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Several mechanisms have been proposed that control the amount of plasticity in neuronal circuits and guarantee dynamic stability of neuronal networks. Homeostatic plasticity suggests that the ease with which a synaptic connection is facilitated/suppressed depends on the previous amount of network activity. We describe how such homeostatic-like interactions depend on the time interval between two conditioning protocols and on the duration of the preconditioning protocol. We used transcranial direct current stimulation (tDCS) to produce short-lasting plasticity in the motor cortex of healthy humans. In the main experiment, we compared the aftereffect of a single 5-min session of anodal or cathodal tDCS with the effect of a 5-min tDCS session preceded by an identical 5-min conditioning session administered 30, 3, or 0 min beforehand. Five-minute anodal tDCS increases excitability for about 5 min. The same duration of cathodal tDCS reduces excitability. Increasing the duration of tDCS to 10 min prolongs the duration of the effects. If two 5-min periods of tDCS are applied with a 30-min break between them, the effect of the second period of tDCS is identical to that of 5-min stimulation alone. If the break is only 3 min, then the second session has the opposite effect to 5-min tDCS given alone. Control experiments show that these shifts in the direction of plasticity evolve during the 10 min after the first tDCS session and depend on the duration of the first tDCS but not on intracortical inhibition and facilitation. The results are compatible with a time-dependent "homeostatic-like" rule governing the response of the human motor cortex to plasticity probing protocols.

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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 D 2 -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 D 2 /D 3 dopamine 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. D 2 -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 D 2 -like receptor activation was evident for focal inhibitory plasticity. In general, our study supports the assumption that modulation of D 2 -like receptor activity exerts dose-dependent inhibitory or facilitatory effects on neuroplasticity in the human motor cortex depending on the topographic specificity of plasticity.

Nicotine improves cognitive performance and modulates neuroplasticity in brain networks. The neurophysiological mechanisms underlying nicotine-induced behavioral changes have been sparsely studied, especially in humans. Global cholinergic activation focuses on plasticity in humans. However, the specific contribution of nicotinic receptors to these effects is unclear. Henceforth, we explored the impact of nicotine on non-focal neuroplasticity induced by transcranial direct current stimulation (tDCS) and focal, synapse-specific plasticity induced by paired associative stimulation (PAS) in healthy non-smoking individuals. Forty-eight subjects participated in the study. Each subject received placebo and nicotine patches combined with one of the stimulation protocols to the primary motor cortex in different sessions. Transcranial magnetic stimulation (TMS)-elicited motor-evoked potential (MEP) amplitudes were recorded as a measure of corticospinal excitability until the evening of the second day following the stimulation. Nicotine abolished or reduced both PAS- and tDCS-induced inhibitory neuroplasticity. Non-focal facilitatory plasticity was also abolished, whereas focal facilitatory plasticity was slightly prolonged by nicotine. Thus, nicotinergic influence on facilitatory, but not inhibitory plasticity mimics that of global cholinergic enhancement. Therefore, activating nicotinic receptors has clearly discernable effects from global cholinergic activation. These nicotine-generated plasticity alterations might be important for the effects of the drug on cognitive function.