7T MRI quantitative susceptibility mapping for magnetic resonance-guided focused ultrasound thalamotomy: methodology and anatomo-clinical correlations in a retrospective pilot study

Introduction

Essential tremor (ET) is the most prevalent movement disorder (1), significantly affecting patients’ quality of life. Over recent decades, a broad range of functional neurosurgical interventions have been developed to modulate dysfunctional neural circuits and effectively reduce tremor (2). Deep brain stimulation (DBS) has long been regarded as the gold standard for functional surgery of movement disorders (3). However, non-invasive lesioning techniques, particularly high-intensity magnetic resonance-guided focused ultrasound (MRgFUS), have gained increasing clinical interest. Incisionless MRgFUS reduces surgical risks and complications, while providing real-time imaging feedback on lesion formation (4-9). In ET, MRgFUS thalamotomy targeting the ventral intermediate nucleus (VIM) of the thalamus has shown promising results in tremor suppression (10). Lesioning the VIM may disrupt the cerebello-thalamic tract (CTT), which is increasingly recognized as a key pathway in tremor pathophysiology (11), although definitive anatomical-clinical associations remain to be established. Despite its clinical efficacy, accurate targeting of the VIM remains challenging due to its small size, deep location, and limited contrast with surrounding structures on conventional 1.5T or 3T T1-, T2-, and diffusion-weighted magnetic resonance imaging (MRI) sequences (12,13). Historically, indirect targeting using stereotactic atlases and anatomical landmarks, such as the anterior and posterior commissures (the Guiot technique), has been the standard approach (14,15). However, individual anatomical variation makes exact localization challenging. Despite intraoperative clinical testing, millimeter-scale deviations can lead to suboptimal tremor control or adverse effects such as weakness or sensory deficits (16). Consequently, there is a growing interest in new imaging techniques that could localize the VIM more reliably or reveal additional anatomical landmarks (17). Among emerging approaches, magnetic susceptibility-based imaging techniques such as quantitative susceptibility mapping (QSM) offer promising capabilities. The complex phase of the nuclear magnetic resonance (NMR) signal—reflecting local magnetic field distortions—is deconvoluted of the dipole kernel in the frequency domain to compute a volumetric map of magnetic susceptibility (18). QSM leverages local magnetic field perturbations generated by tissue susceptibility differences, primarily related to iron content or myelin microstructure, enabling the delineation of many different brain structures and substructures (19,20). By magnifying local field inhomogeneities, higher magnetic field strengths (e.g., 7T) not only boost spatial resolution and SNR but also enhance susceptibility-based contrast for visualizing deep diencephalic structures (21-23).

Recent studies have demonstrated the feasibility of using 7T MRI QSM to help target the VIM for DBS and gamma knife treatment (21). However, 7T MRI QSM integration into the clinical workflow of MRgFUS remains unexplored. MRgFUS is a non-invasive, implant-free technique, which allows clear postoperative imaging and retrospective anatomo-clinical analysis. In contrast, DBS involves the placement of a permanent electrode, which introduces susceptibility artifacts that prevent further high-resolution imaging of the thalamus after surgery. In this pilot study, we aim to evaluate the technical feasibility and potential clinical value of incorporating 7T QSM into the preoperative planning and postoperative assessment of MRgFUS VIM thalamotomy. We hypothesize that QSM data facilitate radio-clinical analysis of the MRgFUS lesioned sub-nuclei and may help in understanding why some patients respond well, whereas others do not, ultimately guiding refinements to VIM targeting strategies.

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Geneva Cantonal Committee for Research Ethics under the reference CCER-2025-0070 and individual consent for this retrospective analysis was waived. In University Hospitals of Geneva (Hôpitaux Universitaires de Genève, HUG), as part of the clinical MRgFUS VIM thalamotomy workup, patients underwent pre- and post-operative (6 weeks) MRI on a 7T MRI (MAGNETOM Terra.X, Siemens Healthineers, Forchheim, Germany) using an 8Tx/32Rx radiofrequency (RF) head coil (Nova Medical, Wilmington, MA, USA), with appropriate head immobilization using a double pneumatic cushion. A three-dimensional (3D) multi-echo gradient-recalled echo (MEGRE) sequence was performed at 0.6 mm isotropic resolution with the following acquisition parameters: orientation = axial anterior commissure-posterior commissure (AC-PC), excitation = slab selective, time of repetition (TR) =31 ms, time of echo (TE) =5.38/10.82/16/21.2/26.39 ms, bandwidth (BW) =260 Hz/pixel, time of acquisition (TA) =9 min 26 s. In addition, a 3D T1w magnetization prepared rapid gradient echo (MPRAGE) dark-cerebrospinal fluid (CSF) sequence [TR =4,000 ms, TE =3.34 ms, time of inversion recovery (TIR) =1,450 ms, TA =4 min 16 s] was acquired immediately after, being physically aligned at the time point of acquisition with the MEGRE sequence and sharing the same spatial resolution, geometry, BW, shimming parameters, and online distortion correction. Indirect targeting of VIM (24) was performed by identifying the usual key anatomical landmarks clearly visible on the MPRAGE sequence. Nulling the signal of the CSF optimized the delineation of the ventricular wall.

To balance susceptibility contrast with motion artifact reduction, particularly relevant in ET patients, a cut-off was defined after the 3^rd echo of the MEGRE sequence, since the 4^th and 5^th echoes were less robust against head motion. Subsequently, the first three of the five echoes were used to compute QSM maps, using the open-source QSM dedicated pipeline QSMxT version 7.1.0 (25) running under the Docker Desktop Engine v26.1.4 on a DELL Precision 5690 personal computer equipped with an Intel Core Ultra 9 185H, 16 cores, 2.50 GHz clock frequency, 64 GB RAM. The set of parameters in the command line of the QSMxT calculation was extensively explored and iteratively optimized, employing (I) MEGRE data not corrupted by head motion; and (II) neuroradiologist/neurosurgeon visual feedback. The following combination was applied to this clinical study: qsm_algorithm tgv, combine_phase on, filling_algorithm morphological, two_pass on, masking_algorithm threshold, masking_input phase; and threshold_algorithm gaussian, obliquity_threshold 5, premade gre, do_qsm, auto_yes.

For the current matrix size of 384×288×288 pixels, the computing time of QSM maps was approximately 20 min. Preoperatively, the QSM maps were merged with the dark-CSF T1w images, after validating the patient head did not move in between. Should a shift of more than 1 pixel be detected, the case was excluded from the study rather than attempting to mathematically co-register the two datasets, which were significantly different in terms of tissue contrast. A grayscale colormap was defined for the QSM signal using two-point calibration. To define the y-intercept, the QSM signal of the internal capsule was assigned to black. To define the slope, the QSM signal of the ventralis oralis anterior nucleus in the axial slice D1.8 was set to the value of the MPRAGE signal of the ventricular wall. Then, the pixel values of the native MPRAGE image (Figure 1A), considered within the thalamus, internal capsule, and red nucleus of the mesencephalon, on the side concerned by the MRgFUS procedure, were replaced by the corresponding grayscale pixels from the recalibrated QSM image (Figure 1B). This resulted in a visually comparable dual contrast called “Hybrid T1-QSM” image (Figure 1C). The first 2–3 mm tissue around the 3^rd ventricle was preserved in the MPRAGE image in an eggshell manner to retain key structural features crucial for indirect targeting, such as the commissures and ventricular wall (see Figure 2). Provided that QSM and MPRAGE information are used for distinct anatomic structures, image blending was not considered. Image quality assurance (QA) was performed against a standard two-dimensional (2D) multi-slice axial T2 turbo spin echo (TSE) sequence [orientation = AC-PC, TR =9,500 ms, TE =62 ms, slice thickness 2 mm, slice gap 10%, slice number =60, in-plane resolution 0.45 mm, generalized autocalibrating partially parallel acquisitions (GRAPPA) =4, number of signal averages (NSA) 2, deep resolve boost = on] to exclude any spatial misalignment that might theoretically occur in the process of QSM computing (e.g., matrix shift or transposition) (see Figure 3). Six weeks after MRgFUS, 7T MRI susceptibility weighted imaging (SWI) 3D images were also acquired to demonstrate the effective ablative lesion [main acquisition parameters: voxel size =0.3×0.33×1 mm³, TR =25 ms, TE =11 ms, GRAPPA =3, partial Fourier (PF) =7/8, flip angle (FA) =10°, BW =400 Hz/pixel]. Note that 3^rd order shim was applied by default on the Terra.X system. The scanner built-in 3D correction for distortion was applied to MEGRE, MPRAGE, and SWI data, and the built-in 2D correction was applied to T2 TSE.

Figure 1 Principle of the hybrid T1-QSM image generation. (A) An axial slice of the 3D T1w MPRAGE dark-CSF sequence is shown at the level of the foramen of Monro. Note the completely dark CSF signal inside the right ventricular atrium (plain arrow) and the left thalamus (dotted arrow). (B) QSM signal shown in a 30 mm radius sphere encompassing the thalamus. The white arrowhead shows an old lesion induced in the left thalamus 9 months before. (C) Hybrid T1-QSM image where the right thalamic and IC T1w MPRAGE pixels were replaced by the values of corresponding QSM pixels, after linear rescaling, to deliver a similar visual contrast. CSF, cerebrospinal fluid; IC, internal capsule; MPRAGE, magnetization prepared rapid gradient echo; QSM, quantitative susceptibility mapping; T1w, T1-weighted.

Figure 2 Further insights on the 7T MRI hybrid T1-QSM image features (A) and a zoom-in (B) on the region of interest. While the QSM pixel values were used in the right thalamus (plain arrow), the ventricular wall was maintained on the T1 MPRAGE data (dotted arrows). These key anatomical reference points are crucial for surgical targeting. MPRAGE, magnetization prepared rapid gradient echo; MRI, magnetic resonance imaging; QSM, quantitative susceptibility mapping.

Figure 3 Illustration of the 7T MRI QA demonstrating the correct alignment of the QSM image (B,D) as compared to the anatomical T2 TSE image (A,C). Identical green ellipses indicate red nucleus (A,B). Identical curved blue lines, pointed out by white arrows, indicate the external border of the internal capsule (C,D). FOV is 100 mm (LR) × 74 mm (AP). No image registration/transformation was applied at this step. AP, anterior-posterior; FOV, field of view; LR, left-right; MRI, magnetic resonance imaging; QA, quality assurance; QSM, quantitative susceptibility mapping; TSE, turbo spin echo.

The postoperative dark-CSF T1w MPRAGE images were registered to the corresponding preoperative dark-CSF T1w MPRAGE images (acquired with identical parameters) by performing a rigid transformation (MATLAB, R2024a, MathWorks) of the central region of the brain: 60 mm [left-right (LR)] × 51 mm [anterior-posterior (AP)] × 48 mm [high-frequency (HF)], encompassing the thalamus. The built-in routine “imregister” was used with following parameters of the optimizer: metric = monomodal, maximum iterations =1,000, gradient magnitude tolerance =10⁻⁵, minimum step length =10⁻⁶, maximum step length =10⁻², relaxation factor =0.6. Computing time at this step was less than 1 min. This transformation enabled the direct ‘back-in-time’ projection, using the pixel coordinates, of the MRgFUS lesion sharply depicted by the postoperative MPRAGE contrast onto the preoperative QSM map (see Figure 4).

Figure 4 “Back-in-time” retro-projection of the MRgFUS lesion onto the 7T MRI preoperative hybrid T1-QSM data. (A) Preoperative hybrid T1-QSM image centered on the thalamus, showing the left-sided lesion from a previous treatment more than 9 months in the past (dotted arrow). (B) Postoperative T1 image mathematically co-registered with the pre-operative hybrid T1-QSM, displaying both the old left thalamic lesion (dotted arrow) and the analyzed new right thalamic lesion (dotted ellipse). (C) Preoperative hybrid T1-QSM image with the projected right thalamic lesion on the corresponding paired pixel coordinates, displaying both the old left thalamic lesion (dotted arrow) and the analyzed new right thalamic lesion (dotted ellipse). The overlay illustrates how the analyzed lesion aligns with the preoperative intra-thalamic anatomy. MRgFUS, magnetic resonance-guided focused ultrasound; MRI, magnetic resonance imaging; QSM, quantitative susceptibility mapping.

Five patients with a history of disabling and/or drug-resistant ET undergoing MRgFUS VIM thalamotomy between November 5, 2024 and April 8, 2025, were selected according to 7T magnetic resonance (MR) image quality. For each patient, the clinical benefit was assessed with the Clinical Rating Scale for Tremor (CRST) (26) for the treated side and axial tremor (27) as follows: sum of Part A (resting, postural, and action tremor for the treated side and face, tongue, trunk, and orthostatic tremor), Part B (handwriting, drawing, and pouring tasks), and Part C for functional disability. We measured quality of life with the QUEST scale (28). Within the scope of this study, side effects were assessed up to 1-month post-MRgFUS, inclusive.

The patients underwent routine clinical MRgFUS thalamotomy for treatment of ET according to the standard Food and Drug Administration (FDA)/European Conformity (CE) procedure implemented on the ExAblate 4000 v.1.1 (Insightec, Haifa, Israel) device, coupled with a 3T intraoperative MRI (Vida, XA60, Siemens Healthineers).

Finally, the clinical outcome was correlated with the tri-dimensional analysis of QSM topology as impacted by the MRgFUS lesion. One illustrative example is shown in Figure 5, together with the theoretical application of Guiot’s scheme in this case for indirect targeting in MRgFUS VIM thalamotomy.

Figure 5 Nine consecutive slices of preoperative 7T MRI hybrid-QSM of 0.6 mm thickness with “back-in-time” retro-projection of the ablative lesion (light blue contour) in the thalamus. Shown FOV per slice is 40 mm × 40 mm. Data correspond to patient 1, having the best clinical outcome in this study. For illustration, the Guiot scheme was applied in the DV0 plane (dorsal-ventral 0 plane). Distances are provided in mm. A 1.8 mm dorsal translation was then applied to determine the conventional target for VIM ablation at the D1.8 level (1.8 mm dorsal to AC-PC plane), that is, the theoretical focal point for MRgFUS, indicated by the yellow cross in the central slice. AC-PC, anterior commissure-posterior commissure; FOV, field of view; MRgFUS, magnetic resonance-guided focused ultrasound; MRI, magnetic resonance imaging; QSM, quantitative susceptibility mapping; VIM, ventral intermediate nucleus.

Results

Clinical outcomes and imaging findings for the five patients are summarized in Table 1. Figure 6 reveals the axial projection onto the QSM landscape of the largest extension of lesion for the five cases.

Figure 6 7T MR thalamic imaging pre- and postoperative (6 weeks) in the five patients included according to Table 1, shown in the axial plane. From top to down: patient 1 (A-C), patient 2 (D-F), patient 3 (G-I), patient 4 (J-L), and patient 5 (M-O). Note the morphological projection of the MRgFUS lesion depicted by the 6 weeks post-operative 7T MRI T1 image (A,D,G,J,M) onto the co-registered pre-operative QSM image (B,E,H,K,N). The third column provides the post-operative 7T MRI SWI MinIP illustration of the corresponding ablative lesion (C,F,I,L,O), and these data were not mathematically co-registered with preoperative T1-QSM. The slice of maximum lesion extension was chosen for each case. For visual convenience, the frames (A-C,J-L) were mirror flipped left-right. *, the internal capsule. Arrow is visual indicator of the lesion, segmented as a white contour. FOV is 60 mm (LR) × 51 mm (AP). AP, anterior-posterior; LR, left-right; MinIP, minimum intensity projection; MR, magnetic resonance; MRgFUS, magnetic resonance-guided focused ultrasound; MRI, magnetic resonance imaging; QSM, quantitative susceptibility mapping; SWI, susceptibility weighted imaging.

Among the cohort, patients 1, 2, and 3 exhibited a marked and clinically significant improvement in tremor symptoms 1 month after MRgFUS thalamotomy, with CRST total score reductions of 89%, 73%, and 60%, respectively. In contrast, patients 4 and 5 demonstrated modest reductions of 27% and 31%, with persistent functional limitations. The thermal ablative lesions are illustrated on the 7T SWI data (Figure 6C,6F,6I,6L,6O). Radiologically, the lesion size and shape were similar between cases, with inter-subject minimum-maximum diameter of 6.2–7.2 mm (LR), 5.1–5.9 mm (AP), and 7.2–8.4 mm [superior-inferior (SI)]. No side lobe lesioning from imperfect high-intensity focused ultrasound (HIFU) beam focusing was detected.

Retrospective tri-dimensional anatomical analysis of the MRgFUS lesions projected onto preoperative QSM data across the five cases revealed straightforward spatial concordance in patients 1 and 2. In these two cases, the lesion was localized in the lateral thalamus, bordering (I) a well-demarcated hypointense medial area; and (II) a well-demarcated hyperintense anterior area. The locus of this lesion was topographically consistent with the presumed location of the VIM as delineated in QSM-based thalamic atlases (21,22). This zone showed similar mediolateral and anteroposterior positioning across both patients, suggesting that successful clinical outcome may be associated with lesion location impacting this susceptibility-tagged locus. The lesion topography in patient 3 was similar to patients 1 and 2 but located slightly more lateral. Although his clinical outcome was successful, he still experienced significant postural tremor 1-month post-treatment. Patients 4 and 5, who experienced suboptimal tremor control, showed lesion locations that deviated from this consistent topographic zone. In patient 4, the clinical presentation was consistent with a lesion located too medially and posteriorly, with partial involvement of the internal medullary lamina and adjacent structures, potentially affecting the proprioceptive capsule of the ventral lateral posterior (VLp) nucleus and the ventral posteromedial (VPM) nucleus—regions not typically associated with effective tremor suppression. Patient 5 presented the largest lesion among the five cases, which appeared more medial, inferior, and slightly anterior than cases 1 and 2. It potentially extended into some regions adjacent to the VIM, such as the ventral lateral anterior (VLa) nucleus, or the parvicellular VPM (VPMpc) nucleus (29). The latter is consistent with persistent mild dysgeusia. It is also possible that clinical factors such as disease severity or chronicity (i.e., a floor effect) contributed to the limited response.

Although this was a non-statistical analysis due to the limited cohort size, these preliminary findings raise the hypothesis that the susceptibility-defined VIM region could serve as a landmark to detect thermal lesions that fail to fully cover the intended target area in MRgFUS thalamotomy.

Discussion

In our pilot study, we established the feasibility and potential value of integrating 7T MRI-based QSM into the clinical workflow of MRgFUS thalamotomy targeting the VIM in ET. By delivering markedly enhanced intra-thalamic contrast, QSM offers improved visualization of the expected region of the VIM and its neighboring sub-nuclei (30), providing enhanced anatomical detail compared to conventional MRI sequences, which often lack the resolution and contrast needed to delineate these deep structures.

Deistung et al. (22) conducted a systematic analysis of QSM at 7T, demonstrating that QSM markedly enhances the delineation of deep gray-matter structures (including the VIM). Their work showed how QSM can reveal sub-nuclei contrast that is often not apparent on conventional magnitude or phase images, supporting the notion of QSM as a form of “in vivo histology”. Our approach of projecting the ablative lesion onto preoperative QSM maps proved effective for retrospective anatomo-clinical analysis. Unlike reference (20), which used 3T MRI data, direct postoperative QSM imaging was avoided due to artifacts related to microbleeds and susceptibility shifts induced by the thermal ablation process, which may obscure the native QSM. Previous neuropathological studies corroborate this interpretation, indicating that susceptibility changes post-lesion are primarily driven by microvascular disruption and iron accumulation (19). The ability to retrospectively analyze lesion placement on preoperative tissue-native QSM maps from ultra-high field MRI could significantly enhance anatomical-clinical correlations. It also holds promise for refining the MRgFUS targeting strategies, aiming to outperform the classical approach where changes to the sonication coordinates are determined based on the patient’s neurological findings.

Future studies may benefit from systematic comparisons of echo numbers and QSM reconstruction algorithms to further enhance visualization of intra-thalamic structures while robustly mitigating motion artifacts in this challenging population.

The hybrid T1-QSM image was technically compatible with the ExAblate 4000 neuro targeting workflow (Figure 7), demonstrating the possibility of real-time clinical support for treatment delivery in the future. The skull was clearly visualized as a signal void compartment in the T1 MPRAGE data, which enabled accurate registration of the skull computer tomography (CT) data, essential for modeling the HIFU propagation through the skull.

Figure 7 Demonstration of the data format and size compatibility between the hybrid T1-QSM image and the MRgFUS planning software (ExAblate, v.1.1, Insightec). (A) Note the co-registered skull CT data (green compartment). (B) Zoom-in of the thalamic region, with theoretical target coordinates (according to Guiot’s scheme), placed for illustration purpose. The red contours delineate the co-registered calcifications as detected from CT data. CT, computer tomography; MRgFUS, magnetic resonance-guided focused ultrasound; QSM, quantitative susceptibility mapping.

The present study has several limitations inherent to pilot and retrospective investigations up to 6 weeks follow-up period, notably the small number of patients included and the absence of statistical analysis correlating lesion characteristics with the clinical outcomes. Longer-term follow-up is also required in future studies. However, the consistent imaging pattern observed across our cases supports the hypothesis that QSM may offer improved anatomical guidance compared to indirect targeting methods, traditionally based solely on anatomical landmarks or atlas coordinates (14,15,24,31). Given the interindividual variability of thalamic anatomy, larger patient cohorts are necessary to validate the generalizability and clinical benefit of QSM-guided MRgFUS targeting.

Owing to future developments, a statistical anatomic atlas of the thalamus sub-nuclei (32,33), will be elastically registered on top of the 7T MRI QSM map, potentially enabling a direct segmentation of the VIM pre-operative, or the volumetric assessment of the individual thalamic sub-nuclei lesioning post-operative. A similar idea has been explored with 3T MR data by He et al. (34), featuring lower resolution (1 mm × 1 mm × 1 mm) than our data (0.6 mm × 0.6 mm × 0.6 mm). Remarkably, both the phase sensitivity to local susceptibility variation and the signal-to-noise ratio are multiplied by a factor of approximately 2.3 at 7T compared to 3T. The present methodology is a novel development which has the potential to enable QSM-based classification of thalamic MRgFUS lesions in statistical clusters in larger cohorts. This would help to overcome inter-individual variability and improve the learning curve and ultimately the targeting precision. Furthermore, merging the 7T MRI QSM and diffusion tensor imaging (DTI) tractography would offer unique cross-validation of the two modalities in the context of the observed anatomo-clinical relationships.

Conclusions

This pilot study highlights the feasibility and potential added value of integrating 7T QSM imaging into the clinical workflow of MRgFUS thalamotomy for ET. By providing superior intra-thalamic contrast and enabling retrospective lesion localization relative to susceptibility-defined anatomy, QSM may hold significant clinical implications for MRgFUS thalamotomy, helping accelerate the learning curve and, therefore, potentially enhancing the efficacy and safety profile. These preliminary findings in a small cohort of five cases suggest that 7T QSM could serve as a biomarker for more accurate MRgFUS treatment planning and outcome prediction. Future prospective studies with larger cohorts and integration of deformable atlas registration are warranted to validate the clinical utility of 7T QSM in functional neurosurgical interventions.

Acknowledgments

The Campus Biotech Foundation of Geneva is acknowledged for providing access to the 7T MRI infrastructure and for its support with patient workflow and technology (Mrs. Loan Mattera, Mrs. Nathalie Philippe, Mrs. Anne-Cerise Bernard, and Dr. Roberto Martuzzi). Siemens Healthineers Switzerland is acknowledged for technical assistance with the 7T MRI scanner operation (Dr. Antoine Klauser, Dr. Gian Franco Piredda, Dr. Ludovica Romanin, and Dr. Tom Hilbert).

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-713/coif). M.N.G. is an employee of Neurological and Neurosurgical Institute (SIFUS) AG, Ostermundigen, Switzerland, for-profit organization. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Geneva Cantonal Committee for Research Ethics under the reference CCER-2025-0070 and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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