Nicotinergic impact on focal and non-focal neuroplasticity induced by non-invasive brain stimulation in non-smoking humans

Abstract

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.

Figures

Figure 1

Illustration of the experimental design. Each subject underwent two experimental sessions. At the beginning of the session, the subjects first received either a placebo or a nicotine patch. After a 6 h break, baseline (BL) motor-evoked potentials (MEPs) of approximately 1 mV amplitude were recorded by single pulse transcranial magnetic stimulation (TMS) over the motor cortical representational area of the abductor digiti minimi muscle (ADM). One of the four stimulation protocols (anodal transcranial direct current stimulation (tDCS)/cathodal tDCS/paired associative stimulation (PAS)-25/PAS-10) was then applied. After-measurements were made immediately following the stimulation and once every 5 min for the first 30 min, then once every 30 for 120 min for both sessions. In addition, MEPs were also recorded the same evening, next morning, and evening for the nicotine patch sessions.

Figure 2

Nicotinergic impact on transcranial direct current stimulation (tDCS)-induced neuroplasticity. Shown are the graphs with motor-evoked potential (MEP) amplitudes standardized to baseline on the Y axis plotted against various time points following the stimulation. (a) In the placebo condition (squares), anodal tDCS enhances motor cortex excitability until 90 min following stimulation. This effect of anodal tDCS is abolished in the nicotine condition (circles). (b) The cathodal tDCS-induced excitability diminution observed in the placebo condition (squares) is also abolished by application of nicotine (circles). Filled symbols indicate statistically significant deviations from baseline and asterisks indicate significant differences between the control and nicotine conditions (Student's t-test, paired, two-tailed, p<0.05). SE, same evening; NM, next morning; NE, next evening. Error bars indicate standard error of mean.

Figure 3

Nicotinergic impact on paired associative stimulation (PAS)-induced neuroplasticity. The graphs show baseline-standardized motor-evoked potential (MEP) amplitudes on the Y axis plotted at different time points following the stimulation. (a) In the placebo condition (squares), PAS-25 induced a clear increase of MEP amplitudes lasting for 90 min after stimulation. With nicotine (circles), the facilitatory after-effect of PAS-25 is slightly prolonged. (b) PAS-10 under placebo medication (squares) induced a prominent decrease of MEP amplitudes significantly until 90 min after stimulation. Nicotine (circles) abolished the inhibitory after-effect of PAS-10. Filled symbols indicate statistically significant deviations from baseline and asterisks indicate significant differences between the control and nicotine conditions (Student's t-test, paired, two-tailed, p<0.05). SE, same evening; NM, next morning; NE, next evening. Error bars indicate standard error of mean.

Figure 4

Effect of nicotine on focal/non-focal neuroplasticity induced in the human motor cortex until 30 min following stimulation. Nicotine shows a focusing effect on facilitatory plasticity. Focal facilitatory plasticity is prolonged, whereas non-focal facilitatory plasticity is abolished under nicotine. Nicotine also abolishes any effect of excitability-reducing plasticity-generating protocols. Each bar represents the mean motor-evoked potential (MEP) amplitude until 30 min after stimulation standardized to the baseline. Error bars indicate standard error of mean.