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Journal Pre-proof
Structural and functional correlates of subthalamic deep brain stimulation-induced
apathy in Parkinson’s disease
Lennard.I. Boon, Wouter.V. Potters, Thomas.J.C. Zoon, Odile.A. van den Heuvel,
Naomi Prent, Rob.M.A.de Bie, Maarten Bot, P.Richard Schuurman, Pepijn van den
Munckhof, Gert J. Geurtsen, Arjan Hillebrand, Cornelis.J. Stam, Anne-Fleur.van
Rootselaar, Henk.W. Berendse
PII: S1935-861X(20)30311-9
DOI: https://doi.org/10.1016/j.brs.2020.12.008
Reference: BRS 1870
To appear in: Brain Stimulation
Received Date: 25 June 2020
Revised Date: 15 November 2020
Accepted Date: 21 December 2020
Please cite this article as: Boon LI, Potters WV, Zoon TJC, van den Heuvel OA, Prent N, Bie RMAd,
Bot M, Schuurman PR, van den Munckhof P, Geurtsen GJ, Hillebrand A, Stam CJ, Rootselaar A-Fv,
Berendse HW, Structural and functional correlates of subthalamic deep brain stimulation-induced apathy
in Parkinson’s disease, Brain Stimulation, https://doi.org/10.1016/j.brs.2020.12.008.
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© 2020 The Author(s). Published by Elsevier Inc.
Lennard I. Boon: Conceptualization, methodology, software, validation, formal analysis,
investigation, data curation, writing – original draft, writing – review and editing,
visualization, project administration.
Wouter V. Potters: Conceptualization, methodology, software, validation, formal analysis,
investigation, data curation, writing – review and editing, visualization, project
administration.
Thomas J.C. Zoon: Investigation, writing – review and editing.
Odile A. van den Heuvel: Conceptualization, validation, investigation, writing – review and
editing.
Naomi Prent: Software, validation, writing – review and editing.
Rob M.A. de Bie: Conceptualization, investigation, writing – review and editing.
Maarten Bot: Investigation, writing – review and editing.
P. Richard Schuurman: Conceptualization, validation, investigation, writing – review and
editing.
Pepijn van den Munckhof: Investigation, writing – review and editing.
Gert J. Geurtsen: Investigation, writing – review and editing.
Arjan Hillebrand: Conceptualization, methodology, software, validation, investigation,
writing – review and editing, visualization.
Cornelis J. Stam: Conceptualization, methodology, software, investigation, resources, writing
– review and editing.
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Anne-Fleur van Rootselaar: Conceptualization, investigation, resources, writing – review and
editing, supervision, project administration, funding acquisition.
Henk W. Berendse: Conceptualization, investigation, resources, data curation, writing –
review and editing, supervision, project administration, funding acquisisition,
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Title
Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in
Parkinson’s disease
Authors
Lennard I. Boon MD MSc
a,b,c
, Wouter V. Potters PhD
c
, Thomas J.C. Zoon MD
d
, Odile A. van
den Heuvel MD PhD
e,f
, Naomi Prent MSc
c
, Rob M.A. de Bie MD PhD
c
, Maarten Bot MD
PhD
g
, P. Richard Schuurman MD PhD
g
, Pepijn van den Munckhof MD PhD
g
, Gert J.
Geurtsen PhD
h
, Arjan Hillebrand PhD
b
, Cornelis J. Stam MD PhD
b
, Anne-Fleur van
Rootselaar MD PhD
c
, Henk W. Berendse MD PhD
a
Affiliations
a
Amsterdam UMC, Vrije Universiteit Amsterdam, Neurology, Amsterdam Neuroscience, De
Boelelaan 1117, Amsterdam, the Netherlands
b
Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Neurophysiology and
Magnetoencephalography Centre, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam,
the Netherlands
c
Amsterdam UMC, University of Amsterdam, Neurology and Clinical Neurophysiology,
Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, the Netherlands
d
Amsterdam UMC, University of Amsterdam, Psychiatry, Amsterdam Neuroscience,
Meibergdreef 9, Amsterdam, the Netherlands
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e
Amsterdam UMC, Vrije Universiteit Amsterdam, Psychiatry, Amsterdam Neuroscience, De
Boelelaan 1117, Amsterdam, the Netherlands
f
Amsterdam UMC, Vrije Universiteit Amsterdam, Anatomy and Neurosciences, Amsterdam
Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands
g
Amsterdam UMC, University of Amsterdam, Neurosurgery, Amsterdam Neuroscience,
Meibergdreef 9, Amsterdam, the Netherlands
h
Amsterdam UMC, University of Amsterdam, Medical Psychology, Amsterdam
Neuroscience, Meibergdreef 9, Amsterdam, the Netherlands
Corresponding author
Lennard I. Boon, Amsterdam UMC, location VUmc, Neurology, Amsterdam Neuroscience,
De Boelelaan 1117, Amsterdam, the Netherlands.
E-mail: l.i.boon@amsterdamumc.nl
Declarations of interest
RDB received unrestricted research grants from Medtronic. PRS is consultant on educational
activities for Medtronic, Boston Scientific and Elekta. All other authors report no declarations
of interest.
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Abstract
Background Notwithstanding the large improvement in motor function in Parkinson’s
disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase.
Postoperative apathy cannot always be related to a dose reduction of dopaminergic
medication and stimulation itself may play a role.
Objective We studied whether apathy in DBS-treated PD patients could be a stimulation
effect.
Methods In 26 PD patients we acquired apathy scores before and >6 months after DBS of the
subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation)
were performed >6 months after DBS placement. Change in apathy severity was correlated
with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii)
stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in
functional connectivity of brain regions that have an alleged role in apathy.
Results Average apathy severity significantly increased after DBS (p<0.001) and the number
of patients considered apathetic increased from two to nine. Change in apathy severity did not
correlate with improvement in motor function or dose reduction of dopaminergic medication.
For the left hemisphere, increase in apathy was associated with a more dorsolateral
stimulation location (p=0.010). The increase in apathy severity correlated with a decrease in
alpha1 functional connectivity of the dorsolateral prefrontal cortex (p=0.006), but not with
changes of the medial orbitofrontal or the anterior cingulate cortex.
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Conclusions The present observations suggest that apathy after STN-DBS is not necessarily
related to dose reductions of dopaminergic medication, but may be an effect of the stimulation
itself. This highlights the importance of determining optimal DBS settings based on both
motor and non-motor symptoms.
Key words
Parkinson’s disease; deep brain stimulation; apathy; magnetoencephalography; functional
connectivity
Abbreviations
STN subthalamic nucleus
dlPFC dorsolateral prefrontal cortex
antCC anterior cingulate cortex
medORB medial orbitofrontal cortex
HPI head position indicator
MDS-UPDRS-III Movement Disorders Society Unified Parkinson’s Disease Rating Scale
(motor part)
tSSS temporal extension of signal space separation
AAL automated anatomical labelling
ROI region of interest
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cAEC corrected amplitude envelope correlation
ANT advanced normalization tools
MNI Montreal Neurological Institute
LEDD levodopa equivalent daily dose
NMSS non motor symptom scale
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Introduction
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for
Parkinson’s disease (PD) patients with disabling fluctuations in motor symptoms[1-3].
Despite excellent effects on motor symptoms, emotional, behavioural and cognitive
disturbances associated with STN-DBS have been reported[4-7]. Apathy is a frequently
observed symptom after STN-DBS in PD (prevalence ~25%) and is associated with a
decrease in the quality of life[8-11].
Apathy can be defined by a lack of motivation, diminished goal-directed behaviour
and decreased emotional involvement[12]. Apathy after DBS has been attributed to
mesolimbic denervation[10] and dose reductions in dopaminergic medication[13], although a
consistent correlation with the latter has not been found[10, 14, 15]. The results of a recent
animal study suggest that impaired motivation may be an effect of the brain stimulation itself
[16]. Moreover, in DBS-treated PD patients apathy scores correlated with the position of
active DBS contacts[4, 17, 18], as well as with DBS-related changes in cortical glucose
metabolism[15]. However, a study in which the functional effects of deep brain stimulation
(DBS-ON versus DBS-OFF) are related to apathy scores is currently lacking.
In the current study, we selected three bilateral brain regions that have an alleged role
in apathy: the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (antCC) and
the medial orbitofrontal cortex (medORB). Functional changes in the antCC and the medORB
appear to be related to emotional-affective apathy[10, 19], whereas functional changes in the
dlPFC are associated with cognitive apathy (mostly via executive cognitive dysfunction)[20,
21].
In a previous magnetoencephalography (MEG) study, we demonstrated that DBS has
widespread effects on oscillatory brain activity and functional connectivity and that changes
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in the latter correlate with DBS-related improvement in motor scores[22]. Based on this
observed correlation between functional connectivity changes and motor effects, we decided
to study apathy-related functional connectivity changes. Specifically, in this MEG study using
a DBS ON-OFF setup, we aimed to determine whether change in pre-to-post-DBS apathy
score correlated with (i) the dose reduction of dopaminergic medication, (ii) the stimulation
location and (iii) changes in functional connectivity of the three pre-selected bilateral cortical
brain regions. In line with a previous case-report from our group[4], we hypothesized that
postoperative apathy can be an effect of stimulation of the ventral (limbic) STN, affecting
brain regions involved in emotional-affective processing.
Materials and methods
Patients
A total of 33 PD patients who had undergone bilateral STN-DBS implantation between 2016
and 2018 at Amsterdam UMC, location AMC, participated in this study (after consecutively
approaching eligible patients) and underwent MEG recordings at least 6 months after DBS
electrode placement (range 6-17 months; median 7 months). Inclusion and exclusion criteria
were previously described[22]. In the context of standard clinical care, the stimulation
parameters were individually determined for optimal therapeutic efficacy (regarding motor
effects) and monopolar stimulation was applied. All patients were implanted with a Boston
Scientific Vercise directional stimulation system (Valencia, CA, USA). Of the 33 PD patients
included in this study, five patients were excluded from further analysis due to excessive
noise in more than ~13 MEG channels during the ON-stimulation recording, which prevented
the use of the temporal extension of Signal Space Separation (tSSS; see MEG data
preprocessing). One patient was excluded because of missing clinical data (pre-DBS apathy
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score) and one patient as a consequence of excessive tremor during the OFF-stimulation
recording. This led to a final study sample of 26 patients. The research protocol describing the
MEG, psychiatric and neuropsychological data collection was approved by the medical
ethical committee of Amsterdam UMC, location VUmc. Ethics review criteria conformed to
the Helsinki declaration. All patients gave written informed consent before participation.
Data acquisition
Study visits took place after an overnight withdrawal of dopaminergic medication (practically
defined off-state). MEG data were recorded using a 306-channel whole-head system (Elekta
Neuromag Oy, Helsinki, Finland) in an eyes-closed resting-state condition, with a sample rate
of 1250 Hz and online anti-aliasing (410 Hz) and high-pass (0.1 Hz) filters. The head position
relative to the MEG sensors was recorded continuously using the signals from five head
position indicator (HPI) coils. For each subject, the total MEG recording time was 55
minutes, consisting of 11 trials of 5 minutes. In each trial different DBS stimulation settings
were used. The first recording was during bilateral stimulation with the standard DBS-settings
of the individual patient (DBS-ON). Subsequently, nine recordings took place in randomized
order, eight of which consisted of unilateral stimulation using a single electrode contact (data
not presented) and one recording during DBS-OFF. The eleventh and last recording was,
again, performed during stimulation using the standard DBS-settings of the individual patient
(DBS-ON2; data not presented). Further details on the MEG acquisition can be found in Boon
et al.[22].
Anatomical images of the head were obtained in the context of standard pre-operative
imaging up to 6 months before surgery using a 3T magnetic resonance imaging (MRI)
scanner (Philips Ingenia, Best, the Netherlands) and a 16-channel receiver coil. We acquired
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post-gadolinium volumetric T1-weighted scans (TR 8.8–9.1ms; TE 4.0–4.2ms; flip angle
(FA) 8°; field of view (FOV) 256×256mm; slice thickness 1.0mm; 1.0×1.0mm; 169 slices)
and T2-weighted scans using a slab covering the brain from the superior cerebellar peduncle
to the top of the lateral ventricles (TR 4000.0–5233.2ms; TE 80.0–87.7ms; FA 90°; FOV
432×432/560×560mm; slice thickness 2mm; 0.5×0.5mm; 46–80 slices). For 21 patients, on
the postoperative day, a multidetector CT-scan of the head was acquired (Philips Medical
System, Best, The Netherlands; slice thickness 1–2mm; FOV 512×512mm; 56–169 slices).
For the five remaining participants, an intra-operative CT-scan was acquired using a
Medtronic O-arm O2 (high definition mode; 20 cm FOV; 192 slices; 120 kV; 150 mAs;
Medtronic Inc., Minneapolis, MN, USA).
Apathy scores reflecting the last 4 weeks[23] were obtained from the patient (helped
by the patient’s relative or caregiver, if possible) using the patient-based version of the
Starkstein apathy scale[24], both at baseline (several days before DBS placement) and after
DBS placement (several days before the study visit) with patients on medication and ON
stimulation in the standard settings of the individual patient. This validated apathy scale
ranges from 0 to 42 and patients with an apathy score >14 were considered apathetic (in line
with [24]). Hamilton Depression Scores and Hamilton Anxiety Scores[25] were also obtained
at baseline and during the study visit. Neuropsychological tests of executive functioning
(Trail Making Test A and B; Stroop Test 1-3) were performed before DBS placement and
after six months of DBS therapy by a licensed clinical neuropsychologist on medication and
ON stimulation. Motor function was scored by trained nurses using the motor part of the
Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III)
both at baseline and, approximately six months after DBS placement, during DBS-ON and
DBS-OFF, off medication.
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Data processing
MEG data
MEG channels that were malfunctioning or noisy were ignored after visual inspection of the
data. Thereafter, the temporal extension of Signal Space Separation (tSSS[26, 27]) in
MaxFilter software (Elekta Neuromag Oy, version 2.2.15) was applied with a subspace
correlation-limit of 0.8 to suppress the strong magnetic artefacts[22]. MEG data of each
patient were co-registered to their T1 MRIs using a surface-matching procedure, with an
estimated accuracy of 4mm[28]. A single sphere was fitted to the outline of the scalp as
obtained from the co-registered MRI, which was used as a volume conductor model for the
beamformer approach described below.
The automated anatomical labelling (AAL) atlas was used to label the voxels in 78
cortical and 12 subcortical regions of interest (ROIs)[29, 30]. We used each ROI’s centroid as
representative for that ROI[31]. Subsequently, an atlas-based beamforming approach[32] was
used to project broad-band (0.5-48 Hz) filtered sensor signals to these centroid voxels,
resulting in broad-band time series for each of the 90 ROIs (see Hillebrand et al.[33] for
details). The source-reconstructed MEG data were visually inspected (by LIB) for tremor-,
motion- and stimulation-related artefacts and drowsiness. The MEG data were cut into ~22
epochs per (5 minute) recording. Epochs were then downsampled from 1250 Hz to 313 Hz
(4x) and contained 4096 samples (13.12 s). For each recording, the 50% epochs with the
lowest peak frequency (estimated within the 4-13 Hz frequency range using automatic
quantification) were discarded in order to minimize the risk of including episodes with
drowsiness. For each condition, 10 epochs with the best quality (visual selection based on the
absence of artefacts and drowsiness) were selected for further analysis. Spectral and
functional connectivity analyses were performed using BrainWave (version 0.9.152.12.26;
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CJS, available from https://home.kpn.nl/stam7883/brainwave.html). For frequency band-
specific analyses, epochs were filtered in five frequency bands (delta (0.5-4 Hz), theta (4-8
Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz) and beta (13-30 Hz), using a Fast Fourier
Transform. The gamma band was not analysed as we had observed stimulation-related
artefact peaks in this band in a previous study[22]. For each epoch, frequency band-specific
functional connectivity was estimated using the corrected Amplitude Envelope Correlation
(cAEC), an implementation of the AEC[34] corrected for volume conduction/field spread,
using a symmetric (pairwise) orthogonalisation procedure[34, 35]. The cAEC was calculated
for all possible pairs of ROIs, leading to a 90x90 adjacency matrix.
Imaging data
To determine the stimulation locations after placement of the DBS system, the electrode
trajectories were reconstructed using Lead-DBS (Lead-DBS, version 2.2; http://www.lead-
dbs.org[36]). To this end, the post- or intra-operative CT-scan was co-registered to the pre-
operative MR image using a two-stage (rigid and affine) registration as implemented in
Advanced Normalization Tools (ANT[37]). In three cases in which only an intra-operative
CT-scan was available, the co-registration failed using ANT. In these cases, co-registration
was successfully performed using FSL FLIRT. Co-registration was followed by a
semiautomatic localization of the electrode positions on the CT data in patient space.
The electrode stimulation positions were then transformed from patient space to Montreal
Neurological Institute space (MNI ICBM 2009b NLIN ASYM space) to facilitate group-level
analyses. The DISTAL Minimal atlas[38] was used as outline of the STN. Next, the
midpoints of stimulation positions were projected on a vector running through the
longitudinal axis of the STN (from ventromedial to dorsolateral), leading to one scalar value
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to indicate each stimulation position, where negative values indicated more ventromedial
stimulation positions.
Statistical analysis
We tested the differences in proportion of apathetic patients (pre- versus post-DBS) using a
chi-square test, change in apathy score, MDS-UPDRS-III score, and levodopa equivalent
daily dose (LEDD)-score using paired t-tests (all pre-DBS versus post-DBS). Correlations
between the change in apathy score and change in LEDD, change in MDS-UPDRS-III score,
stimulation positions, change in depression score, change in anxiety score, and change in
executive functioning (difference in T-scores (mean of 50±10), normed by age and education)
were estimated using Pearson correlations. Next, in order to explore the possibility of
confounding variables explaining change in apathy scores, the abovementioned variables
were combined into a single hierarchical linear regression model using a backward
elimination method (in which change in apathy score functioned as dependent variable).
For each patient, stimulation condition and frequency band separately, functional
connectivity matrices were averaged over 10 epochs. Next, we obtained the average
functional connectivity between one ROI and the rest of the brain by averaging functional
connectivity values over each column of the matrix. We then calculated the change in
functional connectivity (DBS-ON versus DBS-OFF) for three pre-selected cortical brain
regions, the dlPFC (AAL-region: middle frontal gyrus, as previously used by Pretus and co-
workers[39]), antCC and medORB, and correlated these values with the change in pre-to-
post-DBS apathy score. As the functional connectivity data was not normally distributed
(despite attempts to transform the data) this was done using Spearman correlations.
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All analyses were performed using the SPSS Statistics 20.0 software package (IBM
Corporation, New York, USA), using a significance level of 0.05 (two-tailed). Bonferroni
correction was applied for the number of seed regions in the Spearman correlations between
change in apathy score and change in functional connectivity. Due to the exploratory nature of
the study, we did not correct for the number of frequency bands used for the functional
connectivity estimates.
Data availability statement
The data and codes used in this study are available from the corresponding author, upon
reasonable request.
Results
Patients
26 DBS-treated PD patients, whose characteristics are summarized in Table 1, were included
in this study. DBS significantly improved off-dopamine motor function with a mean change
of 51.2% in MDS-UPDRS-III score (t(25)=9.21; p<0.001) and the LEDD was significantly
lowered after DBS placement (t(25)=8.01; p<0.001; see Table 1). The mean number of
excluded MEG channels before running tSSS was 9 for DBS-ON recordings (range: 4-13)
and 6 for DBS-OFF recordings (range: 2-12).
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Apathy
In 24 of the 26 PD patients apathy severity increased after DBS and the number of apathetic
patients increased from 2 pre-DBS to 9 post-DBS (X
2
(1,26)=4.093, p=0.043). Apathy
severity scores were significantly higher during follow-up than at baseline (pre-DBS versus
post-DBS; t(25)=6.47, p<0.001). Increase in apathy severity did not correlate with decrease
in LEDD, neither taking all dopaminergic medication into account (p=0.157; Supplementary
Figure A.1), nor dopamine agonists alone (p=0.503; Supplementary Figure A.2). Change in
apathy severity did not correlate with improvement in motor function (MDS-UPDRS-III;
p=0.518; Supplementary Figure A.3). Change in apathy severity did also not correlate with
change in depression severity (p=0.443; Supplementary Figure B.1), change in anxiety
severity (p=0.710; Supplementary Figure B.2), nor with change in executive functioning
(p=0.693; Supplementary Figure B.3). Lastly, as a recent paper shows that motor asymmetry
can predict emotional outcome of STN-DBS [40], we compared the change in apathy score
for patients with left- and right-sided onset of motor symptoms, but there was not difference
(t(25)=0.68, p=0.501).
Apathy and DBS localization
In Figure 1A, the midpoints of the stimulation positions of all active contact points are
depicted in standard MNI space relative to an atlas representation of the STN. Increases in
apathy scores are color-coded, ranging from no increase (green/yellow) to a strong increase
(dark red) in apathy severity. There was a significant correlation between a more dorsolateral
stimulation position (along a vector) and increase in apathy severity post-DBS for the left side
(p=0.010), but not for the right side (p=0.491; Figure 1B). In contrast, there was no
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relationship between stimulation position (along the same vector) and the degree of
improvement in total motor score (UPDRS-III; Supplementary Figure E).
Next, we performed a hierarchical linear regression model using a backward elimination
method to study the relationship between stimulation location and change in apathy score,
including the following covariates: pre- to post-operative change in executive functioning,
depression score, anxiety score, LEDD total, LEDD of dopamine agonist, and motor function.
For the left side this resulted in the following model: R
2
=0.465 ; change in depression score,
β(standardized)=0.587, p=0.039; stimulation position, β(standardized)=0.727, p=0.015. For
the right side no statistically significant model could be fitted.
Apathy and functional connectivity
The three a priori selected cortical brain regions are depicted in Figure 2A. The centroid
voxel was taken as representative for each individual brain region, and its time-series was
used for the estimation of functional connectivity. A significant negative correlation was
found between the pre-to-post-DBS change in apathy score and the stimulation-related change
in functional connectivity of the bilateral dlPFC with the rest of the brain (alpha1, p=0.006;
alpha level was adjusted to 0.05/3 to correct for multiple comparisons as three seed regions
were studied; Figure 2B). A reduction in stimulation-related functional connectivity was
related to an increase in post-operative apathy. In contrast, no significant correlations were
found for the medORB (alpha1, p=0.298), as well as for the antCC (alpha1, p=0.163).
Correlations with functional connectivity in the other frequency bands can be found in Table
2.
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As a post-hoc visualization, both for patients with weaker (<5) and patients with
stronger (>5) increase in apathy severity (based on a median split of the data) we showed the
distribution of stimulation-related changes in alpha1 functional connectivity of individual
connections linked to the dlPFC (Figure 3). In line with the correlation previously shown, we
observed a stimulation-related lowering in functional connectivity in patients with a stronger
increase in apathy severity. Furthermore, stimulation-related functional connectivity changes
in both groups mostly involved connections with frontal brain regions. Functional
connectivity matrices and functional connectivity of the three seed regions (alpha1; both
DBS-OFF and DBS-ON) averaged over all subjects are provided in Supplementary Figure C
and D.
Discussion
In this study, we investigated apathy after STN-DBS treatment in patients with PD, in
particular the relationship between DBS-related increase in apathy severity and stimulation
location, as well as the association between DBS-related increase in apathy severity and
stimulation-induced changes in functional connectivity. Our results confirm the notion that
apathy severity increases after STN-DBS in PD and that the stimulation itself may play a role
in this increase[15, 17, 18]. The pre-to-post-DBS increase in apathy severity was associated
with a more dorsolateral position of the stimulation for the left hemisphere, as well as a
stimulation-related reduction in alpha1 band functional connectivity of the bilateral dlPFC
with the rest of the brain. The latter could be interpreted as a stimulation-related loss in
connectedness (functional communication) of this brain region with the rest of the brain in
patients who became apathetic.
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We found no significant correlation between the increase in pre-to-post-DBS apathy
score and the degree of reduction of dopaminergic medication in the present study.
Reintroduction of dopaminergic medication has previously been shown to improve post-
operative apathy[13] suggesting a causal role for dopamine withdrawal in the occurrence of
apathy. However, a recent animal study has demonstrated that impaired motivation caused by
deep brain stimulation itself can also be reversed by a dopamine agonist[16]. We
acknowledge that post-operative apathy is a complex and multifactorial phenomenon in which
adjustments of dosages of dopaminergic medication, degeneration of dopaminergic
neurons[41], as well as the stimulation itself may have a role.
The STN occupies a central role in several functionally different basal ganglia circuits and
comprises specific motor (dorsolateral), associative (central) and limbic (ventromedial)
regions[42, 43]. The influence of the stimulation location in or around the STN on the
occurrence of post-DBS apathy is as yet unclear. Two case-studies have described the
induction of apathy by stimulation of the zona incerta[13, 44], located dorsally from the STN,
whereas another case study demonstrated that apathy resolved by switching from a ventrally
located contact point to a more dorsal contact point[4]. By contrast, in one study cohort
(analysed in two publications[17, 18]), apathy scores (non-significantly) decreased in PD
patients after STN-DBS placement. Above-average decreases in apathy scores were related to
stimulation around the ventral border and the sensorimotor subregion of the STN and below-
average decreases were related to stimulation dorsal to the STN[17, 18]. A potential
explanation for the fact that decreases rather than increases in apathy severity were found in
the latter study is that subscores related to apathy derived from the Non Motor Symptom
Scale were used as a measure of apathy, which is not recommended for the assessment of
apathy in PD [23].
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We found a significant increase in apathy severity after STN-DBS. In addition, we
observed a significant correlation between increase in pre-to-post DBS apathy score and a
more dorsolateral stimulation location relative to the STN for the left hemisphere, but not for
the right hemisphere. As the occurrence of apathy has previously not been related to laterality
of DBS[45, 46], we refrain from drawing any conclusions from this left-right difference.
Despite the fact that dorsolateral stimulation positions in the motor part of the STN are
considered as the optimal STN target resulting in the best clinical motor effects (and hence a
stronger reduction in dopaminergic medication dose)[47, 48], increased apathy severity was
not associated with a stronger improvement of motor symptoms. In addition, we did not find a
relation between stimulation position and the degree of improvement in motor score
(Supplementary Figure E), contrasting with the results of the study by Bot and coworkers[48].
Our study differed in several aspects though, including the method of localizing the electrodes
(patient versus standard space), method of quantifying the stimulation location (vector
through the longitudinal axis of the STN versus Euclidian distance to the medial STN border),
and the motor scores used (overall UPDRS-III versus unilateral motor score).
When combining our observations with those of previous studies[13, 17, 18, 44], we
conclude that, in contradiction with the previously proposed mechanism (and our own
hypothesis)[4, 49], stimulation in the ventral part of the STN (the limbic regions) does not
necessarily induce apathy. Our findings even suggest that apathy may worsen by a stimulation
location in proximity to the motor region of the STN. Moreover, the fact that increase in
apathy severity did not correlate with improvement in motor symptoms leads us to conclude
that finding an optimal stimulation location, striking a balance between the least apathy and
the best motor response, seems feasible. Future longitudinal studies using a within-subject
design in which the stimulation in case of post-DBS apathy is switched to an alternative
(more ventral) contact point may shed further light on this matter. In addition, studies that
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take into account individual differences in the division of subregions using structural
connectivity profiles of the STN (using high-resolution MRI techniques) could guide the
search for an optimal stimulation position.
The fact that we found stimulation-related changes in functional connectivity of the dlPFC
to be associated with the pre-to-post-DBS increase in apathy severity, suggests an (executive)
cognitive substrate, rather than an emotional-affective type of apathy (which is more related
to the antCC and medORB). However, recent findings by Irmen and coworkers suggest a
structural link between DBS stimulation, the left prefrontal cortex and depressive
symptoms[50]. Moreover, in our study increases in apathy severity were not associated with
changes in executive functioning, whereas in the multiple regression model there was a
relation between improvement in depression scores and better apathy scores after surgery (in
the context of left-sided stimulation). It remains to be determined whether the occurrence of
apathy after DBS has a cognitive or emotional-affective basis.
Our results on stimulation-related changes in functional connectivity were most outspoken
for the alpha1 band (8-10 Hz). A direct functional loop of resting-state alpha band coherence
has previously been observed between the STN and the ipsilateral temporal cortex[51-53], but
not the dlPFC. This could suggest that the dlPFC is indirectly influenced by DBS via
downstream effects on the thalamus, although there may also be direct antidromic stimulation
effects via the hyperdirect pathway (albeit the latter mechanism would be more likely for the
medial prefrontal cortex than for the dlPFC[54, 55]). The complex balance between
downstream (via the thalamus) and antidromic stimulation effects (hyperdirect pathway) may
also explain the differential effects of stimulation; an increase in FC in some patients and a
decrease in FC in others.
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The present study has some limitations that need to be addressed. (i) We correlated
change in apathy severity over a time interval of >6 months with differences in functional
connectivity between ON-DBS and OFF-DBS conditions recorded on the same day.
Nevertheless, we believe that studying DBS effects (ON versus OFF) on the same day offers
the advantage of a better insight into the effect of brain stimulation itself (in which we
interpret the DBS-ON setting, and not turning off, the stimulation as the intervention), without
any bias of disease progression or change in the dose of (dopaminergic) medication over time.
The occurrence of apathy is generally assessed over a period of four weeks and can therefore
not be tested in a DBS-ON versus DBS-OFF setup[23, 24]. However, since we lacked an ON-
OFF paradigm in the apathy scores, we must be cautious in drawing conclusions on causality
beyond the observed correlation. (ii) We correlated the change in apathy scores obtained on
medication with MEG recordings recorded off medication. The off-medication state of the
subjects may have influenced the MEG signals. However, as the subjects served as their own
controls in this DBS ON-OFF setup, we expect the influence of the off-medication state on
our results to have been minimal. (iii) The correlation between the position of stimulation and
the change in apathy severity was based on the position of the stimulation sites along a vector
running through the longitudinal axis of the STN, from the ventromedial tip in a dorsolateral
direction. Although this correlation analysis does not provide information on the optimal
position of stimulation in 3D, it does give an intuitive idea of the different stimulation
positions throughout the functional subdivision of the STN. (iv) Previously, we described the
potential effects of monopolar DBS on MEG signals[22]. Despite the ability of tSSS and
beamforming to effectively suppress artefacts[56, 57], two sharp peaks remained in the power
spectrum during stimulation, at ~27 Hz and ~35 Hz. As the peaks did not appear to affect the
alpha1 band, we consider the influence of stimulation artefacts on our results to be limited.
Furthermore, the estimation of (changes in) functional connectivity may be influenced by
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modulation of the signal to noise ratio in the seed regions[58]. It is unlikely that our results
can be explained by such modulations, since there was no relation between change in absolute
alpha1 band power and change in functional connectivity in the three seed regions
(Supplementary Figure D). (v) Instead of focusing on the functional effects of stimulation in
all brain regions, we chose to select only three (literature-based) brain regions, which
prevented us from testing an abundance of other possible correlations. In addition, our MEG
analysis lacked the spatial resolution to study subcortical brain regions such as the nucleus
accumbens, which has previously been associated with apathy in PD[59]. As a consequence,
we may have missed brain regions that may be associated with the occurrence of apathy.
However, we assume that, in accordance with a previous PET-study in DBS-patients with
apathy[15] the stimulation-related change in the dlPFC specifically reflects the increased
apathy severity and does not represent a global phenomenon such as stimulation-related
vigilance affecting background alpha-activity. To verify this in a negative control brain
region, we tested whether stimulation-related changes in functional connectivity of the
bilateral inferior occipital lobe correlated with the change in apathy severity and this was not
the case (alpha1, Spearman’s ρ(24)=-0.227; p=0.265).
Important strengths of this study include the DBS ON-OFF setup taking place on the same
day. Second, the use of MEG (instead of EEG) in source-space, in combination with a
leakage-corrected connectivity measure (cAEC), offers good spatial resolution, enabling
interpretation of the findings in an anatomical context. Last, the Starkstein apathy scale used
in our study has very high intra- and interrater reliability[24]. Regarding the scores on post-
DBS apathy, we consider our study sample as representative for the STN-DBS population, as
the average apathy scores were comparable to those in a large longitudinal cohort[11, 60].
In conclusion, we found that increase in apathy severity after STN-DBS might well be an
effect of the stimulation itself. Increased apathy severity scores correlated with a more
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dorsolateral stimulation location (left hemisphere) and with reduced functional connectivity of
the dlPFC, not with decreases in dopaminergic medication dose. Hence, the occurrence of
apathy after DBS might not necessarily be linked to stimulation of the limbic STN, whereas
the correlation with dlPFC connectivity suggests that it may even have a cognitive substrate.
To further validate this hypothesis, future prospective (within-subject) studies are necessary to
determine whether switching stimulation to an alternative, more ventromedially located,
contact point can resolve DBS-induced apathy, preferably without losing clinical
effectiveness on motor symptoms, along with a normalization of functional connectivity of
the dlPFC.
Acknowledgements
We thank all patients for their participation. We thank Gosia Iwan, Miranda Postma, Marije
Scholten, Rosanne Prins and Sharon Stoker-van Dijk for their help with patient inclusions, as
well as the collection of clinical data. We also thank Karin Plugge, Nico Akemann and
Marieke Alting Siberg for the MEG acquisitions.
Study funding
This study was supported by Amsterdam Neuroscience; 05 Amsterdam Neuroscience
Alliantieproject – ND 2016. The funding source had no involvement in the study design,
collection, analysis and interpretation of the data, writing of the report, and in the decision to
submit the article for publication.
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Authors’ roles
Lennard I. Boon: Conceptualization, methodology, software, validation, formal analysis,
investigation, data curation, writing – original draft, writing – review and editing,
visualization, project administration.
Wouter V. Potters: Conceptualization, methodology, software, validation, formal analysis,
investigation, data curation, writing – review and editing, visualization, project
administration.
Thomas J.C. Zoon: Investigation, writing – review and editing.
Odile A. van den Heuvel: Conceptualization, validation, investigation, writing – review and
editing.
Naomi Prent: Software, validation, writing – review and editing.
Rob M.A. de Bie: Conceptualization, investigation, writing – review and editing.
Maarten Bot: Investigation, writing – review and editing.
P. Richard Schuurman: Conceptualization, validation, investigation, writing – review and
editing.
Pepijn van den Munckhof: Investigation, writing – review and editing.
Gert J. Geurtsen: Investigation, writing – review and editing.
Arjan Hillebrand: Conceptualization, methodology, software, validation, investigation,
writing – review and editing, visualization.
Cornelis J. Stam: Conceptualization, methodology, software, investigation, resources, writing
– review and editing.
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Anne-Fleur van Rootselaar: Conceptualization, investigation, resources, writing – review and
editing, supervision, project administration, funding acquisition.
Henk W. Berendse: Conceptualization, investigation, resources, data curation, writing –
review and editing, supervision, project administration, funding acquisisition,
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25
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Figure legends
Figure 1 Stimulation locations of contact points in relation to change in apathy severity
A) Stimulation locations in MNI-space (viewed from respectively dorsolateral right,
anterior and dorsolateral left). The subthalamic nucleus (blue) and red nucleus (red)
were added for reference purposes. Increases in apathy severity are color-coded,
ranging from no increase (green/yellow) to strong increase (dark red).
MNI, Montreal Neurological Institute; R, right; L, left.
B) Stimulation locations were projected on a vector through the longitudinal axis of the
STN, where negative values indicated more ventromedial stimulation positions. There
was a significant correlation between stimulation position and increase in apathy
severity for the left side (r(24)= 0.498, p= 0.010), but not for the right side (r(24)=
0.141, p= 0.491).
Figure 2 Correlations between regional changes in functional connectivity (alpha1) and
change in apathy severity
A) Distribution of the bilateral cortical brain regions studied, the dlPFC (red), medORB
(blue) and antCC (green) displayed on a parcellated template brain viewed from, in
clockwise order, the left, top, right, left midline and right midline.
B) Scatter plots of pre-to-post-DBS change in apathy severity and alpha1 functional
connectivity change (DBS-ON – DBS-OFF), averaged for each of the three regions of
interest. Statistics can be found in Table 2.
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dlPFC, dorsolateral prefrontral cortex; medORB, medial orbitofrontal cortex; antCC, anterior
cingulate cortex.
Figure 3 Functional connectivity changes induced by DBS for individual connections for
patients with weaker (<5; panel A) and with stronger (>5; panel B) increase in apathy
severity.
Distribution of alpha1 cAEC differences induced by DBS stimulation for each individual
connection linked to the dorsolateral prefrontal cortex (yellow nodes) for patients with weaker
(<5; panel A) and with stronger (>5; panel B) increase in apathy severity. Green nodes
represent brain regions, red (blue) connections represent a stimulation-related increase
(decrease) in functional connectivity. Top and bottom views of a template brain are
shown[61]. For visualization purposes, only links with an absolute t-value larger than 1.00 are
shown (arbitrary threshold for visualization purposes).
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Table legends
Table 1 Patient characteristics
mA, milliampère; µs, microseconds; LEDD, Levodopa Equivalent Daily Dose; DA, dopamine
agonist; mg, milligrams; MDS-UPDRS-III, Movement Disorders Society Unified Parkinson’s
Disease Rating Scale motor ratings; DBS, Deep Brain Stimulation; M/F, male/female; L/R,
left/right; D/DM/VM, Dorsal/Dorsomedial/Ventromedial; Med, medication.
Table 2 Correlations of functional connectivity changes with change in apathy severity
Correlations between the changes in cAEC upon stimulation and increase in apathy severity
(Starkstein apathy scale) between baseline (pre-DBS) and follow-up (post-DBS). The
correlations are expressed as a Spearman’s rho. To account for the fact that three seed regions
were compared, alpha levels were adjusted such that p-values smaller than 0.05/3 (using
Bonferroni correction) were considered to be statistically significant, marked in bold.
cAEC, corrected Amplitude Envelope Correlation; DBS, deep brain stimulation.
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Patient Age
(years)
Sex Disease
duration
(years)
Side disease
onset
Stimulation parameters
(stimulation side;
contact; intensity
(mA))
Pulse width and
frequency of
stimulation
LEDD pre-
DBS
(mg/day)
LEDD study
visit (post-DBS
(mg/day))
Motor UPDRS (III) Starkstein apathy score
Pre-DBS
Med off
Med off
/DBS-OFF
Med off
/DBS-ON
Pre-DBS
Post-DBS
(DBS-ON)
1 38 M 8 Right L; DM; 2.9
R; VM; 3.4
60 µs
179 Hz
Total:
1644
DA: 320
Total: 996
DA: 80
73 54 31 3 8
2 63 F 5 Right L; DM; 1.7
R; DM; 1.7
60 µs
130 Hz
Total: 495
DA: 150
Total: 567
DA: 315
43 16 11 2 3
3 65 F 27 Left L; VM; 2.7
R; DM; 1.5
60 µs
130 Hz
Total: 500
DA: -
Total: 400
DA: -
33 20 19 24 25
4 49 F 10 Left L; Dors; 1.9
R; Dors; 2.5
60 µs
130 Hz
Total: 797
DA: 240
Total: 536
DA: 120
35 37 22 12 20
5 69 M 12 Right L; DM; 2.1
R; DM; 2.1
60 µs
130 Hz
Total:
1830
DA: 360
Total: 150
DA: -
56 24 14 12 18
6 60 M 8 Left L; DM; 3.2
R; DM; 1.3
60 µs
179 Hz
Total:
1200
DA: 75
Total: 300
DA: -
57 65 38 4 19
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7 53 M 11 Right L; DM; 2.9
R; DM; 1.9
60 µs
130 Hz
Total:
1567
DA: 240
Total: 1043
DA: 160
60 44 30 2 6
8 66 F 8 Left L; VM; 2.2
R; DM; 1.8
60 µs
130 Hz
Total:
1226
DA: 160
Total: 753
DA: 120
47 37 33 6 5
9 45 M 5 Left L; Dors; 1.7
R; DM; 1.7
60 µs
130 Hz
Total:
1410
DA: -
Total: 283
DA: -
50 80 44 14 19
10 70 F 25 Left L; DM; 2.1
R; DM; 2.4
60 µs
130 Hz
Total:
1590
DA: 450
Total: 555
DA: 37.5
46 33 15 4 12
11 66 M 10 Left L; DM; 2.5
R; DM; 1.8
60 µs
149 Hz
Total: 750
DA: -
Total: 575
DA: -
38 54 27 6 12
12 55 M 8 Right L; DM; 2.7
R; DM; 2.6
60 µs
130 Hz
Total: 950
DA: -
Total: 775
DA: -
42 31 15 5 15
13 57 M 11 Left L; VM; 1.6
R; VM; 1.6
60 µs
130 Hz
Total:
1134
DA: 320
Total: 606
DA: 80
38 21 7 0 12
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14 61 M 7 Left L; VM; 1.5
R; VM; 2.1
60 µs
130 Hz
Total:
1000
DA: -
Total: 375
DA: -
30 27 11 3 16
15 60 M 14 Left L; DM; 2.0
R; VM; 2.5
60 µs
130 Hz
Total:
1073
DA: -
Total: 425
DA: -
55 27 7 6 14
16 57 M 12 Left L; VM; 3.1
R; VM; 2.3
60 µs
130 Hz
Total:
1380
DA: 480
Total: 720
DA: 120
80 52 26 4 9
17 61 M 8 Left L; DM; 1.8
R; DM; 2.3
60 µs
130 Hz
Total:
1726
DA: 360
Total: 946
DA: 80
56 52 21 3 11
18 56 M 12 Right L; DM; 1.4
R; VM; 1.3
60 µs
130 Hz
Total:
2131
DA: 240
Total: 1245
DA: 45
45 20 10 5 6
19 58 M 16 Left L; VM; 1.9
R; DM; 1.9
60 µs
130 Hz
Total:
2032
DA: 160
Total: 613
DA: 80
35 38 14 11 12
20 57 M 12 Left L; VM; 3.0 60 µs Total: Total: 533 38 51 33 8 11
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R; VM; 3.2 130 Hz 1170
DA: 150
DA: -
21 71 F 17 Right L; VM; 1.8
R; VM; 1.7
60 µs
130 Hz
Total:
1940
DA: -
Total: 791
DA: -
56 59 42 3 9
22 57 F 14 Left L; DM; 1.7
R; DM; 2.0
60 µs
130 Hz
Total:
1080
DA: 480
Total: 660
DA: 160
50 40 21 5 12
23 54 F 6 Left L; DM; 2.2
R; DM; 2.4
60 µs
130 Hz
Total:
1600
DA: -
Total: 883
DA: -
71 69 44 6 4
24 55 M 12 Left L; VM; 2.9
R; DM; 2.9
60 µs
130 Hz
Total:
1344
DA: -
Total: 679
DA: -
30 50 17 0 1
25 64 M 22 Left L; DM; 3.7
R; DM; 3.2
60 µs
130 Hz
Total:
2100
DA: 150
Total: 780
DA: 150
59 59 39 13 27
26 48 M 6 Right L; DM; 2.0
R; DM; 1.7
60 µs
130 Hz
Total: 990
DA: 320
Total: 110
DA: 80
14 14 12 5 10
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Mean
(SD)
58 (8) M, n=
18;
F, n= 8
12 (6) L; 2.3 (0.61)
R; 2.1 (0.58)
Total:
1369 (490)
Total: 627
(273)
47.6
(14.8)
41.3 (17.7) 23.2 (11.8) 6 (5) 12 (7)
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Region Frequency band Spearman’s rho
Dorsolateral prefrontal cortex Delta 0.231 (p= 0.256)
Theta -0.261 (p= 0.290)
Alpha1
Alpha2
Beta
-0.520 (p= 0.006)
-0.393 (p= 0.047)
-0.241 (p= 0.235)
Medial orbitofrontal cortex Delta 0.044 (p= 0.829)
Theta -0.151 (p= 0.461)
Alpha1
Alpha2
Beta
-0.212 (p= 0.298)
-0.124 (p= 0.545)
-0.247 (p= 0.224)
Anterior cingulate cortex Delta -0.105 (p= 0.609)
Theta -0.110 (p= 0.593)
Alpha1
Alpha2
Beta
-0.282 (p= 0.163)
-0.108 (p= 0.599)
-0.243 (p= 0.231)
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• Apathy severity increases after deep brain stimulation (DBS) of the subthalamic
nucleus in Parkinson’s disease.
• Post-DBS apathy does not correlate with dose reduction of dopaminergic medication.
• Increased post-operative apathy scores correlate with stimulation position.
• And with stimulation-induced changes in functional connectivity (MEG).
• Apathy after DBS may be an effect of the stimulation itself.
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