Jessica Grundey

Dosage-dependent non-linear effect of l-dopa on human motor cortex plasticity

The neuromodulator dopamine affects learning and memory formation and their likely physiological correlates, long‐term depression and potentiation, in animals and humans. It is known from animal experiments that dopamine exerts a dosage‐dependent, inverted U‐shaped effect on these functions. However, this has not been explored in humans so far. In order to reveal a non‐linear dose‐dependent effect of dopamine on cortical plasticity in humans, we explored the impact of 25, 100 and 200 mg of l‐dopa on transcranial direct current (tDCS)‐induced plasticity in twelve healthy human subjects. The primary motor cortex served as a model system, and plasticity was monitored by motor evoked potential amplitudes elicited by transcranial magnetic stimulation. As compared to placebo medication, low and high dosages of l‐dopa abolished facilitatory as well as inhibitory plasticity, whereas the medium dosage prolonged inhibitory plasticity, and turned facilitatory plasticity into inhibition. Thus the results show clear non‐linear, dosage‐dependent effects of dopamine on both facilitatory and inhibitory plasticity, and support the assumption of the importance of a specific dosage of dopamine optimally suited to improve plasticity. This might be important for the therapeutic application of dopaminergic agents, especially for rehabilitative purposes, and explain some opposing results in former studies.

Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans

Dopamine is one of the major neuromodulators in the CNS, which is involved in learning and memory processes. A nonlinear, inverted U-shaped dose–response curve of its effects on cognition has been observed in animal studies. The basis for this nonlinear effect might be a similar effect of dopamine on neuroplasticity. Whereas it has been shown that dopamine affects paired associative stimulation (PAS)-induced plasticity, which might reflect learning-related processes to a larger degree than other noninvasive plasticity induction protocols in the human motor cortex in principle, its dose-dependency has not been explored previously. We studied the effect of different dosages of the dopamine precursor l-DOPA on motor cortex plasticity induced by facilitatory and inhibitory PAS of the motor cortex in 12 healthy humans. They received 25, 100, or 200 mg of l-DOPA or placebo medication combined with either excitability-enhancing or -diminishing PAS. Cortical excitability level was monitored before and for up to 2 d after plasticity induction by assessment of transcranial magnetic stimulation-induced motor-evoked potentials. Low-dose l-DOPA abolished the aftereffects of PAS and medium-dose l-DOPA prolonged facilitatory plasticity. High-dose l-DOPA reversed the excitability enhancement accomplished by facilitatory PAS to diminution. Thus, the results show a clear nonlinear effect of l-DOPA dosage on associative plasticity, different from that on nonfocal plasticity. This might help to explain dopaminergic effect on cognition and could be relevant for understanding the pathophysiology and treatment of neuropsychiatric diseases accompanied by alterations of the dopaminergic system.

Nicotinergic Impact on Focal and Non-Focal Neuroplasticity Induced by Non-Invasive Brain Stimulation in Non-Smoking Humans

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.

Neuroplasticity in Cigarette Smokers Is Altered under Withdrawal and Partially Restituted by Nicotine Exposition

Nicotine improves cognitive functions by modulating neuroplasticity and cortical excitability in nonsmoking subjects. As shown recently, the positive effect of nicotine on cognition might at least partially be caused by a focusing effect of nicotine on neuroplasticity in these subjects. Concordant to this, smokers under nicotine withdrawal show reduced cognitive abilities, which are at least partially restituted by nicotine consumption. We aimed to explore the neurophysiological foundation of these effects by exploring nonfocal and focal plasticity-inducing protocols in human smokers under nicotine withdrawal and exposition. Focal, synapse-specific plasticity was induced by paired associative stimulation (PAS), while nonfocal plasticity was induced by transcranial direct current stimulation (tDCS). Each subject (12) received placebo and nicotine patches combined with one of the stimulation protocols to the primary motor cortex. Corticospinal excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. In smokers during nicotine withdrawal, facilitatory plasticity induced by tDCS and PAS was abolished, but restituted by nicotine. In contrast, excitability-diminishing plasticity was not affected by nicotine withdrawal. Under nicotine, the inhibitory aftereffects of PAS were delayed and prolonged, while the tDCS-generated excitability reduction was abolished. Thus, absent facilitatory plasticity in smokers during nicotine withdrawal is restituted by nicotine, favoring the deficit-compensating hypothesis of nicotine consumption. These results might shed further light on the proposed mechanism of nicotine on cognition and attention, which might be connected to nicotine addiction and probability of relapse in smokers.

Rapid effect of nicotine intake on neuroplasticity in non-smoking humans

In various studies nicotine has shown to alter cognitive functions in non-smoking subjects. The physiological basis for these effects might be nicotine-generated modulation of cortical structure, excitability, and activity, as mainly described in animal experiments. In accordance, a recently conducted study demonstrated that application of nicotine for hours via nicotine patch in non-smoking humans alters the effects of neuroplasticity-inducing non-invasive brain stimulation techniques on cortical excitability. Specifically, nicotine abolished inhibitory plasticity independent from the focality of the stimulation protocol. While nicotine prevented also the establishment of non-focal facilitatory plasticity, focal synapse-specific facilitatory plasticity was enhanced. These results agree with a focusing effect of prolonged nicotine application on facilitatory plasticity. However, since nicotine induces rapid adaption processes of its receptors, this scenario might differ from the effect of nicotine in cigarette smoking. Thus in this study we aimed to gain further insight in the mechanism of nicotine on plasticity by exploring the effect of nicotine spray on non-focal and focal plasticity-inducing protocols in non-smoking subjects, a fast-acting agent better comparable to cigarette smoking. Focal, synapse-specific plasticity was induced by paired associative stimulation (PAS), while non-focal plasticity was elicited by transcranial direct current stimulation (tDCS). Forty eight non-smokers received nicotine spray respectively placebo combined with one of the following protocols (anodal tDCS, cathodal tDCS, PAS-25, and PAS-10). Corticospinal excitability was monitored via motor-evoked potentials elicited by transcranial magnetic stimulation (TMS). Nicotine spray abolished facilitatory plasticity irrespective of focality and PAS-10-induced excitability diminution, while tDCS-derived excitability reduction was delayed and weakened. Nicotine spray had thus a clear effect on neuroplasticity in non-smoking subjects. However, the effects of nicotine spray differ clearly from those of prolonged nicotine application, which might be due to missing adaptive nicotinic receptor alterations. These results enhance our knowledge about the dynamic impact of nicotine on plasticity, which might be related to its heterogenous effect on cognition.

Effect of the Nicotinic α4β2-receptor Partial Agonist Varenicline on Non-invasive Brain Stimulation-Induced Neuroplasticity in the Human Motor Cortex

Nicotine alters cognitive functions in animals and humans most likely by modification of brain plasticity. In the human brain, it alters plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS), probably by interference with calcium-dependent modulation of the glutamatergic system. We aimed to test this hypothesis further by exploring the impact of the α4β2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity, induced by PAS and tDCS, respectively. We administered low (0.1 mg), medium (0.3 mg), and high (1.0 mg) single doses of varenicline or placebo medication before PAS or tDCS on the left motor cortex of 25 healthy non-smokers. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes up to 36 h after plasticity induction. Whereas low-dose varenicline had no impact on stimulation-induced neuroplasticity, medium-dose abolished tDCS-induced facilitatory after-effects, favoring focal excitatory plasticity. High-dose application preserved cathodal tDCS-induced excitability diminution and focal excitatory PAS-induced facilitatory plasticity. These results are comparable to the impact of nicotine receptor activation and might help to further explain the involvement of specific receptor subtypes in the nicotinic impact on neuroplasticity and cognitive functions in healthy subjects and patients with neuropsychiatric diseases.

Double dissociation of working memory and attentional processes in smokers and non-smokers with and without nicotine.

Nicotine has been shown to affect cortical excitability measured using transcranial magnetic stimulation in smoking and non-smoking subjects in different ways. In tobacco-deprived smokers, administration of nicotine restores compromised cortical facilitation while in non-smokers, it enhances cortical inhibition. As cortical excitability and activity are closely linked to cognitive processes, we aimed to explore whether nicotine-induced physiological alterations in non-smokers and smokers are associated with cognitive changes. Specifically, we assessed the impact of nicotine on working memory performance (n-back letter task) and on attentional processes (Stroop interference test) in healthy smokers and non-smokers. Both tasks have been shown to rely on prefrontal areas, and nicotinic receptors are relevantly involved in prefrontal function. Sixteen smoking and 16 non-smoking subjects participated in the 3-back letter task and 21 smoking and 21 non-smoking subjects in the Stroop test after the respective application of placebo or nicotine patches. The results show that working memory and attentional processes are compromised in nicotine-deprived smokers compared to non-smoking individuals. After administration of nicotine, working memory performance in smokers improved, while non-smoking subjects displayed decreased accuracy with increased number of errors. The effects have been shown to be more apparent for working memory performance than attentional processes. In summary, cognitive functions can be restored by nicotine in deprived smokers, whereas non-smokers do not gain additional benefit. The respective changes are in accordance with related effects of nicotine on cortical excitability in both groups.

Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans

Abstract The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium‐dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor‐dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)‐induced long‐term potentiation‐like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N‐methyl‐d‐aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA‐receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single‐pulse transcranial magnetic stimulation‐induced motor‐evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS‐induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low‐dosage DMO did not affect the impact of NIC on tDCS‐induced plasticity and high‐dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS‐induced plasticity. These results enhance our knowledge about the proposed calcium‐dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.

Diverging effects of nicotine on motor learning performance: Improvement in deprived smokers and attenuation in non-smokers

Nicotine modulates cognition and neuroplasticity in smokers and non-smokers. A possible mechanism for its effect on learning and memory performance is its impact on long-term potentiation (LTP) and long-term depression (LTD). As neuroplasticity is closely connected to learning processes, we aimed to explore the effect of nicotine in healthy, young smokers and non-smokers on performance of the serial reaction time task (SRTT), a sequential motor learning paradigm. 20 nicotine-deprived smokers and 20 non-smokers participated in the study and were exposed to nicotine or placebo medication. Deprived smokers under placebo medication displayed reduced performance in terms of reaction time and error rates compared to the non-smoking group. After application of nicotine, performance in smokers improved while it deteriorated in non-smokers. These results indicate a restituting effect of nicotine in smokers in terms of cognitive parameters. This sheds further light on the proposed mechanism of nicotine on learning processes, which might be linked to the addictive component of nicotine, the probability of relapse and thus needs also be addressed in cessation treatment.

Compromised neuroplasticity in cigarette smokers under nicotine withdrawal is restituted by the nicotinic α4β2-receptor partial agonist varenicline

Nicotine modulates neuroplasticity and improves cognitive functions in animals and humans. In the brain of smoking individuals, calcium-dependent plasticity induced by non-invasive brain stimulation methods such as transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) is impaired by nicotine withdrawal, but partially re-established after nicotine re-administration. In order to investigate the underlying mechanism further, we tested the impact of the α4β2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity in smokers during nicotine withdrawal, induced by PAS and tDCS, respectively. We administered low (0.3 mg) and high (1.0 mg) single doses of varenicline or placebo medication before stimulation over the left motor cortex of 20 healthy smokers under nicotine withdrawal. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes for 36 hours after plasticity induction. Stimulation-induced plasticity was absent under placebo medication, whereas it was present in all conditions under high dose. Low dose restituted only tDCS-induced non-focal plasticity, producing no significant impact on focal plasticity. High dose varenicline also prolonged inhibitory plasticity. These results are comparable to the impact of nicotine on withdrawal-related impaired plasticity in smokers and suggest that α4β2 nicotinic receptors are relevantly involved in plasticity deficits and restitution in smokers.