Article

# Repetitive Transcranial Magnetic Stimulator with Controllable Pulse Parameters (cTMS)

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## Abstract

We describe a novel transcranial magnetic stimulation (TMS) device that uses a circuit topology incorporating two energy-storage capacitors and two insulated-gate bipolar transistors (IGBTs) to generate near-rectangular electric field E-field) pulses with adjustable number, polarity, duration, and amplitude of the pulse phases. This controllable-pulse-parameter TMS (cTMS) device can induce E-field pulses with phase widths of 5-200 µs and positive/negative phase amplitude ratio of 1-10. Compared to conventional monophasic and biphasic TMS, cTMS reduces energy dissipation by 78-82% and 55-57% and decreases coil heating by 15-33% and 31-41%, respectively. We demonstrate repetitive TMS (rTMS) trains of 3,000 pulses at frequencies up to 50 Hz with E-field pulse amplitude and width variability of less than 1.7% and 1%, respectively. The reduced power consumption and coil heating, and the flexible pulse parameter adjustment offered by cTMS could enhance existing TMS paradigms and could enable novel research and clinical applications with potentially enhanced potency.

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... The significant difference between CCPS and traditional power supply is that it requires operation under a wide range of load conditions. Typically, the combination of low-frequency (50 Hz) ac power and high power, large size transformer is used as the CCPS for TMS [5][6][7]. Low-frequency systems typically result in low power conversion efficiency, converters with significant heat generation, and large power converter sizes [8]. Inefficient charging topology in TMS devices limits high-frequency, high-power TMS applications. ...
... The design conditions of the converter are as follows: input dc supply voltage = 30 V, I O = 1.05 A, load capacitances = 3300 μF and switching frequency = 16 kHz. According to the set output current value, input dc voltage, (5) and (12), Z n can be determined as 23.12 Ω. The converter is first configured as LCL-T RC to reflect the effect of parasitic parameters. ...
Article
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To improve the stimulation efficiency of transcranial magnetic stimulation (TMS) and reduce the size and power consumption of the overall circuit, a compact and efficient capacitor charging power supply using an inductor–capacitor–inductor–capacitor resonant converter (LC–LC RC) is designed in this study. The LC–LC RC has the characteristics of low power consumption, high efficiency and uses the voltage gain of the resonant circuit itself and a voltage doubler rectifier circuit instead of the transformer to reduce the size and weight of the overall circuit. A detailed ac analysis with fundamental frequency approximation of the LC–LC RC is presented. Expressions for converter gain, operating condition of the converter as a constant‐current power supply, and condition of the converter voltage and current zero‐phase difference are derived. In addition, RC design value conditions for the minimum resonant network size are derived. An experimental 1.05 A 120 V prototype converter is designed, developed, and tested to verify the theoretical analysis. Experimental results indicate that this circuit is suitable for use in capacitor charging to increase the stimulation performance of TMS.
... As opposed to fully discharging the energy storage capacitor, stimulation circuit architectures that truncate the flow of current in the coil have been developed for use in controllable pulse width transcranial magnetic stimulation (cTMS). This current truncation is achieved using an insulated gate bipolar transistor (IGBT) to enable pulse width control [20,21,22,23]. Modeling suggests continuing the flow of current after it has reached a maximum only results in resistive losses in the coil and coil heating, without a substantive increase in the neural response [20]. ...
... The results described herein support the hypothesis that truncating the current flowing through a magnetic stimulating coil can effectively evoke neuromuscular responses via the PNS with reduced energy consumption compared with nontruncated stimuli. In adapting this cTMS approach towards use in a smaller implantable PNS application, we also generate a current waveform that truncates more quickly than in many cTMS systems [20,21,22,23]. Moreover, the heat developed in the coils is also reduced with stimulus truncation. ...
Article
Current truncating circuit designs used in some controllable pulse width transcranial magnetic stimulation systems can be adapted for use with the peripheral nervous system. Such a scaled-down stimulator produces neuromuscular activation using less stimulus energy than described in previous reports of sciatic nerve stimulation. To evaluate the energy reductions possible with current truncation, we performed six in vivo experiments in rats where the magnetic stimulating coil abutted the sciatic nerve. We used electromyographic data to quantify neuromuscular response, with a criterion level of 20%-of-maximum to indicate a useful level of neuromuscular activation. The energy required to evoke this criterion response from muscles innervated by the sciatic nerve was reduced by approximately 34% from 10.7J with a stimulus waveform lasting 300 ${\mu }\text{s}$ to 7.1J with a waveform lasting 50 ${\mu }\text{s}$ . In water, the 300 ${\mu }\text{s}$ pulse heated the coil by 0.30°C whereas the 50 ${\mu }\text{s}$ pulse heated the coil by 0.15°C. Truncated-waveform magnetic stimulation systems can be used in basic research and clinical applications not requiring rapidly pulsed stimuli. An example of such a clinical application is left vagus nerve stimulation, a treatment that is reported to reduce epileptic partial-onset seizures.
... Recent advances in high voltage DC-DC convertor, IGBT, and capacitor technology [12] [13] [14] [15] has improved TMS instrumentation by allowing adjustable amplitude, duration, number and polarity of the pulsed current [12] [13] [14] [15]. However, the stimulated area is primarily dictated by the coil's geometry. ...
... Recent advances in high voltage DC-DC convertor, IGBT, and capacitor technology [12] [13] [14] [15] has improved TMS instrumentation by allowing adjustable amplitude, duration, number and polarity of the pulsed current [12] [13] [14] [15]. However, the stimulated area is primarily dictated by the coil's geometry. ...
Conference Paper
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A transcranial magnetic stimulation coil built by rectangular braided Litz wire is presented. The rectangular braided Litz wire used in this work is comprised of 2500 ultrafine wires, rated for high currents and voltages necessary for magnetic stimulation (10 kA, and 3 kV). The wire is only 7.3 mm wide and 0.9 mm thick making it amenable to tighter windings yielding high magnetic fields with a small coil diameter, and reduces coil heating issues. The coil is 3.1 cm in diameter and provides a magnetic field higher than the smallest available commercial coil despite being 40% smaller. This potentially expands research and therapeutic functionalities of transcranial magnetic stimulation, especially increases the stimulation specificity for use in neural prosthetic systems and bidirectional brain machine interfaces.
... Note that advanced users can create custom-waveforms e.g. TBS and cTMS 493 (Peterchev et al., 2010) as long as they follow the same format for existing waveforms. 494 . ...
Preprint
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Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique widely used in research and clinical applications. However, its mechanism of action and the neural response to TMS are still poorly understood. Multi-scale modeling can complement experimental research and provide a framework between the physical input parameters and the subcellular neural effects of TMS. At the macroscopic level, sophisticated numerical models exist to estimate the induced electric fields in whole-brain volume conductor models. However, multi-scale computational modeling approaches to predict TMS cellular and subcellular responses, crucial to understanding TMS plasticity inducing protocols, are not available so far. Here, we develop a multi-scale Neuron Modeling for TMS toolbox ( NeMo-TMS ) that enables researchers to easily generate accurate neuron models from morphological reconstructions, couple them to the external electric fields induced by TMS, and to simulate the cellular and subcellular responses of the neurons. Both single-pulse and rTMS protocols can be simulated and results visualized in 3D. We openly share our toolbox and provide example scripts and datasets for the user to explore. NeMo-TMS toolbox ( https://github.com/OpitzLab/NeMo-TMS ) allows researchers a previously not available level of detail and precision in realistically modeling the physical and physiological effects of TMS.
... (1) Optimising parameters such as the pulse number in a burst, the frequency within and between bursts, stimulus intensity, and even TMS waveforms that have now become possible in newer rTMS equipment (Peterchev et al. 2010). Although TBS has shown its effects in the current patterns, there is still a large space for parameter adjustment that would involve the use of systematic dose-response paradigms for a personalised and safe titration of stimulation pulses that would be optimal for use in specific behavioural conditions, and clinical settings. ...
Article
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Repetitive transcranial stimulation (rTMS) paradigms have been used to induce lasting changes in brain activity and excitability. Previous methods of stimulation were long, often ineffective and produced short-lived and variable results. A new non-invasive brain stimulation technique was developed in John Rothwell’s laboratory in the early 2000s, which was named ‘theta burst stimulation’ (TBS). This used rTMS applied in burst patterns of newly acquired 50 Hz rTMS machines, which emulated long-term potentiation/depression-like effects in brain slices. This stimulation paradigm created long-lasting changes in brain excitability, using efficient, very rapid stimulation, which would affect behaviour, with the aim to influence neurological diseases in humans. We describe the development of this technique, including findings and limitations identified since then. We discuss how pitfalls facing TBS reflect those involving both older and newer, non-invasive stimulation techniques, with suggestions of how to overcome these, using personalised, ‘closed loop’ stimulation methods. The challenge in most non-invasive stimulation techniques remains in identifying their exact mechanisms of action in the context of neurological disease models. The development of TBS provides the backdrop for describing John’s contribution to the field, inspiring our own scientific endeavour thanks to his unconditional support, and unfailing kindness.
... Peterchev and colleagues have recently developed a new TMS device, the controllable TMS (cTMS) device, which allows the duration of the TMS output to be altered (92). ...
Conference Paper
Motor response inhibition pertains to the ability to inhibit motor actions. It is hypothesised that a breakdown in motor response inhibition might underlie impulsivity in Parkinson’s disease and tics in Tourette syndrome. This thesis outlines how motor response inhibition is modulated in these clinical disorders by first characterising them in healthy subjects. We use TMS to show that one set of inputs to the motor cortex are inhibited during motor preparation whilst the other inputs reflect uncertainty about potential stopping. In the next chapter, we challenged an assumption that movement preparation during proactive inhibition always preceded movement execution and found that movement preparation and execution are two independent processes. With this in mind, we investigated features of motor response inhibition and movement preparation and execution in patients with Tourette syndrome, finding that these were remarkably similar to healthy controls, suggesting that volitional features of movement and inhibition are normal in Tourette syndrome. However, we did find a specific impairment of automatic inhibition in Tourette syndrome, which correlated with motor tic severity. As dopamine agonists are implicated as triggers for impulsivity in Parkinson’s disease, we first investigated the influence of ropinirole on motor response inhibition in healthy control subjects, finding that motor response inhibition was globally impaired. This was accompanied by analyses suggesting that ropinirole impaired the ability to adjust the decision threshold when stopping might be required. However, investigation of motor inhibition in Parkinson’s disease patients on dopamine agonists showed unremarkable effects compared to patients without dopamine agonist use. Our data provide a novel insight into the basic mechanisms of voluntary movement and propose a new theory for tic generation in Tourette syndrome.
... The selective activation could reduce contamination from different circuits and make monophasic TMS pulses superior to biphasic pulses for plasticity induction. This concept of the superiority of monophasic stimulation was recently used to introduce the new QPS protocol (Hamada et al., 2008) and recently developed cTMS (controllable TMS) has made monophasic rTMS possible at higher frequencies (Peterchev et al., 2010). ...
Article
Full-text available
Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.
... Intervention pulse parameters such as the amplitude, frequency, and duration have not been fully accessed in the conventional TMS devices [25]. These parameters change the induced electric field and the characteristics of the neural response and behavior [26]. In this research, a novel structure is introduced which can adjust pulse parameters over a wide range. ...
Article
Full-text available
This research was performed to investigate the ability of transcranial magnetic stimulation (TMS) to evoke the deeper areas of the brain with a minimal impact on non-target areas. To reach this goal, a novel core design in a semi-hexagonal shape with the arrow tips was utilized to collect a magnetic field in the selected target region. In addition, a new circuit topology was presented to generate stimulative pulses with optimal amplitude, frequency, and duration. For the first time in this research voxel resolution was proposed and exploited to evaluate the TMS system accuracy. To study the induced potential in different parts of the brain and its related resolution, a custom-made recording electrode and a micromanipulator were employed. They provided the linear movement in all Rostral/Caudal, Dorsal/Ventral, and Medial/Lateral orientations. The ARM cortex-M microcontroller managed the stimulation and recording sessions. After performing the finite element analysis, the researcher developed a prototype of the proposed system and tested it in vivo on the intact WAG/Raj rat. The results showed that spatial resolution could be significantly enhanced by employing the proposed TMS concept. The outcomes of animal trials have raised some hopes to apply the knowledge of this article in the clinical contexts.
... The temporal aspects of TMS dosing can be divided into the temporal aspects of each individual pulse (including its shape, width, and directionality), and the train of repeated pulses (including frequency, duration, and number of pulses per train). Two novel developments in the temporal aspects of individual pulses include controllable pulse shape TMS (cTMS) (94)(95)(96) and rotating field TMS (rfTMS) (97). Cortical response to TMS depends on the width of the pulse, and sTMS synchronized transcranial magnetic stimulation, dTMS deep transcranial magnetic stimulation, HF-TMS high-frequency transcranial magnetic stimulation, LF-TMS low-frequency transcranial magnetic stimulation, TBS theta-burst stimulation, iTBS intermittent theta-burst stimulation, cTBS continuous theta-burst stimulation, LFMS low field magnetic stimulation, IAF individual alpha frequency (average 9 Hz), DLPFC dorsolateral prefrontal cortex only recently have we had access to devices that allow independent user control of this aspect of temporal dosing (98). ...
Article
Full-text available
Noninvasive neuromodulation refers to a family of device-based interventions that apply electrical or magnetic fields, either at convulsive or subconvulsive levels, to the brain through the intact skull to modulate neural function. This is a rapidly evolving field, with new research emerging regarding the various roles that these devices can play both in studying the neural mechanisms underlying mood and anxiety disorders, and in treating pharmacoresistant conditions either on their own or in combination with other therapies. Each neuromodulation modality has its pros and cons and should be carefully chosen after weighing the risks and benefits. This manuscript reviews some of the most exciting developments in this field over the past year and emphasizes themes that are emerging as being important for these tools to fulfill their potential to transform how we study and treat mood and anxiety disorders. Key among these themes is the concept of how we understand the “dose” of the stimulation, and how exogenously applied fields interact with endogenous brain activity. Refining the concept of dose will ultimately be important in allowing clinicians and researchers to apply the procedure with precision to engage the targeted network to achieve the desired effects in each individual. The large parameter space defining dose of neuromodulation makes interpreting the literature on safety and efficacy challenging and highlights the need for clear and accurate reporting of the spatial, temporal, and contextual features of dosage to make the emerging literature base as informative as possible. Ultimately, the impact of noninvasive neuromodulation devices is potentially transformational given their utility in providing mechanistic insight into the circuit-based and oscillatory origins of mood and anxiety disorders, as well as providing therapeutic interventions rationally designed to target disease-related processes.
... Conventional TMS devices, however, only allow very limited control over pulse shape. Recent engineering advances in controllable pulse TMS devices (cTMS), however, have now enabled the production of TMS pulses with user controlled characteristics such as pulse width, pulse shape, and directionality (Peterchev et al, 2010a). This device also offers the possibility of possibility of repetitive high-frequency unidirectional stimuli, which studies suggest may be more efficient in inducing plasticity (Sommer et al, 2006). ...
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.
... We also present data on the induced electric field pulse shape and parameter adjustablility, energy use and coil heating, and reliability of the device operation at high frequencies. This work was previously presented in part in conference proceedings [18]. ...
Article
The characteristics of transcranial magnetic stimulation (TMS) pulses influence the physiological effect of TMS. However, available TMS devices allow very limited adjustment of the pulse parameters. We describe a novel TMS device that uses a circuit topology incorporating two energy storage capacitors and two insulated-gate bipolar transistor (IGBT) modules to generate near-rectangular electric field pulses with adjustable number, polarity, duration, and amplitude of the pulse phases. This controllable pulse parameter TMS (cTMS) device can induce electric field pulses with phase widths of 10-310 µs and positive/negative phase amplitude ratio of 1-56. Compared to conventional monophasic and biphasic TMS, cTMS reduces energy dissipation up to 82% and 57% and decreases coil heating up to 33% and 41%, respectively. We demonstrate repetitive TMS trains of 3000 pulses at frequencies up to 50 Hz with electric field pulse amplitude and width variability less than the measurement resolution (1.7% and 1%, respectively). Offering flexible pulse parameter adjustment and reduced power consumption and coil heating, cTMS enhances existing TMS paradigms, enables novel research applications and could lead to clinical applications with potentially enhanced potency.
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d Variability in the response of individuals to various non-invasive brain stimulation protocols is a major problem that limits their potential for clinical applications. Baseline motor-evoked potential (MEP) amplitude is the key predictor of an individual’s response to transcranial magnetic stimulation protocols. However, the factors that predict MEP amplitude and its variability remain unclear. In this study, we aimed to identify the input–output curve (IOC) parameters that best predict MEP amplitude and its variability. We analysed IOC data from 75 subjects and built a general linear model (GLM) using the IOC parameters as regressors and MEP amplitude at 120% resting motor threshold (RMT) as the response variable. We bootstrapped the data to estimate variability of IOC parameters and included them in a GLM to identify the significant predictors of MEP amplitude variability. Peak slope, motor threshold, and maximum MEP amplitude of the IOC were significant predictors of MEP amplitude at 120% RMT and its variability was primarily driven by the variability of peak slope and maximum MEP amplitude. Recruitment gain and maximum corticospinal excitability are the key predictors of MEP amplitude and its variability. Inter-individual variability in motor output may be reduced by achieving a uniform IOC slope.
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Chapter
Brain stimulation in psychiatry encompasses a growing list of tools for therapeutic neuromodulation, transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current polarization (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). This chapter reviews the current state of the evidence for each of the brain stimulation modalities. The various brain stimulation modalities share the common characteristic that they stimulate the brain electrically. Brain stimulation has no metabolites, does not undergo clearance, is not protein bound, and has no known interactions with the metabolism or clearance of psychopharmacological agents. The advances in brain stimulation have prompted a very recent call for consideration of a new subspeciality called interventional psychiatry. The broader goals of this new area of subspecialization include the establishment and provision of evidence-based safe practices and implementation of a nationally recognized credentialing policy for those clinicians providing brain stimulation.
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Transcranial electrical and magnetic stimulation techniques encompass a broad physical variety of stimuli, ranging from static magnetic fields or direct current stimulation to pulsed magnetic or alternating current stimulation with an almost infinite number of possible stimulus parameters. These techniques are continuously refined by new device developments, including coil or electrode design and flexible control of the stimulus waveforms. They allow us to influence brain function acutely and/or by inducing transient plastic after-effects in a range from minutes to days. Manipulation of stimulus parameters such as pulse shape, intensity, duration, and frequency, and location, size, and orientation of the electrodes or coils enables control of the immediate effects and after-effects. Physiological aspects such as stimulation at rest or during attention or activation may alter effects dramatically, as does neuropharmacological drug co-application. Non-linear relationships between stimulus parameters and physiological effects have to be taken into account.
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Although implantable cardioverter-defibrillators have improved significantly in the past decades, the algorithms used in the identification of life-threatening arrhythmias are still not accurate enough. Conventional methods commonly misclassify tachycardias, sometimes initiating an unnecessary and uncomfortable treatment. In this paper, we proposed a new method for the identification of ventricular tachycardias and fibrillations based on the comparison of simultaneous electro-grams. Our method could successfully separate supraventricular tachycardias and normal sinus rhythm, which do not require any treatment, from ventricular tachycardias and fibrillation, which are life-threatening arrhythmias and must be terminated, with a sensitivity of 93.0% and a specificity of 92.7% from the comparison of ventricular electrograms. In future studies, the classification using electrograms from the right heart must be improved.
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Magnetic seizure therapy (MST) is a novel means of performing convulsive therapy using rapidly alternating strong magnetic fields. MST offers greater control of intracerebral current intensity than is possible with electroconvulsive therapy (ECT). These features may result in a superior cognitive side effect profile for MST, while possibly retaining the efficacy of ECT. The objective of this study was to determine whether MST and ECT differ in seizure characteristics, and acute objective and subjective cognitive side effects. A total of 10 inpatients in a major depressive episode referred for ECT were enrolled in this randomized, within-subject, double-masked trial. Seizure threshold was determined with MST and ECT in the first two sessions of a course of convulsive therapy, with order randomized. The remaining two sessions consisted of suprathreshold stimulation with MST and ECT. A neuropsychological battery and side effect rating scale were administered by a masked rater before and after each session. Tonic-clonic seizures were elicited with MST in all patients. Compared to ECT, MST seizures had shorter duration, lower ictal EEG amplitude, and less postictal suppression. Patients had fewer subjective side effects and recovered orientation more quickly with MST than ECT. MST was also superior to ECT on measures of attention, retrograde amnesia, and category fluency. Magnetic seizure induction in patients with depression is feasible, and appears to have a superior acute side effect profile than ECT. Future research will be needed to establish whether MST has antidepressant efficacy.
Article
Electroconvulsive therapy (ECT) is the most effective and most rapidly acting treatment for severe treatment resistant major depression, but its use is limited by its cognitive side effects. Magnetic seizure therapy (MST) is a new form of convulsive therapy using high-dosage repetitive transcranial magnetic stimulation (rTMS) to induce focal cortical seizures under anesthesia. MST is under study as a means of reducing the side effects of ECT through the enhanced control over the sites of seizure initiation and topography of seizure propagation afforded by the relative focality of rTMS. This review traces the stages in the development of MST, from device development, to preclinical testing, to clinical trials. The results of a study on the comparative safety of chronic MST and electroconvulsive shock in non-human primates support the safety of both interventions, and indicate that the seizures induced by MST are more focal and have less impact on deeper brain structures. This non-human primate model and a controlled clinical trial in patients with major depression, suggest that MST may induce fewer side effects and less amnesia than ECT. Ongoing work will yield the first data on the antidepressant efficacy of MST. If ultimately shown to be effective, MST could represent a new, less invasive option for patients with severe treatment resistant depression or other disorders who would otherwise require ECT.
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The energy efficiency of stimulation is an important consideration for battery-powered implantable stimulators. We used a genetic algorithm (GA) to determine the energy-optimal waveform shape for neural stimulation. The GA was coupled to a computational model of extracellular stimulation of a mammalian myelinated axon. As the GA progressed, waveforms became increasingly energy efficient and converged upon an energy-optimal shape. The results of the GA were consistent across several trials, and resulting waveforms resembled truncated Gaussian curves. When constrained to monophasic cathodic waveforms, the GA produced waveforms that were symmetric about the peak, which occurred approximately during the middle of the pulse. However, when the cathodic waveforms were coupled to rectangular charge-balancing anodic pulses, the location and sharpness of the peak varied with the duration and timing (i.e., before or after the cathodic phase) of the anodic phase. In a model of a population of mammalian axons and in vivo experiments on a cat sciatic nerve, the GA-optimized waveforms were more energy efficient and charge efficient than several conventional waveform shapes used in neural stimulation. If used in implantable neural stimulators, GA-optimized waveforms could prolong battery life, thereby reducing the frequency of recharge intervals, the volume of implanted pulse generators, and the costs and risks of battery-replacement surgeries.
Article
In this work we address the problem of stimulating nervous tissue with the minimal necessary energy at reduced/minimal charge. Charge minimization is related to a valid safety concern (avoidance and reduction of stimulation-induced tissue and electrode damage). Energy minimization plays a role in battery-driven electrical or magnetic stimulation systems (increased lifetime, repetition rates, reduction of power requirements, thermal management). Extensive new theoretical results are derived by employing an optimal control theory framework. These results include derivation of the optimal electrical stimulation waveform for a mixed energy/charge minimization problem, derivation of the charge-balanced energy-minimal electrical stimulation waveform, solutions of a pure charge minimization problem with and without a constraint on the stimulation amplitude, and derivation of the energy-minimal magnetic stimulation waveform. Depending on the set stimulus pulse duration, energy and charge reductions of up to 80% are deemed possible. Results are verified in simulations with an active, mammalian-like nerve fiber model.
Article
The intensity of transcranial magnetic stimulation (TMS) is typically adjusted by changing the amplitude of the induced electrical field, while its duration is fixed. Here we examined the influence of two different pulse durations on several physiological parameters of primary motor cortex excitability obtained using single pulse TMS. A Magstim Bistim(2) stimulator was used to produce TMS pulses of two distinct durations. For either pulse duration we measured, in healthy volunteers, resting and active motor thresholds, recruitment curves of motor evoked potentials in relaxed and contracting hand muscles as well as contralateral (cSP) and ipsilateral (iSP) cortical silent periods. Motor thresholds decreased by 20% using a 1.4 times longer TMS pulse compared to the standard pulse, while there was no significant effect on threshold adjusted measurements of cortical excitability. The longer pulse duration reduced pulse-to-pulse variability in cSP. The strength of a TMS pulse can be adjusted both by amplitude or pulse duration. TMS pulse duration does not affect threshold-adjusted single pulse measures of motor cortex excitability. Using longer TMS pulses might be an alternative in subjects with very high motor threshold. Pulse duration might not be relevant as long as TMS intensity is threshold-adapted. This is important when comparing studies performed with different stimulator types.
Article
Article
To optimize the clinical uses of repetitive transcranial magnetic stimulation (rTMS), we compared the effects of rTMS on somatosensory-evoked potentials (SEPs) and regional cerebral blood flow (rCBF) using different phases (monophasic vs. biphasic) or frequencies (0.2Hz vs. 0.8Hz) of stimulation. In the first experiment, different phases were compared (0.2Hz monophasic vs. 0.2Hz biphasic). Biphasic 1Hz or sham condition served as controls. The second experiment was to explore the effect of frequencies (0.2Hz vs. 0.8Hz) using the monophasic stimulation. Substhreshold TMS was applied 250 times over the left premotor cortex. Single photon emission computed tomography (SPECT) was performed before and after monophasic 0.2Hz or biphasic 1Hz rTMS. Monophasic rTMS of both 0.2 and 0.8Hz significantly increased the ratio of N30 amplitudes as compared with sham rTMS, whereas biphasic stimulation showed no significant effects. SPECT showed increased rCBF in motor cortices after monophasic 0.2Hz rTMS, but not after biphasic 1Hz stimulation. Monophasic rTMS exerted more profound effects on SEPs and rCBF than biphasic rTMS over the premotor cortex. Monophasic rTMS over the premotor cortex could be clinically more useful than biphasic rTMS.
Article
We describe the first investigation into the effect on stimulation efficiency of varying the output of a commercial magnetic stimulator based on our original clinical design. Over the range of magnetic field waveforms considered, it is shown that the stored energy required to achieve stimulation, both cortically and in the periphery, varies by approximately 2:1. Greater efficiency is obtained by using shorter risetime magnetic fields. This results in more effective stimuli for the same stored energy, or, for the same stimulus, a decrease in energy storage, power dissipation and peak currents, thus simplifying hardware design. A novel method of processing the data obtained from different waveforms is presented which enables neural membrane time constant to be calculated. Data from normal subjects is presented showing both peripheral and neural time constants to be of order 150 microseconds. The cortical measurements represent the first non-invasive determination of cortical membrane time constant in man. Time constant measurements using magnetic stimulation may be clinically useful because they give information concerning the electrical properties of the nervous system not available from present techniques. Finally a method of quantifying the output of magnetic stimulators and coils is described which enables laboratory comparisons to be made, and takes into account magnetic field waveforms and coil geometry. The proposed symbol for this new measurement is Et150 with units volt seconds/meter.
Article
The use of a time-varying magnetic field to induce a sufficiently strong current to stimulate living tissue was first reported by d'Arsonval in 1896. Since then, there have been many studies in what is now called magnetic stimulation. This paper traces the history of this field from d'Arsonval to its present use in neurophysiology.
Article
Magnetic stimulation of the human brain is performed in clinical and research settings, but the site of activation has not been clearly localized in humans or other species. We used a set of magnetic stimulus coils with different field profiles to isolate movement of single digits at motor threshold and to calculate corresponding electric field strengths at various distances beneath the scalp. Two coils could produce the same electric field intensity at only 1 point. Thus, we could estimate the depth of stimulation by finding the intersection of the electric field plots, which were then superimposed on MRIs of the underlying brain. In each of 3 subjects the field plots intersected at the crown of a gyrus, in the region of the central sulcus, an near the level of the gray-white junction. This position and the electric field orientation support localization to layer VI of cerebral cortex.
Article
The possibility of neural damage during extracranial brain stimulation for motor evoked potentials (MEPs) is discussed from the perspective of animal studies in which the stimulating electrodes were in direct contact with the brain. These data indicate that the charge per phase used in most of the extracranial MEP protocols is sufficient to induce neural damage if the stimulation is applied continuously for several hours. However, in most cases dispersion of the stimulus current in the extracranial tissue and skull is probably adequate to attenuate the stimulus charge density at the brain surface to a safe level (less than approximately 40 microC/cm2 X ph). However, the possibility exists that low resistance paths between the stimulating electrode and the brain may give rise to foci of high charge density. The possibility of such focusing may be less with magnetic field than with direct electrical field stimulation. We stress the need for additional animal studies designed to delineate a range of safe stimulus parameters for this particular technique.
Article
The safety of single and repetitive (paired and quadruple) focal transcranial magnetic stimuli as possible inducers of epileptic discharges or clinically manifest seizures was investigated in 21 patients with intractable epilepsy during invasive presurgical monitoring. Subdural and/or intracerebral depth electrodes had been implanted in close proximity to the suspected epileptogenic zone, and the anticonvulsant medication had been reduced. Focal transcranial magnetic stimuli were applied by a Magstim QuadroPulse magnetic stimulator over the hand area of the motor cortex ipsilateral to the epileptogenic focus at intensities of 120% and 150% of motor threshold and additionally as close as possible to the suspected epileptogenic zone at 40-100% of maximal stimulator output. Stimulation did not induce any complex partial or secondary generalized tonic-clonic seizures. One patient with hippocampal sclerosis experienced an aura associated with rhythmic electroencephalographic discharges restricted to the ipsilateral intrahippocampal depth electrode after stimulation over his left temporal lobe. This patient, however, also had frequent spontaneously occurring auras with focal ictal discharges originating from this hippocampus. Interictal discharges were not influenced significantly by single or repetitive magnetic stimuli. In conclusion, from this study there is no evidence that single or serial focal transcranial magnetic stimuli activate epileptogenic foci. At least four high-frequency repetitive stimuli of high intensity may thus be applied with a low risk of seizure induction even in patients with low seizure threshold.
Article
A detailed analysis of the membrane voltage rise commensurate with the electrical charging circuit of a typical magnetic stimulator is presented. The analysis shows how the membrane voltage is linked to the energy, reluctance, and resonant frequency of the electrical charging circuit. There is an optimum resonant frequency for any nerve membrane depending on its capacitive time constant. The analysis also shows why a larger membrane voltage will be registered on the second phase of a biphasic pulse excitation [1]. Typical constraints on three key quantities voltage, current, and silicone controlled rectifier (SCR) switching time dictate key components such as capacitance, inductance, and choice of turns.
Article
In a blinded cross-over design, 10 healthy controls received 900 monophasic and biphasic repetitive transcranial magnetic stimuli over the primary motor cortex. Stimulation frequency was 1 Hz, and stimulation intensity 90% of the individual resting motor threshold. Suprathreshold stimuli applied at 0.1 Hz before and after repetitive stimulation controlled for changes in corticospinal excitability. We found a lasting corticospinal inhibition that was significantly more pronounced after monophasic than after biphasic repetitive transcranial magnetic stimulation (motor evoked potential amplitude reduced by 35 +/- 20% vs 12 +/- 37%, mean+/- s.d.). We propose that the current flow in the coil plays a significant role in optimising after effects, and asymmetric current flow may be particularly efficient in building up tissue polarization.
Article
Transcranial magnetic stimulation requires a great deal of power, which mandates bulky power supplies and produces rapid coil heating. The authors describe the construction, modeling, and testing of an iron-core TMS coil that reduces power requirements and heat generation substantially, while improving the penetration of the magnetic field. Experimental measurements and numeric boundary element analysis show that the iron-core stimulation coil induces much stronger electrical fields, allows greater charge recovery, and generates less heat than air-core counterparts when excited on a constant-energy basis. These advantages are magnified in constant-effect comparisons. Examples are given in which the iron-core coil allows more effective operation in research and clinical applications.
Article
Transcranial magnetic stimulation (TMS) is a noninvasive technique for direct stimulation of the neocortex. In the last two decades it is successfully applied in the study of motor and sensory physiology. TMS uses the indirect induction of electrical fields in the brain generated by intense changes of magnetic fields applied to the scalp. It encompasses two widely used waveform configurations: mono-phasic magnetic pulses induce a single current in the brain while biphasic pulses induce at least two currents of inverse direction. As has been shown for the motor cortex, efficacy of repetitive transcranial magnetic stimulation (rTMS) may depend on pulse configuration. In order to clarify this question with regard to visual perception, static contrast sensitivities (sCS) were evaluated before, during, immediately after and 10 minutes after monophasic and biphasic low frequency (1 Hz) rTMS applied to the occipital cortex of 15 healthy subjects. The intensity of stimulation was the phosphene threshold of each individual subject. Using 4 c/d spatial frequency, significant sCS loss was found during and immediately after 10 min of monophasic stimulation, while biphasic stimulation resulted in no significant effect. Ten minutes after the end of stimulation, the sCS values were at baseline level again. However, reversed current flow direction resulted in an increased efficacy of biphasic and decreased efficacy of monophasic stimulation. Our results are in agreement with previous findings showing that primary visual functions, such as contrast detection, can be transiently altered by low frequency transcranial magnetic stimulation. However the effect of modulation significantly depends on the current waveform and direction.
Article
Stimulus-response curves for motor evoked potentials (MEPs) induced in a hand muscle by transcranial magnetic stimulation (TMS) were constructed for 42 subjects with the aim of identifying differences related to age and sex. There was no effect of age on the resting threshold to TMS, the maximal amplitude of the MEP that could be evoked (MEP(max)) or the maximal slope of the stimulus-response curve. However, higher stimulus intensities were required to achieve both MEP(max) and the maximal slope in the older subjects. The trial-to-trial variability of MEPs was greater in the older subjects, particularly at intensities near threshold. There was a significant interaction between age, threshold and trial-to-trial variability of MEP amplitude. Overall, MEP variability fell markedly as stimulus intensity increased above threshold but less rapidly in older than in younger subjects. Females tended to have larger MEP variability than males, but age and threshold were much stronger modulators than sex. These differences in input-output characteristics are likely to be due either to a decreased number of spinal motoneurones being activated synchronously in older subjects, or to the activation of the same number of motoneurones in a less synchronous manner, leading to phase cancellation in the surface electromyogram.
Article
To compare motor evoked potentials (MEPs) elicited by short train, monophasic, repetitive transcranial magnetic stimulations (rTMS) with those by short train, biphasic rTMS. Subjects were 13 healthy volunteers. Surface electromyographic (EMG) responses were recorded from the right first dorsal interosseous muscle (FDI) in several different stimulation conditions. We gave both monophasic and biphasic rTMS over the motor cortex at a frequency of 0.5, 1, 2 or 3Hz. To study excitability changes of the spinal cord, we also performed 3Hz rTMS at the foramen magnum level [Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation of corticospinal pathways at the foramen magnum level in humans. Ann Neurol 1994;36:618-24]. We measured the size and latency of each of 20 MEPs recorded in the different stimulation conditions. 2 or 3Hz stimulation with either monophasic or biphasic pulses evoked MEPs that gradually increased in amplitude with the later MEPs being significantly larger than the earlier ones. Monophasic rTMS showed much more facilitation than biphasic stimulation, particularly at 3Hz. Stimulation at the foramen magnum level at 3Hz elicited fairly constant MEPs. The enhancement of cortical MEPs with no changes of responses to foramen magnum level stimulation suggests that the facilitation occurred at the motor cortex. We hypothesize that monophasic TMS has a stronger short-term effect during repetitive stimulation than biphasic TMS because monophasic pulses preferentially activate one population of neurons oriented in the same direction so that their effects readily summate. Biphasic pulses in contrast may activate several different populations of neurons (both facilitatory and inhibitory) so that summation of the effects is not so clear as with monophasic pulses. When single stimuli are applied, however, biphasic TMS is thought to be more powerful than monophasic TMS because the peak-to-peak amplitude of stimulus pulse is higher and its duration is longer when the same intensity of stimulation (the same amount of current is stored by the stimulator) is used. This means that when using rTMS as a therapeutic tool or in research fields, the difference in waveforms of magnetic pulses (monophasic or biphasic) may affect the results.
Article
Specific stimulation of neuronal circuits may promote selective inhibition or facilitation of corticospinal tract excitability. Monophasic stimulation is more likely to achieve direction-specific neuronal excitation. In 10 healthy subjects, we compared four types of repetitive transcranial magnetic stimulation (rTMS), monophasic and biphasic stimuli with the initial current in the brain flowing antero-posteriorly ("posteriorly directed") or postero-anteriorly ("anteriorly directed"). We applied rTMS over the primary motor cortex contralateral to the dominant hand, using 80 stimuli at 5 Hz frequency at an intensity yielding baseline motor evoked potential (MEP) amplitudes of 1 mV. Monophasic stimulation was always more efficient than biphasic. Facilitation was induced by intracerebral anteriorly directed current flow and inhibition by posteriorly oriented current flow, although only initially for approximately 30 pulses. The early inhibition was absent when studied during a tonic muscle contraction. Several mechanisms could account for these findings. They include a more efficient excitation of inhibiting circuits by posteriorly oriented pulses, and a back-propagating D-wave inhibiting early I-waves and thus inducing early inhibition of MEP amplitude. In any case biphasic rTMS results can be explained by a mixture of monophasic opposite stimulations. We propose the use of monophasic pulses for maximizing effects during rTMS.
Article
To compare half sine transcranial magnetic stimuli (TMS) with conventional monophasic and biphasic stimuli, measuring resting and active motor threshold, motor evoked potential (MEP) input/output curve, MEP latency, and silent period duration. We stimulated the dominant hand representation of the motor cortex in 12 healthy subjects utilising two different MagPro stimulators to generate TMS pulses of distinct monophasic, half sine and biphasic shape with anteriorly or posteriorly directed current flow. The markedly asymmetric monophasic pulse with a posterior current flow in the brain yielded a higher motor threshold, a less steep MEP input/output curve and a longer latency than all other TMS types. Similar but less pronounced results were obtained with a less asymmetric half sine pulses. The biphasic stimuli yielded the lowest motor threshold and a short latency, particularly with the posterior current direction. The more asymmetric the monophasic pulse, the stronger the difference to biphasic pulses. The 3rd and 4th quarter cycle of the biphasic waveform make it longer than any other waveform studied here and likely contribute to lowering motor threshold, shortening MEP latency and reversing the influence of current direction. This systematic comparison of 3 waveforms and two current directions allows a better understanding of the mechanisms of TMS.
Article
Optimising stimulus parameters is important in maximising the efficacy of repetitive transcranial magnetic stimulation (rTMS) in treatment applications. RTMS over motor cortex has been reported as more effective in producing corticospinal inhibition when a monophasic rather than a biphasic stimulus waveform is used. However, non-optimal coil orientation and high intensities of monophasic rTMS may have influenced previous results. In eight healthy subjects, we measured motor evoked potentials (MEPs) in a hand muscle after monophasic and biphasic rTMS (1 Hz for 15 min) over the motor cortex with the coil always in the optimal orientation. MEPs were evoked by both monophasic and biphasic stimuli. MEPs were initially significantly reduced after monophasic but not biphasic rTMS. However, a late reduction was seen after biphasic rTMS. These motor cortical findings may not be directly applicable to prefrontal rTMS. This study confirms that low frequency rTMS with monophasic pulses produces more corticospinal inhibition than with biphasic pulses, even when the direction of current and intensity are as well-matched as possible.
Article
We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.
Article
To study differences in the long-term after-effect between high-frequency, monophasic and biphasic repetitive transcranial magnetic stimulation (rTMS). Ten hertz rTMS was delivered over the left primary motor cortex and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle. To probe motor cortex excitability we recorded MEPs at several timings before, during and after several types of conditioning rTMSs. We also recorded F-waves to probe spinal excitability changes. Thousand pulses were given in total, with a train of 10 Hz, 100 pulses delivered every minute (ten trains for 10min). The intensity was fixed at 90% active motor threshold (AMT) or 90% resting motor threshold (RMT) for both monophasic and biphasic rTMS. In addition, we performed a monophasic rTMS experiment using a fixed intensity of 90% RMT for biphasic pulses. At 90% AMT, MEPs were enhanced for a few minutes after both monophasic and biphasic rTMS. On the other hand, at 90% RMT, a larger and longer enhancement of MEPs was evoked after monophasic rTMS than after biphasic rTMS. Monophasic rTMS at an intensity adjusted to biphasic 90% RMT elicited a great enhancement similar to that after monophasic rTMS at monophasic 90% RMT. Neither F-wave amplitude nor its occurrence rate was significantly altered by 90% RMT monophasic rTMS. These results suggest that enhancement after rTMS occurs at the motor cortex. Monophasic rTMS has a stronger after-effect on motor cortical excitability than biphasic rTMS. This is probably because monophasic pulses preferentially activate a relatively uniform population of neurons oriented in the same direction and their effects summate more readily than biphasic rTMS activating differently oriented neurons at slight different timings altogether. The present results suggest that when using rTMS as a therapeutic tool or in research fields, the waveforms of magnetic pulses may affect the results profoundly.
Conference Paper
The authors present measured turn-off losses in IGBTs (insulated-gate bipolar transistors) from six different manufacturers. The rated breakdown-voltage and on-state current are 600 V and 75 A, respectively, for all transistors tested, except the IR-transistor which has 55 A as rate current. Hard switching and switching with a capacitive turn-off snubber are analyzed, both at 25 degrees C and 125 degrees C. The influence of variations in the gate resistance is covered. Conclusions from a similar set of measurements on 1000-1200 V IGBTs are also given. The loss reduction when using a turn-off snubber is larger than expected from experience with bipolar junction transistors. This is mainly due to the fact that the first part of the current fall time until the current tail is reached is shorter when a capacitive snubber is used than in hard switching. The turn-off losses increase strongly with temperature and also with the transistor current at turn-off. There is a significant increase in turn-off losses with increasing gate resistance.< >
Article
The turn-off of IGBTs in hard- and soft-switching converters is analyzed using nonquasi-static analysis. It is shown that while the turn-off current waveform for hard-switching is governed solely by the device for a particular value of on-state current and bus voltage, turn-off current waveform for soft-switching is strongly dependent on device-circuit interactions, so that a trade-off between turn-off loss and switching time can be made using external circuit elements. Models are developed to explain IGBT turn-off for both hard- and soft-switching conditions. Hard-switching considers both inductive and resistive loads. Calculated results are validated by comparison with results of measurements and two-dimensional (2-D) numerical simulations
Article
A novel transcranial magnetic stimulation (TMS) device with controllable pulse width (PW) and near-rectangular pulse shape (cTMS) is described. The cTMS device uses an insulated gate bipolar transistor (IGBT) with appropriate snubbers to switch coil currents up to 6 kA, enabling PW control from 5 mus to over 100 mus. The near-rectangular induced electric field pulses use 2%-34% less energy and generate 67%-72% less coil heating compared to matched conventional cosine pulses. CTMS is used to stimulate rhesus monkey motor cortex in vivo with PWs of 20 to 100 mus, demonstrating the expected decrease of threshold pulse amplitude with increasing PW. The technological solutions used in the cTMS prototype can expand functionality, and reduce power consumption and coil heating in TMS, enhancing its research and therapeutic applications.
Product Information Sheet: MagPro X100 With Option, Technical Data
• A Magventure
MagVenture A/S, Product Information Sheet: MagPro X100 With Option, Technical Data, 2007. [Online]. Available: http://www.magventure.com
Principles of magnetic stimulator design
• R Jalinous
R. Jalinous, "Principles of magnetic stimulator design," in Handbook of Transcranial Magnetic Stimulation, A. Pascual-Leone, N. J. Davey, J. Rothwell, E. M. Wassermann, and B. K. Puri, Eds. London: Arnold, 2002, pp. 30-38.
• K Davey
• C Epstein
Davey K and Epstein C M 2000 Magnetic stimulation coil and circuit design IEEE Trans. Biomed. Eng. 47 1493–9
Snubber Circuits for Power Electronics. SMPS Technology
• R Severns
Severns R 2008 Snubber Circuits for Power Electronics. SMPS Technology. [E-book] Available at www.snubberdesign.com/snubber-book.html
Principles of magnetic stimulator design Handbook of Transcranial Magnetic Stimulation ed A Pascual-Leone
• R J Jalinous
• Davey
• E Rothwell
• B Wassermann
• Puri
Jalinous R 2002 Principles of magnetic stimulator design Handbook of Transcranial Magnetic Stimulation ed A Pascual-Leone, N J Davey, J Rothwell, E M Wassermann and B K Puri (London: Arnold) pp 30–8