No Benefit in Memory Performance after Nocturnal Memory Reactivation Coupled with Theta-tACS.

Targeted memory reactivation (TMR) is an effective technique to enhance sleep-associated memory consolidation. The successful reactivation of memories by external reminder cues is typically accompanied by an event-related increase in theta oscillations, preceding better memory recall after sleep. However, it remains unclear whether the increase in theta oscillations is a causal factor or an epiphenomenon of successful TMR. Here, we used transcranial alternating current stimulation (tACS) to examine the causal role of theta oscillations for TMR during non-rapid eye movement (non-REM) sleep. Thirty-seven healthy participants learned Dutch-German word pairs before sleep. During non-REM sleep, we applied either theta-tACS or control-tACS (23 Hz) in blocks (9 min) in a randomised order, according to a within-subject design. One group of participants received tACS coupled with TMR time-locked two seconds after the reminder cue (time-locked group). Another group received tACS in a continuous manner while TMR cues were presented (continuous group). Contrary to our predictions, we observed no frequency-specific benefit of theta-tACS coupled with TMR during sleep on memory performance, neither for continuous nor time-locked stimulation. In fact, both stimulation protocols blocked the TMR-induced memory benefits during sleep, resulting in no memory enhancement by TMR in both the theta and control conditions. No frequency-specific effect was found on the power analyses of the electroencephalogram. We conclude that tACS might have an unspecific blocking effect on memory benefits typically observed after TMR during non-REM sleep.

Modulating the difficulty of a visual oddball-like task and P3m amplitude.

It is often necessary to modulate the difficulty of an experimental task without changing physical stimulus characteristics that are known to modulate event-related potentials. Here, we developed a new, oddball-like visual discrimination task with varying levels of difficulty despite using almost identical visual stimuli. Gabor patches of one orientation served as frequent standard stimuli with 75% probability. Gabor patches with a slightly different orientation served as infrequent target stimuli (25% probability). Analyzing the behavioral outcomes revealed a successful modulation of task difficulty, i.e. the hard condition revealed decreased d' values and longer reaction times for standard stimuli. In addition, we recorded MEG and computed event-related fields in response to the stimuli. In line with our expectation, the amplitude of the P3m was reduced in the hard condition. We localized the sources of the P3m with a focus on those that are modulated by changes in task difficulty. The sources of P3m modulation by difficulty were found primarily in the centro-parietal regions of both hemispheres. Additionally, we found significant differences in source activity between the easy and hard conditions in parts of the pre and post-central gyrus and inferior parietal lobe. Our findings are in line with previous research suggesting that the brain areas responsible for the conventional P3m generators also contribute to a modulation by task difficulty.

Alpha transcranial alternating current stimulation modulates auditory perception.

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.

ERP-aligned delta transcranial alternating current stimulation modulates the P3 amplitude.

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.

Personalized alpha-tACS targeting left posterior parietal cortex modulates visuo-spatial attention and posterior evoked EEG activity.

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.

Attempting to counteract vigilance decrement in older adults with brain stimulation.

Introduction: Against the background of demographic change and the need for enhancement techniques for an aging society, we set out to repeat a study that utilized 40-Hz transcranial alternating current stimulation (tACS) to counteract the slowdown of reaction times in a vigilance experiment but with participants aged 65 years and older. On an oscillatory level, vigilance decrement is linked to rising occipital alpha power, which has been shown to be downregulated using gamma-tACS. Method: We applied tACS on the visual cortex and compared reaction times, error rates, and alpha power of a group stimulated with 40 Hz to a sham and a 5-Hz-stimulated control group. All groups executed two 30-min-long blocks of a visual task and were stimulated according to group in the second block. We hypothesized that the expected increase in reaction times and alpha power would be reduced in the 40-Hz group compared to the control groups in the second block (INTERVENTION). Results: Statistical analysis with linear mixed models showed that reaction times increased significantly over time in the first block (BASELINE) with approximately 3 ms/min for the SHAM and 2 ms/min for the 5-Hz and 40-Hz groups, with no difference between the groups. The increase was less pronounced in the INTERVENTION block (1 ms/min for SHAM and 5-Hz groups, 3 ms/min for the 40-Hz group). Differences among groups in the INTERVENTION block were not significant if the 5-Hz or the 40-Hz group was used as the base group for the linear mixed model. Statistical analysis with a generalized linear mixed model showed that alpha power was significantly higher after the experiment (1.37 µV2) compared to before (1 µV2). No influence of stimulation (40 Hz, 5 Hz, or sham) could be detected. Discussion: Although the literature has shown that tACS offers potential for older adults, our results indicate that findings from general studies cannot simply be transferred to an old-aged group. We suggest adjusting stimulation parameters to the neurophysiological features expected in this group. Next to heterogeneity and cognitive fitness, the influence of motivation and medication should be considered.

Alpha modulation via transcranial alternating current stimulation in adults with attention-deficit hyperactivity disorder.

Background: One potential therapy treating attention-deficit/hyperactivity disorder (ADHD) is to modulate dysfunctional brain activations using brain stimulation techniques. While the number of studies investigating the effect of transcranial direct current stimulation on ADHD symptoms continues to increase, transcranial alternating current stimulation (tACS) is poorly examined. Previous studies reported impaired alpha brain oscillation (8-12 Hz) that may be associated with increased attention deficits in ADHD. Our aim was to enhance alpha power in adult ADHD patients via tACS, using different methods to explore potential therapeutic effects. Methods: Undergoing a crossover design, adults with ADHD received active and sham stimulation on distinct days. Before and after each intervention, mean alpha power, attention performance, subjective symptom ratings, as well as head and gaze movement were examined. Results: Frequency analyses revealed a significant power increase in the alpha band after both interventions. Despite a trend toward an interaction effect, this alpha power increase was, however, not significantly higher after active stimulation compared to sham stimulation. For the other measures, some additional pre-post effects were found, which were not intervention-related. Conclusion: Our study cannot provide clear evidence for a tACS-induced increase in alpha power in adult ADHD patients, and thus no stimulation related improvement of attention parameters. We provide further recommendations for the future investigation of tACS as a potential ADHD treatment.

The hidden brain-state dynamics of tACS aftereffects.

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.

P300 Modulation via Transcranial Alternating Current Stimulation in Adult Attention-Deficit/Hyperactivity Disorder: A Crossover Study.

Objective: A repeated finding regarding event-related potentials (ERPs) is that patients with ADHD show a reduced P300 amplitude. This raises the question of whether the attention of ADHD patients can be increased by stabilizing the P300. Assuming that the P300 is generated by event-related oscillations (EROs) in the low frequency range (0-8 Hz), one approach to increase the P300 could be to stimulate the patient's P300 underlying ERO by means of transcranial alternating current stimulation (tACS). The aim of this follow-up study was to investigate this hypothesized mechanism of action in adult ADHD patients. Materials and Methods: Undergoing a crossover design, 20 adult ADHD patients (10 female) received an actual stimulation via tACS on one day and a sham stimulation on another day. Before and after each intervention, EEG characteristics (P300 amplitudes, low frequency power) and attention performances (d2 attention test, visual oddball task (VOT)) were recorded. Results: Electrophysiological analyses revealed no evidence for an enhanced P300 amplitude or low frequency power increase after actual stimulation compared to sham stimulation. Instead, a significant effect was found for a stronger N700 amplitude increase after actual stimulation compared to sham stimulation. Consistent with the P300 null results, none of the examined neuropsychological performance measures indicated a tACS-induced improvement in attentional ability. Conclusion: Contrary to a previous study using tACS to modulate the P300 in adult ADHD patients, the current study yields no evidence that tACS can increase the P300 amplitude in adult ADHD patients and that such P300 enhancement can directly improve neuropsychological parameters of attention.

Benchmarking the effects of transcranial temporal interference stimulation (tTIS) in humans.

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.

Evidence of Neuroplastic Changes after Transcranial Magnetic, Electric, and Deep Brain Stimulation.

Electric and magnetic stimulation of the human brain can be used to excite or inhibit neurons. Numerous methods have been designed over the years for this purpose with various advantages and disadvantages that are the topic of this review. Deep brain stimulation (DBS) is the most direct and focal application of electric impulses to brain tissue. Electrodes are placed in the brain in order to modulate neural activity and to correct parameters of pathological oscillation in brain circuits such as their amplitude or frequency. Transcranial magnetic stimulation (TMS) is a non-invasive alternative with the stimulator generating a magnetic field in a coil over the scalp that induces an electric field in the brain which, in turn, interacts with ongoing brain activity. Depending upon stimulation parameters, excitation and inhibition can be achieved. Transcranial electric stimulation (tES) applies electric fields to the scalp that spread along the skull in order to reach the brain, thus, limiting current strength to avoid skin sensations and cranial muscle pain. Therefore, tES can only modulate brain activity and is considered subthreshold, i.e., it does not directly elicit neuronal action potentials. In this review, we collect hints for neuroplastic changes such as modulation of behavior, the electric activity of the brain, or the evolution of clinical signs and symptoms in response to stimulation. Possible mechanisms are discussed, and future paradigms are suggested.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Entrainment and Spike-Timing Dependent Plasticity - A Review of Proposed Mechanisms of Transcranial Alternating Current Stimulation.

Specific frequency bands of neural oscillations have been correlated with a range of cognitive and behavioral effects (e.g., memory and attention). The causal role of specific frequencies may be investigated using transcranial alternating current stimulation (tACS), a non-invasive brain stimulation method. TACS involves applying a sinusoidal current between two or more electrodes attached on the scalp, above neural regions that are implicated in cognitive processes of interest. The theorized mechanisms by which tACS affects neural oscillations have implications for the exact stimulation frequency used, as well as its anticipated effects. This review outlines two main mechanisms that are thought to underlie tACS effects - entrainment, and spike-timing dependent plasticity (STDP). Entrainment suggests that the stimulated frequency synchronizes the ongoing neural oscillations, and is thought to be most effective when the stimulated frequency is at or close to the endogenous frequency of the targeted neural network. STDP suggests that stimulation leads to synaptic changes based on the timing of neuronal firing in the target neural network. According to the principles of STDP, synaptic strength is thought to increase when pre-synaptic events occur prior to post-synaptic events (referred to as long-term potentiation, LTP). Conversely, when post-synaptic events occur prior to pre-synaptic events, synapses are thought to be weakened (referred to as long-term depression, LTD). In this review, we summarize the theoretical frameworks and critically review the tACS evidence for each hypothesis. We also discuss whether each mechanism alone can account for tACS effects or whether a combined account is necessary.

The Influence of the Modulation Index on Frequency-Modulated Steady-State Visual Evoked Potentials.

Based on increased user experience during stimulation, frequency-modulated steady-state visual evoked potentials (FM-SSVEPs) have been suggested as an improved stimulation method for brain-computer interfaces. Adapting such a novel stimulation paradigm requires in-depth analyses of all different stimulation parameters and their influence on brain responses as well as the user experience during the stimulation. In the current manuscript, we assess the influence of different values for the modulation index, which determine the spectral distribution in the stimulation signal on FM-SSVEPs. We visually stimulated 14 participants at different target frequencies with four different values for the modulation index. Our results reveal that changing the modulation index in a way that elevates the stimulation power in the targeted sideband leads to increased FM-SSVEP responses. There is, however, a tradeoff with user experience as increased modulation indices also lead to increased perceived flicker intensity as well as decreased stimulation comfort in our participants. Our results can guide the choice of parameters in future FM-SSVEP implementations.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

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.

tACS phase-specifically biases brightness perception of flickering light.

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.

Discrete sampling in perception via neuronal oscillations-Evidence from rhythmic, non-invasive brain stimulation.

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.

Interindividual variability of electric fields during transcranial temporal interference stimulation (tTIS).

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.

A Comparison of Closed Loop vs. Fixed Frequency tACS on Modulating Brain Oscillations and Visual Detection.

Transcranial alternating current stimulation has emerged as an effective tool for the exploration of brain oscillations. By applying a weak alternating current between electrodes placed on the scalp matched to the endogenous frequency, tACS enables the specific modulation of targeted brain oscillations This results in alterations in cognitive functions or persistent physiological changes. Most studies that utilize tACS determine a fixed stimulation frequency prior to the stimulation that is kept constant throughout the experiment. Yet it is known that brain rhythms can encounter shifts in their endogenous frequency. This could potentially move the ongoing brain oscillations into a frequency region where it is no longer affected by the stimulation, thereby decreasing or negating the effect of tACS. Such an effect of a mismatch between stimulation frequency and endogenous frequency on the outcome of stimulation has been shown before for the parietal alpha-activity. In this study, we employed an intermittent closed loop stimulation protocol, where the stimulation is divided into short epochs, between which an EEG is recorded and rapidly analyzed to determine a new stimulation frequency for the next stimulation epoch. This stimulation protocol was tested in a three-group study against a classical fixed stimulation protocol and a sham-treatment. We targeted the parietal alpha rhythm and hypothesized that this setup will ensure a constant close match between the frequencies of tACS and alpha activity. This closer match should lead to an increased modulation of detection of visual luminance changes depending on the phase of the tACS and an increased rise in alpha peak power post stimulation when compared to a protocol with fixed pre-determined stimulation frequency. Contrary to our hypothesis, our results show that only a fixed stimulation protocol leads to a persistent increase in post-stimulation alpha power as compared to sham. Furthermore, in none of the stimulated groups significant modulation of detection performance occurred. While the lack of behavioral effects is inconclusive due to the short selection of different phase bins and trials, the physiological results suggest that a constant stimulation with a fixed frequency is actually beneficial, when the goal is to produce persistent synaptic changes.

No Evidence for Entrainment: Endogenous Gamma Oscillations and Rhythmic Flicker Responses Coexist in Visual Cortex.

Over the past decades, numerous studies have linked cortical gamma oscillations (∼30-100 Hz) to neurocomputational mechanisms. Their functional relevance, however, is still passionately debated. Here, we asked whether endogenous gamma oscillations in the human brain can be entrained by a rhythmic photic drive >50 Hz. Such a noninvasive modulation of endogenous brain rhythms would allow conclusions about their causal involvement in neurocognition. To this end, we systematically investigated oscillatory responses to a rapid sinusoidal flicker in the absence and presence of endogenous gamma oscillations using magnetoencephalography (MEG) in combination with a high-frequency projector. The photic drive produced a robust response over visual cortex to stimulation frequencies of up to 80 Hz. Strong, endogenous gamma oscillations were induced using moving grating stimuli as repeatedly done in previous research. When superimposing the flicker and the gratings, there was no evidence for phase or frequency entrainment of the endogenous gamma oscillations by the photic drive. Unexpectedly, we did not observe an amplification of the flicker response around participants' individual gamma frequencies (IGFs); rather, the magnitude of the response decreased monotonically with increasing frequency. Source reconstruction suggests that the flicker response and the gamma oscillations were produced by separate, coexistent generators in visual cortex. The presented findings challenge the notion that cortical gamma oscillations can be entrained by rhythmic visual stimulation. Instead, the mechanism generating endogenous gamma oscillations seems to be resilient to external perturbation.SIGNIFICANCE STATEMENT We aimed to investigate to what extent ongoing, high-frequency oscillations in the gamma-band (30-100 Hz) in the human brain can be entrained by a visual flicker. Gamma oscillations have long been suggested to coordinate neuronal firing and enable interregional communication. Our results demonstrate that rhythmic visual stimulation cannot hijack the dynamics of ongoing gamma oscillations; rather, the flicker response and the endogenous gamma oscillations coexist in different visual areas. Therefore, while a visual flicker evokes a strong neuronal response even at high frequencies in the gamma-band, it does not entrain endogenous gamma oscillations in visual cortex. This has important implications for interpreting studies investigating the causal and neuroprotective effects of rhythmic sensory stimulation in the gamma-band.