Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past ten years, tDCS physiological mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodological, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (i) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (ii) methodological aspects related to the clinical research of tDCS as divided according to study phase (i.e., preclinical, phase I, phase II and phase III studies); (iii) ethical and regulatory concerns; (iv) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4×1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4×1 montage (4× cathode, surrounding a single central anode; montage radius ~3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4×1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4×1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4×1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4×1-Ring montage for cortically targeted neuromodulation.

IMPORTANCE Many patients receive suboptimal rehabilitation therapy doses after stroke owing to limited access to therapists and difficulty with transportation, and their knowledge about stroke is often limited. Telehealth can potentially address these issues.OBJECTIVES To determine whether treatment targeting arm movement delivered via a home-based telerehabilitation (TR) system has comparable efficacy with dose-matched, intensity-matched therapy delivered in a traditional in-clinic (IC) setting, and to examine whether this system has comparable efficacy for providing stroke education. DESIGN, SETTING, AND PARTICIPANTSIn this randomized, assessor-blinded, noninferiority trial across 11 US sites, 124 patients who had experienced stroke 4 to 36 weeks prior and had arm motor deficits (Fugl-Meyer [FM] score, 22-56 of 66) were enrolled between September 18, 2015, and December 28, 2017, to receive telerehabilitation therapy in the home (TR group) or therapy at an outpatient rehabilitation therapy clinic (IC group). Primary efficacy analysis used the intent-to-treat population.INTERVENTIONS Participants received 36 sessions (70 minutes each) of arm motor therapy plus stroke education, with therapy intensity, duration, and frequency matched across groups.MAIN OUTCOMES AND MEASURES Change in FM score from baseline to 4 weeks after end of therapy and change in stroke knowledge from baseline to end of therapy.RESULTS A total of 124 participants (34 women and 90 men) had a mean (SD) age of 61 ( 14) years, a mean (SD) baseline FM score of 43 (8) points, and were enrolled a mean (SD) of 18.7 (8.9) weeks after experiencing a stroke. Among those treated, patients in the IC group were adherent to 33.6 of the 36 therapy sessions (93.3%) and patients in the TR group were adherent to 35.4 of the 36 assigned therapy sessions (98.3%). Patients in the IC group had a mean (SD) FM score change of 8.36 (7.04) points from baseline to 30 days after therapy (P < .001), while those in the TR group had a mean (SD) change of 7.86 (6.68) points (P < .001). The covariate-adjusted mean FM score change was 0.06 (95% CI, -2.14 to 2.26) points higher in the TR group (P = .96). The noninferiority margin was 2.47 and fell outside the 95% CI, indicating that TR is not inferior to IC therapy. Motor gains remained significant when patients enrolled early (<90 days) or late (Ն90 days) after stroke were examined separately.CONCLUSIONS AND RELEVANCE Activity-based training produced substantial gains in arm motor function regardless of whether it was provided via home-based telerehabilitation or traditional in-clinic rehabilitation. The findings of this study suggest that telerehabilitation has the potential to substantially increase access to rehabilitation therapy on a large scale.

Theta Burst Stimulation (TBS) protocols have recently emerged as a method to transiently alter cortical excitability in the human brain through repetitive transcranial magnetic stimulation (rTMS). TBS involves applying short trains of stimuli at high frequency repeated at intervals of 200ms. Because rTMS is known to carry a risk of seizures, safety guidelines have been established. TBS has the theoretical potential of conferring an even higher risk of seizure than other rTMS protocols because it delivers high frequency bursts. In light of the recent report of a seizure induced by TBS, the safety of this new protocol deserves consideration. We performed an English language literature search, and reviewed all studies published from May 2004-December 2009 in which TBS was applied. The adverse events were documented and crude risk was calculated. The majority of adverse events attributed to TBS were mild and occurred in 5% of subjects. Based on this review, TBS appears to be a safe and efficacious technique. However, given its novelty, it should be applied with caution. Additionally, this review highlights the need for rigorous documentation of adverse events associated with TBS, as well as intensity dosing studies to assess the seizure risk associated with various stimulation parameters (e.g. frequency, intensity, location).

The eccentric utilization ratio (EUR), which is the ratio of countermovement jump (CMJ) to static jump (SJ) performance, has been suggested as a useful indicator of power performance in athletes. The purpose of the study was to compare the EUR of athletes from a variety of different sports and during different phases of training. A total of 142 athletes from rugby union, Australian Rules Football, soccer, softball, and field hockey were tested. Subjects performed both CMJ and SJ on a force plate integrated with a position transducer. The EUR was measured as the ratio of CMJ to SJ for jump height and peak power. The rugby union, Australian Rules Football, and hockey athletes were tested during off-season and preseason to provide EUR data during different phases of training. For men, EUR for soccer, Australian Rules Football, and rugby was greater than softball (effect size range, 0.83-0.92). For women, EUR for soccer was greater than field hockey and softball (0.86- 1.0). There was a significant difference between the jump height and peak power method for the Australian Rules Football, rugby, and field hockey tests conducted preseason (p < 0.05). For field hockey, there was a significant increase in EUR from off-season to preseason. Athletes in sports such as soccer, rugby union, and Australian Rules Football appear to have higher EUR values, which reflects the greater reliance on stretch shortening activities in these sports. It does appear that EUR can be used to track changes in training with the values significantly increasing from off-season to preseason. The EUR provides the practitioner with information about the performance of athletes and appears to be sensitive to changes in the type of training being undertaken.

Contemporary strategies to promote motor recovery following stroke focus on repetitive voluntary movements. Although successful movement relies on efficient sensorimotor integration, functional outcomes often bias motor therapy toward motor-related impairments such as weakness, spasticity and synergies; sensory therapy and reintegration is implied, but seldom targeted. However, the planning and execution of voluntary movement requires that the brain extracts sensory information regarding body position and predicts future positions, by integrating a variety of sensory inputs with ongoing and planned motor activity. Neurological patients who have lost one or more of their senses may show profoundly affected motor functions, even if muscle strength remains unaffected. Following stroke, motor recovery can be dictated by the degree of sensory disruption. Consequently, a thorough account of sensory function might be both prognostic and prescriptive in neurorehabilitation. This review outlines the key sensory components of human voluntary movement, describes how sensory disruption can influence prognosis and expected outcomes in stroke patients, reports on current sensory-based approaches in post-stroke motor rehabilitation, and makes recommendations for optimizing rehabilitation programs based on sensory stimulation.

The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions.

The reliability of transcranial magnetic stimulation (TMS) measures in healthy older adults and stroke patients has been insufficiently characterized. We determined whether common TMS measures could reliably evaluate change in individuals and in groups using the smallest detectable change (SDC), or could tell subjects apart using the intraclass correlation coefficient (ICC). We used a single-rater test-retest design in older healthy, subacute stroke, and chronic stroke subjects. At twice daily sessions on two consecutive days, we recorded resting motor threshold, test stimulus intensity, recruitment curves, short-interval intracortical inhibition, and facilitation, and long-interval intracortical inhibition. Using variances estimated from a random effects model, we calculated the SDC and ICC for each TMS measure. For all TMS measures in all groups, SDCs for single subjects were large; only with modest group sizes did the SDCs become low. Thus, while these TMS measures cannot be reliably used as a biomarker to detect individual change, they can reliably detect change exceeding measurement noise in moderate-sized groups. For several of the TMS measures, ICCs were universally high, suggesting that they can reliably discriminate between subjects. TMS measures should be used based on their reliability in particular contexts. More work establishing their validity, responsiveness, and clinical relevance is still needed.