# The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life

Inken Tödt, Bassam Al-fatly, Oliver Granert, Andrea A Kühn, Paul Krack, Joern Rau, Lars Timmermann, Alfons Schnitzler, Steffen Paschen, Ann-kristin Helmers, et al.

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Inken Tödt, Bassam Al-fatly, Oliver Granert, Andrea A Kühn, Paul Krack, et al.. The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life. Movement Disorders, 2022, 10.1002/mds.28952. hal-03559813

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RESEARCH ARTICLE

# The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life

Inken Tödt, PhD,<fnref n="1" /> Bassam Al-Fatly, MD,<fnref n="2" /> Oliver Granert,<fnref n="1" /> Andrea A. Kühn, MD, PhD,<fnref n="2" /> Paul Krack, MD, PhD,<fnref n="3" />

Joern Rau,<fnref n="4" /> Lars Timmermann, MD, PhD,<fnref n="5" /> Alfons Schnitzler, MD, PhD,<fnref n="6" /> Steffen Paschen, MD,<fnref n="1" />

Ann-Kristin Helmers, MD,<fnref n="7" /> Andreas Hartmann, MD, PhD,<fnref n="8" />,<fnref n="9" /> Eric Bardinet, MD, PhD,<fnref n="10" />,<fnref n="11" />

Michael Schuepbach, MD,<fnref n="3" />,<fnref n="8" />,<fnref n="9" />,<fnref n="12" /> Michael T. Barbe, MD, PhD,<fnref n="13" /> Till A. Dembek, MD,<fnref n="13" /> Valerie Fraix, MD, PhD,<fnref n="14" />,<fnref n="15" />

Dorothee Kübler, MD,<fnref n="2" /> Christine Brefel-Courbon, MD, PhD,<fnref n="16" /> Alireza Gharabaghi, MD, PhD,<fnref n="17" />

Lars Wojtecki, MD, PhD,<fnref n="18" /> Marcus O. Pinsker, MD, PhD,<fnref n="19" /> Stephane Thobois, MD, PhD,<fnref n="20" />,<fnref n="21" />

Philippe Damier, MD, PhD,<fnref n="22" /> Tatiana Witjas, MD, PhD,<fnref n="23" /> Jean-Luc Houeto, MD, PhD,<fnref n="20" /> Carmen Schade-Brittinger,<fnref n="4" />

Marie Vidailhet, MD, PhD,<fnref n="24" /> Andreas Horn, MD, PhD,<fnref n="2" /> and Günther Deuschl, MD, PhD<fnref n="1" />*

**ABSTRACT:** **Background:** Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL.

**Objectives:** The relation between the stimulated part of the STN and clinical outcomes, including the motor score

of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study.

**Methods:** Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN,

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

*Correspondence to: Prof. Dr. G. Deuschl, Department of Neurology, UKSH, Christian-Albrechts-University Kiel, Rosalind-Fraenklinstr. 10, 24105, Kiel, Germany. E-mail: g.deuschl@neurologie.uni-kiel.de.

Inken Tödt, Bassam Al-Fatly, Andreas Horn, and Günther Deuschl contributed equally to this manuscript.

**Relevant conflicts of interest/financial disclosures:** None.

**Received:** 6 September 2021; **Revised:** 17 January 2022; **Accepted:** 17 January 2022

Published online in Wiley Online Library (wileyonlinelibrary.com). **DOI:** 10.1002/mds.28952

<footnote n="1">¹Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany</footnote>

<footnote n="2">²Department of Neurology, Movement Disorders and Neuromodulation Section, Charité Medicine University of Berlin, Berlin, Germany</footnote>

<footnote n="3">³Department of Neurology, University Hospital Bern and University of Bern, Bern, Switzerland</footnote>

<footnote n="4">⁴Coordinating Center for Clinical Trials, Philipps-University, Marburg, Germany</footnote>

<footnote n="5">⁵Department of Neurology, University Hospital Giessen and Marburg, Marburg, Germany</footnote>

<footnote n="6">⁶Department of Neurology, Institute of Clinical Neuroscience and Medical Psychology, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany</footnote>

<footnote n="7">⁷Department of Neurosurgery, University Hospital Schleswig Holstein, Kiel, Germany</footnote>

<footnote n="8">⁸Assistance-Publique Hôpitaux de Paris, Center d'Investigation Clinique 9503, Institut du Cerveau et de la Moelle épinière, Paris, France</footnote>

<footnote n="9">⁹Département de Neurologie, Université Pierre et Marie Curie-Paris 6 et INSERM, Paris, France</footnote>

<footnote n="10">¹⁰Department of Neurology, NS-PARK/F-CRIN, University Hospital of Besançon, Besançon, France</footnote>

<footnote n="11">¹¹Center de Neuroimagerie de Recherche, Institut du Cerveau et de la Moelle (ICM), Paris, France</footnote>

<footnote n="12">¹²Institute of Neurology, Konolfingen, Switzerland</footnote>

<footnote n="13">¹³Department of Neurology, University of Cologne, Faculty of Medicine, Cologne, Germany</footnote>

<footnote n="14">¹⁴Université Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France</footnote>

<footnote n="15">¹⁵Neurology Department, Grenoble University Hospital, Grenoble, France</footnote>

<footnote n="16">¹⁶Department of Neurology, INSERM Unite 1214, University Hospital Toulouse, Toulouse, France</footnote>

<footnote n="17">¹⁷Department of Neurosurgery and Neurotechnology Institute for Neuromodulation and Neurotechnology, University Hospital and University of Tuebingen, Tuebingen, Germany</footnote>

<footnote n="18">¹⁸Department of Neurology and Neurorehabilitation, Hospital zum Heiligen Geist GmbH & Co.KG Academic Teaching Hospital of the Heinrich-Heine-University Düsseldorf Von-Broichhausen-Allee 1, Kempen, Germany</footnote>

<footnote n="19">¹⁹Department of Neurosurgery, University of Freiburg, Freiburg, Germany</footnote>

<footnote n="20">²⁰Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Center Expert Parkinson, Bron, France</footnote>

<footnote n="21">²¹Université Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud Charles Mérieux, Oullins, France</footnote>

<footnote n="22">²²CHU Nantes, INSERM CIC1413, Hôpital Laënnec, Nantes, France</footnote>

<footnote n="23">²³Department of Neurology, Timone University Hospital UMR 7289, CNRS Marseille, Marseille, France</footnote>

<footnote n="24">²⁴Department of Neurology, Sorbonne Université, ICM UMR1127, INSERM & 1127, CNRS 7225, Salpêtrière University Hospital AP-HP, Paris, France</footnote>
and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters.

**Results:** Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm.

**Conclusions:** The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a

posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. *Movement Disorders* published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

**Key Words:** Parkinson's disease; deep brain stimulation; subthalamic nucleus deep brain stimulation; quality of life

Clinical experience has shown that deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective method for treating motor symptoms in Parkinson's disease (PD). Randomized controlled trials comparing STN-DBS to best medical treatment showed an improvement in motor symptoms between 28% and 41%¹ measured with the Unified Parkinson's Disease Rating Scale (UPDRS III) motor score without medication. Even the nonmotor symptoms that often occur in the context of PD can be improved by DBS²: 23% in the Non-Motor Symptoms Questionnaire and 33% in the Non-Motor Symptoms Scale.³ Moreover, quality of life (QoL), a measure that summarizes various aspects of motor and nonmotor symptoms in the form of a self-assessment, improves significantly.²⁻⁶ Although the positive effects of DBS on all these symptom domains could be demonstrated robustly, the question of the exact topography of the area to be stimulated remains elusive, especially for improvement in QoL. Sweet spots, defined as the optimal DBS target for motor symptoms, have been reported.⁷⁻¹⁰ However, an optimal stimulation target associated for improvement in QoL has not been established so far. First data were provided by Dafsari and colleagues, who showed that an improvement in QoL depends on more anterior and ventral positioning of active contacts.² Further, Petry-Schmelzer and colleagues³ showed an association between an improvement in mood and apathy as part of QoL and a stimulation in the ventral border region of the STN and within the sensorimotor STN. Because the STN resides at the intersection of Forel's and Meynert's axes,¹¹ the term "anterior/posterior" or "dorsal/ventral" is ambiguous. For this paper, as most reports in the neurosurgical literature, we adopt Forel's nomenclature, that is, refer to a superior (toward M1) position with the term "dorsal" and a frontal (toward the frontal pole) position with the term "anterior." Furthermore, it is crucial to note that there is no evidence of septa actually dividing the STN into motor, associative, or limbic domains; the cortical inputs of the structure rather result in a functional gradient that loosely follows its main axis.¹¹ When speaking of the sensorimotor/associative/

limbic functional zones of the structure, we apply the parcellation defined (based on structural connectivity) in Ewert and colleagues.¹²

Here, we used data from the EARLYSTIM cohort¹³ to investigate the relationship between the localization of the STN-DBS electrodes and improvement in clinical parameters, particularly QoL. The major advantage of this cohort over previously used (and mostly retrospective) cohorts⁸,¹⁴⁻¹⁷ is the meticulous clinical characterization over a period of 2 years after stimulation. To examine the STN-DBS effect, we considered the clinical parameters that improved most with DBS, namely motor aspects and QoL. Although STN-DBS does not have a very strong effect on depressive symptoms, this symptom complex is clinically highly relevant for QoL aspects,¹⁸ and therefore, we included it in our considerations. Furthermore, in individual patients, changes in depressive symptoms have been related to contact placement in the past.¹⁹

This study first aims at investigating whether stimulation of the sensorimotor STN is preferable to other STN subdivisions for improving not only motor symptoms but also the QoL. Second, it aims at defining sweet spots for improvement in QoL compared to the ideal stimulation position for improving motor aspects.

# Patients and Methods

## Study Design and Participants

We investigated a sample of 69 patients from the EARLYSTIM cohort, a multicenter, randomized controlled trial conducted in France and Germany.¹³ The original study cohort recruited 251 patients (age <61 years) with PD with a minimum disease duration of 4 years, disabling motor fluctuations lasting for up to 3 years, and at least 50% levodopa responsiveness randomized for STN-DBS or best medical treatment. Of the 124 implanted patients, 69 patients from 12 centers had accessible and technically complete pre- and postoperative imaging (preoperative T1-weighted image and a postoperative magnetic resonance imaging or
computed tomography with sufficient image quality for
localization of the electrodes) and clinical assessment.
Postoperative scans were acquired within 1 week after
surgery. The stimulation target was chosen by each center
according to its best medical practice. The algorithm for
optimizing the stimulation parameters has been published
elsewhere.²⁰ The primary outcome for the optimization
was an improvement due to motor aspects. The detailed
study protocol of the EARLYSTIM has been published
previously.²¹ The ethics committee of the Kiel Medical
Faculty (CAU) approved the study protocol (A 121/06)
and the specific subproject reported here (D 492/19). All
patients provided written informed consent before
randomization.

Clinical Assessment

Clinical assessments were performed before surgery
in an off-medication state and at 24 months follow-up,
including the UPDRS (UPDRS II—worst condition;

UPDRS III—Med off/Stim ON; UPDRS IV), the time
spent with good mobility and without troublesome dys-
kinesia (ON-time without dyskinesia) and depressive
symptoms through the Beck's Depression Inventory
(BDI) II score and the Montgomery-Åsberg Depression
Rating Scale (MADRS). The levodopa equivalent daily
dose (LEDD) was calculated following the approach of
Tomlinson and colleagues.²² The summary index of the
Parkinson's Disease Questionnaire (PDQ-39_SI) was
used to measure aspects of QoL.

DBS Electrode Localization and Estimation of
the Stimulation Volumes

Image preprocessing (coregistration, normalization, and brainshift correction) and DBS electrode localization have been performed using the Lead-DBS toolbox (http://www.lead-dbs.org<sup>15</sup>). The electric fields and the stimulation volumes derived from these were estimated in native space and transferred to Montreal

<figure><img src="image_1.png" /><figcaption>FIG. 1. Intercorrelation structure and FDR-corrected *P*-values (in brackets) of changes in motor aspects following STN-DBS with changes in life quality. Two groups of outcomes affect quality of life (QoL): motor disease severity and depressive symptoms. Only significant correlations (*P* < 0.05, FDR corrected) with QoL are shown. For other correlations, see Supplementary Table S1. Spearman's correlation coefficients are given. BDI, Beck's Depression Inventory; FDR, false discovery rate; LED, levodopa equivalent dose; MADRS, Montgomery-Åsberg Depression Rating Scale; PDQ, Parkinson's Disease Questionnaire; QoL, quality of life; SI, summary index; STN-DBS, subthalamic nucleus deep brain stimulation; UPDRS, Unified Parkinson's Disease Rating Scale.</figcaption></figure>

<figure><img src="image_2.png" /><figcaption>FIG. 2. Schematic representation of significant correlations between stimulation volume-STN overlaps and improvements in motor function (UPDRS III) and QoL (PDQ-39DI numbers represent Spearman's correlation coefficients and permuted *P*-values [in brackets]). A correlation matrix showing the same data can be found in Appendix S1. PDQ, Parkinson's Disease Questionnaire; QoL, quality of life; SI, summary index; STN, subthalamic nucleus; UPDRS, Unified Parkinson's Disease Rating Scale.</figcaption></figure>
<table><caption>TABLE 1 Baseline characteristics and means (±SD) of clinical scores at baseline and 24 months follow-up of the sample analyzed here (DBS cohort, n = 69) and of the excluded patients from the EARLYSTIM cohort (n = 55)</caption><thead><tr><th rowspan="2"></th><th colspan="3">Included patients (n = 69)</th><th rowspan="2">Excluded patients (n = 55)<br>Difference between groups</th></tr><tr><th>Mean ± SD<br>or<br>number of<br>patients (d)</th><th>Absolute<br>improvement<br>(P-value)</th><th>Percentage<br>improvement</th></tr></thead><tbody><tr><td>Age (y)</td><td>52.8 ± 6.8</td><td></td><td></td><td>0.669<sup>a</sup></td></tr><tr><td>Gender—number (%)</td><td></td><td></td><td></td><td>0.834<sup>b</sup></td></tr><tr><td>Male</td><td>53 (76.8)</td><td></td><td>41</td><td></td></tr><tr><td>Female</td><td>16 (23.2)</td><td></td><td>14</td><td></td></tr><tr><td>Duration of Parkinson's disease (y)</td><td>7.4 ± 3.2</td><td></td><td></td><td>0.653<sup>a</sup></td></tr><tr><td>Dyskinesia</td><td></td><td></td><td></td><td></td></tr><tr><td>Number of patients (%)</td><td>43 (62.3)</td><td></td><td>41</td><td>0.178<sup>b</sup></td></tr><tr><td>Motor fluctuations</td><td></td><td></td><td></td><td></td></tr><tr><td>Number of patients (%)</td><td>68 (98.5)</td><td></td><td>53</td><td>0.584<sup>b</sup></td></tr><tr><td>Treatment with levodopa</td><td></td><td></td><td></td><td></td></tr><tr><td>Number of patients (%)</td><td>62 (89.9)</td><td></td><td>49</td><td>1.00<sup>b</sup></td></tr><tr><td>Duration (y)</td><td>4.9 ± 3.8</td><td></td><td>4.5 ± 2.6</td><td>0.917<sup>a</sup></td></tr><tr><td>Levodopa equivalent daily dose (mg)</td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>897 ± 385</td><td>379 (&lt;0.001<sup>c</sup>)</td><td>42.3</td><td>946 ± 447</td></tr><tr><td>24 months follow-up</td><td>518 ± 326</td><td></td><td></td><td>0.525<sup>c</sup></td></tr><tr><td>Treatment with dopamine agonist</td><td></td><td></td><td></td><td></td></tr><tr><td>Number of patients (%)</td><td>64 (92.8)</td><td></td><td>54</td><td>0.226<sup>b</sup></td></tr><tr><td>Duration (y)</td><td>6.1 ± 3.2</td><td></td><td>5.8 ± 2.8</td><td>0.821<sup>a</sup></td></tr><tr><td>UPDRS II (worst condition)</td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>15.8 ± 6.6</td><td>4.8 (&lt;0.001<sup>a</sup>)</td><td>30.4</td><td>14.2 ± 5.4</td></tr><tr><td>24 months follow-up</td><td>11.0 ± 5.2</td><td></td><td></td><td>0.231<sup>a</sup></td></tr><tr><td>UPDRS III</td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline (Med off)</td><td>35.3 ± 10.8</td><td>17.7 (&lt;0.001<sup>c</sup>)</td><td>50.1</td><td>31.7 ± 11.9</td></tr><tr><td>24 months follow-up (Med off/Stim ON)</td><td>17.6 ± 9.8</td><td></td><td></td><td>0.091<sup>c</sup></td></tr><tr><td>UPDRS IV</td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>5.4 ± 3.0</td><td>3.0 (&lt;0.001<sup>a</sup>)</td><td>55.6</td><td>6.1 ± 3.4</td></tr><tr><td>24 months follow-up</td><td>2.4 ± 1.9</td><td></td><td></td><td>0.354<sup>a</sup></td></tr><tr><td>ON-time<sup>a</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>10.8 ± 4.6</td><td>-2.0 (0.014<sup>c</sup>)</td><td>18.5</td><td>9.8 ± 4.7</td></tr><tr><td>24 months follow-up</td><td>12.8 ± 4.4</td><td></td><td></td><td>0.272<sup>c</sup></td></tr><tr><td>MADRS</td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>7.7 ± 6.6</td><td>0.6 (0.407<sup>a,c</sup>)</td><td>7.8</td><td>5.9 ± 4.6</td></tr><tr><td>24 months follow-up</td><td>7.1 ± 5.8</td><td></td><td></td><td>0.252<sup>a</sup></td></tr></tbody></table>

(Continues)
<table><caption>**TABLE 1** Continued</caption><thead><tr><th rowspan="2"></th><th colspan="3">Included patients (n = 69)</th><th rowspan="2">Excluded patients (n = 55)<br>Difference between groups</th></tr><tr><th>Mean ± SD<br>or<br>number of<br>patients (d)</th><th>Absolute<br>improvement<br>(P-value)</th><th>Percentage<br>improvement</th></tr></thead><tbody><tr><td>BDI</td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>10 ± 6.1</td><td>1.0 (0.308<sup>a,c</sup>)</td><td>10</td><td>10 ± 4.7</td><td>0.801<sup>a</sup></td></tr><tr><td>24 months follow-up</td><td>9 ± 6</td><td></td><td></td><td></td><td></td></tr><tr><td>PDQ-39 SI</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Baseline</td><td>28.5 ± 13.4</td><td>4.6 (0.049<sup>c</sup>)</td><td>16.1</td><td>32.2 ± 12.9</td><td>0.117<sup>c</sup></td></tr><tr><td>24 months follow-up</td><td>23.9 ± 13.4</td><td></td><td></td><td></td><td></td></tr></tbody></table>

Improvements after STN-DBS are given as absolute and percentage values for the subgroup analyzed in this study.

Neurosciences Institute (MNI) space based on the individual optimized stimulation parameters using a finite element method approach established within the SimBio-FieldTrip pipeline.¹⁴ A detailed description of this pipeline can be found in Appendix S1.

## Quantification of Neuroanatomical Placement and Sweet Spot Calculation

As a quantification for the neuroanatomical placement of DBS electrodes, we calculated the overlaps between individual stimulation volumes and the atlas-defined STN¹² as implemented in Lead group²³ separately for the left and the right hemispheres.

The sweet spot calculation is based on an effect image (=stimulation volumes × absolute clinical improvement) and a voxel-wise one sample t score to estimate the degree to which the particular voxel would account for clinical improvement (t-image). Only voxels covered by at least 10 stimulation volumes were retained in the model. Rather, we aimed to provide a weighted map of clinical effects that was rather inclusive and then validated the map on out-of-sample (unseen) data points by applying leave-one-out cross-validation. To analyze both sensitivity and specificity of the leave-one-out cross-validation approach for our sweet spot models, we calculated the receiver operator characteristic (ROC) curve across specific sweet spot thresholds. A detailed description of this pipeline can be found in Supplementary Material S2.

## Statistical Analysis

The strongest contrast for clinical outcomes is a comparison of the preoperative medication-off and the postoperative medication-off and stimulation-on situation. We chose this contrast because the postoperative medication off/Stim ON state is the one that our patients experience as the worst in real life, as the stimulator is not switched off after successful implan2wtation. For the clinical baseline, follow-up, and improvement scores that were not normally distributed, we used nonparametric procedures (Shapiro-Wilk tests), otherwise t tests. We calculated Spearman's correlation coefficients between clinical improvement scores and performed a false discovery rate correction²⁴ adjusting the P-values for 28 tests (see Supplementary Table S1; Fig. 1). Correlation coefficients between the overlap of stimulation volume and STN atlases and clinical improvement scores were calculated using Spearman's rho and tested for significance using permutation tests (see Supplementary Table S2; Fig. 2). An α level of 0.05 was chosen. Sweet spot analysis (t test) was validated through a leave-one-patient-out correlation (see sweet spot calculation) with permutation test. All statistical analyses were conducted using R statistics (version 3.3.1²⁵).

## Results

### Patient Characteristics

In this study, we included 69 patients (53 men) with idiopathic PD from the EARLYSTIM cohort, who

<footnote><sup>a</sup>P-value of Wilcoxon test.</footnote>

<footnote><sup>b</sup>P-value of Fisher's test.</footnote>

<footnote><sup>c</sup>P-value of t test.</footnote>

<footnote><sup>d</sup>ON-time without troublesome dyskinesia.</footnote>

<footnote><sup>e</sup>Intragroup changes only. Compared with the best medical treatment group, the difference is significant.</footnote>

<footnote>Abbreviations: SD, standard deviation; DBS, deep brain stimulation; UPDRS, Unified Parkinson's Disease Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; BDI, Beck's Depression Inventory; PDQ, Parkinson's Disease Questionnaire; SI, summary index.</footnote>
<figure><img src="image_3.png" /><figcaption>FIG. 3. Distribution of the active contacts colored for the different centers in a (A) medial and (B) lateral view. Sweet clusters (maximum 15% of the t-values) for UPDRS III (green blob) and PDQ-39_SI (purple blob) exemplary in the right hemisphere in a (C) medial, (D) lateral, and (E) anterior view. Comparing our motor sweet spot to sweet spots published previously, we found high agreement and small distances between them. As an example, we show the motor sweet spot defined by us and the coordinate calculated in a meta-analysis by Caire et al³¹ (F) together with an exemplary directional electrode with two simulated volumes stimulating both sweet clusters. The Euclidian distance between their midpoints was 1.04 mm. PDQ, Parkinson's Disease Questionnaire; UPDRS, Unified Parkinson's Disease Rating Scale.</figcaption></figure>

underwent STN-DBS. We had to exclude 55 patients of the original per-protocol population (n = 124) because of lack of access to the imaging or clinical data (N = 43) or insufficient pre- or postoperative imaging quality (N = 12). Demographic characteristics and a comparison between the subgroup included here and the excluded patients are summarized in Table 1. We found no significant differences between the groups and can therefore assume that the cohort analyzed here represents the entire EARLYSTIM cohort. All clinical

scores except the BDI and MADRS score showed a significant improvement after STN-DBS.

Improvement in Clinical Outcomes and Their
Intercorrelations

Outcomes with a high clinical relevance which are
known to undergo significant changes with DBS and
which are surrogates for different behavioral domains
were selected: we found a significant improvement for
<table><caption>TABLE 2 Sweet spots for the clinical improvement scores and correlation coefficients of the leave-one-patient-out cross-validation method.</caption><thead><tr><th rowspan="3"></th><th colspan="5">Left hemisphere</th><th colspan="5">Right hemisphere</th></tr><tr><th colspan="4">Sweet spot results</th><th colspan="2">Cross-validation results</th><th colspan="4">Sweet spot results</th><th colspan="2">Cross-validation results</th></tr><tr><th>X</th><th>Y</th><th>Z</th><th>T</th><th>R</th><th>P</th><th>x</th><th>Y</th><th>Z</th><th>T</th><th>R</th><th>P</th></tr></thead><tbody><tr><td>UPDRS II</td><td>-14.7</td><td>-12.6</td><td>-4.3</td><td>5.88</td><td><strong>0.28</strong></td><td><strong>0.009</strong></td><td>15.0</td><td>-10.9</td><td>-3.7</td><td>4.92</td><td>0.00</td><td>0.482</td></tr><tr><td>UPDRS III</td><td>-12.3</td><td>-13.1</td><td>-7.2</td><td>9.30</td><td><strong>0.28</strong></td><td><strong>0.005</strong></td><td>11.6</td><td>-13.1</td><td>-6.3</td><td>8.27</td><td><strong>0.19</strong></td><td><strong>0.049</strong></td></tr><tr><td>UPDRS IV</td><td>-12.5</td><td>-12.8</td><td>-7.0</td><td>6.47</td><td>0.08</td><td>0.238</td><td>12.6</td><td>-11.5</td><td>-6.7</td><td>5.19</td><td>0.04</td><td>0.364</td></tr><tr><td>ON-time<sup>a</sup></td><td>-9.4</td><td>-12.8</td><td>-1.9</td><td>1.71</td><td>-0.40</td><td>0.001</td><td>14.1</td><td>-13.7</td><td>-9.6</td><td>1.44</td><td>-0.28</td><td>0.015</td></tr><tr><td>MADRS</td><td>-14.9</td><td>-16.8</td><td>-8.7</td><td>2.37</td><td>0.01</td><td>0.451</td><td>11.7</td><td>-16.1</td><td>-12.5</td><td>2.24</td><td>-0.41</td><td>0.001</td></tr><tr><td>BDI</td><td>-13.6</td><td>-14.2</td><td>-11.6</td><td>2.33</td><td>-0.15</td><td>0.104</td><td>14.8</td><td>-12.2</td><td>-5.2</td><td>3.02</td><td>-0.05</td><td>0.329</td></tr><tr><td>LEDD</td><td>-13.6</td><td>-9.8</td><td>-4.8</td><td>3.29</td><td>-0.12</td><td>0.202</td><td>11.0</td><td>-12.2</td><td>-7.4</td><td>2.66</td><td>-0.18</td><td>0.108</td></tr><tr><td>PDQ-39_SI</td><td>-13.6</td><td>-13.7</td><td>-2.8</td><td>4.18</td><td>0.10</td><td>0.206</td><td>14.8</td><td>-12.4</td><td>-4.3</td><td>5.72</td><td><strong>0.26</strong></td><td><strong>0.013</strong></td></tr></tbody></table>

Here, we report the *P*-values of permutation tests. Significant values (*P* < 0.05) are printed in bold. Note that in a leave-one-out cross-validation design, negative correlation coefficients are not meaningful (represents a null finding) and were therefore not FDR corrected. Coordinates are reported in MNI space.

motor symptoms (UPDRS III, UPDRS II, ON-time without dyskinesia), LEDD and PDQ-39_SI (Table 1). Clinical scores for depression (BDI and MADRS) were added as they were significantly improved compared to the best medical treatment for the whole EARLYSTIM cohort¹³ and as depression has consistent influence on QoL.²⁶

The intercorrelations between clinical improvement scores (Fig. 1; Supplementary Table S1) suggested a complex interaction: UPDRS subscales were intercorrelated except for complications in therapy not being correlated with disease severity. This is meaningful, as the two aspects are not necessarily related at this stage of disease severity. It is also tempting to look at the variables that do not correlate. First, ON-time without dyskinesia and LEDD reduction did not correlate with any of the other variables. Second, the two depression parameters did not correlate with the UPDRS subscales (except for a significant correlation between the MADRS and UPDRS II) and ON-time without dyskinesia. This suggests that the change in the two behavioral dimensions, motor disease severity and mood, was not closely related, in agreement with prior results.¹⁹

Because of the multicenter nature of this study, we used a univariate ANOVA (one-way analysis of variance) to examine systematic differences between centers in LEDD reduction and UPDRS III. To ensure the robustness of the ANOVA, we included only centers with more than 4 subjects. No significant differences were found (LEDD: F6, 49 = 1.302, *P* = 0.274; UPDRS-III: F6, 50 = 1.396, *P* = 0.235).

## Correlation between Clinical Improvements and DBS Localization

We hypothesized that the influence of DBS on the different outcomes could have been mediated by modulating one or more of the subdivisions of the STN, namely the sensorimotor, associative, and limbic functional zones that are integrated into the three cortex-basal ganglia loops. We must emphasize that in reality, the basal ganglia loops rather work along a gradient/continuum and loops are highly interconnected on multiple levels—but the applied model of three divisions would still serve as a useful simplified model here. Therefore, we used the tripartite separation of the STN into its subareas¹² and studied the correlation of the overlap of the individual stimulation volume with the anatomical target area (Supplementary Table S2). We found significant correlations between the extent of the overlap with the sensorimotor STN and the improvement along the UPDRS III (left: *r* = 0.32, *P* = 0.004; right: *r* = 0.29, *P* = 0.010) and the PDQ-39 SI (left: *r* = 0.23, *P* = 0.032; right: *r* = 0.43, *P* < 0.001). The correlation between the improvement in the UPDRS II and the sensorimotor STN overlap was significant only when both hemispheres were included (*r* = 0.21, *P* = 0.044). The overlap with the limbic STN was significantly correlated with the PDQ-39_SI (*r* = 0.28, *P* = 0.011) for the right hemisphere (Fig. 2; Supplementary Table S2).

- As observed in Figure 3, the vast majority of active contacts are within or very close to the boundary of the STN. There were no active contacts placed in

<footnote><sup>a</sup>ON-time without troublesome dyskinesia.</footnote>

<footnote>Abbreviations: UPDRS, Unified Parkinson's Disease Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; BDI, Beck's Depression Inventory; LEDD, levodopa equivalent daily dose; PDQ, Parkinson's Disease Questionnaire; SI, summary index; FDR, false discovery rate.</footnote>
Substantia nigra pars reticulata (SNr) and very few above the STN but still within an acceptable distance.

## Sweet Spots

Table 2 presents the peaks of sweet spot areas. We found significant out-of-sample correlations between the predicted average *t* score and the clinical improvement scores for UPDRS III in both hemispheres (left: $R^2 = 0.28, P = 0.005$; right: $R^2 = 0.19, P = 0.049$) as well as for PDQ-39 SI for the right hemisphere (PDQ SI: $R^2 = 0.26, P = 0.013$) and for UPDRS II for the left hemisphere ($R^2 = 0.28, P = 0.009$) (Table 2). The peak maxima of *t*-maps (sweet spots) for UPDRS III and PDQ-39 differed on the left side by 4.6 mm and on the right side by 3.8 mm. Figure 3 shows the position of the two clusters in the right hemisphere that are close to the border between the motor and associative zones (ie, corresponding to a premotor location) and within the center of the motor area, respectively. ROC curve revealed an area under the curve of 0.64 and 0.57 for the right and left sweet spot models of PDQ, respectively, whereas for UPDRS these were 0.58 and 0.66, respectively, for the right and left sweet spot models.

## Discussion

QoL is influenced by many factors. The aim of this study was to better understand the role of the DBS-electrode location for changes in motor severity (UPDRS III) and QoL (PDQ-39). We calculated the sweet spots of STN-DBS effects for the two outcome parameters of the EARLYSTIM cohort, investigated the relationship between the overlap of individual stimulation volumes and functional subzones of the STN and various clinical improvement scores, and inferred that the larger the stimulated part of the sensorimotor STN is, the higher is the improvement in motor severity and QoL.

## Relationship between Changes in Clinical Parameters Due to DBS

The relationship between changes in the clinical parameters through DBS does not seem to be well investigated, as usually only the relationships at baseline are analyzed.<sup>18,27</sup> However, some studies have also looked for the correlations between the changes in the clinical parameters. These showed low<sup>28</sup> to moderate<sup>17</sup> correlations between the overall QoL and the UPDRS III. Due to the finding that the effect of DBS on disease severity is not very strongly associated with a change in QoL, it makes sense to consider these two very important parameters for the patient separately when analyzing the effect of DBS.

## Electrode Placements Influence Motor Aspects and Quality of Life

Certainly, clinicians would like to know the most efficient spot for stimulation. If different spots have different effects, they would like to choose for individualized treatment, by either electrode placement or DBS programming. Indeed, the analysis of the relationships between different improvement scores has shown that, at the individual patient level, STN-DBS does not affect all parameters in the same direction and with the same intensity. In our study, UPDRS III and QoL were influenced by the topographic distribution of the stimulation volumes with respect to the STN anatomy. For motor improvements, this has been shown repeatedly,<sup>9,14,17,29,30</sup> and sweet spots defined for the best improvement in motor aspects, including the one we defined here, fall closely together.<sup>7,9,31</sup> Similarly, our results suggest that the extent of an improvement in disease severity (UPDRS III) was mainly influenced by stimulation of the sensorimotor STN area. Overlaps with other parts of the STN had no statistical relationship with improvement in motor symptoms. As previously reported in most studies,<sup>9,31,32</sup> the sweet spot related to motor symptoms was within the premotor functional zone of the STN, which would correspond to cortical input by the supplementary motor area.<sup>15,23</sup> We must emphasize that in reality, the basal ganglia loops rather work along a gradient/continuum and loops are highly interconnected on multiple levels. Instead, the functional zones of the STN should be considered as a continuum with cross talk between loops on inter alia, cortical, striato-cortical, thalamo-cortical, and nigro-striatal levels. In the classical anatomical literature, a parcellation into five regions (premotor and oculomotor zones) has conventionally been described.<sup>33</sup> However, the STN receives input from almost all regions of the frontal cortex and even from the primary sensory cortex in its most posterior part.<sup>34</sup>

For nonmotor parameters, there is also early evidence for a valid relationship between the stimulated STN part and the amount of clinical improvement.<sup>2,3</sup> However, the evidence is far from being as advanced as for the relationship between the stimulated STN part and improvement in motor aspects of the disease. Furthermore, some reports associated changes in nonmotor symptoms with stimulating the sensorimotor STN,<sup>35,36</sup> potentially because the motor loop is most affected in early PD and DBS has the strongest effect on affected circuits. Therefore, by rebalancing the affected motor loops, nonmotor effects could emerge due to the aforementioned cross talk between loops.<sup>35</sup>

Furthermore, modulating the anterior regions of the left STN has been associated with a detrimental effect on mood, whereas modulating the same site on the right hemisphere, as well as modulating the motor circuits on both sides, was associated with beneficial
effects on mood.¹⁹ In agreement with these findings, the
optimal stimulation site corresponding to improvements
in QoL we estimated here resided within the right senso-
rimotor part of the STN. This is consistent with the find-
ing of a lateralization toward the nondominant brain
hemisphere for emotional processing.³⁷ Again, this site
corresponds precisely to the loop that is most affected in
(especially early-stage) PD and to the region in which
most elevated pathological β-power has been reported.¹⁰
Again, alluding to the notion that only what is broken
can be fixed, modulating the most affected loop could
lead to the best overall improvement in symptoms and
associated benefits in QoL.³⁶ In agreement, a previous
study investigated the interaction between the stimula-
tion site and mood and apathy, whereby especially
aspects of mood are included in the PDQ, and concluded
that above-average improvement in these symptoms
could be observed at within the sensorimotor parts of
the STN.³ Instead, improvements in neither mood/apa-
thy, attention/memory, nor sleep/fatigue were associated
with more antero-medial stimulation sites (associate lim-
bic domains). Again, our sample consists of patients in
the early stages of the disease, and it has been concluded
previously that the sensorimotor loop degenerates first in
PD.³⁸,³⁹ Because DBS presumably mainly improves loop
functions whose related nigral cells have already started
to degenerate, here, we add to the accumulating evidence
that the optimal target for improving nonmotor symp-
toms is also located in the motor part of the STN (refer-
ences 3,42; for a summary of this line of reasoning, see
reference 41). For instance, Irmen et al reported that
STN-DBS to the motor functional zone not only
improved PD motor symptoms but also normalized
overly risk-averse decision behavior in PD.³⁶ Further,
there is evidence that stimulation of the nonmotor parts
of the STN may lead to cognitive and neuropsychiatric
disturbances rather than improvements.⁴⁰⁻⁴² Therefore,
at this stage of the research, we conclude that stimulation
of the sensorimotor STN increases the perceived QoL.
This hypothesis could be supported by analyzing larger
cohorts of patients, with some of them having their stim-
ulated contacts within the nonmotor regions and thus
would have less improvement in their nonmotor func-
tions (or even nonmotor disturbances). Another aspect to
be discussed is a possible selection bias of those patients
considered for DBS. An indication for DBS is given only
if a patient is severely affected motor-wise and medical
treatment does not provide sufficient improvement. The
presence of nonmotor symptoms that significantly affect
QoL is therefore not a necessary condition for DBS and
not present in all patients.

Limitations

Patients included in our study are in a relative early
stage of the disease. This must be considered when

interpreting the results of this study. Therefore, to con-
firm the interpretations, it is essential to replicate the
results in a sample stimulated at an advanced stage of
the disease. Even better would be a prospective study of
a large sample to increase the chance for a subsample
of patients with a more antero-ventro-medial contact
stimulation. This could be used to systematically com-
pare the differences in the DBS effect on the various
outcome parameters.

In the past, different methods to calculate sweet spots for
clinical outcomes have been used (references9 and43-46; for
an overview, see reference 47). Here, we chose a compara-
tively simple weighting method (by calculating *t* scores
against zero) but used it to cross-predict out-of-sample
results not observed by the model (leave-one-out cross-
validation design).

Electrode localizations from neuroimaging data
(which in our case were heterogeneous and collected at
different centers) are subject to slight inaccuracies
resulting from brain shift, coregistration processes, and
similar neuroimaging problems.³² We applied a modern
pipeline, specifically created for electrode localizations,
that aims at addressing these issues using strategies such
as multispectral normalization,⁴⁸ phantom-validated
electrode localizations,⁴⁹ and correction for brain
shift.¹⁵ However, despite these efforts, a certain degree
of inaccuracy must be assumed.⁵⁰

We describe a similar sweet spot location as most
other studies for the motor aspects of PD (for a recent
review, see reference 36). New methods of sweet spot
calculation have recently been proposed, and future
studies may further refine our findings and compare
statistical methods to the one applied here. Statisti-
cally, a *t* test model comparing to zero has been criti-
cized, in the past, because most patients improve and,
therefore, *t*-values will always be positive.⁴⁷ How-
ever, because we used the *t*-values only as a surrogate
parameter for our maps and not as an indicator of
voxel-wise statistical significance, this problem is only
of little importance.

The applied model for calculating the stimulation vol-
umes is considered rather simple in comparison to more
elaborate axon-cable-based or pathway-activation-
based concepts.⁵¹,⁵² Although more elaborate models
have recently been introduced within the field of open-
source research,⁵³ at present, our methodology is lim-
ited to estimating the stimulation volume based on the
electric field norm (for a comparison of stimulation vol-
ume shapes using different models including our
approach, which represents a good first-order approxi-
mation, see reference 54).⁵⁴

Motor as well as nonmotor symptoms contribute to
QoL.⁵⁵,⁵⁶ It has been shown that nonmotor symptoms
are even strongly correlated to QoL than motor symp-
toms¹⁸,⁵⁷: urinary symptoms, sleep, and fatigue, which
are not covered by our scales, significantly contribute to
QoL⁵⁶ EARLYSTIM did not assess nonmotor symptoms with an adequate scale⁵⁸ as this was not yet available at the time of the study planning. However, having detailed data on these aspects would possibly help explain a larger part of the QoL changes and thereby might better help explain the sweet spot relations.

Finally, our results stem from an exploratory post hoc analysis of data prospectively collected in a randomized trial. Imaging data could not be retrieved from all patients, so a subset is analyzed here. Multiple outcome parameters were related to electrode placement and stimulation volumes, leading to multiple comparisons. Effect sizes of expected relationships between clinical outcomes and placement were not clear up front, so only post hoc power calculations could be performed.

## Conclusion

The study suggests that the improvement in QoL of PD with STN-DBS is mediated mainly through stimulating the sensory-motor loop of the basal ganglia in early PD with fluctuations. However, the sweet spot for QoL is still different from the one for motor symptoms measured with the UPDRS III and is located in a posteroventral spatial location in the STN territory. This location represents the center of the STN. This may indicate that stimulation of other loops than the sensory motor is additionally involved. This needs confirmation by independent cohorts. If confirmed, a different stimulation point to specifically improve different aspects of QoL would be a valuable tool for this treatment. ■

**Acknowledgement:** We thank Val Stoker for continuing support of the scientific evaluation of the Earlystim data. Open Access funding enabled and organized by Projekt DEAL.

## Data Availability Statement

The data that support the findings of this study are available from the corresponding author (acting on behalf the Earlystim steering committee) upon reasonable request.

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## Supporting Data

Additional Supporting Information may be found in the online version of this article at the publisher's web-site.
Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of the first draft, B. Review and critique.

I.T.: 2A, 2B, 2C, 3A

B.A.-F.: 2A, 2B, 2C, 3A

O.G.: 1A, 1B, 1C, 3B

Steering Committee: 1A, 1B, 3B

Other authors: 1C, 3B

A.H: 2A, 2B, 2C, 3B

G.D.: 1A, 1B, 2C, 3B

Full Financial disclosures for the previous 12 months

Inken Tödt

I.T. received grants from the German Society for Parkinson's Disease and Movement Disorders (DPG e.V.) and the German Research Foundation (DFG).

Bassam Al-Fatly

No conflicts of interest.

Oliver Granert

No conflicts of interest.

Paul Krack

P.K. reports research grants from the Swiss National Science Foundation, ROGER DE SPOELBERCH Foundation, Bertarelli Foundation, Annemarie Opprecht Foundation, Parkinson Schweiz, The Michael J. Fox Foundation, Aleva Neurotherapeutics, and Boston Scientific and personal fees (lecturing fees from employing institution/travel expenses to scientific meetings) from Boston Scientific, Bial, and Zambon outside the submitted work.

Joern Rau

Lars Timmermann

Between January 2018 and June 2021 Lars Timmermann received payments as consultant for Boston Scientific, and L.T. received honoraria as a speaker on symposia sponsored by UCB, Desitin, Boston Scientific, AbbVie, Novartis, GlaxoSmithKline, and Diaplan. The institution of L.T., not L.T. personally, received funding from Boston Scientific, the German Research Foundation, the German Ministry of Education and Research, and the Deutsche Parkinson Vereinigung. Neither L.T. nor any member of his family holds stocks, stock options, patents, or financial interests in any of the above-mentioned companies or their competitors.
<table>
   <tr>
    <td>Alfons Schnitzler</td>
    <td>A.S. has received lecture fees from Abbott, Novartis, and Kyowa Kirin, and has been serving as consultant for Abbott, Zambon, and Medtronic. He received royalties from the Georg Thieme Verlag. He is a government employee and receives through his institution funding for his research from the German Research Council, Abbott, and the Brunhilde Moll Foundation.</td>
   </tr>
   <tr>
    <td>Steffen Paschen</td>
    <td>S.P. received lecture fees from Medtronic, Boston Scientific, and Insightec; travel grants from AbbVie; and educational grants from AbbVie and Boston Scientific.</td>
   </tr>
   <tr>
    <td>Ann-Kristin Helmers</td>
    <td>A.-K.H. received support from the German Research Foundation (DFG, CRC 1261).</td>
   </tr>
   <tr>
    <td>Andreas Hartmann<br/>Eric Bardinet</td>
    <td>E.B. received grants from The Michael J. Fox Foundation and Boston Scientific.</td>
   </tr>
   <tr>
    <td>Michael Schuepbach</td>
    <td>M.S. received financial support from the French Programme Hospitalier de Recherche Clinique National (P050909) and from Medtronic as well as consulting honoraria from Medtronic and Innomedia.</td>
   </tr>
   <tr>
    <td>Michael T. Barbe</td>
    <td>M.T.B. received speaker's honoraria from Medtronic, Boston Scientific, Abbott (formerly St. Jude), GE Medical, UCB, Apothekerverband Köln e.V., and Bial as well as research funding from the Felgenhauer-Stiftung, Forschungspool Klinische Studien (University of Cologne), Horizon 2020 (Gondola), Medtronic (ODIS), and Boston Scientific and advisory honoraria for the IQWIG.</td>
   </tr>
   <tr>
    <td>Till A. Dembek</td>
    <td>T.A.D. is supported by the Cologne Clinician Scientist Program (CCSP)/Faculty of Medicine/ University of Cologne and funded by the German Research Foundation (DFG, FI 773/15-1).</td>
   </tr>
   <tr>
    <td>Valerie Fraix</td>
    <td>V.F. received fees from Boston Scientific and Medtronic France for lecturing.</td>
   </tr>
   <tr>
    <td>Dorothee Kübler<br/>Christine Brefel-Courbon</td>
    <td>No conflicts of interest.</td>
   </tr>
   <tr>
    <td>Alireza Gharabaghi</td>
    <td>C.B.-C. received research grants from the Association France Parkinson and PHRC and fees for lecture or consultancies from Aguettant, Orkyn, Zambon, and AbbVie.</td>
   </tr>
   <tr>
    <td>Lars Wojtecki</td>
    <td>A.G. received research grants from Abbott, Boston Scientific, Medtronic, and the German Federal Ministry of Education and Research (all not related to this work).</td>
   </tr>
   <tr>
    <td></td>
    <td>Stock ownership in medically related fields: none; intellectual property rights: none; consultancies/ honoraria/expert testimony: Storz Medical, Dialektica, Merck, Synergia, Zambon, and Merz; advisory boards: Kyowa Kirin and Bial; employment: Hospital Kempen/Artemed and Heinrich-Heine University Duesseldorf; partnership contracts: sponsor collaboration for hospital teaching events from Merck, Teva, Roche, Spektrum, UCB, Bial,</td>
   </tr>
  </table>
Marcus O. Pinsker
Stephane Thobois

Philippe Damier
Tatiana Witjas
Jean-Luc Houeto
Carmen Schade-Brittinger
Marie Vidailhet
Andreas Horn

Günther Deuschl

Desitin, AbbVie, Merz, and Allergan and study honoraria for the hospital from Roche and Deutsche Forschungs Gemeinschaft (DFG) for DC-Train-Aphasia; royalties: none; grants: from Hilde-Ulrichs-Stiftung für Parkinsonforschung; other: none.

No conflicts of interest.

S.T. received honorarium from Boston Scientific and Orion.

Advisory board: Kyowa Kirin; conferences: Roche

No conflicts of interest.

No conflicts of interest.

No conflicts of interest.

A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381-TRR 295) as well as Deutsches Zentrum für Luft-und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND). A.H. is participant in the BIH-Charité Clinician Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.

G.D. has served as consultant for Boston Scientific, Aleva, Cavion, and Functional Neuromodulation. He has received lecture fees from Boston Scientific and royalties from Thieme Publishers. He is a government employee and receives funding for his research through his institution from the German Research Council, the German Ministry of Education and Research, and Medtronic.