Investigation of Methodological and Physiological Factors Influencing Non-Invasive Transcranial Electrical Brain Stimulation

Non-invasive transcranial electrical brain stimulation (tES) techniques, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS), can alter neuronal activity and related brain functions. However, tES effects seem to be modulated by various influencing factors, leading to high inter-individual variability in tES effects and often only low effect sizes, or even no effects. The present thesis therefore aimed to investigate methodological and physiological influencing factors of tDCS, tACS and tRNS that have not been sufficiently examined so far. A first study investigated the influence of montage and individual functional performance level on the effects of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) in healthy adults. Compared with sham stimulation, a multichannel montage led to stronger effects than a bipolar montage. For both montages the effects of stimulation were dependent on the functional performance level of participants. A second study investigated the effects of multichannel tDCS over the left DLPFC in healthy children and adolescents, considering the influence of concurrent target task performance during stimulation and individual head anatomy. tDCS did not influence the target outcome but led to transfer effects on non-target task performance and neurophysiological activity, that were only partly influenced by task performance during stimulation. The individual head anatomy had no influence on stimulation effects. A third study investigated tACS and tRNS effects on motor cortex excitability in healthy children and adolescents in comparison to adults. The individual response to sham stimulation was investigated as marker for the individual physiological brain state. Motor cortex excitability was not modulated by age but by individual response to sham stimulation. All studies provide important insights into the modulatory factors of stimulation effects. Based on these results, future studies should aim at individualising tES application

The Effects of 1 mA tACS and tRNS on Children/Adolescents and Adults: Investigating Age and Sensitivity to Sham Stimulation

The aim of this study was to investigate the effect of transcranial random noise (tRNS) and transcranial alternating current (tACS) stimulation on motor cortex excitability in healthy children and adolescents. Additionally, based on our recent results on the individual response to sham in adults, we explored this effect in the pediatric population. We included 15 children and adolescents (10-16 years) and 28 adults (20-30 years). Participants were stimulated four times with 20 Hz and 140 Hz tACS, tRNS, and sham stimulation (1 mA) for 10 minutes over the left M1HAND. Single-pulse MEPs (motor evoked potential), short-interval intracortical inhibition, and facilitation were measured by TMS before and after stimulation (baseline, 0, 30, 60 minutes). We also investigated aspects of tolerability. According to the individual MEPs response immediately after sham stimulation compared to baseline (Wilcoxon signed-rank test), subjects were regarded as responders or nonresponders to sham. We did not find a significant age effect. Regardless of age, 140 Hz tACS led to increased excitability. Incidence and intensity of side effects did not differ between age groups or type of stimulation. Analyses on responders and nonresponders to sham stimulation showed effects of 140 Hz, 20 Hz tACS, and tRNS on single-pulse MEPs only for nonresponders. In this study, children and adolescents responded to 1 mA tRNS and tACS comparably to adults regarding the modulation of motor cortex excitability. This study contributes to the findings that noninvasive brain stimulation is well tolerated in children and adolescents including tACS, which has not been studied before. Finally, our study supports a modulating role of sensitivity to sham stimulation on responsiveness to a broader stimulation and age range

Stratification of responses to tDCS intervention in a healthy pediatric population based on resting-state EEG profiles

Abstract Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique with a wide variety of clinical and research applications. As increasingly acknowledged, its effectiveness is subject dependent, which may lead to time consuming and cost ineffective treatment development phases. We propose the combination of electroencephalography (EEG) and unsupervised learning for the stratification and prediction of individual responses to tDCS. A randomized, sham-controlled, double-blind crossover study design was conducted within a clinical trial for the development of pediatric treatments based on tDCS. The tDCS stimulation (sham and active) was applied either in the left dorsolateral prefrontal cortex or in the right inferior frontal gyrus. Following the stimulation session, participants performed 3 cognitive tasks to assess the response to the intervention: the Flanker Task, N-Back Task and Continuous Performance Test (CPT). We used data from 56 healthy children and adolescents to implement an unsupervised clustering approach that stratify participants based on their resting-state EEG spectral features before the tDCS intervention. We then applied a correlational analysis to characterize the clusters of EEG profiles in terms of participant’s difference in the behavioral outcome (accuracy and response time) of the cognitive tasks when performed after a tDCS-sham or a tDCS-active session. Better behavioral performance following the active tDCS session compared to the sham tDCS session is considered a positive intervention response, whilst the reverse is considered a negative one. Optimal results in terms of validity measures was obtained for 4 clusters. These results show that specific EEG-based digital phenotypes can be associated to particular responses. While one cluster presents neurotypical EEG activity, the remaining clusters present non-typical EEG characteristics, which seem to be associated with a positive response. Findings suggest that unsupervised machine learning can be successfully used to stratify and eventually predict responses of individuals to a tDCS treatment

Multichannel anodal tDCS over the left dorsolateral prefrontal cortex in a paediatric population

Splittgerber M, Borzikowsky C, Salvador R, et al. Multichannel anodal tDCS over the left dorsolateral prefrontal cortex in a paediatric population. Scientific Reports . 2021;11(1): 21512.Methodological studies investigating transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) in paediatric populations are limited. Therefore, we investigated in a paediatric population whether stimulation success of multichannel tDCS over the lDLPFC depends on concurrent task performance and individual head anatomy. In a randomised, sham-controlled, double-blind crossover study 22 healthy participants (10-17 years) received 2 mA multichannel anodal tDCS (atDCS) over the lDLPFC with and without a 2-back working memory (WM) task. After stimulation, the 2-back task and a Flanker task were performed. Resting state and task-related EEG were recorded. In 16 participants we calculated the individual electric field (E-field) distribution. Performance and neurophysiological activity in the 2-back task were not affected by atDCS. atDCS reduced reaction times in the Flanker task, independent of whether atDCS had been combined with the 2-back task. Flanker task related beta oscillation increased following stimulation without 2-back task performance. atDCS effects were not correlated with the E-field. We found no effect of multichannel atDCS over the lDLPFC on WM in children/adolescents but a transfer effect on interference control. While this effect on behaviour was independent of concurrent task performance, neurophysiological activity might be more sensitive to cognitive activation during stimulation. However, our results are limited by the small sample size, the lack of an active control group and variations in WM performance