Conducting double-blind placebo-controlled clinical trials of transcranial alternating current stimulation (tACS)

Abstract

Many psychiatric and neurological illnesses can be conceptualized as oscillopathies defined as pathological changes in brain network oscillations. We previously proposed the application of rational design for the development of non-invasive brain stimulation for the modulation and restoration of cortical oscillations as a network therapeutic. Here, we show how transcranial alternating current stimulation (tACS), which applies a weak sine-wave electric current to the scalp, may serve as a therapeutic platform for the treatment of CNS illnesses. Recently, an initial series of double-blind, placebo-controlled treatment trials of tACS have been published. Here, we first map out the conceptual underpinnings of such trials with focus on target identification, engagement, and validation. Then, we discuss practical aspects that need to be considered for successful trial execution, with particular regards to ensuring successful study blind. Finally, we briefly review the few published double-blind tACS trials and conclude with a proposed roadmap to move the field forward with the goal of moving from pilot trials to convincing efficacy studies of tACS.

Fig. 1. Successful neural entrainment from tACS is dependent on the Arnold Tongue.

tACS entrains neural oscillations (represented as vertical lines symbolizing action potentials) by a mechanism referred to as the Arnold tongue, which references the inverted triangle shape of the parameter combinations (amplitude, frequency) that allow successful entrainment, i.e. synchronization of neural activity to the rhythmic stimulation waveform.The higher the stimulation amplitude, the more detuning (i.e., mismatch) of the stimulation frequency relative to the endogenous oscillation frequency is allowed to still achieve entrainment. Given the low amplitude of the perturbation to the neuronal membrane voltage by tACS, tuning of the stimulation waveform appears to be an important aspect of rational design of the stimulation waveform. Future tACS clinical trials should apply sine-wave stimulation waveforms that are matched to the endogenous frequency of the targeted oscillation determined by EEG. To what extent this principle predicts outlasting effects of tACS remains unclear given that there is no published preclinical model of these effects and that an attempt to investigate the role of entrainment in the outlasting effects was negative.

Fig. 2. Rational design of clinical trials using tACS.

Top: rational of a tACS intervention comprises 1 target identification (based on known correlations between EEG oscillation features and symptoms), 2 target engagement (demonstration of successful modulation of oscillatory network target), and 3 target validation (demonstration of clinical improvements correlating with change in oscillations by tACS). Bottom: results from a tACS study of target engagement and symptom modulation in patients with chronic low-back pain. In this case, the network oscillation target was pathologically reduced alpha oscillations (top-down inhibition) in the somatosensory-motor cortical pain network.