Individualisation of transcranial electric stimulation to improve motor function after stroke:Current challenges and future perspective

Transcranial electric stimulation (tES) is a non-invasive brain stimulation technique that could potentially improve motor rehabilitation after stroke. However, the effects of tES are in general stronger in healthy individuals compared to people with stroke. Interindividual variability in brain structure and function due to stroke potentially explain this difference in effects. This thesis describes the development of methods to facilitate the individualisation of tES in people with stroke and identifies objective neurophysiological correlates of motor learning that could potentially help to monitor the response to tES.In chapter 2, EEG correlates of explicit motor task learning were derived in healthy, young participants. Chapter 3 investigated the effects of 3 different tDCS configurations (sham, targeting contralateral M1 and targeting the full resting motor network) on corticospinal excitability. Both conventional and motor network tDCS did not increase corticospinal excitability relative to sham stimulation. Chapter 4 describes methods to create head models of people with stroke and assesses the effects of stroke lesions on the electric fields within stimulation targets. Chapter 5 describes a method to experimentally determine the electric conductivity of the stroke lesion. Finally, Chapter 6 analyses the electric fields generated by conventional tDCS in people with stroke and age-matched controls. It is shown that the one-size-fits-all approach results in more variable electric fields in people with stroke compared to controls. Optimisation of the electrode positions to maximise the electric field in stimulation targets increases the electric fields in people with stroke to the same level as found in healthy controls.This thesis shows anatomical and motor function variability exists between people with stroke due to differences in lesion characteristics. While there are several opportunities to individualise tES, more research is needed to investigate if this improves the effects of tES. As such, clinical implementation of tES seems unrealistic in the foreseeable future.<br/

Individualisation of transcranial electric stimulation to improve motor function after stroke:Current challenges and future perspective

Transcranial electric stimulation (tES) is a non-invasive brain stimulation technique that could potentially improve motor rehabilitation after stroke. However, the effects of tES are in general stronger in healthy individuals compared to people with stroke. Interindividual variability in brain structure and function due to stroke potentially explain this difference in effects. This thesis describes the development of methods to facilitate the individualisation of tES in people with stroke and identifies objective neurophysiological correlates of motor learning that could potentially help to monitor the response to tES.In chapter 2, EEG correlates of explicit motor task learning were derived in healthy, young participants. Chapter 3 investigated the effects of 3 different tDCS configurations (sham, targeting contralateral M1 and targeting the full resting motor network) on corticospinal excitability. Both conventional and motor network tDCS did not increase corticospinal excitability relative to sham stimulation. Chapter 4 describes methods to create head models of people with stroke and assesses the effects of stroke lesions on the electric fields within stimulation targets. Chapter 5 describes a method to experimentally determine the electric conductivity of the stroke lesion. Finally, Chapter 6 analyses the electric fields generated by conventional tDCS in people with stroke and age-matched controls. It is shown that the one-size-fits-all approach results in more variable electric fields in people with stroke compared to controls. Optimisation of the electrode positions to maximise the electric field in stimulation targets increases the electric fields in people with stroke to the same level as found in healthy controls.This thesis shows anatomical and motor function variability exists between people with stroke due to differences in lesion characteristics. While there are several opportunities to individualise tES, more research is needed to investigate if this improves the effects of tES. As such, clinical implementation of tES seems unrealistic in the foreseeable future.<br/

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

Left parietal tACS at alpha frequency induces a shift of visuospatial attention

Background Voluntary shifts of visuospatial attention are associated with a lateralization of parieto-occipital alpha power (7-13Hz), i.e. higher power in the hemisphere ipsilateral and lower power contralateral to the locus of attention. Recent noninvasive neuromodulation studies demonstrated that alpha power can be experimentally increased using transcranial alternating current stimulation (tACS). Objective/Hypothesis We hypothesized that tACS at alpha frequency over the left parietal cortex induces shifts of attention to the left hemifield. However, spatial attention shifts not only occur voluntarily (endogenous/ top-down), but also stimulus-driven (exogenous/ bottom-up). To study the task-specificity of the potential effects of tACS on attentional processes, we administered three conceptually different spatial attention tasks. Methods 36 healthy volunteers were recruited from an academic environment. In two separate sessions, we applied either high-density tACS at 10Hz, or sham tACS, for 35–40 minutes to their left parietal cortex. We systematically compared performance on endogenous attention, exogenous attention, and stimulus detection tasks. Results In the endogenous attention task, a greater leftward bias in reaction times was induced during left parietal 10Hz tACS as compared to sham. There were no stimulation effects in either the exogenous attention or the stimulus detection task. Conclusion The study demonstrates that high-density tACS at 10Hz can be used to modulate visuospatial attention performance. The tACS effect is task-specific, indicating that not all forms of attention are equally susceptible to the stimulation

Comparison of two configurations of transcranial direct current stimulation for treatment of aphasia

Objective: To compare 2 configurations of transcranial direct current stimulation (tDCS) for treatment of aphasia. Design: Randomized cross-over study. Subjects: Patients with chronic post-stroke aphasia (n = 13). Methods: TDCS was combined with word-finding therapy in 3 single sessions. In session 1, sham-tDCS/ pseudo-stimulation was applied. In sessions 2 and 3, 2 active configurations were provided in random order: Anodal tDCS over the left inferior frontal gyrus (l-IFG) and anodal tDCS over the left posterior superior temporal gyrus (l-STG). The optimal configuration was determined per individual based on a pre-set improvement in naming trained (> 20%) and untrained picture items (> 10%). Results: Overall, participants improved on trained items (median = 50%; interquartile range = 20-85) and post-treatment performance was highest in the active l-IFG condition (p = 0.040). Of the 13 participants, 6 (46%) showed relevant improvement during active tDCS; either in the l-IFG condition (n = 4; 31%) or in both the l-IFG and l-STG conditions (n = 2; 15%). On the untrained items there was no improvement (median = 0%; interquartile range = 0-0). Conclusion: This randomized cross-over single-session protocol to determine an optimal tDCS configuration for treatment of aphasia suggests that only performance on trained items can be used as guidance for configuration, and that it is relevant for half of the patients. For this subgroup, the l-IFG configuration is the optimal choice

Transcranial Electric Stimulation Entrains Cortical Neuronal Populations in Rats

Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity

Transcranial direct current stimulation in post-stroke sub-acute aphasia: Study protocol for a randomized controlled trial

Background: Transcranial direct current stimulation (tDCS) is a promising new technique to optimize the effect of regular Speech and Language Therapy (SLT) in the context of aphasia rehabilitation. The present study focuses on the effect of tDCS provided during SLT in the sub-acute stage after stroke. The primary aim is to evaluate the potential effect of tDCS on language functioning, specifically on word-finding, as well as generalization effects to verbal communication. The secondary aim is to evaluate its effect on social participation and quality of life, and its cost-effectiveness. Methods: We strive to include 58 stroke patients with aphasia, enrolled in an inpatient or outpatient stroke rehabilitation program, in a multicenter, double-blind, randomized controlled trial with two parallel groups and 6 months' follow-up. Patients will participate in two separate intervention weeks, with a pause of 2 weeks in between, in the context of their regular aphasia rehabilitation program. The two intervention weeks comprise daily 45-minute sessions of word-finding therapy, combined with either anodal tDCS over the left inferior frontal gyrus (1 mA, 20 minutes; experimental condition) or sham-tDCS over the same region (control condition). The primary outcome measure is word-finding. Secondary outcome measures are verbal communication, social participation, quality of life, and cost-effectiveness of the intervention. Discussion: Our results will contribute to the discussion on whether tDCS should be implemented in regular aphasia rehabilitation programs for the sub-acute post-stroke population in terms of (cost-)effectiveness. Trial registration: Nederlands Trail Register: NTR4364. Registered on 21 February 2014

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

Gender Differences in Current Received during Transcranial Electrical Stimulation.

Low current transcranial electrical stimulation (tCS) is an effective but somewhat inconsistent tool for augmenting neuromodulation. In this study, we used 3D MRI guided electrical transcranial stimulation modeling to estimate the range of current intensities received at cortical brain tissues. Combined T1, T2, and proton density MRIs from 24 adult subjects (12 male and 12 female) were modeled with virtual electrodes placed at F3, F4, C3, and C4. Two sizes of electrodes 20 mm round and 50 mm × 45 mm were examined at 0.5, 1, and 2 mA input currents. The intensity of current received was sampled in a 1-cm sphere placed at the cortex directly under each scalp electrode. There was a 10-fold difference in the amount of current received by individuals. A large gender difference was observed with female subjects receiving significantly less current at targeted parietal cortex than male subjects when stimulated at identical current levels (P &lt; 0.05). Larger electrodes delivered somewhat larger amounts of current than the smaller ones (P &lt; 0.01). Electrodes in the frontal regions delivered less current than those in the parietal region (P &lt; 0.05). There were large individual differences in current levels that the subjects received. Analysis of the cranial bone showed that the gender difference and the frontal parietal differences are due to differences in cranial bone. Males have more cancelous parietal bone and females more dense parietal bone (P &lt; 0.01). These differences should be considered when planning tCS studies and call into question earlier reports of gender differences due to hormonal influences