Monitoring Changes in TMS-Evoked EEG and EMG Activity During 1†Hz rTMS of the Healthy Motor Cortex.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique capable of inducing neuroplasticity as measured by changes in peripheral muscle electromyography (EMG) or electroencephalography (EEG) from pre-to-post stimulation. However, temporal courses of neuromodulation during ongoing rTMS are unclear. Monitoring cortical dynamics via TMS-evoked responses using EMG (motor-evoked potentials; MEPs) and EEG (transcranial-evoked potentials; TEPs) during rTMS might provide further essential insights into its mode of action - temporal course of potential modulations. The objective of this study was to first evaluate the validity of online rTMS-EEG and rTMS-EMG analyses, and second to scrutinize the temporal changes of TEPs and MEPs during rTMS. As rTMS is subject to high inter-individual effect variability, we aimed for single-subject analyses of EEG changes during rTMS. Ten healthy human participants were stimulated with 1,000 pulses of 1 Hz rTMS over the motor cortex, while EEG and EMG were recorded continuously. Validity of MEPs and TEPs measured during rTMS was assessed in sensor and source space. Electrophysiological changes during rTMS were evaluated with model fitting approaches on a group- and single-subject level. TEPs and MEPs appearance during rTMS was consistent with past findings of single pulse experiments. Heterogeneous temporal progressions, fluctuations or saturation effects of brain activity were observed during rTMS depending on the TEP component. Overall, global brain activity increased over the course of stimulation. Single-subject analysis revealed inter-individual temporal courses of global brain activity. The present findings are in favor of dose-response considerations and attempts in personalization of rTMS protocols.

Variability of pulse width in transcranial magnetic stimulation.

Objective.There is a high variability in the physiological effects of transcranial magnetic brain stimulation, resulting in limited generalizability of measurements. The cause of the variability is assumed to be primarily based on differences in brain function and structure of the stimulated individuals, while the variability of the physical properties of the magnetic stimulus has so far been largely neglected. Thus, this study is dedicated to the systematic investigation of variability in the pulse width of different TMS pulse sources at different stimulation intensities.Approach.The pulse widths of seven MagVenture® pulse sources were measured at the output of 10%-100% stimulation intensity in 10% increments via Near Field Probe and oscilloscope. The same C-B60 coil was used to deliver biphasic pulses. Pulse widths were compared between pulse sources and stimulation intensities.Main results.The mean sample pulse width was 288.11 ± 0.37µs, which deviates from the value of 280µs specified by the manufacturer. The pulse sources and stimulation intensities differ in their average pulse width (p's< .001). However, the coefficient of variation within the groups (pulse source; stimulation intensity) were moderately low (CV = 0.13%-0.67%).Significance.The technical parameter of pulse width shows deviations from the proposed manufacturer value. According to our data, within a pulse source of the same manufacturer, the pulse width variability is minimal, but varies between pulse sources of the same and other pulse source models. Whether the observed variability in pulse width has potential physiological relevance was tested in a pilot experiment on a single healthy subject, showing no significant difference in motor evoked potential amplitude and significant difference in latencies. Future research should systematically investigate the physiological effects of different pulse lengths. Furthermore, potential hardware ageing effects and pulse amplitude should be investigated.

On the reliability of motor evoked potentials in hand muscles of healthy adults: a systematic review.

Aims: Motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex are used as a neurophysiological marker of cortical excitability in clinical and scientific practice. Though, the reliability of this outcome parameter has not been clarified. Using a systematic approach, this work reviews and critically appraises studies on the reliability of MEP outcome parameters derived from hand muscles of healthy subjects and gives a proposal for most reliable TMS practice. Methods: A systematic literature research was performed in PubMed, according to the PRISMA guidelines. Articles published up to March 2023 that were written in English, conducted repeated measurements from hand muscles of healthy subjects and reliability analysis were included. The risk of publication bias was determined. Two authors conducted the literature search and rated the articles in terms of eligibility and methodological criteria with standardized instruments. Frequencies of the checklist criteria were calculated and inter-rater reliability of the rating procedure was determined. Reliability and stimulation parameters were extracted and summarized in a structured way to conclude best-practice recommendation for reliable measurements. Results: A total of 28 articles were included in the systematic review. Critical appraisal of the studies revealed methodological heterogeneity and partly contradictory results regarding the reliability of outcome parameters. Inter-rater reliability of the rating procedure was almost perfect nor was there indication of publication bias. Identified studies were grouped based on the parameter investigated: number of applied stimuli, stimulation intensity, reliability of input-output curve parameters, target muscle or hemisphere, inter-trial interval, coil type or navigation and waveform. Conclusion: The methodology of studies on TMS is still subject to heterogeneity, which could contribute to the partly contradictory results. According to the current knowledge, reliability of the outcome parameters can be increased by adjusting the experimental setup. Reliability of single pulse MEP measurement could be optimized by using (1) at least five stimuli per session, (2) a minimum of 110% resting motor threshold as stimulation intensity, (3) a minimum of 4 s inter-trial interval and increasing the interval up to 20 s, (4) a figure-of-eight coil and (5) a monophasic waveform. MEPs can be reliably operationalized.

Retest reliability of repetitive transcranial magnetic stimulation over the healthy human motor cortex: a systematic review and meta-analysis.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is used to induce long-lasting changes (aftereffects) in cortical excitability, which are often measured via single-pulse TMS (spTMS) over the motor cortex eliciting motor-evoked potentials (MEPs). rTMS includes various protocols, such as theta-burst stimulation (TBS), paired associative stimulation (PAS), and continuous rTMS with a fixed frequency. Nevertheless, subsequent aftereffects of rTMS are variable and seem to fail repeatability. We aimed to summarize standard rTMS procedures regarding their test-retest reliability. Hereby, we considered influencing factors such as the methodological quality of experiments and publication bias. Methods: We conducted a literature search via PubMed in March 2023. The inclusion criteria were the application of rTMS, TBS, or PAS at least twice over the motor cortex of healthy subjects with measurements of MEPs via spTMS as a dependent variable. The exclusion criteria were measurements derived from the non-stimulated hemisphere, of non-hand muscles, and by electroencephalography only. We extracted test-retest reliability measures and aftereffects from the eligible studies. With the Rosenthal fail-safe N, funnel plot, and asymmetry test, we examined the publication bias and accounted for influential factors such as the methodological quality of experiments measured with a standardized checklist. Results: A total of 15 studies that investigated test-retest reliability of rTMS protocols in a total of 291 subjects were identified. Reliability measures, i.e., Pearson's r and intraclass correlation coefficient (ICC) applicable from nine studies, were mainly in the small to moderate range with two experiments indicating good reliability of 20 Hz rTMS (r = 0.543) and iTBS (r = 0.55). The aftereffects of rTMS procedures seem to follow the heuristics of respective inhibition or facilitation, depending on the protocols' frequency, and application pattern. There was no indication of publication bias and the influence of methodological quality or other factors on the reliability of rTMS. Conclusion: The reliability of rTMS appears to be in the small to moderate range overall. Due to a limited number of studies reporting test-retest reliability values and heterogeneity of dependent measures, we could not provide generalizable results. We could not identify any protocol as superior to the others.

Limited evidence for reliability of low and high frequency rTMS over the motor cortex.

OBJECTIVE: The aim of this study was to investigate the reliability of low-frequency and high-frequency repetitive transcranial magnetic stimulation (rTMS) on healthy individuals over the motor cortex. A secondary outcome was the assessment if low-frequency rTMS results in inhibition and high-frequency rTMS results in facilitation. METHODS: In this experiment, 30 healthy participants received on four consecutive days one session each with application of 1 Hz or 20 Hz rTMS over the left motor cortex. 1 Hz and 20 Hz were applied in alternating order, whereby the starting frequency was randomized. Motor evoked potentials (MEPs) were measured before and after each session. Reliability measures were intraclass and Pearson's correlation coefficient (ICC and r). RESULTS: ICCs and r values were low to moderate. Notably, within subgroups of less confounded measures, we found good r values for 20 Hz rTMS. The group-level analysis did not demonstrate a clear low-frequency inhibition and high-frequency facilitation pattern. At the single-subject level, only one participant exhibited significant changes consistent with the expected pattern, with concurrent decreases in MEPs following 1 Hz sessions and increases following 20 Hz sessions. CONCLUSION: The investigated neuromodulatory protocols show low to moderate reliability. Results are questioning the low-frequency inhibition and high-frequency facilitation pattern. SIGNIFICANCE: Methodological improvements for the usage of rTMS are necessary to increase validity and reliability of non-invasive brain stimulation.

GABAergic Effects of Etifoxine and Alprazolam Assessed by Double Pulse TMS.

INTRODUCTION: There is a need for novel anxiolytics with improved side effect profiles compared to benzodiazepines. A promising candidate with alternative pharmacodynamics is the translocator protein ligand, etifoxine. METHODS: To get further insight into its mechanisms of action and side effects compared to the benzodiazepine alprazolam, we performed a double-blind, placebo-controlled, repeated-measures study in 36 healthy male subjects. Participants were examined for trait anxiety and side effects and underwent repeated transcranial magnetic stimulation (TMS) assessments, including motor evoked potentials (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). RESULTS: We observed attenuation of MEPs by alprazolam but not by etifoxine. SICI was not significantly affected by alprazolam or etifoxine. However, the response pattern indicated a lowered SICI threshold after the administration of etifoxine and alprazolam compared to the placebo. ICF and CSP were influenced by neither medication. Alprazolam led to higher sedation and subjective impairment of concentration compared to etifoxine. Individual anxiety trait scores did not affect TMS parameters. DISCUSSION: This study indicated a favorable side effect profile of etifoxine in healthy volunteers. Moreover, it revealed differential GABA-related effects on neuromuscular function by means of TMS. The side effects and TMS profile of etifoxine are compatible with the involvement of neurosteroidogenesis and a predominant α3 subunit modulation compared to alprazolam.

Semi-automated motor hotspot search (SAMHS): a framework toward an optimised approach for motor hotspot identification.

Background: Motor hotspot identification represents the first step in the determination of the motor threshold and is the basis for the specification of stimulation intensity used for various Transcranial Magnetic Stimulation (TMS) applications. The level of experimenters' experience and the methodology of motor hotspot identification differ between laboratories. The need for an optimized and time-efficient technique for motor hotspot identification is therefore substantial. Objective: With the current work, we present a framework for an optimized and time-efficient semi-automated motor hotspot search (SAMHS) technique utilizing a neuronavigated robot-assisted TMS system (TMS-cobot). Furthermore, we aim to test its practicality and accuracy by a comparison with a manual motor hotspot identification method. Method: A total of 32 participants took part in this dual-center study. At both study centers, participants underwent manual hotspot search (MHS) with an experienced TMS researcher, and the novel SAMHS procedure with a TMS-cobot (hereafter, called cobot hotspot search, CHS) in a randomized order. Resting motor threshold (RMT), and stimulus intensity to produce 1 mV (SI1mV) peak-to-peak of motor-evoked potential (MEP), as well as MEPs with 120% RMT and SI1mV were recorded as outcome measures for comparison. Results: Compared to the MHS method, the CHS produced lower RMT, lower SI1mV and a trend-wise higher peak-to-peak MEP amplitude in stimulations with SI1mV. The duration of the CHS procedure was longer than that of the MHS (15.60 vs. 2.43 min on average). However, accuracy of the hotspot was higher for the CHS compared to the MHS. Conclusions: The SAMHS procedure introduces an optimized motor hotspot determination system that is easy to use, and strikes a fairly good balance between accuracy and speed. This new procedure can thus be deplored by experienced as well as beginner-level TMS researchers.