Electric Field Navigated 1-Hz rTMS for Poststroke Motor Recovery: The E-FIT Randomized Controlled Trial.

BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training-related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil. METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical trial). The sham coil appearance mimicked the active coil but without the weak electric field in the NICHE trial sham coil. Outcomes measured 1 week, and 1, 3, and 6 months after the end of treatment included the following: upper extremity Fugl-Meyer (primary, 6 months after end of treatment), Action Research Arm Test, National Institutes of Health Stroke Scale, quality of life (EQ-5D), and safety. RESULTS: Of 60 participants randomized, 58 completed treatment and were included for analysis. Bayesian analysis of combined data from the E-FIT and the NICHE trials indicated that active treatment was not superior to sham at the primary end point (posterior mean odds ratio of 1.94 [96% credible interval of 0.61-4.80]). For the E-FIT intent-to-treat population, upper extremity Fugl-Meyer improvement ≥5 pts occurred in 60% (18/30) active group and 50% (14/28) sham group. Participants enrolled 3 to 6 months following stroke had a 67% (31%-91% CI) response rate in the active group at the 6-month end point versus 50% in the sham group (21.5%-78.5% CI). There were significant improvements from baseline to 6 months for both active and sham groups in upper extremity Fugl-Meyer, Action Research Arm Test, and EQ-5D (P<0.05). Improvement in National Institutes of Health Stroke Scale was observed only in the active group (P=0.004). Ten serious unrelated adverse events occurred (4 active group, 6 sham group, P=0.72). CONCLUSIONS: Intensive motor rehabilitation 3 to 12 months after stroke improved clinical impairment, function, and quality of life; however, 1 Hz-repetitive transcranial magnetic stimulation was not an effective treatment adjuvant in the present sample population with mixed lesion location and extent. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03010462.

Walking improvement in chronic incomplete spinal cord injury with exoskeleton robotic training (WISE): a randomized controlled trial.

STUDY DESIGN: Clinical trial. OBJECTIVE: To demonstrate that a 12-week exoskeleton-based robotic gait training regimen can lead to a clinically meaningful improvement in independent gait speed, in community-dwelling participants with chronic incomplete spinal cord injury (iSCI). SETTING: Outpatient rehabilitation or research institute. METHODS: Multi-site (United States), randomized, controlled trial, comparing exoskeleton gait training (12 weeks, 36 sessions) with standard gait training or no gait training (2:2:1 randomization) in chronic iSCI (>1 year post injury, AIS-C, and D), with residual stepping ability. The primary outcome measure was change in robot-independent gait speed (10-meter walk test, 10MWT) post 12-week intervention. Secondary outcomes included: Timed-Up-and-Go (TUG), 6-min walk test (6MWT), Walking Index for Spinal Cord Injury (WISCI-II) (assistance and devices), and treating therapist NASA-Task Load Index. RESULTS: Twenty-five participants completed the assessments and training as assigned (9 Ekso, 10 Active Control, 6 Passive Control). Mean change in gait speed at the primary endpoint was not statistically significant. The proportion of participants with improvement in clinical ambulation category from home to community speed post-intervention was greatest in the Ekso group (>1/2 Ekso, 1/3 Active Control, 0 Passive Control, p < 0.05). Improvements in secondary outcome measures were not significant. CONCLUSIONS: Twelve weeks of exoskeleton robotic training in chronic SCI participants with independent stepping ability at baseline can improve clinical ambulatory status. Improvements in raw gait speed were not statistically significant at the group level, which may guide future trials for participant inclusion criteria. While generally safe and tolerable, larger gains in ambulation might be associated with higher risk for non-serious adverse events.

Intensity dependent effects of transcranial direct current stimulation on corticospinal excitability in chronic spinal cord injury.

OBJECTIVE: To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) intensity on corticospinal excitability and affected muscle activation in individuals with chronic spinal cord injury (SCI). DESIGN: Single-blind, randomized, sham-controlled, crossover study. SETTING: Medical research institute and rehabilitation hospital. PARTICIPANTS: Volunteers (N = 9) with chronic SCI and motor dysfunction in wrist extensor muscles. INTERVENTIONS: Three single session exposures to 20 minutes of a-tDCS (anode over the extensor carpi radialis [ECR] muscle representation on the left primary motor cortex, cathode over the right supraorbital area) using 1 mA, 2 mA, or sham stimulation, delivered at rest, with at least 1 week between sessions. MAIN OUTCOME MEASURES: Corticospinal excitability was assessed with motor-evoked potentials (MEPs) from the ECR muscle using surface electromyography after transcranial magnetic stimulation. Changes in spinal excitability, sensory threshold, and muscle strength were also investigated. RESULTS: Mean MEP amplitude significantly increased by approximately 40% immediately after 2mA a-tDCS (pre: 0.36 ± 0.1 mV; post: 0.47 ± 0.11 mV; P = .001), but not with 1 mA or sham. Maximal voluntary contraction measures remained unaltered across all conditions. Sensory threshold significantly decreased over time after 1mA (P = .002) and 2mA (P = .039) a-tDCS and did not change with sham. F-wave persistence showed a nonsignificant trend for increase (pre: 32% ± 12%; post: 41% ± 10%; follow-up: 46% ± 12%) after 2 mA stimulation. No adverse effects were reported with any of the experimental conditions. CONCLUSIONS: The a-tDCS can transiently raise corticospinal excitability to affected muscles in patients with chronic SCI after 2 mA stimulation. Sensory perception can improve with both 1 and 2 mA stimulation. This study gives support to the safe and effective use of a-tDCS using small electrodes in patients with SCI and highlights the importance of stimulation intensity.

Movement-generated afference paired with transcranial magnetic stimulation: an associative stimulation paradigm.

BACKGROUND: A peripheral nerve stimulus can enhance or suppress the evoked response to transcranial magnetic stimulation (TMS) depending on the latency of the preceding peripheral nerve stimulation (PNS) pulse. Similarly, somatosensory afference from the passively moving limb can transiently alter corticomotor excitability, in a phase-dependent manner. The repeated association of PNS with TMS is known to modulate corticomotor excitability; however, it is unknown whether repeated passive-movement associative stimulation (MAS) has similar effects. METHODS: In a proof-of-principal study, using a cross-over design, seven healthy subjects received in separate sessions: (1) TMS (120% of the resting motor threshold-RMT, optimal site for Flexor Carpi Radialis) with muscle at rest; (2) TMS paired with cyclic passive movement during extension cyclic passive movement (400 pairs, 1 Hz), with the intervention order randomly assigned. Normality was tested using the Kolmogorov-Smirnov test, then compared to pre-intervention baseline using repeated measures ANOVA with a Dunnet multiple comparisons test. RESULTS: MAS led to a progressive and significant decrease in the motor evoked potential (MEP) amplitude over the intervention (R(2) = 0.6665, P < 0.0001), which was not evident with TMS alone (R(2) = 0.0068, P = 0.641). Post-intervention excitability reduction, only present with MAS intervention, remained for 20 min (0-10 min = 68.2 ± 4.9%, P < 0.05; 10-20 min = 73.3 ± 9.7%, P < 0.05). CONCLUSION: The association of somatosensory afference from the moving limb with TMS over primary motor cortex in healthy subjects can be used to modulate corticomotor excitability, and may have therapeutic implications.

Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration.

Facilitating axon regeneration in the injured central nervous system remains a challenging task. RAF-MAP2K signaling plays a key role in axon elongation during nervous system development. Here, we show that conditional expression of a constitutively kinase-activated BRAF in mature corticospinal neurons elicited the expression of a set of transcription factors previously implicated in the regeneration of zebrafish retinal ganglion cell axons and promoted regeneration and sprouting of corticospinal tract (CST) axons after spinal cord injury in mice. Newly sprouting axon collaterals formed synaptic connections with spinal interneurons, resulting in improved recovery of motor function. Noninvasive suprathreshold high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) activated the BRAF canonical downstream effectors MAP2K1/2 and modulated the expression of a set of regeneration-related transcription factors in a pattern consistent with that induced by BRAF activation. HF-rTMS enabled CST axon regeneration and sprouting, which was abolished in MAP2K1/2 conditional null mice. These data collectively demonstrate a central role of MAP2K signaling in augmenting the growth capacity of mature corticospinal neurons and suggest that HF-rTMS might have potential for treating spinal cord injury by modulating MAP2K signaling.

Gait training in human spinal cord injury using electromechanical systems: effect of device type and patient characteristics.

OBJECTIVE: To report the clinical improvements in spinal cord injury (SCI) patients associated with intensive gait training using electromechanical systems according to patient characteristics. DESIGN: Prospective longitudinal study. SETTING: Inpatient SCI rehabilitation center. PARTICIPANTS: Adults with SCI (n=130). INTERVENTION: Patients received locomotor training with 2 different electromechanical devices, 5 days per week for 8 weeks. MAIN OUTCOME MEASURES: Lower-extremity motor score, Walking Index for Spinal Cord Injury, and 10-meter walking test data were collected at the baseline, midpoint, and end of the program. Patients were stratified according to the American Spinal Injury Association (ASIA) category, time since injury, and injury etiology. A subgroup of traumatic ASIA grade C and D patients were compared with data obtained from the European Multicenter Study about Human Spinal Cord Injury (EM-SCI). RESULTS: One hundred and five patients completed the program. Significant gains in lower-limb motor function and gait were observed for both types of electromechanical device systems, to a similar degree. The greatest rate of improvement was shown in the motor incomplete SCI patients, and for patients <6 months postinjury. The positive response associated with training was not affected by injury etiology, age, sex, or lesion level. The trajectory of improvement was significantly enhanced relative to patients receiving the conventional standard of care without electromechanical systems (EM-SCI). CONCLUSIONS: The use of electromechanical systems for intensive gait training in SCI is associated with a marked improvement in lower-limb motor function and gait across a diverse range of patients and is most evident in motor incomplete patients, and for patients who begin the regimen early in the recovery process.

An observational report of intensive robotic and manual gait training in sub-acute stroke.

BACKGROUND: The use of automated electromechanical devices for gait training in neurological patients is increasing, yet the functional outcomes of well-defined training programs using these devices and the characteristics of patients that would most benefit are seldom reported in the literature. In an observational study of functional outcomes, we aimed to provide a benchmark for expected change in gait function in early stroke patients, from an intensive inpatient rehabilitation program including both robotic and manual gait training. METHODS: We followed 103 sub-acute stroke patients who met the clinical inclusion criteria for Body Weight Supported Robotic Gait Training (BWSRGT). Patients completed an intensive 8-week gait-training program comprising robotic gait training (weeks 0-4) followed by manual gait training (weeks 4-8). A change in clinical function was determined by the following assessments taken at 0, 4 and 8 weeks (baseline, mid-point and end-point respectively): Functional Ambulatory Categories (FAC), 10 m Walking Test (10 MWT), and Tinetti Gait and Balance Scales. RESULTS: Over half of the patients made a clinically meaningful improvement on the Tinetti Gait Scale (> 3 points) and Tinetti Balance Scale (> 5 points), while over 80% of the patients increased at least 1 point on the FAC scale (0-5) and improved walking speed by more than 0.2 m/s. Patients responded positively in gait function regardless of variables gender, age, aetiology (hemorrhagic/ischemic), and affected hemisphere. The most robust and significant change was observed for patients in the FAC categories two and three. The therapy was well tolerated and no patients withdrew for factors related to the type or intensity of training. CONCLUSIONS: Eight-weeks of intensive rehabilitation including robotic and manual gait training was well tolerated by early stroke patients, and was associated with significant gains in function. Patients with mid-level gait dysfunction showed the most robust improvement following robotic training.

Transcranial magnetic stimulation as an investigative tool for motor dysfunction and recovery in stroke: an overview for neurorehabilitation clinicians.

RATIONALE: An improved understanding of motor dysfunction and recovery after stroke has important clinical implications that may lead to the design of more effective rehabilitation strategies for patients with hemiparesis. SCOPE: Transcranial magnetic stimulation (TMS) is a safe and painless tool that has been used in conjunction with other existing diagnostic tools to investigate motor pathophysiology in stroke patients. Since TMS emerged more than two decades ago, its application in clinical and basic neuroscience has expanded worldwide. TMS can quantify the corticomotor excitability properties of clinically affected and unaffected muscles and can probe local cortical networks as well as remote but functionally related areas. This provides novel insight into the physiology of neural circuits underlying motor dysfunction and brain reorganization during the motor recovery process. This important tool needs to be used with caution by clinical investigators, its limitations need to be understood, and the results should to be interpreted along with clinical evaluation in this patient population. SUMMARY: In this review, we provide an overview of the rationale, implementation, and limitations of TMS to study stroke motor physiology. This knowledge may be useful to guide future rehabilitation treatments by assessing and promoting functional plasticity.

Middle cerebral artery blood flow stability in response to high-definition transcranial electrical stimulation: A randomized sham-controlled clinical trial.

Since neuronal activity is coupled with neurovascular activity, we aimed to analyze the cerebral blood flow hemodynamics during and following high-definition transcranial direct current stimulation (HD-tDCS). We assessed the mean middle cerebral artery blood flow velocity (MCA-BFv) bilaterally using transcranial doppler ultrasound, during and after HD-tDCS, in eleven right-handed healthy adult participants (6 women, 5 men; mean age 31 ± 5.6 years old), with no evidence of brain or cardiovascular dysfunction. The HD-tDCS electrode montage was centered over the right temporo-parietal junction. The stimulation protocol comprised 3 blocks of 2 min at each current intensity (1, 2, and 3 mA) and an inter-stimulus interval of 5 min between blocks. Participants received three electrical stimulation conditions (anode center, cathode center, and sham) on three different days, with an interval of at least 24 h. Stimulation was well tolerated across HD-tDCS conditions tested, and the volunteers reported no significant discomfort related to stimulation. There was no significant difference in the right or the left MCA-BFv during or after the stimulation protocol across all stimulation conditions. We conclude that at a range of intensities, vascular reaction assessed using middle cerebral artery blood flow is not significantly altered during or after HD-tDCS both locally and remotely, which provides further evidence for the safety of HD-tDCS.

Dataset of middle cerebral artery blood flow stability in response to high-definition transcranial electrical stimulation.

This supplementary dataset is supportive of the randomized sham-controlled, double-blind, crossover clinical trial investigating polarity- and intensity-dependent effects of high-definition transcranial electrical stimulation (HD-tDCS) applied over the right temporo-parietal junction on mean middle cerebral artery blood flow velocity (MCA-BFv) bilaterally. Data of eleven healthy right-handed adults (6 women, 5 men; mean age 31 ± 5.6 years old) were analyzed for MCA-BFv, assessed using transcranial doppler ultrasound on the stimulated and the contralateral hemisphere concomitantly, during and after 3 blocks of 2 min HD-tDCS at 1, 2, and 3 mA. Participants received three electrical stimulation conditions (anode center, cathode center, and sham) randomly ordered across different days. The collected data is publicly available at Mendeley Data. This article and the data will inform future related investigations and safety analysis of transcranial non-invasive brain stimulation.

Reversal of TMS-induced motor twitch by training is associated with a reduction in excitability of the antagonist muscle.

BACKGROUND: A single session of isolated repetitive movements of the thumb can alter the response to transcranial magnetic stimulation (TMS), such that the related muscle twitch measured post-training occurs in the trained direction. This response is attributed to transient excitability changes in primary motor cortex (M1) that form the early part of learning. We investigated; (1) whether this phenomenon might occur for movements at the wrist, and (2) how specific TMS activation patterns of opposing muscles underlie the practice-induced change in direction. METHODS: We used single-pulse suprathreshold TMS over the M1 forearm area, to evoke wrist movements in 20 healthy subjects. We measured the preferential direction of the TMS-induced twitch in both the sagittal and coronal plane using an optical goniometer fixed to the dorsum of the wrist, and recorded electromyographic (EMG) activity from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. Subjects performed gentle voluntary movements, in the direction opposite to the initial twitch for 5 minutes at 0.2 Hz. We collected motor evoked potentials (MEPs) elicited by TMS at baseline and for 10 minutes after training. RESULTS: Repetitive motor training was sufficient for TMS to evoke movements in the practiced direction opposite to the original twitch. For most subjects the effect of the newly-acquired direction was retained for at least 10 minutes before reverting to the original. Importantly, the direction change of the movement was associated with a significant decrease in MEP amplitude of the antagonist to the trained muscle, rather than an increase in MEP amplitude of the trained muscle. CONCLUSIONS: These results demonstrate for the first time that a TMS-twitch direction change following a simple practice paradigm may result from reduced corticospinal drive to muscles antagonizing the trained direction. Such findings may have implications for training paradigms in neurorehabilitation.

Robotic Kinematic measures of the arm in chronic Stroke: part 1 - Motor Recovery patterns from tDCS preceding intensive training.

BACKGROUND: Effectiveness of robotic therapy and transcranial direct current stimulation is conventionally assessed with clinical measures. Robotic metrics may be more objective and sensitive for measuring the efficacy of interventions on stroke survivor's motor recovery. This study investigated if robotic metrics detect a difference in outcomes, not seen in clinical measures, in a study of transcranial direct current stimulation (tDCS) preceding robotic therapy. Impact of impairment severity on intervention response was also analyzed to explore optimization of outcomes by targeting patient sub-groups. METHODS: This 2020 study analyzed data from a double-blind, sham-controlled, randomized multi-center trial conducted from 2012 to 2016, including a six-month follow-up. 82 volunteers with single chronic ischemic stroke and right hemiparesis received anodal tDCS or sham stimulation, prior to robotic therapy. Robotic therapy involved 1024 repetitions, alternating shoulder-elbow and wrist robots, for a total of 36 sessions. Shoulder-elbow and wrist kinematic and kinetic metrics were collected at admission, discharge, and follow-up. RESULTS: No difference was detected between the tDCS or sham stimulation groups in the analysis of robotic shoulder-elbow or wrist metrics. Significant improvements in all metrics were found for the combined group analysis. Novel wrist data showed smoothness significantly improved (P < ·001) while submovement number trended down, overlap increased, and interpeak interval decreased. Post-hoc analysis showed only patients with severe impairment demonstrated a significant difference in kinematics, greater for patients receiving sham stimulation. CONCLUSIONS: Robotic data confirmed results of clinical measures, showing intensive robotic therapy is beneficial, but no additional gain from tDCS. Patients with severe impairment did not benefit from the combined intervention. Wrist submovement characteristics showed a delayed pattern of motor recovery compared to the shoulder-elbow, relevant to intensive intervention-related recovery of upper extremity function in chronic stroke. TRIAL REGISTRATION: http://www.clinicaltrials.gov . Actual study start date September 2012. First registered on 15 November 2012. Retrospectively registered. Unique identifiers: NCT01726673 and NCT03562663 .

Robotic Kinematic measures of the arm in chronic Stroke: part 2 - strong correlation with clinical outcome measures.

BACKGROUND: A detailed sensorimotor evaluation is essential in planning effective, individualized therapy post-stroke. Robotic kinematic assay may offer better accuracy and resolution to understand stroke recovery. Here we investigate the added value of distal wrist measurement to a proximal robotic kinematic assay to improve its correlation with clinical upper extremity measures in chronic stroke. Secondly, we compare linear and nonlinear regression models. METHODS: Data was sourced from a multicenter randomized controlled trial conducted from 2012 to 2016, investigating the combined effect of robotic therapy and transcranial direct current stimulation (tDCS). 24 kinematic metrics were derived from 4 shoulder-elbow tasks and 35 metrics from 3 wrist and forearm evaluation tasks. A correlation-based feature selection was performed, keeping only features substantially correlated with the target attribute (R > 0.5.) Nonlinear models took the form of a multilayer perceptron neural network: one hidden layer and one linear output. RESULTS: Shoulder-elbow metrics showed a significant correlation with the Fugl Meyer Assessment (upper extremity, FMA-UE), with a R = 0.82 (P < 0.001) for the linear model and R = 0.88 (P < 0.001) for the nonlinear model. Similarly, a high correlation was found for wrist kinematics and the FMA-UE (R = 0.91 (P < 0.001) and R = 0.92 (P < 0.001) for the linear and nonlinear model respectively). The combined analysis produced a correlation of R = 0.91 (P < 0.001) for the linear model and R = 0.91 (P < 0.001) for the nonlinear model. CONCLUSIONS: Distal wrist kinematics were highly correlated to clinical outcomes, warranting future investigation to explore our nonlinear wrist model with acute or subacute stroke populations. TRIAL REGISTRATION: http://www.clinicaltrials.gov . Actual study start date September 2012. First registered on 15 November 2012. Retrospectively registered. Unique identifiers: NCT01726673 and NCT03562663 .

BrainWave Nets: Are Sparse Dynamic Models Susceptible to Brain Manipulation Experimentation?

Sparse time series models have shown promise in estimating contemporaneous and ongoing brain connectivity. This paper was motivated by a neuroscience experiment using EEG signals as the outcome of our established interventional protocol, a new method in neurorehabilitation toward developing a treatment for visual verticality disorder in post-stroke patients. To analyze the [complex outcome measure (EEG)] that reflects neural-network functioning and processing in more specific ways regarding traditional analyses, we make a comparison among sparse time series models (classic VAR, GLASSO, TSCGM, and TSCGM-modified with non-linear and iterative optimizations) combined with a graphical approach, such as a Dynamic Chain Graph Model (DCGM). These dynamic graphical models were useful in assessing the role of estimating the brain network structure and describing its causal relationship. In addition, the class of DCGM was able to visualize and compare experimental conditions and brain frequency domains [using finite impulse response (FIR) filter]. Moreover, using multilayer networks, the results corroborate with the susceptibility of sparse dynamic models, bypassing the false positives problem in estimation algorithms. We conclude that applying sparse dynamic models to EEG data may be useful for describing intervention-relocated changes in brain connectivity.

Dose and staffing comparison study of upper limb device-assisted therapy.

BACKGROUND: Neurological injuries cause persistent upper extremity motor deficits. Device-assisted therapy is an emerging trend in neuro-rehabilitation as it offers high intensity, repetitive practice in a standardized setting. OBJECTIVE: To investigate the effects of therapy duration and staff-participant configuration on device-assisted upper limb therapy outcomes in individuals with chronic paresis. METHODS: Forty-seven participants with chronic upper extremity weakness due to neurological injury were assigned to a therapy duration (30 or 60 min) and a staff-participant configuration (1-to-1 or 1-to-2). Therapy consisted of 3 sessions a week for 6 weeks using the Armeo®Spring device. Clinical assessments were performed at three timepoints (Pre, Post, and 3 month Follow up). RESULTS: Improvements in upper limb impairment, measured by change in Fugl-Meyer score (FM), were observed following therapy in all groups. FM improvement was comparable between 30 and 60 min sessions, but participants in the 1-to-2 group had significantly greater improvement in FM from Pre-to-Post and from Pre-to-Follow up than the 1-to-1 group. CONCLUSIONS: Device-assisted therapy can reduce upper limb impairment to a similar degree whether participants received 30 or 60 min per session. Our results suggest that delivering therapy in a 1-to-2 configuration is a feasible and more effective approach than traditional 1-to-1 staffing.

On the understanding and development of modern physical neurorehabilitation methods: robotics and non-invasive brain stimulation.

The incidence of physical disability in the community resulting from neurological dysfunction is predicted to increase in the coming years. The impetus for immediate and critical evaluation of physical neurorehabilitation strategies stems from the largely incomplete recovery following neurological damage, questionable efficacy of individual rehabilitation techniques, and the progressive acceptance of evidence-based medicine. The emergent technologies of non-invasive brain stimulation (NBS) and rehabilitation robotics enable a better understanding of the recovery process, as well as the mechanisms and effectiveness of intervention. With a more precise grasp of the relationship between dysfunctional and treatment-related plasticity, we can anticipate a move toward highly controlled and individualised prescription of rehabilitation. Both robotics and NBS can also be used to enhance motor control and learning in patients with neurological dysfunction. The merit of these contemporary methods as investigative and rehabilitation tools requires clarification and discussion. In this thematic series, five cohesive and eloquent papers address this issue from leading clinicians and scientists in the fields of robotics, NBS, plasticity and motor learning.

Using tDCS to facilitate motor learning in speech production: The role of timing.

There exists debate regarding the extent to which transcranial direct current stimulation (tDCS) can affect or enhance human behavior. Here, we examined a previously unexplored domain: speech motor learning. We investigated whether speech motor learning in unimpaired participants can be enhanced using a single-session tDCS experiment, and investigated whether the timing of tDCS relative to a behavioral task affected performance. Participants (N = 80) performed a twenty minute learning task with nonwords containing non-native consonant clusters (e.g., GDEEVOO), and were assigned to groups receiving either sham or active tDCS either immediately before or during the task. Both accuracy and properties of errors were examined throughout the course of the practice task, and then practice was compared to a retention period 30 min later (R1) and two days later (R2). For cluster and whole-(non)word accuracy measures, acquisition was observed for all groups during the practice session. Compared to the beginning of practice, the tDCS-Before group showed significantly greater improvement than both the sham group and the tDCS-During group at R1. An effect was also observed for vowel duration in errors (/gdivu/ â†’ [gədivu]), with the tDCS-Before group showing significant shortening of vowel errors throughout practice. Overall, the findings suggest that tDCS can improve speech motor learning, and that the improvement may be greater when tDCS is applied immediately before practice, warranting further exploration of this new domain for tDCS research.

Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke.

BACKGROUND AND PURPOSE: The potential for adaptive plasticity in the post-stroke brain is difficult to estimate, as is the demonstration of central nervous system (CNS) target engagement of drugs that show promise in facilitating stroke recovery. We set out to determine if paired associative stimulation (PAS) can be used (a) as an assay of CNS plasticity in patients with chronic stroke, and (b) to demonstrate CNS engagement by memantine, a drug which has potential plasticity-modulating effects for use in motor recovery following stroke. METHODS: We examined the effect of PAS in fourteen participants with chronic hemiparetic stroke at five time-points in a within-subjects repeated measures design study: baseline off-drug, and following a week of orally administered memantine at doses of 5, 10, 15, and 20 mg, comprising a total of seventy sessions. Each week, MEP amplitude pre and post-PAS was assessed in the contralesional hemisphere as a marker of enhanced or diminished plasticity. Strength and dexterity were recorded each week to monitor motor-specific clinical status across the study period. RESULTS: We found that MEP amplitude was significantly larger after PAS in baseline sessions off-drug, and responsiveness to PAS in these sessions was associated with increased clinical severity. There was no observed increase in MEP amplitude after PAS with memantine at any dose. Motor threshold (MT), strength, and dexterity remained unchanged during the study. CONCLUSION: Paired associative stimulation successfully induced corticospinal excitability enhancement in chronic stroke subjects at the group level. However, this response did not occur in all participants, and was associated with increased clinical severity. This could be an important way to stratify patients for future PAS-drug studies. PAS was suppressed by memantine at all doses, regardless of responsiveness to PAS off-drug, indicating CNS engagement.

Entropy Analysis of High-Definition Transcranial Electric Stimulation Effects on EEG Dynamics.

A foundation of medical research is time series analysis-the behavior of variables of interest with respect to time. Time series data are often analyzed using the mean, with statistical tests applied to mean differences, and has the assumption that data are stationary. Although widely practiced, this method has limitations. Here we present an alternative statistical approach with sample analysis that provides a summary statistic accounting for the non-stationary nature of time series data. This work discusses the use of entropy as a measurement of the complexity of time series, in the context of Neuroscience, due to the non-stationary characteristic of the data. To elucidate our argument, we conducted entropy analysis on a sample of electroencephalographic (EEG) data from an interventional study using non-invasive electrical brain stimulation. We demonstrated that entropy analysis could identify intervention-related change in EEG data, supporting that entropy can be a useful "summary" statistic in non-linear dynamical systems.