Electroencephalographic ß-band oscillations in the sensorimotor network reflect motor symptom severity in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Resting-state electroencephalography (EEG) holds promise for assessing brain networks in amyotrophic lateral sclerosis (ALS). We investigated whether neural ß-band oscillations in the sensorimotor network could serve as an objective quantitative measure of progressive motor impairment and functional disability in ALS patients. METHODS: Resting-state EEG was recorded in 18 people with ALS and 38 age- and gender-matched healthy controls. We estimated source-localized ß-band spectral power in the sensorimotor cortex. Clinical evaluation included lower (LMN) and upper motor neuron scores, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, fine motor function (FMF) subscore, and progression rate. Correlations between clinical scores and ß-band power were analysed and corrected using a false discovery rate of q = 0.05. RESULTS: ß-Band power was significantly lower in people with ALS than controls (p = 0.004), and correlated with LMN score (R = -0.65, p = 0.013), FMF subscore (R = -0.53, p = 0.036), and FMF progression rate (R = 0.52, p = 0.036). CONCLUSIONS: ß-Band spectral power in the sensorimotor cortex reflects clinically evaluated motor impairment in ALS. This technology merits further investigation as a biomarker of progressive functional disability.

Cortico-muscular coherence in primary lateral sclerosis reveals abnormal cortical engagement during motor function beyond primary motor areas.

Primary lateral sclerosis (PLS) is a slowly progressing disorder, which is characterized primarily by the degeneration of upper motor neurons (UMNs) in the primary motor area (M1). It is not yet clear how the function of sensorimotor networks beyond M1 are affected by PLS. The aim of this study was to use cortico-muscular coherence (CMC) to characterize the oscillatory drives between cortical regions and muscles during a motor task in PLS and to examine the relationship between CMC and the level of clinical impairment. We recorded EEG and EMG from hand muscles in 16 participants with PLS and 18 controls during a pincer-grip task. In PLS, higher CMC was observed over contralateral-M1 (α- and γ-band) and ipsilateral-M1 (ß-band) compared with controls. Significant correlations between clinically assessed UMN scores and CMC measures showed that higher clinical impairment was associated with lower CMC over contralateral-M1/frontal areas, higher CMC over parietal area, and both higher and lower CMC (in different bands) over ipsilateral-M1. The results suggest an atypical engagement of both contralateral and ipsilateral M1 during motor activity in PLS, indicating the presence of pathogenic and/or adaptive/compensatory alterations in neural activity. The findings demonstrate the potential of CMC for identifying dysfunction within the sensorimotor networks in PLS.

Deficits in force production during multifinger tasks demarcate cognitive dysfunction.

BACKGROUND: The multifinger force deficit (MFFD) is the decline in force generated by each finger as the number of fingers contributing to an action is increased. It has been shown to associate with cognitive status. AIMS: The aim was to establish whether a particularly challenging form of multifinger grip dynamometry, that provides minimal tactile feedback via cutaneous receptors and requires active compensation for reaction forces, will yield an MFFD that is more sensitive to cognitive status. METHODS: Associations between measures of motor function, and cognitive status (Montreal Cognitive Assessment [MoCA]) and latent components of cognitive function (derived from 11 tests using principal component analysis), were estimated cross-sectionally using generalized partial rank correlations. The participants (n = 62) were community dwelling, aged 65-87. RESULTS: Approximately half the participants were unable to complete the dynamometry task successfully. Cognitive status demarcated individuals who could perform the task from those who could not. Among those who complied with the task requirements, the MFFD was negatively correlated with MoCA scores-those with the highest MoCA scores tended to exhibit the smallest deficits, and vice versa. There were corresponding associations with latent components of cognitive function. DISCUSSION: The results support the view that neurodegenerative processes that are a feature of normal and pathological aging exert corresponding effects on expressions of motor coordination-in multifinger tasks, and cognitive sufficiency, due to their dependence on shared neural systems. CONCLUSIONS: The outcomes add weight to the assertion that deficits in force production during multifinger tasks are sensitive to cognitive dysfunction.

Deficits in rate of force production during multifinger tasks are associated with cognitive status.

OBJECTIVES: The multifinger force deficit (MFFD) is the decline in force generated by an individual finger as the number of fingers contributing to the action is increased. It has been proposed that as a measure of neural sufficiency rather than muscle status, it provides a means of detecting individuals at risk of cognitive decline. Age-related deficits in central neural drive exert a disproportionate impact on the rate at which force can be generated. We examined whether a MFFD derived from the maximum rate at which force is generated, is more sensitive to individual differences in cognitive status, than one calculated using the maximum level of force. METHODS: Monotonic associations between each of two variants of the MFFD, and cognition (measured with the Montreal Cognitive Assessment), were estimated cross sectionally using generalized partial rank correlations, in which age, level of education and degree of handedness were included as covariates. The participants (n=26) were community dwelling adults aged 66-87. RESULTS: The MFFD derived using the maximum rate of force development was negatively associated with cognitive status. The association for the MFFD based on the maximum level of force, was not statistically reliable. The associations with cognitive status obtained for both variants of the MFFD were of greater magnitude than those reported previously for standard grip strength dynamometry. CONCLUSION: The sensitivity with which the MFFD detects risk of cognitive decline may be enhanced by using the maximum rate of force developed by each finger, rather than the maximum force generated by each finger.

Neuromuscular electrical stimulation-promoted plasticity of the human brain.

The application of neuromuscular electrical stimulation (NMES) to paretic limbs has demonstrated utility for motor rehabilitation following brain injury. When NMES is delivered to a mixed peripheral nerve, typically both efferent and afferent fibres are recruited. Muscle contractions brought about by the excitation of motor neurons are often used to compensate for disability by assisting actions such as the formation of hand aperture, or by preventing others including foot drop. In this context, exogenous stimulation provides a direct substitute for endogenous neural drive. The goal of the present narrative review is to describe the means through which NMES may also promote sustained adaptations within central motor pathways, leading ultimately to increases in (intrinsic) functional capacity. There is an obvious practical motivation, in that detailed knowledge concerning the mechanisms of adaptation has the potential to inform neurorehabilitation practice. In addition, responses to NMES provide a means of studying CNS plasticity at a systems level in humans. We summarize the fundamental aspects of NMES, focusing on the forms that are employed most commonly in clinical and experimental practice. Specific attention is devoted to adjuvant techniques that further promote adaptive responses to NMES thereby offering the prospect of increased therapeutic potential. The emergent theme is that an association with centrally initiated neural activity, whether this is generated in the context of NMES triggered by efferent drive or via indirect methods such as mental imagery, may in some circumstances promote the physiological changes that can be induced through peripheral electrical stimulation.

A Bayesian approach to analysing cortico-cortical associative stimulation induced increases in the excitability of corticospinal projections in humans.

Repeated pairing of transcranial magnetic stimulation (TMS) over left and right primary motor cortex (M1), at intensities sufficient to generate descending volleys, produces sustained increases in corticospinal excitability. In other paired associative stimulation (PAS) protocols, in which peripheral afferent stimulation is the first element, changes in corticospinal excitability achieved when the second stimulus consists of brief bursts of transcranial alternating current stimulation (tACS), are comparable to those obtained if TMS is used instead (McNickle and Carson 2015). The present aim was to determine whether associative effects are induced when the first stimulus of a cortico-cortical pair is tACS, or alternatively subthreshold TMS. Bursts of tACS (500 ms; 140 Hz; 1 mA) were associated (180 stimulus pairs) with single magnetic stimuli (120% resting motor threshold rMT) delivered over the opposite (left) M1. The tACS ended 6 ms prior to the TMS. In a separate condition, TMS (55% rMT) was delivered to right M1 6 ms before (120% rMT) TMS was applied over left M1. In a sham condition, TMS (120% rMT) was delivered to left M1 only. The limitations of null hypothesis significance testing are well documented. We therefore employed Bayes factors to assess evidence in support of experimental hypotheses-defined precisely in terms of predicted effect sizes, that these two novel variants of PAS increase corticospinal excitability. Although both interventions induced sustained (~ 20-30 min) increases in corticospinal excitability, the evidence in support of the experimental hypotheses (over specified alternatives) was generally greater for the paired TMS-TMS than the tACS-TMS conditions.

Inter-hemispheric inhibition sculpts the output of neural circuits by co-opting the two cerebral hemispheres.

'Inter-hemispheric inhibition' is used frequently to describe the action of one hemisphere in suppressing or impeding processing in its counterpart. It is widely believed that this is required in order to prevent a bilateral cerebrum giving rise to simultaneous and potentially competing outputs. It is argued here that a fundamental role of inter-hemispheric inhibition is to support contrast enhancing and integrative functions by co-opting the capacities of the two cerebral hemispheres. Drawing upon an extensive body of empirical data, derived largely from animal models, and associated theoretical modelling, it is demonstrated that inter-hemispheric projections act via mechanisms such as surround/lateral inhibition. The principal functional unit of callosal influence comprises a facilitatory centre and a depressing peripheral zone, which together shape the influence of converging inputs to pyramidal neurons. Inter-hemispheric inhibition is an instance of a more general feature of mammalian neural systems, whereby inhibitory interneurons act not simply to prevent over-excitation but to sculpt the output of specific circuits. The narrowing of the excitatory focus that occurs through crossed surround inhibition is a highly conserved motif of transcallosal interactions in mammalian sensory and motor cortices. A case is presented that the 'inter-hemispheric competition' model has been sustained, and its clinical derivatives promoted, by erroneous assumptions concerning that revealed by investigative techniques such as transcranial magnetic stimulation (TMS). The alternative perspective offered here is also shown to be consistent with known associations between the structural integrity of callosal projections and the magnitude of the motor deficits that are exhibited following stroke.

Structural and Functional Cortical Connectivity Mediating Cross Education of Motor Function.

Cross-education (CE) is the process whereby training with one limb leads to subsequent improvement in performance by the opposite untrained limb. We used multimodal neuroimaging in humans to investigate the mediating neural mechanisms by relating quantitative estimates of functional and structural cortical connectivity to individual levels of interlimb transfer. Resting-state (rs)-fMRI and diffusion weighted imaging (DWI) scans were undertaken before unilateral ballistic wrist flexion training. The rs-fMRI sequence was repeated immediately afterward. The increase in performance of the untrained limb was 83.6% of that observed for the trained limb and significantly greater than that of a control group who undertook no training. Functional connectivity in the resting motor network between right and left supplementary motor areas (SMA) was elevated after training. These changes were not, however, correlated with individual levels of transfer. Analysis of the DWI data using constrained spherical deconvolution-based tractography indicated that fractional anisotropy and apparent fiber density in tracts connecting bilateral SMA were negatively correlated with and predictive of transfer. The findings suggest that interhemispheric interactions between bilateral SMA play an instrumental role in CE and that the structural integrity of the connecting white matter pathways influences the level of transfer.SIGNIFICANCE STATEMENT Strength or skill training with one limb also brings about improvements in the performance of the opposite, untrained limb. This phenomenon, termed cross-education (CE), has obvious potential for the rehabilitation of functional capacity that has been lost through brain insult or musculoskeletal injury. The neural mechanisms that give rise to CE are, however, poorly understood. We used a combination of neuroimaging methods to investigate the pathways in the human brain that mediate CE. We determined that the supplementary motor area (SMA) plays an important role in the interlimb transfer of performance gains and demonstrate that the quality of the white matter fibers connecting right and left SMA predicts the benefit that an individual derives from CE.

Unilateral movement preparation causes task-specific modulation of TMS responses in the passive, opposite limb.

KEY POINTS: Activity in the primary motor cortices of both hemispheres increases during unilateral movement preparation, but the functional role of ipsilateral motor cortex activity is unknown. Ipsilateral motor cortical activity could represent subliminal 'motor planning' for the passive limb. Alternatively, it could represent the state of the active limb, to support coordination between the limbs should a bimanual movement be required. Here we assessed how preparation of forces toward different directions, with the left wrist, alters evoked responses to transcranial magnetic stimulation of left motor cortex. Preparation of a unilateral movement caused excitability increases in ipsilateral motor cortex that reflected forces produced with the active limb in an intrinsic (body-centred), rather than an extrinsic (world-centred), coordinate system. These results suggest that ipsilateral motor cortical activity prior to unilateral action reflects the state of the active limb, rather than subliminal motor planning for the passive limb. ABSTRACT: Corticospinal excitability is modulated for muscles on both sides of the body during unilateral movement preparation. For the effector, there is a progressive increase in excitability, and a shift in direction of muscle twitches evoked by transcranial magnetic stimulation (TMS) toward the impending movement. By contrast, the directional characteristics of excitability changes in the opposite (passive) limb have not been fully characterized. Here we assessed how preparation of voluntary forces towards four spatially distinct visual targets with the left wrist alters muscle twitches and motor-evoked potentials (MEPs) elicited by TMS of left motor cortex. MEPs were facilitated significantly more in muscles homologous to agonist rather than antagonist muscles in the active limb, from 120 ms prior to voluntary EMG onset. Thus, unilateral motor preparation has a directionally specific influence on pathways projecting to the opposite limb that corresponds to the active muscles rather than the direction of movement in space. The directions of TMS-evoked twitches also deviated toward the impending force direction of the active limb, according to muscle-based coordinates, following the onset of voluntary EMG. The data indicate that preparation of a unilateral movement increases task-dependent excitability in ipsilateral motor cortex, or its downstream projections, that reflects the forces applied by the active limb in an intrinsic (body-centred), rather than an extrinsic (world-centred), coordinate system. The results suggest that ipsilateral motor cortical activity prior to unilateral action reflects the state of the active limb, rather than subliminal motor planning for the passive limb.

Repetitive reaching training combined with transcranial Random Noise Stimulation in stroke survivors with chronic and severe arm paresis is feasible: a pilot, triple-blind, randomised case series.

BACKGROUND: Therapy that combines repetitive training with non-invasive brain stimulation is a potential avenue to enhance upper limb recovery after stroke. This study aimed to investigate the feasibility of transcranial Random Noise Stimulation (tRNS), timed to coincide with the generation of voluntary motor commands, during reaching training. METHODS: A triple-blind pilot RCT was completed. Four stroke survivors with chronic (6-months to 5-years) and severe arm paresis, not taking any medications that had the potential to alter cortical excitability, and no contraindications to tRNS or MRI were recruited. Participants were randomly allocated to 12 sessions of reaching training over 4-weeks with active or sham tRNS delivered over the lesioned hemisphere motor representation. tRNS was triggered to coincide with a voluntary movement attempt, ceasing after 5-s. At this point, peripheral nerve stimulation enabled full range reaching. To determine feasibility, we considered adverse events, training outcomes, clinical outcomes, corticospinal tract (CST) structural integrity, and reflections on training through in-depth interviews from each individual case. RESULTS: Two participants received active and two sham tRNS. There were no adverse events. All training sessions were completed, repetitive practice performed and clinically relevant improvements across motor outcomes demonstrated. The amount of improvement varied across individuals and appeared to be independent of group allocation and CST integrity. CONCLUSION: Reaching training that includes tRNS timed to coincide with generation of voluntary motor commands is feasible. Clinical improvements were possible even in the most severely affected individuals as evidenced by CST integrity. TRIAL REGISTRATION: This study was registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR) http://www.ANZCTR.org.au/ACTRN12614000952640.aspx . Registration date 4 September 2014, first participant date 9 September 2014.

Anticipatory planning reveals segmentation of cortical motor output during action observation.

It has been argued that the variation in brain activity that occurs when observing another person reflects a representation of actions that is indivisible, and which plays out in full once the intent of the actor can be discerned. We used transcranial magnetic stimulation to probe the excitability of corticospinal projections to 2 intrinsic hand muscles while motions to reach and grasp an object were observed. A symbolic cue either faithfully indicated the required final orientation of the object and thus the nature of the grasp that was required, or was in conflict with the movement subsequently displayed. When the cue was veridical, modulation of excitability was in accordance with the functional role of the muscles in the action observed. If however the cue had indicated that the alternative grasp would be required, modulation of output to first dorsal interosseus was consistent with the action specified, rather than the action observed--until the terminal phase of the motion sequence during which the object was seen lifted. Modulation of corticospinal output during observation is thus segmented--it progresses initially in accordance with the action anticipated, and if discrepancies are revealed by visual input, coincides thereafter with that of the action seen.

What Do TMS-Evoked Motor Potentials Tell Us About Motor Learning?

Thirty years ago, the first magnetic device capable of stimulating the human brain without discomfort through the intact skull was unveiled in Sheffield, England (Barker et al. in Lancet 1:1106-1107, 1985). Since that time, transcranial magnetic stimulation (TMS) has become the tool of choice for many scientists investigating human motor control and learning. In light of the fact that there are limits to the information that can be provided by any experimental technique, we first make the case that the necessarily restricted explanatory scope of the TMS technique-and the motor-evoked potentials to which it gives rise, is not yet reflected adequately in the research literature. We also argue that this inattention, coupled with the pervasive adoption of TMS as an investigative tool, may be restricting the elaboration of knowledge concerning the neural processes that mediate human motor learning. In order to make these points, we use as an exemplar the study of cross-education-the interlimb transfer of functional capacity.

Paired associative transcranial alternating current stimulation increases the excitability of corticospinal projections in humans.

Many types of non-invasive brain stimulation alter corticospinal excitability (CSE). Paired associative stimulation (PAS) has attracted particular attention as its effects ostensibly adhere to Hebbian principles of neural plasticity. In prototypical form, a single electrical stimulus is directed to a peripheral nerve in close temporal contiguity with transcranial magnetic stimulation delivered to the contralateral primary motor cortex (M1). Repeated pairing of the two discrete stimulus events (i.e. association) over an extended period either increases or decreases the excitability of corticospinal projections from M1, contingent on the interstimulus interval. We studied a novel form of associative stimulation, consisting of brief trains of peripheral afferent stimulation paired with short bursts of high frequency (≥80 Hz) transcranial alternating current stimulation (tACS) over contralateral M1. Elevations in the excitability of corticospinal projections to the forearm were observed for a range of tACS frequency (80, 140 and 250 Hz), current (1, 2 and 3 mA) and duration (500 and 1000 ms) parameters. The effects were at least as reliable as those brought about by PAS or transcranial direct current stimulation. When paired with tACS, muscle tendon vibration also induced elevations of CSE. No such changes were brought about by the tACS or peripheral afferent stimulation alone. In demonstrating that associative effects are expressed when the timing of the peripheral and cortical events is not precisely circumscribed, these findings suggest that multiple cellular pathways may contribute to a long term potentiation-type response. Their relative contributions will differ depending on the nature of the induction protocol that is used.

The effect of altering a single component of a rehabilitation programme on the functional recovery of stroke patients: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of altering a single component of a rehabilitation programme (e.g. adding bilateral practice alone) on functional recovery after stroke, defined using a measure of activity. DATA SOURCES: A search was conducted of Medline/Pubmed, CINAHL and Web of Science. REVIEW METHODS: Two reviewers independently assessed eligibility. Randomized controlled trials were included if all participants received the same base intervention, and the experimental group experienced alteration of a single component of the training programme. This could be manipulation of an intrinsic component of training (e.g. intensity) or the addition of a discretionary component (e.g. augmented feedback). One reviewer extracted the data and another independently checked a subsample (20%). Quality was appraised according to the PEDro scale. RESULTS: Thirty-six studies (n = 1724 participants) were included. These evaluated nine training components: mechanical degrees of freedom, intensity of practice, load, practice schedule, augmented feedback, bilateral movements, constraint of the unimpaired limb, mental practice and mirrored-visual feedback. Manipulation of the mechanical degrees of freedom of the trunk during reaching and the addition of mental practice during upper limb training were the only single components found to independently enhance recovery of function after stroke. CONCLUSION: This review provides limited evidence to support the supposition that altering a single component of a rehabilitation programme realises greater functional recovery for stroke survivors. Further investigations are required to determine the most effective single components of rehabilitation programmes, and the combinations that may enhance functional recovery.

Examining short interval intracortical inhibition with different transcranial magnetic stimulation-induced current directions in ALS.

Objective: To establish if induced current direction across the motor cortex alters the sensitivity of transcranial magnetic stimulation (TMS)-evoked short-interval intracortical inhibition (SICI) as an ALS biomarker. Methods: Threshold tracking-TMS was undertaken in 35 people with ALS and 39 controls. Using a coil orientation which induces posterior-anterior (PA)-directed current across the motor cortex, SICI (1 ms and 3 ms interstimulus intervals) and intracortical facilitation (ICF, 10 ms interstimulus interval) were recorded. SICI3ms was also recorded using a coil orientation which induces anterior-posterior (AP)-directed current across the motor cortex. Results: At group level, SICI3ms-PA (AUROC = 0.7), SICI3ms-AP (AUROC = 0.8) and SICI1ms (AUROC = 0.66) were substantially lower in those with ALS, although there was considerable interindividual heterogeneity. Averaging across interstimulus intervals (ISIs) marginally improved SICIPA sensitivity (AUROC = 0.76). Averaging SICI values across ISIs and orientations into a single SICI measure did not substantially improve sensitivity (AUROC = 0.81) compared to SICI3ms-AP alone. SICI3ms-AP and SICI3ms-PA did not significantly correlate (rho = 0.19, p = 0.313), while SICI1ms-PA and SICI3ms-PA did (rho = 0.37, p = 0.006). Further, those with ALS with the lowest SICI3ms-PA were not those with the lowest SICI3ms-AP. ICF was similar between groups (AUROC = 0.50). Conclusions: SICIPA and SICIAP are uncorrelated measures of motor cortical inhibitory functions which are useful as distinct, unequally affected, measures of disinhibition in ALS. Significance: Examining both SICIPA and SICIAP may facilitate more comprehensive characterisation of motor cortical disinhibition in ALS.

Consensus for experimental design in electromyography (CEDE) project: Checklist for reporting and critically appraising studies using EMG (CEDE-Check).

The diversity in electromyography (EMG) techniques and their reporting present significant challenges across multiple disciplines in research and clinical practice, where EMG is commonly used. To address these challenges and augment the reproducibility and interpretation of studies using EMG, the Consensus for Experimental Design in Electromyography (CEDE) project has developed a checklist (CEDE-Check) to assist researchers to thoroughly report their EMG methodologies. Development involved a multi-stage Delphi process with seventeen EMG experts from various disciplines. After two rounds, consensus was achieved. The final CEDE-Check consists of forty items that address four critical areas that demand precise reporting when EMG is employed: the task investigated, electrode placement, recording electrode characteristics, and acquisition and pre-processing of EMG signals. This checklist aims to guide researchers to accurately report and critically appraise EMG studies, thereby promoting a standardised critical evaluation, and greater scientific rigor in research that uses EMG signals. This approach not only aims to facilitate interpretation of study results and comparisons between studies, but it is also expected to contribute to advancing research quality and facilitate clinical and other practical applications of knowledge generated through the use of EMG.

Vision modulates corticospinal suppression in a functionally specific manner during movement of the opposite limb.

The effect of vision on the excitability of corticospinal projections to the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of right human forearm was investigated before and during discrete movement of the opposite limb. An external force opposed the initial phase of the movement (wrist flexion) and assisted the reverse phase, so that recruitment of the wrist extensors was minimized. Three conditions were used as follows: viewing the inactive right limb (Vision), viewing the mirror image of the moving left limb (Mirror), and with vision of the right limb occluded (No Vision). Transcranial magnetic stimulation was delivered to the left motor cortex: before, at the onset of, or during the left limb movement to obtain motor evoked potentials (MEPs) in the muscles of the right forearm. At and following movement onset, MEPs obtained in the right FCR were smaller in the Vision condition than in the Mirror and No Vision conditions. A distinct pattern of variation was obtained for the ECR. In all conditions, MEPs in this muscle were elevated upon or following movement of the opposite limb. An additional analysis of ipsilateral silent periods indicated that interhemispheric inhibition plays a role in mediating these effects. Activity-dependent changes in corticospinal output to a resting limb during discrete actions of the opposite limb are thus directly contingent upon where one looks. Furthermore, the extent to which vision exerts an influence upon projections to specific muscles varies in accordance with the functional contribution of their homologs to the intended action.

The efficacy of SMART Arm training early after stroke for stroke survivors with severe upper limb disability: a protocol for a randomised controlled trial.

BACKGROUND: Recovery of upper limb function after stroke is poor. The acute to subacute phase after stroke is the optimal time window to promote the recovery of upper limb function. The dose and content of training provided conventionally during this phase is however, unlikely to be adequate to drive functional recovery, especially in the presence of severe motor disability. The current study concerns an approach to address this shortcoming, through evaluation of the SMART Arm, a non-robotic device that enables intensive and repetitive practice of reaching by stroke survivors with severe upper limb disability, with the aim of improving upper limb function. The outcomes of SMART Arm training with or without outcome-triggered electrical stimulation (OT-stim) to augment movement and usual therapy will be compared to usual therapy alone. METHODS/DESIGN: A prospective, assessor-blinded parallel, three-group randomised controlled trial is being conducted. Seventy-five participants with a first-ever unilateral stroke less than 4 months previously, who present with severe arm disability (three or fewer out of a possible six points on the Motor Assessment Scale [MAS] Item 6), will be recruited from inpatient rehabilitation facilities. Participants will be randomly allocated to one of three dose-matched groups: SMART Arm training with OT-stim and usual therapy; SMART Arm training without OT-stim and usual therapy; or usual therapy alone. All participants will receive 20 hours of upper limb training over four weeks. Blinded assessors will conduct four assessments: pre intervention (0-weeks), post intervention (4-weeks), 26 weeks and 52 weeks follow-up. The primary outcome measure is MAS item 6. All analyses will be based on an intention-to-treat principle. DISCUSSION: By enabling intensive and repetitive practice of a functional upper limb task during inpatient rehabilitation, SMART Arm training with or without OT-stim in combination with usual therapy, has the potential to improve recovery of upper limb function in those with severe motor disability. The immediate and long-term effects of SMART Arm training on upper limb impairment, activity and participation will be explored, in addition to the benefit of training with or without OT-stim to augment movement when compared to usual therapy alone. TRIAL REGISTRATION: ACTRN12608000457347.