Rhythmic neuronal activity is ubiquitous in the human brain. These rhythms originate from a variety of different network mechanisms, which give rise to a wide-ranging spectrum of oscillation frequencies. In the last few years an increasing number of clinical research studies have explored transcranial alternating current stimulation (tACS) with weak current as a tool for affecting brain function. The premise of these interventions is that tACS will interact with ongoing brain oscillations. However, the exact mechanisms by which weak currents could affect neuronal oscillations at different frequency bands are not well known and this, in turn, limits the rational optimization of human experiments. Here we review the available in vitro and in vivo animal studies that attempt to provide mechanistic explanations. The findings can be summarized into a few generic principles, such as periodic modulation of excitability, shifts in spike timing, modulation of firing rate, and shifts in the balance of excitation and inhibition. These effects result from weak but simultaneous polarization of a large number of neurons. Whether this can lead to an entrainment or a modulation of brain oscillations, or whether AC currents have no effect at all, depends entirely on the specific dynamic that gives rise to the different brain rhythms, as discussed here for slow wave oscillations (~1 Hz) and gamma oscillations (~30 Hz). We conclude with suggestions for further experiments to investigate the role of AC stimulation for other physiologically relevant brain rhythms.

Transcranial Direct Current Stimulation (tDCS) is investigated for a broad range of neuropsychiatric indications, various rehabilitation applications, and to modulate cognitive performance in diverse tasks. Specificity of tDCS refers broadly to the ability of tDCS to produce precise, as opposed to diffuse, changes in brain function. Practically, specificity of tDCS implies application-specific customization of protocols to maximize desired outcomes and minimize undesired effects. Especially given the simplicity of tDCS and the complexity of brain function, understanding the mechanisms leading to specificity is fundamental to the rational advancement of tDCS. We define the origins of specificity based on anatomical and functional factors. Anatomical specificity derives from guiding current to targeted brain structures. Functional specificity may derive from either activity-selectivity, where active neuronal networks are preferentially modulated by tDCS, or input-selectivity, where bias is applied to different synaptic inputs. Rational advancement of tDCS may require leveraging all forms of specificity.

Despite compelling phenomenological evidence that small electric fields (<5 mV/mm) can affect brain function, a quantitative and experimentally verified theory is currently lacking. Here we demonstrate a novel mechanism by which the nonlinear properties of single neurons “amplify” the effect of small electric fields: when concurrent to suprathreshold synaptic input, small electric fields can have significant effects on spike timing. For low-frequency fields, our theory predicts a linear dependency of spike timing changes on field strength. For high-frequency fields (relative to the synaptic input), the theory predicts coherent firing, with mean firing phase and coherence each increasing monotonically with field strength. Importantly, in both cases, the effects of fields on spike timing are amplified with decreasing synaptic input slope and increased cell susceptibility (millivolt membrane polarization per field amplitude). We confirmed these predictions experimentally using CA1 hippocampal neuronsin vitroexposed to static (direct current) and oscillating (alternating current) uniform electric fields. In addition, we develop a robust method to quantify cell susceptibility using spike timing. Our results provide a precise mechanism for a functional role of endogenous field oscillations (e.g., gamma) in brain function and introduce a framework for considering the effects of environmental fields and design of low-intensity therapeutic neurostimulation technologies.