Cortical stimulation depth of nTMS investigated in a cohort of convexity meningiomas above the primary motor cortex

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Introduction
Transcranial magnetic stimulation is a noninvasive method to induce electric current in the brain.Navigated transcranial magnetic stimulation (nTMS) applies frameless neuronavigation to apply stimuli precisely with the guidance of imaging, achieving a high spatial resolution.For neuronavigation, line-navigated and electric-field nTMS are established techniques.Electric-field nTMS is often preferred, as it can calculate and visualize the induced electric field, including its orientation and angulation on the brain, based on the maximum electric field amplitude (Sollmann et al., 2016).The accuracy of electric-field nTMS was estimated at 6.2 mm in a review by Takahashi et al., whereas other reports found accuracies higher than 4 mm (Nieminen et al., 2022;Takahashi et al., 2013).
Effects of nTMS on the brain, for example, in the preoperative mapping of motor eloquent brain areas, are mostly assumed at the cortical level rather than in the underlying white matter, as the cortex is located closer to the stimulation coil and has a lower electrical resistance (Edgley et al., 1997).Pashut et al. (Pashut et al., 2011) investigated the effect of magnetic stimulation on simplified neurons and full models of cortical neurons (Pashut et al., 2011).In large pyramidal neurons, as present in the primary motor cortex, TMS was found to directly depolarize the soma, leading to the initiation of an action potential in the initial segment of the axon (Pashut et al., 2011).In addition, the orientation of the coil plays a major role, achieving the best effect of nTMS with the coil orientated perpendicular to the gyrus under the coil Abbreviations: LE, lower extremities; MEPs, motor-evoked potentials; MRI, magnetic resonance imaging; nTMS, Navigated transcranial magnetic stimulation; rMT, resting motor threshold; UE, upper extremity.at the site of stimulation (Kammer et al., 2007;Reijonen et al., 2020).However, depending on the coil type, the stimulation intensity, and the resulting electric field, the field of stimulation, including the depth of stimulation, might also affect deeper brain structures.
Until today, evidence of the maximum stimulation depth of nTMS is lacking.The distance between the surface of the scalp and the surface of the cortex varies between brain areas (Davis, 2021).At the primary motor cortex, distances ranging from 14 mm to 25 mm are found (Davis, 2021;Trillenberg et al., 2012).Trillenberg et al. examined the variation of stimulation intensity in TMS in relation to the resulting stimulation depth (Trillenberg et al., 2012).Motor-evoked potentials (MEPs) of the upper extremity were analyzed while increasing the ex-vivo scalp to coil distance (Trillenberg et al., 2012).At a stimulator intensity of 70%, MEPs in ten healthy subjects were derived up to a maximum scalp-to-coil distance of 8 -24 mm in addition to a scalp-to-cortex distance of 14.4 ± 3.0 mm (Trillenberg et al., 2012).The results of this study suggest that nTMS stimulation is capable of stimulating deeper brain structures than superficial cortical areas, as is currently the case in clinical routine.In order to verify these findings for in-vivo stimulation, the maximum stimulation depth of nTMS was evaluated using electric-field nTMS with the ability to compute the applied electric field values.A cohort of patients diagnosed with convexity meningiomas located over the cortical motor representation of the upper and lower extremities of the primary motor cortex was analyzed.This cohort seems optimal, as the meningioma is located above the cortex and therefore leads to a measurable in-vivo increase in the scalp-to-cortex distance.

Ethics
The current study was performed in accordance with the Declaration of Helsinki and its later amendments.It has been approved by the local institutional ethical review board (registration number: 336/17, 192/ 18).Written informed consent was obtained by all patients.

Patients and study inclusion
In total, 17 patients were included in this study.The inclusion criteria were (1) age above 18 years, (2) suspected diagnosis of a convexity meningioma located in close vicinity to the precentral gyrus, and (3) written informed consent.Patients with contraindications for MRI or nTMS examinations, including pregnancy, intracranial metallic implants, cochlear implants, and pacemakers, were excluded.

Anatomical imaging
A three-dimensional (3D) T1-weighted gradient echo sequence with and without application of a contrast agent (gadopentetate dimeglumine; Magnograf, Marotrast GmbH, Jena, Germany) was acquired preoperatively on a 3 T magnetic resonance imaging (MRI) scanner (Achieva; Philips Medical Systems, Best, The Netherlands B.V.) as part of the routine MRI protocol.

nTMS mapping protocol
A contrast-enhanced, T1-weighted gradient echo sequence was uploaded to a Nexstim eXimia NBS system (version 4.3 or 5.1; Nexstim Plc., Helsinki, Finland) for cortical nTMS motor mapping.An infrared tracking device (Polaris Spectra; Polaris, Waterloo, Ontario, Canada) combined with a head tracker with reflective sphere markers attached to the patient's forehead was used to align the patient's head with the MRIbased 3D head model using anatomical landmarks, enabling neuronavigation during the nTMS procedure (Krieg, 2017;Ruohonen and Karhu, 2010).Each patient's individual stimulation intensity was derived by determining the individual resting motor threshold (rMT).
Mapping of UE muscle representations was performed with a stimulation intensity of 110% rMT, whereas for the mapping of LE muscle representations, at least 130% rMT was applied according to clinical routine (Krieg et al., 2013).Continuous electromyography was performed to record induced motor-evoked potentials (MEPs).The M. abductor pollicis brevis, M. abductor digiti minimi, M. flexor carpi radialis, and M. biceps brachii were recorded for the upper extremity (UE) motor representations.For the lower extremities (LEs), the M. tibialis anterior and M. gastrocnemius were analyzed (Krieg, 2017;Krieg et al., 2017).For the identification of motor-positive mapping points, all stimulation sites were reviewed subsequent to the examination (Krieg, 2017;Krieg et al., 2017;Sollmann et al., 2016).MEPs with an amplitude exceeding 50 µV and a constant onset latency within the typical ranges of 15 to 50 ms for UE and LE muscles were defined as motor-positive and included for further analysis (Fig. 1).
Fig. 1 represents the nTMS mapping software (Nexstim eXimia NBS system version 4.3; Nexstim Plc., Helsinki, Finland) during motor mapping in an exemplary patient case, showing nTMS positive stimulation sites below the routine stimulation depth for both upper extremities (A) and lower extremities (B).

Evaluation of nTMS stimulation sites
MEP-positive nTMS stimulation sites were fused to the T1-weighted MRI scans (Fig. 2).All stimulation sites were evaluated in relation to the tumor, estimating the stimulation depth of the cortex.Stimulation sites with an effective stimulation depth > 25 mm to the cortical surface were selected (Fig. 2).
Fig. 2 outlines the measurements of the cortical stimulation depth and the perpendicular distance to the cortex at regular-stimulation levels for both upper (A) and lower extremities (B).The motor-evoked potential (MEP) positive stimulation sites of interest at the present stimulation depth are marked in red.
Furthermore, the lateral distance to the cortical surface was reviewed at a regular level, as false positive in-depth stimulation sites caused by nearby cortical stimulation at a regular stimulation level must be taken into consideration in this scenario (Figs.1,2).In the next step, the corresponding stimulation sessions were reviewed in the nTMS stimulation software (Nexstim eXimia NBS system version 4.3 or 5.1; Nexstim Plc., Helsinki, Finland), analyzing stimulation parameters and computed electric field values for stimulations on the cortical surface underneath the meningioma.The stimulation system creates a threedimensional head model and computes the resulting electric field values for optimal navigation and for each stimulation site and depth.

Data analysis
nTMS mapping data, including rMT, stimulation intensity, and maximum electric field values were analyzed, as well as patient and tumor characteristics.Statistical analyses were performed using Prism (version 9.1.1;GraphPad Software, La Jolla, CA, USA).Descriptive statistics were calculated for the patient-and tumor-related characteristics, including mean, median, minimum, maximum, and standard deviation.

Patient and tumor characteristics
In total, 17 patient cases histopathologically diagnosed with meningioma, located in close vicinity to motor-eloquent cortex, underwent preoperative nTMS examinations.In 5 cases, deep cortical stimulation sites > 25 mm were found, with 2 cases showing only UE MEPs, 2 cases of LE MEPs, and 1 case with UE and LE MEPs.The mean age was 61 ± 9 (45− 67) years, and 4 patients were male.The lesions were histopathologically diagnosed with meningioma classified by the World Health Organization (WHO) as central nervous system (CNS) degree 1 in 2 patients, CNS degree 2 in 2 patients, and CNS degree 3 in 1 patient (Louis et al., 2016).Further patient and tumor characteristics are illustrated in Table 1.
For LE, a maximum distance between the cortical surface and the coil of 33 ± 6 (27− 40) mm with a lateral border of 10 ± 3(6− 12) mm was observed (Table 2).Two comparable MEP-positive sites were found in 1 case, though it was 1 in both other cases.Estimated electric-field values were 71 ± 12 (64− 84) V/m, at a stimulation intensity of 0.64 ± 0.20 (0.50 -0.87;Table 2).Fig. 2 lines up all stimulation-related parameters for motor-evoked potentials (MEPs) for the in-depth cortical stimulation sites derived > 25 mm.

Interpretation of the stimulation results
The findings in this study suggest that nTMS can stimulate motoreloquent cortical brain areas and induce MEPs up to a depth of the cortical surface of 44 mm for conventional stimulation intensities.In 1 patient case, the maximum potential distance to the cortex exceeded the maximum stimulation depth eliciting MEPs -44 mm, while in all other cases, the maximum stimulation depth was limited by the scalp-tocortex distance.When interpreting these results, it must be considered that the stimulation intensity applied in this study was the routine intensity to perform motor mapping and not increased to potentially improve the stimulation depth.Navigated TMS with accurate modeling of the electric field was used, providing relevant information of the local electric field strength.By this, we were able to provide pseudoexperimental evidence that TMS can reach down to 44 mm from skin level and eliciting MEPs there with a still sufficient electric field of 69 V/ m.

Technical considerations on nTMS
This study underlines the potential neuromodulatory effect of nTMS, which reaches beyond superficial cortical stimulation, even when applying conventional stimulation intensities as used in clinical routine.To perform stimulation, a figure-8 coil is routinely used, as the architecture of this coil offers a beneficial balance between stimulation depth on the one side and focality on the other side.(Ueno and Sekino, 2021) In this study, a co-planar figure-8 coil (outer winding diameter of 70 mm) for biphasic stimulation with a calculated focal area of the stimulation hot spot of 0.68 cm 2 was applied for stimulation (Nexstim Ltd., Helsinki, Finland).Technical investigations regarding the increase of the stimulation threshold with an increase in the distance from scalp to coil showed an approximately exponential increase rather than a linear increase (Trillenberg et al., 2012).

Field of clinical applications of nTMS
Preoperatively, nTMS is routinely applied to identify the individual cortical representation of eloquent brain functions noninvasively.Mapping of the primary motor cortex and language function are established in clinical routines (Krieg et al., 2017).Further protocols identifying cortical representations of higher brain functions, such as calculation, the visuospatial system, and the supplementary motor area, are currently being established (Ille et al., 2018;Schaeffner and Welchman, 2017;Schramm et al., 2020).
Beyond its application for diagnostic intent, protocols of repetitive TMS (rTMS) were developed for the modulation of cortical excitability with therapeutic intent.In patients suffering from motor deficits due to stroke or postoperative ischemia, low-frequency rTMS can be applied to suppress the cortical activity in the ipsilateral motor cortex in order to release the damaged hemisphere from potentially excessive transcallosal inhibition (Ille et al., 2021;Mansur et al., 2005).
For the treatment of chronic pain, rTMS is applied to the motor cortex, as it has extensive projections to deep thalamic nuclei, which play a leading role in chronic pain, together with the somatosensory cortex and the limbic system (Mo et al., 2019).Chronic neuropathic pain is associated with disinhibition of the motor cortex, suggesting impaired GABAergic neurotransmission related to aspects of pain or to underlying sensory or motor disturbances (Lefaucheur et al., 2006;Mo et al., 2019).The analgesic effects produced by motor cortex stimulation are assumed to result from restoring defective intracortical inhibitory processes (Lefaucheur et al., 2006).
The primary motor cortex, furthermore, might represent a portal for the modulation of deep brain structures, as its stimulation triggers the corticothalamic output, reaching the brainstem, spinal cord, and also the limbic system, exerting a modulatory effect on these pathways (Najib et al., 2011).
High-frequency repetitive TMS is furthermore applied in the treatment of major depression.The main stimulation target addressed is the dorsolateral prefrontal cortex (McClintock et al., 2018).Stimulation impacts serotonergic receptors in the dorsolateral prefrontal cortex and the hippocampus (Baeken et al., 2011).Strafella et al. showed that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus putamen (Strafella et al., 2001).
Furthermore, Strafella et al. (2003) showed that rTMS of the left primary motor cortex affects dopamine concentration in the left putamen compared to rTMS applied to the left occipital cortex.Paus et al. (2001) applied rTMS to the left mid-dorsolateral frontal cortex and subsequently measured functional connectivity using positron emission tomography.The authors found a strong modulation of brain activity in the fronto-cingulate circuit induced by rTMS (Paus et al., 2001).

Limitations
The findings reported in this study are subject to certain limitations.Firstly, electric-field values given in this study were calculated by a computed head model and did not take potential perturbations of the magnetic field by the meningioma into account.Secondly, the focality of the coil is limited at higher stimulation intensities.Therefore, stimulation of surrounding cortical brain areas at a more superficial spot can be excluded only partially, despite the given lateral margins of 9 mm on average.The invasion of the cortex by the meningioma, which is found predominantly in higher-grade meningioma, must be considered, as it potentially reduces the effective distance between the scalp and cortex.Furthermore, the effect of the meningioma on the cortical excitability of the cortex underneath was not addressed; one patient showed a mild motor impairment due to the local space-occupying effect of the meningioma.

Conclusions
The findings in this study suggest that non-invasive stimulation by means of nTMS can be effective at stimulation depths reaching beyond the cortical level.Crucial elements for stimulation are the resulting electric field and the focality of the coil.
The effect of nTMS is not only limited to superficial cortical stimulation.Depending on electric-field intensity and focality, nTMS stimulation can be effectively applied at the cortical level up to an in-vivo depth of 44 mm.This leads to the assumption that nTMS can also stimulate deeper brain structures at the cortical and subcortical levels.

Declaration of Competing Interest
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.This trial was funded entirely by institutional grants from the Department of Neurosurgery.The authors declare no conflicts of interest.Sebastian Ille, Sandro M. Krieg, and Bernhard Meyer are consultants for Brainlab AG.Sebastian Ille is also a consultant for Icotec AG and Carl Zeiss Meditec AG and has past honoraria from Nexstim AG.Sandro M. Krieg is a consultant for Ulrich Medical and Need Inc. and received honoraria from Nexstim Plc, Spineart Deutschland GmbH, Medtronic, and Carl Zeiss Meditec AG.Bernhard Meyer received honoraria, consulting fees, and research grants from Medtronic, Icotec AG, and Relievant Medsystems Inc., honoraria and research grants from Ulrich Medical, honoraria and consulting fees from Spineart Deutschland GmbH and DePuy Synthes, royalties from Spineart Deutschland GmbH, and has a financial relationship with Medacta.The other authors have no personal, financial, or institutional interest in any drugs, materials, or devices described in this article.

Fig. 1
Fig. 1 illustrates patient characteristics of the 6 patients showing motor evoked potentials (MEPs) for a stimulation depth exceeding 25 mm.

Table 1
Patient characteristics.

Table 2
Stimulation parameters of in-depth cortical stimulation.