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. 2026 Oct 6;11:839–850. doi: 10.1016/j.cnp.2026.10.003

Electric field spread contributes to stimulation intensity-dependent expansion of navigated transcranial magnetic stimulation motor map

Evangelia Chatzikyriakou a, Konstantinos Pastiadis b, Theodoros Samaras c, Nikolaos Foroglou d, Marietta Tzirini c, Symeon Damianidis c, Konstantinos Kouskouras e, Vasilios Papaliagkas f, Evripidis Pityrigkas a, Vasiliki Poulidou a, Ioannis Vlachos a, Dimitris Kugiumtzis g, Vasilios K Kimiskidis a,⁎
PMCID: PMC13675860  PMID: 42893092

Abstract

Objective

Navigated transcranial magnetic stimulation (nTMS) is used for preoperative motor mapping, yet mechanisms of stimulation-intensity (SI)-dependent map expansion remain unclear. We investigated whether the extent of the induced electric field (EF) contributes to map expansion, using anatomical cavities adjacent to motor cortex as a model.

Methods

Two patients with postoperative and developmental cavities underwent nTMS mapping at 105% and 120% of resting motor threshold (rMT). Motor evoked potentials (MEPs) were recorded within cavities and intact cortex. Associations among distance from the cortical margin, rMT, and MEP amplitude were assessed. Map extension from reference points (RPs) was quantified toward cavities and intact tissue. In the postoperative case, finite-element modelling compared EF distributions in native and reconstructed anatomy.

Results

MEPs were elicited within cortex-free cavities despite absent cortical tissue beneath stimulation sites. Increasing distance from the cortical margin was associated with higher rMT and lower MEP amplitude. Higher SI expanded motor maps toward cavities and intact tissue. At 120% rMT, map extent from RPs was greater toward intact tissue, although directional distances are not physiologically equivalent because the functional motor-map boundary over intact cortex is unknown. Finite-element modelling showed high concordance between native and reconstructed anatomies, with a mean absolute EF difference of 1.34 V/m across stimulation sites.

Conclusions

Positive nTMS sites within cortex-free cavities demonstrate spatial dissociation between nominal stimulation sites and the neural elements generating MEPs. Findings support a contribution of EF spatial extent to SI-dependent map expansion.

Significance

Increasing SI improves response detection but may reduce spatial specificity.

Keywords: Navigated transcranial magnetic stimulation, Motor mapping, Motor evoked potentials, Finite-element modelling, Electric field modelling, Preoperative functional mapping, Anatomical cavity

Highlights

  • •

    Motor Evoked Potentials were elicited despite cortex-free cavity stimulation.

  • •

    Higher stimulation intensity expanded motor maps toward cavities and intact tissue.

  • •

    Finite-element modelling showed minimal EF distribution changes post-reconstruction.

1. Introduction

Navigated transcranial magnetic stimulation (nTMS) has become an established component of the preoperative evaluation of patients with intracranial lesions located near the primary motor cortex (Krieg et al., 2017; Raffa et al., 2019; Haddad et al., 2021). By providing non-invasive functional localization of eloquent cortex before surgery, nTMS complements structural neuroimaging and assists surgical planning by identifying cortical regions that should be preserved whenever possible (Leone et al., 2025). Numerous studies have demonstrated good agreement between nTMS and intraoperative direct cortical stimulation, supporting its value in maximizing the extent of tumor resection while reducing the risk of postoperative neurological deficits (Picht et al., 2011; Tarapore et al., 2012; Krieg et al., 2012; Coburger et al., 2013; Krieg et al., 2013; Paiva et al., 2024).

The clinical usefulness of nTMS depends not only on identifying the location of the primary motor cortex but also on accurately defining its spatial extent (Frey et al., 2014; Hendrix et al., 2021). Underestimation of functional motor cortex may increase the risk of postoperative motor deficits, whereas overestimation may unnecessarily restrict the surgical corridor or limit the extent of resection (Rosenstock et al., 2017; Ivren et al., 2023; Eibl et al., 2024). Consequently, understanding the factors that influence the size and morphology of navigated TMS motor maps is of direct clinical relevance (Sondergaard et al., 2021).

One of the most consistent observations in navigated TMS motor mapping is the progressive enlargement of motor maps as stimulation intensity increases (Kallioniemi and Julkunen, 2016; van de Ruit and Grey, 2016; Thordstein et al., 2013; Boyles et al., 2026). This phenomenon has been reported in healthy volunteers and in patients undergoing presurgical mapping and has influenced recommendations regarding stimulation intensity during routine clinical examinations (Krieg et al., 2017). Higher stimulation intensities increase the probability of eliciting motor evoked potentials (MEPs) and improve mapping efficiency, but they also reduce spatial specificity, making interpretation of motor map boundaries more challenging (Demjan et al., 2023; Boyles et al., 2026).

The physiological mechanisms responsible for stimulation intensity-dependent motor map expansion remain incompletely understood. Conventionally, enlargement of motor maps has been attributed to the recruitment of corticospinal neurons with progressively higher activation thresholds located at the periphery of the cortical representation (Thielscher et al., 2011; Weise et al., 2020). While this explanation is well supported experimentally, it may not fully explain responses obtained from stimulation sites that appear anatomically remote from excitable motor cortex.

An alternative, and potentially complementary, explanation is that increasing stimulation intensity enlarges the spatial extent of the induced electric field (EF), allowing activation of preserved corticospinal pathways located some distance from the nominal stimulation site (Opitz et al., 2013; Nieminen et al., 2022). If this is correct, the geometric location of the stimulation coil may not necessarily correspond to the cortical region responsible for generating the recorded motor response (Gomez-Tames et al., 2020; Chen et al., 2023). As stimulation intensity increases, the anatomical interpretation of motor maps therefore becomes subject to increasing spatial uncertainty, defined here as the discrepancy between the nominal stimulation site and the cortical region actually activated by the induced EF (Stenroos and Koponen, 2019; Dannhauer et al., 2024).

Direct investigation of this question is difficult in anatomically intact brains because stimulation is almost invariably delivered over excitable cortex (Nieminen et al., 2022). In contrast, large anatomical cavities adjacent to the primary motor cortex provide a unique physiological model for examining the spatial characteristics of nTMS-derived motor maps. Whether developmental or acquired, these cavities lack normal cortical tissue while remaining immediately adjacent to preserved corticospinal pathways. Consequently, motor responses elicited from stimulation sites located within the cavity are unlikely to result from direct activation of cortex beneath the stimulation site and instead provide an opportunity to investigate the contribution of the spatial extent of the induced electric field to motor map generation.

In the present exploratory study, we examined two patients with anatomically distinct cavities immediately adjacent to the primary motor cortex. In both cases, we stimulated multiple target points within the cavities and investigated the relationships between stimulation distance from the preserved cortical margin and corticomotor excitability (rMT and MEP amplitude). We also evaluated the influence of SI on motor-map expansion and, in response to the anatomical geometry of the paradigm, quantified extension from the same reference points both toward the cavity and toward anatomically intact tissue. Finally, in the postoperative case, patient-specific finite-element modelling compared the induced EF distribution between the native post-resection anatomy and an anatomically reconstructed in silico model. The computational comparison was intended to assess whether the cavity itself materially altered EF propagation, rather than to establish physiological generalizability to the intact brain. By combining clinical neurophysiology with computational modelling, we sought to improve understanding of SI-dependent motor-map expansion and its implications for presurgical functional localization.

2. Materials and methods

2.1. Study design

This prospective exploratory observational case series was conducted at the 1st Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece. The study was designed to investigate physiological mechanisms contributing to SI-dependent expansion of nTMS motor maps using anatomical cavities adjacent to the primary motor cortex (M1) as a natural experimental model.

The study protocol was approved by the Ethics Committee of Aristotle University of Thessaloniki (Approval No. 2.73/27.2.2019). Written informed consent was obtained from both participants before enrolment, and all procedures were performed in accordance with the Declaration of Helsinki and current international safety recommendations for transcranial magnetic stimulation.

2.2. Participants

Case 1 was a 73-year-old right-handed man who had undergone gross total resection of a WHO Grade I glioma involving the left frontal lobe. Twelve months after surgery, structural MRI demonstrated a well-defined postoperative cavity immediately adjacent to the hand representation of the left M1 (Fig. 1). At the time of assessment, the patient was neurologically stable without contraindications to nTMS.

Fig. 1.

Fig. 1

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Case 1: post-operative isotropic T1-weighted brain MRI depicting the target points (TPs 1–14) inside the resection cavity (A) and the reference points (RPs) on the anatomically intact M1 (B). Hotspot is also referred to as TP1. Case 2: isotropic T1-weighted brain MRI depicting TPs 1–10 inside the developmental cavity (C) and RPs on the anatomically intact M1 of Case 2 (D).

Case 2 was a 35-year-old right-handed man with a large developmental cavity involving the left frontal region immediately adjacent to an abnormally located M1 (Fig. 1). Unlike Case 1, the cavity was developmental rather than postoperative, providing an anatomically distinct configuration in which to examine the same physiological question. Case 2 had well-controlled focal epilepsy while receiving four antiseizure medications (gabapentin 1800 mg/24 h, oxcarbazepine 1500 mg/24 h, brivaracetam 200 mg/24 h, and lacosamide 400 mg/24 h).

Both participants completed the study without adverse events.

2.3. MRI acquisition and neuronavigation

High-resolution structural MRI scans were acquired using a 1.5-T Philips Multiva MRI scanner with isotropic T1-weighted sequences (1-mm voxel resolution) and imported into the eXimia Navigated Brain Stimulation (NBS) System (Nexstim Ltd., Helsinki, Finland).

2.4. Electromyographic recordings

Motor evoked potentials (MEPs) were recorded from the contralateral first dorsal interosseous (FDI) muscle using surface Ag/AgCl electrodes in a belly–tendon montage.

Signals were sampled at 3 kHz and band-pass filtered between 10 and 500 Hz. Trials contaminated by voluntary muscle contraction or recording artifacts were excluded before analysis.

2.5. Navigated transcranial magnetic stimulation

Navigated TMS was performed using the eXimia NBS navigation system (Nexstim Ltd., Helsinki, Finland, version 5.1) equipped with a biphasic figure-of-eight stimulation coil (70-mm wing diameter).

The optimal stimulation site (motor hotspot) for the contralateral FDI muscle was identified according to standard clinical procedures. Resting motor threshold (rMT) was determined using the maximum-likelihood threshold-hunting algorithm incorporated into the Nexstim NBS software (Awiszus, 2003). Interstimulus intervals of at least five seconds were employed to minimize carry-over effects and avoid changes in corticospinal excitability related to repetitive stimulation (Asmolova et al., 2025).

2.6. Experimental protocol

The experimental design exploited the presence of anatomical cavities immediately adjacent to M1.

In both cases, multiple sites were stimulated within the cavity, along the cavity margin, and over adjacent anatomically intact cortex (Fig. 1). For each site, the following variables were recorded: three-dimensional stimulation coordinates, rMT, SI, peak-to-peak MEP amplitude, and Euclidean distance from the preserved cortical margin.

The preserved motor cortex and the cortical margin immediately adjacent to each cavity were identified anatomically on the high-resolution T1-weighted MRI incorporated into the neuronavigation system, based on the preserved morphology of the precentral region. Functional motor localization, including inter alia, identification of the optimal stimulation site (motor hotspot) for the contralateral FDI muscle, was additionally performed using nTMS in accordance with established guidelines (Krieg et al., 2017). The reference points (RPs) used for distance measurements belonged to the nTMS-defined motor map and were positioned along the anatomically intact cortical boundary adjacent to the cavity. Thus, the RPs represented nTMS-positive motor-map sites located at the anatomically defined preserved cortical margin; tractography was not used to define these RPs.

For the comparison of map extension in the two directions, the same RPs were used to measure the distance to the farthest MEP-positive stimulation site both toward the cavity and in the opposite direction toward anatomically intact tissue. Importantly, the RPs provide a defined anatomical cortical boundary on the cavity-facing side but do not represent a known physiological boundary of the motor representation on the intact-tissue side.

To model the relationship between stimulation distance and MEP amplitude, we pooled all MEPs recorded across the experimental protocol. MEPs were elicited at each target point (TP; Fig. 1) during determination of the local rMT, repeated stimulation at each TP at 120% of the hotspot rMT, and motor mapping performed at 105% and 120% of the hotspot rMT. Consequently, stimulation intensities ranged from 30% to 79% of maximum stimulator output (MSO) in Case 1 and from 66% to 100% MSO in Case 2.

2.7. Motor mapping

Motor maps were acquired at two clinically relevant stimulation intensities (i.e. 105% & 120% rMT). The lower stimulation intensity represented a conventional clinical mapping protocol, whereas the higher intensity was selected to examine stimulation intensity-dependent changes in motor map morphology.

Mapping sessions were separated by approximately 30 min (Agboada et al., 2025). Motor maps were reconstructed using TMSmap software (Novikov et al., 2018). Only stimulation sites producing MEPs with peak-to-peak amplitudes ≥50 μV were included in the final maps.

For each SI condition and participant, the following motor-map parameters were calculated: map area, map volume, centre of gravity (CoG), maximum mapping distance within the cavity, and spatial extent from the same anatomical RPs toward both the cavity and anatomically intact tissue.

2.8. Computational modelling

For patient-specific computational modelling, finite-element head models were generated from structural MRI using iSeg (https://github.com/ITISFoundation/osparc-iseg).

Two anatomical models were constructed for Case 1: the original postoperative anatomy, and a digitally reconstructed anatomical model in which the postoperative cavity was replaced using mirrored contralateral anatomy, as explained in detail in the Supplementary material. The experimentally recorded coil position, orientation and stimulation intensity were reproduced in both simulations.

Comparison of these models allowed assessment of the influence of the postoperative cavity on the spatial distribution of the EF while maintaining identical stimulation parameters. Computational modelling was intentionally restricted to the postoperative case. Because the developmental cavity involved extensive congenital absence of cortical tissue, reconstruction would have required substantial anatomical assumptions that could not be independently validated. Restricting the simulations to the postoperative case therefore provided a more robust and physiologically interpretable computational framework.

The reconstruction of the brain in Case 2 was not performed because the cavity extends directly to the midline axis, and the intact right medial wall cannot serve as a symmetrical template without introducing severe topological errors (overlapping the longitudinal fissure) and unquantifiable geometric bias into the finite element mesh.

For each experimentally reproduced coil position corresponding to TPs 2–14 in Case 1, the EF magnitude was also extracted at the experimentally defined FDI motor hotspot (TP1). This analysis quantified the EF reaching the preserved hotspot when stimulation was nominally delivered at each target point; it does not, by itself, identify the neural element responsible for the recorded MEP.

2.9. Outcome measures

The primary physiological outcome was the relationship between stimulation distance and corticospinal excitability, assessed using rMT and MEP amplitude.

Secondary outcomes included motor-map area, motor-map volume, CoG, maximum extent of map expansion into the cavity, extension from the same RPs toward anatomically intact tissue, and comparison of motor maps generated at 105% and 120% rMT.

The principal computational outcome was the comparison of EF distributions between the original postoperative anatomy and the reconstructed anatomical model.

2.10. Statistical analysis

Relationships between stimulation distance, rMT and MEP amplitude were initially explored using regression analysis. Because repeated observations were obtained from individual stimulation sites, linear mixed-effects models were subsequently employed to account for within-site correlation while estimating the independent contributions of SI and distance. For details regarding the statistical analysis, please refer to the Supplementary File.

Motor maps acquired at 105% and 120% rMT were compared with respect to map area, map volume, CoG, and spatial extension from the anatomical RPs toward both the cavities and anatomically intact tissue. Given the two-case exploratory design, the directional extension measurements are presented descriptively.

3. Results

Reproducible MEPs were elicited from stimulation sites located within both anatomical cavities despite the absence of normal cortical tissue immediately beneath the nominal stimulation sites. The occurrence of this finding in both a postoperative and a developmental cavity indicates that it was not restricted to the postoperative configuration. The quantitative characteristics of the motor responses are detailed below.

3.1. Relationship between stimulation distance and corticospinal excitability

3.1.1. rMT – distance relationship

rMT increased progressively in both cases as stimulation sites became more distant from the preserved cortical margin.

In Case 1, rMT increased in a U-shaped manner from approximately 35% MSO at 10 mm to around 60% at 30 mm (Fig. 2). rMT remained almost constant (∼35%) for distances <15 mm of TPs from RPs.

Fig. 2.

Fig. 2

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Case 1: rMT values vs distance of stimulation points from each RP. Hot: hotspot. The quadratic model describing rMT vs from various RPs demonstrated excellent fit (e.g Hotspot R2 = 0.922).

In Case 2, the relationship between rMT and distance from the RPs followed a monotonic increasing pattern (Fig. 3). At approximately 5, 10, and 15 mm from the corresponding RP, rMT was approximately 68%, 88%, and 95% MSO, respectively. Importantly, at the more distant target points TP6–TP10, no MEP meeting the predefined response criterion could be elicited even at the maximum stimulator output of 100% MSO; rMT therefore could not be determined at these locations. Thus, compared with Case 1, Case 2 showed a more pronounced loss of corticospinal responsiveness with increasing stimulation distance.

Fig. 3.

Fig. 3

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Case 2: rMT values vs distance of stimulation points from each RP. Hot R2 = 0.9994). Open triangle symbols refer to Target Points TP6-TP10, for which no MEP could be recorded for intensities up to the maximum of 100% MSO, and thus the rMT could not be determined.

3.1.2. MEP amplitude – distance relationship

A linear mixed-effects model demonstrated a significant association between stimulation distance and MEP amplitude and confirmed that distance remained an independent predictor of MEP amplitude after accounting for repeated observations at different SIs obtained from individual stimulation sites. MEP amplitude decreased with increasing stimulation distance, demonstrating a gradual reduction in corticospinal responsiveness as stimulation moved farther from the preserved cortical margin. These relationships were observed in both participants. Fig. 4, Fig. 5 depict the model-predicted MEP-amplitude decay as a function of distance from the reference points at different SIs.

Fig. 4.

Fig. 4

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Case 1: predicted MEP amplitudes vs distance from RP at various stimulation intensity values. Intensities 37% and 42% correspond to 105% rMT and 120% rMT. Lighter shades are the 95% MEP prediction intervals, and darker shades are the 95% Cis for the estimated mean MEP vs distance.

Fig. 5.

Fig. 5

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Case 2: predicted MEP amplitudes vs distance from RP at various SI values. Intensities 67% and 77% correspond to 105% rMT and 120% rMT of hotspot (TP1) respectively. Lighter shades are the 95% MEP prediction intervals, and darker shades are the 95% Cis for the estimated mean MEP vs distance.

In Case 1, at an SI of 42% MSO corresponding to 120% rMT, predicted mean MEP amplitude decreased progressively with increasing distance (Fig. 4).

In Case 2, at an SI of 77% MSO corresponding to 120% rMT, predicted mean MEP amplitude likewise decreased with increasing distance, falling below the conventional 50-μV response criterion at more distant locations (Fig. 5).

Taken together, the rMT and MEP-amplitude findings indicate a progressive reduction in corticospinal responsiveness with increasing distance from the preserved cortical margin rather than an abrupt transition between responsive and non-responsive locations.

3.2. Effect of stimulation intensity on motor map morphology

Motor maps obtained at 105% rMT were consistently smaller than those acquired at 120% rMT in both participants (Fig. 6).

Fig. 6.

Fig. 6

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nTMS motor maps created at 105% r MT and 120% r MT in Case 1 (A and B, respectively) and Case 2 (C and D, respectively) depicting the extension of the maps, in a SI-dependent mode, into the anatomical cavities.

The motor maps generated at 105% rMT (Case 1: 37% MSO; Case 2: 67% MSO) had total areas of 4.83 cm2 and 9.34 cm2 and total volumes of 1297.9 uV*cm2 and 3048.1 uV*cm2 in Cases 1 and 2, respectively. At 120% rMT (Case 1: 42% MSO; Case 2: 77% MSO), both area and volume increased substantially (Case 1: 10.98 cm2 and 4460.6 uV*cm2; Case 2: 19.39 cm2 and 10,164.1 uV*cm2, respectively).

The centers of gravity (CoG; x/y/z) remained highly similar between conditions (Case 1: 105% SI: 66.2/85.2/183.6; 120% SI: 66.0/83.1/182.4; Case 2: 105% SI: 108.2/128.6/155.0; 120% SI: 106.1/119.8/154.8), indicating spatial stability of the core motor representation despite substantial map expansion.

Both maps extended into the respective anatomical cavities. To compare this cavity-facing extension with map extension over anatomically intact tissue, distances from the same RPs were also measured in the opposite direction (Table 1). When zero-distance observations were excluded, in Case 1 mean extension toward the cavity increased from 9.9 mm at 105% rMT to 13.5 mm at 120% rMT (Δ = +3.6 mm), whereas extension toward intact tissue increased from 9.4 to 16.4 mm (Δ = +7.0 mm). In Case 2, extension toward the cavity increased from 7.1 to 12.2 mm (Δ = +5.1 mm), while extension toward intact tissue increased from 10.4 to 18.0 mm (Δ = +7.6 mm). Thus, higher SI expanded the motor map in both directions, while the absolute map extent at 120% rMT was greater toward anatomically intact tissue. Because the RPs define the anatomical cortical margin rather than the unknown physiological boundary of the motor representation on the intact side, these absolute distances should not be interpreted as directly equivalent measures of EF-mediated map extension in the two directions.

Table 1.

Stimulation Intensity-dependent expansion of the motor responses within the cavities.

Case Reference point Cavity: 105% rMT (mm) Cavity: 120% rMT (mm) Δ cavity (mm) Intact tissue: 105% rMT (mm) Intact tissue: 120% rMT (mm) Δ intact (mm)
CASE 1 1LA 0.0 13.2 +13.2 13.1 22.2 +9.1
2LA 0.0 11.3 +11.3 12.9 19.0 +6.1
3LA 0.0 9.8 +9.8 11.9 13.1 +1.2
Hotspot 9.0 14.0 +5.0 12.6 21.9 +9.3
1RA 8.4 13.4 +5.0 9.8 21.9 +12.1
2RA 7.8 12.5 +4.7 11.1 18.0 +6.9
3RA 8.5 11.6 +3.1 4.9 16.3 +11.4
4RA 0.0 9.9 +9.9 0.0 10.6 +10.6
1LB 0.0 16.2 +16.2 10.1 19.2 +9.1
2LB 0.0 14.4 +14.4 9.9 16.0 +6.1
3LB 0.0 12.8 +12.8 8.9 10.1 +1.2
1B 12.0 17.0 +5.0 9.6 18.9 +9.3
1RB 11.4 16.4 +5.0 6.8 18.9 +12.1
2RB 10.8 15.5 +4.7 8.1 15.0 +6.9
3RB 11.5 14.6 +3.1 1.9 13.3 +11.4
4RB 0.0 12.9 +12.9 0.0 7.6 +7.6
Average distance (zero-values excluded) 9.9 13.5 +3.6 9.4 16.4 +7.0
Average distance (zero-values included) 5.0 – – 8.2 – –
CASE 2 3LA 0.0 0.0 0.0 0.0 12.5 +12.5
2LA 2.7 5.5 +2.8 10.9 21.8 +10.9
1LA 5.5 16.9 +11.4 10.9 18.0 +7.1
Hotspot 6.0 16.4 +10.4 8.7 16.4 +7.7
1RA 6.0 11.5 +5.5 11.5 23.5 +12.0
2RA 0.0 4.9 +4.9 16.4 22.9 +6.5
3RA 5.5 10.9 +5.4 15.3 23.5 +8.2
4RA 0.0 5.5 +5.5 12.5 22.4 +9.9
5RA 0.0 10.9 +10.9 12.5 22.4 +9.9
6RA 6.0 5.5 −0.5 9.8 16.9 +7.1
3LB 0.0 0.0 0.0 0.0 8.2 +8.2
2LB 5.5 10.9 +5.4 6.5 16.9 +10.4
1LB 10.9 21.8 +10.9 6.5 13.6 +7.1
1B 11.5 22.4 +10.9 4.4 12.0 +7.6
1RB 11.5 16.9 +5.4 7.1 19.1 +12.0
2RB 0.0 10.4 +10.4 12.0 18.5 +6.5
3RB 10.9 16.4 +5.5 10.9 19.1 +8.2
4RB 0.0 10.9 +10.9 8.7 18.0 +9.3
5RB 0.0 16.4 +16.4 8.7 18.0 +9.3
6RB 11.5 10.9 −0.6 5.5 12.5 +7.0
Average distance (zero-values excluded) 7.1 12.2 +5.1 10.4 18.0 +7.6
Average distance (zero-values included) 4.4 10.6 +6.2 9.1 18.0 +8.9
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Note: The same anatomical RPs were used in both directions. On the cavity-facing side, the RP corresponds to the preserved cortical margin; on the intact-tissue side, it does not represent a known functional motor-map boundary. “Zero-values excluded” averages follow the convention used in the original cavity analysis.

3.3. Patient-specific computational modelling

The original and anatomically reconstructed in silico models of Case 1, along with the simulated locations of the hotspot and TPs 2–14, as well as the resulting EF distributions, are depicted in Fig. 7.

Fig. 7.

Fig. 7

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The original (A) and anatomically reconstructed (B) in silico models of Case 1. In (B), the resection cavity was digitally restored by mirroring homologous tissue structures from the contralateral hemisphere and adapting them to the resection site.

Fig. 8 illustrates the EF magnitude at the experimentally defined FDI motor hotspot (TP1) when the coil was positioned at each of TPs 2–14, under both the original and anatomically reconstructed conditions. The results demonstrate high concordance between the two models, with a mean absolute difference of 1.34 V/m across stimulation sites.

Fig. 8.

Fig. 8

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Electric-field magnitude at the experimentally defined FDI motor hotspot (TP1) generated when the coil was positioned at each experimentally tested target point TP2–TP14. Values are shown for the original postoperative anatomy and the anatomically reconstructed model. Thus, the ordinate represents EF magnitude measured at the motor hotspot rather than at the nominal target point being stimulated.

These findings indicate that, within the assumptions of the computational model, anatomical reconstruction of the postoperative cavity did not substantially alter the modelled EF distribution. They do not, however, establish that the physiological distance-dependent effects observed in the cavity also occur in anatomically intact brain tissue.

4. Discussion

This exploratory study provides physiological and computational evidence that the spatial extent of the induced EF contributes to SI-dependent expansion of navigated transcranial magnetic stimulation motor maps.

The principal observation was that reproducible MEPs could be elicited when the nominal stimulation site lay within large anatomical cavities immediately adjacent to the primary motor cortex despite the absence of cortical tissue immediately beneath the coil. This demonstrates a spatial dissociation between the geometric location assigned to a positive nTMS site and the neural elements generating the response. Across both participants, corticospinal responsiveness decreased progressively with increasing distance from the preserved cortical margin, whereas higher SI expanded the motor maps farther into the cavities and over anatomically intact tissue. Patient-specific computational modelling showed that reconstruction of the postoperative cavity produced only limited changes in the overall EF distribution.

The occurrence of the same fundamental cavity phenomenon in two anatomically distinct configurations—one postoperative and one developmental—argues against an explanation restricted solely to postoperative anatomy. The present two-case study does not, however, establish generalizability to anatomically intact brains.

4.1. Anatomical cavities as a physiological model

A major strength of the present study is the use of anatomical cavities as a natural physiological model for investigating the spatial mechanisms of navigated TMS.

In anatomically intact brains, stimulation is invariably delivered over excitable cortex, making it difficult to determine whether the recorded MEP originates from neurons located directly beneath the stimulation coil or from neighbouring cortical regions activated by the spatial extent of the EF (Opitz et al., 2013; Siebner et al., 2022).

Large anatomical cavities adjacent to preserved motor cortex provide a unique opportunity to address this question. Because normal cortical tissue is absent immediately beneath nominal stimulation sites within the cavity, responses elicited from these locations cannot be attributed to direct activation of cortical neurons directly underneath the coil. Rather, they must reflect activation of excitable elements of the motor system reached by the spatially distributed EF. These may include neuronal elements within adjacent preserved motor cortex and/or corticofugal axons, including corticospinal projections. The present finite-element model estimates EF distribution but does not model neuronal activation and therefore cannot determine which neural elements predominantly generated the recorded MEPs.

Despite marked differences in origin and morphology, both cavities demonstrated the same fundamental relationship between increasing stimulation distance, reduced corticospinal responsiveness, and SI-dependent motor-map expansion. This consistency strengthens the use of the cavity as a physiological model while remaining exploratory because only two participants were studied.

4.2. Mechanisms of motor map expansion

Enlargement of motor maps with increasing stimulation intensity is a well-recognized feature of navigated TMS, but the mechanisms responsible remain incompletely understood (Kallioniemi and Julkunen, 2016; van de Ruit and Grey, 2016).

Traditionally, this phenomenon has been attributed to progressive recruitment of corticospinal neurons with higher activation thresholds located at the periphery of the cortical representation (Kobayashi and Pascual-Leone, 2003; Demjan et al., 2023). Our observations support a complementary interpretation in which increasing SI enlarges the spatial extent of the effective EF and thereby permits activation of excitable motor-system elements located farther from the nominal stimulation site (Thielscher et al., 2011; Siebner et al., 2022).

These mechanisms are not mutually exclusive. Rather, SI-dependent motor map expansion is likely to reflect the combined effects of neuronal recruitment and increased spatial propagation of the effective stimulating field (Spampinato et al., 2023; Massimini et al., 2026).

The additional analysis comparing map extension toward the cavity and toward anatomically intact tissue demonstrated SI-dependent expansion in both directions. At 120% rMT, the absolute map extent measured from the anatomical RPs was greater toward intact tissue than toward the cavity in both participants. This difference is physiologically plausible but cannot be interpreted simply as greater EF propagation over intact tissue, because the same RPs have fundamentally different physiological meanings in the two directions.

On the cavity-facing side, the cortical margin provides a clearly identifiable anatomical boundary: immediately beyond this margin, cortical tissue is absent, and a motor response elicited from a nominal stimulation site within the cavity necessarily reflects activation of neural elements located remotely from that site. In contrast, the anatomical RP is not the true functional boundary of the motor representation on the intact side. As stimulation proceeds away from the RP through intact cortex, the coil may initially overlie genuine motor-output elements and subsequently encounter more peripheral cortical regions. The measured intact-side extent may therefore comprise both the underlying functional motor representation and an additional SI-dependent component arising from recruitment of higher-threshold elements and/or spatial spread of the induced EF.

The greater absolute extent of the map over intact tissue is therefore not unexpected and does not contradict the cavity findings. Rather, the cavity provides the more anatomically constrained physiological model because the contribution of locally underlying cortical generators is removed beyond the cortical margin. Conversely, the intact-side measurements cannot currently distinguish locally generated MEPs from responses resulting from activation of spatially displaced neural elements. Direct cortical stimulation will be required to establish the true functional boundary of the motor representation and thereby determine the spatial specificity of peripheral nTMS-positive sites.

4.3. Relationship to previous studies

Previous studies have consistently demonstrated that motor map size increases with SI in healthy volunteers and patients undergoing presurgical mapping (Thordstein et al., 2013; Kallioniemi and Julkunen, 2016; van de Ruit and Grey, 2016). Computational investigations have likewise shown that increasing stimulator output enlarges the cortical volume exposed to suprathreshold electric fields (Opitz et al., 2013; Stenroos and Koponen, 2019; Dannhauer et al., 2024).

However, direct physiological evidence linking these observations has remained limited because neuronal activation cannot normally be dissociated from the anatomical stimulation site (Siebner et al., 2022).

The present study complements these earlier investigations by exploiting a rare clinical situation in which the absence of cortical tissue provides a physiological model for examining the spatial consequences of electric-field propagation.

4.4. Clinical implications

The findings have several practical implications for clinical navigated TMS.

First, motor responses should not necessarily be interpreted as indicating that eloquent cortex lies directly beneath the nominal stimulation site, particularly when higher stimulation intensities are used (Thordstein et al., 2013; Kallioniemi and Julkunen, 2016). Responses may instead reflect activation of motor-system elements located several millimetres from the nominal stimulation location (Thielscher et al., 2011; Opitz et al., 2013).

Second, SI should be considered when interpreting motor map boundaries during presurgical planning. Although higher stimulation intensities improve response reliability, they also reduce spatial specificity by increasing the volume of tissue exposed to effective stimulation (Thordstein et al., 2013; van de Ruit and Grey, 2016; Pellegrini et al., 2018).

Consequently, increasing SI may also increase spatial uncertainty, defined as the discrepancy between the geometric location of the stimulation coil and the cortical region actually activated by the induced electric field (Opitz et al., 2013; Gomez et al., 2021).

The present findings also highlight an opportunity to improve the anatomical interpretation of navigated TMS through integration with patient-specific computational electric-field modelling. Conventional neuronavigation accurately displays the geometric position of the stimulation coil but does not indicate the spatial distribution of the EF within the individual brain (Stenroos and Koponen, 2019; Dannhauer et al., 2024). As a result, the nominal stimulation site should not necessarily be equated with the site of neuronal activation, particularly in the presence of altered anatomy or when higher stimulation intensities are employed (Wang and Zhang, 2023; Wang et al., 2025).

Advances in MRI-based finite-element modelling now permit estimation of patient-specific E-field distributions using routinely acquired structural imaging (Stenroos and Koponen, 2019; Daneshzand et al., 2021; Dannhauer et al., 2024). Although such modelling is not yet part of standard clinical workflows, it has the potential to provide a more physiologically meaningful representation of the stimulated tissue by accounting for individual anatomy, tissue conductivity, coil orientation and stimulation intensity (Opitz et al., 2013; Matilainen et al., 2023; Wang et al., 2025). Integration of navigated TMS with patient-specific electric-field modelling may therefore improve the spatial interpretation of motor maps and contribute to more accurate preoperative functional localization (Seynaeve et al., 2019; Kubota et al., 2025).

4.5. Strengths and limitations

The principal strength of this study lies in the integration of direct physiological observations with patient-specific computational modelling (Opitz et al., 2013; Dannhauer et al., 2024). The inclusion of both postoperative and developmental cavities demonstrates that the observed cavity phenomenon was not confined to a single anatomical configuration.

Several limitations should be considered when interpreting the findings. First, only two participants were studied, reflecting the rarity of the anatomical configurations required for this experimental paradigm; the observations should therefore be regarded as exploratory and hypothesis-generating rather than population-level evidence. Second, no independent physiological gold standard, such as contemporaneous intraoperative direct cortical stimulation, was available to establish the exact neural origin of individual responses. Third, computational reconstruction was performed only for Case 1 because reconstruction of the extensive developmental cavity in Case 2 would have required substantial assumptions regarding absent anatomy, tissue composition, and conductivity that could not be independently validated (Stenroos and Koponen, 2019). Fourth, finite-element modelling depends on tissue segmentation and assigned electrical conductivities and estimates EF magnitude and distribution rather than neuronal activation itself. The present modelling therefore cannot distinguish whether MEPs elicited with the coil positioned over the cavity originated predominantly from neuronal elements within adjacent preserved motor cortex or corticofugal axons, including corticospinal projections.

A further limitation concerns comparison of map extension toward the cavity with extension toward anatomically intact tissue. On the cavity-facing side, the RP is a defined anatomical cortical margin beyond which local cortical tissue is absent. On the intact side, however, the same RP is not a ground-truth functional boundary of the motor representation. The larger intact-side map therefore potentially reflects both the underlying motor representation and SI-dependent spatial recruitment or EF spread, and the two directional distances cannot be interpreted as physiologically equivalent. Direct cortical stimulation will be required to define the true functional limits of the intact motor representation.

Accordingly, the present findings should be interpreted as mechanistic evidence of spatial dissociation between the nominal stimulation site and the neural elements generating the MEP, rather than as definitive localization of those elements or as validation of the spatial accuracy of individual nTMS-positive sites.

4.6. Future directions

The present findings suggest several directions for future investigation. Prospective multicentre studies including larger numbers of patients with anatomical cavities of different origin would permit assessment of the generalizability of these exploratory observations. An informative experiment would be to compare corticospinal responses elicited by stimulation within an anatomical cavity with responses obtained at comparable distances from M1 over anatomically intact non-motor cortex. Such an approach could directly test whether the distance-dependent effects demonstrated in the cavity also occur in intact brain tissue. Validation against intraoperative direct cortical stimulation and postoperative motor outcomes will be essential to define the true functional motor-map boundary and determine the spatial accuracy of peripheral nTMS-positive sites.

A further priority will be the development of clinically integrated workflows combining navigated TMS with patient-specific EF modelling (Daneshzand et al., 2021; Gomez et al., 2021; Dannhauer et al., 2024). Rather than relying solely on the geometric coil position, such approaches could estimate the neural tissue most strongly exposed under the stimulation conditions used for each patient (Seynaeve et al., 2019; Matilainen et al., 2023). If validated prospectively, this framework may reduce spatial uncertainty and improve the anatomical interpretation of motor maps in precision neurosurgery (Stenroos and Koponen, 2019; Daneshzand et al., 2021).

5. Conclusions

This exploratory study demonstrates that reproducible MEPs can be elicited when the nominal nTMS stimulation site lies within postoperative or developmental anatomical cavities lacking cortical tissue immediately beneath the coil. Corticospinal responsiveness decreased progressively with increasing distance from the preserved cortical margin, whereas higher SI expanded motor responses both toward the cavities and over anatomically intact tissue. These observations demonstrate that the geometric location of a positive nTMS stimulation site does not necessarily correspond to the location of the neural elements generating the response and support a contribution of the spatial extent of the EF to SI-dependent motor-map expansion. Patient-specific finite-element modelling further showed that anatomical reconstruction of the postoperative cavity produced only limited changes in the modelled EF distribution. The present data do not establish the precise neural elements responsible for MEP generation during cavity stimulation and should be considered exploratory. Validation against direct cortical stimulation and larger prospective cohorts will be required to define the true functional motor-map boundary and determine the spatial specificity of nTMS-positive sites.

Informed consent

Written informed consent was obtained from all participants prior to enrolment.

Ethics approval

The study was approved by the Ethics Committee of Aristotle University of Thessaloniki (Approval No. 2.73/27.2.2019) and was conducted in accordance with the ethical principles of the Declaration of Helsinki and its subsequent amendments.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors thank the participants for their willingness to contribute to research aimed at improving the interpretation and clinical application of navigated transcranial magnetic stimulation in preoperative functional mapping.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.cnp.2026.10.003.

Appendix A. Supplementary data

Supplementary material

mmc1.docx (470.4KB, docx)

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Supplementary material

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