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Enhancement of Neuromodulation with Novel Pulse Shapes Generated by Controllable Pulse Parameter Transcranial Magnetic Stimulation

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... The cTMS device allows adjustment of the pulse width [10,11]. It enables optimization, selectively targeting distinct neuronal populations, and quantification of the strength-duration and input-output (IO) behaviors and curves [12,13,14,15,16,17]. ...
... The optimization problems (11) and (12), and the nonlinear equations (10) are solved by using Matlab fmincon and global search interior-point algorithm with random initial guesses. In (11), the upper bound is chosen as t p = t p (max) to search the whole range. It could be set tō t p = t * p is the critical pulse width is known. ...
... with different amplitudes and the same width.-Measure corresponding MEPs.-Tune the pulse width by solving the optimization problem(11).-Tune the pulse amplitude by solving the FIM optimization problem(12). -Administer the pulse and measure the MEP. the most recent data set, estimate -The IO curve and parameters by curve fitting, -The membrane time-constant by solving(10).Yes Functional block diagram of automatic and optimal tuning of pulse amplitude and width in closed-loop EMG-guided cTMS. ...
Preprint
This paper proposes a tool for automatic and optimal tuning of pulse amplitude and width for sequential parameter estimation (SPE) of the membrane time constant and input–output curve in closed-loop electromyography-guided (EMG-guided) controllable transcranial magnetic stimulation (cTMS). A normalized depolarization factor is defined which separates the optimization of the pulse amplitude and width. Then, the pulse amplitude is chosen by the maximization of the Fisher information matrix (FIM), while the pulse width is chosen by the maximization of the normalized depolarization factor. The simulation results confirm satisfactory estimation. The results show that the normalized depolarization factor maximization can identify the critical pulse width, which is an important parameter in the identifiability analysis, without any prior neurophysiological or anatomical knowledge of the neural membrane.
... For statistical analysis, we used repeated measures ANOVA. In addition to calculating the RMTs and input-output curves, the data was used to compute the latencies of MEPs with peak-to-peak amplitudes of 50 µV, 500 µV and 1mV, as done in previous studies [15]. The latency is defined as the time point where rectified EMG signals surpass a mean plus two standard deviations of the 100 ms pre-stimulus EMG level [16] [17]. ...
... It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted November 25, 2021. ; https://doi.org/10.1101/2021.11.24.469832 doi: bioRxiv preprint negative phase of the PWM pulses; other studies report similar results for rectangular pulses [15] [23]. However, further studies are required to confirm this. ...
... The MEP latency is a reliable measure of the microcircuitry site of action potential initiation [15]. This latency is thought to show the number of synapses that the corticospinal volley crossed from the stimulation site to the target muscle. ...
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Objective: We developed a novel transcranial magnetic stimulation (TMS) device to generate flexible stimuli and patterns. The system synthesizes digital equivalents of analog waveforms, relying on the filtering properties of the nervous system. Here, we test the hypothesis that the novel pulses can mimic the effect of conventional pulses on the cortex. Approach: A second-generation programmable TMS (pTMS2) stimulator with magnetic pulse shaping capabilities using pulse-width modulation (PWM) was tested. A computational and an in-human study on twelve healthy participants compared the neuronal effects of conventional and modulation-based stimuli. Main results: Both the computational modeling and the in-human stimulation showed that the PWM-based system can synthesize pulses to effectively stimulate the human brain, equivalent to conventional stimulators. The comparison includes motor threshold, MEP latency and input-output curve measurements. Significance: PWM stimuli can fundamentally imitate the effect of conventional magnetic stimuli while adding considerable flexibility to TMS systems, enabling the generation of highly configurable TMS protocols.
... To validate the estimated MT, we used the results of human experiments reported by [5,8,[27][28][29], in which 50 individuals were exposed to the different magnetic pulses of the cTMS neurostimulator. e data was collected from three types of cTMS waveforms, monophasic, unidirectional, and bidirectional in posterior-anterior (PA) or anterior-posterior (AP) directions. ...
... RU-N : Rectangular unidirectional with initially AP. RU-R : Rectangular unidirectional with initially PA) [28]. ese pulses are shown in Figure 2(c) and the measured RMTs are displayed in Figure 3(d). ...
... e estimated MT values and the experimental values in the defined database can be seen in Figures 3 and 4. e maximum absolute error between the average of the RMT and the AMT for monophasic stimuli (assumed as the true motor threshold) [5,27] and the MTestimates made with the HH model was 5% at 30 μs and 4% at 120 μs PW, respectively. e maximum absolute error between the average of the RMT for the three unidirectional stimuli [8] and the estimated MTs was 8% at 40 μs PW. e error between the x + E 2 y + E 2 z ). 4 Computational Intelligence and Neuroscience average of the RMT for one bidirectional and two unidirectional (in opposite directions) stimuli [28] was 3% for the RU-R pulse. ...
Article
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The motor threshold measurement is a standard in preintervention probing in TMS experiments. We aim to predict the motor threshold for near-rectangular stimuli to efficiently determine the motor threshold size before any experiments take place. Estimating the behavior of large-scale networks requires dynamically accurate and efficient modeling. We utilized a Hodgkin–Huxley (HH) type model to evaluate motor threshold values and computationally validated its function with known true threshold data from 50 participants trials from state-of-the-art published datasets. For monophasic, bidirectional, and unidirectional rectangular stimuli in posterior-anterior or anterior-posterior directions as generated by the cTMS device, computational modeling of the HH model captured the experimentally measured population-averaged motor threshold values at high precision (maximum error ≤ 8%). The convergence of our biophysically based modeling study with experimental data in humans reveals that the effect of the stimulus shape is strongly correlated with the activation kinetics of the voltage-gated ion channels. The proposed method can reliably predict motor threshold size using the conductance-based neuronal models and could therefore be embedded in new generation neurostimulators. Advancements in neural modeling will make it possible to enhance treatment procedures by reducing the number of delivered magnetic stimuli to participants.
... Latest coil designs bring the spatial selectivity, i.e., focality, to its limits [9]. There is mounting evidence that the temporal shape of TMS pulses affects the functional selectivity of neural stimulation as well as the direction and strength of neuromodulation [37,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. For example, monophasic TMS pulses produce stronger and more selective neuromodulation than biphasic pulses [60][61][62][63][64][65]. ...
... Other pulse shapes have been shown to provide activation selectivity, increase the neuromodulation efficacy of pulse trains with that pulse shape, or affect physical features of stimulation, such as coil heating or sound emission. Various asymmetric near-rectangular pulses were shown to increase selectivity and produce stronger neuromodulation effects with similarities to conventional monophasic pulses [42]. Varying the pulse symmetry and pulse duration furthermore apparently allows shifting of the activation balance between different neuron populations [43-47, 56, 58, 59, 72, 73]. ...
Preprint
The temporal shape of a pulse in transcranial magnetic stimulation (TMS) influences which neuron populations are activated preferentially as well as the strength and even direction of neuromodulation effects. Furthermore, various pulse shapes differ in their efficiency, coil heating, sensory perception, and clicking sound. However, the available TMS pulse shape repertoire is still very limited to a few pulses with sinusoidal or near-rectangular shapes. Monophasic pulses, though found to be more selective and stronger in neuromodulation, are generated inefficiently and therefore only available in simple low-frequency repetitive protocols. Despite a strong interest to exploit the temporal effects of TMS pulse shapes and pulse sequences, waveform control is relatively inflexible and only possible parametrically within certain limits. Previously proposed approaches for flexible pulse shape control, such as through power electronic inverters, have significant limitations: Existing semiconductor switches can fail under the immense electrical stress associated with free pulse shaping, and most conventional power inverter topologies are incapable of generating smooth electric fields or existing pulse shapes. Leveraging intensive preliminary work on modular power electronics, we present a modular pulse synthesizer (MPS) technology that can, for the first time, flexibly generate high-power TMS pulses with user-defined electric field shape as well as rapid sequences of pulses with high output quality. The circuit topology breaks the problem of simultaneous high power and switching speed into smaller, manageable portions. MPS TMS can synthesize practically any pulse shape, including conventional ones, with fine quantization of the induced electric field.
... Thus, neuron models are the key to understanding activation dynamics and studying pulse-shape effects. The temporal shape of pulses was reported to substantially affect efficiency and, thus, coil as well as device heating (Goetz & Peterchev, 2012;Goetz et al., 2013b;Niehaus, Meyer, & Weyh, 2000;Peterchev, Murphy, & Lisanby, 2011), to enable selective activation of certain neuron types or populations (Claus, Murray, Spitzer, & Fl€ ugel, 1990;Corthout et al., 2001;Kammer, Beck, Thielscher, Laubis-Herrmann, & Topka, 2001;Kammer et al., 2007;Ni et al., 2011;Peterchev et al., 2013;Sommer et al., 2014b), and to increase neuromodulation strength compared to standard biphasic pulses in repetitive protocols (Antal et al., 2002;Arai et al., 2005Arai et al., , 2007Goetz et al., 2016b;Hannah, Ciocca, Sommer, Hammond, & Rothwell, 2014;Sommer et al., 2014a;Sommer, Lang, Tergau, & Paulus, 2002;Sommer et al., 2013). Finally, neuron models also explain and predict directionality effects of TMS, i.e. why the orientation of the coil affects the threshold and allows activation of different neuron populations (Goetz et al., 2016b;Niehaus et al., 2000). ...
... The temporal shape of pulses was reported to substantially affect efficiency and, thus, coil as well as device heating (Goetz & Peterchev, 2012;Goetz et al., 2013b;Niehaus, Meyer, & Weyh, 2000;Peterchev, Murphy, & Lisanby, 2011), to enable selective activation of certain neuron types or populations (Claus, Murray, Spitzer, & Fl€ ugel, 1990;Corthout et al., 2001;Kammer, Beck, Thielscher, Laubis-Herrmann, & Topka, 2001;Kammer et al., 2007;Ni et al., 2011;Peterchev et al., 2013;Sommer et al., 2014b), and to increase neuromodulation strength compared to standard biphasic pulses in repetitive protocols (Antal et al., 2002;Arai et al., 2005Arai et al., , 2007Goetz et al., 2016b;Hannah, Ciocca, Sommer, Hammond, & Rothwell, 2014;Sommer et al., 2014a;Sommer, Lang, Tergau, & Paulus, 2002;Sommer et al., 2013). Finally, neuron models also explain and predict directionality effects of TMS, i.e. why the orientation of the coil affects the threshold and allows activation of different neuron populations (Goetz et al., 2016b;Niehaus et al., 2000). ...
Article
Magnetic stimulation is a non-invasive neurostimulation technique that can evoke action potentials and modulate neural circuits through induced electric fields. Biophysical models of magnetic stimulation have become a major driver for technological developments and the understanding of the mechanisms of magnetic neurostimulation and neuromodulation. Major technological developments involve stimulation coils with different spatial characteristics and pulse sources to control the pulse waveform. While early technological developments were the result of manual design and invention processes, there is a trend in both stimulation coil and pulse source design to mathematically optimize parameters with the help of computational models. To date, macroscopically highly realistic spatial models of the brain, as well as peripheral targets, and user-friendly software packages enable researchers and practitioners to simulate the treatment-specific and induced electric field distribution in the brains of individual subjects and patients. Neuron models further introduce the microscopic level of neural activation to understand the influence of activation dynamics in response to different pulse shapes. A number of models that were designed for online calibration to extract otherwise covert information and biomarkers from the neural system recently form a third branch of modelling.
... Previous human TMS studies measured the MEP signal pre-and post-TMS administration as the metric to assess the effects of TMS [22,57]. We have adopted a similar approach. ...
Article
Full-text available
Background Theta burst stimulation (TBS) is an efficient noninvasive neuromodulation paradigm that has been widely adopted, clinically. However, the efficacy of TBS treatment remains similarly modest as conventional 10 Hz repetitive transcranial magnetic stimulation (rTMS). Objective/hypothesis To develop a new TBS paradigm that enhances the effects of TMS administration while maintaining high time-efficiency. Methods We describe here a new TMS paradigm, named High-Density Theta Burst Stimulation (hdTBS). This paradigm delivers up to 6 pulses per burst, as opposed to only 3 in conventional TBS, while maintaining the inter-burst interval of 200 ms (or 5 Hz) – a critical parameter in inducing long-term potentiation. This paradigm was implemented on a TMS stimulator developed in-house; its physiological effects were assessed in the motor cortex of awake rats using a rodent specific focal TMS coil. Microwire electrodes were implanted into each rat's limb muscles to longitudinally record motor-evoked potential (MEP). Four different TBS paradigms (3, 4, 5 or 6 pulses per burst, 200 s per session) were tested; MEP signals were recorded immediately before (baseline) and up to 35 min post each TBS session. Results We developed a stimulator based on a printed-circuit board strategy. The stimulator was able to deliver stable outputs of up to 6 pulses per burst. Animal experiments (n = 15) revealed significantly different aftereffects induced by the four TBS paradigms (Friedman test, p = 0.018). Post hoc analysis further revealed that, in comparison to conventional 3-pulse TBS, 5- and 6-pulse TBS enhanced the aftereffects of MEP signals by 56% and 92%, respectively, while maintaining identical time efficiency. Conclusion(s) A new stimulation paradigm is proposed, implemented and tested in the motor cortex of awake rats using a focal TMS coil developed in the lab. We observed enhanced aftereffects as assessed by MEP, with no obvious adverse effects, suggesting the translational potentials of this paradigm.
... Therefore, the biphasic wave may be considered a summated activation of two neuronal populations; PA is activated first and provides the more robust excitatory effect, followed by a delayed and weaker AP activation (49). That different neuronal mechanisms may underlie lowfrequency stimulation is suggested by the lack of effect on 1 Hz biphasic rTMS compared to robust inhibition with AP, PA, and rectangular pulse shapes (bidirectional pulse) (51). Taking this concept a step further, Jung et al. (52) applied quadri-pulse (q) TBS (666 Hz quadruplets with 1.5 ms interpulse intervals) and produced opposing motor plasticity effects when applied as single-or double-sine-waves, and as PA and AP directionality is applied. ...
Article
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Background Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive, effective, and FDA-approved brain stimulation method. However, rTMS parameter selection remains largely unexplored, with great potential for optimization. In this review, we highlight key studies underlying next generation rTMS therapies, particularly focusing on: (1) rTMS Parameters, (2) rTMS Target Engagement, (3) rTMS Interactions with Endogenous Brain Activity, and (4) Heritable Predisposition to Brain Stimulation Treatments. Methods We performed a targeted review of pre-clinical and clinical rTMS studies. Results Current evidence suggests that rTMS pattern, intensity, frequency, train duration, intertrain interval, intersession interval, pulse and session number, pulse width, and pulse shape can alter motor excitability, long term potentiation (LTP)-like facilitation, and clinical antidepressant response. Additionally, an emerging theme is how endogenous brain state impacts rTMS response. Researchers have used resting state functional magnetic resonance imaging (rsfMRI) analyses to identify personalized rTMS targets. Electroencephalography (EEG) may measure endogenous alpha rhythms that preferentially respond to personalized stimulation frequencies, or in closed-loop EEG, may be synchronized with endogenous oscillations and even phase to optimize response. Lastly, neuroimaging and genotyping have identified individual predispositions that may underlie rTMS efficacy. Conclusions We envision next generation rTMS will be delivered using optimized stimulation parameters to rsfMRI-determined targets at intensities determined by energy delivered to the cortex, and frequency personalized and synchronized to endogenous alpha-rhythms. Further research is needed to define the dose-response curve of each parameter on plasticity and clinical response at the group level, to determine how these parameters interact, and to ultimately personalize these parameters.
... Further parameters of TBS pulses may become significant in experiments and also future models, such as the pulse strength, the pulse shape, the number of pulses per TBS, and the frequency of pulses in bursts (Nyffeler et al., 2008;Gamboa et al., 2010;Wu et al., 2012;Goldsworthy et al., 2012;Sasaki et al., 2018;Strzalkowski et al., 2019;Ozdemir et al., 2021;Goetz et al., 2016;D'Ostilio et al., 2016;Shirota et al., 2017;Li et al., 2022). ...
Preprint
Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation (TMS). Among the various neuromodulatory TMS protocols, theta-burst stimulation (TBS) at present is the fastest intervention to generate strong effects. A decade ago, Y.Z. Huang et al. developed a first neuromodulation model to explain the bidirectional effects of TBS based on postsynaptic intracellular calcium concentration elevation. We discover, however, that the published computer code is not consistent with the model formulations in the corresponding paper. Further analysis confirms that the computer model with an index confusion was used for fitting the experimental results, running the simulation, and plotting the corresponding figures in the original publication. This paper intends to fix the computer code and additionally create a non-convex optimisation solution for re-calibrating the model. After re-calibration, the revised model outperforms the initial model in accuracy describing the MEP amplitudes of TBS-induced after-effects under specific situations.
... Experimental brain research, precision medicine, and personalized medicine desire a high level of stimulation selectivity to target only specific groups of neurons, [7,8,9,10,11]. Whereas previously stimulation selectivity was mostly achieved through improving coil focality, limits have been reached [4] and temporal aspects of pulses to exploit the neuronal activation dynamics for a further improvement of stimulation selectivity have gained attention [5,6]. ...
Preprint
Objective To obtain a formalism for real-time concurrent sequential estimation of neural membrane time constant and input–output (IO) curve with transcranial magnetic stimulation (TMS). Approach First, the neural membrane response and depolarization factor, which leads to motor evoked potentials (MEPs) with TMS are analytically computed and discussed. Then, an integrated model is developed which combines the neural membrane time constant and input–output curve. Identifiability of the proposed integrated model is discussed. A condition is derived, which assures estimation of the proposed integrated model. Finally, sequential parameter estimation (SPE) of the neural membrane time constant and IO curve is described through closed-loop optimal sampling and open-loop uniform sampling TMS. Without loss of generality, this paper focuses on a specific case of commercialized TMS pulse shapes. The proposed formalism and SPE method are directly applicable to other pulse shapes. Main results The results confirm satisfactory estimation of the membrane time constant and IO curve parameters. By defining a stopping rule based on five times consecutive convergence of the estimation parameters with a tolerances of 0.01, the membrane time constant and IO curve parameters are estimated with 82 TMS pulses with absolute relative estimation errors (AREs) of less than 4% with the optimal sampling SPE method. At this point, the uniform sampling SPE method leads to AREs up to 16%. The uniform sampling method does not satisfy the stopping rule due to the large estimation variations. Significance This paper provides a tool for real-time closed-loop SPE of the neural time constant and IO curve, which can contribute novel insights in TMS studies. SPE of the membrane time constant enables selective stimulation, which can be used for advanced brain research, precision medicine and personalized medicine.
... At present, magnetic stimulation focuses nearly exclusively on the brain [1]. Administered transcranially, magnetic stimulation can evoke direct effects, such as motor-evoked potentials [2], [3] or phosphenes [4], while certain pulse rhythms or patterns can also modulate neural circuits and shift their excitability with respect to endogenous signals [5]. However, the development of magnetic stimulation has been strongly related to the periphery; even the first successful experiments were performed on lower motor fibers and not the brain [6]. ...
Article
Full-text available
Neuromuscular magnetic stimulation is a promising tool in neurorehabilitation due to its deeper penetration, notably lower distress, and respectable force levels compared to surface electrical stimulation. However, this method faces great challenges from a technological perspective. The systematic design of better equipment and the incorporation into modern training setups requires better understanding of the mechanisms and predictive quantitative models of the recruited forces. This article proposes a model for simulating the force recruitment in isometric muscle stimulation of the thigh extensors based on previous theoretical and experimental findings. The model couples a 3D field model for the physics with a parametric recruitment model. This parametric recruitment model is identified with a mixed-effects design to learn the most likely model based on available experimental data with a wide range of field conditions. This approach intentionally keeps the model as mathematically simple and statistically parsimonious as possible in order to avoid over-fitting. The work demonstrates that the force recruitment particularly depends on the effective, i.e., fiber-related cross section of the muscles, and that the local median electric field threshold amounts to about 65 V/m, which agrees well with values for magnetic stimulation in the brain. The coupled model is able to accurately predict key phenomena observed so far, such as a threshold shift for different distances between coil and body, the different recruiting performance of various coils with available measurement data in the literature, and the saturation behavior with its onset amplitude. The presented recruitment model could also be readily incorporated into dynamic models for biomechanics as soon as sufficient experimental data are available for calibration.
... At present, magnetic stimulation focuses nearly exclusively on the brain (1). Administered transcranially, magnetic stimulation can evoke direct effects, such as motor-evoked potentials (2,3) or phosphenes (4), while certain pulse rhythms or patterns can also modulate neural circuits and shift their excitability with respect to endogenous signals (5). However, the development of magnetic stimulation has been strongly related to the periphery; even the first successful experiments were performed on lower motor fibers and not the brain (6). ...
Preprint
Neuromuscular magnetic stimulation is a promising tool in neurorehabilitation due to its deeper penetration, notably lower distress, and respectable force levels compared to electrical stimulation. However, this method faces great challenges from a technological perspective. The systematic design of better equipment and the incorporation into modern training setups requires better understanding of the mechanisms and predictive quantitative models of the recruited forces. This article proposes a model for simulating the force recruitment in isometric muscle stimulation of the thigh extensors based on previous theoretical and experimental findings. The model couples a 3D field model for the physics with a parametric recruitment model, which is identified with a mixed-effects design to learn the most likely model based on available experimental data with a wide range of field conditions. This approach intentionally keeps the model as mathematically simple and statistically parsimonious as possible in order to avoid over-fitting. The coupled model is able to accurately predict key phenomena observed so far, such as a threshold shift for different distances between coil and body, the different recruiting performance of various coils with available measurement data in the literature, and the saturation behaviour with its onset amplitude. The presented recruitment model could also be readily incorporated into dynamic models for biomechanics as soon as sufficient experimental data are available for calibration.
... With this technology it is possible to stimulate with variable pulse shapes [11], [13]. For further exploration of TMS, a magnetic stimulator with an arbitrary output voltage waveform is needed [14]. Two different types of concepts that use different multilevel inverter topologies are known from [15], [16]. ...
... As we look into the future, advances in neuroengineering continue to yield new tools that push the envelope of what can be accomplished with noninvasive neuromodulation tools, and the pace of that advancement has been accelerated by the NIH BRAIN Initiative [140]. Next-generation TMS devices enable user control of the pulse shape with the prospect of enhanced efficacy and cell-type-specific targeting [141,142]. Next-generation seizure therapy devices induce more focal fields with the prospect of sparing memory [143]. Next-generation drug delivery devices allow focal drug delivery deep in the brain using ultrasonic uncaging of nanospheres carrying pharmacological payloads [144]. ...
Article
More than any other brain region, the prefrontal cortex (PFC) gives rise to the singularity of human experience. It is therefore frequently implicated in the most distinctly human of all disorders, those of mental health. Noninvasive neuromodulation, including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) among others, can—unlike pharmacotherapy—directly target the PFC and its neural circuits. Direct targeting enables significantly greater on-target therapeutic effects compared with off-target adverse effects. In contrast to invasive neuromodulation approaches, such as deep-brain stimulation (DBS), noninvasive neuromodulation can reversibly modulate neural activity from outside the scalp. This combination of direct targeting and reversibility enables noninvasive neuromodulation to iteratively change activity in the PFC and its neural circuits to reveal causal mechanisms of both disease processes and healthy function. When coupled with neuronavigation and neurophysiological readouts, noninvasive neuromodulation holds promise for personalizing PFC neuromodulation to relieve symptoms of mental health disorders by optimizing the function of the PFC and its neural circuits. ClinicalTrials.gov Identifier: NCT03191058.
... MEPs at 30 min post-cTBS were not collected from three participants due to time constraints during the experiment session. Analyses were conducted on 4, 336 MEPs (baseline = 869; 0 min post cTBS = 865; 10 min post-cTBS = 877; 20 min post-cTBS = 902; 30 min post-cTBS = 823) using linear mixed effects modeling (Baayen et al., 2008)-an analysis approach that has been utilized in prior neurophysiological studies of stimulationinduced plasticity (see e.g., Goetz et al., 2016;Moret et al., 2019)-implemented in the lme4 package (Bates et al., 2015) of R version 3.6.3 (R Core Team, 2020). ...
Article
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Objective : To evaluate whether a common polymorphism (Val66Met) in the gene for brain-derived neurotrophic factor (BDNF)—a gene thought to influence plasticity—contributes to inter-individual variability in responses to continuous theta-burst stimulation (cTBS), and explore whether variability in stimulation-induced plasticity among Val66Met carriers relates to differences in stimulation intensity (SI) used to probe plasticity. Methods : Motor evoked potentials (MEPs) were collected from 33 healthy individuals (11 Val66Met) prior to cTBS (baseline) and in 10 min intervals immediately following cTBS for a total of 30 min post-cTBS (0 min post-cTBS, 10 min post-cTBS, 20 min post cTBS, and 30 min post-cTBS) of the left primary motor cortex. Analyses assessed changes in cortical excitability as a function of BDNF (Val66Val vs. Val66Met) and SI. Results : For both BDNF groups, MEP-suppression from baseline to post-cTBS time points decreased as a function of increasing SI. However, the effect of SI on MEPs was more pronounced for Val66Met vs. Val66Val carriers, whereby individuals probed with higher vs. lower SIs resulted in paradoxical cTBS aftereffects (MEP-facilitation), which persisted at least 30 min post-cTBS administration. Conclusions : cTBS aftereffects among BDNF Met allele carriers are more variable depending on the SI used to probe cortical excitability when compared to homozygous Val allele carriers, which could, to some extent, account for the inconsistency of previously reported cTBS effects. Significance : These data provide insight into the sources of cTBS response variability, which can inform how best to stratify and optimize its use in investigational and clinical contexts.
... The IO SCE method is ready to perform with most available devices and primary motor cortex representations of many muscles as they mostly affect the above three parameters of slope, x shift, and trial-to-trial variability [48]. The use of differently strong pulse sources, for instance, primarily scales the x axis, resulting in a scaled slope [47], [49], [50]. The focality of the coil might affect recruitment and therefore slope as well as trial-to-trial variability, but there is little quantitative information on that aspect in TMS yet [51]- [53]; both clinical procedures and safety guidelines assume that focal and unfocal coils are rather comparable with respect to MEPs and motor threshold [54]. ...
Article
This paper discusses some of the practical limitations and issues, which exist for the input--output (IO) slope curve estimation (SCE) in neural, brain and spinal, stimulation techniques. The drawbacks of the SCE techniques by using existing uniform sampling and Fisher-information-based optimal IO curve estimation (FO-IOCE) methods are elaborated. A novel IO SCE technique is proposed with a modified sampling strategy and stopping rule which improve the SCE performance compared to these methods. The effectiveness of the proposed IO SCE is tested on 1000 simulation runs in transcranial magnetic stimulation (TMS), with a realistic model of motor evoked potentials (MEPs). The results show that the proposed IO SCE method successfully satisfies the stopping rule, before reaching the maximum number of TMS pulses in 79.5% of runs, while the estimation based on the uniform sampling technique never converges and satisfies the stopping rule. At the time of successful termination, the proposed IO SCE method decreases the 95th percentile (mean value in the parentheses) of the absolute relative estimation errors (AREs) of the slope curve parameters up to 7.45% (2.2%), with only 18 additional pulses on average compared to that of the FO-IOCE technique. It also decreases the 95th percentile (mean value in the parentheses) of the AREs of the IO slope curve parameters up to 59.33% (16.71%), compared to that of the uniform sampling method. The proposed IO SCE also identifies the peak slope with higher accuracy, with the 95th percentile (mean value in the parentheses) of AREs reduced by up to 9.96% (2.01%) compared to that of the FO-IOCE method, and by up to 46.29% (13.13%) compared to that of the uniform sampling method.
... The induced electric field on the cortex by unidirectional pulses has three different phases: a negative, a positive and again a negative phase. The dominant part of this stimulus is a positive phase and it acts almost like a monophasic pulse [14]. ...
Article
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Quadri-pulse stimulation (QPS), a type of repetitive transcranial magnetic stimulation (rTMS), can induce a considerable aftereffect on cortical synapses. Human experiments have shown that the type of effect on synaptic efficiency (in terms of potentiation or depression) depends on the time interval between pulses. The maturation of biophysically-based models, which describe the physiological properties of plasticity mathematically, offers a beneficial framework to explore induced plasticity for new stimulation protocols. To model the QPS paradigm, a phenomenological model based on the knowledge of spike timing-dependent plasticity (STDP) mechanisms of synaptic plasticity was utilized where the cortex builds upon the platform of neuronal population modeling. Induced cortical plasticity was modeled for both conventional monophasic pulses and unidirectional pulses generated by the cTMS device, in a total of 117 different scenarios. For the conventional monophasic stimuli, the results of the predictive model broadly follow what is typically seen in human experiments. Unidirectional pulses can produce a similar range of plasticity. Additionally, changing the pulse width had a considerable effect on the plasticity (approximately 20% increase). As the width of the positive phase increases, the size of the potentiation will also increase. The proposed model can generate predictions to guide future plasticity experiments. Estimating the plasticity and optimizing the rTMS protocols might effectively improve the safety implications of TMS experiments by reducing the number of delivered pulses to participants. Finding the optimal stimulation protocol with the maximum potentiation/depression can lead to the design of a new TMS pulse generator device with targeted hardware and control algorithms.
... Noninvasive stimulation of the primary motor cortex is used for the diagnosis and localization of motor lesions [13]. Furthermore, the primary motor cortex is a preferred model for studying the neurophysiology, biophysics of brain stimulation, and development of novel technology [14]- [16]. The individual motor threshold is commonly used as a reference for dosage of nonmotor brain targets that do not provide an easily observable response [17]. ...
Article
Motor evoked potentials (MEPs) are widely used for biomarkers and dose individualization in transcranial stimulation. The large variability of MEPs requires sophisticated methods of analysis to extract information fast and correctly. Development and testing of such methods relies on the availability for realistic models of MEP generation, which are presently lacking. This work presents a statistical model that can simulate long sequences of individualized MEP amplitude data with properties matching experimental observations. The MEP model includes three sources of trial-to-trial variability: excitability fluctuations, variability in the neural and muscular pathways, and physiological and measurement noise. It also generates virtual human subject data from statistics of population variability. All parameters are extracted as statistical distributions from experimental data from the literature. The model exhibits previously described features, such as stimulus-intensity-dependent MEP amplitude distributions, including bimodal ones. The model can generate long sequences of test data for individual subjects with specified parameters or for subjects from a virtual population. The presented MEP model is the most detailed to date and can be used for the development and implementation of dosing and biomarker estimation algorithms for transcranial stimulation.
... The coil positioning data were obtained during experiments for a previously published repetitive TMS study [11]. TMS was performed on 21 subjects (age 18-48 years, median 21, 14 females, seven males, all right handed) in one-seven sessions (3.76 sessions per subject on average). ...
Article
Objective: Robotic positioning systems for transcranial magnetic stimulation (TMS) promise improved accuracy and stability of coil placement, but there is limited data on their performance. Investigate the usability, accuracy, and limitations of robotic coil placement with a commercial system, ANT Neuro, in a TMS study. Approach: 21 subjects underwent a total of 79 TMS sessions corresponding to 160 hours under robotic coil control. Coil position and orientation were monitored concurrently through an additional neuronavigation system. Main Results: Robot setup took on average 14.5 min. The robot achieved low position and orientation error with median 1.34 mm and 3.48°. The error increased over time at a rate of 0.4%/minute for both position and orientation. Significance: Robotic TMS systems can provide accurate and stable coil position and orientation in long TMS sessions. Lack of pressure feedback and of manual adjustment of all coil degrees of freedom were limitations of this robotic system.
... The coil positioning data were obtained during experiments for a previously published repetitive TMS study [11]. TMS was performed on 21 subjects (age 18 -48 years, median 21, 14 females, 7 males, all right handed) in 1-7 sessions (3.76 sessions per subject on average). ...
Preprint
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Objective: Robotic positioning systems for transcranial magnetic stimulation (TMS) promise improved accuracy and stability of coil placement, but there is limited data on their performance. This text investigates the usability, accuracy, and limitations of robotic coil placement with a commercial system, ANT Neuro, in a TMS study. Approach: 21 subjects underwent a total of 79 TMS sessions corresponding to 160 hours under robotic coil control. Coil position and orientation were monitored concurrently through an additional neuronavigation system. Main Results: Robot setup took on average 14.5 min. The robot achieved low position and orientation error with median 1.34 mm and 3.48 deg. The error increased over time at a rate of 0.4%/minute for both position and orientation. Significance: After the elimination of several limitations, robotic TMS systems promise to substantially improve the accuracy and stability of manual coil position and orientation. Lack of pressure feedback and of manual adjustment of all coil degrees of freedom were limitations of this robotic system.
... By varying them, it is possible to activate different subsets of inputs to M1. 174,175 This notion can be applied to rTMS as well; indeed, it has been demonstrated that the effects of 1 Hz rTMS are greater when monophasic stimuli delivered via a cTMS device are used when compared with standard biphasic pulses. 176 There is also preliminary evidence that the effects of TBS on M1 are determined more by the pulse characteristics, and thus potentially by the specific neural population recruited, rather than the TBS pattern (intermittent or continuous). 169 A second way to achieve greater specificity of TMS is to use the high time resolution of EEG to deliver TMS pulses according to different states of cortical excitability. ...
... Our results are in agreement with those in the available literature. Our 80 ms unidirectional pulse, which is identical to the "RU-N" pulse applied at 1 Hz by Goetz and colleagues [29], caused robust inhibition very similar to the effect they reported. Also the inhibitory aftereffects found in numerous studies using conventional TMS pulses at 1 Hz [28,30] compare very well with the effects we observed with 40 and 80 ms 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 unidirectional pulses. ...
Article
Introduction: Motor evoked potentials (MEP) in response to anteroposterior transcranial (AP) magnetic stimulation (TMS) are sensitive to the TMS pulse shape. We are now able to isolate distinct pulse properties, such as pulse width and directionality and evaluate them individually. Different pulse shapes induce different effects, likely by stimulating different populations of neurons. This implies that not all neurons respond in the same manner to stimulation, possibly, because individual segments of neurons differ in their membrane properties. Objectives: To investigate the effect of different pulse widths and directionalities of TMS on MEP latencies, motor thresholds and plastic aftereffects of rTMS. Methods: Using a controllable pulse stimulator TMS (cTMS), we stimulated fifteen subjects with quasi-unidirectional TMS pulses of different pulse durations (40 μs, 80 μs and 120 μs) and determined thresholds and MEP AP latencies. We then compared the effects of 80 μs quasi-unidirectional pulses to those of 80 μs pulses with different pulse directionality characteristics (0.6 and 1.0 M ratios). We applied 900 pulses of the selected pulse shapes at 1 Hz. Results: The aftereffects of 1 Hz rTMS depended on pulse shape and duration. 40 and 80 μs wide unidirectional pulses induced inhibition, 120 μs wide pulses caused excitation. Bidirectional pulses induced inhibition during the stimulation but had facilitatory aftereffects. Narrower pulse shapes caused longer latencies and higher resting motor thresholds (RMT) as compared to wider pulse shapes. Conclusions: We can tune the aftereffects of rTMS by manipulating pulse width and directionality; this may be due to the different membrane properties of the various neuronal segments such as dendrites. Significance: To date, rTMS frequency has been the main determinant of the plastic aftereffects. However, we showed that pulse width also plays a major role, probably by recruiting novel neuronal targets.
... However, the spatial distribution of the E-field alone cannot predict the physiological effects of stimulation, and TMS can recruit distinct neural populations or elements based on different temporal dynamics of the E-field waveform (e.g. pulse shape, direction, width, and phase amplitude asymmetry) [8][9][10][11][12] . ...
Preprint
Transcranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements it activates and how stimulation parameters affect the neural response. We integrated detailed neuronal models with TMS-induced electric fields in the human head to quantify the effects of TMS on cortical neurons. TMS activated with lowest intensity layer 5 pyramidal cells at their intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 2/3 pyramidal cells and inhibitory basket cells may be activated too, whereas direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, contrary to theories implicating the field component normal to the cortical surface. Varying the induced current's direction caused a waveform-dependent shift in the activation site and provided a mechanistic explanation for experimentally observed differences in thresholds and latencies of muscle responses. This biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other forms of cortical stimulation.
... Because of lower energy requirements, classical rTMS devices deliver high-frequency biphasic stimuli that activate different cortical circuits and induce a variety of effects that could partly explain interindividual variability in outcomes (Hamada et al., 2013). However the implementation of a novel modifiable device, which can deliver a nearly-triangular monophasic pulse during high frequency rTMS (controllable TMS; (Peterchev et al., 2014), is thought to produce stronger and more reproducible effects on MEP than classical rTMS devices (Goetz et al., 2016). ...
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Neuroplasticity is essential for the establishment and strengthening of neural circuits during the critical period of development, and are required for the brain to adapt to its environment. The mechanisms of plasticity vary throughout life, are generally more difficult to induce in the adult brain, and decrease with advancing age. Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical excitability and shows promise in the treatment of some neurological disorders. Low intensity magnetic stimulation (LI-rTMS), which does not directly elicit action potentials in the stimulated neurons, have also shown some therapeutic effects, and it is important to determine the biological mechanisms underlying the effects of these low intensity magnetic fields, such as would occur in the regions surrounding the central high-intensity focus of rTMS. We have used a focal low-intensity magnetic stimulation (10mT) to address some of these issues in the mouse cerebellum and olivocerebellar path. The cerebellum model is particularly useful as its development, structure, ageing and function are well described which allows us to easily detect eventual modifications. We assessed effects of in vivo or in vitro LI-rTMS on neuronal morphology, behavior, and post-lesion plasticity. We first showed that LI-rTMS treatment in vivo alters dendritic spines and dendritic morphology, in association with improved spatial memory. These effects were age dependent. To optimize stimulation parameters in order to induce post-lesion reinnervation we used our in vitro model of post-lesion repair to systematically investigate the effects of different LI-rTMS stimulation patterns and frequencies. We showed that the pattern of stimulation is critical for allowing repair, rather than the total number of stimulation pulses. Finally, we looked for potential underlying mechanisms participating in the effects of the LI-rTMS, using mouse mutants in vivo or in vitro. We found that the cryptochromes, which have magnetoreceptor properties, must be present for the response to magnetic stimulation to be transduced into biological effects. The ensemble of our results indicate that the effects of LI-rTMS depend upon the presence of magnetoreceptors, the stimulation protocol, and the age of the animal suggesting that future therapeutic strategies must be adapted to the neuronal context in each individual person.
... In these studies, the E fields that are tangential to the neuron's axis have been considered as the cause of neuron stimulation [9], [10]. Besides, optimization in stimulus pulse shape was conducted, leading researchers into designing an optimum stimulator [11]- [13]. While, we use the theory for investigating the blocking the AP in this paper. ...
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Conventional anesthesia methods such as injective anesthetic agents may cause various side effects such as injuries, allergies, and infections. We aim to investigate a noninvasive scheme of an electromagnetic radiator system to block action potential (AP) in neuron fibers. We achieved a high-gradient and unipolar tangential electric field by designing circular geometric coils on an electric rectifier filter layer. An asymmetric sawtooth pulse shape supplied the coils in order to create an effective blockage. The entire setup was placed 5 cm above 50 motor and sensory neurons of the spinal cord. A validated time-domain full-wave analysis code Based on cable model of the neurons and the electric and magnetic potentials is used to simulate and investigate the proposed scheme. We observed action potential blockage on both motor and sensory neurons. In addition, the introduced approach shows promising potential for AP manipulation in the spinal cord.
... Noninvasive stimulation of the primary motor cortex is used for the diagnosis and localization of motor lesions [13]. Furthermore, the primary motor cortex is a preferred model for studying the neurophysiology, biophysics of brain stimulation, and development of novel technology [14][15][16]. According to safety guidelines of repetitive TMS, the motor threshold is the reference of individual dosage also for other brain targets that are silent [17]. ...
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Motor evoked potentials (MEPs) are used for biomarkers or dose individualization in transcranial stimulation. We aimed to develop a statistical model that can generate long sequences of individualized MEP amplitude data with the experimentally observed properties. The MEP model includes three sources of trial-to-trial variability to mimic excitability fluctuations, variability in the neural and muscular pathways, and physiological and measurement noise. It also generates virtual human subject data from statistics of population variability. All parameters are extracted as statistical distributions from experimental data from the literature. The model exhibits previously described features, such as stimulus-intensity-dependent MEP amplitude distributions, including bimodal ones. The model can generate long sequences of test data for individual subjects with specified parameters or for subjects from a virtual population. The presented MEP model is the most detailed to date and can be used for the development and implementation of dosing and biomarker estimation algorithms for transcranial stimulation.
... Technological advancement has similarly focused on new anatomical targets (e.g. invasive and non-invasive forms of current delivery) including new implanted leads [47,48], magnetic induction [49,50], and transcranial electrical targeting [51]. The exploration of waveforms has been relatively limited, often exploring variations in the frequency of tonic stimulation or adopting canonical patterns demonstrated to produce plasticity in human and animal neurophysiology (e.g. ...
Article
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Background: The bursting pattern of thalamocortical (TC) pathway dampens nociception. Whether brain stimulation mimicking endogenous patterns can engage similar sensory gating processes in the cortex and reduce nociceptive behaviors remains uninvestigated. Objective: We investigated the role of cortical parvalbumin expressing (PV) interneurons within the TC circuit in gating nociception and their selective response to TC burst patterns. We then tested if transcranial magnetic stimulation (TMS) patterned on endogenous nociceptive TC bursting modulate nociceptive behaviors. Methods: The switching of TC neurons between tonic (single spike) and burst (high frequency spikes) firing modes may be a critical component in modulating nociceptive signals. Deep brain electrical stimulation of TC neurons and immunohistochemistry were used to examine the differential influence of each firing mode on cortical PV interneuron activity. Optogenetic stimulation of cortical PV interneurons assessed a direct role in nociceptive modulation. A new TMS protocol mimicking thalamic burst firing patterns, contrasted with conventional continuous and intermittent theta burst protocols, tested if TMS patterned on endogenous TC activity reduces nociceptive behaviors in mice. Results: Immunohistochemical evidence confirmed that burst, but not tonic, deep brain stimulation of TC neurons increased the activity of PV interneurons in the cortex. Both optogenetic activation of PV interneurons and TMS protocol mimicking thalamic burst reduced nociceptive behaviors. Conclusions: Our findings suggest that burst firing of TC neurons recruits PV interneurons in the cortex to reduce nociceptive behaviors and that neuromodulation mimicking thalamic burst firing may be useful for modulating nociception.
... The effect of coil orientation on stimulation outcomes over the motor cortex was first described experimentally (Brasil-Neto et al., 1992) and later with biophysical models (Laakso et al., 2014). The effects of coil orientation are likely due to some combination of the fact that there is a preferential coil orientation for the intensity of the induced electric field to be maximized (Laakso et al., 2014;Janssen et al., 2015) and that the direction of the induced intracranial currents in relation to the axis of neurons effects the neurophysiological response to stimulation (Day et al., 1989;Goetz et al., 2016;Hannah and Rothwell, 2016). ...
Article
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Objective: To investigate inter-subject variability with respect to cerebrospinal fluid thickness and brain-scalp distance, and to investigate intra-subject variability with different coil orientations. Methods: Simulations of the induced electric field (E-Field) using a figure-8 coil over the vertex were conducted on 50 unique head models, and varying orientations on 25 models. Metrics exploring stimulation intensity, spread, and localization were used to describe inter-subject variability and effects of non-brain anatomy. Results: Both brain-scalp distance and CSF thickness were correlated with weaker stimulation intensity, and greater spread. Coil rotations show that for the dorsal portion of the stimulated brain, E-Field intensities are highest when the anterior-posterior axis of the coil is perpendicular to the longitudinal fissure, but highest for the medial portion of the stimulated brain when the coil is oriented parallel to the longitudinal fissure. Conclusions: Normal anatomical variation in healthy individuals leads to significant differences in the site of TMS, the intensity and the spread. These variables are generally neglected but could explain significant variability in basic and clinical studies. Significance: This is the first work to show how brain-scalp distance and cerebrospinal fluid thickness influence focality, and to show the disassociation between dorsal and medial TMS.
... Mono-and biphasic TMS pulses result in different patterns of descending motor output (Di Lazzaro et al., 2001) and very recently this has been suggested to affect the TMS map (Stephani, Paulus, & Sommer, 2016). The use of novel controllable TMS stimulators have revealed that not only pulse waveform but also current direction and pulse duration determine the specific interneuronal circuitry activated (D'Ostilio et al., 2016;Goetz et al., 2016;Hannah & FIGURE 9. Results of the linear regression performed to investigate whether improvement in tracking performance could predict change in TMS map area. A correlation analysis was performed to find out if changes in map area of the proximal and distal muscle are correlated. ...
Article
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Motor learning has been linked with increases in corticospinal excitability (CSE). However, the robustness of this link is unclear. In this study, changes in CSE associated with learning a visuomotor tracking task were mapped using transcra-nial magnetic stimulation (TMS). TMS maps were obtained before and after training with the first dorsal interosseous (FDI) of the dominant and nondominant hand, and for a distal (FDI) and proxi-mal (biceps brachii) muscle. Tracking performance improved following 20 min of visuomotor training, while map area was unaffected. Large individual differences were observed with 18%-36% of the participants revealing an increase in TMS map area. This result highlights the complex relationship between motor learning and use-dependent plasticity of the motor cortex.
... Previous MS studies have reported that the efficacy of a timevarying magnetic field could be indirectly evaluated according to the corresponding electric field E or its spatial derivative dE/dr with space variable r [18], [22], [37], [38]. In general, quantitative evaluation of a pulsatile magnetic field is more difficult than that of E and dE/dr, which are considered to directly contribute to neural membrane excitability [39]. ...
Article
Objective: Recent studies have reported that micromagnetic stimulation (μMS), which can activate neural tissue and cells via sub-millimeter inductors, may address several limitations of conventional magnetic stimulation methods. Previous studies have examined the effects of μMS on single neurons, yet little is known about how μMS can affect brain tissue including local neural networks. Here, we propose a new, readily available implantable μMS system and computationally and experimentally evaluate its validity. Methods: We conducted numerical calculations and experiments to evaluate the physical characteristics, including magnetic flux density, temperature, coil impedance, and structural integrity of the flexible board supporting the μMS coils. We then compared sound- and μMS-driven neural responses in the mouse auditory cortex using flavoprotein autofluorescence imaging. Results: Our system successfully activated neural tissue, and we observed activity propagation in local neural networks on the brain surface beyond restricted activation of single neurons. Examining the relationships between stimulation parameters and response characteristics, we found that stimulation amplitude and pulse width were the two most important parameters to effectively induce neural activity. Conclusion: Our μMS device has sufficient potential to drive the brain as an implantable magnetic stimulator for basic neuroscience and clinical applications, although further investigation is required. Significance: μMS can selectively drive and modulate activity in local neural network even at an in vivo tissue level.
... However, the results of these experiments are difficult to interpret given the bidirectional TMS pulses. Recent studies have suggested that the use a of near-rectangular monophasic pulse that is thought to induce a more "unidirectional" electric field can possibly lead to improved effects of repetitive TMS [9]. As such, here we use a new stimulator capable of delivering unidirectional TMS pulses, and ask whether iTBS using PA pulses is differentially modulated by concurrent directional (PA or AP) TDCS applied across the motor cortex. ...
Article
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Background: Polarising currents can modulate membrane potentials in animals, affecting the after-effect of theta burst stimulation (TBS) on synaptic strength. Objective: We examined whether a similar phenomenon could also be observed in human motor cortex (M1) using transcranial direct current stimulation (TDCS) during monophasic intermittent TBS (iTBS). Methods: TDCS was applied during posterior-anterior iTBS using three different conditions: posterioranterior TDCS (anode 3.5 cm posterior to M1, cathode 3.5 cm anterior to M1), anterior-posterior TDCS (cathode 3.5 cm posterior to M1, anode 3.5 cm anterior to M1), and sham TDCS. Results: When the direction of TDCS (posterior-anterior) matched the direction of the electrical field induced by iTBS, we found a 19% non-significant increase in excitability changes in comparison with iTBS combined with sham TDCS. When the TDCS was reversed (anterior-posterior), the excitatory effect of iTBS was abolished. Conclusion: Our findings suggest that excitatory after-effects of iTBS can be modulated by directionallyspecific TDCS.
... Thus the quality and duration of responses seem likely to be influenced by the interactions of interdependent complex systems. The efficacy of standalone NIBS is influenced by its stimulation variables, which include: frequency, intensity, coil positioning, stimulation site, and number of sessions delivered (Nollet et al., 2003;Goetz et al., 2016). Therefore, TMS protocols may be adapted to modulate the motor response through excitatory or depressive methods dependent on stimulation parameters, providing opportunity for custom programs based on the population, person, and pathology. ...
Article
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Upon its inception, repetitive transcranial magnetic stimulation (rTMS) was delivered at rest, without regard to the potential impact of activity occurring during or around the time of stimulation. rTMS was considered an experimental intervention imposed on the brain; therefore, the myriad features that might suppress or enhance its desired effects had not yet been explored. The field of rTMS has since grown substantially and therapeutic benefits have been reported, albeit with modest and inconsistent improvements. Work in this field accelerated following approval of a psychiatric application (depression), and it is now expanding to other applications and disciplines. In the last decade, experimental enquiry has sought new ways to improve the therapeutic benefits of rTMS, intended to enhance underlying brain reorganization and functional recovery by combining it with behavioral therapy. This concept is appealing, but poorly defined and requires clarity. We provide an overview of how combined rTMS and behavioral therapy has been delineated in the literature, highlighting the diversity of approaches. We outline a framework for study design and reporting such that the effects of this emerging method can be better understood.
... Based on previous in vivo parameters (Rodger et al., 2012;Makowiecki et al., 2014), we aimed to obtain a maximal magnetic field strength of 10 mT at the target tissue, with a rise-time of less than 100 µs and pulse length of 300 µs . Because pulse shape alters the efficiency of neuromodulation (Goetz et al., 2016), we used a symmetric trapezoidal pulse with the same rate of current rise-and fall, in keeping with LFMS in humans (Rohan et al., 2014). Hall device (ss94a2d; Honeywell, USA) measurements confirmed the predicted magnetic field strength and pulse waveform FIGURE 3 | Pulse waveform and parameters. ...
Article
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Non-invasive brain stimulation (NIBS) by electromagnetic fields appears to benefit human neurological and psychiatric conditions, although the optimal stimulation parameters and underlying mechanisms remain unclear. Although, in vitro studies have begun to elucidate cellular mechanisms, stimulation is delivered by a range of coils (from commercially available human stimulation coils to laboratory-built circuits) so that the electromagnetic fields induced within the tissue to produce the reported effects are ill-defined. Here, we develop a simple in vitro stimulation device with plug-and-play features that allow delivery of a range of stimulation parameters. We chose to test low intensity repetitive magnetic stimulation (LI-rMS) delivered at three frequencies to hindbrain explant cultures containing the olivocerebellar pathway. We used computational modeling to define the parameters of a stimulation circuit and coil that deliver a unidirectional homogeneous magnetic field of known intensity and direction, and therefore a predictable electric field, to the target. We built the coil to be compatible with culture requirements: stimulation within an incubator; a flat surface allowing consistent position and magnetic field direction; location outside the culture plate to maintain sterility and no heating or vibration. Measurements at the explant confirmed the induced magnetic field was homogenous and matched the simulation results. To validate our system we investigated biological effects following LI-rMS at 1 Hz, 10 Hz and biomimetic high frequency, which we have previously shown induces neural circuit reorganization. We found that gene expression was modified by LI-rMS in a frequency-related manner. Four hours after a single 10-min stimulation session, the number of c-fos positive cells increased, indicating that our stimulation activated the tissue. Also, after 14 days of LI-rMS, the expression of genes normally present in the tissue was differentially modified according to the stimulation delivered. Thus we describe a simple magnetic stimulation device that delivers defined stimulation parameters to different neural systems in vitro. Such devices are essential to further understanding of the fundamental effects of magnetic stimulation on biological tissue and optimize therapeutic application of human NIBS.
... Thus, we expect that applying rTMS protocols with more selective unidirectional pulses ought to produce clearer and more reproducible effects on MEPs. For example, a recent study showed that inhibition after 1 Hz rTMS delivered via a cTMS device is best achieved with a monophasic stimulus waveform compared with standard sinusoidal biphasic pulse (Goetz et al., 2016). Preliminary evidence suggests that higher frequency types of rTMS such as intermittent and continuous TBS (iTBS and cTBS) protocols are also sensitive to pulse parameters. ...
Article
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Repetitive transcranial magnetic stimulation (rTMS) can produce after-effects on the excitability and function of the stimulated cortical site that outlasts the period of stimulation for several minutes or hours (Hamada et al., 2008; Huang et al., 2005; Ridding and Ziemann, 2010; Sommer et al., 2013). These are thought to involve early phases of long term potentiation/depression at cortical synapses. Depending on the area stimulated, the after-effects can influence performance of a variety of cognitive and motor tasks, as well as learning (Parkin et al., 2015; Censor and Cohen, 2011). Reports of beneficial effects on behaviour in healthy populations have led to widespread interest in applying rTMS therapeutically, for example in patients with neuropsychiatric and neurological disorders (George et al., 2013; Lefaucheur et al., 2014; Ridding and Rothwell, 2007). A major issue with rTMS protocols is that the effects vary considerably within and between individuals (Hamada et al., 2013; Lopez-Alonso et al., 2014; Simeoni et al., 2016; Hinder et al., 2014; Vallence et al., 2015; Vernet et al., 2013; Goldsworthy et al., 2014; Maeda et al., 2000), which causes problems in replication of results in a research setting (Heroux et al., 2015), and is an obstacle to using rTMS in a therapeutic setting. A separate, but related, issue is that rTMS over a given cortical area is often assumed to affect all neuronal populations equally and thus affect all behaviours involving that area similarly, but this may not be true. Here we argue that advanced technologies and methodologies, such as controllable pulse parameter TMS (cTMS; (Peterchev et al., 2014)) and combining TMS with electroencephalography (EEG) (Ilmoniemi and Kicic, 2010; Peterchev et al., 2014), might facilitate the development of more selective forms of stimulation targeting particular neuronal populations or brain states, and ultimately improve the reliability and behavioural specificity of rTMS protocols.
... Alternatively or in conjunction, the sharper sensation may reflect the decreasing relative threshold of Aδ fibers compared to C fibers as the pulse width is reduced, due to larger membrane time constant of C fibers [7,8]. Finally, there is the possibility that the various pulse widths differentially affected the left dorsolateral prefrontal cortex target [33,34] and consequently produced different degrees of modulation of pain perception circuits in the brain [4,35,36]. This study, however, does not allow us to dissect mechanisms of the observed effects since it was not designed to differentiate the various contributions such as direct stimulation of nociceptor and receptor fibers, scalp muscle contraction, coil vibration, auditory perception, and direct cortical effects. ...
Article
Background: Scalp sensation and pain comprise the most common side effect of transcranial magnetic stimulation (TMS), which can reduce tolerability and complicate experimental blinding. Objective: We explored whether changing the width of single TMS pulses affects the quality and tolerability of the resultant somatic sensation. Methods: Using a controllable pulse parameter TMS device with a figure-8 coil, single monophasic magnetic pulses inducing electric field with initial phase width of 30, 60, and 120 µs were delivered in 23 healthy volunteers. Resting motor threshold of the right first dorsal interosseus was determined for each pulse width, as reported previously. Subsequently, pulses were delivered over the left dorsolateral prefrontal cortex at each of the three pulse widths at two amplitudes (100% and 120% of the pulse-width-specific motor threshold), with 20 repetitions per condition delivered in random order. After each pulse, subjects rated 0-to-10 visual analog scales for Discomfort, Sharpness, and Strength of the sensation. Results: Briefer TMS pulses with amplitude normalized to the motor threshold were perceived as slightly more uncomfortable than longer pulses (with an average 0.89 point increase on the Discomfort scale for pulse width of 30 µs compared to 120 µs). The sensation of the briefer pulses was felt to be substantially sharper (2.95 points increase for 30 µs compared to 120 µs pulse width), but not stronger than longer pulses. As expected, higher amplitude pulses increased the perceived discomfort and strength, and, to a lesser degree the perceived sharpness. Conclusions: Our findings contradict a previously published hypothesis that briefer TMS pulses are more tolerable. We discovered that the opposite is true, which merits further study as a means of enhancing tolerability in the context of repetitive TMS.
Article
The temporal shape of a pulse in transcranial magnetic stimulation (TMS) influences which neuron populations are activated preferentially as well as the strength and even direction of neuromodulation effects. Furthermore, various pulse shapes differ in their efficiency, coil heating, sensory perception, and clicking sound. However, the available TMS pulse shape repertoire is still very limited to a few biphasic, monophasic, and polyphasic pulses with sinusoidal or near-rectangular shapes. Monophasic pulses, though found to be more selective and stronger in neuromodulation, are generated inefficiently and therefore only available in simple low-frequency repetitive protocols. Despite a strong interest to exploit the temporal effects of TMS pulse shapes and pulse sequences, waveform control is relatively inflexible and only possible parametrically within certain limits. Previously proposed approaches for flexible pulse shape control, such as through power electronic inverters, have significant limitations: Existing semiconductor switches can fail under the immense electrical stress associated with free pulse shaping, and most conventional power inverter topologies are incapable of generating smooth electric fields or existing pulse shapes. Leveraging intensive preliminary work on modular power electronics, we present a modular pulse synthesizer (MPS) technology that can, for the first time, flexibly generate high-power TMS pulses (~ 4,000 V, ~ 8,000 A) with user-defined electric field shape as well as rapid sequences of pulses with high output quality. The circuit topology breaks the problem of simultaneous high power and switching speed into smaller, manageable portions, distributed across several identical modules. In consequence, MPS TMS can use semiconductor devices with voltage and current ratings lower than the overall pulse voltage and distribute the overall switching of several hundred kilohertz among multiple transistors. MPS TMS can synthesize practically any pulse shape, including conventional ones, with fine quantization of the induced electric field. Moreover, the technology allows optional symmetric differential coil driving so that the average electric potential of the coil, in contrast to conventional TMS devices, stays constant to prevent capacitive artifacts in sensitive recording amplifiers, such as electroencephalography (EEG). MPS TMS can enable the optimization of stimulation paradigms for more sophisticated probing of brain function as well as stronger and more selective neuromodulation, further expanding the parameter space available to users.
Article
Repetitive transcranial magnetic stimulation (rTMS) has become an increasingly popular tool to modulate neural excitability and induce neural plasticity in clinical and preclinical models; however, the physiological mechanisms in which it exerts these effects remain largely unknown. To date, studies have primarily focused on characterizing rTMS-induced changes occurring at the synapse, with little attention given to changes in intrinsic membrane properties. However, accumulating evidence suggests that rTMS may induce its effects, in part, via intrinsic plasticity mechanisms, suggesting a new and potentially complementary understanding of how rTMS alters neural excitability and neural plasticity. In this review, we provide an overview of several intrinsic plasticity mechanisms before reviewing the evidence for rTMS-induced intrinsic plasticity. In addition, we discuss a select number of neurological conditions where rTMS-induced intrinsic plasticity has therapeutic potential before speculating on the temporal relationship between rTMS-induced intrinsic and synaptic plasticity.
Article
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Objective: To obtain a formalism for real-time concurrent sequential estimation of neural membrane time constant and input--output (IO) curve with transcranial magnetic stimulation (TMS). Approach: First, the neural membrane response and depolarization factor, which leads to motor evoked potentials (MEPs) with TMS are analytically computed and discussed. Then, an integrated model is developed which combines the neural membrane time constant and input--output curve. Identifiability of the proposed integrated model is discussed. A condition is derived, which assures estimation of the proposed integrated model. Finally, sequential parameter estimation (SPE) of the neural membrane time constant and IO curve is described through closed-loop optimal sampling and open-loop uniform sampling TMS. Without loss of generality, this paper focuses on a specific case of commercialized TMS pulse shapes. The proposed formalism and SPE method are directly applicable to other pulse shapes. Main results: The results confirm satisfactory estimation of the membrane time constant and IO curve parameters. By defining a stopping rule based on five times consecutive convergence of the estimation parameters with a tolerances of 0.01, the membrane time constant and IO curve parameters are estimated with 82 TMS pulses with absolute relative estimation errors (AREs) of less than 4% with the optimal sampling SPE method. At this point, the uniform sampling SPE method leads to AREs up to 16%. The uniform sampling method does not satisfy the stopping rule due to the large estimation variations. Significance: This paper provides a tool for real-time closed-loop SPE of the neural time constant and IO curve, which can contribute novel insights in TMS studies. SPE of the membrane time constant enables selective stimulation, which can be used for advanced brain research, precision medicine and personalized medicine.
Article
Background: Motor-evoked potentials (MEP) are one of the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller responses, e.g., from single motor units. However, available detection and quantization methods suffer from a large noise floor. Objective: This paper develops a detection method that extracts MEPs hidden below the noise floor. With this method, we aim to estimate excitatory activations of the corticospinal pathways well below the conventional detection level. Methods: The presented MEP detection method presents a self-learning matched-filter approach for improved robustness against noise. The filter is adaptively generated per subject through iterative learning. For responses that are reliably detected by conventional detection, the new approach is fully compatible with established peak-to-peak readings and provides the same results but extends the dynamic range below the conventional noise floor. Results: In contrast to the conventional peak-to-peak measure, the proposed method increases the signal-to-noise ratio by more than a factor of 5. The first detectable responses appear to be substantially lower than the conventional threshold definition of 50 µV median peak-to-peak amplitude. Conclusion: The proposed method shows that stimuli well below the conventional 50 µV threshold definition can consistently and repeatably evoke muscular responses and thus activate excitable neuron populations in the brain. As a consequence, the IO curve is extended at the lower end, and the noise cut-off is shifted. Importantly, the IO curve extends so far that the 50 µV point turns out to be closer to the center of the logarithmic sigmoid curve rather than close to the first detectable responses. The underlying method is applicable to a wide range of evoked potentials and other biosignals, such as in electroencephalography.
Article
Objective Investigate the variability previously found with cortical stimulation and handheld transcranial magnetic stimulation (TMS) coils, criticized for its high potential of coil position fluctuations, bypassing the cortex using deep brain electrical stimulation (DBS) of the corticospinal tract with fixed electrodes where both latent variations of the coil position of TMS are eliminated and cortical excitation fluctuations should be absent. Methods Ten input–output curves were recorded from five anesthetized cats with implanted DBS electrodes targeting the corticospinal tract. Goodness of fit of regressions with a conventional single variability source as well as a dual variability source model was quantified using a Schwarz Bayesian Information approach to avoid overfitting. Results Motor evoked potentials (MEPs) through DBS of the corticospinal tract revealed short-term fluctuations in excitability of the targeted neuron pathway reflecting endogenous input-side variability at similar magnitude as TMS despite bypassing cortical networks. Conclusion Input-side variability, i.e., variability resulting in changing MEP amplitudes as if the stimulation strength was modulated, also emerges in electrical stimulation at a similar degree and is not primarily a result of varying stimulation, such as minor coil movements in TMS. More importantly, this variability component is present, although the cortex is bypassed. Thus, it may be of spinal origin, which can include cortical input from spinal projections. Further, the nonlinearity of the compound variability entails complex heteroscedastic non-Gaussian distributions and typically does not allow simple linear averages in statistical analysis of MEPs. As the average is dominated by outliers, it risks bias. With appropriate regression, the net effects of excitatory and inhibitory inputs to the targeted neuron pathways become noninvasively observable and quantifiable. Significance The neural responses evoked by artificial stimulation in the cerebral cortex are variable. For example, MEPs in response to repeated presentations of the same stimulus can vary from no response to saturation across trials. Several sources of such variability have been suggested, and most of them may be technical in nature, but localization is missing.
Article
This paper presents a novel transcranial magnetic stimulation (TMS) pulse generator with a wide range of pulse shape, amplitude, and width. Approach: The novel MM-TMS device is the first to use a modular multi-level circuit topology at full TMS energy levels. It consists of ten cascaded H-bridge modules, each implemented with insulated-gate bipolar transistors, enabling both novel high-amplitude ultrabrief pulses as well as pulses with conventional amplitude and duration. The MM-TMS device has 21 available output voltage levels within each pulse, allowing flexible synthesis of various pulse waveforms and sequences. The circuit further allows charging the energy storage capacitor on each of the ten cascaded modules with a conventional TMS power supply. Main results: The MM-TMS device can output peak coil voltages and currents of 11 kV and 10 kA, respectively, enabling ultrabrief suprathreshold pulses (> 8.25 μs active electric field phase). Further, the MM-TMS device can generate a wide range of near-rectangular monophasic and biphasic pulses, as well as more complex sinusoidal, polyphasic, and amplitude-modulated pulses. At matched estimated stimulation strength, briefer pulses emit less sound, which could enable quieter TMS. Finally, the MM-TMS device can instantaneously increase or decrease the amplitude from one pulse to the next by adding or removing modules in series, which enables rapid pulse sequences and paired-pulse protocols with various pulse shapes. Significance: The MM-TMS device allows unprecedented control of the pulse characteristics which could enable novel protocols and quieter operation.
Article
Peripheral magnetic stimulation is a promising technique for several applications like rehabilitation or diagnose of neuronal pathways. However, most available magnetic stimulation devices are designed for transcranial stimulation and require high-power, expensive hardware. Modern technology such as rectangular pulses allows to adapt parameters like pulse shape and duration in order to reduce the required energy. Nevertheless, the effect of different temporal electromagnetic field shapes on neuronal structures is not yet fully understood. We created a simulation environment to find out how peripheral nerves are affected by induced magnetic fields and what pulse shapes have the lowest energy requirements. Using the electric field distribution of a Figure-of-8 coil together with an axon model in saline solution, we calculated the potential along the axon and determined the required threshold current to elicit an action potential. Further, for the purpose of selective stimulation, we investigated different axon diameters. Our results show that rectangular pulses have the lowest thresholds at a pulse duration of 20 μs. For sinusoidal coil currents, the optimal pulse duration was found to be 40 μs. Most importantly, with an asymmetric rectangular pulse, the coil current could be reduced from 2.3 kA (cosine shaped pulse) to 600 A. In summary, our results indicate that for magnetic nerve stimulation the use of rectangular pulse shapes holds the potential to reduce the required coil current by a factor of 4, which would be a massive improvement.
Preprint
Background: Motor-evoked potentials (MEP) are one of the most prominent responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. Understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smaller responses, e.g., from single motor units. However, available detection and quantization methods suffer from a large noise floor. Objective: This paper develops a detection method that extracts MEPs hidden below the noise floor. With this method, we aim to estimate excitatory activations of the corticospinal pathways well below the conventional detection level. Methods: The presented MEP detection method presents a self-learning matched-filter approach for improved robustness against noise. The filter is adaptively generated per subject through iterative learning. For responses that are reliably detected by conventional detection, the new approach is fully compatible with established peak-to-peak readings and provides the same results but extends the dynamic range below the conventional noise floor. Results: In contrast to the conventional peak-to-peak measure, the proposed method increases the signal-to-noise ratio by more than a factor of 5. The first detectable responses appear to be substantially lower than the conventional threshold definition of 50 μV median peak-to-peak amplitude. Conclusion: The proposed method shows that stimuli well below the conventional 50 μV threshold definition can consistently and repeatably evoke muscular responses and thus activate excitable neuron populations in the brain. As a consequence, the IO curve is extended at the lower end, and the noise cut-off is shifted. Importantly, the IO curve extends so far that the 50 μV point turns out to be closer to the center of the logarithmic sigmoid curve rather than close to the first detectable responses. The underlying method is applicable to a wide range of evoked potentials and other biosignals, such as in electroencephalography.
Article
Full-text available
Interactions from both inhibitory and excitatory interneurons are necessary components of cortical processing that contribute to the vast amount of motor actions executed by humans daily. As transcranial magnetic stimulation (TMS) over primary motor cortex is capable of activating corticospinal neurons trans-synaptically, studies over the past 30 years have provided how subtle changes in stimulation parameters (i.e., current direction, pulse width, and paired-pulse) can elucidate evidence for two distinct neuronal networks that can be probed with this technique. This article provides a brief review of some fundamental studies demonstrating how these networks have separable excitatory inputs to corticospinal neurons. Furthermore, the findings of recent investigations will be discussed in detail, illustrating how each network’s sensitivity to different brain states (i.e., rest, movement preparation, and motor learning) is dissociable. Understanding the physiological characteristics of each network can help to explain why interindividual responses to TMS exist, while also providing insights into the role of these networks in various human motor behaviors.
Article
Background: Transcranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements TMS activates and how stimulation parameters affect the neural response. Objective: To develop a multi-scale computational model to quantify the effect of TMS parameters on the direct response of individual neurons. Methods: We integrated morphologically-realistic neuronal models with TMS-induced electric fields computed in a finite element model of a human head to quantify the cortical response to TMS with several combinations of pulse waveforms and current directions. Results: TMS activated with lowest intensity intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 5 pyramidal cells had the lowest thresholds, but layer 2/3 pyramidal cells and inhibitory basket cells were also activated at most intensities. Direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, rather than the field component normal to the cortical surface. Varying the induced current direction caused a waveform-dependent shift in the activation site and provided a potential mechanism for experimentally observed differences in thresholds and latencies of muscle responses. Conclusions: This biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other cortical stimulation modalities. It also serves as a foundation for more detailed network models of the response to TMS, which may include endogenous activity, synaptic connectivity, inputs from intrinsic and extrinsic axonal projections, and corticofugal axons in white matter.
Conference Paper
Motor-evoked potentials (MEP) are one of the most important responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. The understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smallest responses, e.g., from single motor units, but available detection and quantization methods are rather simple and suffer from a large noise floor. The paper introduces a more sophisticated matched-filter detection method that increases the detection sensitivity and shows that activation occurs well below the conventional detection level. In consequence, also conventional threshold definitions, e.g., as 50 μV median response amplitude, turn out to be substantially higher than the point at which first detectable responses occur. The presented method uses a matched-filter approach for improved sensitivity and generates the filter through iterative learning from the presented data. In contrast to conventional peak-to-peak measures, the presented method has a higher signal-to-noise ratio (≥14 dB). For responses that are reliably detected by conventional detection, the new approach is fully compatible and provides the same results but extends the dynamic range below the conventional noise floor. The underlying method is applicable to a wide range of well-timed biosignals and evoked potentials, such as in electroencephalography.
Article
The influence of pulse width, pulse waveform and current direction on transcranial magnetic stimulation (TMS) outcomes is of critical importance. However, their effects have only been investigated indirectly with motor-evoked potentials (MEP). By combining TMS and EEG it is possible to examine how these factors affect evoked activity from the cortex and compare that with the effects on MEP. We used a new controllable TMS device (cTMS) to vary systematically pulse width, pulse waveform and current direction and explore their effects on global and local TMS-evoked EEG response. In 19 healthy volunteers we measured (1) resting motor threshold (RMT) as an estimate of corticospinal excitability; (2) global mean field power (GMFP) as an estimate of global cortical excitability; and (3) local mean field power (LMFP) as an estimate of local cortical excitability. RMT was lower with monophasic posterior-to-anterior (PA) pulses that have a longer pulse width (p < 0.001). After adjusting for the individual motor threshold of each pulse type we found that (a) GMFP was higher with monophasic pulses (p < 0.001); (b) LMFP was higher with longer pulse width (p = 0.015); (c) early TEP polarity was modulated depending on the current direction (p = 0.01). Despite normalizing stimulus intensity to RMT, we found that local and global responses to TMS vary depending on pulse parameters. Since EEG responses can vary independently of the MEP, titrating parameters of TMS in relation to MEP threshold is not a useful way of ensuring that a constant set of neurons is activated within a cortical area.
Article
Background: Transcranial magnetic stimulation (TMS) with different current directions can activate different sets of neurons. Current direction can also affect the results of repetitive TMS. Objective: To test the influence of uni-directional intermittent theta burst stimulation (iTBS) using different current directions, namely posteroanterior (PA) and anteroposterior (AP), on motor behaviour. Methods: In a cross-over design, PA- and AP-iTBS was applied over the left primary motor cortex in 19 healthy, right-handed volunteers. Performance of a finger-tapping task was recorded before and 0, 10, 20, and 30minutes after the iTBS. The task was conducted with the right and left hands separately at each time point. As a control, AP-iTBS with reduced intensity was applied to 14 participants in a separate session (APweak condition). Results: The finger-tapping count with the left hand was decreased after PA-iTBS. Neither AP- nor APweak-iTBS altered the performance. Conclusions: Current direction had a significant impact on the after-effects of iTBS.
Article
Full-text available
To compare the strength-duration (S-D) time constants of motor cortex structures activated by current pulses oriented posterior-anterior (PA) or anterior-posterior (AP) across the central sulcus. Motor threshold and input-output curve, along with motor evoked potential (MEP) latencies, of first dorsal interosseus were determined at pulse widths of 30, 60, and 120μs using a controllable pulse parameter (cTMS) device, with the coil oriented PA or AP. These were used to estimate the S-D time constant and we compared with data for responses evoked by cTMS of the ulnar nerve at the elbow. The S-D time constant with PA was shorter than for AP stimulation (230.9±97.2 vs. 294.2±90.9μs; p<0.001). These values were similar to those calculated after stimulation of ulnar nerve (197±47μs). MEP latencies to AP, but not PA stimulation were affected by pulse width, showing longer latencies following short duration stimuli. PA and AP stimuli appear to activate the axons of neurons with different time constants. Short duration AP pulses are more selective than longer pulses in recruiting longer latency corticospinal output. More selective stimulation of neural elements may be achieved by manipulating pulse width and orientation. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Article
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Magnetic stimulation is a standard tool in brain research and has found important clinical applications in neurology, psychiatry, and rehabilitation. Whereas coil designs and the spatial field properties have been intensively studied in the literature, the temporal dynamics of the field has received less attention. Typically, the magnetic field waveform is determined by available device circuit topologies rather than by consideration of what is optimal for neural stimulation. This paper analyzes and optimizes the waveform dynamics using a nonlinear model of a mammalian axon. The optimization objective was to minimize the pulse energy loss. The energy loss drives power consumption and heating, which are the dominating limitations of magnetic stimulation. The optimization approach is based on a hybrid global-local method. Different coordinate systems for describing the continuous waveforms in a limited parameter space are defined for numerical stability. The optimization results suggest that there are waveforms with substantially higher efficiency than that of traditional pulse shapes. One class of optimal pulses is analyzed further. Although the coil voltage profile of these waveforms is almost rectangular, the corresponding current shape presents distinctive characteristics, such as a slow low-amplitude first phase which precedes the main pulse and reduces the losses. Representatives of this class of waveforms corresponding to different maximum voltages are linked by a nonlinear transformation. The main phase, however, scales with time only. As with conventional magnetic stimulation pulses, briefer pulses result in lower energy loss but require higher coil voltage than longer pulses.
Article
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The input-output (IO) curve of cortical neuron populations is a key measure of neural excitability and is related to other response measures including the motor threshold which is widely used for individualization of neurostimulation techniques, such as transcranial magnetic stimulation (TMS). The IO curve parameters provide biomarkers for changes in the state of the target neural population that could result from neurostimulation, pharmacological interventions, or neurological and psychiatric conditions. Conventional analyses of IO data assume a sigmoidal shape with additive Gaussian scattering that allows simple regression modeling. However, careful study of the IO curve characteristics reveals that simple additive noise does not account for the observed IO variability. We propose a consistent model that adds a second source of intrinsic variability on the input side of the IO response. We develop an appropriate mathematical method for calibrating this new nonlinear model. Finally, the modeling framework is applied to a representative IO data set. With this modeling approach, previously inexplicable stochastic behavior becomes obvious. This work could lead to improved algorithms for estimation of various excitability parameters including established measures such as the motor threshold and the IO slope, as well as novel measures relating to the variability characteristics of the IO response that could provide additional insight into the state of the targeted neural population.
Article
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The after-effects of repetitive transcranial magnetic stimulation (rTMS) are highly variable between individuals. Because different populations of cortical neurons are stimulated more easily or are more excitable in different people at different times, the variability may not be due to differences between individuals in the plasticity of cortical synapses, but may instead be due to individual differences in the recruitment of cortical neurons. In this study, we examined the effects of rTMS in 56 healthy volunteers. The responses to excitatory and inhibitory theta burst stimulation (TBS) protocols were highly variable between individuals. Surprisingly, the TBS effect was highly correlated with the latency of motor-evoked potentials (MEPs) evoked by TMS pulses that induced an anterior-posterior (AP) directed current across the central sulcus. Finally, we devised a new plasticity protocol using closely timed pairs of oppositely directed TMS current pulses across the central sulcus. Again, the after-effects were related to the latency of MEPs evoked by AP current. Our results are consistent with the idea that variation in response to rTMS plasticity probing protocols is strongly influenced by which interneuron networks are recruited by the TMS pulse.
Article
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Somatic treatments for mood disorders represent a class of interventions available either as a stand-alone option, or in combination with psychopharmacology and/or psychotherapy. Here, we review the currently available techniques, including those already in clinical use and those still under research. Techniques are grouped into the following categories: (1) seizure therapies, including electroconvulsive therapy and magnetic seizure therapy, (2) noninvasive techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and cranial electric stimulation, (3) surgical approaches, including vagus nerve stimulation, epidural electrical stimulation, and deep brain stimulation, and (4) technologies on the horizon. Additionally, we discuss novel approaches to the optimization of each treatment, and new techniques that are under active investigation.
Article
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Randomized controlled trials support the antidepressant efficacy of transcranial magnetic stimulation (TMS); however, there is individual variability in the magnitude of response. Examination of response predictors has been hampered by methodological limitations such as small sample sizes and single-site study designs. Data from a multisite sham-controlled trial of the antidepressant efficacy of TMS provided an opportunity to examine predictors of acute outcome. An open-label extension for patients who failed to improve provided the opportunity for confirmatory analysis. Treatment was administered to the left dorsolateral prefrontal cortex at 10 pulses per second, 120% of motor threshold, for a total of 3000 pulses per day. Change on the Montgomery-Asberg Depression Rating Scale after 4 weeks was the primary efficacy outcome. A total of 301 patients with nonpsychotic unipolar major depression at 23 centers were randomized to active or sham TMS. Univariate predictor analyses showed that the degree of prior treatment resistance in the current episode was a predictor of positive treatment outcome in both the controlled study and the open-label extension trial. In the randomized trial, shorter duration of current episode was also associated with a better outcome. In the open-label extension study, absence of anxiety disorder comorbidity was associated with an improved outcome, but duration of current episode was not. The number of prior treatment failures was the strongest predictor for positive response to acute treatment with TMS. Shorter duration of current illness and lack of anxiety comorbidity may also confer an increased likelihood of good antidepressant response to TMS.
Article
Full-text available
We examined the effect of the orientation of a figure-of-eight coil on the latency of surface electromyographic (EMG) responses and the firing pattern of single motor units evoked in the first dorsal interosseous muscle by transcranial magnetic brain stimulation. Two coil positions were used: the coil held on a parasagittal line either with the induced current in the brain flowing in a postero-anterior direction (PA) or with the current flowing latero-medially (LM). The results were compared with those observed after anodal electrical stimulation. LM stimulation produced surface and single unit responses which occurred 0-3 msec earlier than PA stimulation. In many cases responses to LM stimulation had the same latency as those produced by anodal electrical stimulation. Responses evoked by LM stimulation were less affected by changes in motor cortical excitability (cortico-cortical inhibition and transcallosal inhibition) than those to PA stimulation. We suggest that LM stimulation can sometimes stimulate corticospinal fibres directly, at or near the same site as anodal stimulation. In contrast, PA stimulation tends to activate corticospinal fibres trans-synaptically. The difference in stimulation sites may make a comparison of PA and LM stimulation a useful method of localising changes in corticospinal excitability to a cortical level.
Article
Full-text available
Long-term depression (LTD) is a lasting decrease in synaptic effectiveness that follows some types of electrical stimulation in the hippocampus. Two broad types of LTD may be distinguished. Heterosynaptic LTD can occur at synapses that are inactive, normally during high-frequency stimulation of a converging synaptic input. Homosynaptic LTD can occur at synapses that are activated, normally at low frequencies. Here we discuss the mechanisms of LTD and their possible relevance to hippocampal function.
Article
OBJECTIVE: To compare the strength–duration (S–D) time constants of motor cortex structures activated by current pulses oriented posterior–anterior (PA) or anterior–posterior (AP) across the central sulcus. METHODS: Motor threshold and input–output curve, along with motor evoked potential (MEP) latencies, of first dorsal interosseus were determined at pulse widths of 30, 60, and 120 μs using a controllable pulse parameter (cTMS) device, with the coil oriented PA or AP. These were used to estimate the S–D time constant and we compared with data for responses evoked by cTMS of the ulnar nerve at the elbow. RESULTS: The S–D time constant with PA was shorter than for AP stimulation (230.9 ± 97.2 vs. 294.2 ± 90.9 μs; p < 0.001). These values were similar to those calculated after stimulation of ulnar nerve (197 ± 47 μs). MEP latencies to AP, but not PA stimulation were affected by pulse width, showing longer latencies following short duration stimuli. CONCLUSIONS: PA and AP stimuli appear to activate the axons of neurons with different time constants. Short duration AP pulses are more selective than longer pulses in recruiting longer latency corticospinal output. Significance More selective stimulation of neural elements may be achieved by manipulating pulse width and orientation.
Chapter
This chapter provides overview of the state of the art of transcranial magnetic stimulation (TMS) devices, including pulse sources with flexible control of the output waveform parameters and a wide variety of coil designs. It discusses technologies for accurate TMS targeting, including electric field models, frameless stereotaxy, and robotic coil holders. The chapter addresses technological aspects of ancillary coil effects such as heating, noise, vibration, and scalp stimulation. TMS requires high energy pulses that present a technical challenge for the design of practical, flexible, and efficient pulse sources. The chapter covers technical considerations for the integration of TMS and neuroimaging devices. It discusses various coil configurations and their electric field characteristics as well as technical advances in coil field modelling, positioning systems, efficiency and cooling, noise and scalp stimulation, and sham. The chapter summarizes technical considerations for the integration of TMS and neuroimaging devices.
Article
Transcranial magnetic stimulators have progressed from basic implementations to integrated systems optimized for treatment of pathologies. This article reviews key factors of design of such clinically targeted systems, discussing design principles, procedure-specific features, and clinical safety requirements. A power source, a capacitor, and a high-power switch controlled by a processor form the basic stimulator. The fundamental operating mechanism of a TMS stimulator is to create a changing magnetic field that can induce a current in adjacent conductive material. The clinical TMS system must incorporate patient positioning, patient comfort, coil positioning features, and intuitive user controls and means of managing patient data to be a fully effective system. The most important safety risk with repetitive TMS reported in the literature is the risk of inducing seizure. Other safety considerations include proper use of human factor analysis to minimize improper operation, the biocompatibility of materials touching the patient, and addressing acoustic noise.
Article
To investigate the mechanism of transcranial magnetic stimulation (TMS), we compared the directional effects of two stimulators (Magstim 200 and Magstim Super Rapid). First, stimulating visual cortex and facial nerve with occipital mid-line TMS, we found that, for a particular coil orientation, these two stimulators affected a particular neural structure in opposite hemispheres and that, to affect a particular neural structure in a particular hemisphere, these two stimulators required opposite coil orientations. Second, stimulating a membrane-simulating circuit, we found that, for a particular coil orientation, these two stimulators resulted in a peak induced current of the same polarity but in a peak induced charge accumulation of opposite polarity. We suggest that the critical parameter in TMS is the amplitude of the induced charge accumulation rather than the amplitude of the induced current. Accordingly, TMS would be elicited just before the end of the first (Magstim 200) and second (Magstim Super Rapid) phase of the induced current rather than just after the start of the first phase of the induced current.
Article
Objective: This work aims at flexible and practical pulse parameter control in transcranial magnetic stimulation (TMS), which is currently very limited in commercial devices. Approach: We present a third generation controllable pulse parameter device (cTMS3) that uses a novel circuit topology with two energy-storage capacitors. It incorporates several implementation and functionality advantages over conventional TMS devices and other devices with advanced pulse shape control. cTMS3 generates lower internal voltage differences and is implemented with transistors with a lower voltage rating than prior cTMS devices. Main results: cTMS3 provides more flexible pulse shaping since the circuit topology allows four coil-voltage levels during a pulse, including approximately zero voltage. The near-zero coil voltage enables snubbing of the ringing at the end of the pulse without the need for a separate active snubber circuit. cTMS3 can generate powerful rapid pulse sequences (< 10 ms inter pulse interval) by increasing the width of each subsequent pulse and utilizing the large capacitor energy storage, allowing the implementation of paradigms such as paired-pulse and quadripulse TMS with a single pulse generation circuit. cTMS3 can also generate theta (50 Hz) burst stimulation with predominantly unidirectional electric field pulses. The cTMS3 device functionality and output strength are illustrated with electrical output measurements as well as a study of the effect of pulse width and polarity on the active motor threshold in ten healthy volunteers. Significance: The cTMS3 features could extend the utility of TMS as a research, diagnostic, and therapeutic tool.
Article
Question: Does the current direction influence the effect of intermittent theta burst stimulation (iTBS) on human motor cortex excitability? Methods: We stimulated the dominant hand representation of the motor cortex in 15 healthy subjects, using “unidirectional biphasic” pulses with an M-ratio (i.e, degree of monophasicity) of 0.2, generated by a prototype controllable TMS machine (cTMS-3, Rogue Resolutions Ltd., Cardiff, UK), connected to a standard figure-of-eight coil with physical attributes similar to a Magstim D70 coil. iTBS was applied conventionally, using 20 sequences of 2 seconds iTBS (10 bursts at 5 Hz burst repetition frequency, each burst consisting of 3 pulses of 80% AMT intensity repeated at 50 Hz frequency). In two separate sessions pulses differing in current direction and shape were applied: a) posterio-anterior (PA) current direction in the brain, 75 microseconds (iTBS_PA75). b) AP current direction, 45 microseconds (iTBS_AP45). Before and for 30 minutes after iTBS, we monitored the modulation of motor evoked potential (MEP) amplitude from the dominant first dorsal interosseus using conventional, monophasic, suprathreshold pulses generated by a Magstim 2002 stimulator, inducing PA currents in the brain, at 0.2 Hz frequency. Results: The posterior effective current direction (iTBS_AP45) yielded a pronounced and slightly delayed inhibition of MEP amplitude in all but one subjects. iTBS_PA75 had a variable and inconsistent effect. The relatively consistent effect of iTBS_AP45 was unrelated to the MEP latency differences. The divergent iTBS_PA75 effects was in part related to the latency differenceAP–LM in that long latency differences were correlated with the induction of inhibition rather than facilitation. Conclusions: Current direction influences the outcome of iTBS, with a preference for currents running from anterior to posterior in the motor cortex.
Article
Question: In a companion poster (Sommer et al.) we show that iTBS with a monophasic anterior-posterior (AP) current pulse, which differs from conventional TBS applied with biphasic pulses (Huang et al. 2005), produces reliable suppression of corticospinal excitability. Here we test the effect of applying cTBS with the same monophasic pulses. Methods: We stimulated the dominant hand representation of the motor cortex in 15 healthy subjects, using approximately square wave pulses (see Fig 1 Peterchev et al. 2013), generated by a prototype controllable TMS machine (cTMS-3, Rogue Resolutions Ltd., Cardiff, UK), connected to a standard figure-of-eight coil with an outer diameter of each wing of 70 mm (The Magstim Co. Ltd., Dyfed, United Kingdom). cTBS was applied conventionally (200 bursts at 5 Hz burst repetition frequency, each burst consisting of 3 pulses of 80% AMT intensity repeated at 50 Hz frequency). In two separate sessions, we applied a pulse width of 75 microseconds in the posterio-anterior (PA) current direction in the brain, and of 45 microseconds in the AP direction. Before and every 5 minutes up to 30 minutes after cTBS, we monitored the modulation of motor evoked potential (MEP) amplitude from the dominant first dorsal interosseous using blocks of conventional, monophasic, suprathreshold pulses generated by a Magstim 200-2 stimulator, inducing PA currents in the brain, at 0.2 Hz frequency. Results: There was a large variation in response between individuals such that a rmANOVA using data from all points failed to show any effect of AP or PA stimulation and no difference between them. However, averaging all post-cTBS time points for comparison with baseline showed a significant MEP suppression after AP (mean suppression to 80% control, paired t-test p=0.044) but not PA stimulation. Conclusions: Monophasic AP cTBS (like iTBS) tends to suppress corticospinal excitability but individual variability is high. PA cTBS has no reliable effect. References: Peterchev et al. (2013) Pulse width dependence of motor threshold and input-output curve characterized with controllable pulse parameter transcranial magnetic stimulation, Clin Neurophysiol; Huang et al. (2005) Theta burst stimulation of the human motor cortex, Neuron
Article
Noninvasive brain stimulation techniques have been widely used for studying the physiology of the CNS, identifying the functional role of specific brain structures and, more recently, exploring large-scale network dynamics. Here we review key findings that contribute to our understanding of the mechanisms underlying the physiological and behavioral effects of these techniques. We highlight recent innovations using noninvasive stimulation to investigate global brain network dynamics and organization. New combinations of these techniques, in conjunction with neuroimaging, will further advance the utility of their application.
Article
Here we review the usefulness of transcranial magnetic stimulation (TMS) in modulating cortical networks in ways that might produce performance enhancements in healthy human subjects. To date over sixty studies have reported significant improvements in speed and accuracy in a variety of tasks involving perceptual, motor, and executive processing. Two basic categories of enhancement mechanisms are suggested by this literature: direct modulation of a cortical region or network that leads to more efficient processing, and addition-by-subtraction, which is disruption of processing which competes or distracts from task performance. Potential applications of TMS cognitive enhancement, including research into cortical function, rehabilitation therapy in neurological and psychiatric illness, and accelerated skill acquisition in healthy individuals are discussed, as are methods of optimizing the magnitude and duration of TMS-induced performance enhancement, such as improvement of targeting through further integration of brain imaging with TMS. One technique, combining multiple sessions of TMS with concurrent TMS/task performance to induce Hebbian-like learning, appears to be promising for prolonging enhancement effects. While further refinements in the application of TMS to cognitive enhancement can still be made, and questions remain regarding the mechanisms underlying the observed effects, this appears to be a fruitful area of investigation that may shed light on the basic mechanisms of cognitive function and their therapeutic modulation.
Article
Objective: To demonstrate the use of a novel controllable pulse parameter TMS (cTMS) device to characterize human corticospinal tract physiology. Methods: Motor threshold and input-output (IO) curve of right first dorsal interosseus were determined in 26 and 12 healthy volunteers, respectively, at pulse widths of 30, 60, and 120 μs using a custom-built cTMS device. Strength-duration curve rheobase and time constant were estimated from the motor thresholds. IO slope was estimated from sigmoid functions fitted to the IO data. Results: All procedures were well tolerated with no seizures or other serious adverse events. Increasing pulse width decreased the motor threshold and increased the pulse energy and IO slope. The average strength-duration curve time constant is estimated to be 196 μs, 95% CI [181 μs, 210 μs]. IO slope is inversely correlated with motor threshold both across and within pulse width. A simple quantitative model explains these dependencies. Conclusions: Our strength-duration time constant estimate compares well to published values and may be more accurate given increased sample size and enhanced methodology. Multiplying the IO slope by the motor threshold may provide a sensitive measure of individual differences in corticospinal tract physiology. Significance: Pulse parameter control offered by cTMS provides enhanced flexibility that can contribute novel insights in TMS studies.
Article
Magnetic stimulation pulse sources are very inflexible high-power devices. The incorporated circuit topology is usually limited to a single pulse type. However, experimental and theoretical work shows that more freedom in choosing or even designing waveforms could notably enhance existing methods. Beyond that, it even allows entering new fields of application. We propose a technology that can solve the problem. Even in very high frequency ranges, the circuitry is very flexible and is able generate almost every waveform with unrivaled accuracy. This technology can dynamically change between different pulse shapes without any reconfiguration, recharging or other changes; thus the waveform can be modified also during a high-frequency repetitive pulse train. In addition to the option of online design and generation of still unknown waveforms, it amalgamates all existing device types with their specific pulse shapes, which have been leading an independent existence in the past years. These advantages were achieved by giving up the common basis of all magnetic stimulation devices so far, i.e., the high-voltage oscillator. Distributed electronics handle the high power dividing the high voltage and the required switching rate into small portions.
Article
Magnetic stimulation is a key tool in experimental brain research and several clinical applications. Whereas coil designs and the spatial field properties have been intensively studied in the literature, the temporal dynamics of the field has received little attention. The available pulse shapes are typically determined by the relatively limited capabilities of commercial stimulation devices instead of efficiency or optimality. Furthermore, magnetic stimulation is relatively inefficient with respect to the required energy compared to other neurostimulation techniques. We therefore analyze and optimize the waveform dynamics with a nonlinear model of a mammalian motor axon for the first time, without any pre-definition of waveform candidates. We implemented an unbiased and stable numerical algorithm using variational calculus in combination with a global optimization method. This approach yields very stable results with comprehensible characteristic properties, such as a first phase which reduces ohmic losses in the subsequent pulse phase. We compare the energy loss of these optimal waveforms with the waveforms generated by existing magnetic stimulation devices.
Article
Background: Directional sensitivity is relevant for the excitability threshold of the human primary motor cortex, but its importance for externally induced plasticity is unknown. Objective: To study the influence of current direction on two paradigms inducing neuroplasticity by repetitive transcranial magnetic stimulation (rTMS). Methods: We studied short-lasting after-effects induced in the human primary motor cortex of 8 healthy subjects, using 5 Hz rTMS applied in six blocks of 200 pulses each, at 90% active motor threshold. We controlled for intensity, frequency, waveform and spinal effects. Results: Only biphasic pulses with the effective component delivered in an anterioposterior direction (henceforth posteriorly directed) in the brain yielded an increase of motor-evoked potential (MEP) amplitudes outlasting rTMS. MEP latencies and F-wave amplitudes remained unchanged. Biphasic pulses directed posteroanterior (i.e. anteriorly) were ineffective, as were monophasic pulses from either direction. A 1 Hz study in a group of 12 healthy subjects confirmed facilitation after posteriorly directed biphasic pulses only. Conclusions: The anisotropy of the human primary motor cortex is relevant for induction of plasticity by subtreshold rTMS, with a current flow opposite to that providing lowest excitability thresholds. This is consistent with the idea of TMS primarily targeting cortical columns of the phylogenetically new M1 in the anterior bank of the central sulcus. For these, anteriorly directed currents are soma-depolarizing, therefore optimal for low thresholds, whereas posteriorly directed currents are soma-hyperpolarizing, likely dendrite-depolarizing and bested suited for induction of plasticity. Our findings should help focus and enhance rTMS effects in experimental and clinical settings.
Article
The major repetitive transcranial magnetic stimulation (rTMS) paradigm applied to the treatment of tinnitus has been the 1-Hz variant due to its alleged inhibitory effects. Clinical effects have, however, been hampered by great interindividual variability as well as the fact that TMS includes no explicit mechanism to modulate excitability in circumscribed regions of tonotopically organised auditory fields. Following studies showing that the effect of TMS depends on the activational state preceding the stimulation, participants were exposed to 10 min of either notch- or bandpass-filtered noise prior to 1-Hz rTMS applied to the left auditory cortex. A control group was additionally assessed using bandpass noise - albeit with subsequent sham stimulation - to assess whether effects were due to the differential sounds alone or to a genuine interaction between sound and rTMS. Electroencephalogram was recorded from 128 electrodes before and after the experimental treatment while participants performed an auditory intensity discrimination task. While state-dependency effects from the behavioural data are not conclusive, several condition × (sound) frequency effects (some specific to the stimulated side) could be observed. Importantly, many of these could not be explained by the use of rTMS or the filtered noise alone. The resulting patterns are, however, complex and temporally variable, which currently prohibits recommendations on how to design a clinically effective approach to treat tinnitus. Nevertheless, our study gives the first evidence that state-dependency principles can induce sound frequency-specific effects in the auditory cortex, providing a crucial proof-of-principle upon which future studies can build.
Article
Background: Motor cortex localization and motor threshold determination often guide Transcranial Magnetic Stimulation (TMS) placement and intensity settings for non-motor brain stimulation. However, anatomic variability results in variability of placement and effective intensity. Objective: Post-study analysis of the OPT-TMS Study reviewed both the final positioning and the effective intensity of stimulation (accounting for relative prefrontal scalp-cortex distances). Methods: We acquired MRI scans of 185 patients in a multi-site trial of left prefrontal TMS for depression. Scans had marked motor sites (localized with TMS) and marked prefrontal sites (5 cm anterior of motor cortex by the "5 cm rule"). Based on a visual determination made before the first treatment, TMS therapy occurred either at the 5 cm location or was adjusted 1 cm forward. Stimulation intensity was 120% of resting motor threshold. Results: The "5 cm rule" would have placed stimulation in premotor cortex for 9% of patients, which was reduced to 4% with adjustments. We did not find a statistically significant effect of positioning on remission, but no patients with premotor stimulation achieved remission (0/7). Effective stimulation ranged from 93 to 156% of motor threshold, and no seizures were induced across this range. Patients experienced remission with effective stimulation intensity ranging from 93 to 146% of motor threshold, and we did not find a significant effect of effective intensity on remission. Conclusions: Our data indicates that individualized positioning methods are useful to reduce variability in placement. Stimulation at 120% of motor threshold, unadjusted for scalp-cortex distances, appears safe for a broad range of patients.