Case Report on Deep Brain Stimulation Rescue After Suboptimal MR-Guided Focused Ultrasound Thalamotomy for Essential Tremor: A Tractography-Based Investigation

Abstract

Essential tremor (ET) is the most prevalent movement disorder in adults, and can often be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound (MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for treating ET, optimal targeting during MRgFUS is essential for efficacy and durability. Various studies have reported cases of tremor recurrence following MRgFUS and long-term outcome data is limited to 3–4 years. We present a tractography-based investigation on a case of DBS rescue for medically refractory ET that was treated with MRgFUS that was interrupted due to the development of dysarthria during the procedure. After initial improvement, her hand tremor started to recur within 6 months after treatment, and bilateral DBS was performed targeting the VIM 24 months after MRgFUS. DBS induced long-term tremor control with monopolar stimulation. Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT) and corticothalmic (CTT) tracts being modulated by the procedures to understand the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines, it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for further investigation of targeting the CTT when using neuromodulatory procedures to treat refractory ET for more permanent tremor relief.

Full text

fnhum-14-00191 June 26, 2020 Time: 17:38 # 1
CASE REPORT
published: 26 June 2020
doi: 10.3389/fnhum.2020.00191
Edited by:
Chella Kamarajan,
SUNY Downstate Medical Center,
United States
Reviewed by:
Sagi Harnof,
Rabin Medical Center, Israel
Idit Tamir,
Rabin Medical Center, Israel, in
collaboration with reviewer SH
Manish Ranjan,
West Virginia University, United States
*Correspondence:
Casey H. Halpern
chalpern@stanford.edu
Specialty section:
This article was submitted to
Brain Imaging and Stimulation,
a section of the journal
Frontiers in Human Neuroscience
Received: 20 February 2020
Accepted: 28 April 2020
Published: 26 June 2020
Citation:
Saluja S, Barbosa DAN, Parker JJ,
Huang Y, Jensen MR, Ngo V,
Santini VE, Pauly KB, Ghanouni P,
McNab JA and Halpern CH (2020)
Case Report on Deep Brain
Stimulation Rescue After Suboptimal
MR-Guided Focused Ultrasound
Thalamotomy for Essential Tremor: A
Tractography-Based Investigation.
Front. Hum. Neurosci. 14:191.
doi: 10.3389/fnhum.2020.00191
Case Report on Deep Brain
Stimulation Rescue After Suboptimal
MR-Guided Focused Ultrasound
Thalamotomy for Essential Tremor: A
Tractography-Based Investigation
Sabir Saluja1, Daniel A. N. Barbosa1, Jonathon J. Parker1, Yuhao Huang1,
Michael R. Jensen1, Vyvian Ngo1, Veronica E. Santini2, Kim Butts Pauly3,
Pejman Ghanouni3, Jennifer A. McNab3and Casey H. Halpern1*
1Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States, 2Department
of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States, 3Department
of Radiology, Stanford University School of Medicine, Stanford, CA, United States
Essential tremor (ET) is the most prevalent movement disorder in adults, and can often
be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound
(MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in
the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for
treating ET, optimal targeting during MRgFUS is essential for efficacy and durability.
Various studies have reported cases of tremor recurrence following MRgFUS and
long-term outcome data is limited to 3–4 years. We present a tractography-based
investigation on a case of DBS rescue for medically refractory ET that was treated
with MRgFUS that was interrupted due to the development of dysarthria during
the procedure. After initial improvement, her hand tremor started to recur within 6
months after treatment, and bilateral DBS was performed targeting the VIM 24 months
after MRgFUS. DBS induced long-term tremor control with monopolar stimulation.
Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT)
and corticothalmic (CTT) tracts being modulated by the procedures to understand
the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By
comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that
the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the
size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines,
it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for
further investigation of targeting the CTT when using neuromodulatory procedures to
treat refractory ET for more permanent tremor relief.
Keywords: essential tremor, focused ultrasound, deep brain stimulation, tractography, thalamus, MRI
Frontiers in Human Neuroscience | www.frontiersin.org 1June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 2
Saluja et al. DBS Rescues MRgFUS for ET
INTRODUCTION
Essential tremor (ET) is the most prevalent movement disorder in
adults. Treatment options for medically refractory cases include a
variety of ablative and deep brain stimulation (DBS) procedures,
usually targeting the ventralis intermedius (VIM) nucleus of the
thalamus (Flora et al., 2010;Louis and Ferreira, 2010).
Recently, Elias et al. (2016) reported the results of a
randomized control trial demonstrating the efficacy of unilateral
MRI-guided focused ultrasound (MRgFUS) targeting the VIM
in treating refractory ET. Out of the 56 patients who received
MRgFUS thalamotomy of the VIM, 5 patients (8.9%) experienced
the return of their tremor symptoms within 12 months
postoperatively, with tremor scores worsening by 23% (Elias
et al., 2016). In a 2-year follow up study, however, 4% of the
original cohort subsequently received DBS due to unsuccessful
or suboptimal treatment with MRgFUS (Chang et al., 2018).
A retrospective comparative evaluation of RF thalamotomy,
DBS, or MRgFUS for ET patients revealed this loss of effect
is shared across modalities (Halpern et al., 2019). Moreover,
compared to 6-months post-procedure, the 3-year follow-up
study found that even though the primary outcome metric
for the trial (i.e., the hand combined tremor-motor score) was
significantly improved, there was a slight but significant increase
in the median total Clinical Rating Scale for Tremor (CRST)
score over time (Kim et al., 2017). The mechanism for this
recrudescence remains elusive and is undoubtedly multifactorial,
but a detailed review of the anatomic aspects of a suboptimal
MRgFUS thalamotomy may guide the future management of
these patients (Ravikumar et al., 2017).
One approach for understanding this loss of efficacy is
utilizing diffusion-weighted MRI (dMRI) imaging to assess
the white-matter fiber tracts being modulated by MRgFUS.
Tractography studies have demonstrated that lesions must target
the cerebello-thalamo-cortical network for treatment of ET
(Coenen et al., 2014). The two major groups of white-matter
fiber tracts involved in this network are the dentatorubrothalamic
tract (DRTT) and the corticothalamic tract (CTT). These two
pathways have been found to be necessary targets for the
treatment of ET (Tian et al., 2018).
We present a tractography-based investigation of a patient
treated with MRgFUS thalamotomy for ET, whose procedure was
prematurely aborted due to new onset dysarthria. Immediately
post-procedure, the patient experienced tremor relief and the
dysarthria partially improved, but her tremor symptoms, most
notably hand tremor, began to return 6 months postoperatively.
The patient subsequently received DBS, and the surgery was
well-tolerated and efficacious at the long-term.
Using a multimodal imaging strategy, we reconstructed the
MRgFUS lesion and the volume of activated tissue (VAT)
produced by the DBS electrode and the patient’s specific
programming. We then used probabilistic tractography to assess
the relationships between the MRgFUS lesion, DBS VAT, and
the white matter fiber tracts associated with tremor control. This
methodology offers a unique understanding of the specific fiber
tracts modulated in both MRgFUS and DBS, in order to shed light
on why DBS yielded a better long-term outcome in our patient.
CASE DESCRIPTION
A 70-year-old female with medically refractory ET was evaluated
at our movement disorders clinic after nearly 30 years of tremor.
Her tremor began in her left hand and eventually progressed
to her right hand, head and voice. Eventually, she required
assistance for her activities of daily living, including eating,
writing, and dressing due to the severity of her tremor. She
tried numerous medication therapies including combinations
of propranolol, primodone, and gabapentin, in addition to
chemodenervation with botulinum toxin. Despite all treatment
attempts, she only achieved suboptimal tremor control.
At presentation, she was found to have postural tremors
bilaterally in her upper extremities, significantly worsening with
action and improving with rest. Her handwriting as well as her
straight line and spiral drawing tests were markedly abnormal
(Figure 1). She had head tremor and her voice was tremulous
with audible oscillations. Her bedside cognitive status, as assessed
by the Montreal Cognitive Assessment (MoCA) test, was within
normal limits. There was no evidence of parkinsonism on
examination. The CRST A subscore was 30 at the time of
presentation in 2015, reflecting her postural and kinetic tremors
(Figure 1). The patient presented with options of continued
medical management, bilateral DBS, unilateral DBS, or MRgFUS
as part of an ongoing clinical trial. At the time of initial
presentation and evaluation, the patient was most distressed by
her dominant hand tremor, and thus, after presented with the
options, elected to proceed with MRgFUS focused on relief for
her dominant upper extremity tremor.
The patient underwent a left MRgFUS thalamotomy in August
2015. The series of sonications is described in Supplementary
Table S1. The left VIM nucleus target was guided by 3T MRI
using standard coordinates from the mid-commissural point
(MCP): –13.3 mm, –6 mm, 0 mm (∼10 mm from the ventricular
wall) for sonications 1–19, 1 mm medial from the canonical
stereotactic target. This target was chosen to provide about 2 mm
of a safety margin from the thalamo-capsular boundary based on
the patient’s preoperative MRI imaging. There were adjustments
to the location of the sonication’s focus in order to sonicate
the center of the planned target. By sonication 19, the patient’s
tremor was largely relieved, but the lesion’s boundaries were
approaching the internal capsule. For sonication 20, the target
was moved 1 mm medially to avoid the internal capsule. For
final sonication 21, the target was moved an additional 1 mm
medial to continue the ablation but ensure no breach of the
internal capsule. At the conclusion of sonication 21, transient
dysarthria was noted on the patient’s clinical examination,
and the procedure was terminated. Out of the 21 sonications
performed, four of them reached a temperature greater than
55◦C, and the maximum temperature attained was 61◦C. The
highest energy sonication reached 15940 J (797 W for 20 s). The
SDR was 0.51. There were no cavitations. The procedure was
aborted due to new-onset dysarthria. The patient experienced
a significant improvement in her tremor at 2-week follow-up.
Her only new symptom was transient dysarthria that initiated
during MRgFUS treatment. Over the next 6 months, however,
she noticed progressive tremor recurrence and worsening of
Frontiers in Human Neuroscience | www.frontiersin.org 2June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 3
Saluja et al. DBS Rescues MRgFUS for ET
FIGURE 1 | (A) Clinical timeline of patient’s procedures and DBS programming parameters following FUS and lead implantation. The patient’s tremor was evaluated
using the Clinical Rating Scale for Tremor (CRST) A subsection, which evaluates tremor, including those of the upper extremities. (B) “Archimedes spiral” drawings
(right hand only) during the B subsection of the CRST assessment to evaluate hand tremor at each time point to demonstrate tremor progression over time after
MRgFUS procedure. Spiral A is wide, compared to the narrow spiral B (acquired as part of the CRST B).
her tremor symptoms despite partial improvement of dysarthria
(see Supplementary Table S2).
After discussion with and further evaluation of the patient
through a multidisciplinary DBS review board, she was deemed
a candidate for DBS targeted to the VIM nucleus. Approximately
24 months after her initial left MRgFUS, DBS (Medtronic
Activa PC) leads were bilaterally placed without complication
using frameless robotic-assisted stereotactic navigation (Ho et al.,
2019). Based on the dysarthria previously experienced that
was presumed to be due to the relatively medial location of
the MRgFUS treatment, DBS leads were placed using target
coordinates of -13, -6.5, and 0 mm from the MCP (5.9 mm
anterior to PC). The target was more lateral in order to
minimize dysarthria, and more posterior so that the trajectory
did not enter blood vessels, ventricles, or sulci. Intraoperative
electrophysiological monitoring and postoperative imaging
demonstrated satisfactory lead placement. A standard monopolar
testing protocol was performed to evaluate the threshold of
efficacy for each contact and any adverse effects. With stimulation
at 1.5 V, there were no adverse effects with activation of
contacts C1-C3, however, the patient experienced transient right
lip paresthesia with activation of left hemisphere contact C0,
which was the contact located closest to the MRgFUS lesion.
At 3–4 V, the patient experienced slight dysarthria when left
hemisphere contact C1 was activated. When C1 in the right
hemisphere was activated at 3.0 V, her dysarthria worsened.
Contact C2 was chosen for monopolar activation at 2.7 V
in the left hemisphere and 2.0 V in the right hemisphere,
which maximized her tremor suppression and minimized adverse
effects. At her last evaluation (16-month follow-up after DBS),
she had consistent and effective tremor control, with a CRST
score of 7 (Figure 1). The left lead was active at contact 2
set at 2.8 V, pulse width 60 ms and 100 Hz. The right lead
was active at electrode 10 set at 2.3 V, pulse width 60 ms
and 100 Hz. The patient had excellent tremor suppression
following monopolar activation of the DBS leads, as shown
by sustained decrease in CRST and significant improvement
drawing coherent spirals.
Frontiers in Human Neuroscience | www.frontiersin.org 3June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 4
Saluja et al. DBS Rescues MRgFUS for ET
METHODS
MRI Imaging Acquisition and
Preprocessing
T1-weighted and T2-weighted structural 3T MRI images were
acquired before and after FUS. Diffusion-weighted images were
acquired from the patient before MRgFUS (3T, 2 mm isotropic,
TR/TE = 8500/81.6 ms, b = 2500 s/mm2, 60 directions,
582 s) and before DBS implantation (3T, 2 mm isotropic,
TR/TE = 8000/60.7 ms, b = 1000 s/mm2, 30 directions, 502 s).
Computed tomography (CT) images with 1 mm slice thickness
were obtained postoperatively after DBS implantation. FSL’s
“topup” tool was used to estimate and correct non-zero off-
resonance fields caused by susceptibility distribution of the
subject’s head via analysis of forward and reverse phase encoded
B0image acquisitions (Andersson et al., 2003). FSL’s “eddy” tool
was used to correct for the eddy current caused by rapid switching
on and off of the diffusion gradient (Smith et al., 2004).
Lesion Volume, Electrode
Reconstruction, and Volume of Activated
Tissue Estimation
MRgFUS results in three distinct zones of ablation that can be
viewed on a T2-weighted image (Wintermark et al., 2014). The
lesion region of interest (ROI) was created by including the voxels
that are within the two inner zones (the third outer zone being
vasogenic edema) on an MRI acquired the same day following
MRgFUS thalamotomy. Lead-DBS was used for localization and
visualization of the DBS electrode contacts (Horn et al., 2019).
Linear and nonlinear transformations were computed from the
MNI 152 2009c template to the T1 and T2-weighted images,
as well as the postoperative CT. The DBS Intrinsic Template
Atlas (DISTAL) was subsequently transformed onto the native
T1-weighted images and used to localize the electrodes as well
as the MRgFUS lesion in reference to the VIM (Ewert et al.,
2018). The VAT was estimated using a finite element modeling
method based on the characteristics of the brain tissue activated
and the DBS programming voltage and estimated impedance
(Madler and Coenen, 2012).
Probabilistic Tractography and
Statistical Analysis
Tractography was performed with MRtrix using constrained
spherical deconvolution to estimate the white-matter fiber
orientation distribution from the diffusion signal of the dMRI
images (Smith et al., 2013). Using probabilistic tractography,
the DRTT was filtered to include white-matter tracts that
are seeded at the dentate nucleus and terminate in the
thalamus, along with sending collaterals to the red nucleus.
Freesurfer was used to segment the structural T1-weighted
images to generate ROIs for the thalamus, and dentate
nucleus (Desikan et al., 2006;Fischl, 2012). The red nucleus
was drawn using guidance from an expert neuroradiologist.
The CTT was filtered to include only white-matter tracts
seeded at the precentral gyrus and terminate at the thalamus.
Freesurfer was used to generate masks encompassing the
precentral gyrus.
A mask of the MRgFUS lesion was overlaid on the pre-
MRgFUS tractography streamlines, and a mask of the VAT
was overlaid onto the pre-DBS streamlines. The proportion of
streamlines of each tract that were incorporated by the lesion and
VAT were calculated by dividing the raw number of streamlines
of the DRTT and CTT that intersected the lesion and VAT, by the
total number of streamlines within the DRTT and CTT.
DIAGNOSTIC ASSESSMENT AND
RESULTS
The MRgFUS lesioning procedure in the VIM resulted in
immediate tremor suppression. The patient’s CRST A score
decreased from 30 to 18 as a result. Her tremor suppression
remained stable for 6 months, then began worsening. Twenty-
four months after the MRgFUS procedure, the patient’s CRST A
score had increased to 28, and at this time, the patient received
DBS electrode implantation. Subsequent programming reduced
her tremor, resulting in a CRST A score of 7 after optimizing DBS
programming parameters.
Probabilistic tractography reconstructed streamlines of the
DRTT (Figure 2) and CTT (Figure 3) for the pre-FUS (A)
and pre-DBS (B) diffusion weighted images. The lesion after
MRgFUS, and the VAT from DBS, were overlaid onto each
respective image to select the voxels that were modulated
by each modality.
The MRgFUS lesion’s volume was calculated to be 20.28 mm3.
The estimated VAT from the unilateral left VIM DBS at the
patient’s last programming settings was 233.16 mm3. The VAT’s
x, y, and z coordinates relative to the MCP were -15.5, -2.5, and
-7 mm. The center of the lesion was located 3.75 mm closer to the
midline than the active DBS VAT, and 5 mm more ventral. The
lesion location in the pre-FUS image captured 12.9% of the DRTT
streamlines and 4.4% of the CTT streamlines, while the DBS VAT
location of the pre-DBS image encompassed 13.6% of the DRTT
streamlines and 29.7% of the CTT streamlines, respectively.
For visualization purposes, the lesion and VAT were
reconstructed in 3D alongside the DBS electrodes and the
internal and external nuclei of the VIM, defined by the DISTAL
atlas (Figure 4).
DISCUSSION
Tremor relief that is not sustained after MRgFUS treatment is
troublesome to patients and presents a significant management
challenge. For these patients in whom treatment has failed, it
may be appropriate to offer repeat or rescue procedures (Tuleasca
et al., 2017;Wang et al., 2018;Weidman et al., 2019). However,
in the described case, the scant availability of repeat MRgFUS
efficacy, the side effect of dysarthria, and patient preference
for bilateral therapy made DBS a favorable alterative, not to
mention its ability to be used somewhat reversibly and bilaterally.
Using patient-specific probabilistic tractography, we investigated
Frontiers in Human Neuroscience | www.frontiersin.org 4June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 5
Saluja et al. DBS Rescues MRgFUS for ET
FIGURE 2 | The DRTT shown in the Pre-FUS and Post-FUS volumes. In (A), the lesion after MRgFUS was overlaid onto the pre-FUS image, to isolate the voxels that
encompassed the lesion before the MRgFUS procedure. In (B), the DBS VAT was overlaid onto the Pre-DBS image. The DRTT was isolated from all tracts generated
via probabilistic tractography by only including the streamlines that intersected the ROI masks for the cerebellum white matter (dentate nucleus), thalamus, and red
nucleus.
FIGURE 3 | The CTT shown in the Pre-FUS and Post-FUS volumes. In (A), the lesion after MRgFUS was overlaid onto the pre-FUS image, to isolate the voxels that
encompassed the lesion before the MRgFUS procedure. In (B), the DBS VAT was overlaid onto the Pre-DBS image. The CTT was isolated from all tracts generated
via probabilistic tractography by only including the streamlines that intersected the ROI masks for the precentral gyrus and thalamus.
this case of medically refractory ET treated with MRgFUS and
subsequently DBS to retrospectively evaluate the topography and
fiber tracts modulated in both procedures in order to understand
their differential efficacy and side-effect profile. Importantly,
the MRgFUS lesion in this case was not optimized due to
aborting the procedure. However, we feel optimizing targeting
based on reports such as this may prevent future MRgFUS
treatment failures.
Our technique of comparing the overlap in the lesion/VAT
module volume with patient-specific tracts suggested the
difference in treatment outcomes may be explained in part by
the DBS VAT. The MRgFUS lesion was located ventromedially
to the VAT (Figure 4), and was also significantly smaller,
comprising roughly 10% of the volume of the VAT. The MRgFUS
lesion was placed medially to avoid heat extending into the
internal capsule, and thus sonications were moved serially
more medially as the procedure continued to avoid heating of
the pyramidal tract. DBS electrodes were placed in a similar
trajectory, with the most distal contact (contact 0) bordering the
lesion location. During programming, the patient received the
most tremor suppression when contact 2 was activated, moving
the VAT dorsolaterally.
Frontiers in Human Neuroscience | www.frontiersin.org 5June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 6
Saluja et al. DBS Rescues MRgFUS for ET
FIGURE 4 | Bilateral DBS (left hemisphere on right side, right hemisphere on left side) 3D lead reconstruction and VAT generation in LEAD-DBS. DBS electrode
contact spacing models design of Medtronic 3389. The dashes represent the directionality of the induced electric field from the activated contact, in this case
contact 2. The lesion and VAT are localized alongside the internal and external segments of the VIM (VIM-i and VIM-e, respectively) defined by the DISTAL atlas.
Although the tractography findings suggest that more accurate
targeting and larger VAT resulted in more sustained tremor relief,
our case also adds to a further body of evidence about the variable
efficacy of MRgFUS thalamotomy. It is noteworthy that despite
suboptimal targeting and premature cessation of sonications due
to dysarthria, the initial MRgFUS treatment resulted in tremor
relief, albeit temporarily. The onset of tremor recurrence within
1 year postoperatively has been reported in numerous cases in the
literature, even without lesions complicated by dysarthria (Wang
et al., 2018;Halpern et al., 2019). This suggests several plausible
explanations for loss of tremor suppression efficacy over time
after MRgFUS. First, the lesion created may have a penumbra
region of edemanous brain where reversible neuromodulatory
rather than neuroablative effects predominate. Additionally,
ongoing pathologic remodeling occurring among Purkinje and
other cell types in the cerebello-thalamic tremor circuit may lead
to progressive worsening of tremor (Louis and Faust, 2020) in
the face of a well-targeted MRgFUS lesion. Further investigation
should be conducted on the time course of cellular mechanisms
of thalamic MRgFUS lesions in tremor model systems as well as
neuroimaging studies to uncover predictive imaging biomarkers
for tremor recurrence.
Additionally, our tractography analysis here investigates a
single patient’s structural connectivity, but insight can be drawn
into the differences in streamline counts within the DRTT and
CTT, which have been reported to be necessary when using
tractography to define patient-specific neuromodulatory targets
for ET (Coenen et al., 2014). The negligible difference in the
proportion of DRTT streamlines modulated by MRgFUS and
DBS indicates that both modalities targeted this tract in a
similar way, although a different location within the DRTT
was modulated in each procedure. However, when comparing
DBS stimulation to MRgFUS, we found a large increase in the
proportion of CTT streamlines residing within the DBS VAT,
compared to those found within the patient’s MRgFUS lesion
volume. Although prior work has shown that disruption of
cerebellar input into the ventral thalamus is necessary to disrupt
tremor pathophysiology (Gallay et al., 2016), the pattern suggests
that targeting the DRTT alone may not be sufficient, thus future
investigations should explore the role of modulating the CTT to
maintain clinical effectiveness of tremor relief and balancing the
use of imaging to guide targets with intra-procedural findings.
This is in line with findings by Tian et al., which report that the
most efficacious target, in a cohort of ET patients who received
MRgFUS thalamotomy, encompassed both the CTT and DRTT
(Coenen et al., 2014).
Our findings demonstrate modeling white-matter fiber tracts
using probabilistic tractography may serve as a method to inform
and optimize targeting of initial MRgFUS lesions and tailor
rescue procedures for those with recurrent or persistent tremor.
We have demonstrated that the larger size of the DBS VAT,
compared to the MRgFUS lesion, incorporates a larger area of
white-matter to be targeted, allowing for the inclusion of more
fibers of the CTT, as it has been reported that the size of the
lesion is positively correlated to improved treatment outcome
(Federau et al., 2018).
Dysarthria is a common adverse effect of neuromodulatory
procedures targeting the VIM, including both MRgFUS and
DBS. While every attempt is made to mitigate this effect across
procedural modalities, indirect targeting of VIM lends itself to
suboptimal accuracy of sonications and DBS lead placement.
This effect may be caused by stimulation or sonications of the
Frontiers in Human Neuroscience | www.frontiersin.org 6June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 7
Saluja et al. DBS Rescues MRgFUS for ET
posterior limb of the internal capsule. Activation of ventral
contacts in the VIM have also shown to stimulate the homuncular
representation of the head (Montgomery, 2010). Moreover, the
patient’s absence of dysarthria after successful DBS treatment
suggested the dysarthria was due to medial sonications as the
DBS lead was relatively lateral. Using tractography to optimize
targeting is one approach that we highlight in this case study
to attempt to mitigate such troublesome adverse effects. We
believe our case underscores the importance of tractography-
based targeting, which becomes particularly relevant given that
VIM targeting is indirect due to our inability to segment
thalamic nuclei via conventional MRI (Coenen et al., 2014).
There have been reported attempts to directly modulate white-
matter tracts via DBS, such as the DRTT through targeting the
posterior subthalamic area (PSA), which appear to be effective
at suppressing tremor (Dembek et al., 2020). The findings of
our case report further support the idea that indirect VIM
targeting may not be sufficient alone to optimize outcomes for ET
(Benabid et al., 1991). Tractography utilizes the diffusion signal
of the white matter tracts in the brain, which is personalized
to each patient and more directly tells us where to target.
In particular, the canonically activated contacts for VIM DBS
are usually ventrally located (Gallay et al., 2016), but the
most effective contact in our patient was the more superior
contact 2. Moreover, Boutet et al. (2018) have shown that
medially placed lesions in the VIM were associated with 41
times the likelihood of speech adverse effects. Our case report
supports these findings.
A limitation of this work comes from the relatively low spatial
resolution of dMRI at roughly 2 mm isotropic. This indicates
that tractography-based targeting should be used alongside other
targeting methods, such as atlas coregistration, intraoperative
microelectrode recordings, and/or real-time patient examination,
to ensure accurate tract localization. Another limitation includes
that our dMRI acquisitions taken pre-MRgFUS and pre-DBS
had different acquisition parameters. We have accounted for this
difference by comparing the proportion of streamlines targeted
by each method, rather than the raw streamline count, which
may be more affected by varying acquisition parameters. It is
also important to note that in this case, the DRTT was within
the lesional zone of the MRgFUS, and the CTT was additionally
included within the DBS VAT; further investigation should be
conducted to determine the effects of including CTT targeting
by MRgFUS. The findings of this report highlight the need
for prospective validation of tractography-based targeting and
modeling of modulation by lesioning and electrical stimulation
modalities such as DBS.
DATA AVAILABILITY STATEMENT
The datasets generated for this study are available on request to
the corresponding author.
ETHICS STATEMENT
Written informed consent was obtained from the patient for the
publication of this case report.
AUTHOR CONTRIBUTIONS
SS was the main author on this case report. DB, JP, YH, MJ, and
VN helped with data acquisition, analysis, and editing. VS was
the neurologist involved with clinical evaluation and care of the
patient. PG, VS, KP, and JM were involved in the clinical trial for
MRI-guided Focused Ultrasound that our patient was enrolled
in and assisted with the methodologies for data acquisition and
analysis. CH was the neurosurgeon in the clinical trial involved
in the localization of the lesions and assessments post-procedure.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fnhum.
2020.00191/full#supplementary-material
REFERENCES
Andersson, J. L., Skare, S., and Ashburner, J. (2003). How to correct susceptibility
distortions in spin-echo echo-planar images: application to diffusion tensor
imaging. Neuroimage 20, 870–888. doi: 10.1016/s1053-8119(03)00336- 7
Benabid, A. L., Pollak, P., Gervason, C., Hoffmann, D., Gao, D. M., Hommel, M.,
et al. (1991). Long-term suppression of tremor by chronic stimulation of the
ventral intermediate thalamic nucleus. Lancet 337, 403–406. doi: 10.1016/0140-
6736(91)91175-t
Boutet, A., Ranjan, M., Zhong, J., Germann, J., Xu, D., Schwartz, M. L., et al.
(2018). Focused ultrasound thalamotomy location determines clinical benefits
in patients with essential tremor. Brain 12, 3405–3414. doi: 10.1093/brain/
awy278
Chang, J. W., Park, C. K., Lipsman, N., Schwartz, M. L., Ghanouni, P., Henderson,
J. M., et al. (2018). A prospective trial of magnetic resonance-guided focused
ultrasound thalamotomy for essential tremor: results at the 2-year follow-up.
Ann. Neurol. 83, 107–114. doi: 10.1002/ana.25126
Coenen, V. A., Allert, N., Paus, S., Kronenbürger, M., Urbach, H., and Mädler, B.
(2014). Modulation of the cerebello-thalamo-cortical network in thalamic deep
brain stimulation for tremor: a diffusion tensor imaging study. Neurosurgery 6,
657–669; discussion 669–670. doi: 10.1227/NEU.0000000000000540
Dembek, T. A., Petry-Schmelzer, J. N., Reker, P., Wirths, J., Hamacher, S., Steffen,
J., et al. (2020). PSA and VIM DBS efficiency in essential tremor depends
on distance to the dentatorubrothalamic tract. Neuroimage Clin. 26:102235.
doi: 10.1016/j.nicl.2020.102235
Desikan, R. S., Segonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker,
D., et al. (2006). An automated labeling system for subdividing the human
cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage
31, 968–980. doi: 10.1016/j.neuroimage.2006.01.021
Elias, W. J., Lipsman, N., Ondo, W. G., Ghanouni, P., Kim, Y. G., Lee, W., et al.
(2016). A randomized trial of focused ultrasound thalamotomy for essential
tremor. N. Engl. J. Med. 375, 730–739. doi: 10.1056/NEJMoa1600159
Ewert, S., Plettig, P., Li, N., Chakravarty, M. M., Collins, D. L., Herrington,
T. M., et al. (2018). Toward defining deep brain stimulation targets in MNI
space: a subcortical atlas based on multimodal MRI, histology and structural
connectivity. Neuroimage 170, 271–282. doi: 10.1016/j.neuroimage.2017.05.015
Federau, C., Goubran, M., Rosenberg, J., Henderson, J., Halpern, C. H., Santini,
V., et al. (2018). Transcranial MRI−guided high−intensity focused ultrasound
Frontiers in Human Neuroscience | www.frontiersin.org 7June 2020 | Volume 14 | Article 191

fnhum-14-00191 June 26, 2020 Time: 17:38 # 8
Saluja et al. DBS Rescues MRgFUS for ET
for treatment of essential tremor: a pilot study on the correlation between
lesion size, lesion location, thermal dose, and clinical outcome. J. Magn. Reson.
Imaging 48, 58–65. doi: 10.1002/jmri.25878
Fischl, B. (2012). FreeSurfer. Neuroimage 62, 774–781. doi: 10.1016/j.neuroimage.
2012.01.021
Flora, E. D., Perera, C. L., Cameron, A. L., and Maddern, G. J. (2010). Deep
brain stimulation for essential tremor: a systematic review. Mov. Disord. 25,
1550–1559. doi: 10.1002/mds.23195
Gallay, M. N., Moser, D., Rossi, F., Pourtehrani, P., Magara, A. E., Kowalski,
M., et al. (2016). Incisionless transcranial MR-guided focused ultrasound in
essential tremor: cerebellothalamic tractotomy. J. Ther. Ultrasound 4, 5. doi:
10.1186/s40349-016- 0049-8
Halpern, C. H., Ghanouni, P., Santini, V., Lipsman, N., Lozano, A., Schwartz, M. L.,
et al. (2019). Three-year follow-up of prospective trial of focused ultrasound
thalamotomy for essential tremor. Neurology 93, e2284–e2293. doi: 10.1212/
WNL.0000000000008561
Ho, A. L., Pendharkar, A. V., Brewster, R., Martinez, D. L., Jaffe, R. A., Xu,
L. W., et al. (2019). Frameless robot-assisted deep brain stimulation surgery:
an initial experience. Oper. Neurosurg. (Hagerstown) 17, 424–431. doi: 10.1093/
ons/opy395
Horn, A. K. E., Li, N., Dembek, T. A., Kappel, A., Boulay, C., Ewert, S., et al. (2019).
Lead-DBS v2: towards a comprehensive pipeline for deep brain stimulation
imaging. Neuroimage 184, 293–316. doi: 10.1016/j.neuroimage.2018.
08.068
Kim, M., Jung, N. Y., Park, C. K., Chang, W. K., Jung, H. H., and Chang,
J. W. (2017). Comparative evaluation of magnetic resonance-guided focused
ultrasound surgery for essential tremor. Stereotact. Funct. Neurosurg. 95, 279–
286. doi: 10.1159/000478866
Louis, E. D., and Faust, P. L. (2020). Essential tremor pathology: neurodegeneration
and reorganization of neuronal connections. Nat. Rev. Neurol. 16, 69–83. doi:
10.1038/s41582-019- 0302-1
Louis, E. D., and Ferreira, J. J. (2010). How common is the most common adult
movement disorder? Update on the worldwide prevalence of essential tremor.
Mov. Disord. 25, 534–541. doi: 10.1002/mds.22838
Madler, B., and Coenen, V. A. (2012). Explaining clinical effects of deep brain
stimulation through simplified target-specific modeling of the volume of
activated tissue. Am. J. Neuroradiol. 33, 1072–1080. doi: 10.3174/ajnr.A2906
Montgomery, E. B. Jr. (2010). Deep Brain Stimulation Programming: Principles and
Practice. New York, NY: Oxford University Press.
Ravikumar, V. K., Parker, J. J., Hornbeck, T. S., Santini, V. E., Pauly, K. B.,
Wintermark, M., et al. (2017). Cost−effectiveness of focused ultrasound,
radiosurgery, and DBS for essential tremor. Mov. Disord. 32, 1165–1173. doi:
10.1002/mds.26997
Smith, R. E., Tournier, J.-D., Calamante, F., and Connelly, A. (2013). SIFT:
spherical-deconvolution informed filtering of tractograms. Neuroimage 67,
298–312. doi: 10.1016/j.neuroimage.2012.11.049
Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckmann, C. F., Behrens, T. E.,
Johansen-Berg, H., et al. (2004). Advances in functional and structural MR
image analysis and implementation as FSL. Neuroimage 23(Suppl. 1), S208–
S219.
Tian, Q., Wintermark, M., Elias, J. W., Ghanouni, P., Halpern, C. H., Henderson,
J. M., et al. (2018). Diffusion MRI tractography for improved transcranial
MRI-guided focused ultrasound thalamotomy targeting for essential tremor.
Neuroimage Clin. 19, 572–580. doi: 10.1016/j.nicl.2018.05.010
Tuleasca, C., Pralong, E., Najdenovska, E., Cuadra, M. B., Marques, J. R. F.,
Vingerhoets, F., et al. (2017). Deep brain stimulation after previous gamma
knife thalamotomy of the Vim for essential tremor is feasible! Clinical,
electrophysiological and radiological findings. Acta Neurochir. (Wien) 159,
1371–1373. doi: 10.1007/s00701-017- 3227-8
Wang, T. R., Dallapiazza, R. F., Moosa, S., Huss, D., Shah, B. B., and Elias, W. J.
(2018). Thalamic deep brain stimulation salvages failed focused ultrasound
thalamotomy for essential tremor: a case report. Stereotact. Funct. Neurosurg.
96, 60–64. doi: 10.1159/000486646
Weidman, E. K., Kaplitt, M. G., Strybing, K., and Chazen, J. L. (2019). Repeat
magnetic resonance imaging-guided focused ultrasound thalamotomy for
recurrent essential tremor: case report and review of MRI findings. J. Neurosurg.
132, 211–216. doi: 10.3171/2018.10.JNS181721
Wintermark, M., Druzgal, J., Huss, D. S., Khaled, M. A., Monteith, S., Raghavan,
P., et al. (2014). Imaging findings in MR imaging-guided focused ultrasound
treatment for patients with essential tremor. AJNR Am. J. Neuroradiol. 35,
891–896. doi: 10.3174/ajnr.A3808
Conflict of Interest: PG, VS, and CH did receive percent effort support from
Insightec during the pivotal trial, in which this patient was included.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2020 Saluja, Barbosa, Parker, Huang, Jensen, Ngo, Santini, Pauly,
Ghanouni, McNab and Halpern. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
Frontiers in Human Neuroscience | www.frontiersin.org 8June 2020 | Volume 14 | Article 191