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Startseite > Forschung > Publikationen / Publications > Moliadze

Dr. rer. nat. Moliadze

2021

Brauer, H., Breitling-Ziegler, C., Moliadze, V., Galling, B., & Prehn-Kristensen, A. (2021). Transcranial direct current stimulation in attention-deficit/hyperactivity disorder: A meta-analysis of clinical efficacy outcomes. In Kadosh, R. C., Zaehle, T., & Krauel, K. (Eds.), Non-invasive Brain Stimulation (NIBS) in Neurodevelopmental Disorders (pp. 91–116). Elsevier.

Background: Evidence for the application of transcranial direct current stimulation (tDCS) in the clinical care of attention-deficit/hyperactivity disorder (ADHD) is limited. Therefore, we aimed to summarize study results using meta-analyses of measures of the cardinal symptoms of ADHD. Methods: We conducted a systematic literature search (PubMed/pubpsych/PsychInfo/WOS) until 01/05/2020 for randomized controlled trials (RCTs) evaluating tDCS vs. control condition in patients with ADHD. A random effects meta-analysis of symptom-related outcomes was performed separately for data on the immediate effect and follow-up. Subgroup- and metaregression analyses for patient characteristics and tDCS parameters were included. Results: Meta-analyzing 13 studies (n = 308, age = 23.7± 13.3), including 20 study arms, tDCS had an immediate effect on overall symptom severity, inattention, and impulsivity, but not on hyperactivity. Results were significant in children and adolescents (8 studies, n = 133, age = 12.4 ± 3.0). Follow-up data (3 days–4 weeks after stimulation) suggested an ongoing beneficial effect regarding overall symptom severity and a delayed effect on hyperactivity. Discussion: TDCS seems to be a promising method to treat clinical symptoms in ADHD with long-lasting effects. Still, more research considering the individual neuropsychological and anatomical dispositions of the subjects is needed to optimize tDCS protocols and efficacy. Safety issues of tDCS treatment in children and adolescents are addressed.

Hunold, A., Haueisen, J., Freitag, C. M., Siniatchkin, M., & Moliadze, V. (2021). Cortical current density magnitudes during transcranial direct current stimulation correlate with skull thickness in children, adolescent and young adults. In Kadosh, R. C., Zaehle, T., & Krauel, K. (Eds.), Non-invasive Brain Stimulation (NIBS) in Neurodevelopmental Disorders (pp. 41–56). Elsevier.

Transcranial direct current stimulation protocols are often applied with a fixed parameter set to all subjects participating in an interventional study. This might lead to considerable effect variation in inhomogeneous subject groups or when transferring stimulation protocols to different age groups. The aim of this study was to evaluate magnitude differences of the electric current density distribution on the gray matter surface in children, adolescent and adults in correlation with the individual volume conductor geometry. We generated individual six compartment finite element models from structural magnetic resonance images of four children (age: 10.95 a ± 1.32 a), eight adolescents (age: 15.10 a ± 1.16 a) and eight young adults (age: 21.62 a ± 2.45 a). We determined the skull thickness in the models as Euclidean distance between the surface of the cerebrospinal fluid compartment and outer skull boundary. For tDCS simulations, we modeled 5 × 7 cm patch electrodes impressing 1 mA current intensity as anode and cathode over the left M1 and the right fronto-polar orbit, respectively. The resulting current density was analyzed on the gray matter surface. Our results demonstrate higher cortical current density magnitudes in children compared to adults for a given tDCS current strength. Above the evaluated cortex, the skull thickness increased with age. In conclusion, we underline the importance of age-dependent and individual models in tDCS simulations.

Kandić, M., Moliadze, V., Andoh, J., Flor, H., & Nees, F. (2021). Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation. Frontiers in Neurology, 12, 1526. doi:10.3389/fneur.2021.732034.

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed.

Moliadze, V., Stenner, T., Matern, S., Siniatchkin, M., Nees, F., & Hartwigsen, G. (2021). Online Effects of Beta-tACS Over the Left Prefrontal Cortex on Phonological Decisions. Neuroscience, 463, 264–271. PMID:33722674, doi:10.1016/j.neuroscience.2021.03.002.

The left posterior inferior frontal gyrus in the prefrontal cortex is a key region for phonological aspects of language processing. A previous study has shown that alpha-tACS over the prefrontal cortex applied before task processing facilitated phonological decision-making and increased task-related theta power. However, it is unclear how alpha-tACS affects phonological processing when applied directly during the task. Moreover, the frequency specificity of this effect is also unclear since the majority of neurostimulation studies tested a single frequency only. The present study addressed the question whether and how 10 Hz online tACS affects phonological decisions. To this end, 24 healthy participants received tACS at 10 Hz or 16.18 Hz (control frequency) or sham stimulation over the left prefrontal cortex during task processing in three sessions. As an unexpected finding, 16.18 Hz significantly impaired task accuracy relative to sham stimulation, without affecting response speed. There was no significant difference in phonological task performance between 10 Hz and 16.18 Hz tACS or between 10 Hz and sham stimulation. Our results support the functional relevance of the left prefrontal cortex for phonological decisions and suggest that online beta-tACS may modulate language comprehension.

Salvador, R., Biagi, M. C., Puonti, O., Splittgerber, M., Moliadze, V., …, & Ruffini, G. (2021). Personalization of Multi-electrode Setups in tCS/tES: Methods and Advantages. In Makarov, S., & , Noetscher, Gregory, Nummenmaa, A. (Eds.), Brain Hum. Body Model. 2020 (1st ed., pp. 119–135). Cham: Springer International Publishing.

2020

Moliadze, V.*, Brodski-Guerniero, A.*, Schuetz, M., Siemann, J., Lyzhko, E., …, & Siniatchkin, M. (2020). Significance of Beta-Band Oscillations in Autism Spectrum Disorders During Motor Response Inhibition Tasks: A MEG Study. Brain Topogr., 33(3), 355–374. PMID:32303950, doi:10.1007/s10548-020-00765-6.

In Autism Spectrum Disorders (ASD), impaired response inhibition and lack of adaptation are hypothesized to underlie core ASD symptoms, such as social communication and repetitive, stereotyped behavior. Thus, the aim of the present study was to compare neural correlates of inhibition, post-error adaptation, and reaction time variability in ASD and neuro-typical control (NTC) participants by investigating possible differences in error-related changes of oscillatory MEG activity. Twelve male NTC (mean age 20.3 ± 3.7) and fourteen male patients with ASD (mean age 17.8 ± 2.9) were included in the analysis. Subjects with ASD showed increased error-related reaction time variability. MEG analysis revealed decreased beta power in the ASD group in comparison to the NTC group over the centro-parietal channels in both, the pre-stimulus and post-response interval. In the ASD group, mean centro-parietal beta power negatively correlated with dimensional autism symptoms. In both groups, false alarms were followed by an early increase in temporo-frontal theta to alpha power; and by a later decrease in alpha to beta power at central and posterior sensors. Single trial correlations were additionally studied in the ASD group, who showed a positive correlation of pre-stimulus beta power with post-response theta, alpha, and beta power, particularly after hit trials. On a broader scale, the results deliver important insights into top-down control deficits that may relate to core symptoms observed in ASD.

Sierawska, A., Moliadze, V., Splittgerber, M., Rogge, A., Siniatchkin, M., & Buyx, A. (2020). First Epileptic Seizure and Initial Diagnosis of Juvenile Myoclonus Epilepsy (JME) in a Transcranial Direct Current Stimulation (tDCS) Study– Ethical Analysis of a Clinical case. Neuroethics, 13(3), 347–351. doi:10.1007/s12152-020-09444-6.

We discuss an epileptic incident in an undiagnosed 13-year old girl participating in a clinical study investigating the effects of transcranial direct current stimulation (tDCS) in healthy children and adolescents. This incident poses important research ethics questions with regard to study design, especially pertaining to screening and gaining informed consent. Potential benefits and problems of the incident also need to be considered. The ethical analysis of the case presented in this paper has been informed by an in-depth interview conducted after the incident with the child and the accompanying parent. We discuss the ethical implications of the epileptic incident, the need for improving screening procedures for studies with minors and for providing more effective communication. This case also underscores the problem of undetected teenage epilepsy in neuropsychological clinical studies and the necessity of raising more awareness of this issue. Since research in tDCS is an active and expanding field, we conclude with providing some recommendation that could ensure that future research on tDCS, or other therapies and neuro-interventions where there is a risk of triggering an epileptic seizure, take into account the specifics of teenage epilepsy and the need for more thorough provision of information during the process of gaining informed consent.

Splittgerber, M.*, Japaridze, N.*, Sierawska, A., Gimenez, S., …, Siniatchkin, M., & Moliadze, V. (2020). First generalized tonic clonic seizure in the context of pediatric tDCS – A case report. Neurophysiol. Clin., 50(1), 69–72. PMID:31848082, doi:10.1016/j.neucli.2019.11.002.
Splittgerber, M., Suwelack, J. H., Kadish, N. E.*, & Moliadze, V.*. (2020). The Effects of 1 mA tACS and tRNS on Children/Adolescents and Adults: Investigating Age and Sensitivity to Sham Stimulation. Neural Plast., 2020, 1–14. PMID:32855633, doi:10.1155/2020/8896423.

The aim of this study was to investigate the effect of transcranial random noise (tRNS) and transcranial alternating current (tACS) stimulation on motor cortex excitability in healthy children and adolescents. Additionally, based on our recent results on the individual response to sham in adults, we explored this effect in the pediatric population. We included 15 children and adolescents (10–16 years) and 28 adults (20–30 years). Participants were stimulated four times with 20 Hz and 140 Hz tACS, tRNS, and sham stimulation (1 mA) for 10 minutes over the left M1 HAND . Single-pulse MEPs (motor evoked potential), short-interval intracortical inhibition, and facilitation were measured by TMS before and after stimulation (baseline, 0, 30, 60 minutes). We also investigated aspects of tolerability. According to the individual MEPs response immediately after sham stimulation compared to baseline (Wilcoxon signed-rank test), subjects were regarded as responders or nonresponders to sham. We did not find a significant age effect. Regardless of age, 140 Hz tACS led to increased excitability. Incidence and intensity of side effects did not differ between age groups or type of stimulation. Analyses on responders and nonresponders to sham stimulation showed effects of 140 Hz, 20 Hz tACS, and tRNS on single-pulse MEPs only for nonresponders. In this study, children and adolescents responded to 1 mA tRNS and tACS comparably to adults regarding the modulation of motor cortex excitability. This study contributes to the findings that noninvasive brain stimulation is well tolerated in children and adolescents including tACS, which has not been studied before. Finally, our study supports a modulating role of sensitivity to sham stimulation on responsiveness to a broader stimulation and age range.

Splittgerber, M., Salvador, R., Brauer, H., Breitling-Ziegler, C., …, Moliadze, V.*, & Siniatchkin, M.*. (2020). Individual Baseline Performance and Electrode Montage Impact on the Effects of Anodal tDCS Over the Left Dorsolateral Prefrontal Cortex. Front. Hum. Neurosci., 14. doi:10.3389/fnhum.2020.00349.

2019

Kortuem, V., Kadish, N. E., Siniatchkin, M., & Moliadze, V. (2019). Efficacy of tRNS and 140 Hz tACS on motor cortex excitability seemingly dependent on sensitivity to sham stimulation. Exp. Brain Res., 237(11), 2885–2895. PMID:31482197, doi:10.1007/s00221-019-05640-w.

This study investigates the effect of corticospinal excitability during sham stimulation on the individual response to transcranial non-invasive brain stimulation (tNIBS). Thirty healthy young adults aged 24.2 ± 2.8 S.D. participated in the study. Sham, as well as 1 mA of tRNS and 140 Hz tACS stimulation were applied for 10 min each at different sessions. The effect of each stimulation type was quantified by recording TMS-induced, motor evoked potentials (MEPs) before (baseline) and at fixed time points after stimulation (T0, T30, T60 min.). According to the individual response to sham stimulation at T0 in comparison to baseline MEPs, subjects were regarded as responder or non-responder to sham. Following, MEPs at T0, T30 and T60 after verum or sham stimulation were assessed with a repeated measures ANOVA with the within-subject factor stimulation (sham, tRNS, 140 Hz tACS) and the between-subjects factor group (responder vs non-responder). We found that individuals who did not show immediately changes in excitability in sham stimulation sessions were the ones who responded to active stimulation conditions. On the other hand, individuals who responded to sham condition, by either increases or decreases in MEPS, did not respond to active verum stimulation. This result suggests that the presence or lack of responses to sham stimulation can provide a marker for how individuals will respond to tRNS/tACS and thus provide an explanation for the variability in interindividual response. The results of this study draw attention to the general reactivity of the brain, which can be taken into account when planning future studies using tNIBS.

Moliadze, V., Sierau, L., Lyzhko, E., Stenner, T., …, Siniatchkin, M., & Hartwigsen, G. (2019). After-effects of 10 Hz tACS over the prefrontal cortex on phonological word decisions. Brain stimulation, 12(6), 1464–1474. PMID:31278060, doi:10.1016/j.brs.2019.06.021.

Introduction: Previous work in the language domain has shown that 10 Hz rTMS of the left or right posterior inferior frontal gyrus (pIFG) in the prefrontal cortex impaired phonological decision-making, arguing for a causal contribution of the bilateral pIFG to phonological processing. However, the neurophysiological correlates of these effects are unclear. The present study addressed the question whether neural activity in the prefrontal cortex could be modulated by 10 Hz tACS and how this would affect phonological decisions. Methods: In three sessions, 24 healthy participants received tACS at 10 Hz or 16.18 Hz (control frequency) or sham stimulation over the bilateral prefrontal cortex before task processing. Resting state EEG was recorded before and after tACS. We also recorded EEG during task processing. Results: Relative to sham stimulation, 10 Hz tACS significantly facilitated phonological response speed. This effect was task-specific as tACS did not affect a simple control task. Moreover, 10 Hz tACS significantly increased theta power during phonological decisions. The individual increase in theta power was positively correlated with the behavioral facilitation after 10 Hz tACS. Conclusion: Our results show a facilitation of phonological decisions after 10 Hz tACS over the bilateral prefrontal cortex. This might indicate that 10 Hz tACS increased task-related activity in the stimulated area to a level that was optimal for phonological performance. The significant correlation with the individual increase in theta power suggests that the behavioral facilitation might be related to increased theta power during language processing.

Muthuraman, M.*, Moliadze, V.*, Boecher, L., Siemann, J., …, & Siniatchkin, M. (2019). Multimodal alterations of directed connectivity profiles in patients with attention-deficit/hyperactivity disorders. Sci. Rep. PMID:31882672, doi:10.1038/s41598-019-56398-8.

Functional and effective connectivity measures for tracking brain region interactions that have been investigated using both electroencephalography (EEG) and magnetoencephalography (MEG) bringing up new insights into clinical research. However, the differences between these connectivity methods, especially at the source level, have not yet been systematically studied. The dynamic characterization of coherent sources and temporal partial directed coherence, as measures of functional and effective connectivity, were applied to multimodal resting EEG and MEG data obtained from 11 young patients (mean age 13.2 ± 1.5 years) with attention-deficit/hyperactivity disorder (ADHD) and age-matched healthy subjects. Additionally, machine-learning algorithms were applied to the extracted connectivity features to identify biomarkers differentiating the two groups. An altered thalamo-cortical connectivity profile was attested in patients with ADHD who showed solely information outflow from cortical regions in comparison to healthy controls who exhibited bidirectional interregional connectivity in alpha, beta, and gamma frequency bands. We achieved an accuracy of 98% by combining features from all five studied frequency bands. Our findings suggest that both types of connectivity as extracted from EEG or MEG are sensitive methods to investigate neuronal network features in neuropsychiatric disorders. The connectivity features investigated here can be further tested as biomarkers of ADHD.

Sierawska, A., Prehn-Kristensen, A., Moliadze, V., Krauel, K., …, Siniatchkin, M., & Buyx, A. (2019). Unmet Needs in Children With Attention Deficit Hyperactivity Disorder—Can Transcranial Direct Current Stimulation Fill the Gap? Promises and Ethical Challenges. Front. Psychiatry, 10. doi:10.3389/fpsyt.2019.00334.

Attention deficit hyperactivity disorder (ADHD) is a disorder most frequently diagnosed in children and adolescents. Although ADHD can be effectively treated with psychostimulants, a significant proportion of patients discontinue treatment because of adverse events or insufficient improvement of symptoms. In addition, cognitive abilities that are frequently impaired in ADHD are not directly targeted by medication. Therefore, additional treatment options, especially to improve cognitive abilities, are needed. Because of its relatively easy application, well-established safety, and low cost, transcranial direct current stimulation (tDCS) is a promising additional treatment option. Further research is needed to establish efficacy and to integrate this treatment into the clinical routine. In particular, limited evidence regarding the use of tDCS in children, lack of clear translational guidelines, and general challenges in conducting research with vulnerable populations pose a number of practical and ethical challenges to tDCS intervention studies. In this paper, we identify and discuss ethical issues related to research on tDCS and its potential therapeutic use for ADHD in children and adolescents. Relevant ethical issues in the tDCS research for pediatric ADHD center on safety, risk/benefit ratio, information and consent, labeling problems, and nonmedical use. Following an analysis of these issues, we developed a list of recommendations that can guide clinicians and researchers in conducting ethically sound research on tDCS in pediatric ADHD.

2018

Brauer, H., Kadish, N. E., Pedersen, A., Siniatchkin, M., & Moliadze, V. (2018). No Modulatory Effects when Stimulating the Right Inferior Frontal Gyrus with Continuous 6 Hz tACS and tRNS on Response Inhibition: A Behavioral Study. Neural Plast., 2018, 1–11. PMID:30425735, doi:10.1155/2018/3156796.

Response inhibition is the cognitive process required to cancel an intended action. During that process, a “go” reaction is intercepted particularly by the right inferior frontal gyrus (rIFG) and presupplementary motor area (pre-SMA). After the commission of inhibition errors, theta activity (4–8 Hz) is related to the adaption processes. In this study, we intend to examine whether the boosting of theta activity by electrical stimulation over rIFG reduces the number of errors and the reaction times in a response inhibition task (Go/NoGo paradigm) during and after stimulation. 23 healthy right-handed adults participated in the study. In three separate sessions, theta tACS at 6 Hz, transcranial random noise (tRNS) as a second stimulation condition, and sham stimulation were applied for 20 minutes. Based on behavioral data, this study could not show any effects of 6 Hz tACS as well as full spectrum tRNS on response inhibition in any of the conditions. Since many findings support the relevance of the rIFG for response inhibition, this could mean that 6 Hz activity is not important for response inhibition in that structure. Reasons for our null findings could also lie in the stimulation parameters, such as the electrode montage or the stimulation frequency, which are discussed in this article in more detail. Sharing negative findings will have (1) positive impact on future research questions and study design and will improve (2) knowledge acquisition of noninvasive transcranial brain stimulation techniques.

Brodski-Guerniero, A., Naumer, M. J., Moliadze, V., Chan, J., …, & Wibral, M. (2018). Predictable information in neural signals during resting state is reduced in autism spectrum disorder. Hum. Brain Mapp. PMID:29617056, doi:10.1002/hbm.24072.

The neurophysiological underpinnings of the nonsocial symptoms of autism spectrum disorder (ASD) which include sensory and perceptual atypicalities remain poorly understood. Well-known accounts of less dominant top–down influences and more dominant bottom–up processes compete to explain these characteristics. These accounts have been recently embedded in the popular framework of predictive coding theory. To differentiate between competing accounts, we studied altered information dynamics in ASD by quantifying predictable information in neural signals. Predictable information in neural signals measures the amount of stored information that is used for the next time step of a neural process. Thus, predictable information limits the (prior) information which might be available for other brain areas, for example, to build predictions for upcoming sensory information. We studied predictable information in neural signals based on resting-state magnetoencephalography (MEG) recordings of 19 ASD patients and 19 neurotypical controls aged between 14 and 27 years. Using whole-brain beamformer source analysis, we found reduced predictable information in ASD patients across the whole brain, but in particular in posterior regions of the default mode network. In these regions, epoch-by-epoch predictable information was positively correlated with source power in the alpha and beta frequency range as well as autocorrelation decay time. Predictable information in precuneus and cerebellum was negatively associated with nonsocial symptom severity, indicating a relevance of the analysis of predictable information for clinical research in ASD. Our findings are compatible with the assumption that use or precision of prior knowledge is reduced in ASD patients.

Moliadze, V., Lyzhko, E., Schmanke, T., Andreas, S., …, & Siniatchkin, M. (2018). 1 mA cathodal tDCS shows excitatory effects in children and adolescents: Insights from TMS evoked N100 potential. Brain Res. Bull., 140, 43–51. PMID:29625151, doi:10.1016/j.brainresbull.2018.03.018.

In children and adolescents, 1 mA transcranial direct current stimulation (tDCS) may cause “paradoxical” effects compared with adults: both 1 mA anodal and cathodal tDCS increase amplitude of the motor evoked potential (MEP) as revealed by a single pulse transcranial magnetic stimulation (TMS) of the motor cortex. Here, EEG based evoked potentials induced by a single pulse TMS, particularly the N100 component as marker of motor cortex inhibition, were investigated in order to explain effects of tDCS on the developing brain. In nineteen children and adolescents (11–16 years old), 1 mA anodal, cathodal, or sham tDCS was applied over the left primary motor cortex for 10 min. The TMS-evoked N100 was measured by 64-channel EEG before and immediately after stimulation as well as every 10 min after tDCS for one hour. 1 mA Cathodal stimulation suppressed the N100 amplitude compared with sham stimulation. In contrast, anodal tDCS did not modify the N100 amplitude. It seems likely that the increase of the motor cortex activity under cathodal tDCS in children and adolescents as shown in previous studies can be attributed to a reduce inhibition. Based on TMS evoked N100, the study provides an insight into neuromodulatory effects of tDCS on the developing brain.

2017

Antal, A., Alekseichuk, I., Bikson, M., Brockmöller, J., …, Moliadze, V., …, & Paulus, W. (2017). Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin. Neurophysiol., 128(9), 1774–1809. PMID:28709880, doi:10.1016/j.clinph.2017.06.001.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1–2 mA and during tACS at higher peak-to-peak intensities above 2 mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity ‘conventional' TES defined as <4 mA, up to 60 min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3–13 A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10 mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in G{\"{o}}ttingen, Germany, on September 6–7, 2016 and were refined thereafter by email correspondence.

2015

Lyzhko, E., Hamid, L., Makhortykh, S., Moliadze, V.*, & Siniatchkin, M.*. (2015). Comparison of three ICA algorithms for ocular artifact removal from TMS-EEG recordings. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. IEEE Eng. Med. Biol. Soc. Annu. Int. Conf., 2015, 1926–1929. PMID:26736660, doi:10.1109/EMBC.2015.7318760.

The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a powerful tool to investigate brain excitability and information processing in brain networks. However, EEG-TMS recordings are challenging because EEG is contaminated by powerful TMS-related artifacts. Because of these artifacts, different EEG-driven analyses (for instance, source analysis and analysis of information flow on the sensors and source level) reveal incorrect results. The aim of this study was to remove ocular artifacts from TMS-EEG recordings following stimulation of motor cortex using three independent component analysis (ICA) algorithms and to evaluate the effectiveness of these algorithms. We showed that the temporal ICA algorithm better separates those components that contain time-locked eye blink artifacts.

Moliadze, V., Andreas, S., Lyzhko, E., Schmanke, T., …, & Siniatchkin, M. (2015). Ten Minutes of 1mA Transcranial Direct Current Stimulation Was Well Tolerated by Children and Adolescents: Self-Reports and Resting State EEG Analysis. Brain Research Bulletin, 119, 25–33. PMID:26449209, doi:10.1016/j.brainresbull.2015.09.011.
Moliadze, V., Schmanke, T., Andreas, S., Lyzhko, E., …, & Siniatchkin, M. (2015). Stimulation intensities of transcranial direct current stimulation have to be adjusted in children and adolescents. Clin. Neurophysiol. PMID:25468234, doi:10.1016/j.clinph.2014.10.142.

Objective: The aim of the present study was to investigate the effect of the transcranial direct current stimulation (tDCS) on motor cortex excitability in healthy children and adolescents. Methods: We applied 1. mA anodal or cathodal tDCS for 10. min on the left primary motor cortex of 19 healthy children and adolescents (mean age 13.9 ± 0.4. years). In order to prove whether the effects of tDCS may be attributed to the stimulation intensity, 10 children and adolescents were studied again using 0.5. mA anodal and cathodal tDCS. Sham stimulation was used as a control. Results: Compared with sham stimulation, both 1. mA anodal and cathodal tDCS resulted in a significant increase of Motor evoked potentials (MEP) amplitudes which remained to be prominent even one hour after the end of stimulation. Interestingly, the 0.5. mA cathodal tDCS decreased cortico-spinal excitability whereas the 0.5. mA anodal stimulation did not result in any effect. Conclusion: For the first time, the study demonstrates age-specific influences of tDCS on cortical excitability of the primary motor cortex. Significance: Thus, the stimulation protocols of the tDCS have to be optimized according to age by planning studies in pediatric population.

Muthuraman, M.*, Moliadze, V.*, Mideksa, K. G., Anwar, A. R., …, & Siniatchkin, M. (2015). EEG-MEG integration enhances the characterization of functional and effective connectivity in the resting state network. PLoS One. PMID:26509448, doi:10.1371/journal.pone.0140832.

At the sensor level many aspects, such as spectral power, functional and effective connectivity as well as relative-power-ratio ratio (RPR) and spatial resolution have been comprehensively investigated through both electroencephalography (EEG) and magnetoencephalography (MEG). Despite this, differences between both modalities have not yet been systematically studied by direct comparison. It remains an open question as to whether the integration of EEG and MEG data would improve the information obtained from the above mentioned parameters. Here, EEG (64-channel system) and MEG (275 sensor system) were recorded simultaneously in conditions with eyes open (EO) and eyes closed (EC) in 29 healthy adults. Spectral power, functional and effective connectivity, RPR, and spatial resolution were analyzed at five different frequency bands (delta, theta, alpha, beta and gamma). Networks of functional and effective connectivity were described using a spatial filter approach called the dynamic imaging of coherent sources (DICS) followed by the renormalized partial directed coherence (RPDC). Absolute mean power at the sensor level was significantly higher in EEG than in MEG data in both EO and EC conditions. At the source level, there was a trend towards a better performance of the combined EEG+MEG analysis compared with separate EEG or MEG analyses for the source mean power, functional correlation, effective connectivity for both EO and EC. The network of coherent sources and the spatial resolution were similar for both the EEG and MEG data if they were analyzed separately. Results indicate that the combined approach has several advantages over the separate analyses of both EEG and MEG. Moreover, by a direct comparison of EEG and MEG, EEG was characterized by significantly higher values in all measured parameters in both sensor and source level. All the above conclusions are specific to the resting state task and the specific analysis used in this study to have general conclusion multi-center studies would be helpful.

2014

Antal, A., Chaieb, L., Moliadze, V., Zarrouki, D. B., …, & Paulus, W. (2014). BDNF Gene Polymorphisms and Motor Cortical Plasticity in Healthy Humans: When Should We Consider It. J. Neurosci. Rehabil. doi:10.17653/2374-9091.ss0004.

AbstrAct Background: The brain-derived neurotrophic factor (BDNF) gene is in-volved in mechanisms of synaptic plasticity in the brain and has been demonstrated to also play a role in influencing brain plasticity induced by transcranial magnetic and electrical stimulation.

Moliadze, V., Fritzsche, G., & Antal, A. (2014). Comparing the efficacy of excitatory transcranial stimulation methods measuring motor evoked potentials. Neural Plast. PMID:24804104, doi:10.1155/2014/837141.

The common aim of transcranial stimulation methods is the induction or alterations of cortical excitability in a controlled way. Significant effects of each individual stimulation method have been published; however, conclusive direct comparisons of many of these methods are rare. The aim of the present study was to compare the efficacy of three widely applied stimulation methods inducing excitability enhancement in the motor cortex: 1 mA anodal transcranial direct current stimulation (atDCS), intermittent theta burst stimulation (iTBS), and 1 mA transcranial random noise stimulation (tRNS) within one subject group. The effect of each stimulation condition was quantified by evaluating motor-evoked-potential amplitudes (MEPs) in a fixed time sequence after stimulation. The analyses confirmed a significant enhancement of the M1 excitability caused by all three types of active stimulations compared to sham stimulation. There was no significant difference between the types of active stimulations, although the time course of the excitatory effects slightly differed. Among the stimulation methods, tRNS resulted in the strongest and atDCS significantly longest MEP increase compared to sham. Different time courses of the applied stimulation methods suggest different underlying mechanisms of action. Better understanding may be useful for better targeting of different transcranial stimulation techniques. {\textcopyright}2014 Vera Moliadze et al.

2013

Batsikadze, G., Moliadze, V., Paulus, W., Kuo, M. F., & Nitsche, M. A. (2013). Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. J. Physiol., 591(7), 1987–2000. PMID:23339180, doi:10.1113/jphysiol.2012.249730.

Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm2 has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI and ICF towards inhibition. No significant changes were observed in the other protocols. Sham tDCS did not induce significant MEP alterations. These results suggest that an enhancement of tDCS intensity does not necessarily increase efficacy of stimulation, but might also shift the direction of excitability alterations. This should be taken into account for applications of the stimulation technique using different intensities and durations in order to achieve stronger or longer lasting after-effects. {\textcopyright}2013 The Authors. The Journal of Physiology {\textcopyright}2013 The Physiological Society.

Wach, C., Krause, V., Moliadze, V., Paulus, W., …, & Pollok, B. (2013). Effects of 10Hz and 20Hz transcranial alternating current stimulation (tACS) on motor functions and motor cortical excitability. Behav. Brain Res., 241(1), 1–6. PMID:23219965, doi:10.1016/j.bbr.2012.11.038.

Synchronized oscillatory activity at alpha (8-12. Hz) and beta (13-30. Hz) frequencies plays a key role in motor control. Nevertheless, its exact functional significance has yet to be solved. Transcranial alternating current stimulation (tACS) allows the frequency-specific modulation of ongoing oscillatory activity. The goal of the present study was to investigate the effect of 10 and 20. Hz tACS over left primary motor cortex (M1) on motor functions and cortical excitability in healthy subjects. To this end, tACS was applied for 10. min. Sham stimulation served as control condition. Movement speed and accuracy of the right hand were assessed in 15 right-handed subjects before and after (0, 30 and 60. min) tACS of M1. Cortical silent period (CSP) and motor evoked potentials (MEPs) were determined as measures of M1 excitability. While 10. Hz tACS particularly increased movement variability, especially in tasks requiring internal pacing, 20. Hz tACS resulted in movement slowing. Behavioural effects occurred in distinct time windows. While 10. Hz effects developed over 30. min after stimulation, 20. Hz tACS effects were found immediately after stimulation. Following 10. Hz tACS these effects were significantly correlated with CSP duration, indicating interference with inhibitory pathways. The present findings suggest differential effects of stimulation frequency on motor behaviour and M1 excitability. {\textcopyright}2012.

Wach, C., Krause, V., Moliadze, V., Paulus, W., …, & Pollok, B. (2013). The effect of 10 Hz transcranial alternating current stimulation (tACS) on corticomuscular coherence. Front. Hum. Neurosci. doi:10.3389/fnhum.2013.00511.

Synchronous oscillatory activity at alpha (8-12 Hz), beta (13-30 Hz), and gamma (30-90 Hz) frequencies is assumed to play a key role for motor control. Corticomuscular coherence (CMC) represents an established measure of the pyramidal system's integrity. Transcranial alternating current stimulation (tACS) offers the possibility to modulate ongoing oscillatory activity. Behaviorally, 20 Hz tACS in healthy subjects has been shown to result in movement slowing. However, the neurophysiological changes underlying these effects are not entirely understood yet. The present study aimed at ascertaining the effects of tACS at 10 and 20 Hz in healthy subjects on CMC and local power of the primary sensorimotor cortex. Neuromagnetic activity was recorded during isometric contraction before and at two time points (2-10 min and 30-38 min) after tACS of the left primary motor cortex (M1), using a 306 channel whole head magnetoencephalography (MEG) system. Additionally, electromyography (EMG) of the right extensor digitorum communis (EDC) muscle was measured. TACS was applied at 10 and 20 Hz, respectively, for 10 min at 1 mA. Sham stimulation served as control condition. The data suggest that 10 Hz tACS significantly reduced low gamma band CMC during isometric contraction. This implies that tACS does not necessarily cause effects at stimulation frequency. Rather, the findings suggest cross-frequency interplay between alpha and low gamma band activity modulating functional interaction between motor cortex and muscle. {\textcopyright}2013 Wach, Krause, Moliadze, Paulus, Schnitzler and Pollok.

2012

Moliadze, V., Atalay, D., Antal, A., & Paulus, W. (2012). Close to threshold transcranial electrical stimulation preferentially activates inhibitory networks before switching to excitation with higher intensities. Brain Stimul., 5(4), 505–511. PMID:22445135, doi:10.1016/j.brs.2011.11.004.

Background: Recently we have shown that transcranial random noise (tRNS) and 140 Hz transcranial alternating current stimulations (tACS), applied over the primary motor cortex (M1) and using 10 min stimulation duration and 1 mA intensity, significantly increases cortical excitability as measured by motor evoked potentials at rest before and after stimulation. Objective/hypothesis: Here, by decreasing the stimulation intensity in 0.2 mA steps from 1.0 mA, we investigate to what extent intensity depends on the induced after-effects. Methods: All twenty-five subjects participated in two different experimental sessions each. They received tACS using 140 Hz frequency and full spectrum tRNS at five different intensities on separate days. Sham stimulation was used as a control. Results: Instead of receiving a simple threshold, unexpectedly, in these two independent data sets at threshold intensities of 0.4 mA we found a switch of the already known excitation achieved with an intensity of 1 mA to inhibition. The intermediate intensity ranges of 0.6 and 0.8 mA had no effect at all. Interestingly, the inhibition produced by 140 Hz tACS was stronger than that induced by tRNS. Conclusions: In summary, we have shown here the possibility of selectively controlling the enhancement or reduction of M1 excitability by applying different intensities of high frequency transcranial electrical stimulation. {\textcopyright}2012 Elsevier Inc. All rights reserved.

Schade, S., Moliadze, V., Paulus, W., & Antal, A. (2012). Modulating neuronal excitability in the motor cortex with tDCS shows moderate hemispheric asymmetry due to subjects' handedness: A pilot study. Restorative Neurology and Neuroscience, 30(3), 191–198. PMID:22377833, doi:10.3233/RNN-2012-110175.

PURPOSE: Transcranial direct current stimulation (tDCS) has proven to be a useful tool for fundamental brain research as well as for attempts in therapy of neurological and psychiatric diseases by modulating neuronal plasticity. Little is understood about the effects of tDCS are influenced by hemispheric dominance, even less in terms of handedness. The aim of our pilot study was to investigate whether tDCS induced neuroplastic changes may be different in right- and left-handed individuals due to existing differences in hemispheric lateralisation.\n\nMETHODS: We measured changes in motor evoked potentials (MEPs) after application of tDCS in 8 right-handers, 8 left-handers and 8 mixed-handers according to the Edinburgh Handedness Inventory (EHI). In double-blind sessions, we applied either anodal or cathodal tDCS for 5 minutes for each hemisphere.\n\nRESULTS: While motor thresholds (MT) seem to be not influenced by handedness significantly, in right-handed subjects we reproduced the well-known effects of tDCS: anodal stimulation increased while cathodal stimulation decreased MEP amplitudes. However, left-and mixed-handed subjects differed from right-handed subjects. After anodal stimulation of the left hemisphere the increase of the MEP amplitudes was stronger in right handed subjects than in left and mixed handed subjects. Interestingly, after cathodal stimulation of the left hemisphere this difference was less marked. The stimulation of the right hemisphere showed the same tendency, but results were not significant.\n\nCONCLUSIONS: For the first time, we are able to demonstrate that the modulating effects of tDCS on corticospinal excitability differ moderately in the left-and mixed-handed population compared to right-handed subjects. The shown differences according to handedness should be taken into account in further studies.

2011

Gamboa, O. L., Antal, A., Laczo, B., Moliadze, V., …, & Paulus, W. (2011). Impact of repetitive theta burst stimulation on motor cortex excitability. Brain Stimul. PMID:21777874, doi:10.1016/j.brs.2010.09.008.

Theta burst stimulation (TBS) alters cortical excitability in inhibitory or facilitatory directions depending on the pattern of stimulation used. Although continuous TBS (cTBS) decreases motor cortex excitability, intermittent TBS (iTBS) increases excitability by introducing an 8-second stimulation interval after 2 seconds of TBS. The after-effects induced by TBS last from 30 minutes up to 1 hour. Optimization of TBS techniques might be possible through manipulation of a variety of parameters such as number of pulses, stimulus intensity, duration of stimulation, and repetitive stimulation. The aim of this study was to assess the after-effects induced by introducing an interval between two TBS interventions to identify more efficient protocols. The study was divided in two groups, iTBS protocols and cTBS protocols, each of them with four sessions: classical TBS, TBS - 2 minutes - TBS, TBS - 5 minutes - TBS, TBS - 20 minutes - TBS. Our results show that cTBS - 20 minutes - cTBS and iTBS - 2 minutes - iTBS resulted in similar after-effects as those accomplished by a single TBS session, whereas a suppression of after-effects was observed in the other break durations. Repeated TBS with short break durations does not seem to be suitable to prolong the duration of excitability changes accomplished by single TBS. These results might be relevant for clinical applications of TBS, when long-lasting excitability alterations are needed. {\textcopyright}2011 Elsevier Inc. All rights reserved.

2010

Antal, A., Chaieb, L., Moliadze, V., Monte-Silva, K., …, & Paulus, W. (2010). Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape cortical plasticity in humans. Brain Stimul. PMID:20965453, doi:10.1016/j.brs.2009.12.003.

Background The brain-derived neurotrophic factor (BDNF) gene is involved in mechanisms of synaptic plasticity in the adult brain. It has been demonstrated that BDNF also plays a significant role in shaping externally induced human brain plasticity. Plasticity induced in the human motor cortex by intermittent thetaburst stimulation (iTBS) was impaired in individuals expressing the Val66Met polymorphism. Methods To explore whether this polymorphism is also important for other neuroplasticity-inducing tools in humans with modes of action differing from that of iTBS, namely, transcranial direct current (tDCS) and random noise stimulation (tRNS), we retrospectively analyzed the data of 64 subjects studied in our laboratory with regard to BDNF genotype. Results Fifteen subjects with the Val66Met allele, 46 subjects with the Val66Val allele, and 3 Met66Met carriers were identified. The response of the Val66Met allele carriers to stimulation differed in two protocols compared with the response of Val66Val individuals. For iTBS (15 subjects, 5 heterozygotes), plasticity could be only induced in the Val66Val allele carriers. However, for facilitatory tDCS (24 subjects, 10 heterozygotes), as well as for inhibitory tDCS, (19 subjects, 8 heterozygotes), carriers of the Val66- Met allele displayed enhanced plasticity, whereas for transcranial random noise stimulation (29 subjects, 8 heterozygotes), the difference between groups was not so pronounced. Conclusions BDNF polymorphism has a definite impact on plasticity in humans, which might differ according to the mechanism of plasticity induction. This impact of BDNF on plasticity should be taken into account for future studies, as well as having wider ranging implications for the treatment of neuropsychiatric disorders with transcranial stimulation tools, as it may predetermine their efficacy for the treatment of disease and rehabilitation. {\textcopyright}2010 Elsevier Inc. All rights reserved.

Gamboa, O. L., Antal, A., Moliadze, V., & Paulus, W. (2010). Simply longer is not better: Reversal of theta burst after-effect with prolonged stimulation. Exp. Brain Res. PMID:20567808, doi:10.1007/s00221-010-2293-4.

From all rTMS protocols at present, the theta burst stimulation (TBS) is considered the most efficient in terms of number of impulses and intensity required during a given stimulation. The aim of this study was to investigate the effects of inhibitory and excitatory TBS protocols on motor cortex excitability when the duration of stimulation was doubled. Fourteen healthy volunteers were tested under four conditions: intermittent theta bust stimulation (iTBS), continuous theta burst stimulation (cTBS), prolonged intermittent theta bust stimulation (ProiTBS) and prolonged continuous theta burst stimulation (ProcTBS). The prolonged paradigms were twice as long as the conventional TBS protocols. Conventional facilitatory iTBS converted into inhibitory when it was applied for twice as long, while the normally inhibitory cTBS became facilitatory when the stimulation duration was doubled. Our results show that TBS-induced plasticity cannot be deliberately enhanced simply by prolonging TBS protocols. Instead, when stimulating too long, after-effects will be reversed. This finding supplements findings at the short end of the stimulation duration range, where it was shown that conventional cTBS is excitatory in the first half and switches to inhibition only after the full length protocol. It is relevant for clinical applications for which an ongoing need for further protocol improvement is imminent. {\textcopyright}2010 Springer-Verlag.

Moliadze, V., Antal, A., & Paulus, W. (2010). Electrode-distance dependent after-effects of transcranial direct and random noise stimulation with extracephalic reference electrodes. Clin. Neurophysiol. PMID:20554472, doi:10.1016/j.clinph.2010.04.033.

Objective: To evaluate the importance of the distance between stimulation electrodes, in various montages, on the ability to induce sustained cortical excitability changes using transcranial direct and random noise stimulation. Methods: Twelve healthy subjects participated in four different experimental conditions. The stimulation electrode was always placed over the primary motor cortex; the reference electrode was placed at the contralateral orbit or at the ipsilateral/contralateral arm. MEPs were recorded in order to measure changes in cortical excitability over time. Results: The distance between the two electrodes correlates negatively with the duration and magnitude of induced after-effects. Conclusions: In particular when using extracephalic reference electrodes with transcranial electric stimulation techniques, the stimulation intensity has to be adapted to account for interelectrode distance. Significance: Electrode distance plays a critical role in the induction for stimulation after-effects in tDCS and tRNS studies, and must be taken into account in future studies and also when making comparisons with the published literature. {\textcopyright}2010 International Federation of Clinical Neurophysiology.

Moliadze, V., Antal, A., & Paulus, W. (2010). Boosting brain excitability by transcranial high frequency stimulation in the ripple range. J. Physiol. PMID:20962008, doi:10.1055/s-0030-1250984.

Objective: To test the effects of high frequency transcranial alternating current stimulation (tACS) applied in the ripple range, in a frequency-dependent fashion on cortical excitability. Background: Two distinct populations of high frequency oscillations called ripples (80-200 Hz) and fast ripples (250-500 Hz) have been reported in animals and humans. Higher frequencies in the ripple range are intensively used in deep brain stimulation for treatment of Parkinson's disease and recently received attention as a possible correlate to epileptic activity. Here, for the first time we have tested the effects of 80, 140 and 250Hz oscillations on motor evoked potential (MEP) amplitude. Methods: Subjects received on separate days AC-(80Hz, 140Hz, 250Hz,) and sham stimulations in a randomized order. Stimulation was delivered by a battery-driven electrical stimulator (NeuroConn GmbH, Ilmenau, Germany) through conductive-rubber electrodes. To detect changes of excitability MEPs of the right first dorsal interosseus muscle (FDI) were recorded during and following stimulation of its motor-cortical representation field by single-pulse tarnscranial magnetic stimulation (TMS). For the TMS train during the AC stimulation, the MEPs were subdivided into successive groups of 15, each covering a time range of 1 min, and the means for each group were calculated. Following stimulation, 20 single test-pulse MEPs were recorded at, i.e., 0, 5, and 10 min after stimulation and then every 10 min up to 60 min. Results: Using tACS we could immediately increase motor cortex (M1) excitability as measured by TMS during 140 Hz stimulation with an induced aftereffect of 1 hour. Controls by sham and 80 Hz stimulation were without any effect. Furthermore, 250 Hz was effective only with a delayed induction and reduced duration. Interestingly, in our study, 140 Hz stimulation excitatory after-effects are not sensitive to the physiological state of stimulating neurons. Conclusions: In summary we were able to show that high frequency stimulation enhances human M1 excitability in a frequencydependent fashion. Our findings are expected to be of importance to engender research in several directions. It represents a further step to more targeted plasticity modulating protocols and also may have important implications for neurological disease accompanied by pathological oscillations and motor deficits.

2008

Terney, D., Chaieb, L., Moliadze, V., Antal, A., & Paulus, W. (2008). Increasing Human Brain Excitability by Transcranial High-Frequency Random Noise Stimulation. J. Neurosci. PMID:19109497, doi:10.1523/JNEUROSCI.4248-08.2008.

For >20 years, noninvasive transcranial stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) and direct current stimulation (tDCS) have been used to induce neuroplastic-like effects in the human cortex, leading to the activity-dependent modification of synaptic transmission. Here, we introduce a novel method of electrical stimulation: transcranial random noise stimulation (tRNS), whereby a random electrical oscillation spectrum is applied over the motor cortex. tRNS induces consistent excitability increases lasting 60 min after stimulation. These effects have been observed in 80 subjects through both physiological measures and behavioral tasks. Higher frequencies (100-640 Hz) appear to be responsible for generating this excitability increase, an effect that maybe attributed to the repeated opening of Na+ channels. In terms of efficacy tRNS appears to possess at least the same therapeutic potential as rTMS/tDCS in diseases such as depression, while furthermore avoiding the constraint of current flow direction sensitivity characteristic of tDCS. Copyright {\textcopyright}2008 Society for Neuroscience.

2006

Aydin-Abidin, S., Moliadze, V., Eysel, U. T., & Funke, K. (2006). Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration. J. Physiol., 574(2), 443–455. PMID:16690713, doi:10.1113/jphysiol.2006.108464.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to alter cortical excitability that lasts beyond the duration of rTMS application itself. High-frequency rTMS leads primarily to facilitation, whereas low-frequency rTMS leads to inhibition of the treated cortex. However, the contribution of rTMS train duration is less clear. In this study, we investigated the effects of nine different rTMS protocols, including low and high frequencies, as well as short and long applications (1, 3 and 10 Hz applied for 1, 5 and 20 min), on visual cortex excitability in anaesthetized and paralysed cats by means of visual evoked potential (VEP) and electroencephalography (EEG) recordings. Our results show that 10 Hz rTMS applied for 1 and 5 min significantly enhanced early VEP amplitudes, while 1 and 3 Hz rTMS applied for 5 and 20 min significantly reduced them. No significant changes were found after 1 and 3 Hz rTMS applied for only 1 min, and 10 Hz rTMS applied for 20 min. EEG activity was only transiently (<20 s) affected, with increased delta activity after 1 and 3 Hz rTMS applied for 1 or 5 min. These findings indicate that the effects of rTMS on cortical excitability depend on the combination of stimulus frequency and duration (or total number of stimuli): short high-frequency trains seem to be more effective than longer trains, and low-frequency rTMS requires longer applications. Changes in the spectral composition of the EEG were not correlated to changes in VEP size. {\textcopyright}2006 The Authors. Journal compilation {\textcopyright}2006 The Physiological Society.

2005

Moliadze, V., Giannikopoulos, D., Eysel, U. T., & Funke, K. (2005). Paired-pulse transcranial magnetic stimulation protocol applied to visual cortex of anaesthetized cat: Effects on visually evoked single-unit activity. J. Physiol. PMID:15919717, doi:10.1113/jphysiol.2005.086090.

In this study, we tested the paired-pulse transcranial magnetic stimulation (ppTMS) protocol - a conditioning stimulus (CS) given at variable intervals prior to a test stimulus (TS) - for visually evoked single-unit activity in cat primary visual cortex. We defined the TS as being supra-threshold when it caused a significant increase or decrease in the visually evoked activity. By systematically varying the interstimulus interval (ISI) between 2 and 30 ms and the strength of CS within the range 15-130% of TS, we found a clear dependence of the ppTMS effect on CS strength but little relation to ISI. The CS effect was strongest with an ISI of 3 ms and steadily declined for longer ISIs. A switch from enhancement of intracortical inhibition at short ISIs (2-5 ms, SICI) to intracortical facilitation (ICF) at longer ISIs (7-30 ms), as demonstrated for human motor cortex, was not evident. Whether the CS caused facilitation or suppression of the TS effect mainly depended on the strength of CS and the polarity of the TS effect: within a range of 60-130% a positive correlation between ppTMS and TS effect was evident, resulting in a stronger facilitation if the TS caused facilitation of visual activity, and more suppression if the TS was suppressive by itself. The correlation inverted when CS was reduced to 15-30%. The ppTMS effect was not simply the sum of the CS and TS effect, it was much smaller at weak CS strength (15-50%) but stronger than the sum of CS and TS effects at CS strength 60-100%. Differences in the physiological state between sensory and motor cortices and the interactions of paired synaptic inputs are discussed as possible reasons for the partly different effects of ppTMS in cat visual cortex and human motor cortex. {\textcopyright}The Physiological Society 2005.

2003

Moliadze, V., Zhao, Y., Eysel, U., & Funke, K. (2003). Effect of transcranial magnetic stimulation on single-unit activity in the cat primary visual cortex. J. Physiol. PMID:12963791, doi:10.1113/jphysiol.2003.050153.

Transcranial magnetic stimulation (TMS) has become a well established procedure for testing and modulating the neuronal excitability of human brain areas, but relatively little is known about the cellular processes induced by this rather coarse stimulus. In a first attempt, we performed extracellular single-unit recordings in the primary visual cortex (area 17) of the anaesthetised and paralysed cat, with the stimulating magnetic field centred at the recording site (2 × 70 mm figure-of-eight coil). The effect of single biphasic TMS pulses, which induce a lateral-to-medial electric current within the occipital pole of the right hemisphere, was tested for spontaneous as well as visually evoked activity. For cat visual cortex we found that a single TMS pulse elicited distinct episodes of enhanced and suppressed activity: in general, a facilitation of activity was found during the first 500 ms, followed thereafter by a suppression of activity lasting up to a few seconds. Strong stimuli exceeding 50% of maximal stimulator output could also lead to an early suppression of activity during the first 100-200 ms, followed by stronger (rebound) facilitation. Early suppression and facilitation of activity may be related to a more or less direct stimulation of inhibitory and excitatory interneurons, probably with different thresholds. The late, long-lasting suppression is more likely to be related to metabotropic or metabolic processes, or even vascular responses. The time course of facilitation/inhibition may provide clues regarding the action of repetitive TMS application.