Niamh C. Kennedy

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.

Attitudes of children towards peers with acquired brain injury (ABI)

Research objective: Children with acquired brain injury (ABI) can experience severe problems in establishing peer relationships. The attitudes peers hold toward a child with an ABI can significantly impact on their willingness to befriend. The present work sought to investigate the attitudes peers hold toward a fictional child with ABI. Methods and procedures: Fifty children from a primary school were compared against a similar number from a secondary school. Gender was evenly split across both groups. A vignette describing a young boy acquiring a brain injury, and his subsequent change in behaviour, was presented to the children. The Friendship Activity Scale (FAS) was then used to judge how likely the children were to befriend the fictional character. Outcomes and results: Results showed a statistically significant interaction between gender and age [F(1, 96) 6.285, p = 0.014] with older males expressing more positive attitudes than younger males. Conclusion: The study suggests that children with ABI are more likely to experience negative attitudes in primary school, and concludes in calling for additional research to more fully explore the social experience of children with ABI.

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.

FAST INdiCATE Trial protocol. Clinical efficacy of functional strength training for upper limb motor recovery early after stroke: Neural correlates and prognostic indicators

Rationale Functional strength training in addition to conventional physical therapy could enhance upper limb recovery early after stroke more than movement performance therapy plus conventional physical therapy. Aims To determine (a) the relative clinical efficacy of conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy for upper limb recovery; (b) the neural correlates of response to conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy; (c) whether any one or combination of baseline measures predict motor improvement in response to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Design Randomized, controlled, observer-blind trial. Study The sample will consist of 288 participants with upper limb paresis resulting from a stroke that occurred within the previous 60 days. All will be allocated to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Functional strength training and movement performance therapy will be undertaken for up to 1·5 h/day, five-days/week for six-weeks. Outcomes and Analysis Measurements will be undertaken before randomization, six-weeks thereafter, and six-months after stroke. Primary efficacy outcome will be the Action Research Arm Test. Explanatory measurements will include voxel-wise estimates of brain activity during hand movement, brain white matter integrity (fractional anisotropy), and brain–muscle connectivity (e.g. latency of motor evoked potentials). The primary clinical efficacy analysis will compare treatment groups using a multilevel normal linear model adjusting for stratification variables and for which therapist administered the treatment. Effect of conventional physical therapy combined with functional strength training versus conventional physical therapy combined with movement performance therapy will be summarized using the adjusted mean difference and 95% confidence interval. To identify the neural correlates of improvement in both groups, we will investigate associations between change from baseline in clinical outcomes and each explanatory measure. To identify baseline measurements that independently predict motor improvement, we will develop a multiple regression model.

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 Downs 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.

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

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 Downs 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.

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.