Prediction of the effects of STN-DBS on gait

and balance disorders in Parkinson’s disease

patients

Master 2 Scientific project 2022 - 2023

Emilie Pons

05 December 2022
Master 2

Contents
Abstract ................................................................................................................................................... 3
1 Introduction .................................................................................................................................... 3
Background ......................................................................................................................................... 3
2 Objectives and approaches ............................................................................................................. 5
3 Materials and methods ................................................................................................................... 5
3.1 Patients ................................................................................................................................... 5
3.1.1 Inclusion criteria:............................................................................................................. 5
3.1.2 Exclusion criteria: ............................................................................................................ 6
3.2 Methods .................................................................................................................................. 6
3.2.1 Proposed Design of the study ......................................................................................... 6
3.2.2 Description of the randomization and blinding procedure ............................................ 6
3.3 Material used .......................................................................................................................... 7
3.3.1 Electrodes........................................................................................................................ 7
3.3.2 Stimulator........................................................................................................................ 7
3.3.3 Local potential fields ....................................................................................................... 7
3.3.4 Force platform ................................................................................................................ 7
3.4 Procedure ................................................................................................................................ 8
3.4.1 (M0): Inclusion visit ......................................................................................................... 8
3.4.2 (M1): at 15 days .............................................................................................................. 8
3.4.3 (M7): Evaluation of the effects of directional and single ring STN-DBS on gait ............. 8
3.4.4 (M7): Evaluation of the effects of directional and single ring STN-DBS on gait ..... Error!
Bookmark not defined.
3.4.5 (M8): Evaluation of the effects of directional STN-DBS on gait ...................................... 8
3.4.6 (M13): Evaluation of the effects of STN-DBS on gait ...................................................... 8
3.5 Description of the research procedures ................................................................................. 9
3.5.1 Collection of electrode data............................................................................................ 9
3.5.2 Gait recording system ..................................................................................................... 9
3.5.3 Magnetic Resonance Imaging study ............................................................................. 10
4 Expected results ............................................................................................................................ 10
5 References .................................................................................................................................... 12

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Abstract
Parkinson Disease (PD) affects approximately 100 000 to 200 000 persons in France and as the
population is ageing, its prevalence has doubled in the last 30 years. PD corresponds to the loss of
different neurons in the brain and in particular dopaminergic nigrostriatal neurons. It is clinically
characterized by motor (akinesia, rigidity and tremor) and non-motor (anxiety, apathy or depression)
signs. With disease progression, freezing of gait (FOG) episodes and falls occur more often and are
less responsive to dopaminergic treatment. Deep brain stimulation (DBS) of the subthalamic nucleus
(STN) is highly efficient to treat motor and non-motor signs with good long-term benefits. However,
its effects on FOG and falls are variable among patients and no preoperative factor linked to
postoperative effect of STN-DBS could be clearly identified so far. A more central position of the
electrode within the STN has been identified as the best target to decrease FOG severity and it is
linked to higher connectivity with the sensorimotor cortical areas. In this study, the effects of
directional STN-DBS applied in different STN subareas will be assessed both on gait and postural
control of PD patients, using validated clinical scales and gait recordings. The volume of tissue
activated (VTA) and cortico-subthalamic tracts involved in gait improvement will also be recorded.
Ultimately, the aim of this internship is to identify preoperative kinetic factors that could be related
to post-operative FOG and falls outcomes.

1 Introduction
Background
With the ageing of the population, two major health problems have emerged over the last three
decades: dementia and falls. The falls, caused by gait and balance disorders result in higher rates of
morbidity, mortality and a lower quality of life. This also leads to higher healthcare costs. It is
estimated that about 60% of the falls are caused by neurological disorders (Demain, 2014). Within
these disorders, Parkinsonian syndromes form a major sub-order, and encompass a wide spectrum
of gait and postural deficits. Parkinson’s disease (PD) affects 100 to 200/100,000 people in the
French population and represents the second highest cause of motor disability in the ageing
population.
Gait and balance disorders represent the main motor disability (Fasano et al., 2015) in advanced PD.
As time passes, these motor signs progressively worsen and become a heavier burden on the patient
with increased frequency of both falls and the freezing of gait (FOG) phenomenon. FOG is
characterised by an inability to lift the feet from the ground with patients feeling ‘glued to the floor’.

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These motor symptoms are partially and inconsistently improved by the dopaminergic treatment
and become resistant as the disease progresses.
For more than 35 years now, about 10% of the PD patients are offered a surgical option to help
reduce symptoms called deep brain stimulation of the subthalamic nucleus (STN-DBS). It is
recognised as an efficient mean to alleviate some of the major symptoms of PD patients, in
particular for motor symptoms such as akinesia, tremor or bradykinesia but not only. It was also
reported to have some benefits on apathy and on the patient’s quality of life (Czernecki, V.et al.,
2005 for example).
However, the effects of STN-DBS on gait and balance disorders, FOG and falls are varied among
patients. In a large retrospective study performed on 383 PD patients operated with STN-DBS in the
Salpêtrière Hospital, it was found that about a third of patients developed or aggravated their FOG
and/or fall frequencies in the year following surgery (Karachi et al., 2019). In this study,
postoperative FOG was found to be correlated with the existence of preoperative FOG without
dopaminergic medication. No clear preoperative factor has so far been found to be a good predictor
with postoperative falls after surgery.
In an open label study performed on 40 PD patients, multiple-source current steering, also called
“directional” DBS induced a 64% reduction in motor disability one year after surgery, with a 62%
decrease in the dopaminergic treatment and significant improvement in activities of daily living and
quality of life, with no serious adverse event related to stimulation (Timmermann, Jain et al., 2015).
In a randomized controlled trial comparing directional versus single-ring STN DBS for short-term DBS,
stimulation in the individual best direction resulted in significantly larger therapeutic windows,
higher side-effects threshold, and more improvement in hand movements than single-ring DBS
(Dembek et al., 2017).
Some authors pointed out that demographic factors, disease duration, in particular old age, or the
severity of gait disorders before surgery could play a role in explaining variability of axial responses
(Fasano et al., 2015). FOG is associated with perception (Almeida et al., 2010), attention (Shine et al.,
2013) among others, suggesting that its dysfunction could also be linked to connectivity deficiencies.
In particular the dysfunction of the network linking the primary motor cortex and the Mesencephalic
locomotor region (MLR) is partly responsible for Gait and balance deficits (Demain et al., 2014).
It was also shown by Ferraye et al., in 2010 that gait disorders are not improved by pharmacology.
Meanwhile, dramatic consequences of FOG and falls cannot be neglected (Bloem et al., 2004) and a
symptomatic treatment is highly desirable.
So far, three different approaches have been reported:

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 Stimulation location change: It was shown that long term, there was no disadvantage to use
STN-DBS although may be the cuneiform nucleus just dorsal to the pedunculopontine
nucleus (PPN), may be a superior target to promote gait initiation (Chang et al., 2021)
 Stimulation frequency change: It was shown that there was no benefit in terms of gait in
using 60 Hz rather than the common 130 Hz (Phibbs et al., 2014). However, it was also
shown that decreasing DBS stimulating frequency to 80 Hz could reverse cognitive
interference during gait initiation in PD (Varriale et al., 2018)
 Sweet spot locations: Lately some study suggests some “sweet spot” which could be used
with directional electrodes in the STN in order to reduce PD motor symptoms (Dembek et
al., 2019). Karachi et al. in 2019, also reported that in the 383 patient retrospective study a
“sweet spot” for improving FOG was located in the centre of the STN, just beyond the
posterior sensorimotor part of the nucleus. Moreover, a retrospective machine learning
study has also tried to find “hot” and “cold” spots in relation to four of the major PD
symptoms using a retrospective study of 275 patients and is suggested that STN may be the
correct target in term of gait (Boutet et al., 2021). Lastly, in a recent prospective study
(Temiz et al, 2022), it was also found that lower FOG severity after surgery correlated with
higher recruitment of sensorimotor cortico-subthalamic fibres in STN-DBS.

2 Objectives and approaches

The objective of this study is to test the effects of directional “hotspot FOG” STN-DBS in 30 PD
patients in a prospective randomized controlled study, relative to sensorimotor, and single-ring
STN-DBS. Patients will be assessed before and after surgery with STN-DBS using validated clinical
scales and gait recordings. The goal is also to identify preoperative kinetics biomarkers that could be
related to the best postoperative outcome for FOG and falls including all patients assessed before
and after surgery in the Brain institute for gait recordings (n=40 patients)

3 Materials and methods

3.1 Patients
In this study, we plan to include 30 people with PD candidate to deep brain stimulation of the
subthalamic nucleus.

3.1.1 Inclusion criteria:

Patient should:
 Be between 18 and 70 years old
 Be diagnosed with PD; as defined by the United Kingdom Parkinson’s Disease Society Brain
Bank (UKPDSBB) criteria

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 Be eligible to subthalamic bilateral deep brain stimulation (STN-DBS) according to local

inclusion criteria
 Have freezing of gait in the OFF dopa condition with falls (item 2.13 of the MDS-UPDRS > 0)
in usual life
 Have read and understood the information letter and signed the Informed Consent Form
 Be affiliated with, or beneficiary of a social security category
 Have no other medical disorder involving stability or no research protocol interference
 If female of childbearing potential, have had an effective contraception according to WHO
definition (oestrogen-progestin or intrauterine device or tubal ligation) for at least 3 months
(negative urinary pregnancy test at inclusion).

3.1.2 Exclusion criteria:

Patient should not:
 Have an actual and severe psychiatric pathology or other neurological disorder (Dementia
with MMS <24/30)
 Have a contraindication to research MRI (without contrast product)
 Have a contraindication to surgery: hemostasis trouble, anticoagulants or antiagregants
treatments, ongoing infection
 Be hypersensitive to contrast agents
 Be under guardianship, tutorship or any other administrative or judicial measure of
deprivation of rights and liberty
 Be participating at the time of exclusion in any other biomedical research or therapeutic trial
 If female, be pregnant or parturient or lactating woman or for women of childbearing age,
have a lack of proven and effective contraception according to WHO definition (oestrogen-
progestin or intra-uterine device or tubal ligation).

3.2 Methods
3.2.1 Proposed Design of the study
Here, we propose to analyse the gait kinetics as well as the kinematic parameters recorded before
and after surgery with both single ring and directional STN-DBS in two prospective research
programs.
3.2.2 Description of the randomization and blinding procedure
Single-ring stimulation parameters as well as current settings will be chosen and applied by the
neurologist, in line with the location of the electrode visualised on the basal ganglia atlas.
The STN-DBS stimulation order will be randomized and assessments will be performed blinded from
the stimulation condition, so as to be totally independent from each other. The effects of STN-DBS
on gait recordings will be assessed 20 patients with an additional 10 PD patients recorded with single
ring STN-DBS.
Conditions are as follows: 1. Single ring DBS
2. Gait ‘hot spot’ current shaping
3. Dorsal STN

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4. Ventral STN
5. Narrow fibre tracts.

The assessments will be performed in the mornings of two consecutive days. First chronic STN DBS
will be stopped for 30 minutes before the start of the session. Each DBS condition will be maintained
for at least 30 minutes before being assessed. One investigator will perform DBS programming and
one investigator will perform the clinical and gait recordings independently of each other so the
blind conditions are assured.

3.3 Material used

3.3.1 Electrodes
Boston Scientific Neuromodulation (BSN) Vercise TM System
The VERCISE deep brain stimulation is a CE marked system used in standard care in the destination
of CE marking (see Figure 1).

Figure 1: The VERCISE Deep Brain Stimulation system includes a stimulator and two 4-contact pacing electrodes.
3.3.2 Stimulator
The stimulator VERCISE allows the delivery of a constant electric current with the following
characteristics: Amplitude: 0.1-20 mA; Frequency: 2-255 Hz; Pulse duration: 20-450 μs.
3.3.3 Local potential fields
The stimulation electrodes will also collect neuronal activities in local potential fields, using 4
platinum-iridium cylindrical contacts.
3.3.4 Force platform
The force platform AMTI (0.8x1.2 m) allows to record forces and moments in the 3 anteroposterior,
mediolateral and vertical axes (Figure 2).
The VICON system allows to record displacements or markers positioned on the body joints and
reconstructed full body movements in 3D.

Figure 2: AMTI Platform

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3.4 Procedure

3.4.1 (M0): Inclusion visit

 Signing of the information and consent form after verification of inclusion and non-inclusion
criteria
 General physical exam
 Urinary Pregnancy test (when required)
 Cerebral MRI at 3 Tesla (CENIR platform, ICM) including 3D-T1, 3D-T2 and multi-shells
diffusion sequences for all patients.
3.4.2 (M1): at 15 days
 Surgery for STN-DBS electrodes implantation
 Placement of stimulation electrodes according to the usual procedure, including a MRI with
contrast product
 Intraoperative electrophysiological recordings
 Intraoperative clinical evaluation
 Intraoperative identification of the electrodes and final position with X-Ray
 Post-operative 3D helical TDM without iode injection
 STN-LFP recordings during gait initiation performed 3 to 5 days after surgery
 Placement of the neurostimulator (5 days after surgery)
 Acute testing of STN-DBS for first parameters setting programming
 Follow-up of the patient with outpatient visits as usually performed in PD patients operated
for STN-DBS with progressive adaptation of parameters settings using single-ring stimulation.
3.4.3 (M7): Evaluation of the effects of directional and single ring STN-DBS on gait
 Patients will be hospitalized for 48 hours in the neurosurgery or neurology departments to
test the effects of STN-DBS
 Three directional stimulation settings (gait “hotspot”, motor STN, ventral STN and fibre tract)
and one single ring stimulation setting per electrode will be defined according to anatomic
localisation of implanted electrodes
 The STN-DBS will be stopped for at least 30 minutes with patients having stopped their
antiparkinsonian treatment for at least 12 hours
 The 4 stimulation conditions will be tested in a randomized order with double-blind
assessments
 The effects of each stimulation condition will be tested after at least 30 minutes of continuous
stimulation and will include a
 Clinical assessment with MDS-UPDRS part III, Gait and balance scale, Stand-walk sit test and
 A neurophysiological assessment of gait initiation with and without cognitive interference
task, using force platform, motion capture and EMG recordings.
3.4.4 (M8): Evaluation of the effects of directional STN-DBS on gait
 The effects of chronic directional STN-DBS will be tested in the morning without
antiparkinsonian treatment for at least 12 hours
 Clinical assessment with MDS-UPDRS part III, Gait and balance scale, Stand-walk sit test and
 A neurophysiological assessment of gait initiation with and without cognitive interference
task, using force platform, motion capture and EMG recordings.
3.4.5 (M13): Evaluation of the effects of STN-DBS on gait
 The effects of chronic directional STN-DBS will be tested in the morning without
antiparkinsonian treatment for at least 12 hours

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 Clinical assessment with MDS-UPDRS part III, Gait and balance scale, Stand-walk sit test and
 A neurophysiological assessment of gait initiation with and without cognitive interference
task, using force platform, motion capture and EMG recordings.
3.5 Description of the research procedures
3.5.1 Collection of electrode data
One to five days after surgery, local field potentials recordings of the STN (LFP-STN) will be
performed during gait initiation task using the implanted electrodes, externalised and connected to
an EEG recording system (Figure 3).

Figure 3: example of local potential recordings

The signal collected is the potential difference between two electrode pads (0-1, 1-2, 2-3, 3-4, 4-5, 5-
6 and 6-7). For these recordings, the extensions will be connected to the amplifier. The amplifier
used for recording brain activity in local potential has been specifically designed to collect signals, so
no electric current can be emitted and will communicate with the wireless acquisition software.
3.5.2 Gait recording system
The acquisition of neurophysiologic gait parameters will be achieved through the use of a Vicon®
system, surface EMG electrodes and a force platform AMTI. Markers will be positioned on different
member segments, and will be recognized by a camera on the wall. A 3D movement analysis
reconstruction will be performed. The neurophysiologic gait parameter acquisition will be done in
presence of the investigator so as to prevent fall occurrences. If needed, a safety harness could be
used.
The force platform will be in the ground, the subject will be on bare feet. It will record the centre of
gravity acceleration and will also be able to measure ground reaction forces and moments in 3-D.
From the curves obtained, displacement and speed of the anteroposterior centre of the foot will be
deducted as well as its centre of gravity vertical velocity.
EMG activities of the lower muscles are recorded simultaneously using Cometa Wave wireless
system. The electrodes will be placed according to the recommendations of the SENIAM project
(Surface Electromyography for Non-Invasive Assessment of Muscle, SENIAM 5). For each muscle, the
motor points are identified and the electrodes will be positioned on each studied muscle. The
reference electrode will be placed on the right wrist. The correct positioning of the electrodes will be
verified in real time (See Figure 4).

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Figure 4: Measuring freezing with a force platform. The force platform is in the ground, the subject is bare feet. Here the
ground reaction force is shown in 3-D.

3.5.3 Magnetic Resonance Imaging study

All patients will be scanned on the Siemens 3-Tesla Prisma MRI located in the CENIR facilities of the
Brain and Spine Institute, before STN DBS surgery. Contrast product will not be required for this MRI.
Anatomical MR imaging will consist in a 3D T1-weighted image and T2*-weighted images. We will
also acquire a 3D T2-weighted image providing interesting contrasts at the level of the STN.
Some diffusion images will also be collected.

4 Expected results
One of the expected outcomes of this study is that the main contribution to the principal
components analysis (PCA) realised to explain the variations during two different conditions, i.e. the
Euclidean distance, would significantly change during gait initiation depending on what conditions
are being assessed.
In a previous study performed in ICM Paris, it was found that PD patients had significant changes
during gait initiation with an increased Euclidean distance contribution to PCA compared to average
controls scores (Figure 5 A). It was also noted that this Euclidean distance significantly decreased
during simple gait initiation with both levodopa treatment (ON-dopa) and STN-DBS compared to the
condition without treatment (OFF-dopa) (Figure 5 B). When gait initiation was coupled with
cognitive loading, a significant increase in the Euclidian distance contribution to PCA was observed
with STN-DBS. This was not the case in the OFF and ON-dopa conditions.
Another expected outcome of this study is that single ring stimulation will increase this Euclidian
distance during the cognitive loading task whereas directional “Gait hot spot” will induce a
significant decrease.

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It is also hypothesised that directional “gait hot spot” DBS will have a better effect on gait relative to
“STN motor spot” DBS. In line with some previous data (Karachi et al., 2019), a difference of 0.7
between these two STN-DBS conditions is expected. “Gait hot spot” is also expected to have a better
effect compared to the “STN motor-dorsal part” condition with a difference of 0.35 between those
two STN-DBS conditions. Assuming these values are verified, a sample of 19 patients will be
sufficient to prove this hypothesis with a power of 80% (alpha=5%, Mann Whitney Wilcoxon Test).

Figure 5: A) Results of Principal Component analysis: Component accounting for more than 11.1% of the total variance (i.e.
Kaiser Criteria, blue line) were kept as representative components, with 3 main contributions representing 68.3% of total variance.
B) The Euclidian distance is significantly decreased during simple gait initiation with both levodopa treatment (ON-dopa)
and STN-DBS compared to the condition without treatment (OFF-dopa)
C) When gait initiation was coupled with cognitive loading, a significant increase in the Euclidian distance contribution to
PCA was observed with STN-DBS. This was not the case in the OFF and ON-dopa conditions

If time permits, some further analysis of MRI and local field potentials data collected during the
study will be realised.

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5 References
1. Almeida, Q. J. and C. A. Lebold (2010). "Freezing of gait in Parkinson's disease: a perceptual cause for a motor
impairment?" J Neurol Neurosurg Psychiatry 81(5): 513-518.
2. Bloem, B. R., J. M. Hausdorff, J. E. Visser and N. Giladi (2004). "Falls and freezing of gait in Parkinson's disease: a review of
two interconnected, episodic phenomena." Mov Disord 19(8): 871-884.
3. Boutet A, Germann J, Gwun D, Loh A, Elias GJB, Neudorfer C, Paff M, Horn A, Kuhn AA, Munhoz RP, Kalia SK, Hodaie M,
Kucharczyk W, Fasano A, Lozano AM. Sign-specific stimulation 'hot' and 'cold' spots in Parkinson's disease validated with
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deficits correlate with the severity of freezing of gait in Parkinson's disease." Parkinsonism Relat Disord 19(3): 388-390.
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C., Welter M.L., “Freezing of gait depends on cortico-subthalamic network recruitment following STN-DBS in PD
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