SCS is consistent with Shapiro’s (1968) definition of a placebo, in that the participant does not know which treatment is being applied, and the treatment probably has no effect on the person. While there may be quibbles over specific deliveries of TMS or tCS (such as clicking from the coil, or itching at the scalp), SCS could fairly be called a placebo, especially if these factors were identical in active and sham sessions. But what about OAS? The key is the word ‘specific’: if the stimulation is delivered to a brain area that is known (inasmuch as this Cyclopamine solubility dmso is possible) not to be involved in a task, the stimulation might

indeed be considered a placebo. However, ACS differs markedly from the usual medical idea of a placebo, in that the stimulation is being delivered somewhere. While the task-related brain area may be unaffected in the OAS condition, nevertheless the person’s brain tissue is being affected in some way. While Histone Methyltransferase inhibitor the stimulation levels used in most experimental settings are well within physiologically ‘safe’ limits (Jahanshahi et al., 1997; Bikson et al., 2009; Datta et al., 2009), it is still possible that small changes in neural excitability could induce deleterious effects. There are some cases in which an active control is necessary. For example, high-intensity tACS around the frontal or occipital areas is likely to cause visual disturbances due

to stimulation of the retina or visual cortex (Kanai et al., 2008; Schutter & Hortensius, 2010). In this case the participant is always aware of the stimulated conditions. It would therefore be sensible to choose two separate electrode montages, with one over the target brain area and the other over a neutral location that would produce the same visual sensations. However, stimulating one area of the scalp is likely to feel very different from stimulating another: even a naïve participant will realize that TMS over dorsolateral prefrontal cortex has different sensory consequences

from vertex stimulation. A primary purpose of a control condition in an experiment or trial is to show the specificity of the effect to the primary condition; therefore, the control must replicate as closely as possible the ‘active’ condition but Metalloexopeptidase the hypothesized brain area should not be stimulated. In this view, OAS gives the fairest comparison of active with sham conditions, as the only difference between the conditions is the position of the electrodes or stimulating coil. We recommend that active control brain stimulation be used as a last resort, and that appropriate safety checks are employed. First, the impact of the control stimulation on the brain should be understood, ideally through current density modelling or through relating the planned stimulation parameters to known physiological measures.