# Quantitative tremor monitoring before, during and after MR-guided focused ultrasound thalamotomy for essential tremor with MR compatible accelerometers

Thomas Bancel, Mohammed Bashaiweth, Thomas J Manuel, Benoît Béranger, Cécile Galléa, Mathieu Santin, Mélanie Didier, Eric Bardinet, Pierre Pouget, Mickael Tanter, et al.

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Thomas Bancel, Mohammed Bashaiweth, Thomas J Manuel, Benoît Béranger, Cécile Galléa, et al. Quantitative tremor monitoring before, during and after MR-guided focused ultrasound thalamotomy for essential tremor with MR compatible accelerometers. International Journal of Hyperthermia, 2025, 42 (1), pp.2481153. 10.1080/02656736.2025.2481153. hal-05335773

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# Quantitative tremor monitoring before, during and after MR-guided focused ultrasound thalamotomy for essential tremor with MR compatible accelerometers

Thomas Bancel, Mohammed Bashaiweth, Thomas J. Manuel, Benoît Béranger, Cécile Galléa, Mathieu Santin, Mélanie Didier, Eric Bardinet, Pierre Pouget, Mickael Tanter, Stéphane Lehéricy, Marie Vidailhet, David Grabli, Nadya Pyatigorskaya, Carine Karachi, Elodie Hainque & Jean-François Aubry

**To cite this article:** Thomas Bancel, Mohammed Bashaiweth, Thomas J. Manuel, Benoît Béranger, Cécile Galléa, Mathieu Santin, Mélanie Didier, Eric Bardinet, Pierre Pouget, Mickael Tanter, Stéphane Lehéricy, Marie Vidailhet, David Grabli, Nadya Pyatigorskaya, Carine Karachi, Elodie Hainque & Jean-François Aubry (2025) Quantitative tremor monitoring before, during and after MR-guided focused ultrasound thalamotomy for essential tremor with MR compatible accelerometers, *International Journal of Hyperthermia*, 42:1, 2481153, DOI: 10.1080/02656736.2025.2481153

**To link to this article:** https://doi.org/10.1080/02656736.2025.2481153

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# Quantitative tremor monitoring before, during and after MR-guided focused ultrasound thalamotomy for essential tremor with MR compatible accelerometers

Thomas Bancel<sup>a†</sup>, Mohammed Bashaiweth<sup>a†</sup>, Thomas J. Manuel<sup>a</sup>, Benoît Béranger<sup>b</sup>, Cécile Galléa<sup>b</sup>, Mathieu Santin<sup>b</sup>, Mélanie Didier<sup>b</sup>, Eric Bardinet<sup>b</sup>, Pierre Pouget<sup>c</sup>, Mickael Tanter<sup>a</sup>, Stéphane Lehéricy<sup>d</sup>, Marie Vidailhet<sup>c,e</sup>, David Grabli<sup>e</sup>, Nadya Pyatigorskaya<sup>f</sup>, Carine Karachi<sup>g</sup>, Elodie Hainque<sup>et†</sup> and Jean-François Aubry<sup>et†</sup>

<sup>a</sup>Physics for Medicine Paris, INSERM U1273, CNRS UMR 8063, ESPCI Paris, Paris Science Lettres University (PSL), Paris, France; <sup>b</sup>Center of Neuroimaging Research (CENIR), Paris Brain Institute (ICM), Sorbonne University, CNRS 7225, Inserm 1127, Paris, France; <sup>c</sup>MOV'IT team (Movement Investigations and Therapeutics), INSERM U 1127, CNRS UMR 7225, ICM, Sorbonne Université UMRS 1127, Paris, France; <sup>d</sup>MOV'IT team (Movement Investigations and Therapeutics), Center of Neuroimaging Research (CENIR), Paris Brain Institute (ICM), Sorbonne University, CNRS 7225, Inserm 1127; Neuroradiology Department, Hopital Pitie-Salpetriere, Paris, France; <sup>e</sup>Neurology Department, Hopital Pitie-Salpetriere; Paris Brain institute (ICM), Sorbonne University, CNRS 7225, Inserm 1127, Paris, France; <sup>f</sup>Neuroradiology Department, Hopital Pitie-Salpetriere; Paris Brain institute (ICM), Sorbonne University, CNRS 7225, Inserm 1127, Paris, France; <sup>g</sup>Neurosurgery Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France & Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Paris, France

## ABSTRACT

**Background:** MR-guided focused ultrasound (MRgFUS) has been developed to treat essential tremor effectively and noninvasively. Currently, clinical examination is used to identify therapeutic efficacy during treatment, but MRgFUS surgery could benefit from real-time, rater-independent quantitative monitoring of tremor, such as accelerometry data.

**Methods:** Fourteen patients with medically refractory essential tremor underwent MRgFUS thalamotomy. Patients were instructed to hold postures during treatment. Tremor was monitored during each ultrasonic thermal sonication with MR-compatible accelerometers. Real-time feedback based on tremor amplitude in the 2–20 Hz band was calculated to evaluate the efficacy of each thermal ablation.

**Results:** On average 6±2 ablative sonifications only were required to induce improvement in tremor on the clinical rating scale for tremor (CRST) of 89±11% at D+7, 79±12% at M+1, 74±19% at M+3 and 72±23% at M+12. The overall predictive efficacy measured with accelerometry during the treatment was 70±30%. The tremor amplitude reduction measured with accelerometry was correlated with CRST scores tremor reduction at multiple timepoints (ρ=0.79 at D+7, ρ=0.75 at M+1, ρ=0.86 at M+3, and ρ=0.63 at M+12) and accelerometric data gathered during treatment predicted CRST tremor improvement at M+3 (0.88 area under ROC curve).

**Conclusion:** This exploratory study is a proof of concept suggesting that accelerometry measurements can provide real-time feedback on tremor reduction and can complement visual evaluation. In the future, the use of the outcome prediction introduced in this paper may shorten procedure time and limit adverse events by reducing the number of ablative administered sonifications.

## ARTICLE HISTORY

Received 4 December 2024
Revised 10 February 2025
Accepted 14 March 2025

## KEYWORDS

Focused ultrasound;
essential tremor; thermal
effects; accelerometry;
thalamotomy; thermal dose

## Introduction

MR-guided focused ultrasound (MRgFUS) thalamotomy is an emerging promising option for treating medically refractory Essential Tremor (ET) [1–11]. MRgFUS offers a noninvasive alternative to radio-frequency thalamotomy, gamma knife radiosurgical thalamotomy, and deep brain stimulation (DBS) [12], with the advantage of real-time targeting and monitoring of adverse effects with MR. Several studies reported the sustained effectiveness of MRgFUS in the short and long term [10,11]. Despite these promising findings, there is a need to optimize targeting and sonication protocols to

improve the procedure [5,13]. A quantitative intraoperative tremor assessment could be helpful to improve targeting and to optimize the number of sonifications.

The current protocols for MRgFUS thalamotomy still present certain challenges with target selection and number of ablative sonifications. Clinical scales are the currently accepted measure to assess tremor, but the evaluation is time consuming and difficult to implement inside the MR-bore. For these reasons, tremor rating scales are evaluated a few hours or days after treatment [14,15]. The current treatment protocol uses low intensity pulses inducing peak temperatures below the ablation threshold but visible in the MR-thermometry

## CONTACT

Mohammed Bashaiweth mohammed.bashaiweth@espci.fr
†These authors contributed equally

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Supplemental data for this article can be accessed online at https://doi.org/10.1080/02656736.2025.2481153.

© 2025 The Author(s). Published with license by Taylor & Francis Group, LLC

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

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INSERM U1273, Physics for Medicine Paris, ESPCI, Paris Science Lettres University (PSL), Paris, France.
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images to evaluate potential targets within the ventral intermediate nucleus (VIM) [16]. Between these alignment sonifications, patients are taken out of the MR-bore for the neurologist to visually inspect and iteratively evaluate the current target's effect on the tremor. A real-time tremor metric could speed up the procedure and provide a quantitative assessment. Additionally, a metric recorded within the MR-bore which correlates with clinical outcome would better inform the neurosurgical team when to stop the treatment and avoid unnecessary sonifications. Additional sonifications are often performed to remove residual tremor, but their efficacy and necessity is difficult to evaluate without a clear metric. In a meta-review [4] an average of 18±6 number of sonifications are performed during the whole surgical procedure; it is not certain that all of them were necessary and useful.

Accelerometry has been used for more than 40 years in the clinical evaluation of movement disorders and assessment of the effects of pharmacological treatments or surgical procedures by measuring reduction in tremor amplitude [17,18]. Accelerometry has been applied during deep brain stimulation procedures: Ushe et al. [19] used accelerometry to measure the impact of the stimulation frequency, and Papapetropoulos et al. [20] reported a 97% tremor amplitude reduction on a patient suffering from ET using a pen accelerometer. MR-compatible accelerometers may provide a quantitative and real-time measure within the MR-bore [21].

In this study, we synchronized MR-compatible accelerometers with the MRgFUS device to provide real-time neurophysiological feedback during ultrasonic thermal ablation. Each sonication's efficacy was computed in real-time and displayed in the MR control room. Such information was used to assess the efficacy of the treatment retrospectively. Together with temperature information, offline analyses were performed, and the overall treatment efficacy was also evaluated. The tremor was assessed at seven days, one, three and twelve-months with both clinical tremor rating scale and accelerometry.

# Materials and methods

## Patients

Fourteen patients suffering from ET and resistant to medication were enrolled in this study, and programmed for unilateral thalamotomy with the Exablate Neuro device (Insightec, Tirat, Israel). The age ranged between 46 and 79 years. Patients underwent one inclusion visit prior to treatment and four control visits after treatment (seven days (D+7), one month (M+1), three months (M+3), and one year (M+12) after treatment). Inclusion and exclusion criteria are summarized in Supplementary Materials A.

## Clinical evaluation during inclusion and control visits

During the inclusion and control visits, the tremor was evaluated by the neurologist using the Fahn-Tolosa-Marin clinical rating scale for tremor (CRST) [14]. For each patient, tremor was assessed at rest, posture, action/intention (CRST A) and for specific tasks (CRST B) at inclusion, D+7, M+1, M+3 and M+12. CRST A+B sub-scores for treated and control hand were then calculated. The CRST tremor reduction (ΔCRST) was defined by subtracting the CRST of each control visit

from the CRST at inclusion. The CRST tremor improvement (%CRST) was calculated by dividing the CRST scores of each control visit by the CRST scores at inclusion. We defined a successful treatment as a %CRST > 62% at M+3 based on the results of a previous meta-analysis [4].

## Accelerometry measurement during inclusion and control visits

The tremor was assessed with accelerometers (Acceleration Sensor MR – 3D – BrainVision) taped on the back of the patients' hands during the inclusion and the control visits at D+7, M+1, M+3, M+12. Patients held a batwing posture [22] for 30 s followed by 10 s rest (with arms on their legs). This task was repeated 20 times during each inclusion and control visits. The accelerometry signal was pre-amplified and sampled at 5 kHz. The spectrograms of all accelerometry signals were calculated within [2–20] Hz [23,24] with a 6-s window and a 5-s overlap. The tremor power between 2 and 20 Hz was then computed by integrating the averaged spectrograms and averaging the four most intense spectrograms. Tremor power reduction is determined as the ratio between the tremor power at a given visit over the tremor power at inclusion visit. The tremor amplitude reduction was computed by taking the square root of the tremor power reduction as such:

$$t_{\text{power reduction}} = \left[ 1 - \frac{\tilde{P}_{\text{visit}}}{\tilde{P}_{\text{inclusion}}} \right] * 100 \quad (1)$$

and

$$t_{\text{amplitude reduction}} = \left[ 1 - \frac{\tilde{A}_{\text{visit}}}{\tilde{A}_{\text{inclusion}}} \right] * 100, \text{ with } \tilde{A} = \sqrt{\tilde{P}}. \quad (2)$$

MRI noise in accelerometry data corresponding to the vibrations of the MR coils corresponded to a noise level of 10⁻³ (a.u.) in tremor power. Measurements acquired in the MR during the treatment procedure that fell below this noise levels were excluded from analysis.

## Treatment preparation

The Exablate Neuro clinical procedure was applied. Patients were installed on the MR bed with the stereotactic frame fixed to their head and to the bed to avoid motion. Water was filled between the transducer and the patients' heads. When entering the MR-bore, patients were trained by the neurologist to hold a posture in the constrained environment. Later during the treatment (more details in the next section), patients were instructed to repeat the same posture to monitor the impact of the treatment in real-time.

Anatomical T1-weighted MR images were acquired to identify the position of the anterior and posterior commissures (AC/PC) and the midline. The targeted thalamic region for ablation was the ventral intermediate nucleus (VIM). Its position was determined with respect to the AC-PC coordinates using the Guiot atlas [25], helped by our in-house histological and deformable basal ganglia atlas (YeB) and refined using individual probabilistic tractography. The center of the
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ultrasound transducer was then mechanically adjusted to coincide with the VIM within a 1-mm error margin [26]. Alignment sonifications were necessary for each patient to electronically adjust the target. During such sonifications, the temperature was slightly increased (between 5 and 10°C) on the MR thermometry maps but was not sufficient to permanently thermo-ablate the tissues [16]. The position of thermal rise was used to correct for fine mechanical positioning errors or aberration correction inaccuracies. During the alignment procedure, the temperature at target was kept under 47°C for all patients.

## Accelerometry-based monitoring during thermo-ablation

During the thermo-ablation phase of the treatment, the acoustic energy was incrementally increased for each patient to reach a temperature higher than 55°C at target. During each sonication, the neurologist was present inside the MR room instructing the patient to hold the posture before the sonication started, and to release it at the end. Three to ten ablative sonifications were performed on each patient (Table 1). The maximum temperature reached at target was between 41 and 67°C, the sonication duration between 10 and 45s and the applied electrical power between 250 and 1093W.

Accelerometry data was used to compute tremor amplitude. The Euclidian norm of the 3-axis accelerometry data was calculated, the spectrogram extracted with a 6-s moving window with 5-s overlap, and the amplitude between [2–20]

Hz calculated from the spectrogram. The result was displayed to the neurosurgeon in real-time in the MR control room using a custom MATLAB software.

Offline analyses were additionally performed after the treatment. The thermometry maps were extracted from the Insightec workstation at the end of each treatment. The temperature was monitored at the target and at a control point located 3 cm away. The thermal isoeffect dose in CEM₄₃, defined in cumulated equivalent minute at 43°C (CEM₄₃) [27,28] was extracted from the thermal maps. It describes the equivalent time needed for the reference temperature of 43°C to induce the same effect in a given tissue. The maximum thermal dose reached during each sonication was calculated in addition to the median of the thermal dose necessary to induce an 80% tremor power reduction in all patients. Accelerometry data (including acceleration, spectrogram and tremor power) were synchronized with the beginning and the end of each sonication. Finally, the average and standard deviation of the tremor amplitude between 2 and 20Hz was computed at the beginning (Ãᵢ<sup>start</sup>) and at the end (Ãᵢ<sup>end</sup>) of each sonication over a window of ±3s. The tremor amplitude reduction for each sonication was calculated as the ratio between the averaged tremor amplitude at the end of the sonication over the averaged tremor amplitude at the beginning of the first sonication. The beginning of the first sonication served as the baseline for subsequent sonifications for each patient. Sonifications that resulted in a maximum temperature at target below 51°C (low intensity treatment temperature limit using the Exablate Neuro device [26]) were

<table><caption>Table 1. Patient information and details of inclusion, treatment and control visits.</caption><thead><tr><th></th><th>Patient #1</th><th>Patient #2</th><th>Patient #3</th><th>Patient #4</th><th>Patient #5</th><th>Patient #6</th><th>Patient #7</th></tr></thead><tbody><tr><td>Age (years)</td><td>64</td><td>73</td><td>79</td><td>69</td><td>69</td><td>65</td><td>57</td></tr><tr><td>Sex</td><td>Male</td><td>Female</td><td>Male</td><td>Female</td><td>Female</td><td>Female</td><td>Male</td></tr><tr><td>Skull density ratio</td><td>0.59</td><td>0.49</td><td>0.43</td><td>0.54</td><td>0.55</td><td>0.53</td><td>0.42</td></tr><tr><td>CRST A-B</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Inclusion</td><td>29</td><td>44</td><td>32</td><td>35</td><td>52</td><td>37</td><td>23</td></tr><tr><td>D+7</td><td>13</td><td>26</td><td>15</td><td>15</td><td>19</td><td>16</td><td>9</td></tr><tr><td>M+1</td><td>13</td><td>29</td><td>19</td><td></td><td>22</td><td>18</td><td>15</td></tr><tr><td>M+3</td><td>16</td><td>32</td><td>24</td><td>14</td><td>25</td><td>16</td><td>11</td></tr><tr><td>M+12</td><td>19</td><td>35</td><td>23</td><td>16</td><td>29</td><td>13</td><td>10</td></tr><tr><td>CRST A-B (treated)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Inclusion</td><td>14</td><td>20</td><td>12</td><td>15</td><td>18</td><td>19</td><td>8</td></tr><tr><td>D+7</td><td>2</td><td>6</td><td>1</td><td>1</td><td>4</td><td>4</td><td>0</td></tr><tr><td>M+1</td><td>2</td><td>8</td><td>5</td><td></td><td>4</td><td>3</td><td>2</td></tr><tr><td>M+3</td><td>5</td><td>12</td><td>4</td><td>2</td><td>4</td><td>3</td><td>2</td></tr><tr><td>M+12</td><td>6</td><td>13</td><td>4</td><td>1</td><td>7</td><td>1</td><td>1</td></tr><tr><td># total son</td><td>7</td><td>11</td><td>9</td><td>13</td><td>12</td><td>9</td><td>7</td></tr><tr><td># ablation son</td><td>3</td><td>7</td><td>5</td><td>6</td><td>7</td><td>4</td><td>4</td></tr><tr><td></td><th>Patient #8</th><th>Patient #9</th><th>Patient #10</th><th>Patient #11</th><th>Patient #12</th><th>Patient #13</th><th>Patient #14</th></tr><tr><td>Age (years)</td><td>75</td><td>62</td><td>69</td><td>71</td><td>46</td><td>59</td><td>72</td></tr><tr><td>Sex</td><td>Male</td><td>Male</td><td>Male</td><td>Female</td><td>Male</td><td>Male</td><td>Male</td></tr><tr><td>Skull density ratio</td><td>0.72</td><td>0.44</td><td>0.49</td><td>0.35</td><td>0.46</td><td>0.38</td><td>0.35</td></tr><tr><td>CRST A-B</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Inclusion</td><td>31</td><td>33</td><td>25</td><td>34</td><td>33</td><td>26</td><td>41</td></tr><tr><td>D+7</td><td>18</td><td>22</td><td>15</td><td>14</td><td>19</td><td>16</td><td>26</td></tr><tr><td>M+1</td><td>20</td><td>32</td><td>11</td><td>13</td><td>16</td><td>13</td><td>28</td></tr><tr><td>M+3</td><td>20</td><td>23</td><td>13</td><td>12</td><td>10</td><td>14</td><td>32</td></tr><tr><td>M+12</td><td>19</td><td>27</td><td>15</td><td>13</td><td>9</td><td>16</td><td>34</td></tr><tr><td>CRST A-B (treated)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Inclusion</td><td>11</td><td>13</td><td>17</td><td>13</td><td>16</td><td>10</td><td>18</td></tr><tr><td>D+7</td><td>0</td><td>6</td><td>4</td><td>0</td><td>0</td><td>0</td><td>2</td></tr><tr><td>M+1</td><td>1</td><td>10</td><td>5</td><td>1</td><td>1</td><td>1</td><td>5</td></tr><tr><td>M+3</td><td>3</td><td>6</td><td>6</td><td>0</td><td>0</td><td>1</td><td>11</td></tr><tr><td>M+12</td><td>2</td><td>9</td><td>8</td><td>1</td><td>1</td><td>1</td><td>12</td></tr><tr><td># total son</td><td>14</td><td>12</td><td>15</td><td>11</td><td>8</td><td>11</td><td>9</td></tr><tr><td># ablation son</td><td>5</td><td>6</td><td>10</td><td>5</td><td>5</td><td>7</td><td>5</td></tr></tbody></table>
excluded from the analysis. Additionally, measurements which resulted in an overall tremor power under $10^{-3}$ (a.u.) corresponding to the pre-determined MRI noise were excluded from our analysis as the corresponding recordings during baseline and control visits were excluded as well. Some patients exhibited such large tremor within the MR bore that they were not asked to hold postures as the medical team feared that it could induce a movement of the patient's head despite the stereotactic frame, which would compromise the clinical treatment. In such cases data were not acquired.

For each patient, we defined a predictive efficacy of treatment [Equation (3)] representing the overall tremor reduction:

$$t_{reduction} = \left[ 1 - \max\left( \frac{\tilde{A}_{i}^{end}}{\tilde{A}_{i}^{start}} \right) \right] * 100 \quad (3)$$

where $\tilde{A}_{i}^{start}$ is the tremor amplitude averaged over ± 3s at the beginning of the first sonication, and $\tilde{A}_{i}^{end}$ is the tremor amplitude averaged over ±3s at the end of sonication i.

## Statistical analysis

We performed the nonparametric Friedman test to assess the statistical significance of the ablative treatment on the treated hand's CRST scores and accelerometric data for all visits. Subsequent Conover's post-hoc tests with Bonferroni correction were conducted to adjust for multiple comparisons for all control visits. In assessing the correlation between CRST and accelerometric data, we calculated the coefficient of determination $R^2$ and the nonparametric Spearman's rank correlation coefficient for all control visits. Significance levels were set at $\alpha=0.05$ to examine the statistical significance of the correlations. Tukey's Fences method of outlier detection was performed on the averaged accelerometric data for each

<figure><img src="image_17.png" /><figcaption>Figure 1. Example accelerometric data of (son. 2 of patient #4). Top: spectrogram between [2–20] Hz. Bottom: Tremor power between [2–20] Hz. Vertical red lines indicate sonication start and end times. Dashed red curve: control temperature located 3 cm away from the target. Blue dashed horizontal line: 37°C.</figcaption></figure>

visit and each patient. Patients that were identified as outliers (outside of the interquartile range) in all control visits, using this test, were excluded from analysis.

To illustrate the validity and robustness of our accelerometric data during treatment, a receiver operating characteristics (ROC) curve analysis was conducted on the predictive efficacy during treatment. The classification threshold was defined as 62% of tremor improvement at $M+3$ in the CRST scores [4].

## Results

### Tremor reduction during treatment measured with accelerometers

Figure 1 illustrates the data acquired during a sonication. In this case, the tremor was significantly reduced between the beginning and the end of the sonication, as seen on the spectrogram (Figure 1 top) and the tremor power (Figure 1 bottom).

Figure 2 shows an example of the tremor amplitude reduction (blue curve) during a sonication and its related increase of the thermal dose (red curve).

The gray bands in Figure 2 indicate the ±3s window that were used to compute the average tremor amplitude at the start ($\tilde{A}_{i}^{start}$) and the end ($\tilde{A}_{i}^{end}$) of the sonifications. Those average tremor amplitudes were computed offline for all patients as described in the Materials and Methods (Accelerometry-based monitoring during thermo-ablation). Figure 3 illustrates the results obtained for one patient (#4). Sonication #1 exhibits a 63% tremor amplitude reduction. However, the tremor amplitude at the beginning of the second sonication indicates that this reduction was temporary. The maximum temperature was 56°C and the thermal dose for this sonication was 39 in $CEM_{43}$. During sonication #2, the same target was sonicated with a maximum temperature of 62°C and a thermal dose of 6138 in $CEM_{43}$. Subsequently, the tremor reduction was sustained and maintained until the end of the procedure. Three additional sonifications were performed to remove the residual tremor by shifting the target 1.0mm upward from the initial VIM target. However, no clear improvement was visible on accelerometry.

<figure><img src="image_18.png" /><figcaption>Figure 2. Example of accelerometry data for the first sonication of patient #7. Tremor power in the [2–20] Hz band (blue) superimposed with the thermal dose (red). Gray boxes indicate the ±3s window to compute $\tilde{A}_{i}^{start}$ and $\tilde{A}_{i}^{end}$.</figcaption></figure>
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<figure><img src="image_20.png" /><figcaption>**Figure 3.** Tremor amplitude at the beginning and at the end of each sonication for patient #4. Data at the top of each sonication give the total CEM₄₃ during the whole sonication, the maximum temperature obtained at target, and the shift in target location as compared to the target of the first sonication (in mm).</figcaption></figure>

The tremor amplitude reduction of each individual sonication, as well as maximum temperature and total thermal dose at target during each sonication are summarized in Table 2. Blank cells in Table 2 correspond to excluded data as explained in Materials and Methods. The predictive efficacy measured by accelerometry was computed offline. The value of the overall predictive efficacy, as defined by Equation (3), was on average 70±30%. The mean number of ablative sonications for the fourteen patients was 6±2, and the total number of sonications (including the alignment sonications) was 11±3. Additionally, the median value of the thermal dose necessary to induce an 80% tremor power reduction was 162 CEM₄₃ and the average maximum thermal dose corresponding for each patient to the maximum ablation sonication was 14006 CEM₄₃.

## Correlation between CRST scores and accelerometric tremor reduction during control visits

Table 1 summarizes patients' information and CRST scores of inclusion and control visits. A more detailed version including ablation sonications is in Supplementary Materials B.

The nonparametric Tukey's Fences approach revealed that patient #9 only was an outlier across all control visits for both treated and control hand. The tremor change between baseline and control visits quantified by CRST scores and accelerometer recordings is visualized in Figure 4 for all patients except the outlier (patient #9).

The nonparametric Friedman test revealed a statistically significant effect of time for both CRST scores [$\chi^2$ = 36.9, df = 4, *p* < 0.001] and accelerometric data [$\chi^2$ = 22.3, df = 4, *p* < 0.001]. Post-hoc tests were conducted using Conover's tests with Bonferroni correction to adjust for multiple comparisons. ΔCRST for the treated hand was 12.8±2.4 [*p* < 0.001]

at D+7, 11.5±3.0 [*p* = 0.005] at M+1, 10.6±3.4 [*p* = 0.008] at M+3 and 10.2±3.6 [*p* = 0.07] at M+12 on average. This corresponded to an 89±11% at D+7, 79±12% at M+1, 74±19% at M+3, and 72±23% at M+12 of tremor improvement on the treated side in the CRST scale for all patients treated. Tremor amplitude reduction for the treated side for all patients with available accelerometry data was 81±22% [*p* = 0.009] at D+7, 76±25% [*p* = 0.006] at M+1, 76±23% [*p* = 0.011] at M+3 and 85±11% [*p* = 0.005] at M+12.

We observed a positive correlation between CRST tremor reduction (ΔCRST) and tremor amplitude reduction at D+7, M+1, M+3 and M+12 respectively. The results of the correlation analysis are displayed in Table 3 and Figure 5.

Interestingly, a slight improvement on the control side (non-treated side) was observed at D+7, M+1, M+3 and M+12 on the clinical scale (Figure 4). Although not statistically significant (*p* ≫ 0.05 for all visits), the ΔCRST at D+7, M+1, M+3, and M+12 was 1.8±5.0, 1.8±4.9, 2.2±3.4 and 1.8±3.5. This corresponded to %CRST of 6.7±26%, 8.2±24%, 13±16% and 11±17%. Such tremor reduction on the control side was also visible on the accelerometer (Figure 4).

At one year, 3 of our patients had slight to moderate sensitive disorders as perioral hypesthesia (n=2) or proprioceptive hypesthesia of the hand (n=1); 3 of our patients still had abnormal gait on clinical testing without functional disturbance. No patient developed dysarthria or swallowing disorder.

## Tremor reduction during treatment and clinical outcome

Figure 6 shows a ROC curve for the predictive efficacy during treatment and the %CRST at M+3 visit with 62% tremor improvement taken as a successful response to treatment. The AUC (area under ROC curve) value is 0.88 and the optimal cutoff value is 70% of the predictor (Figure 6).
<figure><img src="image_21.png" /><figcaption>**Table 2.** Tremor amplitude reduction (%) for each ablative sonication compared to the baseline, maximum average temperature and total thermal dose (CEM<sub>43</sub>) for each ablative sonication.</figcaption></figure>

<table><thead><tr><th></th><th></th><th>Son. 1</th><th>Son. 2</th><th>Son. 3</th><th>Son. 4</th><th>Son. 5</th><th>Son. 6</th><th>Son. 7</th><th>Son. 8</th><th>Son. 9</th><th>Son. 10</th></tr></thead><tbody><tr><td rowspan="3">Patient 1</td><td>Tremor reduction (%)</td><td></td><td>27</td><td>94</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>49.4</td><td>52.4</td><td>64.5</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>2</td><td>51</td><td>6138</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 2</td><td>Tremor reduction (%)</td><td>-16</td><td>-30</td><td>32</td><td>-</td><td>27</td><td>12</td><td>18</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>54.2</td><td>60.2</td><td>60.2</td><td>49.3</td><td>53.6</td><td>59.3</td><td>61.3</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>17</td><td>1743</td><td>1721</td><td>2</td><td>18</td><td>29</td><td>2069</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 3</td><td>Tremor reduction (%)</td><td></td><td>70</td><td>48</td><td>70</td><td>21</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>50.7</td><td>59.0</td><td>61.2</td><td>67.3</td><td>66.9</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>6</td><td>264</td><td>2844</td><td>10908</td><td>94339</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 4</td><td>Tremor reduction (%)</td><td></td><td>63</td><td>76</td><td>86</td><td>81</td><td>71</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>49.0</td><td>55.9</td><td>61.5</td><td>62.9</td><td>51.7</td><td>53.6</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>1</td><td>39</td><td>6138</td><td>3601</td><td>8</td><td>503</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 5</td><td>Tremor reduction (%)</td><td></td><td>48.2</td><td>45.9</td><td>52.1</td><td>48.7</td><td>56.5</td><td>51.9</td><td>56.8</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>2</td><td>0.4</td><td>23</td><td>8</td><td>476</td><td>32</td><td>456</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>11</td><td>98</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 6</td><td>Tremor reduction (%)</td><td></td><td>52.5</td><td>54.6</td><td>63.2</td><td>65.9</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>5</td><td>62</td><td>3654</td><td>313</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>56</td><td>89</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 7</td><td>Tremor reduction (%)</td><td></td><td>49.2</td><td>51.1</td><td>58.8</td><td>53.2</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>1</td><td>3</td><td>450</td><td>34</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>3</td><td>22</td><td>-</td><td>-</td><td>20</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 8</td><td>Tremor reduction (%)</td><td></td><td>49.5</td><td>62.3</td><td>56.1</td><td>62.3</td><td>62.3</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>9</td><td>5232</td><td>115</td><td>31914</td><td>1760</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>50.2</td><td>57.2</td><td>59.5</td><td>54.9</td><td>52.4</td><td>60.3</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 9</td><td>Tremor reduction (%)</td><td></td><td>4</td><td>140</td><td>799</td><td>197</td><td>61</td><td>2479</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>-40</td><td>82</td><td>23</td><td>14</td><td>52</td><td>45</td><td>89</td><td>-</td><td>-</td><td>95</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>51.0</td><td>54.8</td><td>56.3</td><td>56.2</td><td>57.8</td><td>59.6</td><td>66.8</td><td>49.9</td><td>52.5</td><td>58.8</td></tr><tr><td rowspan="3">Patient 10</td><td>Tremor reduction (%)</td><td></td><td>3</td><td>32</td><td>168</td><td>68</td><td>515</td><td>429</td><td>42659</td><td>3</td><td>10</td><td>1693</td></tr><tr><td>T (°C)</td><td>41.3</td><td>52.3</td><td>53.8</td><td>54.6</td><td>60.5</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>0</td><td>4</td><td>30</td><td>112</td><td>2295</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 11</td><td>Tremor reduction (%)</td><td></td><td>49.0</td><td>50.9</td><td>56.5</td><td>58.0</td><td>59.0</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>2</td><td>7</td><td>165</td><td>366</td><td>1318</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>49.1</td><td>49.1</td><td>56.5</td><td>55.0</td><td>58.7</td><td>55.8</td><td>55.7</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Patient 12</td><td>Tremor reduction (%)</td><td></td><td>2</td><td>2</td><td>85</td><td>47</td><td>886</td><td>333</td><td>292</td><td>-</td><td>-</td><td>-</td></tr><tr><td>T (°C)</td><td>50.5</td><td>51.9</td><td>55.7</td><td>55.4</td><td>57.2</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Thermal dose (CEM<sub>43</sub>)</td><td>4</td><td>26</td><td>256</td><td>527</td><td>1269</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr></tbody></table>

Dashed cells indicate that no sonication was performed. Blank cells correspond to missing accelerometric data (either it was not recorded or the recording was below the noise threshold).

Discussion

The objective of our study was to confirm the feasibility of tremor monitoring during MRgFUS thalamotomy procedures in ET patients. We also demonstrated the usefulness of real-time tremor monitoring; tremor amplitude reduction recorded by an accelerometer during MRgFUS thalamotomy could predict the clinical outcome at three months. Furthermore, we showed that accelerometric tremor reduction during the control visits was correlated with the clinical improvement observed one week, one, three or even twelve months after the surgery.

We incorporated accelerometers into MRgFUS thalamotomy and measured tremor amplitude during and after procedures. The accelerometric tremor amplitude reduction after procedures was 81% at D+7, 76% at M+1, 76% at M+3 and 85% at M+12. Use of accelerometers to quantify the tremor in ET has already been reported in the literature as in pharmacological studies [17,18], in a DBS clinical case [20] or thalamotomy surgery [29]. Our results are in line with the literature, including a 76% and 60% accelerometric tremor amplitude reduction with primidone and propranolol

respectively after 10 days period on the maximum dose of each treatment course [17], a 70% and 74% accelerometric tremor amplitude reduction after a month of treatment with phenobarbital and propranolol respectively [18], and a 97% accelerometric tremor amplitude reduction reported in intraoperative reading using a tremor pen in an ET patient treated by DBS [20]. The consistency of tremor amplitude measurements with accelerometry across treatment methods highlights the robustness of this measure.

The outcome of the patients treated here are consistent with the efficacy of the reduction in tremor with conventional MRgFUS thalamotomy treatments without accelerometry measurements. Using the CRST scores of the treated side, we measured an average tremor improvement of 89% at D+7, 79% at M+1, 74% at M+3 and 72% at M+12. Pioneering works reported 75% at M+12 and 81% at M+3 improvement on the treated side on the FTM tremor rating scale [1,2]. A meta-analysis of 8 published clinical studies showed a post-treatment tremor improvement on the CRST scale of 62% [4].

Accelerometric analysis of tremor is particularly useful and relevant to peri-therapeutic monitoring and post-operative
<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /><figcaption>Figure 4. Tremor evolution on the treated and control side measured using the accelerometer(left) and the CRST score (right) (n = 13).</figcaption></figure>

<table><caption>Table 3. Correlation coefficients between CRST tremor reduction and tremor amplitude reduction with accelerometric data on the treated side.</caption><thead><tr><th></th><th>D+7</th><th>M+1</th><th>M+3</th><th>M+12</th></tr></thead><tbody><tr><td>Spearman's ρ</td><td>0.79 [p=0.004]</td><td>0.75 [p=0.013]</td><td>0.86 [p=0.005]</td><td>0.63 [p=0.077]</td></tr><tr><td>Spearman's ρ all patients*</td><td>0.83 [p=0.001]</td><td>0.81 [p=0.003]</td><td>0.89 [p=0.001]</td><td>0.73 [p=0.017]</td></tr><tr><td>R<sup>2</sup></td><td>0.57 [p=0.007]</td><td>0.62 [p=0.007]</td><td>0.52 [p=0.028]</td><td>0.28 [p=0.144]</td></tr><tr><td>R<sup>2</sup> all patients*</td><td>0.59 [p=0.004]</td><td>0.73 [p=0.001]</td><td>0.45 [p=0.034]</td><td>0.36 [p=0.066]</td></tr></tbody></table>

evaluation; clinical scales are ordinal whereas tremor is a continuous clinical manifestation. Because of the non-linearity of the clinical scales and the threshold effects they generate [30], those scales provide limited information in the context of real-time and effective ablative therapies such as MRgFUS surgery. Studies have shown the effectiveness of MRgFUS thalamotomy to treat ET [2,4]. However, a quantitative and real-time feedback evaluation of tremor during and after treatment could further improve clinical results of ultrasound treatments. MR-compatible accelerometers provide a metric correlating with clinical scales used to evaluate tremor [30]. However, given the ordinal and non-linear nature of the CRST, its correlation with a continuous and linear metric as the tremor amplitude reduction measured with the accelerometer will not be ideal. Non-parametric tests such as Spearman's rank correlation may be more appropriate in this scenario. We observed high correlation values throughout the study (ρ=0.79 at D+7, ρ=0.75 at M+1, ρ=0.86 at M+3, and ρ=0.63 at M+12) compared to what was previously reported (correlation of 0.61 between CRST part A and total tremor power) [30]. These correlations demonstrate the feasibility of recording tremor with an accelerometer. It is worth noting that when taking into account all patients, including patient 9, the overall correlation between CRST tremor reduction and tremor amplitude reduction increased. However, caution is needed when interpreting this change in correlation value because of the outlier effect of patient 9. This is due to the fact that patient 9 did not respond well to the treatment, which is reflected in both metrics.

We also measured tremor amplitude during the MRgFUS thalamotomy procedure. Monitoring tremor reduction feedback during treatment could improve targeting and reduce the number of effective ablative sonifications. During alignment sonifications, patients have been reported previously to elicit transient tremor reduction [2]. In the future, patients could be asked to hold postures while performing medium temperature sonifications and sampling tremor power. Monitoring transient effects could inform the neurosurgical team to better define the target and reduce targeting errors and side effects. Moreover, this may reduce the number of sonifications by providing quantitative real-time feedback of the efficacy of each sonication. For example, patient #4 could perhaps have been treated only 2 or even 3 times instead of 5 (Figure 3). Studies reported that fewer ablative sonifications correlates with better treatment outcomes [5,13]. Our preliminary work sets the ground for online accelerometry measurements. It enabled us to acquire and process the data but at this stage the measurements were not used to decide when to stop the treatment. One important outcome is that the optimal cutoff value for the predictor is 70%. It means that the treatment could be stopped when the overall tremor reduction calculated with Equation (3) reaches 70%. Nevertheless, it remains to be validated by future clinical trials on larger cohorts whether the impact of such a decision to stop the treatment is actually beneficial to the efficacy and the safety of the treatment.

The large value of the AUC obtained by ROC curve analysis (0.88) revealed that tremor improvement three months

<footnote>*All treated patients including the outlier (patient 9).</footnote>
<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /><figcaption>**Figure 5.** Correlation between the tremor reduction on the CRST scale on the treated side (vertical axis) and the tremor amplitude reduction with the accelerometers on the treated side (horizontal axis) between the inclusion and the control visits.</figcaption></figure>

<figure><img src="image_26.png" /><figcaption>**Figure 6.** Roc curve for overall tremor amplitude reduction during treatment compared to 62% tremor improvement of CRST score at M+3 (n=10).</figcaption></figure>

after the thalamotomy is well predicted by our quantification of the tremor based on the accelerometric recording and that Equation (3) is an appropriate definition of a predictive efficacy indicator. An accelerometric based reduction in tremor amplitude of 70% during the ablative procedure predicts an improvement judged to be clinically significant and corresponding to the average improvement in a meta-analysis [4]. In practice, an appropriate indication for the treating physician to stop the treatment would be when the overall tremor reduction calculated with Equation (3) reaches 70%. Nevertheless, it is important to note variability observed across patients. As seen in Tables 1 and 2, some patients exhibited a good tremor reduction during treatment whereas the clinical outcome during the control visits was poor (See for example patient 10). Other patients showed the opposite response, as their accelerometric data did not reflect a promising reduction, but the clinical outcome at control visits revealed a positive effect of the treatment (See for example patient 8). As a result, the area under the ROC curve is significantly lower than 1. An AUC of 0.88 is nonetheless an encouraging result.
<figure><img src="image_27.png" /></figure>

In this study, on average the maximum thermal dose was 14,006 CEM<sub>43</sub>. The maximum thermal dose necessary to induce damage in different normal tissues in various species is 240 CEM<sub>43</sub> [27]. It is the reason why a threshold of 240 CEM<sub>43</sub> is typically used in high intensity focused ultrasound to determine the volume of the lesions, in particular for uterine fibroid treatments [31] or thalamotomy [32]. While this confirms the effectiveness of our protocol and device to thermally ablate brain tissues, the thermal dose levels reached during the procedure are substantially higher than the reported threshold. This provides further evidence for the need of a real-time and quantitative monitoring of tremor and thermal dose that would permit avoiding unnecessary sonications or to shorten sonication duration once the clinical threshold of ablation of 240 CEM<sub>43</sub> is reached. However, the threshold necessary to induce thermal damage in brain tissue is lower. The lowest threshold was reported in dog brains [33]: 10 CEM<sub>43</sub>. In humans, the probability for thermal damage in ET patients was estimated to be 50% at 13.6 CEM<sub>43</sub> and suggested that a 17 CEM<sub>43</sub> threshold was on average a good predictor for thermal lesions in human brain [34]. Our study highlights a higher threshold to induce a clinically acceptable reduction in tremor power: the median thermal dose necessary to induce an 80% reduction of tremor power was 162 CEM<sub>43</sub>. It was higher than the lesioning threshold and one can hypothesize that it was related to the volume of tissues affected by ultrasound. It opens the door to automatic feedback loop control to stop the sonication as soon as a significant reduction of tremor is observed, rather than as soon as a given thermal dose is achieved.

Overall, our study obtained an overall tremor amplitude reduction of 70% during the treatment. Interestingly, this value was lower than that observed at a distance from the surgery, even at 12 months. This result brings two new insights into the field of ultrasound treatments. Firstly, it is unnecessary to seek the complete disappearance of the tremor during the lesioning because the final effect will be greater than that obtained during treatment due to the evolution of the lesion during the days following the procedure. Secondly, this indirectly demonstrates the dynamic nature of the thermal lesion. The per-operative effect results from different ultrasound mechanisms including neuromodulation [35], the edematous reaction and finally the necrotic lesion itself [36].

Larger cohorts with combined recording of clinical and accelerometric data must be evaluated to confirm our initial results. In our study including 14 patients with MR-compatible accelerometers, 13 patients had usable data. For the accelerometric data during treatment, only 10 had usable data meeting the inclusion criteria. The accelerometry data was not obtained for 4 of 14 patients because the clinical team was concerned that the tremor inside the MR bore was too high when holding the posture and could lead to some movement during sonication, thus affecting the treatment. In such patients, it would be interesting to perform the measurements in postures with less extensive tremor. Therefore, analysis of accelerometric recordings is an additional aid that cannot replace clinical assessment. Further studies are needed to show that the use of an MR-compatible accelerometer during ultrasound ablative therapy is superior to the conventional procedure in terms of clinical outcome (i.e., reduction in tremor and control of side effects) at 3 or even 12 months. Lastly, due to

the lack of data, we could not examine the correlation between CRST scores and the logarithm of tremor amplitude. This could have revealed more subtle variations [37].

## Conclusion

We performed the first online quantitative tremor monitoring during MRgFUS ET sonifications for thalamotomy. We used synchronized MR-compatible accelerometers to assess the efficacy of each sonication and evaluate the overall treatment outcome. The treatment efficacy assessed with accelerometers correlated with the improvement in the CRST scale during the control visits. More importantly, the reduction of tremor during the sonifications predicted the clinical outcome at three months. MR-compatible accelerometers thus provide valuable real-time feedback about the tremor during treatment and could help reduce the number of necessary sonifications in the future while maintaining the same level of tremor improvement for patients.

## Acknowledgments

The authors thank Vincent Degos, Anais Hervé and Clémentine Trosch for their management of the anesthesia and patient care. This work was achieved in collaboration and with the financial support of Insightec Ltd, to which we are grateful. This work was supported by the Bettencourt Schueller Foundation and the 'Agence Nationale de la Recherche' under the program "Future Investments" with the reference ANR-10-EQPX-15. The work was performed with the support of the ART (Technological Research Accelerator) biomedical ultrasound program of INSERM and the Focused Ultrasound Foundation Center of Excellence program (Physics for Medicine Paris).

## Competing interests

JFA received a research grant from Insightec for preclinical work on transtranquilating ultrasound.

## Author contributions

All authors contributed to writing and proofreading this manuscript. SL, MV, DG, NP, CK, EH, MT and JFA designed the clinical trial, TB, BB, CG and JFA designed the accelerometer experiments and performed the acquisitions, M Didier, EB, SFV, EH and CK performed the planning, MS acquired the MR data. TB, MB, DA and JFA analyzed the results, TB, EH, MB, TM and JFA wrote the first draft of the paper.

## Disclosure statement

JFA received a research grant from Insightec for preclinical work on transtranquilating ultrasound.

## Study design

This was a prospective phase 1, open-label, single-arm clinical trial at la Pitié Salpétrière Hospital (NCT04074031) approved by an independent CPP Ethical Committee (N° IDRCB: 2019-A01791-56). Eligible patients included those between 18 and 80 years of age with diagnosis of essential tremor according to the criteria of the Consensus Statement of the Movement Disorders Society and with stable drug therapy for at least 30 days prior to inclusion. Eligibility criteria are described Supplementary Materials A.
<figure><img src="image_28.png" /></figure>

## Funding

This work was achieved in collaboration and with the financial support of Insightsc Ltd, to which we are grateful. This work was supported by the Bettencourt Schueller Foundation and the 'Agence Nationale de la Recherche' under the program 'Future Investments' with the reference ANR-10-EQPX-15. The work was performed with the support of the ART (Technological Research Accelerator) biomedical ultrasound program of INSERM and the Focused Ultrasound Foundation Center of Excellence program (Physics for Medicine Paris).

## Data availability statement

Due to the nature of the research some of the data cannot be shared publicly due to the confidentiality of the patient. Some of the data can be made available upon request directed to the corresponding author. Proposals will be reviewed based on the basis of scientific merit, ethical review and regulatory requirements.

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