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BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. 84 participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSION: Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD. NATIONAL CLINICAL TRIAL: NCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)” https://www.clinicaltrials.gov/ct2/show/NCT03449979

Neuromodulation has gained attention as a potential non-pharmacological intervention for mild cognitive impairment (MCI). However, no studies have directly compared the effects of transcranial alternating current stimulation (tACS) with transcranial direct current stimulation (tDCS) on MCI patients. We aimed to identify the more promising and efficient therapeutic option between tACS and tDCS for cognitive enhancement in MCI patients. We compared the effects of gamma-tACS with tDCS on cognitive function and electroencephalography (EEG) in MCI patients. In this sham-controlled, double-blinded, repeated-measures study with the order of the stimulation counterbalanced across patients (n = 20), both gamma-tACS (40 H z) and tDCS were administered at the same intensity (2 mA) in the dorsolateral prefrontal cortex for 30 min. Cognitive tests (Stroop and Trail-Making-Test [TMT]) and EEG were performed before and after single-session stimulation. Gamma-tACS improved the Stroop-color in comparison with tDCS (p = .044) and sham (p = .010) and enhanced the TMT-B in comparison with sham (p = .021). However, tDCS was not significantly different from sham in changes of any cognitive test scores. In EEG analysis, gamma-tACS increased beta activity in comparison with sham and tDCS, whereas tDCS decreased delta and theta activity in comparison with sham. Gamma-tACS also increased beta 2 source activity in the anterior cingulate, compared to sham. The cognitive benefits of tACS in MCI patients appeared superior to those of tDCS. tACS facilitated cognitive function by increasing beta activity, while tDCS delayed the progression of MCI symptoms by decreasing slow-frequency activity. Thus, tACS could be used as a new therapeutic option for MCI.

BACKGROUND: Noninvasive transcranial electrical stimulation (tES) research has been plagued with inconsistent effects. Recent work has suggested neuroanatomical and neurophysiological variability may alter tES efficacy. However, direct evidence is limited. OBJECTIVE: We have previously replicated effects of transcranial alternating current stimulation (tACS) on improving multitasking ability in young adults. Here, we attempt to assess whether these stimulation parameters have comparable effects in older adults (aged 60–80 years), which is a population known to have greater variability in neuroanatomy and neurophysiology. It is hypothesized that this variability in neuroanatomy and neurophysiology will be predictive of tACS efficacy. METHODS: We conducted a pre-registered study where tACS was applied above the prefrontal cortex (between electrodes F3-F4) while participants were engaged in multitasking. Participants were randomized to receive either 6-Hz (theta) tACS for 26.67 minutes daily for three days (80 minutes total; Long Exposure Theta group), 6-Hz tACS for 5.33 minutes daily (16-minutes total; Short Exposure Theta group), or 1-Hz tACS for 26.67 minutes (80 minutes total; Control group). To account for neuroanatomy, magnetic resonance imaging data was used to form individualized models of the tACS-induced electric field (EF) within the brain. To account for neurophysiology, electroencephalography data was used to identify individual peak theta frequency. RESULTS: Results indicated that only in the Long Theta group, performance change was correlated with modeled EF and peak theta frequency. Together, modeled EF and peak theta frequency accounted for 54% – 65% of the variance in tACS-related performance improvements, which sustained for a month. CONCLUSION: These results demonstrate the importance of individual differences in neuroanatomy and neurophysiology in tACS research and help account for inconsistent effects across studies.

Objective We examined the effects of caffeine, time of day, and alertness fluctuation on plasticity effects after transcranial alternating current stimulation (tACS) or 25 ms paired associative stimulation (PAS25) in caffeine-naive and caffeine-adapted subjects. Methods In two randomised, double-blinded, cross-over or placebo-controlled (caffeine) studies, we measured sixty subjects in eight sessions (n = 30, Male: Female = 1:1 in each study). Results We found caffeine increased motor cortex excitability in caffeine naive subjects. The aftereffects in caffeine naive subjects were enhanced and prolonged when combined with PAS 25. Caffeine also increased alertness and the motor evoked potentials (MEPs) were reduced under light deprivation in caffeine consumers both with and without caffeine. In caffeine consumers, the time of day had no effect on tACS-induced plasticity. Conclusions We conclude that caffeine should be avoided or controlled as confounding factor for brain stimulation protocols. It is also important to keep the brightness constant in all sessions and study groups should not be mixed with caffeine-naive and caffeine consuming participants. Significance Caffeine is one of the confounding factors in the plasticity induction studies and it induces different excitability effects in caffeine-naive and caffeine-adapted subjects. This study was registered in the ClinicalTrials.gov with these registration IDs: 1) NCT03720665 https://clinicaltrials.gov/ct2/results?cond=NCT03720665&term=&cntry=&state=&city=&dist= 2) NCT04011670 https://clinicaltrials.gov/ct2/results?cond=&term=NCT04011670&cntry=&state=&city=&dist=

Background it is well-known that the cerebellum is critical for the integrity of motor and cognitive actions. Applying non-invasive brain stimulation techniques over this region results in neurophysiological and behavioural changes, which have been associated with the modulation of cerebellar-cerebral cortex connectivity. Here, we investigated whether online application of cerebellar transcranial alternating current stimulation (tACS) results in changes to this pathway. Methods thirteen healthy individuals participated in two sessions of cerebellar tACS delivered at different frequencies (5Hz and 50Hz). We used transcranial magnetic stimulation to measure cerebellar-motor cortex (M1) inhibition (CBI), short-intracortical inhibition (SICI) and short-afferent inhibition (SAI) before, during and after the application of tACS. Results we found that CBI was specifically strengthened during the application of 5Hz cerebellar tACS. No changes were detected immediately following the application of 5Hz stimulation, nor at any time point with 50Hz stimulation. We also found no changes to M1 intracortical circuits (i.e. SICI) or sensorimotor interaction (i.e. SAI), indicating that the effects of 5Hz tACS over the cerebellum are site-specific. Conclusions cerebellar tACS can modulate cerebellar excitability in a time- and frequency-dependent manner. Additionally, cerebellar tACS does not appear to induce any long-lasting effects (i.e. plasticity), suggesting that stimulation enhances oscillations within the cerebellum only throughout the stimulation period. As such, cerebellar tACS may have significant implications for diseases manifesting with abnormal cerebellar oscillatory activity and also for future behavioural studies., Highlights • Cerebellar tACS increases the inhibitory tone that the cerebellum exerts over M1 (CBI). • CBI changes were found only during the online application of 5Hz tACS and not immediately following stimulation. • The effects are specific to the cerebellum, as no changes were found in intracortical measures (e.g. SICI and SAI).

Nearly one billion people worldwide suffer from obsessive-compulsive behaviors(1,2), yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning(3,4), which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing(5,6). We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.

Objective The main limitation of neuromodulation techniques is inter-subject variability. Combining theta-burst stimulation (TBS) with gamma-transcranial alternating current stimulation (γ-tACS) allows to shape cortical plasticity. However, it is unknown whether γ-tACS modifies TBS-induced response variability. In this study, we measured the inter-subject variability of TBS-γ tACS and controlled the effect of the Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism. Methods Intermittent TBS (iTBS)-sham tACS, iTBS-γ tACS, continuous TBS (cTBS)-sham tACS, and cTBS-γ tACS were applied in randomised sessions. Inter-subject variability was measured using grand average and clustering methods. TBS-γ tACS effects on motor evoked potentials (MEP) were compared between Val/Val and Met carriers. Results We found that γ-tACS boosted iTBS-induced MEP facilitation and cancelled cTBS-induced MEP depression. Grand average analysis showed that γ-tACS prominently increased the percentage of iTBS responders and cTBS non-responders. The clustering method demonstrated that TBS-γ tACS response varied between subjects, a phenomenon unrelated to the BDNF genotype. Conclusions Enhancing γ oscillations through tACS boosts iTBS-induced LTP-like plasticity and suppresses cTBS-induced LTD-like plasticity of the primary motor cortex in a reliable manner. The BDNF Val66Met polymorphism does not influence these effects. Significance Since γ-tACS significantly increases the number of iTBS responders, it may be used in clinical settings.

Major depression is one of the most common psychiatric disorders with a high rate of treatment resistance where new treatment options are urgently warranted. One of these new options are non-invasive brain stimulation techniques like transcranial magnetic or electric stimulation. One of the latter is transcranial Alternating Current Stimulation (tACS) in various frequencies. Here, we report a case series of six patients suffering from major depression treated with tACS in gamma (40 Hz) frequency. Patients were randomized to two groups, receiving either two 10-min stimulations (group 1) or a 20-min stimulation or per day (group 2) over ten days. Hamilton Depression Rating Scale and Beck Depression Inventory decreased during treatment in both study groups by 85% and 78% (group 1), or 62% and 24% respectively (group 2). Results also showed an improvement in cognitive functions assessed by word fluency and n-back test. It is hypothesized that gamma tACS could help to synchronize disturbed frequency bands in frontal and prefrontal cortex areas and thus restore dysbalanced neural connectivity in psychiatric disorders.

Transcranial alternating current stimulation (tACS) is a non-invasive method of brain stimulation that modulates oscillatory neural activity in the cortical area under the electrodes. Gamma (γ)-tACS applied over the primary motor cortex (M1) and cerebellar hemisphere is known to improve motor performance; however, it is not yet known whether it affects motor learning. Thus, here we investigated whether γ-tACS applied over the M1 and cerebellar hemisphere affects motor learning. This study involved 30 healthy subjects (14 females, 16 males) performing a visuomotor control task (eight trials) during an administration of either γ-tACS or a sham stimulation (15 subjects per condition) over their right M1 and left cerebellar hemisphere. Each subject performed five trials after 24 h. The motor learning efficiency, motor learning retention and re-motor learning efficiency in each condition were compared. The motor learning retention in the γ-tACS condition was significantly higher than that in the sham condition (p = 0.031). Thus, subjects who were administered γ-tACS maintained their motor performance the next day better than sham-stimulated subjects. There was no significant difference between the conditions in the motor learning efficiency and those in the re-motor learning efficiency. Our results demonstrate that γ-tACS administered over the M1 and cerebellar hemisphere during a motor learning task can enhance motor learning retention.

Background : Antidepressant use in pregnancy is associated with high levels of decision-making difficulty for patients, and psychotherapy may not be effective for severe symptoms. Alternative treatment options are needed. We conducted a systematic review of the clinical effects and tolerability of non-invasive neurostimulation: repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), trigeminal nerve stimulation (TNS), and transcutaneous vagus nerve stimulation (tVNS) for the treatment of antenatal depression. Methods : We searched PubMed, Google Scholar and Scopus for published articles in English (1990 to June 2019). Two reviewers reviewed full-text articles, assessed quality, and extracted data on maternal psychiatric, pregnancy and neonatal outcomes. Results : Of 565 articles, 21 met inclusion criteria: two RCTs (1 rTMS; 1 tDCS), four open-label studies (3 rTMS; 1 tDCS), three case series (3 rTMS), and twelve case reports (9 rTMS; 1 tDCS; 1 tACS; 1 TNS). In all but one published study (1 rTMS), non-invasive neurostimulation resulted in either response or remission of antenatal depression. Minor maternal side effects were reported in rTMS and tDCS studies, but not in other modalities. Fetal adverse effects were not reported in any intervention. A small proportion of participants dropped out of treatment (rTMS, tDCS). Limitations : Very few randomized trials have been conducted and there is significant heterogeneity in the parameters of the modalities that have been studied. Conclusions : Non-invasive neurostimulation holds promise as a potentially effective and feasible alternative treatment for antenatal depression. Strategies to enhance recruitment of pregnant women into non-invasive neurostimulation trials that have longitudinal follow-up are needed.

Background Recording electroencephalography (EEG) from the targeted cortex immediately before and after focal transcranial electrical stimulation (TES) remains a challenge. Methods We introduce a hybrid stimulation-recording approach where a single EEG electrode is inserted into the inner electrode of a double-ring montage for focal TES. The new combined electrode was placed at the C3 position of the EEG 10–20 system. Neuronal activity was recorded in two volunteers before and after 20 Hz alternating-current TES at peak-to-peak intensities of 1 and 2 mA. TES-induced electric field distributions were simulated with SIMNIBS software. Results Using the hybrid stimulation-recording set-up, EEG activity was successfully recorded directly before and after TES. Simulations revealed comparable electrical fields in the stimulated cortex for the pseudomonopolar montage with and without embedded EEG electrode. Conclusion The hybrid TES-EEG approach can be used to probe after-effects of focal TES on neuronal activity in the targeted cortex.

Background Transcranial alternating current stimulation (tACS) can entrain and enhance cortical oscillatory activity in a frequency-dependent manner. In our previous study (Nakazono et al., 2016), 20 Hz (β) tACS significantly increased excitability of primary motor cortex compared with 10 Hz (α) tACS. α oscillations are a prominent feature of the primary visual cortex (V1) in a resting electroencephalogram. Hence, we investigated whether α and β tACS can differentially influence multiple visual functions. Methods Firstly, we evaluated the after-effects of α and β tACS on pattern-reversal (PR) and focal-flash (FF) visual evoked potentials (VEPs). Secondly, we determined the relationship between resting α oscillations and PR-VEPs modulated by tACS. Thirdly, the behavioral effects of tACS were assessed by contrast sensitivity. Results α tACS modulated the amplitudes of PR-VEPs, compared with β tACS, but did not modulate the FF-VEPs. Time-frequency analysis revealed that α tACS facilitated event-related α phase synchronizations without increasing power, which consequently increased the PR-VEP amplitudes. There was a significant positive correlation between PR-VEP amplitudes and resting α oscillations. These findings suggested that α tACS modulated α oscillations, and affected visual functions of contrast and spatial frequency. Indeed, α tACS also improved subjects’ contrast sensitivity at the behavioral level. Conversely, β tACS increased posterior α activity, but did not change VEP amplitudes. Conclusions α tACS can influence different neuronal populations from those influenced by β tACS. Thus, our results provide evidence that α tACS sharpens multiple visual functions by modulating α oscillations in V1.

Objective Conventional polysomnographic recordings reflect brain dynamics associated with sleep architecture. We hypothesized that noninvasive tools like transcranial alternating current stimulation (tACS) and acoustic stimulation (for generating event related potentials [ERPs]) would help to predict sleep stability and provide a window to actively assess brain activity during sleep. Materials and methods Twelve healthy male volunteers participated in the multiple whole-night polysomnography (PSG) recording protocol. Acoustic tones (100 msec duration) were presented throughout night to evaluate ERP during sleep. Furthermore, 30 sec tACS were presented during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep on subsequent two nights without disturbing the subject's sleep. For ERP analysis, event-locked artifact-free epochs from each sleep stage were averaged separately. For tACS analysis, 30 sec prestimulus and poststimulus artifact-free EEG epochs were subjected to bootstrapping-based comparison of power spectral values. Results Acoustic stimulation generated sleep stage-dependent ERP components (N350, N550, and P900) in all participants. The tACS stimulation during NREM sleep (0.75 Hz) increased parietal delta power but decreased frontocentral theta and increased frontal gamma power when delivered during REM sleep (40Hz). These interventions provide details on sleep stability as larger N550-P900 ERP-complex correlated with lower NREM disruptions (Spearman's rho = -0.553; p = 0.049; n = 10) and tACS-related theta power perturbation with higher REM disruptions (Spearman's rho = 0.734; p = 0.030; n = 7). Conclusions Noninvasive brain stimulation approaches such as sleep ERP and sleep tACS are reliable tools to evaluate sleep stability during NREM and REM sleep, respectively, but more large-sample studies are warranted.

Transcranial alternating current stimulation (tACS) has been shown to modulate neural connectivity in the cortical area under experimental electrodes. Although gamma tACS over the M1 region and the cerebellar hemisphere has been shown to improve motor performance, the optimal stimulation method has not been clarified. In this study, we aimed to clarify whether the effect of gamma tACS over M1 and the cerebellar hemisphere depends on current intensity. Twenty healthy adults performed a visuomotor control task using their right index finger for 30 s during tACS (70 Hz) over the left M1 and the right cerebellar hemisphere. Each subject participated in 10 trials, separated by intervals of 3 min. Three stimulation conditions were applied: (1) pseudo-stimulation (sham condition), (2) tACS with a current intensity of 1.0 mA and (3) tACS with a current intensity of 2.0 mA. Our results indicated that regardless of the current intensity, participants with the lower motor performance had better motor performance under both tACS conditions. Such a correlation was not observed under the sham condition. Collectively, our findings demonstrated that the effect of gamma tACS over M1 and the cerebellar hemisphere does not depend on current intensity, and that motor performance slightly improved in both tACS conditions for participants with lower motor performance.

Cortical activity in frontal, parietal, and motor regions during sequence observation correlates with performance on sequence reproduction. Increased cortical activity observed during observation has therefore been suggested to represent increased learning. Causal relationships have been demonstrated between M1 and motor sequence reproduction and between parietal cortex and bimanual learning. However, similar effects have not been reported for frontal regions despite a number of reports implicating its involvement in encoding of motor sequences. Investigating causal relations between cortical activity and reproduction of motor sequences in parietal, frontal and primary motor regions can disentangle whether specific regions during simple observation can be selectively ascribed to encoding or reproduction or both. We designed a sensorimotor paradigm that included a strong motor sequence component, and tested the impact of individually adjusted transcranial alternating current stimulation (IAF-tACS) to prefrontal, parietal, and primary motor regions on electroencephalographic motor rhythms (alpha and beta bandwidths) during motor sequence observation and the ability to reproduce the observed sequences. Independently of the stimulated region, IAF-tACS led to a reduction in suppression in the lower beta-range relative to sham. Prefrontal IAF-tACS however, led to significant improvement in motor sequence reproduction, pinpointing the crucial role of prefrontal regions in motor sequence reproduction.

Low frequency oscillations such as alpha (8-12 Hz) are hypothesized to rhythmically gate sensory processing, reflected by 40-100 Hz gamma band activity, via the mechanism of pulsed inhibition. We applied transcranial alternating current stimulation (TACS) at individual alpha frequency (IAF) and flanking frequencies (IAF-4 Hz, IAF+4 Hz) to the occipital cortex of healthy human volunteers during concurrent magnetoencephalography (MEG), while participants performed a visual detection task inducing strong gamma-band responses. Occipital (but not retinal) TACS phasically suppressed stimulus-induced gamma oscillations in the visual cortex and impaired target detection, with stronger phase-to-amplitude coupling predicting behavioral impairments. Retinal control TACS ruled out retino-thalamo-cortical entrainment resulting from (subthreshold) retinal stimulation. All TACS frequencies tested were effective, suggesting that visual gamma-band responses can be modulated by a range of low frequency oscillations. We propose that TACS-induced membrane potential modulations mimic the rhythmic change in cortical excitability by which spontaneous low frequency oscillations may eventually exert their impact when gating sensory processing via pulsed inhibition.

Background We have previously demonstrated that transcranial alternating current stimulation (tACS) can generate positive effects on multitasking performance and associated neurophysiological measures when it is applied with anti-phase theta band stimulation across bilateral prefrontal cortex (PFC) and a short (1-min) inter-session interval (ISI). However, it is unclear how altering the phase of stimulation and the duration of the ISI might impact positive tACS effects. Here, we investigated the role of tACS parameters in engendering performance improvements by manipulating these two stimulation parameters (i.e. phase and ISI) in two experiments. Methods Repetitive sessions of bilateral PFC theta-tACS were applied with in-phase stimulation + 1-min ISI (experiment 1) and anti-phase stimulation + 5-min ISI (experiment 2) while participants were engaged in a multitasking challenge accompanied by electroencephalography (EEG) data collection. Results Compared to the control group, in-phase stimulation + 1-min ISI showed an enhancement of multitasking performance coupled with a modulation of posterior alpha (8–12 Hz) and beta (13–30 Hz) activities. However, repetitive sessions of anti-phase tACS + 5-min ISI did not generate significant enhancement in multitasking performance, nor changes in neural oscillatory activities compared to the control group. Conclusion The results revealed that the previous reported positive tACS effects on multitasking performance are not affected by manipulating the phase of current polarity. Yet, changing the ISI of the stimulation protocol eliminated the previous observed performance improvements. Taken together, these results stress the importance of stimulation protocol for generating positive tACS effects on cognitive function and neural oscillations.

Non-invasive and invasive electrical neurostimulation are promising tools to better understand brain function and ultimately treat its malfunction. In current open-loop approaches, a clinician chooses a fixed set of stimulation parameters, informed by observed therapeutic benefits and previous empirical evidence. However, this procedure leads to a large intra- and inter-subject variability often introducing side-effects and low effect sizes. Closed-loop electrical neurostimulation (CLENS) approaches strive to alleviate these limitations by tailoring the stimulation parameters to an ongoing electrophysiological biomarker. Here, we review the current status of closed-loop, supraspinal electrical stimulation in humans, presenting our vision of potential control frameworks, and support the idea of creating synergies with the field of brain-machine interfacing. Finally, we pinpoint two pivotal challenges that, in our view, need to be overcome for this technology to become a reality: dealing with the electrical stimulation artifacts, and dissociating the pathological from physiological information within the targeted biomarker.

Exploring ones surroundings may yield unexpected rewards, but is associated with uncertainty and risk. Alternatively, exploitation of certain outcomes is related to low risk, yet potentially better outcomes remain unexamined. As such, risk-taking behavior depends on perceived uncertainty and a trade-off between exploration-exploitation. Previously, it has been suggested that risk-taking may relate to theta activity in the prefrontal cortex. Furthermore, previous studies hinted at a relationship between a right-hemispheric bias in frontal theta asymmetry and risky behavior. In the present double-blind sham-controlled within-subject study, we applied bifrontal transcranial alternating current stimulation (tACS) at the theta frequency (5 Hz) on eighteen healthy volunteers during a gambling task. Two tACS montages with either left-right or posterior-anterior current flow were employed at an intensity of 1 mA. Results showed that, compared to sham, theta tACS increased perceived uncertainty irrespective of current flow direction. Despite this observation, no direct effect of tACS on exploration behavior and general risk-taking was observed. Furthermore, frontal theta asymmetry was more right-hemispherically biased after posterior-anterior tACS, compared to sham. Finally, we used electric field simulation to identify which regions were targeted by the tACS montages as an overlap in regions may explain why the two montages resulted in comparable outcomes. Our findings provide a first step towards understanding the relationship between frontal theta oscillations and different features of risk-taking.Highlights–Risk taking is related to uncertainty, exploration and exploitation–Frontal theta tACS was applied to modulate aspects of risk taking–tACS did increase perceived uncertainty, but not exploration behavior–tACS induced a right hemispheric shift in frontal theta asymmetry

Motor function can be modulated by transcranial alternating current stimulation (tACS) in alpha, beta, and high-gamma frequencies. However, few studies have investigated tACS-induced behavioral changes in combination with endogenous oscillatory neural activity in detail. Herein, we investigated the effect of tACS on motor learning capacity and endogenous oscillatory neural activity. Fifty-two healthy volunteers were randomly assigned to four stimulation groups (10 Hz, 20 Hz, 70 Hz, or sham) and performed a visually cued button press motor learning task before and after tACS, which was delivered at the left primary motor area. Oscillatory neural activities during the motor learning task were measured using magnetoencephalography (MEG). Following tACS, the capacity for motor learning was significantly increased for 70 Hz tACS compared to sham stimulation. Oscillation analysis revealed a significant increase in beta-band power after 70-Hz tACS but not in the other stimulation groups. Our finding that capacity for motor learning and endogenous oscillatory beta activity were modulated in parallel after 70-Hz tACS suggests that 70-Hz tACS may increase the motor learning capacity by cross-modulating beta oscillatory activity. Because high gamma and beta oscillatory activity have been shown to reflect the activity of excitatory and inhibitory interneuron, our results may derive from the modulation of excitatory and inhibitory interneurons in M1 by 70-Hz tACS.

Background Transcranial Alternating Current Stimulation (tACS) consists in delivering electric current to the brain using an oscillatory pattern that may entrain the rhythmic activity of cortical neurons. When delivered at gamma frequency, tACS modulates motor performance and GABA-A-ergic interneuron activity. Objective Since interneuronal discharges play a crucial role in brain plasticity phenomena, here we co-stimulated the primary motor cortex (M1) in healthy subjects by means of tACS during intermittent theta-burst stimulation (iTBS), a transcranial magnetic stimulation paradigm known to induce long-term potentiation (LTP)-like plasticity. Methods We measured and compared motor evoked potentials before and after gamma, beta and sham tACS-iTBS. While we delivered gamma-tACS, we also measured short-interval intracortical inhibition (SICI) to detect any changes in GABA-A-ergic neurotransmission. Results Gamma, but not beta and sham tACS, significantly boosted and prolonged the iTBS-induced after-effects. Interestingly, the extent of the gamma tACS-iTBS after-effects correlated directly with SICI changes. Conclusions Overall, our findings point to a link between gamma oscillations, interneuronal GABA-A-ergic activity and LTP-like plasticity in the human M1. Gamma tACS-iTBS co-stimulation might represent a new strategy to enhance and prolong responses to plasticity-inducing protocols, thereby lending itself to future applications in the neurorehabilitation setting.

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.

Performance in the attentional blink task has been demonstrated to be directly influenced by alpha and beta neural oscillatory activity. In two experiments we stimulated the right parietal cortex and left frontal cortex with transcranial alternating current stimulation. For the first experiment we targeted only the right parietal cortex and found a non-significant increase in performance from 20 Hz stimulation. In the second experiment we applied two stimulators to the right parietal and left frontal cortex and found a significant increase in performance from 20 Hz tACS with a phase difference of 180°. Since low intensity stimulation has been shown to inhibit cortical excitability, and anti-phasic stimulation has been hypothesized to decrease presynaptic activation in one region and drive postsynaptic spikes in the other, we suggest that low intensity anti-phasic 20 Hz stimulation inhibited the parietal cortex, thereby disinhibiting the frontal cortex. This visual attention mechanism supposedly reduces processing of distractor stimuli and enhances processing of target stimuli. This study reveals that the frontal-parietal visual attention network may be modulated with low intensity 20 Hz anti-phase tACS.

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.

Contains fulltext : 237106.pdf (Publisher’s version ) (Open Access) In decision-making with uncertain outcomes people may rely on external cues, such as expert advice, even if this information has no predictive value. While the fronto-parietal event-related potential (ERP) components feedback-related negativity (FRN) and P3 are associated with both reward/punishment feedback processing, the relationship between ERP modulation and expert advice during decision making remains unclear. In this double-blind sham-controlled within-subject study transcranial alternating current stimulation (tACS) at an intensity of 1 mA was applied to the frontal cortex in twenty-four healthy volunteers. The aim was to decrease reliance on expert advice by targeting FRN, P3a and P3b components. Following administration of frontal delta (2.5 Hz), theta (5 Hz) and sham tACS, ERPs and advice-guided decision making were evaluated. Results showed a tentative behavioral effect of delta tACS in the response bias. In contrast, theta tACS significantly lowered P3b and P3a amplitudes, but no effects of tACS were observed for the FRN. Effects on electrophysiology and advice following behavior were uncorrelated. Our findings suggest that theta tACS may modulate electrocortical signals and delta tACS advice following, yet the relationship between both remains unresolved. 11 p.

Large-scale synchronization of neural oscillations is a key mechanism for functional information exchange among brain areas. Dual-site Transcranial Alternating Current Stimulation (ds-TACS) has been recently introduced as non-invasive technique to manipulate the temporal phase relationship of local oscillations in two connected cortical areas. While the frequency of ds-TACS is matched, the phase of stimulation is either identical (in-phase stimulation) or opposite (anti-phase stimulation) in the two cortical target areas. In-phase stimulation is thought to synchronize the endogenous oscillations and hereby to improve behavioral performance. Conversely, anti-phase stimulation is thought to desynchronize neural oscillations in the two areas, which is expected to decrease performance. Critically, in- and anti-phase ds-TACS should only differ with respect to temporal phase, while all other stimulation parameters such as focality and stimulation intensity should be matched to enable an unambiguous interpretation of the behavioral effects. Using electric field simulations based on a realistic head geometry, we tested how well this goal has been met in studies, which have employed ds-TACS up to now. Separating the induced electrical fields in their spatial and temporal components, we investigated how the chosen electrode montages determined the spatial field distribution and the generation of phase variations in the injected electric fields. Considering the basic physical mechanisms, we derived recommendations for an optimized stimulation montage. The latter allows for a principled design of in- and anti-phase ds-TACS conditions with matched spatial distributions of the electric field. This knowledge will help cognitive neuroscientists to design optimal ds-TACS configurations, which are suited to probe unambiguously the causal contribution of phase coupling to specific cognitive processes in the human brain.

Although previous studies have reported correlations between alpha oscillations and the “retention” sub-process of working memory (WM), no direct causal evidence has been established in human neuroscience. Here, we developed an online phase-locking closed-loop transcranial alternating current stimulation (tACS) system capable of precisely controlling the phase difference between tACS and concurrent endogenous oscillations. This system permits both up- and down-regulation of brain oscillations at the target stimulation frequency, and is here applied to empirically demonstrate that parietal alpha oscillations causally relate to WM retention. Our experimental design included both in-phase and anti-phase alpha-tACS applied to 39 participants during the retention intervals of a modified Sternberg paradigm. Compared to in-phase alpha-tACS, anti-phase alpha-tACS decreased both WM performance and alpha activity. Moreover, the in-phase tACS-induced changes in WM performance were positively correlated with alpha oscillatory activity. These findings strongly support a causal link between alpha oscillations and WM retention, and illustrate the broad application prospects of phase-locking tACS.

Visual motion discrimination involves reciprocal interactions in the alpha band between the primary visual cortex (V1) and mediotemporal areas (V5/MT). We investigated whether modulating alpha phase synchronization using individualized multisite transcranial alternating current stimulation (tACS) over V5 and V1 regions would improve motion discrimination. We tested 3 groups of healthy subjects with the following conditions: (1) individualized In-Phase V1alpha-V5alpha tACS (0° lag), (2) individualized Anti-Phase V1alpha-V5alpha tACS (180° lag) and (3) sham tACS. Motion discrimination and EEG activity were recorded before, during and after tACS. Performance significantly improved in the Anti-Phase group compared to the In-Phase group 10 and 30Â min after stimulation. This result was explained by decreases in bottom-up alpha-V1 gamma-V5 phase-amplitude coupling. One possible explanation of these results is that Anti-Phase V1alpha-V5alpha tACS might impose an optimal phase lag between stimulation sites due to the inherent speed of wave propagation, hereby supporting optimized neuronal communication.

Neural oscillations at the network level synchronize activity between regions and temporal scales. Transcranial alternating current stimulation (tACS), the delivery of low-amplitude electric current to the scalp, provides a tool for investigating the causal role of neural oscillations in cognition. The parameter space for tACS is vast and optimization is required in terms of temporal and spatial targeting. We review emerging techniques and suggest novel approaches that capitalize on the non-sinusoidal and transient nature of neural oscillations and leverage the flexibility provided by a customizable electrode montage and electrical waveform. The customizability and safety profile of tACS make it a promising tool for precision intervention in psychiatric illnesses.

Contains fulltext : 177245.pdf (Publisher’s version ) (Open Access) Spatial updating is essential to maintain an accurate representation of our visual environment when we move. A neural mechanism that contributes to this ability is called remapping: the transfer of visual information from neural populations that code a location before the motion to those that encode it after the motion. While there is ample evidence for neural remapping in conjunction with eye movements, only recent findings suggest a role of this mechanism for whole-body motion updating, based on the observation that alpha band (10 Hz) activity is selectively reorganized during remapping. This study tested whether alpha oscillations directly contribute to whole-body motion updating using transcranial alternating current stimulation (tACS). In a double blind sham controlled design, healthy volunteers received 10 Hz tACS at an intensity of 1 mA over either the left or right posterior hemisphere during a whole-body motion updating task. Updating performance was assessed psychometrically and indices of gain and precision were obtained. No tACS-related effects on updating gain were found, irrespective of whether the remapping was across or within the hemispheres. In contrast, updating precision was enhanced when a target representation had to be internally remapped to the stimulated hemisphere, but not in other remapping conditions. Our observations suggest that alpha band oscillations do not directly affect the transfer of target representations during remapping, but increase the fidelity of the updated representation by attenuating interference of afferent information. 8 p.

BackgroundTranscranial alternating current stimulation (tACS) is widely used to entrain or modulate brain oscillations in order to investigate causal relationships between oscillations and cognition.ObjectiveIn a series of experiments we here addressed the question of whether event-related, transient tACS in the beta frequency range can be used to entrain beta oscillations in two different domains: episodic memory formation and motor cortex excitability.MethodsIn experiments 1 and 2, 72 healthy human participants engaged in an incidental encoding task of verbal and non-verbal material while receiving tACS to the left and right inferior frontal gyrus (IFG) at 6.8Hz, 10.7Hz, 18.5Hz, 30Hz, 48Hz and sham stimulation for 2s during stimulus presentation.In experiment 3, tACS was administered to M1 at the individual motor beta frequency of eight subjects. We investigated the relationship between the size of TMS induced MEPs and tACS phase.ResultsBeta tACS did not affect memory performance compared to sham stimulation in experiments 1 and 2. Likewise, in experiment 3, MEP size was not modulated by the tACS phase.ConclusionsOur findings suggest that event-related, transient tACS in the beta frequency range cannot be used to modulate the formation of episodic memories or motor cortex excitability. These null-results question the effectiveness of event-related tACS to entrain beta oscillations and modulate cognition.

Transcranial magnetic stimulation induces changes in the cerebral cortex functions, either unilaterally or bilaterally. Here, we combined evoked potential recording and functional brain imaging to analyze the modulating effects of continuous theta burst stimulation in bilateral motor regions of the adult human cortex. We detected concurrent inhibition of the bilateral motor regions following stimulation, as evidenced by both the electrophysiological and imaging results. Our findings supported the notion that magnetic stimulation is able to modulate the contralateral hemisphere through the callosal connectivity.

Human rhythmic movements spontaneously entrain to external rhythmic stimuli. Such sensory-motor entrainment can attract movements to different tempi and enhance their efficiency, with potential clinical applications for motor rehabilitation. Here we investigate whether entrainment of self-paced rhythmic movements can be induced via transcranial alternating current stimulation (tACS), which uses alternating currents to entrain spontaneous brain oscillations at specific frequencies. Participants swung a handheld pendulum at their preferred tempo with the right hand while tACS was applied over their left or right primary motor cortex at frequencies equal to their preferred tempo (Experiment 1) or in the alpha (10Hz) and beta (20Hz) ranges (Experiment 2). Given that entrainment generally occurs only if the frequency difference between two rhythms is small, stimulations were delivered at frequencies equal to participants' preferred movement tempo (≈1Hz) and ±12.5% in Experiment 1, and at 10Hz and 20Hz, and ±12.5% in Experiment 2. The comparison of participants' movement frequency, amplitude, variability, and phase synchrony with and without tACS failed to reveal entrainment or movement modifications across the two experiments. However, significant differences in stimulation-related side effects reported by participants were found between the two experiments, with phosphenes and burning sensations principally occurring in Experiment 2, and metallic tastes reported marginally more often in Experiment 1. Although other stimulation protocols may be effective, our results suggest that rhythmic movements such as pendulum swinging or locomotion that are low in goal-directedness and/or strongly driven by peripheral and mechanical constraints may not be susceptible to modulation by tACS.

Background While the role of beta (∼20 Hz), theta (∼5 Hz) and alpha (∼10 Hz) oscillations in the motor areas have been repeatedly associated with defined properties of motor performance, the investigation of gamma (∼40–90 Hz) oscillatory activity is a more recent and still not fully understood component of motor control physiology, despite its potential clinical relevance for motor disorders. Objective/hypothesis We have implemented an online neuromodulation paradigm based on transcranial alternating current stimulation (tACS) of the dominant motor cortex during a visuo-motor coordination task. This approach would allow a better understanding of the role of gamma activity, as well as that of other oscillatory bands, and their chronometry throughout the task. Methods We tested the effects of 5 Hz, 20 Hz, 60 Hz (mid-gamma) 80 Hz (high-gamma) and sham tACS on the performance of a sample of right-handed healthy volunteers, during a custom-made unimanual tracking task addressing several randomly occurring components of visuo-motor coordination (i.e., constant velocity or acceleration pursuits, turns, loops). Results Data showed a significant enhancement of motor performance during high-gamma stimulation – as well as a trending effect for mid-gamma – with the effect being prominent between 200 and 500 ms after rapid changes in tracking trajectory. No other effects during acceleration or steady pursuit were found. Conclusions Our findings posit a role for high-frequency motor cortex gamma oscillations during complex visuo-motor tasks involving the sudden rearrangement of motor plan/execution. Such a “prokinetic” effect of high-gamma stimulation might be worth to be tested in motor disorders, like Parkinson’s disease, where the switching between different motor programs is impaired.

Highlights • No serious adverse effects have been reported in experiments using either tDCS or tACS. • Persistent adverse effects of tDCS are mainly skin problems; for tACS, none have been reported. • Further safety investigations are needed., Transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) have been applied to many research issues because these stimulation techniques can modulate neural activity in the human brain painlessly and non-invasively with weak electrical currents. However, there are no formal safety guidelines for the selection of stimulus parameters in either tDCS or tACS. As a means of gathering the information that is needed to produce safety guidelines, in this article, we summarize the adverse events of tDCS and tACS. In both stimulation techniques, most adverse effects are mild and disappear soon after stimulation. Nevertheless, several papers have reported that, in tDCS, some adverse events persist even after stimulation. The persistent events consist of skin lesions similar to burns, which can arise even in healthy subjects, and mania or hypomania in patients with depression. Recently, one paper reported a pediatric patient presenting with seizure after tDCS, although the causal relationship between stimulation and seizure is not clear. As this seizure is the only serious adverse events yet reported in connection with tDCS, tDCS is considered safe. In tACS, meanwhile, no persistent adverse events have been reported, but considerably fewer reports are available on the safety of tACS than on the safety of tDCS. Therefore, to establish the safety of tDCS and tACS, we need to scan the literature continuously for information on the adverse events of both stimulation techniques. Further safety investigations are also required.

Transcranial electrical stimulation (TES) is a proposed tool for noninvasively modulating human brain circuits, but its ability to affect cortical physiology remains unclear. A recent study merged TES with live animal and human cadaveric recordings to verify intracranial electrical effects, then used these findings to develop a novel neuromodulation protocol.

International audience; In pandemic times, when visual speech cues are masked, it becomes particularly evident how much we rely on them to communicate. Recent research points to a key role of neural oscillations for cross-modal predictions during speech perception. This article bridges several fields of researchneural oscillations, cross-modal speech perception and brain stimulationto propose ways forward for research on human communication. Future research can test: (1) whether "speech is special" for oscillatory processes underlying cross-modal predictions; (2) whether "visual control" of oscillatory processes in the auditory system is strongest in moments of reduced acoustic regularity; and (3) whether providing information to the brain via electric stimulation can overcome deficits associated with cross-modal information processing in certain pathological conditions.

Transcranial alternating current stimulation (tACS) is a type of noninvasive brain stimulation technique that has been shown to modulate motor, cognitive and memory function. Direct electrophysiological evidence of an interaction between tACS and the auditory cortex excitability has rarely been reported. Different stimulation parameters and areas of tACS may have different influence on the regulatory results. In this study, 11-Hz tACS was applied to the auditory cortex of 12 subjects with normal hearing in order to explore its effects on the auditory steady-state response (ASSR). The results indicate that tACS has an inhibitory effect on 40-Hz ASSR. In addition, EEG source analysis shows that 11-Hz tACS may enhance the activity of the middle temporal gyrus under both sham and real conditions, while the estimated source activity of the posterior cingulate gyrus may be reduced under real condition. The results reveal that tACS applied to the temporal lobe of humans will make the 40-Hz ASSR a tendency to decrease, and help improve the understanding of modulation of tACS-induced auditory cortex excitability changes in humans.

The frontoparietal mirror network is activated when an individual performs a goal-directed action and observes another person's intentional action. It has been speculated that the distinct frontal and parietal regions might work together to participate in the imitation process, which translates an observed movement into an identical action. We aimed to determine the relationship between the frontoparietal mirror network and imitation by applying transcranial alternating current stimulation (tACS) to exogenously modulate oscillatory neural activity in the left inferior frontal gyrus and the left inferior parietal lobule. In total, 45 young adults participated in this study. The participants were randomly assigned to the three tACS groups (synchronous, desynchronous, and sham; 55 Hz enveloped by 6 Hz). Before and during tACS, the participants performed the gesture matching task and the gesture imitation task. Application of synchronous tACS over the left frontoparietal cortices significantly improved the performance of gesture matching and the meaningless gesture imitation relative to the baseline performance. Desynchronous tACS deteriorated the gesture matching performance relative to the baseline results. The oscillatory entrainment of neural activity between components of the frontoparietal mirror network is considered to alter imitation performance by modulating neural information relating to the goals of actions in the frontal cortex and the means of observed actions in the parietal cortex. To the best of our knowledge, this is the first study that reveals that the rhythmic communication between components of the frontoparietal mirror network has a functional role in imitation.

Transcranial alternating current stimulation (tACS) is a promising tool for modulating brain oscillations. Combining tACS with functional magnetic resonance imaging (fMRI), we recently showed that tACS applied over the occipital cortex did not exert its strongest effect on regions below the electrodes, but mainly on more distant fronto-parietal regions. Theoretically, this effect could be explained by tACS-induced modulation of functional connectivity between directly stimulated areas and more distant but anatomically and functionally connected regions. In the present study, we aimed to characterize the effect of tACS on low frequency fMRI signal fluctuations. We employed simultaneous fMRI-tACS in 20 subjects during resting state (eyes open with central fixation for ~8min). Subjects received tACS at different frequencies (10, 16, 40Hz) and with different electrode montages (Cz-Oz, P5-P6) previously used in behavioral studies. Electric field simulations showed that tACS over Cz-Oz directly stimulates occipital cortex, while tACS over P5-P6 primarily targets parietal cortices. Group-level simulation-based functional connectivity maps for Cz-Oz and P5-P6 resembled the visual and fronto-parietal control resting-state networks, respectively. The effects of tACS were frequency and partly electrode montage dependent. In regions where frequency-dependent effects of tACS were observed, 10 and 40Hz tACS generally induced opposite effects. Most tACS effects on functional connectivity were observed between, as opposed to within, resting-state networks. The left fronto-parietal control network showed the most extensive frequency-dependent modulation in functional connectivity, mainly with occipito-parietal regions, where 10Hz tACS increased and 40Hz tACS decreased correlation values. Taken together, our results show that tACS modulates local spontaneous low frequency fluctuations and their correlations with more distant regions, which should be taken into account when interpreting tACS effects on brain function.

Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), oscillating transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs.