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. 2019 Mar 13;40(10):2933–2942. doi: 10.1002/hbm.24569

Microstructural changes of the dentato‐rubro‐thalamic tract after transcranial MR guided focused ultrasound ablation of the posteroventral VIM in essential tremor

Jose A Pineda‐Pardo 1,2,✉, Raul Martínez‐Fernández 1,2, Rafael Rodríguez‐Rojas 1,2, Marta Del‐Alamo 1, Frida Hernández 1, Guglielmo Foffani 1,3, Michele Dileone 1, Jorge U Máñez‐Miró 1, Esther De Luis‐Pastor 4, Lydia Vela 1,2, José A Obeso 1,2
PMCID: PMC6865586  PMID: 30865338

Abstract

Essential tremor is the most common movement disorder in adults. In patients who are not responsive to medical treatment, functional neurosurgery and, more recently, transcranial MR‐guided focused ultrasound thalamotomy are considered effective therapeutic approaches. However, the structural brain changes following a thalamotomy that mediates the clinical improvement are still unclear. In here diffusion weighted images were acquired in a cohort of 24 essential tremor patients before and 3 months after unilateral transcranial MR‐guided focused ultrasound thalamotomy targeting at the posteroventral part of the VIM. Microstructural changes along the DRTT were quantified by means of probabilistic tractography, and later related to the clinical improvement of the patients at 3‐months and at 1‐year after the intervention. In addition the changes along two neighboring tracts, that is, the corticospinal tract and the medial lemniscus, were assessed, as well as the relation between these changes and the presence of side effects. Thalamic lesions produced local and distant alterations along the trajectory of the DRTT, and each correlated with clinical improvement. Regarding side effects, gait imbalance after thalamotomy was associated with greater impact on the DRTT, whereas the presence of paresthesias was significantly related to a higher overlap between the lesion and the medial lemniscus. This work represents the largest series describing the microstructural changes following transcranial MR‐guided focused ultrasound thalamotomy in essential tremor. These results suggest that clinical benefits are specific for the impact on the cerebello‐thalamo‐cortical pathway, thus reaffirming the potential of tractography to aid thalamotomy targeting.

Keywords: essential tremor, MR guided focused ultrasound, tractography

1. INTRODUCTION

Essential tremor (ET) is the most frequent movement disorder and, in some cases, it causes functional disability and impairment in quality of life (Bhatia et al., 2018). For those patients with medically‐refractory and disabling tremor, functional neurosurgical approaches such as radiofrequency thalamotomy or thalamic deep brain stimulation (DBS) represent a therapeutic alternative (Louis, Rios, & Henchcliffe, 2010). Both treatments are equivalent in terms of efficacy but stimulation has been classically favored over lesion mainly on the grounds of its reversibility and its safer profile when applied bilaterally (Niranjan et al., 2017; Schuurman, Bosch, Merkus, & Speelman, 2008). The recent development of less invasive techniques to produce lesions in deep brain structures without skull opening, such as gamma knife and transcranial magnetic resonance guided focused ultrasound (tcMRgFUS; Arvanitis, Livingstone, & McDannold, 2013; Jolesz & McDannold, 2014; Krack, Martinez‐Fernandez, del Alamo, & Obeso, 2017), has opened new and less‐invasive options for the treatment of patients with tremor and other movement disorders (Weintraub & Elias, 2017). Unlike gamma knife, tcMRgFUS allows real‐time clinical and imaging monitoring to enhance target accuracy and it has immediate clinical effects (Elias et al., 2016; Lipsman et al., 2013; Schreglmann et al., 2017). This novel technique therefore seems ideal to study the action mechanisms of therapeutic brain lesions.

Although the mechanisms underlying ET are not clearly defined, a dysfunction of the cerebello‐thalamo‐cortical network has been proposed (Buijink et al., 2015; Fang et al., 2015; Schnitzler, Münks, Butz, Timmermann, & Gross, 2009). The ventral intermediate nucleus (VIM) of the thalamus, which receives cerebellar output from the dentate nuclei and projects to the motor cortex (Kwon et al., 2011), is considered the optimal target for ET (Krack et al., 2017). Ablation of the VIM is well known to provide benefit in cases of tremor (Krack et al., 2017; Speelman, Schuurman, de Bie, Esselink, & Bosch, 2002), which is believed to be mediated by impact on the dentato‐rubro‐thalamic tract (DRTT) (Klein et al., 2012). However, the exact mechanisms by which this modulation occurs and results in tremor improvement are still unclear.

Using diffusion‐weighted MRI it is possible to: (a) Study the microstructural properties in the brain white matter and (b) Define the boundaries of specific anatomical pathways using tractography. The combination of these two approaches makes it possible to characterize microstructural changes along a certain anatomical pathway occurring after a perturbation at some point along its trajectory. The aim of this study was to characterize the thalamotomy‐induced structural effects in ET patients. To this end, we mapped the DRTT, the cortico‐spinal tract and the medial lemniscus using probabilistic tractography, and characterized microstructural changes along their trajectory. These changes were subsequently related to the clinical effects of thalamotomy. This study is ultimately intended to shed light on the mechanisms underlying tremor improvement after tcMRgFUS thalamotomy.

2. METHODS

2.1. Participants

Patients suffering from medication‐refractory ET were included in the study. A neurologist who specializes in movement disorders confirmed the diagnosis of ET. Twenty‐four patients with disabling and medication‐refractory ET (7 women, 22 right‐handed, mean age 68.0 ± 10.1) underwent tcMRgFUS thalamotomy targeting the posteroventral VIM nucleus contralateral to the clinically more affected hemibody. Average disease duration was 18.6 ± 12.8 years. tcMRgFUS was performed in an ExAblate 4000 system (InSightec, Haifa, Israel). The target was localized one‐quarter of the intercommissural distance anterior to the posterior commissure (PC), and 11.5 mm lateral from the wall of the third ventricle. Once the thermal alignment with the target was confirmed, the sonication energy was gradually increased to ablative temperatures (55–60°). Stopping criteria were tremor relapse and a minimum of three sonications over 55°C. During treatment a second target location was defined displacing the focus along the posteroventral axis, attempting to cover the afferent dentato‐rubro‐thalamic fibers. Patients were awake during the procedure, and neurological examination was carried out after each sonication to evaluate tremor response and to detect any possible side effects. Clinical and radiological data were acquired prospectively. The study was performed according to the Declaration of Helsinki and approved by the local Ethics Committee. All patients provided written informed consent before treatment and MRI acquisition. Further methodological details regarding the thalamotomy procedure are described in Supporting Information.

2.2. Clinical and neuroimaging follow‐up

Clinical examination included the validated Fahn‐Tolosa‐Marín (FTM) clinical rating scale for tremor (Stacy, Elble, Ondo, Wu, & Hulihan, 2007), which was assessed at baseline, at month 3 and at 1 year. The FTM scale range from 0 to 156 and is divided into three parts: (a) presence and severity of tremor in each body part (range 0–88); (b) writing and four different hand tasks (range 0–36); and (c) disability in daily living activities associated with tremor (range 0–32). The more frequently affected side was the right hemibody (in 21 of 24 patients). Brain MRI was acquired on a 3 T GE scanner (Discovery 750w, GE Healthcare, Milwaukee, WI) at baseline, 24 hr following tcMRgFUS thalamotomy, and at 3 months. The imaging protocol included: 1. 3D T1‐weighted (TR/TE/TI 9352/4.02/450 ms, flip‐angle 10°, FoV 256 mm, acquisition matrix 256 × 256, slice thickness 1 mm), axial T2‐weighted (TR/TE 8093/94.08 ms, flip‐angle 111°, FoV 256 mm, acquisition matrix 320 × 320, slice thickness 2 mm), and axial susceptibility‐weighted images (SWI; TR/TE 56.7/23.176 ms, flip‐angle 30°, FoV 220 mm, acquisition matrix 384 × 256, slice thickness 2 mm). The baseline and 3‐month imaging protocols also included diffusion weighted imaging (DWI) using a single‐shot 2D spin‐echo EPI sequence (TR/TE 13500/106.9 ms, FoV 256 mm, acquisition matrix 128 × 128 and 2 mm slice thickness). Diffusion was measured along 60 encoding directions with b = 1000 s/mm2. In addition, four images with b = 0 s/mm2 and another four with phase encoding direction reversed were acquired. In order to match brain lesion location across all subjects, the MRI of the three patients performing right‐hemisphere thalamotomy were flipped along the interhemispheric axis.

2.3. Image analysis

Post‐treatment MRI exams, including T1w, T2w, and SWI, were realigned to the baseline T1w images. Lesion tissue at 24 hr and at Month 3 was manually segmented using ITK‐Snap, and lesion volumes were computed (Vol 24hr, Vol 3m). Lesion voxels were identified as those showing T1w or SWI hypo‐intensities, and T2w hyper‐intensities (see Figure 1a). Baseline T1w images were denoised, and nonbrain tissue was removed using BET in FSL‐FMRIB. BET‐T1w images were co‐registered using affine transformation to an MNI T1w template and normalized using the nonlinear symmetric registration algorithm “SyN” available in ANTS. These transformations were inverted and applied to several ROIs within specific atlases to conduct the tractography mapping. See Supporting Information Figure S1(a) for a summary of these ROIs.

Figure 1.

Figure 1

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(a) Sample images showing tissue lesions. The first row shows the lesion 1‐day postintervention and the second row shows the 3‐months postintervention. Lesions at different contrasts are outlined in red; (b) Probabilistic lesion map and anatomical projections. Axial slice on MNI space showing the average lesion (1‐day post‐treatment) and the reconstruction of the anatomical pathways traveling in the vicinity of the lesion, that is, dentato‐rubro‐thalamic tract (DRTT), corticospinal tract (CST), and medial lemniscus (ML); (c) Probabilistic lesion map and topography of the lesions across subjects. It represents in what percentage of the patients a voxel was identified as lesioned tissue. VIM: ventral intermediate nucleus; VLa: ventral lateral anterior nucleus; VPL: ventral posterior lateral nucleus; VPM: ventral posterior medial nucleus; STh: subthalamic nucleus [Color figure can be viewed at http://wileyonlinelibrary.com]

DWI was denoised and nonbrain tissue was removed using BET. The b0 images with opposing phase encoding directions were combined using the TOPUP‐FSL, and a susceptibility‐induced fieldmap was estimated. EDDY‐FSL was run to correct for motion and field inhomogeneity related geometrical distortions using the previously estimated fieldmap. DWI was transformed to T1w native space using an affine transformation. Diffusion encoding directions were rotated following motion estimations and DWI to T1w transformation. Fiber orientation distributions (FODs) were estimated using constrained spherical deconvolution in MRtrix. Diffusion tensor images (DTIs) were generated using a weighted linear least‐squares estimator. From the DTI we computed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) maps. DTI based measures are biased by extra‐cellular water diffusion, and so to improve the characterization of microstructural changes, we also estimated the apparent fiber density (AFD) maps (Raffelt et al., 2012). AFD is related to the FOD amplitude, and provides a relative measure of the intra‐axonal volume occupied by fibers.

The DRTT was generated using the dentate nucleus as seed and the superior cerebellar peduncle, the contralateral red nucleus, the contralateral thalamus, and the contralateral precentral gyrus as inclusion regions (Kwon et al., 2011). The corticospinal tract (CST) was generated using the cerebral penduncle as seed, the ipsilateral thalamus as a rejection region, and the posterior internal capsule and the precentral gyrus as inclusion regions. Finally, the medial lemniscus (ML) was reconstructed using a disk‐shaped ROI at the ventral pons as seed and the ipsilateral thalamus and the postcentral gyrus as inclusion regions. All probabilistic reconstructions were performed in MRtrix using the following seeding parameters: cut‐off value = 0.1, step‐size = 1 mm, limit angle = 45° and max/min length = 220/15 mm. All tractography reconstructions were projected to MNI and merged, and 100 orthogonal disk‐shaped ROIs were defined along the merged reconstructions. Then a group probability map was created for each of the six tracts, representing the probability of a pathway reaching a voxel (see Supporting Information Figure S1[b]). These maps were thresholded at a 0.1% probability. Then the subjects' DTI and AFD maps were normalized to MNI and DTI scores were extracted in the intersection between the thresholded probability maps and the ROIs.

2.3.1. Statistics

DTI scores were averaged within the lesion boundaries, taking both the lesion segmented 1‐day and 3‐months post‐treatment, and compared between baseline and post‐treatment datasets using a parametric paired t‐test statistical comparison. The different measures were extracted along the anatomical pathways and compared across subjects between baseline and 3‐months post‐treatment datasets using a paired t‐test analysis. Microstructural changes associated with gait imbalance were evaluated using a nonparametric Wilcoxon rank‐sum test. Clusters of at least three neighboring ROIs showing significant differences (p < 0.01) were used for posterior correlation analysis with the clinical improvement after treatment, using Pearson linear correlations. For the correlation analysis, DTI changes and clinical improvement were quantified as relative increments between baseline and follow‐up.

3. RESULTS

3.1. Clinical outcomes and side effects

Total FTM score decreased by 55.6% at 3 months and by 50.4% at 1‐year as compared to baseline (see Table 1). By the 3‐months follow‐up visit, six (25%) of all 24 patients reported subjective instability and had normal examination of the equilibrium, and another one presented mild gait ataxia in the neurological examination which persisted at 1 year. Four patients (17%) reported mild and nondisabling paresthesias, and one patient presented mild speech disturbance, these both side effects persisted at 1 year. No other side effects were reported.

Table 1.

Clinical outcomes after tMRgFUS thalamotomy in a sample of 24 essential tremor patients

Baseline 3 months 1 year
FTM item Score Score Change from baseline (%) Score Change from baseline (%)
A 13.6 (4.7) [6–22] 7.3 (2.9) [1–13]* 44.8 (19.1) [0–90] 7.1 (3.1) [2–14]* 46.9 (19.8) [13–86]
Atreated‐side 5.6 (1.8) [3–9] 1.0 (0.9) [0–3]* 81.8 (21.1) [0–100] 1.5 (1.3) [0–4]* 73.0 (27.9) [0–100]
B 21.7 (6.1) [12–32] 12.9 (5.5) [5–29]* 40.2 (18.4) [−3–76] 14.1 (5.5) [4–28]* 35.7 (16.2) [0–71]
C 17.3 (4.8) [7–25] 4.2 (4.1) [0–15]* 75.5 (26.0) [6–100] 5.4 (4.9) [0–19]* 66.9 (29.5) [−19–100]
Total 52.9 (13.0) [35–77] 23.8 (8.3) [9–40]* 55.6 (9.3) [34–74] 26.4 (11.3) [4–48]* 50.4 (18.4) [6–89]
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Note. Asterisks indicate statistical significance (paired t‐test p < 0.00001) in the comparison between baseline and 3 months after intervention.

3.2. Lesion topography and DTI changes within the target

One day after tcMRgFUS, lesions were visible on T1w, T2w, and SWI for all subjects. At Month 3 only SWI showed a clear lesion for all subjects. Average lesion volume, including both necrosis and perilesional edema (Zones 1 and 2 in [Wintermark et al., 2014a]), was 242 mm3 24 hr post‐treatment, and was reduced to an average volume of 108 mm3 3‐months post‐treatment. The coordinates of the lesions at 24 hr and Month 3 are presented in Table 2. On average, the core of the lesion was located 15 mm lateral from intercommissural line (ICL), and 25% of the intercommissural distance anterior to the PC. The average lesion across subjects covered the trajectory of the DRTT and the posteroventral part of the VIM nucleus (see Figure 1b,c). The lesion was mostly restricted to the DRTT, with an overlap of 74 mm3 on average at 3 months, representing 68% of the total lesion volume. However, there was also some degree of overlap with the neighboring tracts, that is, the CST (18 mm3) and the medial lemniscus (31 mm3; see Table 2). Higher overlap between the lesion and the ML was related to the presence of paresthesias, (24 hr lesion p = 0.0034; 3 months lesion p = 0.0409). No association was found between the lesion occupancy of the DRTT and the presence of gait imbalance or other side effects (see Table 3).

Table 2.

Lesion topography 1‐day and 3‐months post‐treatment

Time dICL (mm) dPC (mm) dPC (%) Vol. (mm3) CBTT (mm3) CST (mm3) ML (mm3)
24 hr Avg. 14.8 6.2 25.0 242.3 155.0 18.4 52.0
SD 1.3 1.0 3.5 83.9 43.3 30.1 35.9
3 months Avg. 15.3 6.3 25.2 107.8 73.8 18.0 30.8
SD 1.4 1.0 3.8 50.2 27.7 28.8 24.5
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Note. The last three columns contain the volume overlaps between the lesions and the probabilistic tracts. dICL: distance to the intercommissural line, dPC: distance to the posterior commissure.

Table 3.

Volume overlaps between the lesions and the probabilistic tracts after segregating the subjects according to the presence of gait imbalance, or paresthesias

DRTT (mm3) ML (mm3)
Time Imbalance (N = 7) No imbalance Paresthesias (N = 4) No paresthesias
24 hr Avg. 151.9 156.2 102.5 41.9
SD 63.4 34.3 30.3 27.8
3 months Avg. 77.7 72.2 47.5 27.5
SD 26.1 28.9 26.0 23.4
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DRTT: dentato‐rubro‐thalamic tract; ML: medial lemniscus.

DTI metrics were averaged within the lesion boundaries. FA and AD decreased significantly at 3 months (p FA < 0.001, p AD < 0.01; see Figure 2). No changes were observed for RD or MD within the lesion (see Figure 2). In order to compensate for different lesion sizes or topographies affecting this result, we repeated this analysis but comparing only the DTI metrics in the voxel at the centroid of the lesion. The same findings were observed (see Supporting Information Figure S2). The severity of these changes was unrelated to the presence of side effects.

Figure 2.

Figure 2

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Bar plots representing average values and standard deviations across subjects in DTI scores within the lesion borders. Light red/blue colors indicate values computed within the 1‐day lesion borders at baseline and 3‐months post‐treatment DTI. Dark colors represent the same values within the 3‐months lesion borders. Statistical significance was compared pairwise using parametric paired t‐tests (*p < 0.05; **p < 0.01; ***p < 0.001) [Color figure can be viewed at http://wileyonlinelibrary.com]

3.3. DTI findings along the anatomical projections

The anatomical projections ipsilateral to the lesion site showed microstructural changes, that is, variations of DTI and AFD measures, at different points along their trajectories (see Figure 3). In the DRTT FA was reduced at the level of the superior cerebellar peduncle before decussation, in the thalamic and subthalamic area, and in the subcortical white matter below the motor cortex. These changes in FA were accompanied by an increase in RD and MD at the superior cerebellar peduncle and at the subcortical white matter, and with an increase in RD and AD in the thalamic and subthalamic area. Furthermore, AFD was decreased in the thalamic area. The CST showed FA reduction in the posterior internal capsule and in the subcortical white matter, together with RD and MD increase in the subcortical white matter below the motor cortex. Finally, the medial lemniscus ipsilateral to the lesion showed FA and AD reduction, together with an increase in RD, in the thalamic area. No significant microstructural changes were observed in the contralateral projections to the lesion (see Figure 4). The microstructural changes were unrelated to the volume of the lesion, either at 24 hr or Month 3. Next, we considered the intersecting volume, that is, the volume of tissue in which lesion and each tract overlap. AFD change along the DRTT was correlated to the intersecting volume between the lesion and this tract (r AFD[47–50],Vol24 hr =−0.55, p = 0.0049). No other correlations were found along this pathway. The intersection of the lesion and the medial lemniscus was also correlated to AD changes in this projection (r AD(26–28),Vol24 hr = −0.71, p = 0.0001; r AD(26–28),Vol3 m = −0.82, p < 0.0001), and the same result was observed for the CST (r AD(22–26),Vol24 hr = −0.51, p = 0.0117; r AD(22–26),Vol3 m = −0.58, p = 0.0032).

Figure 3.

Figure 3

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Microstructural changes along the anatomical pathways in the target hemisphere. (a) Tractography maps of the three reconstructed pathways in MNI space. From left to right: the dentato‐rubro‐thalamic tract in green, the cortico‐spinal tract in orange, and the medial lemniscus in blue. (b–d) Representation of the differences in the DTI metrics (FA, MD, RD, AD) and AFD between baseline and 3 months post‐treatment for the dentato‐rubro‐thalamic tract (b), the cortico‐spinal tract (c) and the medial lemniscus (d). The x‐axis represent the 100 orthogonal ROIs to the pathways' trajectories, being ROI = 1 the most ventral, and ROI = 100 the most dorsal, that is, in the white matter below the motor cortex. Dark lines represent average differences across subjects, and shaded regions represent the standard errors. Above the axes there are red‐blue (increase–decrease) colorbars that indicate the statistical power of the differences thresholded at p < 0.01 [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4.

Figure 4

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Microstructural changes along the anatomical pathways in the nontarget hemisphere. (a) Tractography maps of the three reconstructed pathways in MNI space. From left to right: the dentato‐rubro‐thalamic tract in green, the cortico‐spinal tract in orange, and the medial lemniscus in blue. (b–d). Representation of the differences in the DTI metrics (FA, MD, RD, AD) and AFD between baseline and 3 months post‐treatment for the dentato‐rubro‐thalamic tract (B), the cortico‐spinal tract (C) and the medial lemniscus (D). The x‐axis represents the 100 orthogonal ROIs to the pathways' trajectories, ROI = 1 being the most ventral, and ROI = 100 the most dorsal, that is, in the white matter below the motor cortex. Dark lines represent average differences across subjects, and shaded regions represent the standard errors. Above the axes there are red‐blue (increase–decrease) colorbars that indicate the statistical power of the differences thresholded at p < 0.01 [Color figure can be viewed at http://wileyonlinelibrary.com]

In order to elucidate the mechanism underlying the most frequent side effect, that is, gait instability, changes along the DRTT of the subjects that still presented imbalance at 3 months were compared to those that did not. Relaxing the significance criteria (p < 0.05), the group that reported instability 3 months after treatment (n = 7) showed a larger change in MD and FA at the level of the decussation, and also a larger change in AFD at the thalamic level (see Supporting Information Figure S2). Furthermore, although the differences were not significant, the different profiles of microstructural changes suggested that the side effects group had a larger impact on the DRTT than the safer group.

3.4. Correlations with the clinical improvement

The relative change in total FTM at 3‐months was correlated with the microstructural changes along the DRTT. We found significant correlations with the FA decrease at the subcortical white matter (r FA,T = −0.57, p = 0.0033); the increase in MD, RD, and AD at the level of the superior cerebellar peduncle correlated (r MD,T = 0.47, p = 0.0197; r RD,T = 0.45, p = 0.0276; r AD,T = 0.49, p = 0.0154); and with the increase in RD and the decrease in AFD at the thalamic level (r RD,T = 0.47, p = 0.0192; r AFD,T = −0.46, p = 0.0230). Nineteen out of twenty‐four subjects had also the clinical evaluation at 1‐year after the intervention. For these subjects the relative change in total FTM was correlated with the decrease in FA and the increase in RD at the thalamic level (r FA,T = −0.47, p = 0.0399; r RD,T = 0.64, p = 0.0034). These correlations were stable when controlling for age, lesion volume and disease duration. No correlations were found between the volumes of the lesion within the DRTT, or lesion‐specific DTI changes with the clinical outcome.

4. DISCUSSION

In this study, we mapped the impact of unilateral thalamotomy on the white matter in a group of 24 ET patients. We used probabilistic tractography and diffusion MRI based measures to characterize the changes in the microstructural integrity of the anatomical pathways running through the VIM and its vicinity. We found that, 3‐months after the thalamotomy, the DRTT is affected both locally at the entry point in the VIM and distantly along its trajectory, and that these changes are related to the clinical improvement of the patients. In addition, we found that a larger extent of the changes along the DRTT could be the trigger for imbalance. Finally, we found that the occupation of the medial lemniscus by the lesion accounts for the presence of paresthesias in keeping with classic understanding for this side effect. The findings here reported confirm that the clinical improvement in tremor is mainly, if not only, associated with the lesion impacting tremor‐related circuitries, and that the anatomical guidance during tcMRgFUS using tractography could be useful to preserve the integrity of the surrounding anatomical pathways in order to achieve a better risk‐to‐benefit ratio.

Although targeting the VIM nucleus has been traditionally favored both in DBS and ablative interventions (Speelman et al., 2002), another target, the posterior subthalamic area, has also shown potential for controlling tremor in ET patients (Gallay et al., 2016; Schreglmann et al., 2017). The clinical benefit of posterior subthalamic area ablation has been attributed to the direct impact on the dentato‐rubro‐thalamic fibers; however, the implications of the lesion extending into the zona incerta cannot be disregarded (Neudorfer & Maarouf, 2018). In here we have targeted the posteroventral part of the VIM, taking as initial coordinates the proposed in Benabid et al. (1991) but expanding the lesion also towards a posteroventral direction. The final lesion was centred at the posteroventral extension of the VIM, extending through the fields of Forel and the dentato‐rubro‐thalamic fibers. The average tremor improvement of the patients in this study at 3 months follow‐up matches with those of similar series targeting either the VIM or the posterior subthalamic area (Elias et al., 2013; Gallay et al., 2016; Lipsman et al., 2013; Schreglmann et al., 2017). This strategy to control tremor has already been applied in ET using radiofrequency ablation (Mohadjer, Goerke, Milios, Etou, & Mundinger, 1990; Mundinger, 1965). Furthermore recent work on DBS suggested the anti‐tremor efficacy of this target (Coenen et al., 2014). However, this is the first time that this targeting has been performed using tcMRgFUS. Our experience confirms that this variation of the classical VIM thalamotomy is successful in improving tremor.

Combining tractography with several measures of microstructural integrity, we showed that: (a) the DRTT was the tract affected most, both locally in the lesion area and distantly in the superior cerebellar peduncle and the subcortical white matter below the motor cortex; (b) the CST was affected locally in the lesion vicinity and distantly below the motor cortex; and (c) the medial lemniscus was affected locally close to the lesion. Our findings along the dentato‐rubro‐thalamic projection are in agreement with previous publications (Buijink et al., 2014; Wintermark et al., 2014b). However, Buijink et al. (2014) focused their analysis on the superior and medial cerebellar peduncles using FA and MD, while Wintermark et al. (2014a) and Wintermark et al. (2014b) only studied FA whole‐brain on a voxel‐wise analysis. Our analyses, instead, aimed at discriminating the impact among the anatomical projections that travel through or in the vicinity of the VIM, and in addition, we reported the changes not only in all available DTI measures but also in a novel microstructural measure related to the intra‐axonal volume. This was achieved by segmenting anatomical projections using tractography before characterizing their integrity, an approach that provides advantages with respect to the ROI based or voxel‐based methodologies usually applied (Yeatman, Dougherty, Myall, Wandell, & Feldman, 2012). It allowed us to observe a different profile of microstructural changes between the centrum semiovale and the impacted superior cerebellar peduncle. This finding could be explained by different mechanisms of tissue degeneration that have been previously proposed (Beaulieu, 2002): myelin clearance at the white matter below the motor cortex and axonal degeneration in the superior cerebellar peduncle. Furthermore, microstructural changes were restricted ipsilaterally to the lesion site, indicating that the anatomical changes subsequent to the lesion do not include major collateral effects in distant anatomical pathways.

No patient presented serious or severe side effects. Of those side effects that were present 3 months after the intervention, the most frequent was imbalance, which was however, objectively noticeable in only one patient (4%). Another four patients developed mild oral and/or distal upper limb paresthesias. The clinical experience shows us that patients still have room for improvement 3 months after thalamotomy and, indeed, this was the case for all the patients reported here who had already been followed for more than one year. Gait imbalance after either thalamotomy or thalamic DBS is supposed to be directly mediated by the impact on the DRTT (Levesque & Fabre‐Thorpe, 1990). Although we did not find a significant association between this side effect and the microstructural change in the DRTT, we observed a trend for a larger alteration within the tract in the group of patients reporting imbalance than in those who did not. This result is consistent with findings from thalamic DBS for tremor showing that supratherapeutic stimulation worsens ataxia while maintaining clinical benefit (Fasano et al., 2012; Groppa et al., 2014). Thus, our finding supports the idea that an over‐impact of the DRTT could be related to the development of this side effect. Finally, paresthesias are also common after thalamotomy (Fishman et al., 2018), and are believed to be caused by the collateral impact in the sensory thalamus along the trajectory of the medial lemniscus (Kuncel, Cooper, & Grill, 2008; Shintani, Tsuruoka, & Shiigai, 2000). The four subjects in our series who developed sensory disturbances had a larger overlap between the lesion and the medial lemniscus, in keeping with this previous evidence.

Even though the ipsilateral CST was altered, no motor side effects were reported. This finding has been previously described (Wintermark et al., 2014b). It is noteworthy that, in the context of a parallel study (unpublished data), corticospinal conduction time (by transcranial magnetic stimulation) was normal in all the same patients. This discrepancy between the clinical neurophysiological findings and diffusion MRI based measures could be due to intrinsic limitations of DTI in assessing microstructural changes. In the presence of free‐water diffusion (e.g., vasogenic edema) DTI values would be biased (Pasternak, Sochen, Gur, Intrator, & Assaf, 2009). AFD is free of this limitation, and this could be the reason why it does not show any effects along either the CST or the medial lemniscus. Furthermore, CST changes in the subcortical white matter could also be explained due to limitations of the tractography reconstruction algorithms, as dentato‐rubro‐thalamic and the CSTs merge their trajectories below the motor cortex making it hard to distinguish between them at this level.

Thalamotomy for tremor is aimed to impact on the anatomical connections within the cerebello‐thalamo‐cortical system, specifically the DRTT, stopping the tremor activity from propagating from the cerebellum to the motor cortex. Using tractography it is possible to define the anatomical boundaries of this tract (Akram et al., 2018; Meola, Yeh, Fellows‐Mayle, Weed, & Fernandez‐Miranda, 2016; Nowacki, Schlaier, Debove, & Pollo, 2018), and so the number of studies encouraging the tractography‐based segmentation of the DRTT for targeting in either thalamotomy or DBS is growing (Akram et al., 2018; Coenen et al., 2014; Sammartino et al., 2016; Tian et al., 2018; Tsolaki, Downes, Speier, Elias, & Pouratian, 2018). Our results are in line with these studies, and suggest that tractography based guidance during tcMRgFUS treatment strategy could be very beneficial. The segmentation of the tracts in the vicinity of our target, that is, the VIM, would allow us to set anatomical boundaries that should be monitored intraprocedurally and would serve to minimize the appearance of thalamotomy related side effects, while maximizing the therapeutic effect (Chazen et al., 2017; Krishna et al., 2018).

The FTM scale is the most common tremor assessment in this type of study (Elias et al., 2016; Lipsman et al., 2013; Schreglmann et al., 2017). However, this questionnaire represents a subjective characterization of tremor, thus limiting inter‐rater reproducibility. Here, different raters performed the clinical assessment, which could have introduced variability in the scores assigned (Stacy et al., 2007). An objective clinical assessment, for example, using accelerometers, could be beneficial at this point in order to decrease uncertainty in the association between clinical and objective MRI‐based structural measures. Furthermore, microstructural changes were measured 3 months after tcMRgFUS thalamotomy. Although it has been proposed that functional changes stabilize between 1 week and 3 months after tcMRgFUS thalamotomy (Park et al., 2017), how these changes behave at longer follow‐ups has not yet been explored. Characterization of microstructural changes after longer periods is required to better describe long‐lasting effects and their correlation to clinical benefit, and to see if the resolution of the side effects is related to the shrinkage of the lesion, or to other distant effects, such as any contralateral compensatory mechanisms. Finally, the diffusion weighted MRI acquisition scheme employed has margin for improvement; we acquired a single shell in q‐space with a moderate b‐value, which could have limited the accuracy of the obtained tractography maps. Furthermore, DTI measures are limited by several factors including fiber organization or axonal density. To compensate for this, we included another measure to characterize microstructure, the apparent fiber density, which is able to map the contribution of independent fiber populations in the same voxel, solving one of the intrinsic limitations of DTI.

This study suggests that tcMRgFUS thalamotomy provides clinical benefit to patients with ET and that this effect is well balanced with the presence of side effects. Thalamotomy results in a structural impact spatially distributed along the ipsilateral DRTT with these microstructural changes being related to a clinical improvement. In terms of side effects, imbalance is associated with a larger impact on the DRTT, while paresthesias are related to the perturbation of the medial lemniscus. Longer follow‐ups are required to understand what microstructural changes remain, and to monitor distant alterations that could reflect the presence of any compensatory mechanisms. This study paves the way to a better understanding of the action mechanisms of tcMRgFUS thalamotomy, and highlights the advantages of using tractography to guide targeting and treatment monitoring.

Supporting information

Appendix S1: Supporting Information

Click here for additional data file. (2.7MB, pdf)

ACKNOWLEDGMENT

This study was supported by the Fundación de investigación HM Hospitales (Madrid) and Insightec. The authors thank Dr. Lawrence Phillips for language correction. José Angel Pineda‐Pardo was supported by the Spanish Ministry of Education through the National Program Juan de la Cierva (FJCI‐2015‐25095).

Pineda‐Pardo JA, Martínez‐Fernández R, Rodríguez‐Rojas R, et al. Microstructural changes of the dentato‐rubro‐thalamic tract after transcranial MR guided focused ultrasound ablation of the posteroventral VIM in essential tremor. Hum Brain Mapp. 2019;40:2933–2942. 10.1002/hbm.24569

Funding information Fundación de investigación HM Hospitales (Madrid) ; Insightec, Grant/Award Number: ET002; Spanish Ministry of Education; National Program Juan de la Cierva, Grant/Award Number: FJCI‐2015‐25095

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Supplementary Materials

Appendix S1: Supporting Information

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