Clinical Study
Stereotact Funct Neurosurg 2017;95:79–85
DOI: 10.1159/000452674
Intraoperative Thresholds for Capsular
Stimulation Are Reliable for Chronic Pallidal Deep
Brain Stimulation in Dystonia
René Reese a, c Martin M. Reich c Daniela Falk b Günther Deuschl a
H. Maximilian Mehdorn b Jens Volkmann a, c
Departments of a Neurology and b Neurosurgery, University Hospital Schleswig-Holstein, Kiel, and c Department of
Neurology, University Hospital Würzburg, Würzburg, Germany
Keywords
Dystonia · Pallidum · Deep brain stimulation · Anaesthesia ·
Capsular stimulation
Abstract
Background: The threshold current for inducing muscle
contractions by stimulation of pyramidal tract fibres ad-
jacent to the globus pallidus internus (GPi) is, besides mi-
croelectrode recordings for the determination of nuclear
boundaries, currently the only neurophysiological marker
for intraoperative refinement of the anatomically planned
target point for pallidal deep brain stimulation (GPi-DBS) in
dystonia. Objectives: To determine the relationship be-
tween intraoperative thresholds for muscle contractions
under general anaesthesia and postoperative thresholds
in GPi-DBS. Methods: Intraoperatively, current amplitude
thresholds (120 μs, 130 Hz) were determined in 6 dystonic
patients under general anaesthesia (through the uninsulat-
ed tip of the microelectrode guide tube). Postoperative lo-
calization of chronic stimulation electrodes by MRI and im-
age fusion with the stereotactic planning determined the
stimulation contact for comparing thresholds with intraop-
erative values. Results: Current thresholds were 3.3 ± 0.8 mA
intraoperatively (follow-up 0, FU0; n = 12), 2.9 ± 1.2 mA with-
© 2017 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/sfn
Received: December 2, 2015
Accepted after revision: October 18, 2016
Published online: February 16, 2017
in 1 week after surgery (FU1; n = 12), and 3.5 ± 1.6 mA after
6–17 months (FU2; n = 8). FU0 and FU1 differed by trend, and
FU1 and FU2 were significantly different (Friedman test, p =
0.0048; post hoc Dunn multiple comparison test, p < 0.05).
FU0 and FU2 were not different. Discussion: The threshold
amplitude to induce tonic muscular contractions may con-
stitute a valid approach of functionally refining the anatom-
ically guided electrode placement in GPi-DBS for dystonia,
because intraoperative values are predictive for postopera-
tive thresholds with the chronically implanted neurostimu-
lation system. © 2017 S. Karger AG, Basel
Introduction
Deep brain stimulation of the globus pallidus internus
(GPi-DBS) is remarkably effective in the treatment of pri-
mary dystonias [1–6], but the optimal target area within
the GPi is a matter of debate. Kinaesthetic cells can be
found within the central, posterior, and ventral portion of
the medial GPi [7–10], and electrical stimulation within
this subregion of the GPi has been shown to alleviate dys-
tonia. According to technical restrictions of the surgical
procedure and due to patients’ inability to lay quiet and
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Prof. Dr. Jens Volkmann
Freie Universität Berlin
Department of Neurology, University Hospital Würzburg
Josef-Schneider-Strasse 11
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DE–97080 Würzburg, (Germany)
E-Mail volkmann_j @ ukw.de
relaxed for several hours, the whole surgical procedure is
usually performed under general anaesthesia. The impact
of anaesthesia on the intraoperative neurophysiological
readings is unknown, and verification of the anatomical-
ly planned GPi target remains difficult in contrast to
awake DBS surgery for Parkinson disease. The individual
distance of the stimulation electrode to the internal cap-
sule, which forms the medial and posterior border of the
GPi, is crucial for the postoperative therapeutic window
of DBS. Guiding techniques such as microelectrode re-
cordings or intraoperative MRI provide only indirect in-
formation about the stimulation parameters which can
safely be applied at a certain target without inducing side
effects. Tonic muscle contractions due to current spread
to the internal capsule do not habituate over time and
may limit the clinically tolerated current levels necessary
to control dystonic movements.
Electrode locations allowing current intensities of 3–4
mA (pulse width 90–120 μs, frequency 130 Hz) without
inducing visible contractions are empirically accepted
[11]. On the other hand, higher thresholds may suggest a
lateral or anterior deviation of the electrode from the pre-
sumed optimal GPi target (away from the internal cap-
sule), which could also result in a less potent antidyston-
ic effect of chronic stimulation. Our implantation tech-
niques for GPi-DBS in dystonia patients encompass
intraoperative microstimulation for estimating the thera-
peutic window for chronic DBS [11, 12]. The influence of
anaesthesia on thresholds for the induction of side effects
by DBS has not been investigated. We here evaluate
whether intraoperative thresholds for capsular stimula-
tion determined under general anaesthesia could predict
thresholds in dystonia patients chronically stimulated in
the GPi.
Patients and Methods
The study was carried out in 6 consecutively operated patients
suffering from severe primary dystonia (for demographics, see Ta-
ble 1). The study was approved by the local ethics committee (pro-
tocol approval A170/08), and all patients provided written in-
formed consent for participation in the study and publication of
their data. Primary dystonia was diagnosed by a movement disor-
der neurologist (G.D. or J.V.), and GPi-DBS was indicated accord-
ing to a multidisciplinary board (H.M.M., G.D., and J.V.).
Anaesthesia
Patients were premedicated with midazolam (7.5 mg, oral ap-
plication) 60–90 min prior to the expected anaesthesia induction
time. Anaesthesia was then induced and maintained by continu-
ous intravenous infusion of remifentanil (0.3–0.5 μg/kg body
weight) and propofol (2–5 mg/kg body weight). Muscle relaxation
80 Stereotact Funct Neurosurg 2017;95:79–85
DOI: 10.1159/000452674
was achieved by a single shot of rocuronium (0.6mg/kg body
weight) to facilitate endotracheal intubation. General anaesthesia
was tapered in dosage to the level of tolerance of the endotracheal
tube during all neurophysiological tests.
Surgery
All technical details of the whole procedure have been de-
scribed elsewhere [11, 12]. We used a combined targeting strategy
which starts with standard stereotactic coordinates followed by an
anatomical refinement according to the visualization of the target
structures in the individual stereotactic MRI. The initial stereotac-
tic coordinates were 20 mm lateral to the midline and 3 mm ante-
rior and 2 mm below the mid-commissural point. These parame-
ters were adjusted to the individual stereotactic MRI (Achieva 1.5
T; Philips, Best, The Netherlands) using a PC-based planning soft-
ware (iPlan, version 1.1; Feldkirchen, Germany). Up to 5 parallel
rigid cannulas were introduced at about 10 mm above target to
guide microelectrodes for recordings within the GPi target region
(FHC Inc., Bowdoin, ME, USA). After electrophysiological deter-
mination of the nuclear boundaries, microelectrodes were drawn
back into the guiding cannulas, and the latter were then lowered
onto target position. The current threshold for tonic muscle con-
tractions due to the stimulation of fibres of the internal capsule
surrounding the GPi was determined at the stereotaxically planned
target point in all available trajectories via the uninsulated tip of
the introduced guiding cannulas (Medtronic LeadPoint® system;
frequency 130 Hz, pulse width 120 μs) and in the case of unsatis-
factory thresholds also below or above the intended target. Thresh-
olds between 3 and 5 mA were accepted, and a quadripolar elec-
trode was implanted (model 3389; Medtronic). The final electrode
position was confirmed by intraoperative X-ray and a postopera-
tive MRI scan. Individual visualization of the electrode within the
GPi was achieved by merging pre- and postoperative MRI scans
using a specialized software (SureTune®; Sapiens Medtronic Inc.).
Postoperative Programming of DBS
Programming of the neurostimulator was initially done 4–5
days after surgery, after a monopolar review had been done of all
contacts of the quadripolar electrode for each hemisphere separate-
ly (case served as anode; constant voltage mode, pulse width 90–120
μs, frequency 130 Hz). The implanted pulse generator (Activa PC;
Medtronic) is provided with 2 different stimulation modes: voltage
constant and current constant. In the latter, current amplitude is
programmed and the required voltage is adapted by the system, de-
pendent on tissue impedance according to Ohm’s law. Constant
voltage mode means that voltage amplitude is programmed and the
resulting current may change over time depending on tissue imped-
ance. If apparent, acute clinical improvement and voltage-limiting
side effects were recorded. For chronic stimulation, the most ven-
tral contact within the GPi with an acceptable adverse event thresh-
old (typically approx. 3–4 V) was chosen and programmed with a
voltage at 10–20% below the threshold for side effects.
Thresholds for Capsular Stimulation
To compare intra- and postoperative thresholds for capsular
side effects we could examine all 6 patients at 4–5 days after surgery
(follow-up 1, FU1) and 4 patients also at 6–17 months (FU2) after
surgery.
Postoperatively, individual positions of the chronic stimulation
electrodes were determined by MRI. Image fusion with the preop-
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Freie Universität Berlin
Volkmann
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Table 1. Demographic data of the patients, ratings of dystonia severity, and stimulation parameters at long-term follow-up

Pa- Age, Disease Diagnosis Insufficient Preoperative Postoperative Implanted Follow-up, BFMDRS Stimulation
tient/ years duration, medical trials medication medication device months (pre/ parameters
sex years follow-up) (Contact settings,
voltage, pulse
duration/frequency)

1/F 40 10 cervical botulinum toxin A/B, botulinum none Kinetra 17 6/2 GPi left: C+9- 3.0 V,
dystonia trihexyphenidyl, toxin A/B, 90 μs/130 Hz
levodopa levodopa, GPi right: C+1- 3.2
trihexyphenidyl V, 90 μs/130 Hz
2/M 57 37 dystonic propranolol, none none PC 9 4/2 GPi left: C+8- 2.8 V,
head primidon, 90 μs/130 Hz
tremor trihxyphenidyl, GPi right: C+1- 2.3
botulinum toxin A/B V, 90μs/130Hz
3/M 50 42 segmental beta-blocker, dantrolene, clonazepam PC 8 14/3 GPi left: C+9- 3.0 V,
dystonia trihexyphenidyl, clonazepam 120 μs/130 Hz
levodopa GPi right: C+1- 3.0
V, 120 μs/130 Hz
4/M 68 11 Cervical tetrabenazin, none none PC 6 8/4 GPi left: C+8- 4.0 V,
dystonia botulinum toxin A/B 120 μs/130 Hz
GPi right: C+0- 4.0
V, 120 μs/130 Hz
5/F 66 4 Meige botulinum toxin A/B, clonazepam n.a. PC n.a. 19/n. a. n.a.
syndrome tetrabenazin,
clonazepam, tiaprid,
sulpirid, biperiden
6/F 57 5 Meige botulinum toxin A/B, clonazepam n.a. PC n.a. 9/n.a. n.a.
syndrome clonazepam,
trihexyphenidyl,
levetiracetam,
tetrabenazin, doxepin

Age indicates age at surgery. Implanted devices were from Medtronic. n.a., not applicable; C, case.

erative stereotactic planning MRI was done to define the stimula-
tion contact of the chronic stimulation electrode which was nearest
the anatomical target. The latter was thought to best reflect the in-
traoperatively stimulated target, which could not be determined
directly as we did not use intraoperative MR or CT imaging. We
performed a monopolar constant current stimulation in patients
2–6 (case served as anode; pulse width 120 μs, frequency 130 Hz).
In patient 1 we had to use constant voltage stimulation because of
hardware restrictions (Kinetra; Medtronic) and calculated the cur-
rent according to Ohm’s law after reviewing the impedance. The
threshold was defined similarly to the intraoperative assessment by
the lowest current to induce clinically visible muscle contractions.
The parameters current amplitude, pulse width, and stimula-
tion frequency applied by the impulse generator for DBS define a
certain volume of tissue, in which action potentials may be initi-
ated by electrical stimulation through the implanted electrode.
This volume is called “VTA” (volume of tissue activated). We used
a computer model to display the estimated VTA within the indi-
vidual GPi of each patient (SureTune software; Sapiens Medtronic
Inc.). This software tool assesses the position of the electrode for
chronic GPi-DBS within the patient-specific MRI space by merg-
ing pre- and postoperative MRI scans [13].
Motor Assessment
Motor impairments were video documented in each patient ac-
cording to the Burke-Fahn-Marsden dystonia rating scale (BFM-
DRS) and rated retrospectively by a movement disorders neurolo-
gist (R.R.) for the time points FU0 (preoperative assessments; all
patients) and FU2 (patients 1–4).
Statistics
We compared the intraoperatively determined thresholds for
capsular side effects to FU1 and FU2. For statistical testing we per-
formed non-parametrical tests: Wilcoxon matched-pairs signed-
rank test (FU0 vs. FU1; n = 12) or Friedman test with post hoc
Dunn multiple comparison test (FU0 vs. FU1 vs. FU2; n = 8). Lin-
ear regression was done to evaluate whether the intraoperative
thresholds may predict postoperative measures (FU0 vs. FU1, n =
12; FU1 vs. FU2, n = 8). In addition, we assessed the clinical out-
come of the patients comparing the BFMDRS preoperatively to
FU2 under continuous bilateral GPi-DBS. All data are shown as
mean ± standard deviation. Statistical analysis and graph creation
was achieved with GraphPad Prism® software (version 5.04;
GraphPad software, Inc., San Diego, CA, USA). A probability lev-
el of p < 0.05 was estimated to be significant.
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Capsular Thresholds of Pallidal Stereotact Funct Neurosurg 2017;95:79–85 81

Freie Universität Berlin

Stimulation in Dystonia DOI: 10.1159/000452674

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 8 8
R2 = 0.82

Capsular thresholds at FU1, mA

6 6
Threshold, mA

4 4

2 2

0 0
Intraoperatively Postoperatively 0 2 4 6
a b Capsular thresholds at FU0, mA

8 8
*
R2 = 0.85

Capsular thresholds at FU2, mA

6 6
Threshold, mA

4 4

2 2

0 0
Intraoperatively Postoperatively Follow-up 0 2 4 6
c d Capsular thresholds at FU0, mA

Fig. 1. Course of individual thresholds for capsular side effects. and FU1. c Bihemispheric thresholds intraoperatively, a few days
a Bihemispheric thresholds intraoperatively and a few days postop- postoperatively, and at long-term follow-up in 4 patients (n = 8;
eratively in all patients (n = 12; p = 0.056, Wilcoxon matched-pairs Friedman test, p = 0.0048; post hoc Dunn multiple comparison test,
signed-rank test). b Linear regression of capsular thresholds at FU0 p < 0.05). d Linear regression of capsular thresholds at FU1 and FU2.

Results term follow-up there were significantly lower thresholds

We initially included 6 consecutive patients in the
study, but only 4 of them could be followed up in the long
term.
Thresholds for Capsular Side Effects
The mean stimulation thresholds for inducing tonic
muscle contractions were 3.3 ± 0.8 mA intraoperatively
(n = 12, both brain hemispheres were separately assessed),
2.9 ± 1.2 mA (n = 12) at FU1, and 3.5 ± 1.6 mA (n = 8) at
FU2 (Fig. 1a, b). There was a trend for a lower threshold
at FU1 compared to FU0 (p = 0.056, Wilcoxon matched-
pairs signed-rank test). Among patients who had a long-
at FU1 compared to FU2: Friedman test, p = 0.0048 (FU0
vs. FU1 vs. FU2), post hoc Dunn multiple comparison
test, p < 0.05 (FU1 vs. FU2). Linear regression showed
intraoperative thresholds predictive for postoperative
thresholds at both FU1 (R2 = 0.82, p < 0.0001; n = 12) and
FU2 (R2 = 0.85, p = 0.01; n = 8). Individual stimulation
thresholds at each time of assessment and the respective
somatotopies are listed in Table 2. Additionally, the VTA
due to parameters for chronic stimulation and at the
threshold for capsular stimulation (FU2) are visualized
for each patient in Figure 2. An axonal diameter of 2 μm
was chosen to model the VTA for activating axons of the
internal capsule [14].
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DOI: 10.1159/000452674 Volkmann

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 Color version available online
Fig. 2. Individual VTA for chronic stimula-
tion parameters (green cloud) and at the
threshold for capsular stimulation at FU2
(red cloud). VTA were modelled with pre-
dictions for axons with a diameter of 2 μm.
The corresponding MRI plane is on the lev-
el of the active contact for chronic stimula-
tion at FU2.

Table 2. Individual thresholds for tonic muscle contractions and somatotopy by pallidal stimulation during surgery (FU0), a few days
postoperatively (FU1), and at long-term follow-up (FU2)

Patient/ FU0 FU1 FU2

sex
hemisphere threshold, topography hemisphere threshold, topography hemisphere threshold, topography
mA mA mA

1/F left 3.3 hand left 2.4 face left 2.5 face/hand
right 2.8 tongue right 2.3 face/hand right 2.6 face/hand
2/M left 2.7 hand/tongue left 1.7 face left 2.2 face/hand
right 2.3 hand right 1.8 face/hand right 2.3 face/hand
3/M left 2.6 finger left 2.2 face/hand left 3.5 face/hand
right 3.2 lip/tongue right 2.7 face right 3.5 hand
4/M left 5.3 lower jaw left 6.0 hand left 7.0 hand/dysarthria
right 3.7 tongue/ right 2.5 hand/ right 4.0 hand
lower jaw dysarthria
5/F left 2.8 lower jaw left 3.2 face left n.a. n.a.
right 2.9 lower jaw right 2.0 face right
6/F left 3.5 tongue/jaw left 3.6 tongue left n.a. n.a.
right 4.0 eyelid right 4.0 eyelid right

Threshold: 120 μs/130 Hz. n.a., not applicable.

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Capsular Thresholds of Pallidal Stereotact Funct Neurosurg 2017;95:79–85 83

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Stimulation in Dystonia DOI: 10.1159/000452674

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 Clinical Efficacy
We could assess dystonia severity in all patients with
the BFMDRS prior to surgery and at FU2 (stimulation
on) in patients 1–4. Higher scores in the BFMDRS reflect
more severe dystonia, and every BFMDRS subitem rep-
resents a distinct body region: face (subitems A, B, C;
eyes, mouth, speak/swallow); body axis (D, G; neck,
trunk); upper extremities (E, F); lower extremities (H, I).
The individual score of each subitem is the product of a
provocation factor, the severity factor (each weighted
from 0 to 4), and a weighting factor (0.5: items A, B, D;
1.0: items C, E, F, G, H, I). Mean improvement was 66%
in BFMDRS (2.75 ± 0.96 compared to baseline 8.0 ± 4.3).
Individual ratings are listed in Table 1.
All 6 patients in this study showed a relevant reduction
of dystonia. In a prospective study, there was a great vari-
ability in clinical response to GPi-DBS in dystonia, rang-
ing from less than 25% to more than 75% [4], and there
was also a risk of treatment failure in about 25% of the
cases (defined as less than 25% improvement). The rea-
son, especially for the latter, is unknown but is probably
a combination of multiple factors (disease heterogeneity,
lead placement, and programming issues).
Adverse Events
The surgical procedure was well tolerated in all cases.
No relevant stimulation-induced side effects were report-
ed in the long term except for 1 patient. Within weeks
under continuous GPi-DBS and paralleled by a markedly
reduced cervical dystonia, patient 5 developed a Parkin-
sonian syndrome including bradykinesia, rigidity, hand
tremor, and severe freezing of gait, which we found to be
neurostimulation related. The full clinical details of this
case have been published elsewhere [15].
Discussion
The intraoperatively determined threshold for tetanic
muscle contractions closely matched the thresholds de-
termined with the chronically implanted DBS device in
the long-term follow-up of this study (Fig.  1b). Hence,
intraoperative stimulation proved to be a useful marker
for refining the electrode position with respect to the
therapeutic window of chronic neurostimulation.
Several factors may influence efficacy and adverse
event thresholds of acute intraoperative neurostimula-
tion compared to chronic DBS. A parenchymal micro-
trauma due to the insertion of the electrodes may change
tissue impedance. Due to current-constant stimulation
84 Stereotact Funct Neurosurg 2017;95:79–85
DOI: 10.1159/000452674
(or calculation of the resulting current applied) this factor
should be negligible as should be the impedance of the
electrodes used for stimulation.
Anaesthesia was maintained by propofol and remifen-
tanil in this study. The sedative effect of propofol has been
attributed to the tubero-mammillary nucleus of the hypo-
thalamus [16], and the motor immobility effect may be
caused due to a GABAA receptor agonism at the ventral
horn of the spinal cord [17]. Studies in humans using in-
travenous bolus applications of propofol have demon-
strated a decrease in spinal F-wave amplitudes, suggest-
ing reduced excitability of spinal cord α-motoneurons
[18]. In addition to this direct pharmacological influence,
it is well known that voluntary muscular pre-innervation
facilitates motor neuron excitability as demonstrated by
motor-evoked potentials induced by transcranial mag-
netic stimulation [19]. Muscle tone and pre-innervation
were intraoperatively suppressed due to sedation, which
may explain the slightly lower postoperative thresholds
for stimulation-induced muscle contractions (see Results
and Fig.  1b). Rocuronium, inducing muscle relaxation
during intubation, should have washed out at the time of
neurophysiological testing as neurophysiological assess-
ments were done about 4 h after drug application, which
is about 8 times the clinically relevant muscle relaxation
time [20]. It is, moreover, possible that due to intraopera-
tive leakage of cerebrospinal fluid or intracranial air in-
clusion, the electrode/brain interface may have been tran-
siently impaired at the target site due to a relative move-
ment of the electrode (which is fixed to the skull) to the
brain. This may additionally contribute to the slightly re-
duced capsular thresholds a few days after surgery. Nev-
ertheless, these thresholds of GPi-DBS were almost iden-
tical to the intraoperative values in the long-term follow-
up.
Despite potentially confounding factors, we could
show that intraoperatively determined thresholds of py-
ramidal tract stimulation predict the chronic adverse
event threshold in GPi-DBS. Using the threshold ampli-
tude for evaluating the proximity of the stimulating elec-
trode to the internal capsule may, therefore, constitute a
valid approach of functionally refining the anatomically
guided electrode placement by this neurophysiological
method.
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