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This review aims to demonstrate the connections between event-related potentials (ERPs), event-related oscillations (EROs), and non-invasive brain stimulation (NIBS), with a specific focus on transcranial alternating current stimulation (tACS). We begin with a short examination and discussion of the relation between ERPs and EROs. Then, we investigate the diverse fields of NIBS, highlighting tACS as a potent tool for modulating neural oscillations and influencing cognitive performance. Emphasizing the impact of tACS on individual ERP components, this article offers insights into the potential of conventional tACS for targeted stimulation of single ERP components. Furthermore, we review recent articles that explore a novel approach of tACS: ERP-aligned tACS. This innovative technique exploits the temporal precision of ERP components, aligning tACS with specific neural events to optimize stimulation effects and target the desired neural response. In conclusion, this review combines current knowledge to explore how ERPs, EROs, and NIBS interact, particularly highlighting the modulatory possibilities offered by tACS. The incorporation of ERP-aligned tACS introduces new opportunities for future research, advancing our understanding of the complex connection between neural oscillations and cognitive processes., (© 2024. The Author(s).)

Theta oscillations support memory formation, but their exact contribution to the communication between prefrontal cortex (PFC) and the hippocampus is unknown. We tested the functional relevance of theta oscillations as a communication link between both areas for memory formation using transcranial alternating current stimulation (tACS). Healthy, young participants learned two lists of Dutch-German word pairs and retrieved them immediately and with a 30-min delay. In the encoding group (N = 30), tACS was applied during the encoding of list 1. List 2 was used to test stimulation aftereffects. In the retrieval group (N = 23), we stimulated during the delayed recall. In both groups, we applied tACS bilaterally at prefrontal and tempo-parietal sites, using either individualized theta frequency or 15 Hz (as control), according to a within-subject design. Stimulation with theta-tACS did not alter overall learning performance. An exploratory analysis revealed that immediate recall improved when word-pairs were learned after theta-tACS (list 2). Applying theta-tACS during retrieval had detrimental effects on memory. No changes in the power of the respective frequency bands were observed. Our results do not support the notion that impacting the communication between PFC and the hippocampus during a task by bilateral tACS improves memory. However, we do find evidence that direct stimulation had a trend for negatively interfering effects during immediate and delayed recall. Hints for beneficial effects on memory only occurred with aftereffects of the stimulation. Future studies need to further examine the effects during and after stimulation on memory formation., (© 2024. The Author(s).)

Background: Studies using transcranial alternating current stimulation (tACS), a type of non-invasive brain stimulation, have demonstrated a relationship between the positive versus negative phase of both alpha and delta/theta oscillations with variable near-threshold auditory perception. These findings have not been directly compared before. Furthermore, as perception was better in the positive versus negative phase of two different frequencies, it is unclear whether changes in polarity (independent of a specific frequency) could also modulate auditory perception., Objective: We investigated whether auditory perception depends on the phase of alpha, delta/theta, or polarity alone., Methods: We stimulated participants with alpha, delta, and positive and negative direct current (DC) over temporal and central scalp sites while they identified near-threshold tones-in-noise. A Sham condition without tACS served as a control condition. A repeated-measures analysis of variance was used to assess differences in proportions of hits between conditions and polarities. Permutation-based circular-logistic regressions were used to assess the relationship between circular-predictors and single-trial behavioral responses. An exploratory analysis compared the full circular-logistic regression model to the intercept-only model., Results: Overall, there were a greater proportion of hits in the Alpha condition in comparison to Delta, DC, and Sham conditions. We also found an interaction between polarity and stimulation condition; post-hoc analyses revealed a greater proportion of hits in the positive versus negative phase of Alpha tACS. In contrast, no significant differences were found in the Delta, DC, or Sham conditions. The permutation-based circular-logistic regressions did not reveal a statistically significant difference between the obtained RMS of the sine and cosine coefficients and the mean of the surrogate distribution for any of the conditions. However, our exploratory analysis revealed that circular-predictors explained the behavioral data significantly better than an intercept-only model for the Alpha condition, and not the other three conditions., Conclusion: These findings suggest that alpha tACS, and not delta nor polarity alone, modulates auditory perception., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CSH has filed a patent application on brain stimulation and received honoraria as editor from Elsevier Publishers, Amsterdam. SV and MF do not have any conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The underlying mechanisms of the event-related potential (ERP) generation are still under debate. One popular model considers the ERP as a superposition of phase-resets of ongoing endogenous oscillations of different frequencies. Brain oscillations have been shown to be modulated by transcranial alternating current stimulation (tACS). Thus, it seems feasible, that an ERP could be altered by modulating the contributing oscillations using tACS. One possible approach would be to target a frequency-matched stimulation signal to a specific ERP-component. One possible target for such an approach is the P3, which appears as delta/theta oscillations in the frequency-domain. Thus, an ERP-aligned stimulation in the delta/theta-range might be suitable to force synchronization in the stimulated frequency band and thus increase the amplitude of the P3 component. Building on an existing paradigm, in the present study 21 healthy participants received individualized ERP-aligned delta tACS and control stimulation while performing a visual task. The visual stimulation was matched to the continuous tACS in order to align the tACS peak with the P3 peak. Both the P3 amplitude and the evoked delta power were significantly increased after ERP-aligned tACS but not after control stimulation. The investigated behavioral parameter showed no stimulation dependent effect. Our results may provide new insights into the debate on the contribution of phase-reset mechanisms to the generation of ERPs and offer new opportunities for clinical trials., Competing Interests: Declaration of competing interest CSH holds a patent on brain stimulation and cooperates with Neuroconn GmbH, a manufacturer of brain stimulation devices. CB and HIS declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Covert visuo-spatial attention is marked by the anticipatory lateralization of neuronal alpha activity in the posterior parietal cortex. Previous applications of transcranial alternating current stimulation (tACS) at the alpha frequency, however, were inconclusive regarding the causal contribution of oscillatory activity during visuo-spatial attention., Objective: Attentional shifts of behavior and electroencephalography (EEG) after-effects were assessed in a cued visuo-spatial attention paradigm. We hypothesized that parietal alpha-tACS shifts attention relative to the ipsilateral visual hemifield. Furthermore, we assumed that modulations of behavior and neurophysiology are related to individual electric field simulations., Methods: We applied personalized tACS at alpha and gamma frequencies to elucidate the role of oscillatory neuronal activity for visuo-spatial attention. Personalized tACS montages were algorithmically optimized to target individual left and right parietal regions that were defined by an EEG localizer., Results: Behavioral performance in the left hemifield was specifically increased by alpha-tACS compared to gamma-tACS targeting the left parietal cortex. This hemisphere-specific effect was observed despite the symmetry of simulated electric fields. In addition, visual event-related potential (ERP) amplitudes showed a reduced lateralization over posterior sites induced by left alpha-tACS. Neuronal sources of this effect were localized in the left premotor cortex. Interestingly, accuracy modulations induced by left parietal alpha-tACS were directly related to electric field magnitudes in the left premotor cortex., Conclusion: Overall, results corroborate the notion that alpha lateralization plays a causal role in covert visuo-spatial attention and indicate an increased susceptibility of parietal and premotor brain regions of the left dorsal attention network to subtle tACS-neuromodulation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CSH holds a patent on brain stimulation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-invasive techniques to electrically stimulate the brain such as transcranial direct and alternating current stimulation (tDCS/tACS) are increasingly used in human neuroscience and offer potential new avenues to treat brain disorders. Previous research has shown that stimulation effects may depend on brain-states. However, this work mostly focused on experimentally induced brain-states over the course of several minutes. Besides such global, long-term changes in brain-states, previous research suggests, that the brain is likely to spontaneously alternate between states in sub-second ranges, which is much closer to the time scale at which it is generally believed to operate. Here, we utilized Hidden Markov Models (HMM) to decompose magnetoencephalography data obtained before and after tACS into spontaneous, transient brain-states with distinct spatial, spectral and connectivity profiles. Only one out of four spontaneous brain-states, likely reflecting default mode network activity, showed evidence for an effect of tACS on the power of spontaneous α-oscillations. The identified state appears to disproportionally drive the overall (non-state resolved) tACS effect. No or only marginal effects were found in the remaining states. We found no evidence that tACS influenced the time spent in each state. Although stimulation was applied continuously, our results indicate that spontaneous brain-states and their underlying functional networks differ in their susceptibility to tACS. Global stimulation aftereffects may be disproportionally driven by distinct time periods during which the susceptible state is active. Our results may pave the ground for future work to understand which features make a specific brain-state susceptible to electrical stimulation., Competing Interests: Declaration of Competing Interest CSH holds a patent on brain stimulation. FHK, declares no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Deep brain stimulation (DBS) provides clinical benefits for several neurological and psychiatric conditions. By overcoming the limitations and risks of conventional DBS, transcranial temporal interference stimulation (tTIS) has the potential to offer non-invasive stimulation of deep brain regions. However, research that investigates the efficacy of tTIS is limited to animal studies or computer simulations and its capability to modulate neural oscillations in humans has not been demonstrated so far. The method of tTIS is hypothesized to elicit its effects via neural entrainment, corresponding to the supposed mechanism of action underlying transcranial alternating current stimulation (tACS), another, more established non-invasive brain stimulation technique. Physiological effects of tACS are well established for cortical brain oscillations, but not for deep brain structures. In particular, aftereffects on the power of parieto-occipital alpha oscillations have been shown repeatedly. In a first attempt to test the efficacy of tTIS in the human brain, the current study thus seeks to compare the effects of tTIS to the well-studied aftereffect of tACS in the cortex. To investigate this research question, the current study compared MEG-recorded brain activity during a simple visual change detection task in 34 healthy subjects pre- and post-tTIS. Additionally, the effects of tTIS were contrasted to conventional tACS and a control stimulation. We expected that the parieto-occipital α-power will increase after tTIS and tACS, in contrast to the control stimulation. Overall, no difference between the experimental groups (tTIS, tACS and control stimulation) were found regarding the source-projected increase in α-power. Based on the results of the study two hypothesis can be made: tTIS, tACS and the control stimulation condition don't have an effect on human brain oscillations in the α-band, or, any experimental conditions of the current study can modulate brain oscillations in the α-band. Both hypotheses emphasize the importance of further studies investigating different carrier frequencies, and the comparison to sham stimulation., Competing Interests: Declaration of competing interest CSH holds a patent on brain stimulation. KS is the manufacturer of the advanced DC stimulator plus (Neuroconn, Ilmenau, Germany). JC, FHK, BCB and AA declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A variety of perceptual phenomena suggest that, in contrast to our everyday experience, our perception may be discrete rather than continuous. The possibility of such discrete sampling processes inevitably prompts the question of how such discretization is implemented in the brain. Evidence from neurophysiological measurements suggest that neural oscillations, particularly in the lower frequencies, may provide a mechanism by which such discretization can be implemented. It is hypothesized that cortical excitability is rhythmically enhanced or reduced along the positive and negative half-cycle of such oscillations. In recent years, rhythmic non-invasive brain stimulation approaches such as rhythmic transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) are increasingly used to test this hypothesis. Both methods are thought to entrain endogenous brain oscillations, allowing them to alter their power, frequency, and phase in order to study their roles in perception. After a brief introduction to the core mechanisms of both methods, we will provide an overview of rTMS and tACS studies probing the role of brain oscillations for discretized perception in different domains and will contrast these results with unsuccessful attempts. Further, we will discuss methodological pitfalls and challenges associated with the methods., (© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility., (© 2022. © The Author(s).)

Background: Visual phenomena like brightness illusions impressively demonstrate the highly constructive nature of perception. In addition to physical illumination, the subjective experience of brightness is related to temporal neural dynamics in visual cortex., Objective: Here, we asked whether biasing the temporal pattern of neural excitability in visual cortex by transcranial alternating current stimulation (tACS) modulates brightness perception of concurrent rhythmic visual stimuli., Methods: Participants performed a brightness discrimination task of two flickering lights, one of which was targeted by same-frequency electrical stimulation at varying phase shifts. tACS was applied with an occipital and a periorbital active control montage, based on simulations of electrical currents using finite element head models., Results: Experimental results reveal that flicker brightness perception is modulated dependent on the phase shift between sensory and electrical stimulation, solely under occipital tACS. Phase-specific modulatory effects by tACS were dependent on flicker-evoked neural phase stability at the tACS-targeted frequency, recorded prior to electrical stimulation. Further, the optimal timing of tACS application leading to enhanced brightness perception was correlated with the neural phase delay of the cortical flicker response., Conclusions: Our results corroborate the role of temporally coordinated neural activity in visual cortex for brightness perception of rhythmic visual input in humans. Phase-specific behavioral modulations by tACS emphasize its efficacy to transfer perceptually relevant temporal information to the cortex. These findings provide an important step towards understanding the basis of visual perception and further confirm electrical stimulation as a tool for advancing controlled modulations of neural activity and related behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Transcranial temporal interference stimulation (tTIS) is a novel non-invasive brain stimulation technique for electrical stimulation of neurons at depth. Deep brain regions are generally small in size, making precise targeting a necessity. The variability of electric fields across individual subjects resulting from the same tTIS montages is unknown so far and may be of major concern for precise tTIS targeting. Therefore, the aim of the current study is to investigate the variability of the electric fields due to tTIS across 25 subjects. To this end, the electric fields of different electrode montages consisting of two electrode pairs with different center frequencies were simulated in order to target selected regions-of-interest (ROIs) with tTIS. Moreover, we set out to compare the electric fields of tTIS with the electric fields of conventional tACS. The latter were also based on two electrode pairs, which, however, were driven in phase at a common frequency. Our results showed that the electric field strengths inside the ROIs (left hippocampus, left motor area and thalamus) during tTIS are variable on single subject level. In addition, tTIS stimulates more focally as compared to tACS with much weaker co-stimulation of cortical areas close to the stimulation electrodes. Electric fields inside the ROI were, however, comparable for both methods. Overall, our results emphasize the potential benefits of tTIS for the stimulation of deep targets, over conventional tACS. However, they also indicate a need for individualized stimulation montages to leverage the method to its fullest potential., (© 2021. The Author(s).)

Transcranial alternating current stimulation (tACS) is a unique form of non-invasive brain stimulation. Sinusoidal alternating electric currents are delivered to the scalp to affect mostly cortical neurons. tACS is supposed to modulate brain function and, in turn, cognitive processes by entraining brain oscillations and inducing long-term synaptic plasticity. Therefore, tACS has been investigated in cognitive neuroscience, but only recently, it has been also introduced in psychiatric clinical trials. This review describes current concepts and first findings of applying tACS as a potential therapeutic tool in the field of psychiatry. The current understanding of its mechanisms of action is explained, bridging cellular neuronal activity and the brain network mechanism. Revisiting the relevance of altered brain oscillations found in six major psychiatric disorders, putative targets for the management of mental disorders using tACS are discussed. A systematic literature search on PubMed was conducted to report findings of the clinical studies applying tACS in patients with psychiatric conditions. In conclusion, the initial results may support the feasibility of tACS in clinical psychiatric populations without serious adverse events. Moreover, these results showed the ability of tACS to reset disturbed brain oscillations, and thus to improve behavioural outcomes. In addition to its potential therapeutic role, the reactivity of the brain circuits to tACS could serve as a possible tool to determine the diagnosis, classification or prognosis of psychiatric disorders. Future double-blind randomised controlled trials are necessary to answer currently unresolved questions. They may aim to detect response predictors and control for various confounding factors.

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disease with a prevalence of 2%-7.5% among the population. It is characterized by three core symptoms: hyperactivity, impulsivity, and inattention. Although the majority of ADHD patients respond to a combination of psychotherapy and standard pharmacotherapy with Methylphenidate, there is a significant minority of patients that do not respond to these substances. Additionally, the treatment with Methylphenidate can cause a variety of side effects like insomnia, headache, decreased appetite, and xerostomia. It would be favorable to have an alternative treatment-option that could circumnavigate the shortcomings of traditional pharmacological treatments. Recent results show that transcranial electrical stimulation (tES) might offer a promising approach. Since research has shown that ADHD is associated with various alterations in brain activity, brain stimulation methods targeting different facets of neuronal functions are currently under investigation. In this article, we briefly review different tES techniques like transcranial random noise stimulation (tRNS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) and explain the modes of action of these brain stimulations. We will specifically focus on transcranial alternating current stimulation (tACS) as a potential method of treating ADHD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Oscillatory phase has been proposed as a key parameter defining the spatiotemporal structure of neural activity. To enhance our understanding of brain rhythms and improve clinical outcomes in pathological conditions, modulation of neural activity by transcranial alternating current stimulation (tACS) emerged as a promising approach. However, the phase-specificity of tACS effects in humans is still critically debated., Objective: Here, we investigated the phase-specificity of tACS on visually evoked steady state responses (SSRs) in 24 healthy human participants., Methods: We used an intermittent electrical stimulation protocol and assessed the influence of tACS on SSR amplitude in the interval immediately following tACS. A neural network model served to validate the plausibility of experimental findings., Results: We observed a modulation of SSR amplitudes dependent on the phase shift between flicker and tACS. The tACS effect size was negatively correlated with the strength of flicker-evoked activity. Supported by simulations, data suggest that strong network synchronization limits further neuromodulation by tACS. Neural sources of phase-specific effects were localized in the parieto-occipital cortex within flicker-entrained regions. Importantly, the optimal phase shift between flicker and tACS associated with strongest SSRs was correlated with SSR phase delays in the tACS target region., Conclusions: Overall, our data provide electrophysiological evidence for phase-specific modulations of rhythmic brain activity by tACS in humans. As the optimal timing of tACS application was dependent on cortical SSR phase delays, our data suggest that tACS effects were not mediated by retinal co-stimulation. These findings highlight the potential of tACS for controlled, phase-specific modulations of neural activity., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Orienting spatial attention has been associated with interhemispheric asymmetry of power in the α- and γ-band. Specifically, increased α-power has been linked to the inhibition of unattended sensory streams (e.g. the unattended visual field), while increased γ-power is associated with active sensory processing. Here, we aimed to differentially modulate endogenous and exogenous visual-spatial attention using transcranial alternating current stimulation (tACS). In a single-blind, within-subject design, participants performed several blocks of a spatial cueing task comprised of endogenous and exogenous cues while receiving lateralized α- or γ-tACS or no stimulation over left or right occipital-parietal areas. We found a significant, differential effect of α- and γ-tACS on endogenous (top-down) spatial attention but not on exogenous (bottom-up) attention. The effect was specific to tACS applied to the left hemisphere and driven by a modulation of attentional disengagement and re-orientation as measured during invalid trials. Our results indicate a causal role of α-/γ-oscillations for top-down (endogenous) attention. They may further suggest a left hemispheric dominance in controlling interhemispheric α-/γ-power asymmetry. The absence of an effect on exogenous attention may be indicative of a differential role of α-/γ-oscillations during different attention types or spatially distinct attentional subsystems.

Gamma oscillations (30-80 Hz) are well-known for their role in cortical signal transmission and cognitive brain functions. Aberrant gamma activity has been observed in various neuropsychiatric disorders, but the clinical potential of restoring gamma oscillations via noninvasive brain stimulation has been widely neglected. Only recently, therapeutic effects of gamma entrainment were documented in mouse models of Alzheimer's dementia (AD) using rhythmic sensory stimulation. In the present review, we first summarize the current status of the research on gamma entrainment in mouse models of AD and human AD patients. Then, we suggest transcranial alternating current stimulation (tACS) as an alternative brain stimulation technique and review the recent literature on the effects of gamma tACS in healthy volunteers and neuropsychiatric diseases to document the efficacy of gamma tACS in improving cognitive functions. We discuss several advantages of tACS compared to rhythmic sensory stimulation for the entrainment of gamma oscillations in the human brain and emphasize the need for more clinical studies applying tACS to drive gamma oscillations and, in turn, to improve cognitive functioning not only in AD but also in patients suffering from other neuropsychiatric disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The visual system has one of the most complex structures of all sensory systems and is perhaps the most important sense for everyday life. Its functional organization was extensively studied for decades in animal and humans, for example by correlating circumscribed anatomical lesions in patients with the resulting visual dysfunction. During the past two decades, significant achievements were accomplished in characterizing and modulating visual information processing using non-invasive stimulation techniques of the normal and damaged human eye and brain. Techniques include transcranial magnetic stimulation (TMS) and low intensity electric stimulation using either direct or alternating currents applied transcranially (tDCS or tACS) near or above the visual cortex, or alternating currents applied transorbitally (trACS). In the case of transorbital stimulation of the visual system the electrodes are attached near the eye, to the eyelids (transpalpebral electrical stimulation - TPES) or the cornea (tanscorneal electrical stimulation TcES). Here, we summarize the state-of-the-art of visual system magnetic and electric stimulation as a method to modulate normal vision, induce brain plasticity, and to restore visual functions in patients. We review this field's history, models of current flow paths in the eye and brain, neurophysiological principles (e.g. entrainment and after-effects), the effects on vision in normal subjects and the clinical impact on plasticity and vision restoration in patients with low vision, with a particular focus on "off-line" or "after-effects". With regard to the therapeutic possibilities, ACS was demonstrated to be effective in patients affected by glaucoma and optic neuropathy, while tDCS and random noise stimulation (tRNS) are most promising for the treatment of amblyopia, hemianopia and myopia. In addition, rTMS applied above the occipital area is a promising approach to treat migraine, neglect and hemianopia. Although the response to these treatment options is better than to sham stimulation in double blinded clinical studies, the clinical efficacy is still rather variable and a proportion of patients do not respond. It is therefore imperative to better understand the mechanisms of action to be able to optimize treatment protocols possibly through personalization of brain stimulation protocols. By identifying the current opportunities and challenges in the field, we hope to provide insights to help improve neuromodulation protocols to restore visual function in patients with visual system damage., Competing Interests: Declaration of Competing Interest We would like to declare that B.A. Sabel is shareholder of a vision rehabilitation day clinic. The other authors have no conflicts of interest, financial or otherwise, and all concur with the conditions of submission of the manuscript in the present form., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Self-motion perception is a key aspect of higher vestibular processing, suggested to rely upon hemispheric lateralization and alpha-band oscillations. The first aim of this study was to test for any lateralization in the EEG alpha band during the illusory sense of self-movement (vection) induced by large optic flow stimuli. Visual stimuli flickered at alpha frequency (approx. 10 Hz) in order to produce steady state visually evoked potentials (SSVEPs), a robust EEG measure which allows probing the frequency-specific response of the cortex. The first main result was that differential lateralization of the alpha SSVEP response was found during vection compared with a matched random motion control condition, supporting the idea of lateralization of visual-vestibular function. Additionally, this effect was frequency-specific, not evident with lower frequency SSVEPs. The second aim of this study was to test for a causal role of the right hemisphere in producing this lateralization effect and to explore the possibility of selectively modulating the SSVEP response. Transcranial alternating current stimulation (tACS) was applied over the right hemisphere simultaneously with SSVEP recording, using a novel artefact removal strategy for combined tACS-EEG. The second main result was that tACS enhanced SSVEP amplitudes, and the effect of tACS was not confined to the right hemisphere. Subsequent control experiments showed the effect of tACS requires the flicker frequency and tACS frequency to be closely matched and tACS to be of sufficient intensity. Combined tACS-SSVEPs are a promising method for future investigation into the role of neural oscillations and for optimizing tACS., (© 2019 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Studies examining event-related potentials (ERP) in patients affected by attention deficit/hyperactivity disorder (ADHD) have found considerable evidence of reduced target P300 amplitude across different perceptual modalities. P300 amplitude has been related to attention-driven context comparison and resource allocation processes. Altered P300 amplitude in ADHD can be reasonably assumed to be related to ADHD typical cognitive performance deficits. Transcranial alternating current stimulation (tACS) can increase the amplitude of endogenous brain oscillations. Because ERP components can be viewed as event-related oscillations (EROs), with P300 translating into the delta (0-4 Hz) and theta (4-8 Hz) frequency range, an increase of delta and theta ERO amplitudes by tACS should result in an increase of P300 amplitudes in ADHD patients. In this pilot study, 18 adult ADHD patients (7 female) performed three consecutive blocks of a visual oddball task while the electroencephalogram (EEG) was recorded. Patients received either 20 min of tACS or sham stimulation at a stimulation intensity of 1 mA. Individual stimulation frequency was determined using a time-frequency decomposition of the P300. Our preliminary results demonstrate a significant increase in P300 amplitude in the stimulation group which was accompanied by a decrease in omission errors pre-to-post tACS. However, studies including larger sample sizes are advised.

Recent research provides evidence for a functional role of brain oscillations for perception. For example, auditory temporal resolution seems to be linked to individual gamma frequency of auditory cortex. Individual gamma frequency not only correlates with performance in between-channel gap detection tasks but can be modulated via auditory transcranial alternating current stimulation. Modulation of individual gamma frequency is accompanied by an improvement in gap detection performance. Aging changes electrophysiological frequency components and sensory processing mechanisms. Therefore, we conducted a study to investigate the link between individual gamma frequency and gap detection performance in elderly people using auditory transcranial alternating current stimulation. In a within-subject design, twelve participants were electrically stimulated with two individualized transcranial alternating current stimulation frequencies: 3 Hz above their individual gamma frequency (experimental condition) and 4 Hz below their individual gamma frequency (control condition), while they were performing a between-channel gap detection task. As expected, individual gamma frequencies correlated significantly with gap detection performance at baseline and in the experimental condition, transcranial alternating current stimulation modulated gap detection performance. In the control condition, stimulation did not modulate gap detection performance. In addition, in elderly, the effect of transcranial alternating current stimulation on auditory temporal resolution seems to be dependent on endogenous frequencies in auditory cortex: Elderlies with slower individual gamma frequencies and lower auditory temporal resolution profit from auditory transcranial alternating current stimulation and show increased gap detection performance during stimulation. Our results strongly suggest individualized transcranial alternating current stimulation protocols for successful modulation of performance., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Transcranial electrical stimulation (tES) of the brain can have variable effects, plausibly driven by individual differences in neuroanatomy and resulting differences of the electric fields inside the brain. Here, we integrated individual simulations of electric fields during tES with source localization to predict variability of transcranial alternating current stimulation (tACS) aftereffects on α-oscillations. In two experiments, participants received 20-min of either α-tACS (1 mA) or sham stimulation. Magnetoencephalogram (MEG) was recorded for 10-min before and after stimulation. tACS caused a larger power increase in the α-band compared to sham. The variability of this effect was significantly predicted by measures derived from individual electric field modeling. Our results directly link electric field variability to variability of tACS outcomes, underline the importance of individualizing stimulation protocols, and provide a novel approach to analyze tACS effects in terms of dose-response relationships.

Transcranial alternating current stimulation (tACS) is increasingly used as a tool to non-invasively modulate brain oscillations in a frequency specific manner. A growing body of neuroscience research utilizes tACS to probe causal relationships between neuronal oscillations and cognitive processes or explore its capability of restoring dysfunctional brain oscillations implicated in various neurological and psychiatric disease. However, the underlying mechanisms of action are yet poorly understood. Due to a massive electromagnetic artifact, overlapping with the frequency of interest, direct insights to effects during stimulation from electrophysiological signals (i.e. EEG/MEG) are methodologically challenging. In the current review, we provide an overview of analysis approaches to recover brain signals in M/EEG during tACS, detailing their underlying concepts as well as limitations and methodological and interpretational pitfalls. While different analysis strategies can achieve strong attenuation of the tACS artifact in M/EEG signals, a compete removal of it is not feasible so far. However, we argue that with a combination of careful experimental designs, robust outcome measures and appropriate control analyses, valid and important insights to online effects of tACS can be revealed, enriching our understanding of its basic underlying mechanisms.

Transcranial direct current stimulation (tDCS) is a noninvasive method that delivers current through the scalp to enhance or suppress brain activity. The standard way of applying tDCS is by the use of two large rectangular sponge electrodes on the scalp. The resulting currents often stimulate a broad region of the brain distributed over brain networks. In order to address this issue, recently, multi-electrode transcranial direct current stimulation with optimized montages has been used to stimulate brain regions of interest (ROI) with improved trade-off between focality and intensity of the electrical current at the target brain region. However, in many cases only the location of target region is considered and not the orientation. Here we emphasize the importance of calculating the individualized target location and orientation by combined electroencephalography and magnetoencephalography (EMEG) source analysis in individualized skull-conductivity calibrated finite element method (FEM) head models and stimulate the target region by four different tDCS montages. We have chosen the generator of the P20/N20 component, located at Brodmann area 3b and oriented mainly from posterior to anterior directions as our target for stimulation because it can be modeled as a single dipole source with a fixed position and orientation. The simulations will deliver optimized excitatory and inhibitory electrode montages that are in future investigations compared to standard and sham tDCS in a somatosensory experiment. We also present a new constrained maximum intensity (CMI) optimization approach that better distributes the currents over multiple electrodes, therefore should lead to less tingling and burning sensations at the skin, and thus allows an easier realization of the sham condition significantly reducing the current intensity parallel to the target.

Amplitude modulated transcranial alternating current stimulation (AM-tACS) has been recently proposed as a possible solution to overcome the pronounced stimulation artifact encountered when recording brain activity during tACS. In theory, AM-tACS does not entail power at its modulating frequency, thus avoiding the problem of spectral overlap between brain signal of interest and stimulation artifact. However, the current study demonstrates how weak non-linear transfer characteristics inherent to stimulation and recording hardware can reintroduce spurious artifacts at the modulation frequency. The input-output transfer functions (TFs) of different stimulation setups were measured. Setups included recordings of signal-generator and stimulator outputs and M/EEG phantom measurements. 6 th -degree polynomial regression models were fitted to model the input-output TFs of each setup. The resulting TF models were applied to digitally generated AM-tACS signals to predict the frequency of spurious artifacts in the spectrum. All four setups measured for the study exhibited low-frequency artifacts at the modulation frequency and its harmonics when recording AM-tACS. Fitted TF models showed non-linear contributions significantly different from zero (all p < .05) and successfully predicted the frequency of artifacts observed in AM-signal recordings. Results suggest that even weak non-linearities of stimulation and recording hardware can lead to spurious artifacts at the modulation frequency and its harmonics. These artifacts were substantially larger than alpha-oscillations of a human subject in the MEG. Findings emphasize the need for more linear stimulation devices for AM-tACS and careful analysis procedures, taking into account low-frequency artifacts to avoid confusion with effects of AM-tACS on the brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Indicators for a decrement in vigilance are a slowdown in reaction times and an increase in alpha power in the electroencephalogram in posterior regions of the brain. Transcranial alternating current stimulation (tACS) is a neuropsychological technique that has been found to interact with intrinsic brain oscillations and is able to enhance cognitive and behavioral performance. Recent studies show that tACS in the gamma frequency range (30-80 Hz) is able to downregulate amplitudes in the alpha frequency range (8-12 Hz), in accordance to the effect referred to as cross-frequency coupling, where intrinsic alpha and gamma waves modulate each other. We applied 40 Hz gamma-tACS to the visual cortex during a vigilance experiment and investigated if stimulation improves reaction times and error rates with time-on-task. In our sham controlled experiment, participants completed two blocks of 30 minutes duration while performing the same visual two-choice task. The first block was used as BASELINE. A statistical analysis with a linear mixed model revealed a significantly lower increase of modeled reaction times over time in the INTERVENTION-block of the tACS-group as compared with their BASELINE-block whereas there was no significant change between the BASELINE- and INTERVENTION-block for the SHAM-group. Error rates did not differ between groups. This paper indicates that gamma-tACS can enhance performance in vigilance tasks as it significantly decreased the slowdown of reaction times in our study.

Non-invasive approaches to modulate oscillatory activity in the brain are increasingly popular in the scientific community. Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations in a frequency-specific manner. However, due to a massive stimulation artifact at the targeted frequency, little is known about effects of tACS during stimulation. It remains unclear how the continuous application of tACS affects event-related oscillations during cognitive tasks. Depending on whether tACS influences pre- or post-stimulus oscillations, or both, the endogenous, event-related oscillatory dynamics could be pushed in various directions or not at all. A better understanding of these effects is crucial to plan, predict, and understand outcomes of solely behavioral tACS experiments. In the present study, a recently proposed procedure to suppress tACS artifacts by projecting MEG data into source-space using spatial filtering was utilized to recover event-related power modulations in the alpha-band during a mental rotation task. MEG data of 25 human subjects was continuously recorded. After 10-minute baseline measurement, participants received either 20 minutes of tACS at their individual alpha frequency or sham stimulation. Another 40 minutes of MEG data were acquired thereafter. Data were projected into source-space and carefully examined for residual artifacts. Results revealed strong facilitation of event-related power modulations in the alpha-band during tACS application. These results provide first direct evidence that tACS does not counteract top-down suppression of intrinsic oscillations, but rather enhances pre-existent power modulations within the range of the individual alpha (= stimulation) frequency.

Background: Spatial attention relatively increases the power of neural 10-Hz alpha oscillations in the hemisphere ipsilateral to attention, and decreases alpha power in the contralateral hemisphere. For gamma oscillations (>40 Hz), the opposite effect has been observed. The functional roles of lateralised oscillations for attention are currently unclear., Hypothesis: If lateralised oscillations are functionally relevant for attention, transcranial stimulation of alpha versus gamma oscillations in one hemisphere should differentially modulate the accuracy of spatial attention to the ipsi-versus contralateral side., Methods: 20 human participants performed a dichotic listening task under continuous transcranial alternating current stimulation (tACS, vs sham) at alpha (10 Hz) or gamma (47 Hz) frequency. On each trial, participants attended to four spoken numbers on the left or right ear, while ignoring numbers on the other ear. In order to stimulate a left temporo-parietal cortex region, which is known to show marked modulations of alpha power during auditory spatial attention, tACS (1 mA peak-to-peak amplitude) was applied at electrode positions TP7 and FC5 over the left hemisphere., Results: As predicted, unihemispheric alpha-tACS relatively decreased the recall of targets contralateral to stimulation, but increased recall of ipsilateral targets. Importantly, this spatial pattern of results was reversed for gamma-tACS., Conclusions: Results provide a proof of concept that transcranially stimulated oscillations can enhance spatial attention and facilitate attentional selection of speech. Furthermore, opposite effects of alpha versus gamma stimulation support the view that states of high alpha are incommensurate with active neural processing as reflected by states of high gamma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Non-invasive brain stimulation to target specific network activity patterns, e.g. transcranial alternating current stimulation (tACS), has become an essential tool to understand the causal role of neuronal oscillations in cognition and behavior. However, conventional sinusoidal tACS limits the ability to record neuronal activity during stimulation and lacks spatial focality. One particularly promising new tACS stimulation paradigm uses amplitude-modulated (AM) high-frequency waveforms (AM-tACS) with a slow signal envelope that may overcome the limitations. Moreover. AM-tACS using high-frequency carrier signals is more tolerable than conventional tACS, e.g. in terms of skin irritation and occurrence of phosphenes, when applied at the same current intensities (e.g. 1-2 mA). Yet, the fundamental mechanism of neuronal target-engagement by AM-tACS waveforms has remained unknown. We used a computational model of cortex to investigate how AM-tACS modulates endogenous oscillations and compared the target engagement mechanism to the case of conventional (unmodulated) low-frequency tACS. Analysis of stimulation amplitude and frequency indicated that cortical oscillations were phase-locked to the envelope of the AM stimulation signal, which thus exhibits the same target engagement mechanism as conventional (unmodulated) low frequency tACS. However, in the computational model substantially higher current intensities were needed for AM-tACS than for low-frequency (unmodulated) tACS waveforms to achieve pronounced phase synchronization. Our analysis of the carrier frequency suggests that there might be a trade-off between the use of high-frequency carriers and the stimulation amplitude required for successful entrainment. Together, our computational simulations support the use of slow-envelope high frequency carrier AM waveforms as a tool for noninvasive modulation of brain oscillations. More empirical data will be needed to identify the optimal stimulation parameters and to evaluate tolerability and safety of both, AM- and conventional tACS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cortical entrainment of the auditory cortex to the broadband temporal envelope of a speech signal is crucial for speech comprehension. Entrainment results in phases of high and low neural excitability, which structure and decode the incoming speech signal. Entrainment to speech is strongest in the theta frequency range (4-8 Hz), the average frequency of the speech envelope. If a speech signal is degraded, entrainment to the speech envelope is weaker and speech intelligibility declines. Besides perceptually evoked cortical entrainment, transcranial alternating current stimulation (tACS) entrains neural oscillations by applying an electric signal to the brain. Accordingly, tACS-induced entrainment in auditory cortex has been shown to improve auditory perception. The aim of the current study was to modulate speech intelligibility externally by means of tACS such that the electric current corresponds to the envelope of the presented speech stream (i.e., envelope-tACS). Participants performed the Oldenburg sentence test with sentences presented in noise in combination with envelope-tACS. Critically, tACS was induced at time lags of 0-250 ms in 50-ms steps relative to sentence onset (auditory stimuli were simultaneous to or preceded tACS). We performed single-subject sinusoidal, linear, and quadratic fits to the sentence comprehension performance across the time lags. We could show that the sinusoidal fit described the modulation of sentence comprehension best. Importantly, the average frequency of the sinusoidal fit was 5.12 Hz, corresponding to the peaks of the amplitude spectrum of the stimulated envelopes. This finding was supported by a significant 5-Hz peak in the average power spectrum of individual performance time series. Altogether, envelope-tACS modulates intelligibility of speech in noise, presumably by enhancing and disrupting (time lag with in- or out-of-phase stimulation, respectively) cortical entrainment to the speech envelope in auditory cortex., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Temporal resolution of cortical, auditory processing mechanisms is suggested to be linked to peak frequency of neuronal gamma oscillations in auditory cortex areas (individual gamma frequency, IGF): Individuals with higher IGF tend to have better temporal resolution., Hypothesis: Modulating ongoing gamma activity with transcranial alternating current stimulation (tACS) is expected to improve performance in gap detection (GD) tasks (shorter GD thresholds) if the frequency is higher and to decrease GD performance (longer GD thresholds) if the frequency is lower than IGF., Methods: For 26 healthy participants the IGF and temporal resolution were identified using an auditory steady state response (ASSR) paradigm and a between-channel GD task. Finite element modelling was used to generate an optimized tACS electrode montage (one channel per hemisphere: FC5-TP7/P7 and FC6-TP8/P8). Afterwards, GD thresholds were examined during tACS (tACS frequency group A: above IGF, tACS frequency group B: below IGF). Relative changes of GD thresholds were compared between groups. Additionally, effects of tACS on oscillatory activity were investigated comparing relative changes of ASSR amplitudes before and after stimulation., Results: Performance of group-A-participants improved significantly during tACS in comparison to performance of group-B-participants. Significant relative changes of ASSR amplitudes were found in both groups., Conclusion: The possibility to improve gap detection with individualized stimulation protocols for tACS further supports the link between oscillatory activity and temporal resolution, whereby the improvement of temporal resolution is particularly relevant for the clinical aspect of auditory tACS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m 2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence., (Copyright © 2017 International Federation of Clinical Neurophysiology. All rights reserved.)

Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Despite recent success in analyzing brain oscillations recorded during transcranial alternating current stimulation (tACS), the field still requires further research to establish standards in artifact removal methods. This includes taking a step back from the removal of the tACS artifact and thoroughly characterizing the to-be-removed artifact. A recent study by Noury et al. (2016) contributed importantly to this endeavour by showing the existence of nonlinear artefacts in the tACS signal as seen by MEG and EEG. Unfortunately however this paper conveys the message that current artifact removal attempts have failed altogether and that-based on these available tools-brain oscillations recorded during tACS cannot be analyzed using MEG and EEG. Here we want to balance this overly pessimistic conclusion: In-depth reanalyses of our own data and phantom-head measurements indicate that nonlinearities can occur, but only when technical limits of the stimulator are reached. As such they are part of the "real" stimulation and not a specific MEG analysis problem. Future tACS studies should consider these technical limits to avoid any nonlinear modulations of the tACS artifact. We conclude that even with current approaches, brain oscillations recorded during tACS can be meaningfully studied in many practical cases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cross-frequency coupling (CFC) has been suggested to constitute a highly flexible mechanism for cortical information gating and processing, giving rise to conscious perception and various higher cognitive functions in humans. In particular, it might provide an elegant tool for information integration across several spatiotemporal scales within nested or coupled neuronal networks. However, it is currently unknown whether low-frequency (theta/alpha) or high-frequency gamma oscillations orchestrate cross-frequency interactions, raising the question of who is master and who is slave. While correlative evidence suggested that at least two distinct CFC modes exist, namely, phase-amplitude-coupling (PAC) and amplitude-envelope correlations (AEC), it is currently unknown whether they subserve distinct cortical functions. Novel non-invasive brain stimulation tools, such as transcranial alternating current stimulation (tACS), now provide the unique opportunity to selectively entrain the low- or high-frequency component and study subsequent effects on CFC. Here, we demonstrate the differential modulation of CFC during selective entrainment of alpha or gamma oscillations. Our results reveal that entrainment of the low-frequency component increased PAC, where gamma power became preferentially locked to the trough of the alpha oscillation, while gamma-band entrainment enhanced AECs and reduced alpha power. These results provide causal evidence for the functional role of coupled alpha and gamma oscillations for visual processing., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To explore the relationship between transcranial current stimulation (tCS) and the electroencephalography (EEG) forward problem, we investigate and compare accuracy and efficiency of a reciprocal and a direct EEG forward approach for dipolar primary current sources both based on the finite element method (FEM), namely the adjoint approach (AA) and the partial integration approach in conjunction with a transfer matrix concept (PI). By analyzing numerical results, comparing to analytically derived EEG forward potentials and estimating computational complexity in spherical shell models, AA turns out to be essentially identical to PI. It is then proven that AA and PI are also algebraically identical even for general head models. This relation offers a direct link between the EEG forward problem and tCS. We then demonstrate how the quasi-analytical EEG forward solutions in sphere models can be used to validate the numerical accuracies of FEM-based tCS simulation approaches. These approaches differ with respect to the ease with which they can be employed for realistic head modeling based on MRI-derived segmentations. We show that while the accuracy of the most easy to realize approach based on regular hexahedral elements is already quite high, it can be significantly improved if a geometry-adaptation of the elements is employed in conjunction with an isoparametric FEM approach. While the latter approach does not involve any additional difficulties for the user, it reaches the high accuracies of surface-segmentation based tetrahedral FEM, which is considerably more difficult to implement and topologically less flexible in practice. Finally, in a highly realistic head volume conductor model and when compared to the regular alternative, the geometry-adapted hexahedral FEM is shown to result in significant changes in tCS current flow orientation and magnitude up to 45° and a factor of 1.66, respectively., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Many studies have proven transcranial alternating current stimulation (tACS) to manipulate brain activity. Until now it is not known, however, how these manipulations in brain activity are represented in brain metabolism or how spatially specific these changes are. Alpha-tACS has been shown to enhance the amplitude of the individual alpha frequency (IAF) and a negative correlation between alpha amplitude and occipital BOLD signal was reported in numerous EEG/fMRI experiments. Thus, alpha-tACS was chosen to test the effects of tACS on the BOLD signal. A reduction thereof was expected during alpha-tACS which shows the spatial extent of tACS effects beyond modeling studies. Three groups of subjects were measured in an MRI scanner, receiving tACS at either their IAF (N=11), 1Hz (control; N=12) or sham (i.e., no stimulation - a second control; N=11) while responding to a visual vigilance task. Stimulation was administered in an interleaved pattern of tACS-on runs and tACS-free baseline periods. The BOLD signal was analyzed in response to tACS-onset during resting state and in response to seldom target stimuli. Alpha-tACS at 1.0mA reduced the task-related BOLD response to visual targets in the occipital cortex as compared to tACS-free baseline periods. The deactivation was strongest in an area where the BOLD signal was shown to correlate negatively with alpha amplitude. A direct effect of tACS on resting state BOLD signal levels could not be shown. Our findings suggest that tACS-related changes in BOLD activity occur only as a modulation of an existing BOLD response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Transcranial alternating current stimulation (tACS) is used to modulate brain oscillations to measure changes in cognitive function. It is only since recently that brain activity in human subjects during tACS can be investigated. The present study aims to investigate the phase relationship between the external tACS signal and concurrent brain activity. Subjects were stimulated with tACS at individual alpha frequency during eyes open and eyes closed resting states. Electrodes were placed at Cz and Oz, which should affect parieto-occipital areas most strongly. Source space magnetoencephalography (MEG) data were used to estimate phase coherence between tACS and brain activity. Phase coherence was significantly increased in areas in the occipital pole in eyes open resting state only. The lag between tACS and brain responses showed considerable inter-individual variability. In conclusion, tACS at individual alpha frequency entrains brain activity in visual cortices. Interestingly, this effect is state dependent and is clearly observed with eyes open but only to a lesser extent with eyes closed.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain., (Copyright © 2015 International Federation of Clinical Neurophysiology. All rights reserved.)

Background. Transcranial alternating current stimulation (tACS) is a relatively recent method suited to noninvasively modulate brain oscillations. Technically the method is similar but not identical to transcranial direct current stimulation (tDCS). While decades of research in animals and humans has revealed the main physiological mechanisms of tDCS, less is known about the physiological mechanisms of tACS. Method. Here, we review recent interdisciplinary research that has furthered our understanding of how tACS affects brain oscillations and by what means transcranial random noise stimulation (tRNS) that is a special form of tACS can modulate cortical functions. Results. Animal experiments have demonstrated in what way neurons react to invasively and transcranially applied alternating currents. Such findings are further supported by neural network simulations and knowledge from physics on entraining physical oscillators in the human brain. As a result, fine-grained models of the human skull and brain allow the prediction of the exact pattern of current flow during tDCS and tACS. Finally, recent studies on human physiology and behavior complete the picture of noninvasive modulation of brain oscillations. Conclusion. In future, the methods may be applicable in therapy of neurological and psychiatric disorders that are due to malfunctioning brain oscillations.

Transcranial alternating current stimulation (tACS) is a new technique for the modulation of oscillatory brain activity as measured in the electroencephalogram (EEG). In contrast to well-established stimulation techniques, such as transcranial direct current stimulation and transcranial magnetic stimulation, tACS applies a sinusoidal alternating current at a specific frequency. This enables the modulation of the amplitude and frequency of endogenous brain oscillations as well as related cognitive processes. Therefore, the use of tACS has the possibility to evaluate well-known correlations between brain oscillations and cognitive processes in terms of causality. Such causal relationships have been documented in numerous neurocognitive studies on sensory, motor and perceptual processes; however, the clinical application of tACS is still in its infancy. In principle, any pathology that can reliably be connected with brain oscillations of a defined frequency is treatable. A current main focus of clinical research is on symptoms of Parkinson's disease and to a lesser degree, tinnitus. For an effective application of tACS it is important to choose the electrode positions as well as the frequency, intensity and duration of the stimulation in a theory-based and symptom-related manner. A successful therapeutic intervention requires the persistence of the tACS effect after stimulation has ceased. A mechanism that offers not only an explanation to the origin of persistent tACS effects but is also of high therapeutic benefit is neural plasticity. Therefore, one current focus of research aims at a better understanding of tACS after effects.

Brain oscillations are supposedly crucial for normal cognitive functioning and alterations are associated with cognitive dysfunctions. To demonstrate their causal role on behavior, entrainment approaches in particular aim at driving endogenous oscillations via rhythmic stimulation. Within this context, transcranial electrical stimulation, especially transcranial alternating current stimulation (tACS), has received renewed attention. This is likely due to the possibility of defining oscillatory stimulation properties precisely. Also, measurements comparing pre-tACS with post-tACS electroencephalography (EEG) have shown impressive modulations. However, the period during tACS has remained a blackbox until now, due to the enormous stimulation artifact. By means of application of beamforming to magnetoencephalography (MEG) data, we successfully recovered modulations of the amplitude of brain oscillations during weak and strong tACS. Additionally, we demonstrate that also evoked responses to visual and auditory stimuli can be recovered during tACS. The main contribution of the present study is to provide critical evidence that during ongoing tACS, subtle modulations of oscillatory brain activity can be reconstructed even at the stimulation frequency. Future tACS experiments will be able to deliver direct physiological insights in order to further the understanding of the contribution of brain oscillations to cognition and behavior., (Copyright © 2015. Published by Elsevier Inc.)

Background: Non-invasive brain stimulation with transcranial alternating currents (tACS) has been shown to entrain slow cortical oscillations and thereby influence various aspects of visual perception. Much less is known about its potential effects on auditory perception., Objective: In the present study, we apply a novel variant that enables near-equivalent stimulation of both auditory cortices to investigate the causal role of the phase of 4-Hz cortical oscillations for auditory perception., Methods: We measured detection performance for near-threshold auditory stimuli (4-Hz click trains) that were presented at various moments during ongoing tACS (two synchronous 4-Hz alternating currents applied transcranially to the two cerebral hemispheres)., Results: We found that changes in the relative timing of acoustic and electric stimulation cause corresponding perceptual changes that oscillate predominantly at the 4-Hz frequency of the electric stimulation, which is consistent with previous results based on 10-Hz tACS., Conclusion: TACS at various frequencies can affect auditory perception. Together with converging previous results based on acoustic stimulation (rather than tACS), this finding implies that fundamental aspects of auditory cognition are mediated by the temporal coherence of sound-induced cortical activity with ongoing cortical oscillations at multiple time scales., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Oscillatory neuronal synchronization between cortical areas has been suggested to constitute a flexible mechanism to coordinate information flow in the human cerebral cortex. However, it remains unclear whether synchronized neuronal activity merely represents an epiphenomenon or whether it is causally involved in the selective gating of information. Here, we combined bilateral high-density transcranial alternating current stimulation (HD-tACS) at 40 Hz with simultaneous electroencephalographic (EEG) recordings to study immediate electrophysiological effects during the selective entrainment of oscillatory gamma-band signatures. We found that interhemispheric functional connectivity was modulated in a predictable, phase-specific way: In-phase stimulation enhanced synchronization, anti-phase stimulation impaired functional coupling. Perceptual correlates of these connectivity changes were found in an ambiguous motion task, which strongly support the functional relevance of long-range neuronal coupling. Additionally, our results revealed a decrease in oscillatory alpha power in response to the entrainment of gamma band signatures. This finding provides causal evidence for the antagonistic role of alpha and gamma oscillations in the parieto-occipital cortex and confirms that the observed gamma band modulations were physiological in nature. Our results demonstrate that synchronized cortical network activity across several spatiotemporal scales is essential for conscious perception and cognition., Competing Interests: The authors have declared that no competing interests exist.