[Transcranial magnetic stimulation (TMS), inhibition processes and attention deficit/hyperactivity disorder (ADHD) - an overview]. / Transkranielle Magnetstimulation (TMS), Inhibitionsprozesse und Aufmerksamkeitsdefizit-/ Hyperaktivitätsstörung (ADHS).

Motor system excitability can be tested by transcranial magnetic stimulation CFMS). In this article, an overview of recent methodological developments and research findings related to attention deficit/hyperactivity disorder (ADHD) is provided. Different TMS parameters that reflect the function of interneurons in the motor cortex may represent neurophysiological markers of inhibition in ADHD, particularly the so-called intracortical inhibition. In children with a high level of hyperactivity and impulsivity, intracortical inhibition was comparably low at rest as shortly before the execution of a movement. TMS-evoked potentials can also be measured in the EEG so that investigating processes of excitability is not restricted to motor areas in future studies. The effects of methylphenidate on motor system excitability may be interpreted in the sense of a 'fine-tuning' with these mainly dopaminergic effects also depending on genetic parameters (DAT1 transporter). A differentiated view on the organization of motor control can be achieved by a combined analysis of TMS parameters and event-related potentials. Applying this bimodal approach, strong evidence for a deviant implementation of motor control in children with ADHD and probably compensatory mechanisms (with involvement of the prefrontal cortex) was obtained. These findings, which contribute to a better understanding of hyperactivity/impulsivity, inhibitory processes and motor control in ADHD as well as the mechanisms of medication, underline the relevance of TMS as a neurophysiological method in ADHD research.

A bimodal neurophysiological study of motor control in attention-deficit hyperactivity disorder: a step towards core mechanisms?

Knowledge about the core neural mechanisms of attention-deficit hyperactivity disorder, a pathophysiologically heterogeneous psychiatric disorder starting in childhood, is still limited. Progress may be achieved by combining different methods and levels of investigation. In the present study, we investigated neural mechanisms of motor control in 19 children with attention-deficit hyperactivity disorder (aged 9-14 years) and 21 age-matched typically developing children by relating neural markers of attention and response control (using event-related potentials) and measures of motor excitability/inhibition (evoked by transcranial magnetic stimulation). Thus, an interplay of processes at a subsecond scale could be studied. Using a monetary incentives-based cued Go/No-Go task, parameters that are well-known to be reduced in attention-deficit hyperactivity disorder were analysed: event-related potential components P3 (following cue stimuli; in Go and No-Go trials) and contingent negative variation as well as the transcranial magnetic stimulation-based short-interval intracortical inhibition measured at different latencies in Go and No-Go trials. For patient and control groups, different associations were obtained between performance, event-related potential and transcranial magnetic stimulation measures. In children with attention-deficit hyperactivity disorder, the P3 amplitude in Go trials was not correlated with reaction time measures but with short-interval intracortical inhibition at rest (r=0.56, P=0.01). In No-Go trials, P3 and short-interval intracortical inhibition after inhibiting the response (at 500 ms post-stimulus) were correlated in these children only (r=0.62; P=0.008). A classification rate of 90% was achieved when using short-interval intracortical inhibition (measured shortly before the occurrence of a Go or No-Go stimulus) and the amplitude of the P3 in cue trials as input features in a linear discriminant analysis. Findings indicate deviant neural implementation of motor control in children with attention-deficit hyperactivity disorder reflecting compensatory cognitive mechanisms as a result of a basal motor cortical inhibitory deficit (reduced activation of inhibitory intracortical interneurons). Both deviant inhibitory and attentional processes, which are not related to each other, seem to be characteristic for attention-deficit hyperactivity disorder at the neural level in motor control tasks. The underlying neural mechanisms, which are probably not restricted to the motor cortex and the posterior attention network, may play a key role in the pathophysiology of this child psychiatric disorder. The high classification rate can further be interpreted as a step towards the development of neural markers. In summary, the bimodal neurophysiological concept may contribute to developing an integrative framework for attention-deficit hyperactivity disorder.

Motor cortical inhibition in ADHD: modulation of the transcranial magnetic stimulation-evoked N100 in a response control task.

The N100 component, evoked by transcranial magnetic stimulation (TMS) and electroencephalography is associated with the activation of inhibitory cortical circuits and has recently been suggested as a potential marker of inhibition in attention-deficit/hyperactivity disorder (ADHD). The aim of the present ADHD study was to investigate the modulation of the TMS-N100 in go and nogo trials of a response control task considering stages of response preparation, activation, execution and inhibition. Eighteen children with ADHD and 19 typically developing children, aged 10-14 years, were assessed. TMS was delivered over the left motor cortex, the TMS-N100 was measured at electrode P3. The TMS-N100 was determined at rest and at different time points (50 ms before S2; 150, 300 and 500 ms after S2) in a cued go/nogo task (S1-S2 paradigm). Correlations between the TMS-N100 measures, MEP-related TMS measures (e.g., short-interval intracortical inhibition) and performance measures were calculated. At rest, the amplitude of TMS-N100 was not found to be significantly reduced in the ADHD group. During the go/nogo task, children with ADHD showed a smaller increase of TMS-N100 amplitude in go trials and a smaller decrease after inhibiting a response. In go trials, a lower TMS-N100 was associated with a smaller variability of reaction times. A smaller TMS-N100 modulation extends the picture of cortical inhibition deficits in ADHD. Findings suggest a functional involvement of the mechanisms underlying the TMS-N100 at the motor output stage.

Time course analysis of motor excitability in a response inhibition task according to the level of hyperactivity and impulsivity in children with ADHD.

Short interval intracortical inhibition (SICI) of motor cortex, measured by transcranial magnetic stimulation (TMS) in a passive (resting) condition, has been suggested as a neurophysiological marker of hyperactivity in attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to determine motor excitability in a go/nogo task at stages of response preparation, activation and suppression in children with ADHD, depending on the level of hyperactivity and impulsivity. Motor evoked potentials were recorded in 29 typically developing children and 43 children with ADHD (subdivided in two groups with higher and lower levels of hyperactivity/impulsivity; H/I-high and H/I-low). In the H/I-high group, SICI was markedly reduced in the resting condition and during response preparation. Though these children were able to increase SICI when inhibiting a response, SICI was still reduced compared to typically developing children. Interestingly, SICI at rest and during response activation were comparable, which may be associated with their hypermotoric behaviour. In the H/I-low group, response activation was accompanied by a pronounced decrease of SICI, indicating reduced motor control in the context of a fast motor response. In summary, different excitability patterns were obtained for the three groups allowing a better understanding of dysfunctional response activation and inhibition processes within the motor cortex in children with ADHD.

Interplay of neuronal processes during response inhibition: results from a combined event-related potentials (ERPs)/transcranial magnetic stimulation (TMS) study on methylphenidate.

The neuronal processes underlying response inhibition are often studied using either event-related potentials (ERPs) or by applying transcranial magnetic stimulation (TMS) to investigate excitatory and inhibitory processes in the motor system. We performed a more refined analysis of response inhibition by combining both approaches with the aim of identifying an interplay between ERPs and TMS parameters. During a go/nogo task, motor system excitability was measured using TMS single and double pulses and brain electrical activity was recorded in healthy adults (n=14). Each participant completed two testing sessions, once on placebo and once on methylphenidate (double-blind, crossover design). Studying the effects of methylphenidate served as an example application for this combined approach. Developing regression models, inhibition-related TMS measures (e.g., short intracortical inhibition) and the contingent negative variation explained about 85% of the variance of the nogo-P3 under both MPH and placebo medication. The smaller the inhibitory effect in the motor system, the more terminal response control was required and the more resources were allocated for the evaluation of the inhibitory process, respectively, as indicated by a larger P3. Thus, an interplay between processes in the motor system (cortex) and control processes with sources in the prefrontal cortex and the anterior cingulate cortex (ACC) may take place, acting complementarily to facilitate a correct nogo-response. While ERPs rather represent initiation and monitoring of inhibitory processes and response control, motor inhibition may be best analyzed using TMS. A combined ERP/TMS analysis may allow for the development of distinct models concerning the interplay of processes involved in response inhibition.

Seizure in a nonpredisposed individual induced by single-pulse transcranial magnetic stimulation.

Seizure induction is a rare, but serious adverse effect of the otherwise very safe method of transcranial magnetic stimulation (TMS). There are only very few single case reports concerning seizure in single-pulse TMS. All of these reports describe individuals with neurological disorders or epileptogenic medication. To our knowledge, we are the first to describe a healthy subject who developed symptoms of a seizure after single-pulse TMS during motor threshold estimation. This case report provides evidence that single-pulse TMS may provoke a seizure even in the absence of neurological risk factors. Differential diagnoses of a classic neurological seizure, that is, convulsive syncope and psychogenic seizure, are discussed. Neurogenic seizure after TMS and convulsive syncope are the most probable hypotheses, although clear specification of this singular incident remains impossible. Therefore, to minimize the risk for such rare adverse effects, existing and new suggestions are combined to provide reasonable precautions to be taken before and during TMS application.