Clinical Neurology and Neurosurgery 138 (2015) 16–19

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Clinical Neurology and Neurosurgery
journal homepage: www.elsevier.com/locate/clineuro

A prospective, randomized, blinded assessment of multitarget
thalamic and pallidal deep brain stimulation in a case of hemidystonia
Philipp J. Slotty a,b , Anujan Poologaindran a , Christopher R. Honey a,∗
a
b

Division of Neurosurgery, University of British Columbia, Vancouver, Canada
Department of Stereotactic and Functional Neurosurgery, Heinrich-Heine University, Düsseldorf, Germany

a r t i c l e

i n f o

Article history:
Received 3 June 2015
Received in revised form 13 July 2015
Accepted 14 July 2015
Available online 29 July 2015
Keywords:
Deep brain stimulation
Hemidystonia
Pallidal
Thalamic
Secondary dystonia
Multitarget

a b s t r a c t
Objective: Dystonia is increasingly being interpreted as a multi-nodal “network” disorder. We aimed to
investigate multitarget DBS (pallidal and thalamic) versus each target alone in a prospective, randomized,
blinded trial in a case of hemidystonia secondary to putaminal stroke.
Methods: DBS leads were implanted in the GPi and Vim/Vop and each stimulation combination (GPi,
Vim/Vop, and both) was tested for three months in a single patient. Burke–Fahn–Marsden Dystonia
Rating Scale (BFMDRS) and Short-Form 36 (SF-36) were completed at the end of each trial period.
Results: Multitarget (GPi + Vim/Vop) stimulation was clinically the most effective treatment and resulted
in the most improvement in function and quality of life. The patient’s hemidystonia improved by 25% as
measured by the BFMDRS during the multitarget stimulation trial period and at the 6-month follow-up.
The patient’s quality of life improved by 86% and 59% during the multitarget stimulation trial period and
at the 6 month follow-up respectively.
Conclusion: Multitarget thalamic and pallidal DBS proved to be the most effective therapy for this patient
with secondary hemidystonia due to a putaminal stroke. A single-lead approach may not be sufficient in
neuromodulating a highly disorganized motor network seen in hemidystonia. Multitarget DBS should be
further explored in post-stroke dystonia and may offer improved outcome in other forms of secondary
dystonia with limited response to GPi DBS.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction
In primary dystonia, the internal pallidum (GPi) is the most common target for deep brain stimulation (DBS) and provides good
to excellent results in the majority of patients [1,2]. In secondary
dystonia, however, GPi DBS has a less impressive efficacy [3–5].
Alternative targets and multitarget stimulation have therefore been
tried in these patients to improve results. One alternative target is
the thalamus.
The Vim has historically been lesioned for dystonia and has
recently been reinvestigated with Vim DBS in tardive dystonia
[6,7]. Thalamic lesioning and DBS in some studies has been shown
to be more effective in patients with secondary dystonia [8–11].
We therefore undertook a prospective, randomized, blinded study
to compare the outcome of GPi DBS versus Vim/Vop DBS versus
simultaneous stimulation of both targets – multitarget DBS – in

∗ Corresponding author at: Division of Neurosurgery, Department of Surgery,
8101-2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada.
E-mail address: chris.honey@telus.net (C.R. Honey).
http://dx.doi.org/10.1016/j.clineuro.2015.07.012
0303-8467/© 2015 Elsevier B.V. All rights reserved.

a case of stroke-induced hemidystonia. GPi DBS is thought to
influence dystonia via modulation of the striato-pallido-thalamocortical pathways. The Vim/Vop area was chosen as it is part of the
cerebello-thalamo-cortical network suspected to also be involved
in the pathophysiology of hemidystonia [12].
The literature on thalamic surgery can be difficult to interpret
due to the different nomenclatures used to describe the nuclei
[18]. We will use Hassler’s thalamic nomenclature and the Schaltenbrand and Wahren stereotactic atlas [18,19].
2. Methods
Three years after a left putaminal stroke due to a heart aneurysm
at age six, the patient developed a right-sided hemidystonia. At age
22, she remained disabled by her condition despite medical treatment and botox therapy and was therefore considered a candidate
for DBS. In light of the limited response to GPi DBS in these patients
reported in the literature and in our experience, it was decided to
test multitarget thalamic and pallidal stimulation. Hereafter, we
will use the term multitarget DBS to describe simultaneous DBS
in two different nuclei within the same hemisphere. This is to be

P.J. Slotty et al. / Clinical Neurology and Neurosurgery 138 (2015) 16–19

17

Fig. 1. Location of electrodes is shown with a post-operative CT (windowed to show metal) merged to a pre-operative MRI (T1 with gadolinium). (A) Axial image 4 mm
below AC–PC line shows electrode in GPi (long arrow). (B) Axial image at AC–PC shows electrode in Vim (short arrow). Artifact of GPi electrode (long arrow) is seen passing
just medial to the area of putaminal stroke.

distinguished from multiple electrodes within the same nucleus,
which could be called multifocal DBS or simultaneous stimulation
of the same nucleus in both hemispheres – commonly called bilateral DBS.
Institutional Review Board ethics was obtained to conduct
this study in a blinded and randomized fashion. Left Vim/Vop
(Medtronic 3387) and posteroventral GPi (Medtronic 3389) DBS
electrodes were implanted and connected to an implantable
neurostimulator (Medtronic Activa PC). Post-operative imaging
confirmed the deepest pallidal contact was at x = −20, y = +2, z = −4
relative to the midcomissural point. The deepest thalamic contact
was at x = −13, y = −6, z = 0 in the Vim with a shallow ring angle of
55◦ that kept the more proximal contacts within Vop. Fig. 1 shows
the location of the implanted electrodes on a post-operative CT
merged to a pre-operative MRI.
Programming began one month later and was blinded to both
the patient and examiner. The pallidal lead configuration was set
to single bipolar: case off, contacts 0−, 1+, 2 off, 3 off (distal to
proximal). Pallidal stimulation parameters were 185 Hz, 90 ␮s, and
4.0 V. The thalamic lead configuration was set to wide bipolar: case
off, 8+, contact 9 & 10 off, and 11−. Thalamic stimulation parameters
were 185 Hz, 60 ␮s, and 4.0 V. Each combination of stimulation (GPi
only, Vim/Vop only, GPi + Vim/Vop) was tested in a randomized and
double-blinded manner.
After 3 months of stimulation in each setting, the BFMDRS and
SF-36 were completed. A follow-up unblinded assessment of BFMDRS and SF-36 after six months of multi-target stimulation was
added to the analysis.
3. Results
Vim/Vop or GPi stimulation alone slightly improved reported
quality of life and was felt by the patient to be subjectively better
than their baseline but did not result in improvement of dystonic
movement as rated by the BFMDRS. Vim/Vop stimulation resulted
in a higher increase in SF-36 compared to GPi stimulation; this was
attributed to a significant reduction in the patient’s overall pain
level.
Multitarget (GPi + Vim/Vop) stimulation was preferred by the
patient and resulted in the best functional improvement measured by the BFMDRS and the highest improvement in quality

Table 1
Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) and SF-36 quality of life
measured pre-operatively, after three-months of stimulation in each setting, and at
six-month follow-up with multitarget stimulation. Score and percentage improvement from baseline provided.

Pre-operative
GPi stimulation
Vim/Vop stimulation
GPi + Vim/Vop stimulation
6 month follow-up GPi + Voa/Vop

BFMDRS (%
improvement)

SF-36 (%
improvement)

24
24 (0%)
24 (0%)
18 (25%)
18 (25%)

45
54 (15%)
66 (46%)
81 (86%)
76 (59%)

of life as measured by the SF-36. Additionally a decrease of her
dystonia related pain was reported by the patient compared to
baseline. Based on the results of the blinded trial, multitarget stimulation was chosen as the final setting. Six month follow-up data
showed continued benefits regarding the BFMDRS and a slight
reduction in SF-36 compared to early GPi + Vim/Vop stimulation.
Final stimulation parameters at the 6-month follow-up for multitarget stimulation did not change for the Vim/Vop target. Pallidal
lead configuration and frequency (185 Hz) did not change; while
stimulation voltage was adjusted from 4.0 to 4.5 V and pulse width
changed from 90 to 120 ␮s.
Multitarget DBS specifically improved the dystonia in her right
limbs. Dystonic posturing of the right upper limb above her head
stopped. The patient reported decreased pain and cramping, especially in her right shoulder and foot. Furthermore, headaches were
less frequent and the right ankle was more flexible. The patient’s
quality of life improved by 86% and 59% during the GPi + Vim/Vop
simultaneous stimulation trial and at the 6 month follow-up
respectively. The Burke-Fahn Marsden Disability Scale (BFMDS)
and Short-Form 36 (SF-36) quality of life data outcome measures
are provided in Table 1. The location of electrode placement is provided in Fig. 1.
4. Discussion
The best improvement in dystonic symptoms and quality of
life for this patient with stroke-induced hemidystonia was seen
following multitarget thalamic and pallidal DBS compared with
stimulation of either target alone. The clinical benefit of multitarget

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DBS in this case raises questions about the mechanisms underpinning secondary dystonia and how best to treat it.fMRI studies
have found that patients suffering from hemidystonia have altered
patterns of basal ganglia connectivity when compared to healthy
subjects [12]. These changes include both a decrease of connectivity in some networks and a marked increase in others. Specifically,
hemidystonia was associated with decreased activation in the contralateral thalamus, globus pallidus, and medial temporal cortex
with dystonic arm task execution. In the ‘hypokinetic’ hemidystonic
group, widespread bilateral over-activity was observed [12].
Many of the effects seen are thought to be compensatory mechanisms all playing an active role in the development of secondary
dystonia. The delayed onset commonly observed in secondary dystonia (and present in our case) is indirect evidence of maladaptive
neural plasticity taking place [14]. The pathophysiology of dystonia appears to involve abnormalities in sensory function, loss of
intracortical inhibition, and changes in plasticity within the sensorimotor cortex [21].
Hemidystonia, however, can be seen in patients with lesions
somewhere in either the cortico-striato-pallido-thalamo-cortical
pathways or the cerebello-thalamo-cortical pathways and there is
a growing body of evidence suggesting brain regions other than the
basal ganglia are clearly involved in the etiology of dystonia [12].
Dystonia more likely has to be interpreted as a network disorder or a
disease caused by “defective interactions among different nodes in
a motor network, rather than a defect in motor pathways” [15,16].
The minor effect of either single target stimulation in this
trial suggests that both the cerebello-thalamo-cortical and the
striato-pallido-thalamo-cortical pathways participate in the network disorder of post-putaminal stroke dystonia and that both
nodes of this network need to be modulated for optimum clinical
benefit.
An electrode within the GPi could influence the cortico-striatopallido-thalamo-cortical network but might not influence the
cerebello-thalamo-cortical pathway (and vice versa for an electrode in the Vim/Vop). Since both pathways appear to be involved
in the pathophysiology of this type of dystonia both pathways may
need to be treated. Using the multitarget DBS approach we present,
both electrodes are likely acting in a complimentary way in modulating cortical activity.
The role of the cerebellar pathways in dystonia has been discussed recently and the Vop is believed to be involved in the
cerebello-thalamic connectivity (whereas Voa is more involved in
pallido-thalamic pathways) [16]. In their publication on DBS for
focal hand dystonia in the Voa/Vop area, Goto et al. did not find a
clear difference in outcome compared to GPi stimulation and their
questions whether Voa or Vop stimulation is the effective component of thalamic DBS remained unsolved.
We targeted the Vim/Vop area with the deepest contact (anode)
in the Vim region. The cathode was chosen as proximal as possible to put current through the Vop. The electrical stimulation
did not spread posteriorly into the VC nucleus, as the patient
did not experience paresthesia. Current may have spread anteriorly to the Voa nucleus but this cannot be definitively confirmed;
it is possible that this pallidal outflow relay nucleus may have
been affected by thalamic stimulation. Nevertheless, it is clear
that the addition of direct pallidal stimulation improved the
patient’s clinical outcome more than just with thalamic stimulation
alone.
The concept of simultaneous stimulation of multiple functional
targets is not limited to one hemisphere: bilateral GPi DBS has
recently been described to result in improved outcome compared to
unilateral stimulation in a case of striatal stroke induced hemidystonia [17]. This is not surprising since changes in interhemispheric
motor circuitry connectivity have also been described in secondary
dystonia [13,14].

Secondary dystonia is a heterogeneous disorder with respect
to its cause and clinical presentation and different types of secondary dystonia may require individualized treatment [20]. The
mechanism of dystonia induction by putaminal stroke is most likely
unique and whether multitarget DBS delivers reproducible results
in other forms of secondary dystonia or even in secondary dystonia caused by stroke in locations other than the putamen remains
unclear at this time. In the past, the thalamus was regarded as
an advantageous avenue to target in secondary dystonia; this was
prior to the validation of posteroventral lateral GPi as the best
first-line target [21]. In the pre-DBS era, thalamotomies and subthalamotomies were employed to treat choreo-athetotic cerebral
palsy and secondary dystonias [21–23], but the choice of thalamic
nucleus target was highly variable among surgeons.
Finally, the anatomy of the thalamus and basal ganglia is often
distorted by the very insult (i.e., stroke) that causes secondary dystonia. We recommend that direct anatomical targeting may be the
best method to accommodate this distortion. While this patient had
targeting from internal landmarks (AC–PC line) with guidance from
awake macroelectrode stimulation, our center is moving toward
direct anatomical targeting in future cases.
While it is the first double-blinded, randomized assessment of
multitarget DBS in hemidystonia, the conclusions that can be drawn
are limited by the fact that we report on a single case. Finally,
it is important to appreciate that hemi-dystonia (and segmental
dystonia) patients are typically less functionally impaired (as measured by the BFMDRS) compared to patients with primary dystonia.
Thus, their degree of functional improvement after surgery may
appear smaller and not as dramatic. We believe this is important recognize when interpreting results in the literature regarding
hemi-dystonia. Other scales such as quality of life and modified
dystonia scales should be relied on to account for this inherent
limitation.
5. Conclusion
Multitarget (Vim/Vop + GPi) DBS proved to be the most effective therapy for this patient suffering from secondary, childhood
onset hemidystonia due to a putaminal stroke. Using a single-lead
approach may not be sufficient in neuromodulating a highly disorganized motor network seen in hemidystonia patients. We believe
that multitarget DBS in different nuclei requires further investigation for secondary dystonia with limited response to GPi DBS.
The recent emergence of dystonia being interpreted as a “network
disorder” warrants this exploration.
Authors’ roles
CRH designed the study, performed DBS implantation and critically revised the final manuscript. AP collected/analyzed data and
revised the final manuscript, PJS analyzed data and wrote the
manuscript draft. All authors approved the final version of the
manuscript.
Financial disclosures
CRH has received speaking honoraria and consultation fees from
Medtronic. PJS and AP declare no conflicts of interest.
Conflict of interest
The authors declare no conflict of interest regarding the methods and materials investigated in this study. This study was not
funded.

P.J. Slotty et al. / Clinical Neurology and Neurosurgery 138 (2015) 16–19

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