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.

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.

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.

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.

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.

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.

Fractional Anisotropy of Thalamic Nuclei Is Associated With Verticality Misperception After Extra-Thalamic Stroke.

Verticality misperception after stroke is a frequent neurological deficit that leads to postural imbalance and a higher risk of falls. The posterior thalamic nuclei are described to be involved with verticality perception, but it is unknown if extra-thalamic lesions can have the same effect via diaschisis and degeneration of thalamic nuclei. We investigated the relationship between thalamic fractional anisotropy (FA, a proxy of structural integrity), and verticality perception, in patients after stroke with diverse encephalic extra-thalamic lesions. We included 11 first time post-stroke patients with extra-thalamic primary lesions, and compared their region-based FA to a group of 25 age-matched healthy controls. For the patient sample, correlation and regression analyses evaluated the relationship between thalamic nuclei FA and error of postural vertical (PV) and haptic vertical (HV) in the roll (PVroll/HVroll) and pitch planes (PVpitch/HVpitch). Relative to controls, patients showed decreased FA of anterior, ventral anterior, ventral posterior lateral, dorsal, and pulvinar thalamic nuclei, despite the primary lesions being extra-thalamic. We found a significant correlation between HVroll, and FA in the anterior and dorsal nuclei, and PVroll with FA in the anterior nucleus. FA in the anterior, ventral anterior, ventral posterior lateral, dorsal and pulvinar nuclei predicted PV, and FA in the ventral anterior, ventral posterior lateral and dorsal nuclei predicted HV. While prior studies indicate that primary lesions of the thalamus can result in verticality misperception, here we present evidence supporting that secondary degeneration of thalamic nuclei via diaschisis can also be associated with verticality misperception after stroke.

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.

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.

NeuroMeasure: A Software Package for Quantification of Cortical Motor Maps Using Frameless Stereotaxic Transcranial Magnetic Stimulation.

The recent enhanced sophistication of non-invasive mapping of the human motor cortex using MRI-guided Transcranial Magnetic Stimulation (TMS) techniques, has not been matched by refinement of methods for generating maps from motor evoked potential (MEP) data, or in quantifying map features. This is despite continued interest in understanding cortical reorganization for natural adaptive processes such as skill learning, or in the case of motor recovery, such as after lesion affecting the corticospinal system. With the observation that TMS-MEP map calculation and quantification methods vary, and that no readily available commercial or free software exists, we sought to establish and make freely available a comprehensive software package that advances existing methods, and could be helpful to scientists and clinician-researchers. Therefore, we developed NeuroMeasure, an open source interactive software application for the analysis of TMS motor cortex mapping data collected from Nexstim® and BrainSight®, two commonly used neuronavigation platforms. NeuroMeasure features four key innovations designed to improve motor mapping analysis: de-dimensionalization of the mapping data, fitting a predictive model, reporting measurements to characterize the motor map, and comparing those measurements between datasets. This software provides a powerful and easy to use workflow for characterizing and comparing motor maps generated with neuronavigated TMS. The software can be downloaded on our github page: https://github.com/EdwardsLabNeuroSci/NeuroMeasure. AIM: This paper aims to describe a software platform for quantifying and comparing maps of the human primary motor cortex, using neuronavigated transcranial magnetic stimulation, for the purpose of studying brain plasticity in health and disease.

Clinical improvement with intensive robot-assisted arm training in chronic stroke is unchanged by supplementary tDCS.

BACKGROUND: Intensive robot-assisted arm training in the chronic phase of stroke recovery can lead to clinical improvement. Combinatorial therapeutic approaches are sought to further optimize stroke recovery. Transcranial direct current stimulation (tDCS) is one candidate to combine with robotic training, as transient increases in excitability and improvements in motor behavior have separately been reported. OBJECTIVE: To determine whether tDCS, delivered prior to robotic training, could augment clinical improvement. METHODS: We conducted a dual-site, randomized controlled trial in 82 chronic ischemic stroke patients (inclusion > 6 m post-injury, dominant hemisphere, first stroke; residual hemiparesis) who were split into two groups to receive tDCS (M1-SO montage, anode ipsilesional, 5×7 cm electrodes, 2 mA, 20 mins) or sham tDCS, prior to robotic upper-limb training (12 weeks; 36 sessions; shoulder-elbow robot or wrist robot on alternating sessions). The primary end-point was taken after 12 weeks of training, and assessed with the Upper Extremity Fugl-Meyer impairment scale (FM). Corticomotor conduction was assessed with transcranial magnetic stimulation (TMS). RESULTS: For the combined group (n = 82; post-training) robotic training increased the FM by 7.36 points compared to baseline (p < 0.0001). There was no difference in the FM increase between the tDCS and sham groups (6.97 and 7.73 respectively, p = 0.46). In both groups, clinically meaningful improvement (≥5 points) from baseline was evident in the majority of patients (56/77), was sustained six months later (54/72), and could be attained in severe, moderate and mild baseline hemiparesis. Clinical improvement was associated with increased excitability in the affected hemisphere as assessed by resting motor threshold (pre-post p = 0.029; pre-post 6 months p = 0.029), but not with threshold-adjusted assessment of MEP amplitude (pre-post p = 0.09; pre-post 6 months p = 0.15). Participants with motor evoked potentials were more likely to improve clinically than those without (17/18, 94%, versus 39/59, 66%, p = 0.018). CONCLUSIONS: Our study confirms the benefit of intensive robot-assisted training in stroke recovery, and indicates that conventional tDCS does not confer further advantage to robotic training. We also showed that corticospinal integrity, as assessed by TMS, is a predictor of clinically meaningful response to intensive arm therapy in chronic stroke.

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.

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS).

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS.

Manipulation of Human Verticality Using High-Definition Transcranial Direct Current Stimulation.

Background: Using conventional tDCS over the temporo-parietal junction (TPJ) we previously reported that it is possible to manipulate subjective visual vertical (SVV) and postural control. We also demonstrated that high-definition tDCS (HD-tDCS) can achieve substantially greater cortical stimulation focality than conventional tDCS. However, it is critical to establish dose-response effects using well-defined protocols with relevance to clinically meaningful applications. Objective: To conduct three pilot studies investigating polarity and intensity-dependent effects of HD-tDCS over the right TPJ on behavioral and physiological outcome measures in healthy subjects. We additionally aimed to establish the feasibility, safety, and tolerability of this stimulation protocol. Methods: We designed three separate randomized, double-blind, crossover phase I clinical trials in different cohorts of healthy adults using the same stimulation protocol. The primary outcome measure for trial 1 was SVV; trial 2, weight-bearing asymmetry (WBA); and trial 3, electroencephalography power spectral density (EEG-PSD). The HD-tDCS montage comprised a single central, and 3 surround electrodes (HD-tDCS3x1) over the right TPJ. For each study, we tested 3x2 min HD-tDCS3x1 at 1, 2 and 3 mA; with anode center, cathode center, or sham stimulation, in random order across days. Results: We found significant SVV deviation relative to baseline, specific to the cathode center condition, with consistent direction and increasing with stimulation intensity. We further showed significant WBA with direction governed by stimulation polarity (cathode center, left asymmetry; anode center, right asymmetry). EEG-PSD in the gamma band was significantly increased at 3 mA under the cathode. Conclusions: The present series of studies provide converging evidence for focal neuromodulation that can modify physiology and have behavioral consequences with clinical potential.

Normative data for human postural vertical: A systematic review and meta-analysis.

Perception of verticality is required for normal daily function, yet the typical human detection error range has not been well characterized. Vertical misperception has been correlated with poor postural control and functionality in patients after stroke and after vestibular disorders. Until now, all the published studies that assessed Subjective Postural Vertical (SPV) in the seated position used small groups to establish a reference value. However, this sample size does not represent the healthy population for comparison with conditions resulting in pathological vertical. Therefore, the primary objective was to conduct a systematic review with meta-analyses of Subjective Postural Vertical (SPV) data in seated position in healthy adults to establish the reference value with a representative sample. The secondary objective was to investigate the methodological characteristics of different assessment protocols of SPV described in the literature. A systematic literature search was conducted using Medline, EMBASE, and Cochrane libraries. Mean and standard deviation of SPV in frontal and sagittal planes were considered as effect size measures. Sixteen of 129 identified studies met eligibility criteria for our systematic review (n = 337 subjects in the frontal plane; n = 187 subjects in sagittal plane). The meta-analyses measure was estimated using the pooled mean as the estimator and its respective error. Mean reference values were 0.12°±1.49° for the frontal plane and 0.02°±1.82° for the sagittal plane. There was a small variability of the results and this systematic review resulted in representative values for SPV. The critical analysis of the studies and observed homogeneity in the sample suggests that the methodological differences used in the studies did not influence SPV assessment of directional bias in healthy subjects. These data can serve as a reference for clinical studies in disorders of verticality.