Conditions for numerically accurate TMS electric field simulation

BackgroundComputational simulations of the E-field induced by transcranial magnetic stimulation (TMS) are increasingly used to understand its mechanisms and to inform its administration. However, characterization of the accuracy of the simulation methods and the factors that affect it is lacking.ObjectiveTo ensure the accuracy of TMS E-field simulations, we systematically quantify their numerical error and provide guidelines for their setup.MethodWe benchmark the accuracy of computational approaches that are commonly used for TMS E-field simulations, including the finite element method (FEM) with and without superconvergent patch recovery (SPR), boundary element method (BEM), finite difference method (FDM), and coil modeling methods.ResultsTo achieve cortical E-field error levels below 2%, the commonly used FDM and 1st order FEM require meshes with an average edge length below 0.4 mm, 1st order SPR-FEM requires edge lengths below 0.8 mm, and BEM and 2nd (or higher) order FEM require edge lengths below 2.9 mm. Coil models employing magnetic and current dipoles require at least 200 and 3000 dipoles, respectively. For thick solid-conductor coils and frequencies above 3 kHz, winding eddy currents may have to be modeled.ConclusionBEM, FDM, and FEM all converge to the same solution. Compared to the common FDM and 1st order FEM approaches, BEM and 2nd (or higher) order FEM require significantly lower mesh densities to achieve the same error level. In some cases, coil winding eddy-currents must be modeled. Both electric current dipole and magnetic dipole models of the coil current can be accurate with sufficiently fine discretization.     

Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study

ObjectiveTo compare the ability of an H-coil and figure-8 coil to stimulate different motor cortex regions.MethodsThe resting (rMT) and active (aMT) motor thresholds were measured for the right hand APB and leg AHB muscles in 10 subjects, using an H-coil and a figure-8 coil. The electric field distribution induced by the coils was measured in a head model. The combination of the hand and leg MTs with the field measurements was used to determine the depth of hand and leg motor areas via the intersection points.ResultsThe rMT and aMT of both APB and AHB were significantly lower for the H-coil. The ratio and difference between the leg and hand rMT and aMT were significantly lower for the H-Coil. Electric field measurements revealed significantly more favorable depth profile and larger volume of stimulation for the H-coil. The averaged intersection for the APB was at a distance from coil of 1.83 ± 0.54 cm and at an intensity of 97.8 ± 21.4 V/m, while for the AHB it was at a distance of 2.73 ± 0.44 cm and at an intensity of 118.6 ± 21.3 V/m.ConclusionThe results suggest a more efficient activation of deeper motor cortical regions using the H-coil.SignificanceThe combined evaluation of MTs by H- and figure-8 coils allows measurement of the individual depth of different motor cortex regions. This could be helpful for optimizing stimulation parameters for TMS treatment.     

Effect of individual anatomy on resting motor threshold-computed electric field as a measure of cortical excitability

Introduction

Transcranial magnetic stimulation (TMS) is used for assessing the excitability of cortical neurons and corticospinal pathways by determining the subject-specific motor threshold (MT). However, the MT is dependent on the TMS instrumentation and exhibits large variation. We hypothesized that between-subject differences in scalp-to-cortex distance could account for the variation in the MT. Computational electric field (EF) estimation could theoretically be applied to reduce the effect of anatomical differences, since it provides a more direct measure of corticospinal excitability.

Methods

The resting MT of the thenar musculature of 50 healthy subjects (24 male and 26 female, 22-69 years) was determined bilaterally at the primary motor cortex with MRI-navigated TMS using monophasic and biphasic stimulation. The TMS-induced maximum EF was computed at a depth of 25 mm from the scalp (EF_25 mm) and at the individual depth of the motor cortex (EF_cortex) determined from MRI-scans.

Results

All excitability parameters (MT, EF_25 mm and EF_cortex) correlated significantly with each other (p < 0.001). EF_cortex at MT intensity was 95 ± 20 V/m for biphasic and 120 ± 24 V/m for monophasic stimulation. The MT did not correlate with the anatomical scalp-to-cortex distance, whereas the coil-to-cortex distance was found to correlate positively with the MT and negatively with EF_cortex (p < 0.05).

Discussion

In healthy subjects, the scalp-to-cortex distance is not a significant determinant of the MT, and thus the use of EF_cortex does not offer substantial advantages. However, it provides a purposeful and promising tool for studying non-motor cortical areas or patient groups with possible disease-related anatomical alterations.     

The effect of meninges on the electric fields in TES and TMS. Numerical modeling with adaptive mesh refinement

BackgroundWhen modeling transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) in the brain, the meninges – dura, arachnoid, and pia mater – are often neglected due to high computational costs.ObjectiveWe investigate the impact of the meningeal layers on the cortical electric field in TES and TMS while considering the headreco segmentation as the base model.MethodWe use T1/T2 MRI data from 16 subjects and apply the boundary element fast multipole method with adaptive mesh refinement, which enables us to accurately solve this problem and establish method convergence at reasonable computational cost. We compare electric fields in the presence and absence of various meninges for two brain areas ($\text{M}{1}_{\text{HAND}}$ and $\text{DLPFC}$) and for several distinct TES and TMS setups.ResultsMaximum electric fields in the cortex for focal TES consistently increase by approximately 30% on average when the meninges are present in the CSF volume. Their effect on the maximum field can be emulated by reducing the CSF conductivity from 1.65 S/m to approximately 0.85 S/m. In stark contrast to that, the TMS electric fields in the cortex are only weakly affected by the meningeal layers and slightly (～6%) decrease on average when the meninges are included.ConclusionOur results quantify the influence of the meninges on the cortical TES and TMS electric fields. Both focal TES and TMS results are very consistent. The focal TES results are also in a good agreement with a prior relevant study. The solver and the mesh generator for the meningeal layers (compatible with SimNIBS) are available online.     

Multi-locus transcranial magnetic stimulation system for electronically targeted brain stimulation

BackgroundTranscranial 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.ObjectiveTo develop an mTMS system that allows adjusting the location and orientation of the E-field maximum within a cortical region.MethodsWe 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.ResultsThe 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.ConclusionThe developed mTMS system enables electronically targeted brain stimulation within a cortical region.     

Motor evoked potentials from masseter muscle induced by transcranial magnetic stimulation of the pyramidal tract: the importance of coil orientation

BACKGROUND: Reliable recording of motor evoked potentials (MEPs) of the masseter muscle by transcranial magnetic stimulation (TMS) has proved more difficult than from facial or intrinsic hand muscles. Up to now it was unclear whether this difficulty was due to methodological and/or anatomical reasons. METHODS: The mechanism of pyramidal cell activation in masseter MEPs was investigated by using magnetic and electric transcranial stimulation. Analysing the effect of magnetic coil positioning and orientation over the scalp, and scrutinizing the masseter recording technique to avoid compound motor action potential (CMAP) contamination from facial muscles, an optimized method of masseter MEPs was developed. RESULTS: In particular, an antero-lateral inducing current orientation in the stimulating coil, approximately paralleling the central sulcus, proved clearly more effective for the masseter muscles than the postero-lateral orientation (P=0.005) found optimal for intrinsic hand muscles. The thus evoked masseter MEPs by transcranial magnetic stimulation (TMS) were found to be identical in shape, amplitude and latency as those evoked by transcranial electric stimulation (TES), evidencing a direct rather than trans-synaptic activation of the pyramidal cells. CONCLUSIONS: We conclude that in TMS evoked MEPs of masseter muscles, the direct stimulation of the pyramidal tract is more easily achieved than the trans-synaptic activation, which is in contrast to the intrinsic hand muscles. We hypothesize that the presynaptic projections to pyramidal cells of the masticatory muscles are less abundant than in hand muscles, and are therefore less accessible to trans-synaptic stimulation.     

Atlas of optimal coil orientation and position for TMS: A computational study

Background

Transcranial magnetic stimulation (TMS) activates target brain structures in a non-invasive manner. The optimal orientation of the TMS coil for the motor cortex is well known and can be estimated using motor evoked potentials. However, there are no easily measurable responses for activation of other cortical areas and the optimal orientation for these areas is currently unknown.

TMS with fast and accurate electronic control: Measuring the orientation sensitivity of corticomotor pathways

BackgroundTranscranial magnetic stimulation (TMS) coils allow only a slow, mechanical adjustment of the stimulating electric field (E-field) orientation in the cerebral tissue. Fast E-field control is needed to synchronize the stimulation with the ongoing brain activity. Also, empirical models that fully describe the relationship between evoked responses and the stimulus orientation and intensity are still missing.ObjectiveWe aimed to (1) develop a TMS transducer for manipulating the E-field orientation electronically with high accuracy at the neuronally meaningful millisecond-level time scale and (2) devise and validate a physiologically based model describing the orientation selectivity of neuronal excitability.MethodsWe designed and manufactured a two-coil TMS transducer. The coil windings were computed with a minimum-energy optimization procedure, and the transducer was controlled with our custom-made electronics. The electronic E-field control was verified with a TMS characterizer. The motor evoked potential amplitude and latency of a hand muscle were mapped in 3° steps of the stimulus orientation in 16 healthy subjects for three stimulation intensities. We fitted a logistic model to the motor response amplitude.ResultsThe two-coil TMS transducer allows one to manipulate the pulse orientation accurately without manual coil movement. The motor response amplitude followed a logistic function of the stimulus orientation; this dependency was strongly affected by the stimulus intensity.ConclusionThe developed electronic control of the E-field orientation allows exploring new stimulation paradigms and probing neuronal mechanisms. The presented model helps to disentangle the neuronal mechanisms of brain function and guide future non-invasive stimulation protocols.     

Impact of pulse duration in single pulse TMS

Objective

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.

Methods

A Magstim Bistim² 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.

Results

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.

Conclusions

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.

Significance

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.     

Neuronavigation maximizes accuracy and precision in TMS positioning: Evidence from 11,230 distance,angle, and electric field modeling measurements

BackgroundResearchers and clinicians have traditionally relied on elastic caps with markings to reposition the transcranial magnetic stimulation (TMS) coil between trains and sessions. Newer neuronavigation technology co-registers the patient's head and structural magnetic resonance imaging (MRI) scan, providing the researcher with real-time feedback about how to adjust the coil to be on-target. However, there has been no head to head comparison of accuracy and precision across treatment sessions.Objective/Hypothesis: In this two-part study, we compared elastic cap and neuronavigation targeting methodologies on distance, angle, and electric field (E-field) magnitude values.MethodsIn 42 participants receiving up to 50 total accelerated rTMS sessions in 5 days, we compared cap and neuronavigation targeting approaches in 3408 distance and 6816 angle measurements. In Experiment 1, TMS administrators saved an on-target neuronavigation location at Beam F3, which served as the landmark for all other measurements. Next, the operators placed the TMS coil based on cap markings or neuronavigation software to measure the distance and angle differences from the on-target sample. In Experiment 2, we saved each XYZ coordinate of the TMS coil from cap and neuronavigation targeting in 12 participants to compare the E-field magnitude differences at the cortical prefrontal target in 1106 cap and neuronavigation models.ResultsCap targeting was significantly off-target for distance, placing the coil an average of 10.66 mm off-target (Standard error of the mean; SEM = 0.19 mm) compared to 0.3 mm (SEM = 0.03 mm) for neuronavigation (p < 0.0001). Cap targeting also significantly deviated for angles off-target, averaging 7.79 roll/pitch degrees (SEM = 1.07°) off-target and 5.99 yaw degrees (SEM = 0.12°) off-target; in comparison, neuronavigation targeting positioned the coil 0.34 roll/pitch degrees (SEM = 0.01°) and 0.22 yaw (SEM = 0.004°) off-target (both p < 0.0001). Further analyses revealed that there were significant inter-operator differences on distance and angle positioning for F3 (all p < 0.05), but not neuronavigation. Lastly, cap targeting resulted in significantly lower E-fields at the intended prefrontal cortical target, with equivalent E-fields as 110.7% motor threshold (MT; range = 58.3–127.4%) stimulation vs. 119.9% MT (range = 115–123.3%) from neuronavigated targeting with 120% MT stimulation applied (p < 0.001).ConclusionsCap-based targeting is an inherent source of target variability compared to neuronavigation. Additionally, cap-based coil placement is more prone to differences across operators. Off-target coil placement secondary to cap-based measurements results in significantly lower amounts of stimulation reaching the cortical target, with some individuals receiving only 48.6% of the intended on-target E-field. Neuronavigation technology enables more precise and accurate TMS positioning, resulting in the intended stimulation intensities at the targeted cortical level.     

Comparison of electric field modeling pipelines for transcranial direct current stimulation

ObjectivesElectric field modeling utilizes structural brain magnetic resonance images (MRI) to model the electric field induced by non-invasive transcranial direct current stimulation (tDCS) in a given individual. Electric field modeling is being integrated with clinical outcomes to improve understanding of inter-individual variability in tDCS effects and to optimize tDCS parameters, thereby enhancing the predictability of clinical effects. The successful integration of modeling in clinical use will primarily be driven by choice of tools and procedures implemented in computational modeling. Thus, the electric field predictions from different modeling pipelines need to be investigated to ensure the validity and reproducibility of tDCS modeling results across clinical or translational studies.MethodsWe used T1w structural MRI from 32 healthy volunteer subjects and modeled the electric field distribution for a fronto-temporal tDCS montage. For five different computational modeling pipelines, we quantitatively compared brain tissue segmentation and electric field predicted in whole-brain, brain tissues and target brain regions between the modeling pipelines.ResultsOur comparisons at various levels did not reveal any systematic trend with regards to similarity or dissimilarity of electric field predicted in brain tissues and target brain regions. The inconsistent trends in the predicted electric field indicate variation in the procedures, routines and algorithms used within and across the modeling pipelines.ConclusionOur results suggest that studies integrating electric field modeling and clinical outcomes of tDCS will highly depend upon the choice of the modeling pipelines and procedures. We propose that using these pipelines for further research and clinical applications should be subject to careful consideration, and indicate general recommendations.     

Multi-locus transcranial magnetic stimulation—theory and implementation

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.

Sound comparison of seven TMS coils at matched stimulation strength

BackgroundAccurate data on the sound emitted by transcranial magnetic stimulation (TMS) coils is lacking.MethodsWe recorded the sound waveforms of seven coils with high bandwidth. We estimated the neural stimulation strength by measuring the induced electric field and applying a strength–duration model to account for different waveforms.ResultsAcross coils, at maximum stimulator output and 25 cm distance, the sound pressure level (SPL) was 98–125 dB(Z) per pulse and 76–98 dB(A) for a 20 Hz pulse train. At 5 cm distance, these values were estimated to increase to 112–139 dB(Z) and 90–112 dB(A), respectively.ConclusionsThe coils’ airborne sound can exceed some exposure limits for TMS subjects and, in some cases, for operators. These findings are consistent with the current TMS safety guidelines that recommend the use of hearing protection.     

Reliability of the 'observation of movement' method for determining motor threshold using transcranial magnetic stimulation

The aim of this study was to establish the reliability of the observation of movement (OM) method for obtaining motor threshold (MT) in transcranial magnetic stimulation (TMS). MTs were obtained on separate days, following separate hunting procedures, for both left and right motor cortex (M1), with one or multiple estimates obtained from the same hemisphere within a single session. MTs obtained using the OM method were highly reliable and reproducible on different days (left M1: r = .98, p < .0001; right M1: r = .97, p < .0001). MTs were not influenced by the order of acquisition when two hemispheres were stimulated in the same session [F(1,22) = .12, p = .73] or by the collection of additional MTs as part of the distance-adjusted procedure [F(1,23) = .74, p = .40]. The results verify the reliability of the OM method and confirm its viability for the safe and efficient application of TMS to the left and right M1. The OM method is a reliable technique for obtaining MT and is relatively simple and quick to run. It therefore provides an effective procedure for research and clinical applications.     

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19.ObjectiveTo facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS).MethodsThe present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research – with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics.ResultsA model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described.ConclusionThere is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.     

TMS of primary motor cortex with a biphasic pulse activates two independent sets of excitable neurones

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.

A reexamination of motor and prefrontal TMS in tobacco use disorder: Time for personalized dosing based on electric field modeling?

ObjectiveIn this study, we reexamined the use of 120% resting motor threshold (rMT) dosing for transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) using electric field modeling.MethodsWe computed electric field models in 38 tobacco use disorder (TUD) participants to compare figure-8 coil induced electric fields at 100% rMT over the primary motor cortex (M1), and 100% and 120% rMT over the DLPFC. We then calculated the percentage of rMT needed for motor-equivalent induced electric fields at the DLPFC and modeled this intensity for each person.ResultsElectric fields from 100% rMT stimulation over M1 were significantly larger than what was modeled in the DLPFC using 100% rMT (p < 0.001) and 120% rMT stimulation (p = 0.013). On average, TMS would need to be delivered at 133.5% rMT (range = 79.9 to 247.5%) to produce motor-equivalent induced electric fields at the DLPFC of 158.2 V/m.ConclusionsTMS would have to be applied at an average of 133.5% rMT over the left DLPFC to produce equivalent electric fields to 100% rMT stimulation over M1 in these 38 TUD patients. The high interindividual variability between motor and prefrontal electric fields for each participant supports using personalized electric field modeling for TMS dosing to ensure that each participant is not under- or over-stimulated.SignificanceThese electric field modeling in TUD data suggest that 120% rMT stimulation over the DLPFC delivers sub-motor equivalent electric fields in many individuals (73.7%). With further validation, electric field modeling may be an impactful method of individually dosing TMS.     

Where and what TMS activates: Experiments and modeling

Background

Despite recent developments in navigation and modeling techniques, the type and location of the structures that are activated by transcranial magnetic stimulation (TMS) remain unknown.