The individual properties of visual objects, like form or color, are represented in different areas in our visual cortex. In order to perceive one coherent object, its features have to be bound together. This was found to be achieved in cat and monkey brains by temporal correlation of the firing rates of neurons which code the same object. This firing rate is predominantly observed in the gamma frequency range (approx. 30-80 Hz, mainly around 40 Hz). In addition, it has been shown in humans that stimuli which flicker at gamma frequencies are processed faster by our brains than when they flicker at different frequencies. These effects could be due to neural oscillators, which preferably oscillate at certain frequencies, so-called resonance frequencies. It is also known that neurons in visual cortex respond to flickering stimuli at the frequency of the flickering light. If neural oscillators exist with resonance frequencies, they should respond more strongly to stimulation with their resonance frequency. We performed an experiment, where ten human subjects were presented flickering light at frequencies from 1 to 100 Hz in 1-Hz steps. The event-related potentials exhibited steady-state oscillations at all frequencies up to at least 90 Hz. Interestingly, the steady-state potentials exhibited clear resonance phenomena around 10, 20, 40 and 80 Hz. This could be a potential neural basis for gamma oscillations in binding experiments. The pattern of results resembles that of multiunit activity and local field potentials in cat visual cortex.

Non-invasive electrical stimulation of the human cortex by means of transcranial direct current stimulation (tDCS) has been instrumental in a number of important discoveries in the field of human cortical function and has become a well-established method for evaluating brain function in healthy human participants. Recently, transcranial alternating current stimulation (tACS) has been introduced to directly modulate the ongoing rhythmic brain activity by the application of oscillatory currents on the human scalp. Until now the efficiency of tACS in modulating rhythmic brain activity has been indicated only by inference from perceptual and behavioural consequences of electrical stimulation. No direct electrophysiological evidence of tACS has been reported. We delivered tACS over the occipital cortex of 10 healthy participants to entrain the neuronal oscillatory activity in their individual alpha frequency range and compared results with those from a separate group of participants receiving sham stimulation. The tACS but not the sham stimulation elevated the endogenous alpha power in parieto-central electrodes of the electroencephalogram. Additionally, in a network of spiking neurons, we simulated how tACS can be affected even after the end of stimulation. The results show that spike-timing-dependent plasticity (STDP) selectively modulates synapses depending on the resonance frequencies of the neural circuits that they belong to. Thus, tACS influences STDP which in turn results in aftereffects upon neural activity.The present findings are the first direct electrophysiological evidence of an interaction of tACS and ongoing oscillatory activity in the human cortex. The data demonstrate the ability of tACS to specifically modulate oscillatory brain activity and show its potential both at fostering knowledge on the functional significance of brain oscillations and for therapeutic application.

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

Novel methods for neuronal entrainment [1-4] provide the unique opportunity to modulate perceptually relevant brain oscillations [5, 6] in a frequency-specific manner and to study their functional impact on distinct cognitive functions. Recently, evidence has emerged that tACS (transcranial alternating current stimulation) can modulate cortical oscillations [7-9]. However, the study of electrophysiological effects has been hampered so far by the absence of concurrent electroencephalogram (EEG) recordings. Here, we applied 10 Hz tACS to the parieto-occipital cortex and utilized simultaneous EEG recordings to study neuronal entrainment during stimulation. We pioneer a novel approach for simultaneous tACS-EEG recordings and successfully separate stimulation artifacts from ongoing and event-related cortical activity. Our results reveal that 10 Hz tACS increases parieto-occipital alpha activity and synchronizes cortical oscillators with similar intrinsic frequencies to the entrainment frequency. Additionally, we demonstrate that tACS modulates target detection performance in a phase-dependent fashion highlighting the causal role of alpha oscillations for visual perception.

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Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1–2 mA and during tACS at higher peak-to-peak intensities above 2 mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity ‘conventional’ TES defined as <4 mA, up to 60 min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3–13 A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10 mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6–7, 2016 and were refined thereafter by email correspondence.

The interest in transcranial alternating current stimulation (tACS) has significantly increased in the past decade. It has potential to modulate brain oscillations in a frequency specific manner, offering the possibility to demonstrate a causal nature of oscillation behavior relationships. TACS is a strong candidate as a tool for clinical applications, however, to fulfill this potential, certain parameters have yet to be evaluated. First, little is known about long-lasting after-effects of tACS with respect to the modulations of rhythmic brain activity. Second, the power of endogenous brain oscillations might play a crucial role in the efficacy of tACS. We hypothesize that the after-effects of tACS depend on the endogenous power of oscillations. To this end, we modulated the power of endogenous occipital alpha oscillations via tACS. In two experiments, participants either had their eyes open or closed to keep endogenous alpha power either low or high while they were stimulated for 20 min with their individual alpha frequency (IAF) and simultaneously performing a vigilance task. After-effects on IAF power were evaluated over a course of 30 min with a pre stimulation period serving as baseline. After-effects were strongly dependent on IAF power. Enhanced IAF power was observed for at least 30 min after tACS under conditions of low endogenous IAF power, whereas, IAF power could not be further enhanced by tACS under conditions of high IAF power. The current study demonstrates, for the first time, a long lasting effect after tACS on endogenous EEG power in the range of the stimulation frequency. Additionally, we present conclusive evidence that the power of the endogenous oscillations has a critical impact on tACS efficacy. Long lasting after-effects foster the role of tACS as a tool for non-invasive brain stimulation and demonstrate the potential for therapeutic application to reestablish the balance of altered brain oscillations.

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