Title: Shaping the Optimal Repetition Interval for Cathodal Transcranial Direct Current 1 Stimulation (tdcs) 2 3

36 37 38 Transcranial direct current stimulation (tDCS) is a plasticity-inducing non39 invasive brain stimulation tool with various potential therapeutic applications in 40 neurological and psychiatric diseases. Currently, the duration of the after-effects of 41 stimulation is restricted. For future clinical applications, stimulation protocols are 42 required that produce after-effects lasting for days or weeks. Options to prolong the 43 effects of tDCS are further prolongation or repetition of tDCS. Nothing is known so far 44 about optimal protocols in this behalf, although repetitive stimulation is already 45 performed in clinical applications. Thus we explored the effects of different break 46 durations on cathodal tDCS-induced cortical excitability alterations. In 12 subjects, two 47 identical periods of cathodal tDCS (9 minute duration; 1 mA) with an inter-stimulation 48 interval of 0 (no break), 3 or 20 minutes or 3 or 24 hours were performed. The results 49 indicate that doubling stimulation duration without a break prolongs the after-effects 50 from 60 to 90 min after tDCS. When the second stimulation was performed during the 51 after-effects of the first, a prolongation and enhancement of tDCS-induced effects for up 52 to 120 min after stimulation was observed. In contrast, when the second stimulation 53 followed after 3 or 24 hours, the after-effects were initially attenuated, or abolished, but 54 for the 24h condition prolonged for up to 120 min after tDCS. These results suggest that 55 for prolonging the after-effects of cathodal tDCS, stimulation interval might be 56 important. 57