Article

# Controllable pulse parameter transcranial magnetic stimulator with enhanced circuit topology and pulse shaping

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## Abstract

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.

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... For example, controllable TMS (cTMS) devices were introduced in 2008, 2011 and 2014 with three different architectural variations. These designs generated a near-rectangular stimulus whose pulse width is adjustable [4] [5] [6]. Pulse amplitude (so-called TMS intensity) setup was performed separately using adjunctive equipment. ...
... The small side of the rectangular pick-up coil was located 1 mm away from the surface of the coil. The value of the induced electric field can be estimated by dividing the measured electromotive force (EMF) by the search coil width (w), as (6). ...
... The motor threshold value may also be changed by adjusting the stimulus frequency (or pulse width) [6] [31] [35]. In cases where the maximum output intensity at high frequencies does not reach the motor threshold, pulses with lower frequencies can be used. ...
Article
Full-text available
Objective: A transcranial magnetic stimulation system with programmable stimulus pulses and patterns is presented. The stimulus pulses of the implemented system expand beyond conventional damped cosine or near-rectangular pulses and approach an arbitrary waveform. Methods: The desired stimulus waveform shape is defined as a reference signal. This signal controls the semiconductor switches of an H-bridge inverter to generate a high-power imitation of the reference. The design uses a new paradigm for TMS, applying pulse-width modulation with a non-resonant, high-frequency switching architecture to synthesize waveforms that leverages the low-pass filtering properties of neuronal cells. The modulation technique enables control of the waveform, frequency, pattern, and intensity of the stimulus. Results: A system prototype was developed to demonstrate the technique. The experimental measurements demonstrate that the system is capable of generating stimuli up to 4 kHz with peak voltage and current values of ±1000 V and ±3600 A, respectively. The maximum transferred energy measured in the experimental validation was 100.4 Joules. To characterize repetitive TMS modalities, the efficiency of generating consecutive pulse triplets and quadruplets with interstimulus intervals of 1 ms was tested and verified. Conclusion: The implemented TMS device can generate consecutive rectangular pulses with a predetermined time interval, widths and polarities, enables the synthesis of a wide range of magnetic stimuli. Significance: New waveforms promise functional advantages over the waveforms generated by current-generation TMS systems for clinical neuroscience research.
... At interfaces or gradients between different electrical conductivities, the current transiently builds up charge accumulations, which in turn generate an additional, often called secondary electric field according to Gauss' law. This secondary electric field superimposes the induced electric field and strongly depends on the individual brain anatomy, as well as the position of the coil orientation (D'Ostilio et al., 2014;Kammer, Vorwerg, & Herrnberger, 2007;Laakso, Hirata, & Ugawa, 2014;Mills, Boniface, & Schubert, 1992; Figure 1. (a) Early repetitive stimulators such as the depicted monophasic stimulator with maximum repetition rates of more than 30 Hz, peak voltage of 5000 V, and variable rise-time provided by adjustable capacitance between 40-200 lF allowed neuromuscular magnetic stimulation in the periphery and neuromodulatory protocols in the brain for the first time (Schmid et al., 1993). ...
... The demonstrated cloverleaf coil design is composed of two perpendicular figure-of-eight coils, and requires two standard biphasic stimulators that are fired with a time delay that corresponds to a 90 phase shift of the underlying sinusoidal pulse. In experiments using conventional coils, neuronal activation is dependent on coil orientation; this directional sensitivity could be overcome with the rotating field coil design (D'Ostilio et al., 2014(D'Ostilio et al., , 2016Laakso et al., 2014;Mills et al., 1992;Rotem et al., 2014). ...
... Recent developments have achieved overcoming the pulse-shape limitation and allow for adjusting the shape during operation. Several refinements of a TMS technology that enables the configuration of pulse parameters (cTMS) have been demonstrated and are available commercially (Figure 6(c)) (Peterchev, D'Ostilio, Rothwell, & Murphy, 2014;Peterchev, Jalinous, & Lisanby, 2008;Peterchev et al., 2011). cTMS splits a pulse into few near-rectangular voltage segments, which can be adjusted in amplitude and duration. ...
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.
... Furthermore, differences have been shown in the response to rTMS protocols delivered with monophasic and asymmetric biphasic pulses [2,25]. We therefore used a novel controllable pulse parameter TMS (cTMS; [26]) device to modulate the relative amplitude of the first and second phases of a symmetrical pulse, exploring the effects on resting and active motor threshold, motor evoked potential (MEP) I/O curve, MEP latency, as well as contralateral silent period duration (cSP). We expected that activation of the lower threshold PA-sensitive elements with PA pulses would be less effective with symmetric biphasic compared with monophasic pulses. ...
... We used a prototype cTMS machine (Brainsight cTMS3; (manufactured by Rogue Research, Montreal, Quebec, Canada. Supplied by Rogue Resolutions Ltd, Cardiff, United Kingdom; see also [26] for details) connected to a standard figure-eight-coil with an outer diameter of each wing of 70 mm (The Magstim Co. Ltd., Whitland, United Kingdom). In a pilot study, we used a single-loop search coil placed underneath the TMS coil and connected to a digital storage oscilloscope (SmartDS, Owon Technology Ltd, Kingston upon Thames, United Kingdom) to record "positive monophasic" waveforms generated by the cTMS device at a range of different "Mratios". ...
... Motivated by the I/O curve recordings using different pulse widths by the Duke group who developed the cTMS [26], we recorded the MEP I/O curves applying intensities starting at 11% MSO (the lowest intensity technically achievable) and increasing to 48%MSO (the maximum intensity available for all types of stimuli), recording one MEP for each percent point of intensity increase. We refrained from randomizing the intensities, since this would have been difficult to implement using the manual intensity controls of the cTMS, and its putative advantage [29] has been questioned [30]. ...
Article
Full-text available
Background: Biphasic pulses produced by most commercially available TMS machines have a cosine waveform, which makes it difficult to study the interaction between the two phases of stimulation. Objective: We used a controllable pulse TMS (cTMS) device delivering quasi-rectangular pulse outputs to investigate whether monophasic are more effective than biphasic pulses. Methods: Temporally symmetric ("biphasic") or highly asymmetric ("monophasic") charge-balanced biphasic stimuli were used to target the hand area of motor cortex in the anterior-posterior (AP) or posterior-anterior (PA) initial current direction. Results: We observed the lowest motor thresholds and shortest motor evoked potential (MEP) latencies with initial PA pulses, and highest thresholds and longest latencies with AP pulses. Increasing pulse symmetry tended to increase threshold with a PA direction whereas it lowered thresholds and shortened latencies with an AP direction. Furthermore, it steepened the MEP input-output curve with both directions. Conclusions: "Biphasic" TMS pulses can be viewed as two monophasic pulses of opposite directions, each stimulating a different set of interneurons with different thresholds (PA < AP). At threshold, the reverse phase of an initially PA pulse increases threshold compared with "monophasic" stimulation. At higher intensities, the reverse phase begins to activate AP-sensitive neurones and increase the effectiveness of stimulation above that of a "monophasic" PA pulse. "Biphasic" stimulation with initially AP pulses is dominated at threshold by activation produced by the lower threshold reverse (PA) phase. Significance: The effects of biphasic stimulation are best understood as the summed output of two independent sets of directionally selective neural populations.
... Standard TMS devices generate sinusoidal pulses with a fixed shape and duration. More advanced devices allow some adjustment of the pulse duration and shape [8][9][10][11]. Such devices have enabled important findings regarding the effect of pulse shape and duration on neural activation thresholds [12], differential neural recruitment in the brain [13][14][15][16][17][18], lasting neuromodulatory effects [19,20], as well as the sensation of scalp stimulation [21]. However, these devices still have a restricted range of the shape (e.g., only sinusoidal or only rectangular), duration (e.g., lacking very brief and very long pulses), and amplitude (e.g., insufficient amplitude for suprathreshold brief or complex pulses) [5,7,22]. ...
... As shown in figure 1(b), each module employs an H-bridge circuit [36], implemented with high-voltage, high-current insulated-gate bipolar transistor (IGBT) switches and appropriate snubber and gate drive circuits, following our approach for prior, simpler TMS device designs [8][9][10]29]. The module's output voltage, Vi, depends on the switches' states and is equal to VCi, 0, or −VCi, where VCi denotes the energy storage capacitor of module i. ...
... States 1-4 actively define the output voltage, which is determined by the commanded transistor states, regardless of the load condition. These states are typically used during all pulse phases except for the last one, allowing the pulse waveform to be accurately controlled [9][10][11]. For states 0 and 5-8, the module output voltage depends on the diode states, which in turn depend on the circuit voltages and currents applied to the diodes. ...
Preprint
Objective: This article presents a novel transcranial magnetic stimulation (TMS) pulse generator with a wide range of pulse shape, amplitude, and width. Approach: Based on a modular multilevel TMS (MM-TMS) topology we had proposed previously, we realized the first such device operating 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 can output pulses including up to 21 voltage levels with a step size of up to 1100 V, allowing relatively flexible generation 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 suprathreshold ultrabrief 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 staircase-approximated 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 in discrete steps by adding or removing modules in series, which enables rapid pulse sequences and paired-pulse protocols with variable pulse shapes and amplitudes. Significance: The MM-TMS device allows unprecedented control of the pulse characteristics which could enable novel protocols and quieter pulses.
... In contrast to monophasic TMS, biphasic devices do not intentionally use any damping resistor to shape the pulse and can recycle a large share of the energy in the pulse capacitor after a pulse and only replenish the loss through a power supply [93]. Changing the pulse shape requires rewiring of the circuit, e.g., by increasing the capacitance or adding damping resistors, but is technologically cumbersome and practically yields only a handful of pulse options with limited repetition rates [49,52,57,[94][95][96][97]. ...
... We previously developed controllable pulse parameter TMS (cTMS) to address some of these limitations of conventional TMS devices [95,[98][99][100]. cTMS and related approaches, such as flexTMS [101,102], use switching between one or two oscillators with large capacitors to enable electric field pulses with nearly rectangular shape and some control over the pulse width and, in some cases, the amplitude ratio between the positive and negative pulse phases ( Figure 1C) [95,99,103]. ...
... We previously developed controllable pulse parameter TMS (cTMS) to address some of these limitations of conventional TMS devices [95,[98][99][100]. cTMS and related approaches, such as flexTMS [101,102], use switching between one or two oscillators with large capacitors to enable electric field pulses with nearly rectangular shape and some control over the pulse width and, in some cases, the amplitude ratio between the positive and negative pulse phases ( Figure 1C) [95,99,103]. Coupling various capacitors and inductors has been suggested to bring pulse-shape flexibility [104][105][106][107]. ...
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.
... 28 right-handed volunteers (13 females; age 25 ± 4 years), who reported no contraindications to TMS, participated in two experiments involving TMS over the representation of the right first dorsal interosseous (FDI) muscle. Conditioning pulses were delivered via a figure-of-eight coil (70mm; Magstim Company Ltd, UK) connected to a prototype controllable-pulse parameter TMS device (cTMS3, Rogue Research Inc., Canada; [6]) secured over the top of a flat, elliptical coil connected to a standard TMS device (Magstim 200 2 , Magstim Company Ltd., UK) ( Fig. 1A), which delivered test pulses. MEPs were recorded via surface electromyography. ...
... F. SICI in Experiment 2 with anterior-posterior conditioning pulses delivered at intervals up to 20 ms prior to the test pulse. Repeated measures ANOVA revealed that short duration pulses elicited less SICI than long duration pulses (main effect of pulse duration: F [1,14] ¼ 12.368, P ¼ 0.003; main effect of inter-stimulus interval: F [6,84] ¼ 8.83, P < 0.001). Moreover, an interaction of pulse duration Â inter-stimulus interval (F [3.67,51.34] ...
... 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]- [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]- [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.
... This device utilized one DC-link source and a H-bridge structure to manage the LC resonance at different time intervals. To enhance magnetic stimulation flexibility, Peterchev et al. have designed a controllable TMS (cTMS) device to generate flexible nearrectangular pulse shapes [13]. Four insulated-gate bipolar transistor (IGBT) switches incorporating freewheeling diodes, which form the two half-bridges architecture, were utilized to connect the stimulation coil to the energy storage capacitors, as shown in Fig. 1sb. ...
... Another limitation in the particular implementation of the cTMS device reported in [13] is the current overload imposed on the switches (the peak current was shown to be up to 2.5 times the nominal IGBT values). In powerelectronic systems, power semiconductor elements are one of the most fragile components [14]. ...
Article
Full-text available
In this study we present the new power electronic circuit implementation to create the arbitrary near-rectangular electromagnetic pulse. To this end, we develop a parallel- Insulated-gate bipolar transistors (IGBT)-based magnetic pulse generator utilizing the H-bridge architecture. This approach effectively reduces the current stress on the power switches while maintaining a simple structure using a single DC source and energy storage capacitor. Experimental results from the circuit characterization show that the proposed circuit is capable of repeatedly generating near-rectangular magnetic pulses and enables the generation of configurable and stable magnetic pulses without causing excessive device stresses. The introduced device enables the production of near-rectangular pulse trains for modulated magnetic stimuli. The maximum positive pulse width in the proposed neurostimulator is up to 600 µs, which is adjustable by the operator at the step resolution of 10 µs. The maximum transferred energy to the treatment coil was measured to be 100.4 J. The proposed transcranial magnetic stimulator (TMS) device enables more flexible magnetic stimulus shaping by H-bridge architecture and parallel IGBTs, which can effectively mitigate the current stress on power switches for repetitive treatment protocols. Supplementary information: The online version contains supplementary material available at 10.1007/s42452-021-04420-y.
... However, reproducibility of TMS physiological responses can be challenging mostly due to interindividual differences in anatomy (Opitz et al., 2013), brain states (Ferreri et al., 2014) and stimulation parameters (Hannah and Rothwell, 2017;Rothkegel et al., 2010;Souza et al., 2017). Moreover, it is well known that small variations in TMS parameters such as pulse amplitude, stimulation frequency, inter-train interval (ITI), and waveform shape might induce distinct physiological outcomes (Arns et al., 2010;Cash et al., 2017;Koponen et al., 2018;Peterchev et al., 2014) Several strategies are adopted to decrease variability in TMS responses, for instance, coil placement using neuronavigation systems (Ruohonen and Karhu, 2010;Souza et al., 2018a), and adjustment of stimulus intensity according to individual motor or phosphene thresholds (Deblieck et al., 2008). However, these strategies do not consider possible changes arising from limitations of the electronic components, the materials wear or equipment fatigue. ...
... With the development of controllable pulse TMS devices (Peterchev et al., 2014), several studies are now investigating the effects of timing properties of TMS pulses on biological responses (Koponen et al., 2018). For instance, changing pulse duration increase, or decrease cortical excitability by recruiting different cortical circuits (Hannah and Rothwell, 2017;Rothkegel et al., 2010). ...
Article
Background: Small variations in TMS parameters, such as pulse frequency and amplitude may elicit distinct neurophysiological responses. Assessing the mismatch between nominal and experimental parameters of TMS stimulators is essential for safe application and comparisons of results across studies. New method: A search coil was used to assess exactness and precision errors of amplitude and timing parameters such as interstimulus interval, the period of pulse repetition, and intertrain interval of TMS devices. The method was validated using simulated pulses and applied to six commercial stimulators in single-pulse (spTMS), paired-pulse (ppTMS), and repetitive (rTMS) protocols, working at several combinations of intensities and frequencies. Results: In a simulated signal, the maximum exactness error was 1.7% for spTMS and the maximum precision error 1.9% for ppTMS. Three out of six TMS commercial devices showed exactness and precision errors in spTMS amplitude higher than 5%. Moreover, two devices showed amplitude exactness errors higher than 5% in rTMS with parameters suggested by the manufactures. Comparison with existing methods: Currently available tools allow characterization of induced electric field intensity and focality, and pulse waveforms of a single TMS pulse. Our method assesses the mismatch between nominal and experimental values in spTMS, ppTMS and rTMS protocols through the exactness and precision errors of amplitude and timing parameters. Conclusion: This study highlights the importance of evaluating the physical characteristics of TMS devices and protocols, and provides a method for on-site quality assessment of multiple stimulation protocols in clinical and research environments.
... The mTMS system is based on independently controlled H-bridge circuits (Fig. 1B) [9,[16][17][18][19]. The electronics can be roughly categorized into the following modules ( Fig. 1A): control unit, charging unit, channels, coils, and auxiliary electronics. ...
... The operation of the mTMS device is based on forced current feed through the transducer coils, which is achieved by manipulating the electrical topologies of the coil-specific bridge circuits; see [16,18,19,21,22]. Depending on the states of the IGBTs, a bridge circuit either connects its respective pulse capacitor in series with the coil connected to the channel ( Fig. 2A,C), resulting in a damped oscillator circuit, or cuts the capacitor completely out of the circuit while also shortcircuiting the coil's ends (Fig. 2B). ...
Article
Full-text available
Background Transcranial magnetic stimulation (TMS) allows non-invasive stimulation of the cortex. In multi-locus TMS (mTMS), the stimulating electric field (E-field) is controlled electronically without coil movement by adjusting currents in the coils of a transducer. Objective To develop an mTMS system that allows adjusting the location and orientation of the E-field maximum within a cortical region. Methods We designed and manufactured a planar 5-coil mTMS transducer to allow controlling the maximum of the induced E-field within a cortical region approximately 30 mm in diameter. We developed electronics with a design consisting of independently controlled H-bridge circuits to drive up to six TMS coils. To control the hardware, we programmed software that runs on a field-programmable gate array and a computer. To induce the desired E-field in the cortex, we developed an optimization method to calculate the currents needed in the coils. We characterized the mTMS system and conducted a proof-of-concept motor-mapping experiment on a healthy volunteer. In the motor mapping, we kept the transducer placement fixed while electronically shifting the E-field maximum on the precentral gyrus and measuring electromyography from the contralateral hand. Results The transducer consists of an oval coil, two figure-of-eight coils, and two four-leaf-clover coils stacked on top of each other. The technical characterization indicated that the mTMS system performs as designed. The measured motor evoked potential amplitudes varied consistently as a function of the location of the E-field maximum. Conclusion The developed mTMS system enables electronically targeted brain stimulation within a cortical region.
... Recently, the use of isolated-gate bipolar transistors (IGBTs) instead of thyristors, as well as the implementation of H-bridge structures, has enabled more control over the stimulation parameters. Peterchev et al. developed a series of transcranial magnetic stimulators with controllable pulse parameters (cTMS) [14] [15] [16] that produce both monophasic and biphasic stimuli of different frequencies and allow more pulses per second than conventional TMS devices. However, the high current stress on the IGBTs and the limited number of pulses that can be selected limit the achievable protocols [17]. ...
... doi: bioRxiv preprint4. DISCUSSIONPower converters have been gaining popularity in TMS equipment owing to their potential to emulate arbitrary magnetic stimuli[16] ...
Preprint
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A bstract Background Transcranial magnetic stimulation (TMS) is a clinically effective therapeutic instrument used to modulate neural activity. Despite three decades of research, two challenging issues remain, the possibility of changing the 1) stimulated spot and 2) stimulation type (real or sham) without physically moving the coil. Objective In this study, a second-generation programmable TMS (pTMS2) device with advanced stimulus shaping is introduced that uses a 5-level cascaded H-bridge inverter and phase-shifted pulse-width modulation (PWM). The principal idea of this research is to obtain real, sham, and multi-locus stimulation with the same TMS system. Methods We propose a two-channel modulation-based magnetic pulse generator and a novel coil arrangement, consisting of two circular coils with a physical distance of 20 mm between the coils and a control method for modifying the effective stimulus intensity, which leads to the live steerability of the location and type of stimulation. Results Based on the measured system performance, the stimulation profile can be steered ± 20 mm along a line from the centroid of the coil locations by modifying the modulation index. Conclusion The proposed system supports electronic control of the stimulation spot without physical coil movement, resulting in tunable modulation of targets, which is a crucial step towards automated TMS machines.
... For reference, 100% MA of this cTMS device corresponds to 95% MA of the Magstim 200 2 . More detailed discussion of the cTMS device output and comparison with other devices is provided by Peterchev et al. (2014). ...
... cTMS electric field pulse waveforms recorded with a search coil and normalized to unity amplitude for pulse widths of 30, 60 and 120 ls. Reproduced fromPeterchev et al. (2014). ...
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.
... The software enables navigation and use of the target interface without an individual MRI by means of the MNI152 brain template (Fonov et al., 2011). InVesalius Navigator can be used with any TMS coil model, or any other instrument, and might be customizable to operate with recently developed controllable (Peterchev et al., 2014) and multi-locus TMS devices (Koponen et al., 2018). The software also provides methods for image and data manipulation such as segmentation and processing tools, and might be integrated straightforwardly to existing tools for neuroimaging analysis and TMS control such as MNE (Gramfort, 2013) and MagPy (McNair, 2017). ...
Article
Background: Neuronavigation provides visual guidance of an instrument during procedures of neurological interventions, and has been shown to be a valuable tool for accurately positioning transcranial magnetic stimulation (TMS) coils relative to an individual's anatomy. Despite the importance of neuronavigation, its high cost, low portability, and low availability of magnetic resonance imaging facilities limit its insertion in research and clinical environments. New method: We have developed and validated the InVesalius Navigator as the first free, open-source software for image-guided navigated TMS, compatible with multiple tracking devices. A point-based, co-registration algorithm and a guiding interface were designed for tracking any instrument (e.g. TMS coils) relative to an individual's anatomy. Results: Localization, precision errors, and repeatability were measured for two tracking devices during navigation in a phantom and in a simulated TMS study. Errors were measured in two commercial navigated TMS systems for comparison. Localization error was about 1.5 mm, and repeatability was about 1 mm for translation and 1º for rotation angles, both within limits established in the literature. Comparison with existing methods: Existing TMS neuronavigation software programs are not compatible with multiple tracking devices, and do not provide an easy to implement platform for custom tools. Moreover, commercial alternatives are expensive with limited portability. Conclusions: InVesalius Navigator might contribute to improving spatial accuracy and the reliability of techniques for brain interventions by means of an intuitive graphical interface. Furthermore, the software can be easily integrated into existing neuroimaging tools, and customized for novel applications such as multi-locus and/or controllable-pulse TMS.
... Thus, the motor hot spot should be found with the assistance of neuronavigation and the MT is estimated with EMG recordings (noise below 50 µV and muscles completely relaxed). However, one should not forget that the focality and the accuracy of each stimulation derives from the shape and duration of the TMS pulses 32 . ...
Article
Full-text available
Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).
... 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). ...
Thesis
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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.
... The aim of the present experiments was to provide more direct evidence that PA and AP inputs play distinct roles in motor behavior by showing: (i) that their excitability is differentially modulated during a motor task; and (ii) that directly preconditioning each set of inputs produces specific effects on simple motor performance. To do this, we used a novel controllable pulse parameter TMS (cTMS) device [7]. We previously found that using monophasic AP pulses of short duration (30μs; AP S ) and long duration PA pulses (120μs; PA L ) more reliably activate different inputs [2]. ...
Conference Paper
Different aspects of motor behaviour may engage distinct interneuron circuits in the human motor cortex. If so, the behavioural effects of repetitive transcranial magnetic stimulation (rTMS) protocols may critically depend on the specific circuit stimulated. We used TMS of the hand area to activate two distinct synaptic inputs to corticospinal neurons by altering the direction of current induced in the brain: posterior-anterior (PA inputs) and anterior-posterior (AP inputs). We found AP inputs to be preferentially suppressed during motor preparation in a reaction time task. We also show that preconditioning PA, but not AP, inputs with via rTMS facilitates performance of a ballistic motor task. These results suggest that behavioural effects of rTMS may be most evident when relevant interneuron circuits are targeted.
... Standard TMS was carried out with a Magstim 200 2 device connected to a 70-mm figure-of-eight coil (Magstim Company Limited, Whitland, UK), which produces monophasic pulses with a pulse width of~80 ms. For cTMS, we used a prototype device (cTMS-3, Rogue Research Inc., Montreal, Canada) able to produce both monophasic and biphasic pulses with independent control of pulse width and ratio between the pulse phases [28]; [31]. The cTMS was connected to a standard 70-mm figure-of-eight coil (Magstim Company Limited, Whitland, UK) and was controlled with an NI PCI-7831R control/acquisition board. ...
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.
... A controllable pulse parameter TMS (cTMS) device opens up a new parameter-space for TMS, i.e. pulse shape. It is capable of producing near rectangular pulse shapes by the use of two capacitors, and two bipolar semiconductor transistors that alternate the current between the capacitors [15]. The cTMS rectangular pulse platform provides a sufficient flexibility of pulse shapes by altering the phase widths, heights (intensity) and also the relation between positive and negative components of the pulse (directionality, defined as the M ratio). ...
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.
... The implemented IGBTs have a repetitive peak collector load of 2,000 A. Since the maximum peak current flow of the biphasic device is up to 5,200 A the specified current ratings are exceeded by a factor of approximately 2.5. This overload is tolerable due to the expedient duty cycle [12][13][14]. For a worst-case consideration we can assume a qTBS protocol with 100 quadripulses per second, which leads to 400 pulses doi: 10 per second. ...
... [168][169][170][171][172] Part of this problem might be addressed by increasing the specificity of TMS by changing the stimulation parameters. Novel TMS devices, such as controllable TMS (cTMS), 173 allow changes in the duration and shape of magnetic stimuli. 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. ...
... The device comprises control and power electronics for both channels, which are essentially copies of our custom-made TMS design [19]. This mTMS device allows similar pulse waveforms in both coils: it features controllable-pulse-waveform electronics similar to the design of Peterchev et al. [23] with high capacitance and nearrectangular pulse waveforms, the pulse duration being independent of the coil inductance. The device comprises two insulatedgate bipolar transistor (ABB 5SNA 1500E330305, www.abb.com) ...
Article
Background: Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method: a magnetic field pulse from a TMS coil can excite neurons in a desired location of the cortex. Conventional TMS coils cause focal stimulation underneath the coil centre; to change the location of the stimulated spot, the coil must be moved over the new target. This physical movement is inherently slow, which limits, for example, feedback-controlled stimulation. Objective: To overcome the limitations of physical TMS-coil movement by introducing electronic targeting. Methods: We propose electronic stimulation targeting using a set of large overlapping coils and introduce a matrix-factorisation-based method to design such sets of coils. We built one such device and demonstrated the electronic stimulation targeting in vivo. Results: The demonstrated two-coil transducer allows translating the stimulated spot along a 30-mm-long line segment in the cortex; with five coils, a target can be selected from within a region of the cortex and stimulated in any direction. Thus, far fewer coils are required by our approach than by previously suggested ones, none of which have resulted in practical devices. Conclusion: Already with two coils, we can adjust the location of the induced electric field maximum along one dimension, which is sufficient to study, for example, the primary motor cortex.
... All sessions were separated by > five days. TMS was delivered through a figure-of-eight coil (70 mm; Magstim Company Ltd, UK) connected to a cTMS device ( [18]: cTMS3; Rogue Resolutions Ltd., UK) over the representation of the right first dorsal interosseous (FDI) muscle. MEPs were recorded via surface electromyography. ...
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.
... (ii) A controllable pulse parameter TMS device allows the implementation of QPS paradigms (Peterchev et al. 2014). (iii) Quadripulse theta burst stimulation is also being studied as an NIBS method merging QPS and theta burst stimulation that can bidirectionally induce neural plasticity in M1 (Jung et al. 2016). ...
Article
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Quadripulse stimulation (QPS) is a newly developed stimulation method to induce neural plasticity in humans. One stimulation burst consisting of four monophasic pulses is given every 5 s for 30 min. A total of 360 bursts (1440 pulses) are given in one session. Short-interval QPS potentiates the target cortical excitability and long-interval QPS depresses it. QPS at an inter-pulse interval of 5 ms (QPS5) induces long-term potentiation (LTP)-like effects most efficiently and QPS50 induces long-term depression (LTD)-like effects most effectively in the primary motor cortex. In this mini-review, we briefly introduce QPS: (i) principle and cortical plasticity (stimulators and protocols, synaptic plasticity, underlying mechanisms, meta-plasticity, axonal plasticity, and drug effects), (ii) robust and strong neural plasticity induction (variability, influence of phasic muscle contraction, independency of BDNF polymorphism, sensory cortical plasticity, neural plasticity in the contralateral hemisphere, on-line effects on the brain networks, studies of normal brain physiology, and visuomotor sequence learning), (iii) therapeutic applications to neurological and psychiatric disorders (Parkinson’s disease, epilepsy, cerebrovascular disease, and major depression), (iv) safety, and (v) future issues. Based on this evidence, we propose that QPS is currently the most powerful and reliable non-invasive brain stimulation method to induce neural plasticity in humans.
... As conventional magnetic brain stimulators have relatively fixed pulse characteristics (other than amplitude), it has not been previously possible to assess this variable with TMS. However, technological advances have enabled development of stimulators with controllable pulse parameters (103,104), and these have been used to estimate strength-duration time constants of the neuronal circuits activated by TMS by modifying pulse-duration (105). In an attempt to further characterize the intracortical circuits activated by different current directions, D'Ostilio et al. (106) used this approach to assess strength-duration time constants for PA and AP stimulation. ...
Article
Objectives: The corticospinal volley produced by application of transcranial magnetic stimulation (TMS) over primary motor cortex consists of a number of waves generated by trans‐synaptic input from interneuronal circuits. These indirect (I)‐waves mediate the sensitivity of TMS to cortical plasticity and intracortical excitability and can be assessed by altering the direction of cortical current induced by TMS. While this methodological approach has been conventionally viewed as preferentially recruiting early or late I‐wave inputs from a given populations of neurons, growing evidence suggests recruitment of different neuronal populations, and this would strongly influence interpretation and application of these measures. The aim of this review is therefore to consider the physiological, functional, and clinical evidence for the independence of the neuronal circuits activated by different current directions. Materials and Methods To provide the relevant context, we begin with an overview of TMS methodology, focusing on the different techniques used to quantify I‐waves. We then comprehensively review the literature that has used variations in coil orientation to investigate the I‐wave circuits, grouping studies based on the neurophysiological, functional, and clinical relevance of their outcomes. Results Review of the existing literature reveals significant evidence supporting the idea that varying current direction can recruit different neuronal populations having unique functionally and clinically relevant characteristics. Conclusions Further research providing greater characterization of the I‐wave circuits activated with different current directions is required. This will facilitate the development of interventions that are able to modulate specific intracortical circuits, which will be an important application of TMS.
... The phase durations of the paired pulses differed based on the CS intensity, as specified in Table 1. The stimulus intensity in paired-pulse mTMS was adjusted by varying the rising-phase duration of each pulse [31,32], following the procedure described in [33]. The E-field orientation across the central sulcus will be referred to as the AM orientation. ...
Article
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Besides stimulus intensities and interstimulus intervals (ISI), the electric field (E-field) orientation is known to affect both short-interval intracortical inhibition (SICI) and facilitation (SICF) in paired-pulse transcranial magnetic stimulation (TMS). However, it has yet to be established how distinct orientations of the conditioning (CS) and test stimuli (TS) affect the SICI and SICF generation. With the use of a multi-channel TMS transducer that provides electronic control of the stimulus orientation and intensity, we aimed to investigate how changes in the CS and TS orientation affect the strength of SICI and SICF. We hypothesized that the CS orientation would play a major role for SICF than for SICI, whereas the CS intensity would be more critical for SICI than for SICF. In eight healthy subjects, we tested two ISIs (1.5 and 2.7 ms), two CS and TS orientations (anteromedial (AM) and posteromedial (PM)), and four CS intensities (50, 70, 90, and 110% of the resting motor threshold (RMT)). The TS intensity was fixed at 110% RMT. The intensities were adjusted to the corresponding RMT in the AM and PM orientations. SICI and SICF were observed in all tested CS and TS orientations. SICI depended on the CS intensity in a U-shaped manner in any combination of the CS and TS orientations. With 70% and 90% RMT CS intensities, stronger PM-oriented CS induced stronger inhibition than weaker AM-oriented CS. Similar SICF was observed for any CS orientation. Neither SICI nor SICF depended on the TS orientation. We demonstrated that SICI and SICF could be elicited by the CS perpendicular to the TS, which indicates that these stimuli affected either overlapping or strongly connected neuronal populations. We concluded that SICI is primarily sensitive to the CS intensity and that CS intensity adjustment resulted in similar SICF for different CS orientations.
... The axon diameters 1 µm and 2 µm are outside the simulation limit of 60 kA and are therefore not shown. [62], this type of magnetic stimulator is not yet widely used. In another experiment, we investigated the differences in phrenic nerve stimulation with a rectangular wave pulse compared to a sinusoidal pulse. ...
Preprint
p>In this work, we present a simulation environment that makes it possible to determine threshold currents for magnetic peripheral nerve stimulation. Using the phrenic nerve as an example, we show that coil currents as low as 600 A are sufficient to trigger an action potential. These findings may help to advance research into artificial respiration using magnetic stimulation. </p
... Repetitive TMS protocols, particularly monophasic paradigms, have always been associated with an energy recovery challenge [1]. Recently, the use of state-of-the-art power electronic instruments has permitted more control over the waveform parameters [2] [3] [4]. A novel technique utilizing pulse width modulation (PWM), called programmable TMS or pTMS [5], enables the imitation of a wide range of arbitrary pulses. ...
Preprint
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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.
... Other approaches which, for example, use fully controllable switches such as IGBTs to enable the output of squarewave voltage pulses with variable widths have previously been explored., this is known as controllable pulse width TMS (cTMS) [11]. In [12], the authors present a prototype cTMS using IGBTs with a nominal DC link voltage of 2 kV and a peak current of about 3 kA. With this technology it is possible to stimulate with variable pulse shapes [11], [13]. ...
... The operation of the mTMS device is based on forced current feed through the transducer coils, which is achieved by manipulating the electrical topologies of the coil-specific bridge circuits; see Fig. 2 [17][18][19][20][21]. Depending on the states of the IGBTs, a bridge circuit either connects its respective pulse capacitor in series with the coil connected to the channel ( Fig. 2A,C), resulting in a damped oscillator circuit, or cuts the capacitor completely out of the circuit while also short-circuiting the coil's ends (Fig. 2B). ...
Preprint
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Background Transcranial magnetic stimulation (TMS) allows non-invasive stimulation of the cortex. In multi-locus TMS (mTMS), the stimulating electric field (E-field) is controlled electronically without coil movement by adjusting currents in the coils of a transducer. Objective To develop an mTMS system that allows adjusting the location and orientation of the E-field maximum within a cortical region. Methods We designed and manufactured a planar 5-coil mTMS transducer to allow controlling the maximum of the induced E-field within a cortical region approximately 30 mm in diameter. We developed electronics with a design consisting of independently controlled H-bridge circuits to drive up to six TMS coils. To control the hardware, we programmed software that runs on a field-programmable gate array and a computer. To induce the desired E-field in the cortex, we developed an optimization method to calculate the currents needed in the coils. We characterized the mTMS system and conducted a proof-of-concept motor-mapping experiment on a healthy volunteer. In the motor mapping, we kept the transducer placement fixed while electronically shifting the E-field maximum on the precentral gyrus and measuring electromyography from the contralateral hand. Results The transducer consists of an oval coil, two figure-of-eight coils, and two four-leaf-clover coils stacked on top of each other. The technical characterization indicated that the mTMS system performs as designed. The measured motor evoked potential amplitudes varied consistently as a function of the location of the E-field maximum. Conclusion The developed mTMS system enables electronically targeted brain stimulation within a cortical region.
... The controllable pulse parameter TMS device (cTMS3, Rogue Research Inc., Montreal, QC, Canada) allows varying the duration of its near-rectangular pulses using two capacitors and four transistors that alternate the current between the capacitors (Peterchev et al., 2014). The ratio of capacitor voltages is defined as the M-ratio, which determines the relative amplitudes of the different phases of the pulse waveform. ...
Article
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Introduction: High frequency repetitive transcranial magnetic stimulation applied to the motor cortex causes an increase in the amplitude of motor evoked potentials (MEPs) that persists after stimulation. Here, we focus on the aftereffects generated by high frequency controllable pulse TMS (cTMS) with different directions, intensities, and pulse durations. Objectives: To investigate the influence of pulse duration, direction, and amplitude in correlation to induced depolarization on the excitatory plastic aftereffects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) using bidirectional cTMS pulses. Methods: We stimulated the hand motor cortex with 5 Hz rTMS applying 1,200 bidirectional pulses with the main component durations of 80, 100, and 120 μs using a controllable pulse stimulator TMS (cTMS). Fourteen healthy subjects were investigated in nine sessions with 80% resting motor threshold (RMT) for posterior-anterior (PA) and 80 and 90% RMT anterior-posterior (AP) induced current direction. We used a model approximating neuronal membranes as a linear first order low-pass filter to estimate the strength–duration time constant and to simulate the membrane polarization produced by each waveform. Results: PA and AP 5 Hz rTMS at 80% RMT produced no significant excitation. An exploratory analysis indicated that 90% RMT AP stimulation with 100 and 120 μs pulses but not 80 μs pulses led to significant excitation. We found a positive correlation between the plastic outcome of each session and the simulated peak neural membrane depolarization for time constants >100 μs. This correlation was strongest for neural elements that are depolarized by the main phase of the AP pulse, suggesting the effects were dependent on pulse direction. Conclusions: Among the tested conditions, only 5 Hz rTMS with higher intensity and wider pulses appeared to produce excitatory aftereffects. This correlated with the greater depolarization of neural elements with time constants slower than the directly activated neural elements responsible for producing the motor output (e.g., somatic or dendritic membrane). Significance: Higher intensities and wider pulses seem to be more efficient in inducing excitation. If confirmed, this observation could lead to better results in future clinical studies performed with wider pulses.
... e cTMS circuit structure with the parameters presented in [11] was simulated in the MAT-LAB Simulink environment (Powergui blockset, R2020a). e circuit model of this device and its typical parameters are shown in Figure 1S, supplementary data. ...
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.
... Therefore, it increases the size and cost of the required QPS system. To address this need, a new TMS device, called controllable TMS or cTMS, was introduced by Peterchev et al. [13]. Using new power electronic switches and circuit architectures, the cTMS is able to generate consecutive stimuli with a minimum ISI of 2 ms, as well as change the pulse width (i.e. the pulse waveform). ...
Article
Full-text available
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.
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
Background: Transcranial magnetic stimulation (TMS) allows focal, non-invasive stimulation of the cortex. A TMS pulse is inherently weakly coupled to the cortex; thus, magnetic stimulation requires both high current and high voltage to reach sufficient intensity. These requirements limit, for example, the maximum repetition rate and the maximum number of consecutive pulses with the same coil due to the rise of its temperature. Objective: To develop methods to optimise, design, and manufacture energy-efficient TMS coils in realistic head geometry with an arbitrary overall coil shape. Methods: We derive a semi-analytical integration scheme for computing the magnetic field energy of an arbitrary surface current distribution, compute the electric field induced by this distribution with a boundary element method, and optimise a TMS coil for focal stimulation. Additionally, we introduce a method for manufacturing such a coil by using Litz wire and a coil former machined from polyvinyl chloride. Results: We designed, manufactured, and validated an optimised TMS coil and applied it to brain stimulation. Our simulations indicate that this coil requires less than half the power of a commercial figure-of-eight coil, with a 41% reduction due to the optimised winding geometry and a partial contribution due to our thinner coil former and reduced conductor height. With the optimised coil, the resting motor threshold of abductor pollicis brevis was reached with the capacitor voltage below 600 V and peak current below 3000 A. Conclusion: The described method allows designing practical TMS coils that have considerably higher efficiency than conventional figure-of-eight coils.
Article
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Transcranial magnetic stimulation (TMS) is widely applied on humans for research and clinical purposes. TMS studies on small animals, e.g., rodents, can provide valuable knowledge of the underlying neurophysiological mechanisms. Administering TMS on small animals is, however, prone to technical difficulties, mainly due to their small head size. In this study, we aimed to develop an energy-efficient coil and a compatible experimental set-up for administering TMS on rodents. We applied a convex optimization process to develop a minimum-energy coil for TMS on rats. As the coil windings of the optimized coil extend to a wide region, we designed and manufactured a holder on which the rat lies upside down, with its head supported by the coil. We used the set-up to record TMS–electromyography, with electromyography recorded from limb muscles with intramuscular electrodes. The upside-down placement of the rat allowed the operator to easily navigate the TMS without the coil blocking their field of view. With this paradigm, we obtained consistent motor evoked potentials from all tested animals.
Conference Paper
Transcranial magnetic stimulation (TMS) for treatment of depression during pregnancy is an appealing alternative to fetus-threatening drugs. However, no studies to date have been performed that evaluate the safety of TMS for a pregnant mother patient and her fetus. A full-body FEM model of a pregnant woman with about 100 tissue parts has been developed specifically for the present study. This model allows accurate computations of induced electric field in every tissue given different locations of a shape-eight coil, a biphasic pulse, common TMS pulse durations, and using different values of the TMS intensity measured in SMT (Standard Motor Threshold) units. Our simulation results estimate the maximum peak values of the electric field in the fetal area for every fetal tissue separately and for the TMS intensity of one SMT unit.
Article
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Changes in neural activity occur in the motor cortex before movement, but the nature and purpose of this preparatory activity is unclear. To investigate this in the human (male and female) brain noninvasively, we used transcranial magnetic stimulation (TMS) to probe the excitability of distinct sets of excitatory inputs to corticospinal neurons during the warning period of various reaction time tasks. Using two separate methods (H-reflex conditioning and directional effects of TMS), we show that a specific set of excitatory inputs to corticospinal neurons are suppressed during motor preparation, while another set of inputs remain unaffected. To probe the behavioral relevance of this suppression, we examined whether the strength of the selective preparatory inhibition in each trial was related to reaction time. Surprisingly, the greater the amount of selective preparatory inhibition, the faster the reaction time was. This suggests that the inhibition of inputs to corticospinal neurons is not involved in preventing the release of movement but may in fact facilitate rapid reactions. Thus, selective suppression of a specific set of motor cortical neurons may be a key aspect of successful movement preparation.
Article
To improve the energy utilization of magnetic field generators for biological applications, a multifunctional energy-saving magnetic field generator (ESMFG) is presented. It is capable of producing both an alternating magnetic field (AMF) and a bipolar pulse magnetic field (BPMF) with high energy-saving and energy-reuse rates. Based on a theoretical analysis of an RLC second-order circuit, the energy-saving and energy-reuse rates of both types of magnetic fields can be calculated and are found to have acceptable values. The results of an experimental study using the proposed generator show that for the BPMF, the peak current reaches 130 A and the intensity reaches 70.3 mT. For the AMF, the intensity is 11.0 mT and the RMS current is 20 A. The energy-saving and energy-reuse rates for the AMF generator are 61.3% and 63.5%, respectively, while for the BPMF generator, the energy-saving rate is 33.6%. Thus, the proposed ESMFG has excellent potential for use in biomedical applications.
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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.
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Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation commonly used to modulate neural activity. Despite three decades of examination, the generation of flexible magnetic pulses is still a challenging technical question. It has been revealed that the characteristics of pulses influence the bio-physiology of neuromodulation. In this study, a second-generation programmable TMS (xTMS) equipment with advanced stimulus shaping is introduced that uses cascaded H-bridge inverters and a phase-shifted pulse-width modulation (PWM). A low-pass RC filter model is used to estimate stimulated neural behavior, which helps to design the magnetic pulse generator, according to neural dynamics. The proposed device can generate highly adjustable magnetic pulses, in terms of waveform, polarity and pattern. We present experimental measurements of different stimuli waveforms, such as monophasic, biphasic and polyphasic shapes with peak coil current and the delivered energy of up to 6 kA and 250 J, respectively. The modular and scalable design idea presented here is a potential solution for generating arbitrary and highly customizable magnetic pulses and transferring repetitive paradigms.
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This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.
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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.
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Since GABAA-mediated intracortical inhibition has been shown to underlie plastic changes throughout the lifespan from development to aging, here, the aging motor system was used as a model to analyze the interdependence of plastic alterations within the inhibitory motorcortical network and level of behavioral performance. Double-pulse transcranial magnetic stimulation (dpTMS) was used to examine inhibition by means of short-interval intracortical inhibition (SICI) of the contralateral primary motor cortex in a sample of 64 healthy right-handed human subjects covering a wide range of the adult lifespan (age range 20-88 years, mean 47.6 ± 20.7, 34 female). SICI was evaluated during resting state and in an event-related condition during movement preparation in a visually triggered simple reaction time task. In a subgroup (N = 23), manual motor performance was tested with tasks of graded dexterous demand. Weak resting-state inhibition was associated with an overall lower manual motor performance. Better event-related modulation of inhibition correlated with better performance in more demanding tasks, in which fast alternating activation of cortical representations are necessary. Declining resting-state inhibition was associated with weakened event-related modulation of inhibition. Therefore, reduced resting-state inhibition might lead to a subsequent loss of modulatory capacity, possibly reflecting malfunctioning precision in GABAAergic neurotransmission; the consequence is an inevitable decline in motor function.
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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.
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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.
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Magnetic stimulation of neural tissue is an attractive technology because neural excitation may be affected without requiring implantation of electrodes. Pulsed discharge circuits are typically implemented for clinical magnetic stimulation systems. However, pulsed discharge systems can confound in-vitro experimentation. As an alternative to pulsed discharge circuits, we present a circuit to deliver asymmetric current pulses for generation of the magnetic field. We scaled the system down by using ferrite cores for the excitation coil. The scaled system allows observation using electrophysiological techniques and preparations not commonly used for investigation of magnetic stimulation. The design was refined using a comprehensive set of design equations. Circuit modeling and simulation demonstrate that the proposed system is effective for stimulating neural tissue with electric-field gradients generated by time-varying magnetic fields. System performance is verified through electrical test.
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Sensory abnormalities have been reported in Parkinson's disease and may contribute to the motor deficits. Peripheral sensory stimulation inhibits the motor cortex, and the effects depend on the interstimulus interval (ISI) between the sensory stimulus and transcranial magnetic stimulation (TMS) to the motor cortex. Short latency afferent inhibition (SAI) occurs at an ISI of approximately 20 ms, and long latency afferent inhibition (LAI) at an ISI of approximately 200 ms. We studied SAI and LAI in 10 Parkinson's disease patients with the aim of assessing whether sensorimotor processing is altered in Parkinson's disease. Patients were studied on and off medication, and the findings were compared with 10 age-matched controls. Median nerve and middle finger stimulation were delivered 20-600 ms before TMS to the contralateral motor cortex. The motor evoked potentials were recorded from the relaxed first dorsal interosseous (FDI) muscle. SAI was normal in Parkinson's disease patients off dopaminergic medications, but it was reduced on the more affected side in Parkinson's disease patients on medication. LAI was reduced in Parkinson's disease patients compared with controls independent of their medication status. LAI reduced long interval intracortical inhibition in normal subjects but not in Parkinson's disease patients. The different results for SAI and LAI indicate that it is likely that separate mechanisms mediate these two forms of afferent inhibition. SAI probably represents the direct interaction of a sensory signal with the motor cortex. This pathway is unaffected by Parkinson's disease but is altered by dopaminergic medication in Parkinson's disease patients and may contribute to the side effects of dopaminergic drugs. LAI probably involves other pathways such as the basal ganglia or cortical association areas. This defective sensorimotor integration may be a non-dopaminergic manifestation of Parkinson's disease.
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Low-frequency median nerve stimulation, paired with suprathreshold transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis (APB) muscle induces a long-lasting increase in the excitability of corticospinal output neurons, if median nerve stimulation is given 25 ms before TMS. Here we employed this protocol of stimulation to assess associative plasticity of the primary motor hand area in 10 patients with writer's cramp and 10 age-matched controls. Motor evoked potentials (MEPs) were recorded from right APB muscle and right first dorsal interosseus (FDI) muscle. Resting and active motor threshold, mean MEP amplitude at rest, short-latency intracortical inhibition (SICI) at an interstimulus interval of 2 ms and the duration of the cortical silent period (CSP) were assessed immediately before and after associative stimulation. In both groups, associative stimulation led to an increase in resting MEP amplitudes which was more pronounced in the right APB muscle. Compared with healthy controls, stimulation-induced facilitation of MEP amplitudes was stronger in patients with writer's cramp. In addition, only patients showed a slight decrease of resting and active motor thresholds after conditioning stimulation. In both groups, associative stimulation induced a prolongation of CSP in the APB and FDI muscles, which was significant only in the APB muscle in healthy controls. Associative stimulation had no effects on SICI in patients and healthy controls. Taken together, in patients with writer's cramp, the motor system exhibited an abnormal increase in corticospinal excitability and an attenuated reinforcement of intracortical inhibitory circuits that generate the CSP in response to associative stimulation. This altered pattern of sensorimotor plasticity may favour maladaptive plasticity during repetitive skilled hand movements and, thus, may be of relevance for the pathophysiology of writer's cramp and other task-specific dystonias.
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The objective of this project was to examine the influence of stimulus waveform and frequency on extracellular stimulation of neurons with their cell bodies near the electrode (local cells) and fibers of passage in the CNS. Detailed computer-based models of CNS cells and axons were developed that accurately reproduced the dynamic firing properties of mammalian motoneurons including afterpotential shape, spike-frequency adaptation, and firing frequency as a function of stimulus amplitude. The neuron models were coupled to a three-dimensional finite element model of the spinal cord that solved for the potentials generated in the tissue medium by an extracellular electrode. Extracellular stimulation of the CNS with symmetrical charge balanced biphasic stimuli resulted in activation of fibers of passage, axon terminals, and local cells around the electrode at similar thresholds. While high stimulus frequencies enhanced activation of fibers of passage, a much more robust technique to achieve selective activation of targeted neuronal populations was via alterations in the stimulus waveform. Asymmetrical charge-balanced biphasic stimuli, consisting of a long-duration low-amplitude cathodic prepulse phase followed by a short-duration high-amplitude anodic stimulus phase, enabled selective activation of local cells. Conversely, an anodic prepulse phase followed by a cathodic stimulus phase enabled selective activation of fibers of passage. The threshold for activation of axon terminals in the vicinity of the electrode was lower than the threshold for direct activation of local cells, independent of the stimulus waveform. As a result, stimulation induced trans-synaptic influences (indirect depolarization/hyperpolarization) on local cells altered their neural output, and this indirect effect was dependent on stimulus frequency. If the indirect activation of local cells was inhibitory, there was little effect on the stimulation induced neural output of the local cells. However, if the indirect activation of the local cells was excitatory, attempts to activate selectively fibers of passage over local cells was limited. These outcomes provide a biophysical basis for understanding frequency-dependent outputs during CNS stimulation and provide useful tools for selective stimulation of the CNS.
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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.
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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.
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Transcranial magnetic stimulation (TMS) is widely used for noninvasive activation of neurons in the brain for research and clinical applications. The strong, brief magnetic pulse generated in TMS is associated with a loud (>100 dB) clicking sound that can impair hearing and that activates auditory circuits in the brain. We introduce a two-pronged solution to reduce TMS noise by redesigning both the pulse waveform and the coil structure. First, the coil current pulse duration is reduced which shifts a substantial portion of the pulse acoustic spectrum above audible frequencies. Second, the mechanical structure of the stimulation coil is designed to suppress the emergence of the sound at the source, diminish down-mixing of high-frequency sound into the audible range, and impede the transmission of residual sound to the coil surface but dissipate it away from the casing. A prototype coil driven with ultrabrief current pulses (down to 45-μs biphasic duration) is demonstrated to reduce the peak sound pressure level by more than 25 dB compared to a conventional TMS configuration, resulting in loudness reduction by more than 14-fold. These results motivate improved mechanical design of TMS coils as well as design of TMS pulse generators with shorter pulse durations and increased voltage limits with the objective of reducing TMS acoustic noise while retaining the neurostimulation strength.
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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
Conference Paper
We compare half-bridge and full-bridge circuit topologies for controllable pulse parameter transcranial magnetic stimulation (cTMS) devices. The full bridge can generate two more distinct coil voltage levels for enhanced pulse shaping, does not need an active snubber circuit, and requires lower semiconductor switch voltage ratings, at the cost of necessitating four semiconductor switches and associated drivers compared to two in the half bridge. In cTMS devices it may be beneficial to use coils with higher number of turns and, hence, higher inductance than that optimal in conventional TMS, since this reduces the required capacitance, stored energy, coil current, and, potentially, conduction losses and heating. However, increasing the number of coil turns raises the required capacitor voltage which presents practical limits on the number of turns, especially for very brief pulses.
Conference Paper
Commercially available transcranial magnetic stimulation (TMS) devices provide very limited control over the pulse parameters. We present a third generation controllable pulse parameter device (cTMS3) that uses a novel full-bridge circuit topology with two energy storage capacitors and incorporates a number of implementation and functionality advantages over conventional TMS devices and previous cTMS devices. cTMS3 is implemented with transistors with lower voltage rating than previous cTMS devices. It provides more flexible pulse shaping since the circuit topology allows four coil voltage levels during a pulse, including zero voltage. The zero coil voltage level 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 bursts (
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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.
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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.
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Hydrolysis of the carcinogenic title compound 1a in 5 vol % CH3CN−H2O, μ = 0.5, 20 °C at pH 7.2 in 0.02 M phosphate buffer, yields the rearranged material 3-(sulfonatooxy)-N-acetyl-4-aminostilbene (4) (23 ± 1%), threo-1,2-dihydroxy-1-phenyl-2-(4-acetamidophenyl)ethane (5) (57 ± 2%), and erythro-1,2-dihydroxy-1-phenyl-2-(4-acetamidophenyl)ethane (6) (20 ± 2%) in the absence of added nucleophiles. Addition of N3- has no effect on the rate constant for decomposition of 1a (ca. 1.9 × 10-2 s-1), but generates a number of adducts that result from trapping of three different electrophilic intermediates. The ortho-N3 adduct 3-azido-N-acetyl-4-aminostilbene (7) is produced from trapping of the nitrenium ion 2. A fit of the product yield data as a function of [N3-] provides the ratio kaz/ks of 280 ± 10 M-1 for competitive trapping of 2 by N3- and H2O. The nucleophilic aromatic substitution product 7 is a minor reaction product. The predominant site of attack by N3- on 2 (ca. 85%) is at the β-vinyl carbon to produce the quinone imide methide 3b. Attack of H2O at the same site produces the analogous intermediate 3a. Both of these electrophilic species are competitively trapped by N3- and H2O with trapping ratios kaz‘/ks‘ for 3b of 107 ± 8 M-1 and kaz‘‘/ks‘‘ for 3a of 39 ± 2 M-1. The reactivity patterns of 2 are unlike those of other N-arylnitrenium ions that undergo predominant nucleophilic aromatic substitution with nucleophiles such as N3-. The quinone imide methides that are produced by nucleophilic attack on the β-carbon of 2 react selectively enough with nonsolvent nucleophiles that they may be physiologically relevant.
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Transcranial magnetic stimulation (TMS) is able to noninvasively excite neuronal populations due to brief magnetic field pulses. The efficiency and the characteristics of stimulation pulse shapes influence the physiological effect of TMS. However, commercial devices allow only a minimum of control of different pulse shapes. Basically, just sinusoidal and monophasic pulse shapes with fixed pulse widths are available. Only few research groups work on TMS devices with controllable pulse parameters such as pulse shape or pulse width. We describe a novel TMS device with a full-bridge circuit topology incorporating four insulated-gate bipolar transistor (IGBT) modules and one energy storage capacitor to generate arbitrary waveforms. This flexible TMS (flexTMS ) device can generate magnetic pulses which can be adjusted with respect to pulse width, polarity, and intensity. Furthermore, the equipment allows us to set paired pulses with a variable interstimulus interval (ISI) from 0 to 20 ms with a step size of 10 μs. All user-defined pulses can be applied continually with repetition rates up to 30 pulses per second (pps) or, respectively, up to 100 pps in theta burst mode. Offering this variety of flexibility, flexTMS will allow the enhancement of existing TMS paradigms and novel research applications.
Article
Since its commercial advent in 1985, transcranial magnetic stimulation (TMS), a technique for stimulating neurons in the cerebral cortex through the scalp, safely and with minimal discomfort, has captured the imaginations of scientists, clinicians and lay observers. Initially a laboratory tool for neurophysiologists studying the human motor system, TMS now has a growing list of applications in clinical and basic neuroscience. Although we understand many of its effects at the system level, detailed knowledge of its actions, particularly as a modulator of neural activity, has lagged, due mainly to the lack of suitable non-human models. Nevertheless, these gaps have not blocked the therapeutic application of TMS in brain disorders. Moderate success has been achieved in treating disorders such as depression, where the U.S. Food and Drug Administration has cleared a TMS system for therapeutic use. In addition, there are small, but promising, bodies of data on the treatment of schizophrenic auditory hallucinations, tinnitus, anxiety disorders, neurodegenerative diseases, hemiparesis, and pain syndromes. Some other nascent areas of study also exist. While the fate of TMS as a therapeutic modality depends on continued innovation and experimentation, economic and other factors may be decisive.
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.
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
Preliminary work suggests that single-pulse transcranial magnetic stimulation (sTMS) could be effective as a treatment for migraine. We aimed to assess the efficacy and safety of a new portable sTMS device for acute treatment of migraine with aura. We undertook a randomised, double-blind, parallel-group, two-phase, sham-controlled study at 18 centres in the USA. 267 adults aged 18-68 years were enrolled into phase one. All individuals had to meet international criteria for migraine with aura, with visual aura preceding at least 30% of migraines followed by moderate or severe headache in more than 90% of those attacks. 66 patients dropped out during phase one. In phase two, 201 individuals were randomly allocated by computer to either sham stimulation (n=99) or sTMS (n=102). We instructed participants to treat up to three attacks over 3 months while experiencing aura. The primary outcome was pain-free response 2 h after the first attack, and co-primary outcomes were non-inferiority at 2 h for nausea, photophobia, and phonophobia. Analyses were modified intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00449540. 37 patients did not treat a migraine attack and were excluded from outcome analyses. 164 patients treated at least one attack with sTMS (n=82) or sham stimulation (n=82; modified intention-to-treat analysis set). Pain-free response rates after 2 h were significantly higher with sTMS (32/82 [39%]) than with sham stimulation (18/82 [22%]), for a therapeutic gain of 17% (95% CI 3-31%; p=0.0179). Sustained pain-free response rates significantly favoured sTMS at 24 h and 48 h post-treatment. Non-inferiority was shown for nausea, photophobia, and phonophobia. No device-related serious adverse events were recorded, and incidence and severity of adverse events were similar between sTMS and sham groups. Early treatment of migraine with aura by sTMS resulted in increased freedom from pain at 2 h compared with sham stimulation, and absence of pain was sustained 24 h and 48 h after treatment. sTMS could be a promising acute treatment for some patients with migraine with aura. Neuralieve.
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.