Transcranial DC stimulation (tDCS) is a plasticity-inducing noninvasive brain stimulation tool with various potential therapeutic applications in neurological and psychiatric diseases. Currently, the duration of the aftereffects of stimulation is restricted. For future clinical applications, stimulation protocols are required that produce aftereffects lasting for days or weeks. Options to prolong the effects of tDCS are further prolongation or repetition of tDCS. Nothing is known thus far about optimal protocols in this behalf, although repetitive stimulation is already performed in clinical applications. Thus we explored the effects of different break durations on cathodal tDCS-induced cortical excitability alterations. In 12 subjects, two identical periods of cathodal tDCS (9-min duration; 1 mA) with an interstimulation interval of 0 (no break), 3, or 20 min or 3 or 24 h were performed. The results indicate that doubling stimulation duration without a break prolongs the aftereffects from 60 to 90 min after tDCS. When the second stimulation was performed during the aftereffects of the first, a prolongation and enhancement of tDCS-induced effects for ≤120 min after stimulation was observed. In contrast, when the second stimulation followed the first one after 3 or 24 h, the aftereffects were initially attenuated, or abolished, but afterwards re-established for up to 120 min after tDCS in the 24-h condition. These results suggest that, for prolonging the aftereffects of cathodal tDCS, stimulation interval might be important.

The neuromodulator dopamine (DA) has multiple modes of action on neuroplasticity induction and modulation, depending on subreceptor specificity, concentration level, and the kind of stimulation-induced plasticity. To determine the dosage-dependent effects of D₂-like receptor activation on nonfocal and focal neuroplasticity in the human motor cortex, different doses of ropinirole (0.125, 0.25, 0.5, and 1.0 mg), a D₂/D₃dopamine agonist, or placebo medication were combined with anodal and cathodal transcranial direct current stimulation (tDCS) protocols, which induce nonfocal plasticity, or paired associative stimulation (PAS, ISI of 10 or 25 ms), which generates focal plasticity, in healthy volunteers. D₂-like receptor activation produced an inverted “U”-shaped dose–response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. Here, high or low dosages of ropinirole impaired plasticity. However, no dose-dependent response effect of D₂-like receptor activation was evident for focal inhibitory plasticity. In general, our study supports the assumption that modulation of D₂-like receptor activity exerts dose-dependent inhibitory or facilitatory effects on neuroplasticity in the human motor cortex depending on the topographic specificity of plasticity.