NMDA receptor-related mechanisms of dopaminergic modulation of tDCS-induced neuroplasticity.

Dopamine is a key neuromodulator of neuroplasticity and an important neuronal substrate of learning, and memory formation, which critically involves glutamatergic N-methyl-D-aspartate (NMDA) receptors. Dopamine modulates NMDA receptor activity via dopamine D1 and D2 receptor subtypes. It is hypothesized that dopamine focuses on long-term potentiation (LTP)-like plasticity, i.e. reduces diffuse widespread but enhances locally restricted plasticity via a D2 receptor-dependent NMDA receptor activity reduction. Here, we explored NMDA receptor-dependent mechanisms underlying dopaminergic modulation of LTP-like plasticity induced by transcranial direct current stimulation (tDCS). Eleven healthy, right-handed volunteers received anodal tDCS (1 mA, 13 min) over the left motor cortex combined with dopaminergic agents (the D2 receptor agonist bromocriptine, levodopa for general dopamine enhancement, or placebo) and the partial NMDA receptor agonist D-cycloserine (dosages of 50, 100, and 200 mg, or placebo). Cortical excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potentials. We found that LTP-like plasticity was abolished or converted into LTD-like plasticity via dopaminergic activation, but reestablished under medium-dose D-cycloserine. These results suggest that diffuse LTP-like plasticity is counteracted upon via D2 receptor-dependent reduction of NMDA receptor activity.

Consolidation of motor sequence learning eliminates susceptibility of SMAproper to TMS: a combined rTMS and cTBS study.

Earlier research suggested that after 210 practice trials, the supplementary motor area (SMA) is involved in executing all responses of familiar 6-key sequences in a discrete sequence production (DSP) task (Verwey, Lammens, and van Honk, 2002). This was indicated by slowing of each response 20 and 25 min after the SMA had been stimulated for 20 min using repetitive transcranial magnetic stimulation (rTMS). The present study used a similar approach to assess the effects of TMS to the more posterior SMAproper at the end of practice and also 24 h later. As expected stimulation of SMAproper with 20 min of 1 Hz rTMS and 40 s of continuous theta burst stimulation (cTBS) immediately after practice slowed sequence execution relative to a sham TMS condition, but stimulation on the day following practice did not cause slowing. This indicates that offline consolidation makes learning robust against stimulation of SMAproper. Execution of all responses in the sequence was disrupted 0, 20, and 40 min after rTMS, but after cTBS, this occurred only after 40 min. The results suggest that it is implicit sequence knowledge that is processed by the SMAproper and that consolidates.

Phase synchronized 6 Hz transcranial electric and magnetic stimulation boosts frontal theta activity and enhances working memory.

Network-level synchronization of theta oscillations in the cerebral cortex is linked to many vital cognitive functions across daily life, such as executive functions or regulation of arousal and consciousness. However, while neuroimaging has uncovered the ubiquitous functional relevance of theta rhythms in cognition, there remains a limited set of techniques for externally enhancing and stabilizing theta in the human brain non-invasively. Here, we developed and employed a new phase-synchronized low-intensity electric and magnetic stimulation technique to induce and stabilize narrowband 6-Hz theta oscillations in a group of healthy human adult participants, and then demonstrated how this technique also enhances cognitive processing by assaying working memory. Our findings demonstrate a technological advancement of brain stimulation methods, while also validating the causal link between theta activity and concurrent cognitive behavior, which may ultimately help to not only explain mechanisms, but offer perspectives for restoring deficient theta-band network activity observed in neuropsychiatric diseases.

Dosage-Dependent Impact of Acute Serotonin Enhancement on Transcranial Direct Current Stimulation Effects.

BACKGROUND: The serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals. METHODS: Twelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation. RESULTS: Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60-120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated. CONCLUSIONS: Acute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.

Noradrenergic Enhancement of Motor Learning, Attention, and Working Memory in Humans.

BACKGROUND: Noradrenaline has an important role as a neuromodulator of the central nervous system. Noradrenergic enhancement was recently shown to enhance glutamate-dependent cortical facilitation and long term potentiation-like plasticity. As cortical excitability and plasticity are closely linked to various cognitive processes, here we aimed to explore whether these alterations are associated with respective cognitive performance changes. Specifically, we assessed the impact of noradrenergic enhancement on motor learning (serial reaction time task), attentional processes (Stroop interference task), and working memory performance (n-back letter task). METHODS: The study was conducted in a cross-over design. Twenty-five healthy humans performed the respective cognitive tasks after a single dose of the noradrenaline reuptake inhibitor reboxetine or placebo administration. RESULTS: The results show that motor learning, attentional processes, and working memory performance in healthy participants were improved by reboxetine application compared with placebo. CONCLUSIONS: The results of the present study thus suggest that noradrenergic enhancement can improve memory formation and executive functions in healthy humans. The respective changes are in line with related effects of noradrenaline on cortical excitability and plasticity.

Nonlinear Effects of Dopamine D1 Receptor Activation on Visuomotor Coordination Task Performance.

Dopamine plays an important role in the modulation of neuroplasticity, which serves as the physiological basis of cognition. The physiological effects of dopamine depend on receptor subtypes, and the D1 receptor is critically involved in learning and memory formation. Evidence from both animal and human studies shows a dose-dependent impact of D1 activity on performance. However, the direct association between physiology and behavior in humans remains unclear. In this study, four groups of healthy participants were recruited, and each group received placebo or medication inducing a low, medium, or high amount of D1 activation via the combination of levodopa and a D2 antagonist. After medication, fMRI was conducted during a visuomotor learning task. The behavioral results revealed an inverted U-shaped effect of D1 activation on task performance, where medium-dose D1 activation led to superior learning effects, as compared to placebo as well as low- and high-dose groups. A respective dose-dependent D1 modulation was also observed for cortical activity revealed by fMRI. Further analysis demonstrated a positive correlation between task performance and cortical activation at the left primary motor cortex. Our results indicate a nonlinear curve of D1 modulation on motor learning in humans and the respective physiological correlates in corresponding brain areas.

Probing the relevance of repeated cathodal transcranial direct current stimulation over the primary motor cortex for prolongation of after-effects.

KEY POINTS: To explore the capability of cathodal transcranial direct current stimulation (tDCS) to induce late-phase long-term depression (LTD) via repeated stimulation. Conventional (1 mA for 15 min) and intensified (3 mA for 20 min) protocols with short (20 min) and long (24 h) intervals were tested. Late-phase plasticity was not induced by a single repetition of stimulation. Repetition reduced the efficacy of stimulation protocols with higher intensities. ABSTRACT: Transcranial direct current stimulation (tDCS) has shown promising results in pilot studies as a therapeutic intervention in disorders of the central nervous system, but more sustained effects are required for clinical application. To address this issue, one possible solution is the use of repeated stimulation protocols. Previous studies indicated the possibility of extending the after-effects of single intervention cathodal tDCS by repeating the tDCS, with relatively short intervals between repetitions being most effective. In this study, we thus investigated the effects of repeated stimulation protocols at short and long intervals, for a conventional tDCS protocol (1 mA for 15 min) and a newly developed optimized protocol (3 mA for 20 min). In 16 healthy participants, we compared single interventions of conventional and optimized protocols, repeated application of these protocols at intervals of 20 min and 24 h, and a sham tDCS session. tDCS-induced neuroplastic after-effects were then monitored with transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) until the following evening after stimulation. The results revealed that the duration of the after-effects of repeated conventional and optimized protocols with short intervals remained nearly unchanged compared to the respective single intervention protocols. For the long-interval (24 h) protocol, stimulation with the conventional protocol did not significantly alter respective after-effects, while it reduced the efficacy of the optimized protocol, compared with respective single interventions. Thus late-phase plasticity could not be induced by a single repetition of stimulation in this study, but repetition reduced the efficacy of stimulation protocols with higher intensities. This study provides further insights into the dependency of tDCS-induced neuroplasticity on stimulation parameters, and therefore delivers crucial information for future tDCS applications.

Efficacy and clinical predictors of response to rTMS treatment in pharmacoresistant obsessive-compulsive disorder (OCD): a retrospective study.

BACKGROUND: Application of repetitive transcranial magnetic stimulation (rTMS) for treating obsessive-compulsive disorder (OCD) has been promising and approved by the Food and Drug Administration in 2018, but effects differ between patients. Knowledge about clinical predictors of rTMS response may help to increase clinical efficacy but is not available so far. METHODS: In a retrospective study, we investigated the efficacy of rTMS over the dorsolateral prefrontal cortex (DLPFC) or supplementary motor area (SMA) in 65 pharmaco-resistant OCD outpatients recruited for rTMS treatment from July 2015 to May 2017. Patients received either SMA rTMS (n = 38) or bilateral DLPFC rTMS (n = 27) in case of reporting higher affective and depressive symptoms in addition to the primary OCD symptoms. OCD symptoms and depression/anxiety states were measured at baseline (before the 1st session) and after the 20th session of rTMS. Additionally, we performed a binary logistic regression analysis on the demographic and clinical variables based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) 3-factor and 2-factor models and individual items to investigate potential predictors of rTMS response. RESULTS: Patients' scores in Y-BOCS and Beck anxiety/depression inventories were significantly decreased following rTMS treatment. 46.2% of all patients responded to rTMS, based on the criterion of at least a 30% reduction in Y-BOCS scores. There was no significant difference between response rates of patients in DLPFC and SMA groups. No significant demographic predictors of rTMS efficacy were identified. The factors "obsession severity", "resistance" and "disturbance" and the "interference due to obsessions" and "resistance against compulsions" items of the Y-BOCS significantly predicted response to rTMS. CONCLUSIONS: In patients with less intrusive/interfering thoughts, and low scores in the "obsession severity", "disturbance", and "resistance" factors, rTMS might have superior effects. Identifying clinical and non-clinical predictors of response is relevant to personalize and adapt rTMS protocols in pharmaco-resistant OCD patients. Interpretation of rTMS efficacy should be done with caution due to the lack of a sham intervention condition.

Nicotine modulates human brain plasticity via calcium-dependent mechanisms.

KEY POINTS: Nicotine (NIC) modulates cognition and memory function by targeting the nicotinic ACh receptor and releasing different transmitter systems postsynaptically. With both NIC-generated mechanisms, calcium influx and calcium permeability can be regulated, which is a key requirement for the induction of long-term potentiation, comprising the physiological basis of learning and memory function. We attempt to unmask the underlying mechanism of nicotinic effects on anodal transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity based on the hypothesis of calcium-dependency. Abolished tDCS-induced neuroplasticity as a result of NIC administration is reversed by calcium channel blockade with flunarizine in a dose-dependent manner. The results of the present study suggest that there is a dose determination of NIC/NIC agonists in therapeutical settings when treating cognitive dysfunction, which partially explains the heterogeneous results on cognition observed in subjects in different experimental settings. ABSTRACT: Nicotine (NIC) modulates neuroplasticity and improves cognitive performance in animals and humans mainly by increased calcium permeability and modulation of diverse transmitter systems. NIC administration impairs calcium-dependent plasticity induced by non-invasive brain stimulation with transcranial direct current stimulation (tDCS) in non-smoking participants probably as a result of intracellular calcium overflow. To test this hypothesis, we analysed the effect of calcium channel blockade with flunarizine (FLU) on anodal tDCS-induced cortical excitability changes in healthy non-smokers under NIC. We applied anodal tDCS combined with NIC patch and FLU at three different doses (2.5, 5 and 10 mg) or with placebo medication. NIC abolished anodal tDCS-induced neuroplasticity. Under medium dosage (but not under low and high dosage) of FLU combined with NIC, plasticity was re-established. For FLU alone, the lowest dosage weakened long-term potentiation (LTP)-like plasticity, whereas the highest dosage again abolished tDCS-induced plasticity. The medium dosage turned LTP-like plasticity in long-term depression-like plasticity. The results of the present study suggest a key role of calcium influx and calcium levels in nicotinic effects on LTP-like plasticity in humans. This knowledge might be relevant for the development of new therapeutic strategies in cognitive dysfunction.

Effects of anodal transcranial direct current stimulation over lower limb primary motor cortex on motor learning in healthy individuals.

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which alters motor functions in healthy humans and in neurological patients. Most studies so far investigated the effects of tDCS on mechanisms underlying improvements in upper limb performance. To investigate the effect of anodal tDCS over the lower limb motor cortex (M1) on lower limb motor learning in healthy volunteers, we conducted a randomized, single-blind and sham-controlled study. Thirty-three (25.81 ± 3.85, 14 female) volunteers were included, and received anodal or sham tDCS over the left M1 (M1-tDCS); 0.0625 mA/cm2 anodal tDCS was applied for 15 min during performance of a visuo-motor task (VMT) with the right leg. Motor learning was monitored for performance speed and accuracy based on electromyographic recordings. We also investigated the influence of electrode size and baseline responsivity to transcranial magnetic stimulation (TMS) on the stimulation effects. Relative to baseline measures, only M1-tDCS applied with small electrodes and in volunteers with high baseline sensitivity to TMS significantly improved VMT performance. The computational analysis showed that the small anode was more specific to the targeted leg motor cortex volume when compared to the large anode. We conclude that anodal M1-tDCS modulates VMT performance in healthy subjects. As these effects critically depend on sensitivity to TMS and electrode size, future studies should investigate the effects of intensified tDCS and/or model-based different electrode positions in low-sensitivity TMS individuals.

Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans.

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.

Effect of acute exposure to toluene on cortical excitability, neuroplasticity, and motor learning in healthy humans.

Toluene is a well-known neurotoxic organic solvent and a major component of many industrial and commercial products such as adhesives, paint thinners and gasoline. Many workers are regularly exposed to toluene in their working environment and occupational exposure limits (OELs) have been set to avoid adverse health effects. These OELs or short-term exposure limits vary from 14 to 300 ppm across countries partly due to heterogeneity of the findings from animal and human studies about its neurotoxic effects and the evaluation of the adversity of the underlying mechanisms. Furthermore, its acute neurophysiological effects remain poorly understood in humans. The purpose of this study was to investigate the effects of acute exposure to toluene on cortical excitability, plasticity, and implicit motor learning in healthy volunteers. Seventeen subjects were assessed with different transcranial magnetic stimulation measurements: motor thresholds, short-latency intracortical inhibition and intracortical facilitation, and short-interval afferent inhibition before and after clean air or toluene (single peak of 200 ppm) administration. Furthermore, we evaluated long-term potentiation-like neuroplasticity induced by anodal transcranial direct current stimulation (tDCS) over the motor cortex, and the participants conducted a motor sequence learning task, the serial reaction time task. Our findings revealed that toluene abolished the plasticity induced by anodal tDCS, attenuated intracortical facilitation, and increased inhibition in the short-latency afferent inhibition measure, while cortico-spinal excitability and intracortical inhibition were not affected. On the behavioural level, toluene did not alter performance of the motor learning task. These results suggest that toluene might act by modulating NMDA receptor activity, as well as cortical glutamatergic and cholinergic neurotransmission in the human brain. This study encourages further research to obtain more knowledge about mechanisms of action and effects of toluene on both naïve and chronically exposed populations.

Acute and chronic effects of noradrenergic enhancement on transcranial direct current stimulation-induced neuroplasticity in humans.

KEY POINTS: Chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) increased and prolonged the long-term potentiation-like plasticity induced by anodal transcranial direct current stimulation (tDCS) for over 24 h. Chronic administration of RBX converted cathodal tDCS-induced long-term depression-like plasticity into facilitation for 120 min. Chronic noradrenergic activity enhancement on plasticity of the human brain might partially explain the delayed therapeutic impact of selective NRIs in depression and other neuropsychiatric diseases. ABSTRACT: Noradrenaline affects cognition and motor learning processes via its impact on long-term potentiation (LTP) and depression (LTD). We aimed to explore the impact of single dose and chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) on plasticity induced by transcranial direct current stimulation (tDCS) in healthy humans via a double-blinded, placebo-controlled, randomized crossover study. Sixteen healthy volunteers received placebo or single dose RBX (8 mg) before anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took RBX (8 mg day-1 ) consecutively for 21 days. During this period, two additional interventions were performed (RBX with anodal or cathodal tDCS), to explore the impact of chronic RBX treatment on plasticity. Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic administration of RBX increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h. Chronic RBX significantly converted cathodal tDCS-induced LTD-like plasticity into facilitation, as compared to the single dose condition, for 120 min after stimulation. The results show a prominent impact of chronic noradrenergic enhancement on plasticity of the human brain that might partially explain the delayed therapeutic impact of selective NRIs in depression and other neuropsychiatric diseases.

Acute and Chronic Noradrenergic Effects on Cortical Excitability in Healthy Humans.

Background: Noradrenaline is a major neuromodulator in the central nervous system, and it is involved in the pathophysiology of diverse neuropsychiatric diseases. Previous transcranial magnetic stimulation studies suggested that acute application of selective noradrenaline reuptake inhibitors enhances cortical excitability in the human brain. However, other, such like clinical effects, usually require prolonged noradrenaline reuptake inhibitor treatment, which might go along with different physiological effects. Methods: The purpose of this study was to investigate the acute and chronic effects of the selective noradrenaline reuptake inhibitor reboxetine on cortical excitability in healthy humans in a double-blind, placebo-controlled, randomized crossover study. Sixteen subjects were assessed with different transcranial magnetic stimulation measurements: motor thresholds, input-output curve, short-latency intracortical inhibition and intracortical facilitation, I-wave facilitation, and short-interval afferent inhibition before and after placebo or reboxetine (8 mg) single-dose administration. Afterwards, the same subjects took reboxetine (8 mg/d) consecutively for 21 days. During this period (subjects underwent 2 experimental sessions with identical transcranial magnetic stimulation measures under placebo or reboxetine), transcranial magnetic stimulation measurements were assessed before and after drug intake. Results: Both single-dose and chronic administration of reboxetine increased cortical excitability; increased the slope of the input-output curve, intracortical facilitation, and I-wave facilitation; but decreased short-latency intracortical inhibition and short-interval afferent inhibition. Moreover, chronic reboxetine showed a larger enhancement of intracortical facilitation and I-wave facilitation compared with single-dose application. Conclusions: The results show physiological mechanisms of noradrenergic enhancement possibly underlying the functional effects of reboxetine regarding acute and chronic application.

The application of tDCS for the treatment of psychiatric diseases.

Neuroplasticity represents the dynamic structural and functional reorganization of the central nervous system, including its connectivity, due to environmental and internal demands. It is recognized as a major physiological basis for adaption of cognition and behaviour, and, thus, of utmost importance for normal brain function. Cognitive dysfunctions are major symptoms in psychiatric disorders, which are often associated with pathological alteration of neuroplasticity. Transcranial direct current stimulation (tDCS), a recently developed non-invasive brain stimulation technique, is able to induce and modulate cortical plasticity in humans via the application of relatively weak current through the scalp of the head. It has the potential to alter pathological plasticity and restore dysfunctional cognitions in psychiatric diseases. In the last decades, its efficacy to treat psychiatric disorders has been explored increasingly. This review will give an overview of pathological alterations of plasticity in psychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects.

Effect of the Nicotinic α4ß2-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 α4ß2-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.

Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans.

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose-response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

Dosage-dependent effect of dopamine D2 receptor activation on motor cortex plasticity in humans.

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects depend on receptor subtypes, affinity, concentration level, and the kind of neuroplasticity induced. In animal experiments, dopamine D2-like receptor stimulation revealed partially antagonistic effects on plasticity, which might be explained by dosage dependency. In humans, D2 receptor block abolishes plasticity, and the D2/D3, but predominantly D3, receptor agonist ropinirol has a dosage-dependent nonlinear affect on plasticity. Here we aimed to determine the specific affect of D2 receptor activation on neuroplasticity in humans, because physiological effects of D2 and D3 receptors might differ. Therefore, we combined application of the selective D2 receptor agonist bromocriptine (2.5, 10, and 20 mg or placebo medication) with anodal and cathodal transcranial direct current stimulation (tDCS), which induces nonfocal plasticity, and with paired associative stimulation (PAS) generating a more focal kind of plasticity in the motor cortex of healthy humans. Plasticity was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. For facilitatory tDCS, bromocriptine prevented plasticity induction independent from drug dosage. However, its application resulted in an inverted U-shaped dose-response curve on inhibitory tDCS, excitability-diminishing PAS, and to a minor degree on excitability-enhancing PAS. These data support the assumption that modulation of D2-like receptor activity exerts a nonlinear dose-dependent effect on neuroplasticity in the human motor cortex that differs from predominantly D3 receptor activation and that the kind of plasticity-induction procedure is relevant for its specific impact.

Parietal transcranial direct current stimulation modulates primary motor cortex excitability.

The posterior parietal cortex is part of the cortical network involved in motor learning and is structurally and functionally connected with the primary motor cortex (M1). Neuroplastic alterations of neuronal connectivity might be an important basis for learning processes. These have however not been explored for parieto-motor connections in humans by transcranial direct current stimulation (tDCS). Exploring tDCS effects on parieto-motor cortical connectivity might be functionally relevant, because tDCS has been shown to improve motor learning. We aimed to explore plastic alterations of parieto-motor cortical connections by tDCS in healthy humans. We measured neuroplastic changes of corticospinal excitability via motor evoked potentials (MEP) elicited by single-pulse transcranial magnetic stimulation (TMS) before and after tDCS over the left posterior parietal cortex (P3), and 3 cm posterior or lateral to P3, to explore the spatial specificity of the effects. Furthermore, short-interval intracortical inhibition/intracortical facilitation (SICI/ICF) over M1, and parieto-motor cortical connectivity were obtained before and after P3 tDCS. The results show polarity-dependent M1 excitability alterations primarily after P3 tDCS. Single-pulse TMS-elicited MEPs, M1 SICI/ICF at 5 and 7 ms and 10 and 15 ms interstimulus intervals (ISIs), and parieto-motor connectivity at 10 and 15 ms ISIs were all enhanced by anodal stimulation. Single pulse-TMS-elicited MEPs, and parieto-motor connectivity at 10 and 15 ms ISIs were reduced by cathodal tDCS. The respective corticospinal excitability alterations lasted for at least 120 min after stimulation. These results show an effect of remote stimulation of parietal areas on M1 excitability. The spatial specificity of the effects and the impact on parietal cortex-motor cortex connections suggest a relevant connectivity-driven effect.

Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases.

Neuroplasticity, which is the dynamic structural and functional reorganization of central nervous system connectivity due to environmental and internal demands, is recognized as a major physiological basis for adaption of cognition, and behavior, and thus of utmost importance for normal brain function. Pathological alterations of plasticity are increasingly explored as pathophysiological foundation of diverse neurological and psychiatric diseases. Non-invasive brain stimulation techniques (NIBS), such as repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), are able to induce and modulate neuroplasticity in humans. Therefore, they have potential to alter pathological plasticity on the one hand, and foster physiological plasticity on the other, in neuropsychiatric diseases to reduce symptoms, and enhance rehabilitation. tDCS is an emerging NIBS tool, which induces glutamatergic plasticity via application of relatively weak currents through the scalp in humans. In the last years its efficacy to treat neuropsychiatric diseases has been explored increasingly. In this review, we will give an overview of pathological alterations of plasticity in neuropsychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects.