REVIEW

The Role of High-Intensity Focused Ultrasound as a Symptomatic

Treatment for Parkinson’s Disease
Shayan Moosa, MD,1 Raul Martínez-Fernández, MD, PhD,2 W. Jeffrey Elias, MD,1 Marta del Alamo, MD,2
Howard M. Eisenberg, MD,3 and Paul S. Fishman, MD, PhD3*

1
Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
2
CINAC (Centro Integral de Neurociencias), University Hospital HM Puerta del Sur, CEU-San Pablo University, Móstoles, Madrid, Spain
3
University of Maryland School of Medicine, Baltimore, Maryland, USA

A B S T R A C T : MR-guided focused ultrasound is a novel,
minimally invasive surgical procedure for symptomatic
treatment of PD. With this technology, the ventral interme-
diate nucleus, STN, and internal globus pallidus have been
targeted for therapeutic cerebral ablation, while also mini-
mizing the risk of hemorrhage and infection from more
invasive neurosurgical procedures. In a double-blinded,
prospective, sham-controlled randomized controlled trial
of MR-guided focused ultrasound thalamotomy for treat-
ment of tremor-dominant PD, 62% of treated patients
demonstrated improvement in tremor scores from base-
line to 3 months postoperatively, as compared to 22% in
the sham group. There has been only one open-label trial
of MR-guided focused ultrasound subthalamotomy for
patients with PD, demonstrating improvements of 71% for
rigidity, 36% for akinesia, and 77% for tremor 6 months
after treatment. Among the two open-label trials of MR-
guided focused ultrasound pallidotomy for patients with
PD, dyskinesia and overall motor scores improved up to
52% and 45% at 6 months postoperatively. Although MR-
guided focused ultrasound thalamotomy is now approved
by the U.S. Food and Drug Administration for treatment of
parkinsonian tremor, additional high-quality randomized
controlled trials are warranted and are underway to deter-
mine the safety and efficacy of MR-guided focused ultra-
sound subthalamotomy and pallidotomy for treatment of
the cardinal features of PD. These studies will be para-
mount to aid clinicians to determine the ideal ablative tar-
get for individual patients. Additional work will be required
to assess the durability of MR-guided focused ultrasound
lesions, ideal timing of MR-guided focused ultrasound
ablation in the course of PD, and the safety of performing
bilateral lesions. © 2019 International Parkinson and
Movement Disorder Society
Key Words: focused ultrasound; movement disorders;
pallidotomy; Parkinson’s disease; stereotactic surgery;
subthalamotomy; thalamotomy

-*Correspondence
- - - - - - - - - - - - - - -to:- - Dr.
- - - Paul
- - - -S.- -Fishman,
- - - - - - - -Department
- - - - - - - - - -of- -Neurology,
----------
Idiopathic Parkinson’s disease (PD) is a neurodegen-
University of Maryland School of Medicine, 110 South Paca Street,
Baltimore, MD 21201, USA; E-mail: pfishman@som.umaryland.edu erative disorder characterized by specific motor impair-
Relevant conflicts of interest/financial disclosures: Dr. Raul ments, including tremor, muscle rigidity, bradykinesia,
Martínez-Fernández has received funding from InSightec and the FUS and postural instability, which can result in physical
Foundation. Dr. W. Jeffrey Elias has received funding from InSightec
and the FUS Foundation. Dr. Howard W. Eisenberg has received and mental disability and accelerated death.1 The path-
funding from InSightec and the FUS Foundation. Dr. Paul S. Fishman ophysiological mechanism for these symptoms is pro-
has received funding from InSightec and the FUS Foundation.
Full financial disclosures and author roles may be found in the online
gressive loss of dopaminergic cells located within the
version of this article. SNpc of the midbrain.2,3 Currently, over 6 million peo-
Funding agencies: This review summarizes a special session pres-
ented at the 6th annual International Focused Ultrasound symposium
ple worldwide suffer from PD, a number that has dou-
on October 20, 2019. The session was sponsored by the Focused bled within the past generation.4 Prevalence of PD
Ultrasound Foundation. steadily increases with age; thus, given that the average
Received: 9 April 2019; Revised: 30 April 2019; Accepted: 2 May 2019 age among populations of developed countries con-
Published online 00 Month 2019 in Wiley Online Library
tinues to increase, we can expect a drastic rise in the
(wileyonlinelibrary.com). DOI: 10.1002/mds.27779 global burden of PD in the coming decades.5

Movement Disorders, 2019 1

M O O S A E T A L
The first symptomatic treatments for PD consisted of vari-
ous modalities of cerebral lesioning beginning in the late
1930s. This started with cortical resection of the precentral
gyrus and later transitioned to other parts of the pyramidal
tract, including the spinal cord, internal capsule, and
cerebral peduncle.6-10 Russell Meyers performed the
first “extrapyramidal” lesioning procedure for hemi-
parkinsonism in 1939,11 and he inspired others to lesion
distinct areas of the basal ganglia using open approaches, as
well as stereotaxis after 1947.12-15 Irving Cooper serendipi-
tously performed the first pallidotomy after accidental liga-
tion of the anterior choroidal artery in 1952, which
subsequently resolved a patient’s postencephalitic tremor.16
He also found that this technique reduced bradykinesia. He
later worked with Bravo to perform stereotactic lesioning of
the ventrolateral thalamic nucleus to treat parkinsonian
tremor.17 These lesioning procedures were gradually aban-
doned after the discovery of levodopa replacement in the
1960s, and this remains the first-line treatment for reduction
of motor symptoms from PD.18,19 Despite a late revival of
surgery for medication-related side effects, lesioning again
lost favor with the advent of DBS. This was not necessarily
attributed to stronger antiparkinsonian effects with DBS,
but rather for its practical convenience among neurologists,
given that DBS was considered safer, easier to adapt, and
reversible.20 DBS of the ventral intermediate nucleus (Vim)
of the thalamus,21 STN,22 and internal globus pallidus
(GPi)23 are currently mainstay surgical treatments for reduc-
tion of motor symptoms of PD and medication-related side
effects from chronic dopamine replacement.24,25 Since the
development of transcranial focused ultrasound (FUS), a
third era of cerebral lesioning is being considered.
High-intensity focused ultrasound (HIFU) was first used
to create cerebral ablations in the 1950s by Russel Meyers
and William and Francis Fry.26 At the time, this technology
was limited by the requirement for a craniotomy to effec-
tively transmit ultrasound energy to the desired target, ulti-
mately causing it to be abandoned.27 Modern advances in
transcranial acoustic delivery of ultrasound, coupled with
MR thermography, now allow for less-invasive cerebral les-
ioning with submillimeter precision.28-30 Based on two
multicenter, randomized, sham-controlled clinical trials,
MR-guided focused ultrasound (MRgFUS) has been
approved by the U.S. Food and Drug Administration (FDA)
for treatment of essential tremor (ET) and, more recently,
PD.31,32 In this article, we will review studies that have used
HIFU for symptomatic treatment of PD. We will discuss
each of the surgical targets utilized to date, explore parame-
ters for target selection, and highlight important future direc-
tions for this technology for symptomatic treatment of PD.
Thalamotomy
The primary lesional or neuromodulatory target for
tremor-dominant movement disorders is the Vim. Schlesinger
2 Movement Disorders, 2019
and colleagues published the first case series describing the
use of MRgFUS for symptomatic treatment of tremor-
dominant PD.33 In this unblinded, single-center, prospective
study, 7 patients with severe refractory tremor-dominant
PD underwent thalamotomy contralateral to the more dis-
abling side. The Vim was targeted 25% of the anterior com-
missure (AC)/posterior commissure (PC) distance anterior
to the PC and 14 mm lateral to the intercommissural line
(ICL), or 11.5 mm lateral to the wall of the third ventricle in
patients with ventriculomegaly, at the same dorsoventral
level as the ICL. Mean patient follow-up time was 8 months,
ranging from 3 to 12 months. Tremor severity was mea-
sured using the total UPDRS, and quality of life was mea-
sured using the 39-Item Parkinson’s Disease Questionnaire
(PDQ-39). The researchers reported that the mean total
UPDRS score decreased 49.7% from baseline to 1 week
postoperatively (37.4–18.8), and the mean PDQ-39 score
decreased 48.9% in the same time period (42.3–21.6). One
patient also experienced immediate improvement in rigidity,
which interestingly was later described again in a case report
by Ito and colleagues following MRgFUS thalamotomy for
PD.34 Three patients experienced mild recurrence at 1 week,
1 month, and 6 months postoperatively, although UPDRS
scores are not provided at any follow-up time points after
1 week. Lasting adverse events included hypogeusia in
1 patient and gait imbalance in 2 patients that later resolved.
A similar study performed by the same group assessed
tremor and disability improvement after MRgFUS
thalamotomy in 30 patients with PD and ET.35 Nine were
diagnosed with tremor-dominant PD, 7 of whom were
included in the earlier study, and another 3 were diagnosed
with ET with PD symptoms that developed several years
later. Mean follow-up time for all patients was approxi-
mately 1 year, ranging from 6 months to 2 years. Among
the 12 patients with PD, the mean motor UPDRS score (Part
III) on medication decreased 34.1% from baseline to
1 month postoperatively (24.9–16.4) and 46.2% from
baseline to 6 months postoperatively (24.9–13.4). Mean
PDQ-39 score decreased 32.4% from baseline to 1 month
postoperatively (38.6–26.1) and 46.6% from baseline to
6 months postoperatively (38.6–20.6). Four of the
12 patients (33.3%) experienced tremor recurrence within
6 months after the procedure. The researchers state that
tremor recurrence was significantly less disabling than the
baseline tremor in all but 1 of the patients. The most com-
mon lasting adverse event was unsteady gait, which resolved
within 3 months following the procedure in all patients.
Fasano and colleagues described a single-blinded, single-
center, prospective study of 6 patients who underwent uni-
lateral Vim MRgFUS for non-ET tremor syndromes, 3 of
whom were diagnosed with tremor-dominant PD.36 All
patients were followed to a maximum of 6 months, except
for 1 with PD who expired from aspiration pneumonia
4 months postoperatively. Six months after the procedure,
the remaining 5 patients exhibited a 52.9% decrease in
single-blinded assessments of contralateral tremor using
 F O C U S E D U L T R A S O U N D
the Tremor Rating Scale (Parts A and B). Patients with PD
underwent unblinded assessments of mean scores from
subsections of the UPDRS. Whereas they demonstrated a
32.3% reduction in the activities of daily living portion of
the UPDRS from baseline to the latest follow-up
(17.0–11.5), there was no significant change for the motor
portion (27.0 at baseline to 26.5 at the latest follow-up).
Aside from tremor, no other signs of PD were observed to
be improved from this treatment. The patient with PD who
died from pneumonia experienced persistent hemiparesis
with hemihypesthesia following the procedure. Another
patient with PD experienced decay in benefit after the pro-
cedure. He underwent repeat MRgFUS thalamotomy
18 months after the first procedure and experienced
improvement in contralateral tremor, but also persistent
mild hemiparetic gait and hemibody ataxia.37
Bond and colleagues published the results of a double-
blinded, two-center, prospective, sham-controlled random-
ized controlled trial (RCT) of MRgFUS ablation of the
Vim in patients with tremor-dominant PD. Of the
27 patients with medication-refractory, severe tremor-
dominant PD included in this study, 20 were randomized
to the treatment group and 7 to the sham group. The Vim
was targeted 25% of the ICL distance anterior to the PC
and lateral to the midline by 14.0 to 14.5 mm at the dorso-
ventral level of the ICL. An example of the radiographic
findings following MRgFUS thalamotomy is shown in
Figure 1. Multiple double-blinded assessments of hand
tremor using the Clinical Rating Scale for Tremor (CRST)
Parts A and B, motor UPDRS, and PDQ-39 were per-
formed in the on-medication state up to the 3-month time
point, after which patients were unblinded. Following
unblinding, 6 of the 7 patients in the sham group elected to
crossover to undergo open-label treatment. Among the
20 patients in the original treatment group, 6 did not
return for assessment at 1 year postoperatively. The
researchers report a 62% improvement from baseline to
3 months postoperatively of median CRST A + B scores in
the treatment group, compared to 22% in the sham group.
This significant placebo response has been demonstrated in
previous sham-controlled trials for PD.38 After taking the
placebo response into account, the extent of improvement
in tremor scores is consistent with another RCT of Vim
MRgFUS in treatment of ET.31 In addition, an 8-point
improvement was observed in terms of on-medication
median motor UPDRS score in the thalamotomy group
from baseline to 3 months postoperatively, whereas there
was only a single-point improvement in the sham group.
Similarly, median PDQ-39 score in the thalamotomy
group improved to a greater extent than the sham group.
The treatment group exhibited improvements in terms of
UPDRS treated hand resting tremor and postural or action
tremor, whereas the sham group did not. Persistent adverse
events included paresthesias in 19% and ataxia in 4%.
Two patients experienced mild hemiparesis with gradual
improvement to their baseline. This occurred early in the
F O R S Y M P T O M A T I C T R E A T M E N T O F P D
study and was attributed to unintentional heating of the
internal capsule. A separate analysis of nonmotor out-
comes and quality of life by Sperling and colleagues
reported no differences in measurements of cognition,
mood, or behavior between the two groups at the 3-month
blinded assessment, whereas measures of quality of life and
activities of daily living were significantly improved in the
treatment group.39 All in all, of the ablative procedures
using MRgFUS for symptomatic treatment of PD,
thalamotomy has been the most extensively studied and
appears to be both safe and efficacious for tremor control.
Subthalamotomy
The STN was newly considered as a potential neurosur-
gical target for the treatment of PD along with develop-
ment of the pathophysiological model of the basal ganglia
in the 1980s.40,41 It was shown that in the parkinsonian
state, the STN is hyperactive and overdrives the inhibitory
output nuclei to the cortex and brainstem.42 Following this
rationale, STN lesioning was attempted successfully in the
MPTP monkey model, eliciting improvement in all parkin-
sonian cardinal signs, including rigidity, akinesia, and
tremor.43-45 These findings were followed by a number of
open studies that described the effect of subthalamotomy
in PD patients that, by and large, showed improvement of
UPDRS.46 The largest reported experience described
89 patients followed for up to 36 months.47 Meaningful
reductions in the off-medication motor UPDRS were noted
at 12 (50%), 24 (30%), and 36 months (18%) following
unilateral subthalamotomy. This benefit was achieved rela-
tively safely and with a low and acceptable risk of
subthalamotomy-induced dyskinesias. Indeed, occurrence
of this feared complication is known to be diminished by
enlarging STN lesions dorsally, aiming to impact
pallidothalamic fibers.48 In a limited number of patients,
bilateral staged (n = 7) and simultaneous (n = 11) sub-
thalamotomies were carried out with net motor improve-
ment and no major adverse effects.49
To date, MRgFUS subthalamotomy has only been evalu-
ated in one open trial with a series of 10 PD patients.50 The
results of this study showed improvements of 53% in the
motor score of the International Parkinson and Movement
Disorder Society (MDS)-UPDRS of the body side contra-
lateral to the subthalamotomy in the off-medication condi-
tion 6 months after treatment. A 47% improvement was
shown in the on-medication state. When separating each
specific motor subitem, tremor and rigidity improved 77%
and 71%, respectively, whereas akinesia improved up to
36%. In the on-medication condition, improvements of
88% for rigidity, 23% for akinesia, and 80% for tremor
were observed. One patient developed right upper-limb
chorea a few days after subthalamotomy, which was not
severe and waned until disappearing at 6 and 12 months
posttreatment. Most side effects were transient and
Movement Disorders, 2019 3
M O O S A E T A L
FIG. 1. Postoperative imaging following transcranial MRgFUS thalamotomy of the left Vim. Axial (A) and coronal (B) T2-weighted MRI scans 1 day after
the procedure. Of note, the lesion has a T2-hypointense core and T2-hyperintense rim, suggestive of coagulation necrosis. The surrounding, less-
hyperintense area is suggestive of cytogenic edema.
resolved within the first few weeks. Gait instability was the
most frequent transient adverse effect (6 of 10 patients). In
addition, subthalamotomy did not affect any cognitive or
behavioral domain in the neuropsychological assessment
3 months after treatment. Total MDS-UPDRS (Part III)
improved by 35% in the off-drug state and by 25% in the
on-drug state. In addition, the L-dopa equivalent dosage
was reduced by a mean of 24%. These preliminary, but
promising, results warranted a larger RCT to increase
the level of evidence, which is currently ongoing
(NCT03454425). An example of the radiographic findings
following MRgFUS subthalamotomy is shown in Figure 2.
Pallidotomy
Stereotactic surgical intervention targeting the GPi has
been shown to benefit PD motor symptoms.51-53 Radio-
frequency pallidotomy results in a substantial decrease in
dyskinesis induced by years of treatments with carbidopa/
54,55
L-dopa (L-dopa–induced dyskinesias). Cardinal motor
signs of PD, such as tremor, bradykinesia, and rigidity,
are also improved contralateral to a pallidotomy, specifi-
cally in the off–L-dopa state in patients with a fluctuating
response to L-dopa.56-58
DBS of the GPi was introduced, in part, to reduce the neu-
rological complications of radiofrequency pallidotomy such
as weakness, imbalance, cognitive abnormalities, and visual
field defects.59-64 Beneficial effects of GPi DBS that are simi-
lar to that of pallidotomy are well documented using this
strategy to ameliorate motor features of PD.25,65-67 DBS is,
however, still an open surgical procedure and shares with
radiofrequency pallidotomy the risk of intracranial bleeding
and infection.68,69
4 Movement Disorders, 2019
The small experience with GPi ablation in PD patients
utilizing MRgFUS thus far is encouraging. An initial goal
has been comparable improvement of motor signs and
symptoms of PD, but with less morbidity than the more-
invasive stereotactic open ablation. The first report of
MRgFUS appeared as recently as 2015, in which a
55-year-old woman with PD showed reduction in scores
on a standardized patient- and physician-based measure of
dyskinesia severity and impact, the Unified Dyskinesia Rat-
ing Scale (UDysRS). There was 62% reduction from the
baseline score at 3 months after a unilateral FUS-mediated
pallidotomy. As expected from previous ablative studies,
there was also a 61.9% reduction in motor score severity
on Part III of the MDS-UPDRS in the off-medication
state.70 Although most of the improvement was observed
on the body side contralateral to the lesion, as previously
noted in open pallidotomy, some ipsilateral improvement
was noted as well. In a recently published open-label study
by Jung and collegaues, 10 patients with PD underwent
unilateral MRgFUS pallidotomy.71 Of the 8 patients who
successfully completed the procedure (ablative levels of
temperature elevation could not be obtained in 2 patients,
which may uncommonly occur in patients with unfavor-
able skull characteristics), 6 completed the 1-year evalua-
tion period. They showed an improvement in total
UDysRS by 52.7% and had 30.2% reduction in UPDRS
off-mediation scores at 6 months. One patient experienced
dysarthria and hemiparesis during the procedure, which
resolved after 2 days. This study also included a battery of
neuropsychologic tests, which showed no significant
changes after treatment. All successfully treated patients
demonstrated radiographic lesions on MRI within 1 week
after treatment, which resolved 6 months later.
 F O C U S E D U L T R A S O U N D
FIG. 2. Postoperative imaging following transcranial MRgFUS subthalamotomy. Axial (A) and coronal (B) T2-weighted MRI scans 1 day after right
subthalamotomy.
The authors (H.M.E., W.J.E. and P.S.F.) were part of a
recently completed larger multicenter open-label study of
MRgFUS pallidotomy for PD (unpublished data). Because
of previous reports of adverse effects on cognition with
bilateral radiofrequency pallidotomy, this team elected to
perform only unilateral lesions.61-64 In light of this design
limitation, only patients who had either unilateral or highly
asymmetric motor signs of PD were included in the study.
Because previous literature supported a direct ant-
idyskinesia effect of pallidotomy, these patients not only
had functionally interfering dose fluctuations (with a score
of at least 3 in response to question 4.2 of the MDS-
UPDRS), but also had bothersome L-dopa–induced dyski-
nesias with baseline total UDysRS mean scores of 36.1.
Targeting was performed using both standard stereotactic
coordinates for the GPi (20 mm lateral of midline, 3–4 mm
anterior to the midpoint between AC and PC, and 3 mm
inferior to the ICL) and direct imaging of the GPi using fast
gray matter acquisition T1 inversion recovery (FGATIR)
MRI sequences. Subjects received a mean of 15 sonications
during treatment (standard deviation [SD]: 3.0) with a
mean power of 605.6 J (SD, 164.9). Mean maximum soni-
cation power was 1,045.1 J (SD, 233.3). An example of
the radiographic findings following MRgFUS pallidotomy
is shown in Figure 3.
The patients had a mean age of 56.8 years, were an
average of 9.9 years from diagnosis, and had a mean daily
L-dopa equivalent dose of 1,039 mg. Of the 20 patients
enrolled, 19 completed evaluations at least 6 months post-
operatively, where there was a highly significant 50.4%
reduction (from the mean score 36.1 [SD, 11.12] to mean
score 17.9 [SD, 14.88]; P < 0.0001) in total dyskinesia
score at 6 months with comparable improvement in both
the historical and exam components. A similar reduction
F O R S Y M P T O M A T I C T R E A T M E N T O F P D
in cardinal motor signs of PD was also noted as measured
by a highly significant 45% change in baseline scores on
the MDS-UPDRS Part III (for the treated body side) at
6 months after treatment (from mean score 20.0 [SD,
5.62] to mean score 11.0 [SD, 3.20]; P < 0.0001). This
larger treatment effect than observed in the previous
open-labeled study for motor signs of PD may reflect the
more asymmetrical features of our patients. Treatment
was also followed by highly significant improvement in
UPDRS measures of motor experiences of daily living
(from mean score of 14.0 [SD, 7.53] to mean score of 9.5
[SD, 5.5]; P = 0.0007, based on Part II of the MDS-
UPDRS) and motor complications (mean score of 11.1
[SD, 5.61] to mean score of 6.4 [SD, 3.86]; P = 0.0007,
based on Part IV of the MDS-UPDRS) at 6 months. All
changes noted were not only statistically significant, but
were also of a magnitude associated with clinically mean-
ingful improvement.72-74
The profile of adverse effects observed in this study was
consistent with both previous studies of MRgFUS and
radiofrequency pallidotomy.75 The majority of adverse
effects were mild and transient, including headache/head
pain related to the placement of the stereotactic frame or
the sonication (one moderate adverse effect). Neurological
adverse events related to the procedure and historically
observed with radiofrequency pallidotomy included only
one visual field deficit, which was mild and transient, and
dysarthria (two mild and two moderate, but three of
which persisted for the duration of the study). Neuropsy-
chological testing revealed only 1 patient who showed sig-
nificant decline on one domain (memory). Fine motor
deficits (two mild, one persistent), facial weakness (one
mild), and balance difficulties (one moderate and persis-
tent) were also observed. There were no serious adverse
Movement Disorders, 2019 5
M O O S A E T A L
FIG. 3. Axial MRI scans from a PD patient 1 day after MRgFUS-mediated pallidotomy shows increased signal on DWI (A) and FGATIR (B) sequences in
the GPi. Courtesy of Dr. Dheeraj Gandhi. DWI, diffusion-weighted imaging.
events (as defined by the FDA). As expected for this inci-
sionless procedure, no intracranial bleeding or infection
occurred.
Although the total number of patients treated has been
relatively small, the experience thus far with MRgFUS-
mediated pallidotomy compares favorably with previous
studies of radiofrequency pallidotomy for PD, where up
to several percent of patients showed reportable neurolog-
ical deficits that were serious and persistent. Both the effi-
cacy and safety of pallidal FUS provide support for its
expanded clinical investigation in the form of an ade-
quately powered, blinded, controlled study for treatment
of patients with significantly asymmetric PD and a fluctu-
ating motor response to medications, including dyskine-
sia. Successful development of this technology will
provide PD patients with a new minimally invasive treat-
ment option with the potential for benefits comparable to
pallidal DBS.
Target Selection
The optimal brain target for the treatment of PD has his-
torically been the focus of a long-lasting debate in func-
tional neurosurgery, and it still remains controversial.76
The hitherto limited evidence with MRgFUS does not allow
us to draw definitive specific conclusions (refer to Table 1
for a listing of all published trials of FUS thalamotomy, sub-
thalamotomy, and pallidotomy for symptomatic treatment
of PD). However, there are abundant data from the previ-
ous era of radiofrequency-induced lesions as well as the
many DBS trials. As mentioned above, whereas radio-
frequency Vim thalamotomy has been applied for decades
6 Movement Disorders, 2019
for treatment of medically refractory PD tremor,20 pallidot-
omy for PD was revitalized by Laitinen in 1985 and had
started to be performed by many groups worldwide.24 A
few years later, the STN began to be targeted77 and showed
sustained benefit in PD motor features and higher postoper-
ative reductions in medication dosage than pallidotomy.
Nevertheless, the classical concern about inducing chorea-
ballism by subthalamotomy, which has not formally been
evaluated, led to the popularization of pallidotomy. In fact,
pallidal ablation still is recommended by the MDS
Evidence-Based Medicine Task Force as an efficacious
treatment for motor fluctuations and dyskinesias, whereas
STN lesions remain investigational because of “insufficient
evidence.”78 The abandonment of ablative procedures with
the development of DBS took away the chance for head-to-
head comparisons between ablation of different targets. As
a consequence, despite clinical experience that suggests effi-
cacy of both pallidotomy and subthalamotomy to improve
cardinal features of PD and of thalamotomy as an effective
treatment for parkinsonian tremor, the lack of data with a
high level of evidence in the ablative literature does not
allow us to definitely favor one target over the other.
Opportunely, this is not the case in the DBS field. Hence,
whereas thalamic stimulation for PD is currently limited to
very selected tremor-predominant patients because of lim-
ited benefit against other motor features, the STN has
become the main preferred surgical target for stimulation in
PD.25 Direct comparisons in randomized trials between
bilateral subthalamic and pallidal stimulation have some-
what contradictory results; however, they suggest a better
effect of the former to improve cardinal motor features and
a greater range of dopaminergic drug reduction than GPi-
DBS. As expected, pallidal stimulation is more effective for
 F O C U S E D U L T R A S O U N D F O R S Y M P T O M A T I C T R E A T M E N T O F P D

TABLE 1. Published trials of focused ultrasound thalamotomy, subthalamotomy, and pallidotomy for the symptomatic
treatment of PD

No. of PD
Trial Type Target Indication patients treated Follow-up

Schlesinger et al., 201533 Unblinded, prospective observational study Vim Tremor-dominant PD 7 1 year
Zaroor et al., 201835 Unblinded, prospective observational study Vim Tremor-dominant PD 12a 1 year
Fasano et al., 201736 Single-blind, prospective observational study Vim Tremor-dominant PD 3 6 months
Bond et al., 201732 Double-blind RCT Vim Tremor-dominant PD 27 1 year
Martinez-Fernandez et al., 201850 Unblinded open-label pilot study STN Asymmetric parkinsonism 10 6 months
Jung et al., 201871 Unblinded, open-label pilot study GPi Dyskinesia-dominant PD 10 1 year
a
Seven patients were included in previous study by Schlesinger and colleagues, 2015.33

control of L-dopa–induced dyskinesias.23,79 In terms of
safety, whereas a decrease in verbal fluency has been fre-
quently associated with bilateral STN-DBS and not with
pallidal stimulation, it has also been claimed that STN-DBS
could result in a higher rate of neuropsychiatric complica-
tions in the long term, such as depression and cognitive
decline.80 However, the latter suggestion is controversial81
and could be mediated by a greater reduction in medication
or by differences in disease progression rather than by the
subthalamic stimulation itself.25
Finally, among all these considerations in terms of tar-
get selection, we must also include the feasibility of per-
forming bilateral lesions. The evidence from surgical
pallidotomy and thalamotomy suggests a substantial risk
of permanent side effects such as speech disturbance and
ataxia.82-84 However, the available, but limited, informa-
tion suggests that bilateral STN ablation in PD is not
accompanied by such catastrophic complications.49 The
progressive clinically controlled performance of a FUS
lesion could help to address this possible limitation and
provide evidence for target selection when bilateral lesions
are attempted.
Conclusions and Future Directions
MRgFUS is a relatively new technology that is being
investigated as a method for performing incisionless cere-
bral ablations for treatment of movement disorders. In
unilateral treatment of tremor-dominant PD, MRgFUS
thalamotomy appears to provide tremor control compara-
possibility of treating patients in very early PD stages
because of the less-invasive nature of FUS, will also need
to be addressed in the near future. We expect the answers
to these questions to arise over the next decade, poten-
tially enhancing the MRgFUS procedure in ways that will
provide for a more effective, safe, and comfortable experi-
ence for the patient.
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