Influence of layered skull modeling on the frequency sensitivity and target accuracy in simulations of transcranial current stimulation.

With the development of electrical stimulation technology, especially the emergence of temporally interfering (TI) stimulation, it is necessary to discuss the influence of current frequency on stimulation intensity. Accurate skull modeling is important for transcranial current stimulation (tCS) simulation prediction because of its large role in dispersing current. In this study, we simulated different frequencies of transcranial alternating current stimulation (tACS) and TI stimulation in single-layer and layered skull model, compared the electric field via error parameters such as the relative difference measure and relative magnification factor. Pearson correlation analysis and t-test were used to measure the differences in envelope amplitude. The results showed that the intensity of electric field in the brain generated by per unit of stimulation current will increase with current frequency, and the layered skull model had a better response to frequency. An obvious pattern difference was found between the electric fields of the layered and single-layer skull individualized models. For TI stimulation, the Pearson correlation coefficient between the envelope distribution of the layered skull model and the single-layer skull was only 0.746 in the individualized model, which is clearly lower than the correlation coefficient of 0.999 determined from the spherical model. Higher carrier frequencies seemed to be easier to generate a large enough brain electric field envelope in TI stimulation. In conclusion, we recommend using layered skull models instead of single-layer skull models in tCS (particularly TI stimulation) simulation studies in order to improve the accuracy of the prediction of stimulus intensity and stimulus target.

The Effects of Transcranial Direct Current Stimulation on Depression, Anxiety, and Stress in Patients with Epilepsy: A Randomized Clinical Trial.

Background: Epilepsy is a chronic disorder that affects both sexes and causes some physiological and psychological disabilities. The present study aimed to examine the effects of transcranial direct current stimulation (tDCS) on the psychological profile of patients with epilepsy. Methods: The design of the present study was a randomized clinical trial with a pretest-posttest and a control group. The statistical population comprised patients with epilepsy, who were referred for treatment to a private health center in Urmia in 2019. The sample consisted of 30 patients with epilepsy selected via the convenience sampling method. Data collection was performed through the use of the Depression, Anxiety, and Stress Scale-21 (DASS-21) questionnaire. After the pretest, 15 subjects were randomly assigned to the intervention group, and 15 subjects were placed in the control group. The intervention was performed in 10 sessions, and the duration of stimulation was 20 minutes. The anode was placed in the F3 region (left hemisphere), the cathode in the F4 (right hemisphere), and the current intensity was 1.5 mA. After the intervention, the posttest was conducted for both groups, and the data were analyzed using a univariate covariance analysis in the SPSS software, version 23. A P value of less than 0.05 was considered statistically significant. Results: The results of the ANCOVA analyses revealed significant differences between the intervention and control groups. The tDCS group represented a significant decrease in the scales of depression, anxiety, and stress in the posttest in comparison with the pretest (P≤0.001). Conclusion: The results showed that tDCS could reduce depression, anxiety, and stress with the changes caused in the brain system. Trial Registration Number: IRCT20190803044417N1.

Perturbing fMRI brain dynamics using transcranial direct current stimulation.

The dynamic nature of resting-state functional magnetic resonance imaging (fMRI) brain activity and connectivity has drawn great interest in the past decade. Specific temporal properties of fMRI brain dynamics, including metrics such as occurrence rate and transitions, have been associated with cognition and behaviors, indicating the existence of mechanism distruption in neuropsychiatric disorders. The development of new methods to manipulate fMRI brain dynamics will advance our understanding of these pathophysiological mechanisms from native observation to experimental mechanistic manipulation. In the present study, we applied repeated transcranial direct current stimulation (tDCS) to the right dorsolateral prefrontal cortex (rDLPFC) and the left orbitofrontal cortex (lOFC), during multiple simultaneous tDCS-fMRI sessions from 81 healthy participants to assess the modulatory effects of stimulating target brain regions on fMRI brain dynamics. Using the rDLPFC and the lOFC as seeds, respectively, we first identified two reoccurring co-activation patterns (CAPs) and calculated their temporal properties (e.g., occurrence rate and transitions) before administering tDCS. The spatial maps of CAPs were associated with different cognitive and disease domains using meta-analytical decoding analysis. We then investigated how active tDCS compared to sham tDCS in the modulation of the occurrence rates of these different CAPs and perturbations of transitions between CAPs. We found that by enhancing neuronal excitability of the rDLPFC and the lOFC, the occurrence rate of one CAP was significantly decreased while that of another CAP was significantly increased during the first 6 min of stimulation. Furthermore, these tDCS-associated changes persisted over subsequent testing sessions (both during and before/after tDCS) across three consecutive days. Active tDCS could perturb transitions between CAPs and a non-CAP state (when the rDLPFC and the lOFC were not activated), but not the transitions within CAPs. These results demonstrate the feasibility of modulating fMRI brain dynamics, and open new possibilities for discovering stimulation targets and dynamic connectivity patterns that can ensure the propagation of tDCS-induced neuronal excitability, which may facilitate the development of new treatments for disorders with altered dynamics.

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee.

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.

Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders.

BACKGROUND: Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects. OBJECTIVE: We convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson's disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction. METHODS: Experts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies. RESULTS: Although most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson's disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy). CONCLUSION: All recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs.

The visual system as target of non-invasive brain stimulation for migraine treatment: Current insights and future challenges.

The visual network is crucially implicated in the pathophysiology of migraine. Several lines of evidence indicate that migraine is characterized by an altered visual cortex excitability both during and between attacks. Visual symptoms, the most common clinical manifestation of migraine aura, are likely the result of cortical spreading depression originating from the extrastriate area V3A. Photophobia, a clinical hallmark of migraine, is linked to an abnormal sensory processing of the thalamus which is converged with the non-image forming visual pathway. Finally, visual snow is an increasingly recognized persistent visual phenomenon in migraine, possibly caused by increased perception of subthreshold visual stimuli. Emerging research in non-invasive brain stimulation (NIBS) has vastly developed into a diversity of areas with promising potential. One of its clinical applications is the single-pulse transcranial magnetic stimulation (sTMS) applied over the occipital cortex which has been approved for treating migraine with aura, albeit limited evidence. Studies have also investigated other NIBS techniques, such as repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), for migraine prophylaxis but with conflicting results. As a dynamic brain disorder with widespread pathophysiology, targeting migraine with NIBS is challenging. Furthermore, unlike the motor cortex, evidence suggests that the visual cortex may be less plastic. Controversy exists as to whether the same fundamental principles of NIBS, based mainly on findings in the motor cortex, can be applied to the visual cortex. This review aims to explore existing literature surrounding NIBS studies on the visual system of migraine. We will first provide an overview highlighting the direct implication of the visual network in migraine. Next, we will focus on the rationale behind using NIBS for migraine treatment, including its effects on the visual cortex, and the shortcomings of currently available evidence. Finally, we propose a broader perspective of how novel approaches, the concept of brain networks and the integration of multimodal imaging with computational modeling, can help refine current NIBS methods, with the ultimate goal of optimizing a more individualized treatment for migraine.

Utilizing transcranial direct current stimulation to enhance laparoscopic technical skills training: A randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that delivers constant, low electrical current resulting in changes to cortical excitability. Prior work suggests it may enhance motor learning giving it the potential to augment surgical technical skill acquisition. OBJECTIVES: The aim of this study was to test the efficacy of tDCS, coupled with motor skill training, to accelerate laparoscopic skill acquisition in a pre-registered (NCT03083483), double-blind and placebo-controlled study. We hypothesized that relative to sham tDCS, active tDCS would accelerate the development of laparoscopic technical skills, as measured by the Fundamentals of Laparoscopic Surgery (FLS) Peg Transfer task quantitative metrics. METHODS: In this study, sixty subjects (mean age 22.7 years with 42 females) were randomized into sham or active tDCS in either bilateral primary motor cortex (bM1) or supplementary motor area (SMA) electrode configurations. All subjects practiced the FLS Peg Transfer Task during six 20-min training blocks, which were preceded and followed by a single trial pre-test and post-test. The primary outcome was changes in laparoscopic skill performance over time, quantified by group differences in completion time from pre-test to post-test and learning curves developed from a calculated score accounting for errors. RESULTS: Learning curves calculated over the six 20-min training blocks showed significantly greater improvement in performance for the bM1 group than the sham group (t = 2.07, p = 0.039), with the bM1 group achieving approximately the same amount of improvement in 4 blocks compared to the 6 blocks required of the sham group. The SMA group also showed greater mean improvement than sham, but exhibited more variable learning performance and differences relative to sham were not significant (t = 0.85, p = 0.400). A significant main effect was present for pre-test versus post-test times (F = 133.2, p < 0.001), with lower completion times at post-test, however these did not significantly differ for the training groups. CONCLUSION: Laparoscopic skill training with active bilateral tDCS exhibited significantly greater learning relative to sham. The potential for tDCS to enhance the training of surgical skills, therefore, merits further investigation to determine if these preliminary results may be replicated and extended.

Mind the stimulation site: Enhancing and diminishing sentence comprehension with anodal tDCS.

In a previous sham-controlled study, we showed the feasibility of increasing language comprehension in healthy participants by applying anodal transcranial direct current stimulation (atDCS) over the left inferior frontal gyrus (LIFG). In the present work, we present a follow-up experiment targeting with atDCS the left inferior parietal cortex (LIPC) while participants performed the same auditory comprehension task used in our previous experiment. Both neural sites (LIFG and LIPC) are crucial hubs of Baddeley's model of verbal short-term memory (vSTM). AtDCS over LIPC decreased accuracy as compared to sham and LIFG stimulation, suggesting the involvement of this area in sentence comprehension. Crucially, our results highlighted that applying tDCS over different hubs of the same neural network can lead to opposite behavioural results, with relevant implications from a clinical perspective.

Understanding time perception through non-invasive brain stimulation techniques: A review of studies.

The present review includes transcranial magnetic and transcranial electric stimulation studies on time perception and shows that the neural processing of time requires the activity of wide range-distributed brain networks. Moreover, a critical discussion regarding non-invasive brain stimulation in the study of time processing is included to give the reader insights into the study of temporal processing in neuroscience. The cerebellum and auditory cortex seem most crucial when participants are required to estimate the passage of sub-seconds intervals and this conclusion holds independently of the modality used to mark the temporal intervals. Conversely, the primary visual area and MT/V5 seem to process primarily visual stimuli. The areas included in the prefrontal cortex are mostly implicated in the processing of supra-second time intervals and when time is processed in conjunction with other cognitive functions. Although previous fMRI studies showed activation in the supplementary motor area during sub-second timing tasks, TMS studies failed to confirm these observations. We conclude that the contribution of these strongly interconnected structures in the processing of temporal information is not fixed; their contribution depends not only on the duration of the time interval to be assessed by the brain but also on the cognitive set involved in the chosen task and on the stimulus modality used for marking time. Critical observations regarding the specificity of each method of stimulation as well as limitations and criticisms of the studies that used brain stimulation techniques will be also discussed.

Cost of focality in TDCS: Interindividual variability in electric fields.

BACKGROUND: In transcranial direct current stimulation (TDCS), electric current is applied via two large electrodes to modulate brain activity. Computational models have shown that large electrodes produce diffuse electric fields (EFs) in the brain, which depends on individual head and brain anatomy. Recently, smaller electrodes as well as novel electrode arrangements, including high-definition TDCS (HD-TDCS) montages, have been introduced to improve the focality of EFs. Here, we investigated whether the EFs of focal montages are more susceptible to interindividual anatomical differences. METHODS: Thirteen TDCS montages, including conventional M1-contralateral forehead montages with different stimulating electrode sizes as well as 4 × 1 HD and bipolar HD montages, producing varying EF focalities were modeled using the finite element method in 77 subjects, with individual anatomically realistic models based on magnetic resonance images. RESULTS: Interindividual variability of predicted EFs increased with EF focality for conventional M1-contralateral forehead and 4 × 1 HD montages. 4 × 1 HD-TDCS was found to have the highest EF focality and greatest variability. Bipolar HD montages targeting the region between two small electrodes did not follow this pattern, but produced EF magnitudes comparable to those of 4× 1 HD-TDCS, with a minor decrease in focality and lower interindividual variability. CONCLUSIONS: EF focality in TDCS was achieved at the cost of increased interindividual variability. Hence, individual modeling is required to plan EF doses when focal montages are used. Among the studied montages, bipolar HD montages provided a compromise between inter-individual variability, focality and magnitude of the predicted EFs.

Investigation into the effect of transcranial direct current stimulation on cardiac pacemakers.

BACKGROUND: Studies investigating the therapeutic applications of transcranial direct current stimulation (tDCS) in the treatment of age-related neurodegenerative disease have been promising. However, exclusion criteria for these studies invariably disqualify patients implanted with internal cardiac pacemakers, citing safety concerns. Because the majority of cardiac pacemaker implantees are over 65, this criterion may limit candidacy for tDCS based research and/or treatment of age-related neurodegenerative disease. OBJECTIVE/HYPOTHESIS: We will test the hypothesis that tDCS impacts pacemaker function. Strong electrical potentials, such as those generated by external defibrillators (∼500 V, ∼10 A), are known to occasionally damage pacemaker circuitry and software, but it seems unlikely tDCS would damage a pacemaker because it involves about 1/200th the energy (∼12 V, ∼2 mA) of an external defibrillator. METHODS: We delivered tDCS to seven participants (ages 70-92) with bipolar non-dependent pacemakers and subsequently collected data from the internal memory of the pacemakers to assess the tDCS signal detection, as well as alterations in mode switches, impedance levels, and pacing. Subsequently, similar assessments were carried out in participants who were pacemaker-dependent (ages 89-91). RESULTS: After a review of the recordings, it was found that tDCS had no impact on the non-dependant, as well as the dependent, pacemakers. There were zero mode switches nor any impact on impedance levels. CONCLUSION: Results in this small series of cases found no evidence that tDCS interferes with the function of the pacemakers and suggests tDCS can be delivered to patients equipped with a cardiac pacemaker. Further studies are needed to generalize these results to other pacemakers.

Dose-controlled tDCS reduces electric field intensity variability at a cortical target site.

BACKGROUND: Variable effects limit the efficacy of transcranial direct current stimulation (tDCS) as a research and therapeutic tool. Conventional application of a fixed-dose of tDCS does not account for inter-individual differences in anatomy (e.g. skull thickness), which varies the amount of current reaching the brain. Individualised dose-control may reduce the variable effects of tDCS by reducing variability in electric field (E-field) intensities at a cortical target site. OBJECTIVE: To characterise the variability in E-field intensity at a cortical site (left primary motor cortex; M1) and throughout the brain for conventional fixed-dose tDCS, and individualised dose-controlled tDCS. METHODS: The intensity and distribution of the E-field during tDCS was estimated using Realistic Volumetric Approach to Simulate Transcranial Electric Stimulation (ROAST) in 50 individual brain scans taken from the Human Connectome Project, for fixed-dose tDCS (1 mA & 2 mA) and individualised dose-controlled tDCS targeting left M1. RESULTS: With a fixed-dose (1 mA & 2 mA), E-field intensity in left M1 varied by more than 100% across individuals, with substantial variation observed throughout the brain as well. Individualised dose-control ensured the same E-field intensity was delivered to left M1 in all individuals. Its variance in other regions of interest (right M1 and area underneath the electrodes) was comparable with fixed- and individualised-dose. CONCLUSIONS: Individualised dose-control can eliminate the variance in E-field intensities at a cortical target site. Assuming that the current delivered to the brain directly determines its physiological and behavioural consequences, this approach may allow for reducing the known variability of tDCS effects.

Augmenting the unified protocol for transdiagnostic treatment of emotional disorders with transcranial direct current stimulation in individuals with generalized anxiety disorder and comorbid depression: A randomized controlled trial.

BACKGROUND: The aim of the current study was to compare the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) with and without transcranial direct current stimulation (tDCS) in individuals suffering from generalized anxiety disorder (GAD) and comorbid depression. METHODS: A total of 43 individuals diagnosed with GAD and comorbid depression enrolled in a randomized controlled trial (IRCT20140929019334N1). Participants were randomly assigned to three groups including UP with tDCS (UP+tDCS; n = 15), UP alone (UP; n = 13) or wait-list control (n = 15). GAD and depression symptoms, worry severity, anxiety sensitivity, and intolerance of uncertainty were assessed at baseline, post-treatment and 3-month follow-up. RESULTS: Treatment with both UP+tDCS and UP alone resulted in significant lower ratings across all measures relative to wait-list controls at post-treatment and 3-month follow-up (all p-values <0.001). UP+tDCS showed significantly greater reductions in anxiety (p = 0.001 post-treatment; p = 0.003 follow-up), worry (p = 0.001 post-treatment; p = 0.002 follow-up), and anxiety sensitivity (p = 0.003 post-treatment; p = 0.002 follow-up) relative to UP alone. LIMITATIONS: The present study had some limitations. First, the sample size was low. Another limitation was the use of a short-term follow-up. CONCLUSIONS: These results suggest augmenting UP treatment with tDCS may be an efficacious strategy to improve treatment outcomes in GAD with comorbid depression. Trial registration reference is IRCT20140929019334N1 (see https://irct.ir/trial/27988).

Value and limitations of intracranial recordings for validating electric field modeling for transcranial brain stimulation.

Comparing electric field simulations from individualized head models against in-vivo intra-cranial recordings is considered the gold standard for direct validation of computational field modeling for transcranial brain stimulation and brain mapping techniques such as electro- and magnetoencephalography. The measurements also help to improve simulation accuracy by pinning down the factors having the largest influence on the simulations. Here we compare field simulations from four different automated pipelines against intracranial voltage recordings in an existing dataset of 14 epilepsy patients. We show that modeling differences in the pipelines lead to notable differences in the simulated electric field distributions that are often large enough to change the conclusions regarding the dose distribution and strength in the brain. Specifically, differences in the automatic segmentations of the head anatomy from structural magnetic resonance images are a major factor contributing to the observed field differences. However, the differences in the simulated fields are not reflected in the comparison between the simulations and intra-cranial measurements. This apparent mismatch is partly explained by the noisiness of the intra-cranial measurements, which renders comparisons between the methods inconclusive. We further demonstrate that a standard regression analysis, which ignores uncertainties in the simulations, leads to a strong bias in the estimated linear relationship between simulated and measured fields. Ignoring this bias leads to the incorrect conclusion that the models systematically misestimate the field strength in the brain. We propose a new Bayesian regression analysis of the data that yields unbiased parameter estimates, along with their uncertainties, and gives further insights to the fit between simulations and measurements. Specifically, the unbiased results give only weak support for systematic misestimations of the fields by the models.

Unification of optimal targeting methods in transcranial electrical stimulation.

One of the major questions in high-density transcranial electrical stimulation (TES) is: given a region of interest (ROI) and electric current limits for safety, how much current should be delivered by each electrode for optimal targeting of the ROI? Several solutions, apparently unrelated, have been independently proposed depending on how "optimality" is defined and on how this optimization problem is stated mathematically. The least squares (LS), weighted LS (WLS), or reciprocity-based approaches are the simplest ones and have closed-form solutions. An extended optimization problem can be stated as follows: maximize the directional intensity at the ROI, limit the electric fields at the non-ROI, and constrain total injected current and current per electrode for safety. This problem requires iterative convex or linear optimization solvers. We theoretically prove in this work that the LS, WLS and reciprocity-based closed-form solutions are specific solutions to the extended directional maximization optimization problem. Moreover, the LS/WLS and reciprocity-based solutions are the two extreme cases of the intensity-focality trade-off, emerging under variation of a unique parameter of the extended directional maximization problem, the imposed constraint to the electric fields at the non-ROI. We validate and illustrate these findings with simulations on an atlas head model. The unified approach we present here allows a better understanding of the nature of the TES optimization problem and helps in the development of advanced and more effective targeting strategies.

Application of Transcranial Direct Current Stimulation in Psychiatry.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique, which noninvasively alters cortical excitability via weak polarizing currents between two electrodes placed on the scalp. Since it is comparably easy to handle, cheap to use and relatively well tolerated, tDCS has gained increasing interest in recent years. Based on well-known behavioral effects, a number of clinical studies have been performed in populations including patients with major depressive disorder followed by schizophrenia and substance use disorders, in sum with heterogeneous results with respect to efficacy. Nevertheless, the potential of tDCS must not be underestimated since it could be further improved by systematically investigating the various stimulation parameters to eventually increase clinical efficacy. The present article briefly explains the underlying physiology of tDCS, summarizes typical stimulation protocols and then reviews clinical efficacy for various psychiatric disorders as well as prevalent adverse effects. Future developments include combined and more complex interactions of tDCS with pharmacological or psychotherapeutic interventions. In particular, using computational models to individualize stimulation protocols, considering state dependency and applying closed-loop technologies will pave the way for tDCS-based personalized interventions as well as the development of home treatment settings promoting the role of tDCS as an effective treatment option for patients with mental health problems.

Machine learning validation of EEG+tACS artefact removal.

OBJECTIVE: Electroencephalography (EEG) recorded during transcranial alternating current simulation (tACS) is highly desirable in order to investigate brain dynamics during stimulation, but is corrupted by large amplitude stimulation artefacts. Artefact removal algorithms have been presented previously, but with substantial debates on their performance, utility, and the presence of any residual artefacts. This paper investigates whether machine learning can be used to validate artefact removal algorithms. The postulation is that residual artefacts in the EEG after cleaning would be independent of the experiment performed, making it impossible to differentiate between different parts of an EEG+tACS experiment, or between different behavioural tasks performed. APPROACH: Ten participates undertook two tasks (nBack and backwards digital recall) during simultaneous EEG+tACS, exercising different aspects of working memory. Stimulations during no task and sham conditions were also performed. A previously reported tACS artefact removal algorithm from our group was used to clean the EEG and a linear discriminant analysis was trained on the cleaned EEG to differentiate different parts of the experiment. MAIN RESULTS: Baseline, baseline during tACS, working memory task without tACS, and working memory task with tACS data segments could be differentiated with accuracies ranging from 65%-94%, far exceeding chance levels. EEG from the nBack and backwards digital recall tasks could be separated during stimulation, with an accuracy exceeding 72%. If residual tACS artefacts remained after the EEG cleaning these did not dominate the classification process. SIGNIFICANCE: This helps in building confidence that true EEG information is present after artefact removal. Our methodology presents a new approach to validating tACS artefact removal approaches.

Current challenges: the ups and downs of tACS.

The non-invasive delivery of electric currents through the scalp (transcranial electrical stimulation) is a popular tool for neuromodulation, mostly due to its highly adaptable nature (waveform, montage) and tolerability at low intensities (< 2 mA). Applied rhythmically, transcranial alternating current stimulation (tACS) may entrain neural oscillations in a frequency- and phase-specific manner, providing a causal perspective on brain-behaviour relationships. While the past decade has seen many behavioural and electrophysiological effects of tACS that suggest entrainment-mediated effects in the brain, it has been difficult to reconcile such reports with the weak intracranial field strengths (< 1 V/m) achievable at conventional intensities. In this review, we first describe the ongoing challenges faced by users of tACS. We outline the biophysics of electrical brain stimulation and the factors that contribute to the weak field intensities achievable in the brain. Since the applied current predominantly shunts through the scalp-stimulating the nerves that innervate it-the plausibility of transcutaneous (rather than transcranial) effects of tACS is also discussed. In examining the effects of tACS on brain activity, the complex problem of salvaging electrophysiological recordings from artefacts of tACS is described. Nevertheless, these challenges by no means mark the rise and fall of tACS: the second part of this review outlines the recent advancements in the field. We describe some ways in which artefacts of tACS may be better managed using high-frequency protocols, and describe innovative methods for current interactions within the brain that offer either dynamic or more focal current distributions while also minimising transcutaneous effects.