from inception to August 2020: MEDLINE, AMED, EMBASE, PUBMED, COCHRANE, CINHAL, PROQUEST and OPEN GREY. ELIGIBILITY CRITERIA: Studies that investigated virtual reality-augmented exercise-based training for the upper limb in adults with stroke, and, measured motor impairment and neurophysiological outcomes. Studies that combined VR with another technology were excluded. DATA EXTRACTION AND SYNTHESIS: Using pre-prepared proformas, three reviewers independently: identified eligible studies, assessed potential risk-of-bias, and extracted data. A critical narrative synthesis was conducted. A meta-analysis was not possible because of heterogeneity in participants, interventions and outcome measures. RESULTS: Of 1387 records identified, four studies were eligible and included in the review. Overall, included studies were assessed as having high potential risk-of-bias. The VR equipment, and control interventions varied between studies. Two studies measured motor impairment with the Fugl-Meyer Assessment but there was no commonality in the use of neurophysiological measures. One study found improvement in neurophysiological measures only. The other three studies found a reduction in motor impairment and changes in neurophysiological outcomes, but did not calculate correlation coefficients. CONCLUSION: There is insufficient evidence to identify the neurophysiological changes that are correlated with, or accompany, reduction in upper limb motor impairment in response to virtual reality-augmented exercise-based training after stroke. Systematic Review Registration Number PROSPERO 2017 CRD42017071312.

Challenges and Opportunities for the Future of Brain-Computer Interface in Neurorehabilitation.

Brain-computer interfaces (BCIs) provide a unique technological solution to circumvent the damaged motor system. For neurorehabilitation, the BCI can be used to translate neural signals associated with movement intentions into tangible feedback for the patient, when they are unable to generate functional movement themselves. Clinical interest in BCI is growing rapidly, as it would facilitate rehabilitation to commence earlier following brain damage and provides options for patients who are unable to partake in traditional physical therapy. However, substantial challenges with existing BCI implementations have prevented its widespread adoption. Recent advances in knowledge and technology provide opportunities to facilitate a change, provided that researchers and clinicians using BCI agree on standardisation of guidelines for protocols and shared efforts to uncover mechanisms. We propose that addressing the speed and effectiveness of learning BCI control are priorities for the field, which may be improved by multimodal or multi-stage approaches harnessing more sensitive neuroimaging technologies in the early learning stages, before transitioning to more practical, mobile implementations. Clarification of the neural mechanisms that give rise to improvement in motor function is an essential next step towards justifying clinical use of BCI. In particular, quantifying the unknown contribution of non-motor mechanisms to motor recovery calls for more stringent control conditions in experimental work. Here we provide a contemporary viewpoint on the factors impeding the scalability of BCI. Further, we provide a future outlook for optimal design of the technology to best exploit its unique potential, and best practices for research and reporting of findings.

Kinematic Components of the Reach-to-Target Movement After Stroke for Focused Rehabilitation Interventions: Systematic Review and Meta-Analysis.

Background: Better upper limb recovery after stroke could be achieved through tailoring rehabilitation interventions directly at movement deficits. Aim: To identify potential; targets for therapy by synthesizing findings of differences in kinematics and muscle activity between stroke survivors and healthy adults performing reach-to-target tasks. Methods: A systematic review with identification of studies, data extraction, and potential risk of bias was completed independently by two reviewers. Online databases were searched from their inception to November 2017 to find studies of reach-to-target in people-with-stroke and healthy adults. Potential risk-of-bias was assessed using the Down's and Black Tool. Synthesis was undertaken via: (a) meta-analysis of kinematic characteristics utilizing the standardized mean difference (SMD) [95% confidence intervals]; and (b), narrative synthesis of muscle activation. Results: Forty-six studies met the review criteria but 14 had insufficient data for extraction. Consequently, 32 studies were included in the meta-analysis. Potential risk-of-bias was low for one study, unclear for 30, and high for one. Reach-to-target was investigated with 618 people-with-stroke and 429 healthy adults. The meta-analysis found, in all areas of workspace, that people-with-stroke had: greater movement times (seconds) e.g., SMD 2.57 [0.89, 4.25]; lower peak velocity (millimeters/second) e.g., SMD -1.76 [-2.29, -1.24]; greater trunk displacement (millimeters) e.g. SMD 1.42 [0.90, 1.93]; a more curved reach-path-ratio e.g., SMD 0.77 [0.32, 1.22] and reduced movement smoothness e.g., SMD 0.92 [0.32, 1.52]. In the ipsilateral and contralateral workspace, people-with-stroke exhibited: larger errors in target accuracy e.g., SMD 0.70 [0.39, 1.01]. In contralateral workspace, stroke survivors had: reduced elbow extension and shoulder flexion (degrees) e.g., elbow extension SMD -1.10 [-1.62, -0.58] and reduced shoulder flexion SMD -1.91 [-1.96, -0.42]. Narrative synthesis of muscle activation found that people-with-stroke, compared with healthy adults, exhibited: delayed muscle activation; reduced coherence between muscle pairs; and use of a greater percentage of muscle power. Conclusions: This first-ever meta-analysis of the kinematic differences between people with stroke and healthy adults performing reach-to-target found statistically significant differences for 21 of the 26 comparisons. The differences identified and values provided are potential foci for tailored rehabilitation interventions to improve upper limb recovery after stroke.

Getting a kinematic handle on reach-to-grasp: a meta-analysis.

BACKGROUND AND OBJECTIVES: Reach-to-grasp is an essential everyday activity that is often impaired after stroke. The objectives of this review are: (1) identify differences in the kinematic characteristics of reach-to-grasp between individuals with and without stroke, and (2) determine the influence of object location on kinematics. DATA SOURCES: MEDLINE, AMED, and Embase databases. ELIGIBILITY CRITERIA: Studies investigating individuals with stroke and neurologically intact control participants completing reach-to-grasp (paretic upper limb) of an object assessed via kinematic assessment (motion analysis). REVIEW METHODS: Following Cochrane Collaboration guidelines a meta-analysis comparing kinematic characteristics of reach-to-grasp between individuals with and without stroke. Potential risk of bias was assessed using the Down's and Black Tool. Data were synthesised by calculating the standardised mean difference (SMD) in kinematic characteristics between adults with and without stroke. RESULTS: Twenty-nine studies met the review criteria, mainly of observational design; 460 individuals with stroke and 324 control participants. Kinematic differences in reach-to-grasp were identified in the central and ipsilateral workspace for example, individuals with stroke exhibited significantly lower peak velocity SMD -1.48 (95% CI -1.94, -1.02), and greater trunk displacement SMD 1.55 (95% CI 0.85, 2.25) than control participants. Included studies were assessed as demonstrating unclear or high potential risk-of-bias. CONCLUSIONS: Differences in kinematic characteristics between individuals with and without stroke were identified which may be different reaching in the ipsilateral and central workspace. Suggesting, that object location may influence some kinematic characteristics and not others which may be pertinent when re-training reach-to-grasp. PROSPERO: CRD42014009479.

Functional Strength Training and Movement Performance Therapy for Upper Limb Recovery Early Poststroke-Efficacy, Neural Correlates, Predictive Markers, and Cost-Effectiveness: FAST-INdiCATE Trial.

BACKGROUND: Variation in physiological deficits underlying upper limb paresis after stroke could influence how people recover and to which physical therapy they best respond. OBJECTIVES: To determine whether functional strength training (FST) improves upper limb recovery more than movement performance therapy (MPT). To identify: (a) neural correlates of response and (b) whether pre-intervention neural characteristics predict response. DESIGN: Explanatory investigations within a randomised, controlled, observer-blind, and multicentre trial. Randomisation was computer-generated and concealed by an independent facility until baseline measures were completed. Primary time point was outcome, after the 6-week intervention phase. Follow-up was at 6 months after stroke. PARTICIPANTS: With some voluntary muscle contraction in the paretic upper limb, not full dexterity, when recruited up to 60 days after an anterior cerebral circulation territory stroke. INTERVENTIONS: Conventional physical therapy (CPT) plus either MPT or FST for up to 90 min-a-day, 5 days-a-week for 6 weeks. FST was "hands-off" progressive resistive exercise cemented into functional task training. MPT was "hands-on" sensory/facilitation techniques for smooth and accurate movement. OUTCOMES: The primary efficacy measure was the Action Research Arm Test (ARAT). Neural measures: fractional anisotropy (FA) corpus callosum midline; asymmetry of corticospinal tracts FA; and resting motor threshold (RMT) of motor-evoked potentials. ANALYSIS: Covariance models tested ARAT change from baseline. At outcome: correlation coefficients assessed relationship between change in ARAT and neural measures; an interaction term assessed whether baseline neural characteristics predicted response. RESULTS: 288 Participants had: mean age of 72.2 (SD 12.5) years and mean ARAT 25.5 (18.2). For 240 participants with ARAT at baseline and outcome the mean change was 9.70 (11.72) for FST + CPT and 7.90 (9.18) for MPT + CPT, which did not differ statistically (p = 0.298). Correlations between ARAT change scores and baseline neural values were between 0.199, p = 0.320 for MPT + CPT RMT (n = 27) and -0.147, p = 0.385 for asymmetry of corticospinal tracts FA (n = 37). Interaction effects between neural values and ARAT change between baseline and outcome were not statistically significant. CONCLUSIONS: There was no significant difference in upper limb improvement between FST and MPT. Baseline neural measures did not correlate with upper limb recovery or predict therapy response. TRIAL REGISTRATION: Current Controlled Trials: ISRCT 19090862, http://www.controlled-trials.com.

Characteristics of corticospinal projections to the intrinsic hand muscles in skilled harpists.

The process of learning to play a musical instrument necessarily alters the functional organisation of the cortical motor areas that are involved in generating the required movements. In the case of the harp, the demands placed on the motor system are quite specific. During performance, all digits with the sole exception of the little finger are used to pluck the strings. With a view to elucidating the impact of having acquired this highly specialised musical skill on the characteristics of corticospinal projections to the intrinsic hand muscles, focal transcranial magnetic stimulation (TMS) was used to elicit motor evoked potentials (MEPs) in three muscles (of the left hand): abductor pollicis brevis (APB); first dorsal interosseous (FDI); and abductor digiti minimi (ADM) in seven harpists. Seven non-musicians served as controls. With respect to the FDI muscle-which moves the index finger, the harpists exhibited reliably larger MEP amplitudes than those in the control group. In contrast, MEPs evoked in the ADM muscle-which activates the little finger, were smaller in the harpists than in the non-musicians. The locations on the scalp over which magnetic stimulation elicited discriminable responses in ADM also differed between the harpists and the non-musicians. This specific pattern of variation in the excitability of corticospinal projections to these intrinsic hand muscles exhibited by harpists is in accordance with the idiosyncratic functional demands that are imposed in playing this instrument.

Modulation of human corticospinal excitability by paired associative stimulation.

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation.

Characterizing changes in the excitability of corticospinal projections to proximal muscles of the upper limb.

BACKGROUND: There has been an explosion of interest in methods of exogenous brain stimulation that induce changes in the excitability of human cerebral cortex. The expectation is that these methods may promote recovery of function following brain injury. To assess their effects on motor output, it is typical to assess the state of corticospinal projections from primary motor cortex to muscles of the hand, via electromyographic responses to transcranial magnetic stimulation. If a range of stimulation intensities is employed, the recruitment curves (RCs) obtained can, at least for intrinsic hand muscles, be fitted by a sigmoid function. OBJECTIVE/HYPOTHESIS: To establish whether sigmoid fits provide a reliable basis upon which to characterize the input-output properties of the corticospinal pathway for muscles proximal to the hand, and to assess as an alternative the area under the (recruitment) curve (AURC). METHODS: A comparison of the reliability of these measures, using RCs obtained for muscles that are frequently the targets of rehabilitation. RESULTS: The AURC is an extremely reliable measure of the state of corticospinal projections to hand and forearm muscles, which has both face and concurrent validity. Construct validity is demonstrated by detection of widely distributed (across muscles) changes in corticospinal excitability induced by paired associative stimulation (PAS). CONCLUSION(S): The parameters derived from sigmoid fits are unlikely to provide an adequate means to assess the effectiveness of therapeutic regimes. The AURC can be employed to characterize corticospinal projections to a range of muscles, and gauge the efficacy of longitudinal interventions in clinical rehabilitation.

The effect of simultaneous contractions of ipsilateral muscles on changes in corticospinal excitability induced by paired associative stimulation (PAS).

Consideration was given to means of increasing the reliability and muscle specificity of paired associative stimulation (PAS) by utilising the phenomenon of crossed-facilitation. Eight participants completed three separate sessions: isometric flexor contractions of the left wrist at 20% of maximum voluntary contraction (MVC) simultaneously with PAS (20s intervals; 14 min duration) delivered at the right median nerve and left primary motor cortex (M1); isometric contractions at 20% of MVC; and PAS only (14 min). Eight further participants completed two sessions of longer duration PAS (28 min): either alone or in conjunction with flexion contractions of the left wrist. Thirty motor potentials (MEPs) were evoked in the right flexor (rFCR) and extensor (rECR) carpi radialis muscles by magnetic stimulation of left M1 prior to the interventions, immediately post-intervention, and 10 min post-intervention. Both 14 and 28 min of combined PAS and (left wrist flexion) contractions resulted in reliable increases in rFCR MEP amplitude, which were not present in rECR. In the PAS only conditions, 14 min of stimulation gave rise to unreliable increases in MEP amplitudes in rFCR and rECR, whereas 28 min of PAS induced small (unreliable) changes only for rFCR. These results support the conclusion that changes in the excitability of the corticospinal pathway induced by PAS interact with those associated with contraction of the muscles ipsilateral to the site of cortical stimulation. Furthermore, focal contractions applied by the opposite limb increase the extent and muscle specificity of the induced changes in excitability associated with PAS.

Muscle-specific variations in use-dependent crossed-facilitation of corticospinal pathways mediated by transcranial direct current (DC) stimulation.

The tendency for contractions of muscles in the upper limb to give rise to increases in the excitability of corticospinal projections to the homologous muscles of the opposite limb is well known. Although the suppression of this tendency is integral to tasks of daily living, its exploitation may prove to be critical in the rehabilitation of acquired hemiplegias. Transcranial direct current (DC) stimulation induces changes in cortical excitability that outlast the period of application. We present evidence that changes in the reactivity of the corticospinal pathway induced by DC stimulation of the motor cortex interact systematically with those brought about by contraction of the muscles of the ipsilateral limb. During the application of flexion torques (up to 50% of maximum) applied at the left wrist, motor evoked potentials (MEPs) were evoked in the quiescent muscles of the right arm by magnetic stimulation of the left motor cortex (M1). The MEPs were obtained prior to and following 10 min of anodal, cathodal or sham DC stimulation of left M1. Cathodal stimulation counteracted increases in the crossed-facilitation of projections to the (right) wrist flexors that otherwise occurred as a result of repeated flexion contractions at the left wrist. In addition, cathodal stimulation markedly decreased the excitability of corticospinal projections to the wrist extensors of the right limb. Thus changes in corticospinal excitability induced by DC stimulation can be shaped (i.e. differentiated by muscle group) by focal contractions of muscles in the limb ipsilateral to the site of stimulation.