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Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique gaining more attention in neurodevelopmental disorders (NDDs). Due to the phenotypic heterogeneity of NDDs, tDCS is unlikely to be equally effective in all individuals. The present study aimed to establish neuroanatomical markers in typically developing (TD) individuals that may be used for the prediction of individual responses to tDCS. Fifty-seven male and female children received 2 mA anodal and sham tDCS, targeting the left dorsolateral prefrontal cortex (DLPFC left ), right inferior frontal gyrus, and bilateral temporoparietal junction. Response to tDCS was assessed based on task performance differences between anodal and sham tDCS in different neurocognitive tasks ( N -back, flanker, Mooney faces detection, attentional emotional recognition task). Measures of cortical thickness (CT) and surface area (SA) were derived from 3 Tesla structural MRI scans. Associations between neuroanatomy and task performance were assessed using general linear models (GLM). Machine learning (ML) algorithms were employed to predict responses to tDCS. Vertex-wise estimates of SA were more closely linked to differences in task performance than measures of CT. Across ML algorithms, highest accuracies were observed for the prediction of N -back task performance differences following stimulation of the DLPFC left , where 65% of behavioral variance was explained by variability in SA. Lower accuracies were observed for all other tasks and stimulated regions. This suggests that it may be possible to predict individual responses to tDCS for some behavioral measures and target regions. In the future, these models might be extended to predict treatment outcome in individuals with NDDs., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Mindfulness-based processes have been shown to enhance attention and related behavioral responses, including analgesia, which is discussed as an effective method in the context of pain interventions. In the present review, we introduce the construct of mindfulness, delineating the concepts, factors, and processes that are summarized under this term and might serve as relevant components of the underlying mechanistic pathways in the field of pain. We also discuss how differences in factors such as definitions of mindfulness, study design, and strategies in mindfulness-based attention direction may need to be considered when putting the findings from previous studies into a whole framework. In doing so, we capitalize on a potential dynamic process model of mindfulness-based analgesia. In this respect, the so-called mindfulness-based analgesia may initially result from improved cognitive regulation strategies, while at later stages of effects may be driven by a reduction of interference between both cognitive and affective factors. With increasing mindfulness practice, pathways and mechanisms of mindfulness analgesia may change dynamically, which could result from adaptive coping. This is underlined by the fact that the neural mechanism of mindfulness analgesia is manifested as increased activation in the ACC and aINS at the beginner level while increased activation in the pINS and reduced activation in the lPFC at the expert level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Lu, Moliadze and Nees.)

Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique with a wide variety of clinical and research applications. As increasingly acknowledged, its effectiveness is subject dependent, which may lead to time consuming and cost ineffective treatment development phases. We propose the combination of electroencephalography (EEG) and unsupervised learning for the stratification and prediction of individual responses to tDCS. A randomized, sham-controlled, double-blind crossover study design was conducted within a clinical trial for the development of pediatric treatments based on tDCS. The tDCS stimulation (sham and active) was applied either in the left dorsolateral prefrontal cortex or in the right inferior frontal gyrus. Following the stimulation session, participants performed 3 cognitive tasks to assess the response to the intervention: the Flanker Task, N-Back Task and Continuous Performance Test (CPT). We used data from 56 healthy children and adolescents to implement an unsupervised clustering approach that stratify participants based on their resting-state EEG spectral features before the tDCS intervention. We then applied a correlational analysis to characterize the clusters of EEG profiles in terms of participant's difference in the behavioral outcome (accuracy and response time) of the cognitive tasks when performed after a tDCS-sham or a tDCS-active session. Better behavioral performance following the active tDCS session compared to the sham tDCS session is considered a positive intervention response, whilst the reverse is considered a negative one. Optimal results in terms of validity measures was obtained for 4 clusters. These results show that specific EEG-based digital phenotypes can be associated to particular responses. While one cluster presents neurotypical EEG activity, the remaining clusters present non-typical EEG characteristics, which seem to be associated with a positive response. Findings suggest that unsupervised machine learning can be successfully used to stratify and eventually predict responses of individuals to a tDCS treatment., (© 2023. The Author(s).)

Social interactions affect individual behaviours, preferences, and attitudes. This is also critical in the context of experiencing pain and expressing pain behaviours, and may relate to learned emotional responses. In this respect, individual variability in the medial prefrontal cortex (mPFC), which is involved in adjusting an organism's behaviour to its environment by evaluating and interpreting information within the context of past experiences, is important. It is critical for selecting suitable behavioural responses within a social environment and may reinforce maladaptation in chronic pain. In our study, we used brain imaging during appetitive and aversive pavlovian conditioning in persons with chronic back pain (CBP), subacute back pain (SABP), and healthy controls (HC), together with information on spouse responses to pain behaviours. We also examined the relationship of these responses with pain-related interference in the patients. Our findings yielded a significant negative association between mPFC responses to appetitive and aversive learning in CBP. We also observed a significant negative association for mPFC responses during aversive learning and distracting spouse responses, and a significant positive association between mPFC responses during appetitive learning and solicitous spouse responses in CBP. Both significantly predicted pain-related interference in the CBP group (explained variance up to 53%). Significant associations were not found for SABP or HC. Our findings support an association between appetitive and aversive pavlovian learning, related brain circuits and spouse responses to pain in CBP, where appetitive and aversive learning processes seem to be differentially involved. This can inform prevention and early intervention in a mechanistic approach., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Methodological studies investigating transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) in paediatric populations are limited. Therefore, we investigated in a paediatric population whether stimulation success of multichannel tDCS over the lDLPFC depends on concurrent task performance and individual head anatomy. In a randomised, sham-controlled, double-blind crossover study 22 healthy participants (10-17 years) received 2 mA multichannel anodal tDCS (atDCS) over the lDLPFC with and without a 2-back working memory (WM) task. After stimulation, the 2-back task and a Flanker task were performed. Resting state and task-related EEG were recorded. In 16 participants we calculated the individual electric field (E-field) distribution. Performance and neurophysiological activity in the 2-back task were not affected by atDCS. atDCS reduced reaction times in the Flanker task, independent of whether atDCS had been combined with the 2-back task. Flanker task related beta oscillation increased following stimulation without 2-back task performance. atDCS effects were not correlated with the E-field. We found no effect of multichannel atDCS over the lDLPFC on WM in children/adolescents but a transfer effect on interference control. While this effect on behaviour was independent of concurrent task performance, neurophysiological activity might be more sensitive to cognitive activation during stimulation. However, our results are limited by the small sample size, the lack of an active control group and variations in WM performance., (© 2021. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kandić, Moliadze, Andoh, Flor and Nees.)

Anodal transcranial direct current stimulation (tDCS), applied over the left dorsolateral prefrontal cortex (lDLPFC), can produce significant effects on working memory (WM) performance and associated neurophysiological activity. However, results from previous studies are inconsistent and occasionally contradictory. This inconsistency may be attributed to methodological and individual differences during experiments. This study therefore investigated two hypotheses: (1) A multichannel-optimized montage was expected to be more effective than a classical bipolar montage, because of increased focality. (2) The subjects were expected to benefit differently from the stimulation depending on their initial task performance. In a sham-controlled crossover study, 24 healthy participants received bipolar, multichannel, and sham stimulation for 20 min in randomized order, targeting the lDLPFC while performing a 2-back WM task. After stimulation, electroencephalography (EEG) was recorded at rest and during 2-back and nontarget continuous performance task (CPT) performance. Bipolar and multichannel stimulations were both well tolerated and effectively blinded. We found no effect of stimulation on behavioral performance or neuronal oscillations comparing the classical bipolar or multichannel montage with sham stimulation. We did, however, find an interaction between stimulation and initial task performance. For multichannel stimulation, initially low-performing participants tended to improve their WM performance while initially high-performing participants tended to worsen their performance compared to sham stimulation. Both tDCS montages induced changes in neural oscillatory power, which correlated with baseline performance. The worse the participants' initial WM performance was, the more task-related theta power was induced by multichannel and bipolar stimulation. The same effect was observed for alpha power in the nontarget task following multichannel stimulation. Notably, we were not able to show a superiority of multichannel stimulation compared to bipolar stimulation. Still, comparing both montages with sham stimulation, multichannel stimulation led to stronger effects than bipolar stimulation. The current study highlights the importance of investigating different parameters with potential influence on tDCS effects in combination. Our results demonstrate how individual differences in cognitive performance and electrode montages influence effects of tDCS on neuropsychological performance. These findings support the idea of an individualized and optimized stimulation setting, potentially leading to increased tDCS effects., (Copyright © 2020 Splittgerber, Salvador, Brauer, Breitling-Ziegler, Prehn-Kristensen, Krauel, Nowak, Ruffini, Moliadze and Siniatchkin.)

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., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper. All the authors have read the manuscript and have approved this submission., (Copyright © 2020 Maike Splittgerber et al.)

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.

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.

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.

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., (© 2018 Wiley Periodicals, Inc.)

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.

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.

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.

Alleviating the symptoms of neurological diseases by increasing cortical excitability through transcranial stimulation is an ongoing scientific challenge. Here, we tackle this issue by interfering with high frequency oscillations (80–250 Hz) via external application of transcranial alternating current stimulation (tACS) over the human motor cortex (M1). Twenty-one subjects participated in three different experimental studies and they received on separate days tACS at three frequencies (80 Hz, 140 Hz and 250 Hz) and sham stimulation in a randomized order. tACS with 140 Hz frequency increased M1 excitability as measured by transcranial magnetic stimulation-generated motor evoked potentials (MEPs) during and for up to 1 h after stimulation. Control experiments with sham and 80 Hz stimulation were without any effect, and 250 Hz stimulation was less efficient with a delayed excitability induction and reduced duration. After-effects elicited by 140 Hz stimulation were robust against inversion of test MEP amplitudes seen normally under activation. Stimulation at 140 Hz reduced short interval intracortical inhibition, but left intracortical facilitation, long interval cortical inhibition and cortical silent period unchanged. Implicit motor learning was not facilitated by 140 Hz stimulation. High frequency stimulation in the ripple range is a new promising non-invasive brain stimulation protocol to increase human cortical excitability during and after the end of stimulation.

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.

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.

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 x 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.