# Improving Cerebellar TMS Targeting: MRI-Neuronavigation and Landmark-Based Approaches Assessed by E-Field Modeling

Vridhi Rohira, Xavier Corominas-Teruel, Salim Ouarab, Traian Popa, Cécile Gallea, Antoni Valero-Cabré, Martina Bracco

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Vridhi Rohira, Xavier Corominas-Teruel, Salim Ouarab, Traian Popa, Cécile Gallea, et al. Improving Cerebellar TMS Targeting: MRI-Neuronavigation and Landmark-Based Approaches Assessed by E-Field Modeling. Brain Stimulation, 2025, 10.1016/j.brs.2025.05.010. hal-05384927

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Distributed under a Creative Commons Attribution 4.0 International License
Improving Cerebellar TMS Targeting:
MRI-Neuronavigation and Landmark-Based Approaches
Assessed by E-Field Modeling

Vridhi Rohira\*, Xavier Corominas-Teruela,b,c\*, Salim Ouarabd, Traian Popae,f,
Cécile Gallea\#, Antoni Valero-Cabréb,g,h\# & Martina Braccoa,b\#

aSorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm,
CNRS, Mov-it Team, APHP, Hôpital de la Pitié Salpêtrière, Paris, France

bSorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm,
CNRS, Dynamics, Plasticity and Rehabilitation Group, Frontlab Team, APHP,
Hôpital de la Pitié Salpêtrière, Paris, France

cDepartment of Psychology and Research Center for Behaviour Assessment
(CRAMC), Universitat Rovira i Virgili, Neurobehavior and Health Research Group,
NEUROLAB, Tarragona, Spain

dSorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm,
CNRS, Center for NeuroImaging Research (CENIR), APHP, Hôpital de la Pitié
Salpêtrière, Paris, France

eLausanne University Hospital (CHUV), Department of Clinical Neurosciences,
Lausanne, Switzerland

fLake Lucerne Institute (LLUI), Vitznau, Switzerland

gCognitive Neuroscience and Information Tech. Research Program, Open
University of Catalonia (UOC), Barcelona, Spain

hDept. Anatomy and Neurobiology, Laboratory of Cerebral Dynamics, Boston
University School of Medicine, Boston, USA

*Both authors contributed equally.

\# All three authors share senior authorship

Please address correspondence to:

Martina Bracco

Institut du Cerveau - Paris Brain Institute - ICM

Hôpital Pitié-Salpêtrière

47 bd de l'Hôpital, 75013, Paris, France

Email: martina.bracco@icm-institute.org (MB)
Dear Editor,

Transcranial magnetic stimulation (TMS) is widely employed to modulate cerebellar activity [1]. Although neuronavigation is widely used to target cortical regions, cerebellar TMS is still predominantly guided by scalp landmarks (for review; [2]). The most employed approaches involve placing the center of the coil either (1) 1 cm below and 3 cm lateral to the inion (inion-lateral) or (2) halfway between the inion and the mastoid (inion-mastoid). Both are assumed to target cerebellar lobule VIII [2]. Yet, individual anatomical variability in scalp and brain anatomy makes such landmark-based approaches potentially imprecise.

To overcome this limitation, we propose an approach that combines magnetic resonance imaging (MRI)-based neuronavigation based on a cerebellar spatially unbiased atlas template (SUIT; [3]; neuronavigation-guided). It consists of four main steps. First, structural 3D-T1-weighted MRI scans are acquired. Next, the participants' cerebellum is segmented using the SUIT atlas. The image of the target lobule is then binarized, overlaid onto the participant's MRI, and used through neuronavigation to place the TMS coil center at the shortest Euclidian distance from the targeted lobule (Figure 1A).

We compared this method to the two landmark-based approaches by conducting electric field (E-field) simulations in 20 participants (9 women; 24.8±5.9 years; mean±SD). Participants were enrolled in a TMS experiment targeting the right Crus II using the neuronavigation-guided approach to identify the optimal coil position. We recorded its spatial coordinates, along with those of the two landmark-based approaches using the neuronavigation system (Braininsight, Rogue Research Inc., Montréal, QC, Canada), and then exported them for E-field modeling.

We used SimNIBS4.0 and its 'charm' routine [4] to generate individual tetrahedral finite element head models from participants' MRIs. E-fields were estimated by assuming a quasi-static regime with predefined standard isotropic conductive values [5]. For each participant, we modeled the E-fields produced by two TMS coils commonly used for cerebellar stimulation: the Magstim 70 mm figure-of-8 (alpha) coil (D70; initial induced current oriented downward in the cerebellum; dI/dtmax=114.7A/us at 100% Maximum Stimulator Output [MSO]; [6]), and the Magstim double-cone-coil (DCC; dI/dtmax=84.4A/us at 100% MSO; [6]). The dI/dtmax values used for modeling were linearly corrected based on TMS intensity [6]. This was set to the participants' resting motor threshold (rMT; 77.8±8.5 MSO; mean±SD). The rMT was assessed using the Magstim 70 mm figure-of-8 (alpha) coil powered by a Magstim-Rapid2 stimulator (biphasic pulse waveform). The simulated E-fields for the three targeting approaches and two coil types were finally normalized by their specific maximum E-field value (E/Emax; Figure 1B-C), defined as the peak within the cortical surface after removing potential outliers (the top 0.1% of values).

We statistically compared the normalized E-field strength in the right Crus II and the right lobule VIII (average of all voxels within each region). In Crus II,
a 3x2 rmANOVA revealed a significant effect of approach ($F_{(2,38)}$=12.92, *p*<0.001, $\eta_p^2$=0.41; Figure 1D). Specifically, the inion-lateral approach induced a weaker E-field strength than the neuronavigation-guided (neuronavigation-guided vs. inion-lateral: *t*=3.90, *p*=0.001, *d*=0.48) and the inion-mastoid approach (inion-lateral vs. inion-mastoid: *t*=-4.78, *p*<0.001, *d*=-0.58).

Although weaker E-fields were induced in lobule VIII as compared to Crus II (3x2x2 rmANOVA; lobule: $F_{(1,19)}$=809.90, *p*<0.001, $\eta_p^2$=0.98; Crus II vs. lobule VIII: *t*=28.46, *p*<0.001, *d*=3.78), here a similar trend was observed, with the inion-lateral approach inducing a weaker E-field strength than the neuronavigation-guided and the inion-mastoid approach (3x2 rmANOVA, approach: $F_{(2,38)}$=32.58, *p*<0.001, $\eta_p^2$=0.63; neuronavigation-guided vs. inion-lateral: *t*=7.24, *p*<0.001, *d*=0.95; inion-lateral vs. inion-mastoid: *t*=-6.71, *p*<0.001, *d*=-0.89; Figure 1D). Additionally, the DCC coil induced an overall higher E-field strength compared to the Figure-of-8 coil (coil: $F_{(1,19)}$=31.78, *p*<0.001, $\eta_p^2$=0.63). This effect varied by targeting approach (approach x coil: $F_{(2,38)}$=7.26, *p*=0.002, $\eta_p^2$=0.28) with no significant difference between coils when the neuronavigation-guided approach was used (figure-of-8 vs. DCC: *t*=-2.75, *p*=0.14, *d*=-0.63), unlike the landmark-based methods (figure-of-8 vs. DCC: *t*-5.71; *p*<0.001; *d*<-1.30).

We also evaluated the 'spill-over' within the cerebellum by computing the number of voxels above 0.5 of the E/Emax. The DCC coil produced a significantly broader spread (3x2 rmANOVA, coil: $F_{(1,19)}$=21.91, *p*<0.001, $\eta_p^2$=0.54; Figure 1E), but this effect varied across targeting approaches (approach x coil: $F_{(1,19)}$=6.05, *p*=0.005, $\eta_p^2$=0.24; Figure 1E). It produced a greater spread with the inion-lateral and inion-mastoid (figure-of-8 vs. DCC: *t*-4.74; *p*<0.001; *d*<-1.36), but not with the neuronavigation-guided approach (figure-of-8 vs. DCC: *t*-1.94, *p*=0.31, *d*=-0.77).

We finally estimated E/Emax strength in the right lateral occipital cortex [7]. The DCC coil produced an overall greater 'spill-over' (3x2 rmANOVA, coil: $F_{(1,19)}$=13.66, *p*=0.002, $\eta_p^2$=0.42; Figure 1F). However, this difference varied depending on the targeting approach (approaches x coil types; $F_{(2,38)}$=5.26, *p*=0.01, $\eta_p^2$=0.22). While the DCC coil led to a larger 'spill-over' with the inion-lateral and inion-mastoid (figure-of-8 vs. DCC: *t*-3.85, *p*<0.007; *d*<-1.36), this was equivalent to the neuronavigation-guided approach (figure-of-8 vs. DCC: *t*-1.48, *p*=1, *d*=-0.23).

Our results show that, despite the traditional use of landmark-based approaches to target lobule VIII, Crus II consistently displays the highest E-field strength (Figure 1B-C). Physiologically, this suggests that Crus II may be preferentially recruited by TMS, influencing downstream cerebello-cortical activity when other lobules are targeted. Moreover, our findings are consistent with previous studies showing that E-fields are stronger and broader with the DCC coil, but more focused and superficial with the Figure-of-8 coil [6,8], although these comparisons should be interpreted with caution. The intensity used for the DCC coil, while normalized, was not based on its specific rMT, which limits direct comparability. Nevertheless, our results support the notion that DCC and Figure-of-8 coils may recruit distinct cerebellar pathways [9]. The broader reach of the
127 DCC coil may engage both superficial and deeper structures, which may explain
128 its greater effectiveness in modulating cerebellar-brain inhibition (CBI; [2]). In
129 contrast, the focality of the Figure-of-8 coil may reduce the risk of co-activating
130 competing areas/pathways, making it suitable for protocols aiming to fine-tune
131 specific superficial regions, particularly during repetitive TMS protocols [10]. In
132 this study, we did not directly assess whether cerebellar neurons were activated
133 or modulated by stimulation, a limitation of the present study. Further work
134 directly assessing the neural effects of TMS on the cerebellum is needed to clarify
135 the mechanisms underlying the differential effects of DCC and Figure-of-8 coils.
136 Yet, our results emphasize the importance of selecting the most appropriate coil
137 according to the intended purpose (focality/depth trade-off). Additionally,
138 stimulation with Figure-of-8 coils is often reported as less painful due to reduced
139 evoked muscle twitches. This is important to improve participants' comfort and,
140 in TMS-electroencephalography, to minimize the TMS-pulse-related
141 electromagnetic and muscle artifacts, and the impact of multisensory responses
142 on the signal.

143 Finally, our data suggest that the combination of coil and targeting
144 approach has an important role in determining the E-field distribution for
145 cerebellar TMS [8]. We show that the inion-lateral approach induces the weakest
146 E-fields within the cerebellum and the strongest in the occipital cortex, whereas
147 the inion-mastoid targeting strategy results in E-field distribution similar to those
148 of the neuronavigation-guided approach. The difference between the two
149 landmark-based approaches may arise because the former relies on absolute
150 distances, while the latter accounts proportionally for participants' head sizes. In
151 other words, the inion-mastoid approach may suffice in circumstances and
152 settings lacking access to individual MRI-based neuronavigation, computing
153 power, or personnel skilled in cerebellar segmentation (e.g., clinical settings). Yet,
154 our data also show that by using the neuronavigation-guided approach, it is
155 possible to increase the cerebellar surface recruited by the figure-of-8 coil, and to
156 reduce the spread over the occipital cortex by the DCC coil. Thus, the MRI-
157 neuronavigation-guided approach, as implemented in this study, might overcome
158 some key differences between the predicted E-field distributions generated by the
159 two tested coils.

160

161

References

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[9] Sasaki R, Hand B J, Liao W Y, Rogasch N C, Fernandez L, Semmler J G, et al. Utilising TMS-EEG to Assess the Response to Cerebellar-Brain Inhibition 2023;22:544-58. https://doi.org/10.1007/s12311-022-01419-y.

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[10] Kishore A, Popa T, Balachandran A, Chandran S, Pradeep S, Backer F, et al. Cerebellar Sensory Processing Alterations Impact Motor Cortical Plasticity in Parkinson's Disease: Clues from Dyskinetic Patients. Cerebral Cortex 2014;24:2055-67. https://doi.org/10.1093/cercor/bht058.

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## Codes availability

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The scripts will be publicly accessible upon publication through the following link:

208

https://github.com/XavierCorominas/E_field_cerebellar_TMS

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**CRediT authorship contribution statement**

212

Conceptualization: MB, AVC, CG; Formal analysis: VR, SCT, MB; Funding

213

acquisition: MB, AVC, CG; Investigation: VR, SCT, MB; Methodology: SCT, SO,

214

MB; Supervision: MB, AVC, CG; Visualization: VR, SCT, CG, MB; Writing – original

215

draft: VR, SCT, MB; Writing – review and editing: VR, SCT, SO, TP, CG, AVC, MB.

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**Competing interests**

218

The authors declare no competing commercial or financial interests.

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**Acknowledgments**

221

We are grateful to Candice Appriou and Thomas Guenin for their help with the

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data collection, and the MRI and brain stimulation (PANAM) platforms of the

223

neuroimaging center (Centre de Neuroimagerie de Recherche; CENIR) within the

224

Paris Brain Institute (ICM) where experimental work was conducted. This study

225

was supported by the European Union's Horizon 2020 research and innovation

226

program under the Marie Skłodowska-Curie grant agreement 897941 to MB, the

227

Big Brain Theory (BBT-3; FORTE) internal ICM grant to MB, AV-C and CG, and the

228

Agence Nationale de la Recherche in France (ANR-19-CE37-0021 BrainMAG), IHU-

229

ICM CARNOT Maturation grant, and additional funding from Investissements

230

d'avenir (ANR-10-IAIHU-0006) to AVC.
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Figure 1. Neuronavigation-guided approach and simulation results. (A)

T1-weighted MRI scan of a representative participant used for targeted neuronavigation. The region of interest (right Crus II, in yellow), together with the right lobules VIIIa and VIIIb (in light and dark orange, respectively), and the other 31 parcels were delineated using the SUIT toolbox, highlighting their anatomical boundaries and volume. The green lines graphically represent a typical coil position, with its center at the shortest Euclidian distance from the targeted cerebellar lobule. (B) Grand average (N=20) of MNI- and Emax-normalized whole-brain E-field distributions for the three distinct targeting approaches using two different TMS coils (Magstim, D70 Figure-of-8 and Double-Cone-Coil, DCC). The distribution of induced E-field simulations is shown across axial (z=-50 and z=-35 for the cerebellum) and sagittal (x=25 for all) views and a 3D-rendered brain. Horizontal lines in the 3D-rendered image represent the slice positions corresponding to the axial views. TMS coil positions were individually digitized for each participant on an MRI-neuronavigation system, marking the TMS coil center and trajectory for the three different targeted strategies and further exported for *posthoc* biophysical E-field simulations. Implemented TMS intensity was based on the participants' individual rMT defined as the lowest intensity able to induce at least ten out of 20 measurable motor-evoked potentials (>50 µV) in the first dorsal interosseous muscle following stimulation of the primary motor cortex. (C) Grand average (N=20) of the MNI-normalized cerebellar SUIT flat-map projection of the normalized E-field distributions (E/Emax). Max E-field values are expressed as the mean ± standard error of the mean across participants, calculated as the maximum E-field value in the gray matter after removing the top 0.1% of values to eliminate potential outliers. (D) Interaction effects between approach (neuronavigation-guided x inion-lateral x inion-mastoid) and coil type (Figure-of-8 x DCC) for the 3x2 repeated measures ANOVA of the normalized E/Emax strength in cerebellar Crus II and Lobule VIII. (E) Interaction effect on the number of voxels with activation over 0.5 E/Emax (aka. Cerebellar 'spill-over'). (F) Interaction effect for the E/Emax strength in the lateral occipital region (aka. Occipital 'spill-over'). The brain plot represents the region of interest (ROI) corresponding to the right lateral occipital cortex, as defined in [7]. Box plots show the median (horizontal line), the mean (diamond), the interquartile range (IQR; represented by the box spanning the lower quartile [Q1] to the upper quartile [Q3]), the minimum and maximum values within 1.5 times the IQR (whiskers), and outliers (dots), which are values beyond this range. NeurG= neuronavigation-guided approach, inionL = inion-lateral approach, inionM = inion-mastoid approach). DCC = Magstim double-cone coil, Figure-of-8 = Magstim, 70mm Figure-of-8 coil (D70). *** indicates p<0.001; ** indicates p<0.25; * indicates p<0.05 (p values are Bonferroni corrected for post-hoc comparisons).