Intra-individual variability in the effects of transcranial directcurrent stimulation on free choice saccade behaviour

Transcranial direct current stimulation (tDCS) is used as a tool to causally influence neural activity in humans non-invasively. Although most studies recruit a large number of participants in order to uncover population-level effects, growing evidence suggests that tDCS may be expected to induce different effects in different individuals, leading to large inter-individual variability and confounds in population-level testing. Additionally, variability may arise from intra-individual differences and confounds that are difficult to assess in studies with limited to no re-testing. Here, we performed 10 sessions of tDCS each on 5 human participants performing a free choice saccade task while neural activity was measured via EEG. Participants first underwent functional MRI to localize the human right frontal eye field (rFEF) homologue. An HD-tDCS montage was then used to focally target rFEF based on individual MRI localizations, alternating the polarity between anodal or cathodal current over repeated sessions during a 5 week period (twice weekly). On stimulation days, participants performed a free choice task prior to and after administration of tDCS while EEG activity was recorded. To quantify the likelihood that tDCS induced a causal effect on behaviour and neural activity across different levels of analysis, we developed a multilevel causal inference method based on permutation testing of a quasi-experiment (difference-in-differences). We then used this method to assess the likelihood of a causal effect at different levels of abstraction: group-level, participant-level, and paired-session level. At the group-level, we found evidence for an influence of tDCS on choice reaction times, which followed a reaction-time dependent change in EEG activity, and on how choices depended on previous trials. However, individuals showed heterogeneous effects. Further, analysis of paired-session variability often belied the pooled individual effect, suggesting that different sessions of tDCS may have produced markedly different effects in the same participants. In light of this, we discuss potential causes of this variability, and the counterfactuals that should be considered when making data-driven inferences about the effects of tDCS. Author SummaryDeveloping reliable interventions on human neural activity is important for establishing causal relationships in basic research and developing therapeutics for pathological brain states. Transcranial direct current stimulation is a promising technique to intervene on neural activity safely in humans, but it is poorly understood if tDCS reliably impacts brain and behaviour in the same way across sessions. We performed an extensive test-retest study on tDCS in humans, and developed statistical methods to assess variability across sessions. Our results provide strong evidence against a consistent effect of tDCS in the same individual across different sessions. This warrants caution in using tDCS as a predictable intervention on neural activity in research and clinical practices.