Transcranial direct current stimulation and stroke recovery: opportunities and challenges

Transcranial direct current stimulation (tDCS) is one type of neuromodulation, which is an emerging technology that holds promise for the future studies on therapeutic and diagnosis applications in treatment of neurological and psychiatric diseases. However, there is a serious question among developing countries with limited financial and human resources, about the potential returns of an investment in this field and regarding the best time to transfer this technology from controlled experimental settings to health systems in the public and private sectors. This article reviews the tDCS as tools of neuromodulation for stroke and discusses the opportunities and challenges available for clinicians and researchers interested in advancing neuromodulation therapy. The aim of this review is to highlight the usefulness of tDCS and to generate an interest that will lead to appropriate studies that assess the true clinical value of tDCS for brain diseases in developing countries. Methods: Literature review was done on PubMed from 2016 on neuromodulation in under-developed countries (UDCs) by non-invasive brain stimulation methods, using the key words “stroke”, “rehabilitation”, and “tDCS”. Results: We first identified articles and websites, of which were further selected for extensive analysis mainly based on clinical relevance, study quality and reliability, and date of publication. Conclusion: Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity to use in mostly UDCs

Transcranial Direct Current Stimulation of the Leg Motor Cortex Enhances Coordinated Motor Output During Walking With a Large Inter-Individual Variability

Background Transcranial direct current stimulation (tDCS) can augment force generation and control in single leg joints in healthy subjects and stroke survivors. However, it is unknown whether these effects also result in improved force production and coordination during walking and whether electrode configuration influences these effects. Objective We investigated the effect of tDCS using different electrode configurations on coordinated force production during walking in a group of healthy subjects and chronic stroke survivors. Methods Ten healthy subjects and ten chronic stroke survivors participated in a randomized double-blinded crossover study. Subjects walked on an instrumented treadmill before and after 10 minutes of uni-hemispheric (UNI), dual-hemispheric (DUAL) or sham tDCS applied to the primary motor cortex. Results tDCS responses showed large inter-individual variability in both subject populations. In healthy subjects tDCS enhanced the coordinated output during walking as reflected in an increased positive work generation during propulsion. The effects of DUAL tDCS were clearer but still small (4.4% increase) compared to UNI tDCS (2.8% increase). In the chronic stroke survivors no significant effects of tDCS in the targeted paretic leg were observed. Conclusions tDCS has potential to augment multi-joint coordinated force production during walking. The relative small contribution of the motor cortex in controlling walking might explain why the observed effects are rather small. Furthermore, a better understanding of the inter-individual variability is needed to optimize the effects of tDCS in healthy but especially stroke survivors. The latter is a prerequisite for clinical applicability

Transcranial Direct Current Stimulation Technique: A Need of Bangladesh for Stroke Management

Abstract Stroke has been considered as one of the leading cause of death worldwide. It results in reduced excitability, deregulated plastic modifications, and formation of aberrant connections and, these factors hinder recovery from stroke. Transcranial direct current stimulation (tDCS) is a promising technique for the treatment of a wide range of neurological disorders including stroke. Its application could improve the condition of patients having neurological disorders by making functional connections and maintaining existing pathways. In Bangladesh, stroke remains the third leading cause of death with 0.3% prevalence. The number of disability-adjusted life years lost for stroke is 485 per 10000 people, which depicts great economic burden of this disease in the future. Thus, introduction of new technologies such as tDCS in the treatment of stroke will not only improve conditions of stroke patients but also reduce economic burden of this disease in Bangladesh

Does stroke location predict walk speed response to gait rehabilitation?

Objectives Recovery of independent ambulation after stroke is a major goal. However, which rehabilitation regimen best benefits each individual is unknown and decisions are currently made on a subjective basis. Predictors of response to specific therapies would guide the type of therapy most appropriate for each patient. Although lesion topography is a strong predictor of upper limb response, walking involves more distributed functions. Earlier studies that assessed the cortico-spinal tract (CST) were negative, suggesting other structures may be important. Experimental Design: The relationship between lesion topography and response of walking speed to standard rehabilitation was assessed in 50 adult-onset patients using both volumetric measurement of CST lesion load and voxel-based lesion–symptom mapping (VLSM) to assess non-CST structures. Two functional mobility scales, the functional ambulation category (FAC) and the modified rivermead mobility index (MRMI) were also administered. Performance measures were obtained both at entry into the study (3–42 days post-stroke) and at the end of a 6-week course of therapy. Baseline score, age, time since stroke onset and white matter hyperintensities score were included as nuisance covariates in regression models. Principal Observations: CST damage independently predicted response to therapy for FAC and MRMI, but not for walk speed. However, using VLSM the latter was predicted by damage to the putamen, insula, external capsule and neighbouring white matter. Conclusions Walk speed response to rehabilitation was affected by damage involving the putamen and neighbouring structures but not the CST, while the latter had modest but significant impact on everyday functions of general mobility and gait

Effects of bifrontal transcranial direct current stimulation on brain glutamate levels and resting state connectivity: multimodal MRI data for the cathodal stimulation site

Transcranial direct current stimulation (tDCS) over prefrontal cortex (PFC) regions is currently proposed as therapeutic intervention for major depression and other psychiatric disorders. The in-depth mechanistic understanding of this bipolar and non-focal stimulation technique is still incomplete. In a pilot study, we investigated the effects of bifrontal stimulation on brain metabolite levels and resting state connectivity under the cathode using multiparametric MRI techniques and computational tDCS modeling. Within a double-blind cross-over design, 20 subjects (12 women, 23.7 ± 2~years) were randomized to active tDCS with standard bifrontal montage with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC. Magnetic resonance spectroscopy (MRS) was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma aminobutyric acid (GABA) concentration in these areas. Resting-state functional connectivity MRI (rsfcMRI) was acquired before and after the stimulation. The individual distribution of tDCS induced electric fields (efields) within the MRS voxel was computationally modelled using SimNIBS 2.0. There were no significant changes of Glu, Glx and GABA levels across conditions but marked differences in the course of Glu levels between female and male participants~were observed. Further investigation yielded a significantly stronger Glu reduction after active compared to sham stimulation~in female participants, but not in male participants. For rsfcMRI neither significant changes nor correlations with MRS data were observed. Exploratory analyses of the effect of efield intensity distribution on Glu changes showed distinct effects in different efield groups. Our findings are limited by the small sample size, but correspond to previously published results of cathodal tDCS. Future studies should address gender and efield intensity as moderators of tDCS induced effects

Modulation of Corticospinal Excitability Using Cathodal Transcranial Direct Current Stimulation to Improve Walking in Individuals with Chronic Post Stroke Hemiparesis

Background and Purpose: Individuals who have experienced a pyramidal cerebrovascular accident (pCVA) often exhibit impairments to volitional control of corresponding motor tasks. Promising effects in motor response, post-application of transcranial direct current stimulation (tDCS), have been reported in studies on individuals with the ability to achieve independent gait for 20 minutes. These studies mainly examined the effects of combined tDCS with locomotor training on lower extremity function among higher functioning individuals post-stroke. The purpose of this study was to determine the effect of tDCS among individuals post-stroke who may not have independent ambulatory capabilities, focusing on motor response and less demanding outcomes. The results of this study will extend knowledge on tDCS effects among lower functioning individuals post-CVA. Methods: Four individuals with chronic stroke (2.38 ± 0.63 years) randomly received either cathodal stimulation or a sham treatment to their non-lesioned hemisphere. Transcranial magnetic stimulation (TMS) was used in order identify the tibialis anterior hotspot in the motor cortex of their lesioned hemisphere such that we were able to assess and reassess the effects of tDCS at the same hotspot location. Fourteen days later, subjects attended a second session where they received the intervention that they did not receive in the first session (either sham or cathodal tDCS). Lower extremity (LE) function was evaluated by comparing pre and post intervention Timed Up and Go (TUG) scores, as well as Step Length, Stride Length, Stride Width, Stance Time, Swing Time, Gait Velocity, Ambulation Time, and Cadence. Motor response was evaluated by comparing pre and post intervention Motor Evoked Potential (MEP) values. Results: There was a statistically significant change in the MEP value measured before and after cathodal tDCS compared to sham (p = 0.037 \u3c 0.05). There was no statistically significant difference when comparing tDCS to sham interventions for: resting motor threshold maximum stimulator output (rMT MSO%), TUG, Step Length, Stride Length, Stride Width, Stance Time, Swing Time, Gait Velocity, Ambulation Time, and Cadence. Discussion: For those who are living post-stroke, the application of cathodal tDCS may provide a relative increase in cortical excitability of the ipsilesional hemisphere. Future tDCS research should incorporate functional interventions to see if they can promote lasting effects

The impact of brain lesions on tDCS-induced electric fields

Transcranial direct current stimulation (tDCS) can enhance motor and language rehabilitation after stroke. Though brain lesions distort tDCS-induced electric field (E-field), systematic accounts remain limited. Using electric field modelling, we investigated the effect of 630 synthetic lesions on E-field magnitude in the region of interest (ROI). Models were conducted for two tDCS montages targeting either primary motor cortex (M1) or Broca's area (BA44). Absolute E-field magnitude in the ROI differed by up to 42% compared to the non-lesioned brain depending on lesion size, lesion-ROI distance, and lesion conductivity value. Lesion location determined the sign of this difference: lesions in-line with the predominant direction of current increased E-field magnitude in the ROI, whereas lesions located in the opposite direction decreased E-field magnitude. We further explored how individualised tDCS can control lesion-induced effects on E-field. Lesions affected the individualised electrode configuration needed to maximise E-field magnitude in the ROI, but this effect was negligible when prioritising the maximisation of radial inward current. Lesions distorting tDCS-induced E-field, is likely to exacerbate inter-individual variability in E-field magnitude. Individualising electrode configuration and stimulator output can minimise lesion-induced variability but requires improved estimates of lesion conductivity. Individualised tDCS is critical to overcome E-field variability in lesioned brains

The Effect of Scalp Tissue on Current Shunting during Anodal Transcranial Direct Current Stimulation (TDCS)

Transcranial Direct Current Stimulation (tDCS) has been used to treat various mental and neurological illnesses. Rodent models have been used to examine physiological changes in the brain after tDCS, as well as to develop safety standards. However, most animal tDCS studies implant an electrode on the brain, potentially altering the path of current during stimulation. Additionally, no studies have been completed specifically examining maximum safe anodal tDCS limits, and a pilot study conducted to determine an electrode montage to examine biological changes of learning and memory from anodal tDCS indicated brain lesion was occurring before a commonly cited lesion threshold of 142.9 A/m2. Therefore, the goal of this study was to examine both the effects of anodal tDCS and the rodent\u27s scalp on current shunting during anodal tDCS in vivo. Anodal tDCS was applied to the skull of 35 anesthetized male Sprague-Dawley rats for 60 minutes after they were divided into groups either receiving stimulation with an electrode on the skull or scalp tissue. Within each skull and scalp electrode placement group, rats were further separated into groups by tDCS current intensity (µA) received, which was: sham (n=4), 150 µA (n=4), 300 µA (n=4), 500 µA (n=3), 1,000 µA (n=4), and 2,500 µA (n=3) for the skull electrode placement group. For the scalp electrode placement groups, only stimulations that induced lesion during the skull electrode stimulation were chosen: sham iv Distribution A: Approved for public release; distribution unlimited. 88ABW Cleared 11/09/2015; 88ABW-2015-5473. (n=2), 500 µA (n=3), 1,000 µA (n=3), and 2,500 µA (n=3). Brain lesion was quantified using an Olympus BX-63 microscope with Q100 Blue Camera and CellSens software, which showed brain lesion during skull electrode placement first occurring at 500 uA, having a lesion volume of 0.168 mm3. At 1,000 µA and 2,500 µA, the average brain lesion within groups was 6.363 mm3 and 13.013 mm3, respectively. Stimulation of the scalp showed no brain lesion at any of the stimulation groups, suggesting the scalp tissue shunts a portion of the current, and as a result, has different physiological effects on brain lesion development

The impact of large structural brain changes in chronic stroke patients on the electric field caused by transcranial brain stimulation

Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) are two types of non-invasive transcranial brain stimulation (TBS). They are useful tools for stroke research and may be potential adjunct therapies for functional recovery. However, stroke often causes large cerebral lesions, which are commonly accompanied by a secondary enlargement of the ventricles and atrophy. These structural alterations substantially change the conductivity distribution inside the head, which may have potentially important consequences for both brain stimulation methods. We therefore aimed to characterize the impact of these changes on the spatial distribution of the electric field generated by both TBS methods. In addition to confirming the safety of TBS in the presence of large stroke-related structural changes, our aim was to clarify whether targeted stimulation is still possible. Realistic head models containing large cortical and subcortical stroke lesions in the right parietal cortex were created using MR images of two patients. For TMS, the electric field of a double coil was simulated using the finite-element method. Systematic variations of the coil position relative to the lesion were tested. For TDCS, the finite-element method was used to simulate a standard approach with two electrode pads, and the position of one electrode was systematically varied. For both TMS and TDCS, the lesion caused electric field “hot spots” in the cortex. However, these maxima were not substantially stronger than those seen in a healthy control. The electric field pattern induced by TMS was not substantially changed by the lesions. However, the average field strength generated by TDCS was substantially decreased. This effect occurred for both head models and even when both electrodes were distant to the lesion, caused by increased current shunting through the lesion and enlarged ventricles. Judging from the similar peak field strengths compared to the healthy control, both TBS methods are safe in patients with large brain lesions (in practice, however, additional factors such as potentially lowered thresholds for seizure-induction have to be considered). Focused stimulation by TMS seems to be possible, but standard tDCS protocols appear to be less efficient than they are in healthy subjects, strongly suggesting that tDCS studies in this population might benefit from individualized treatment planning based on realistic field calculations. Keywords: Transcranial magnetic stimulation, Transcranial direct current stimulation, Chronic stroke, Brain lesions, Field simulations, Finite element metho