Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson's Disease: Study Protocol for a Randomized Double-blind Crossover Trial

Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson's Disease: Study Protocol for a Randomized Double-blind Crossover Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson's Disease: Study Protocol for a Randomized Double-blind Crossover Trial Gregor Alexander Brandt, Lisa Piotrowsky, Jan Niklas Petry-Schmelzer, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6542345/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Dec, 2025 Read the published version in Trials → Version 1 posted 4 You are reading this latest preprint version Abstract Background : Subthalamic deep brain stimulation (STN-DBS) effectively treats motor symptoms in Parkinson's disease, but individual responses vary. Despite modern directional leads allowing more precise stimulation, optimal contact selection strategies remain undefined. This study compares a standardized imaging-guided contact selection protocol to conventional clinical programming. Methods : We designed a monocentric, randomized, double-blind crossover trial enrolling 30 people with Parkinson's Disease with bilateral directional STN-DBS. Participants will receive both programming approaches: standardized imaging-guided contact selection targeting the dorsolateral STN and conventional contact selection through clinical test stimulations. Each configuration will be applied for one week. The primary outcome is patient preference after both treatments. Secondary outcomes include motor assessments, accelerometric monitoring and questionnaire-based quality of life measures. Discussion : This study addresses a critical gap in standardization of imaging-guided DBS programming. By using patient preference as the primary outcome, we aim to capture clinically meaningful differences that may not be detected with traditional motor scales. The crossover design balances statistical power with clinical feasibility in specialized care settings. Trial Registration : Deutsches Register für Klinische Studien (DRKS00034229, May 27th, 2024) Parkinson’s Disease Deep Brain Stimulation Subthalamic Nucleus Imaging-guided Programming Clinical Trials Figures Figure 1 Figure 2 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson's Disease: Study Protocol for a Randomized Double-blind Crossover Trial Trial registration {2a and 2b}. Deutsches Register für Klinische Studien (DRKS00034229, May 27 h ) 2024) Protocol version CONECT Prüfplan 1.2 (April 5 th , 2025) Funding {4} This study is conducted with internal institutional resources. No external funding was received. Author details {5a} Brandt GA 1,3 , Piotrowsky L 1 , Petry-Schmelzer JN 1 , van der Linden C 1 , Schedlich-Teufer C 1 , Visser-Vandewalle V 2 , Dembek TA 1 , Barbe MT 1 . 1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology 2 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Stereotactic and Functional Neurosurgery 3 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Neurology with Experimental Neurology Name and contact information for the trial sponsor {5b} Universität zu Köln Albertus-Magnus-Platz 50923 Köln D - Germany Role of sponsor {5c} No external entity had any role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication. All decisions related to the research process remained solely with the investigator team, with no external authoritative oversight or influence. Introduction Background and rationale {6a} Subthalamic Deep Brain Stimulation (DBS) is a well-established neuromodulation therapy used to alleviate the motor symptoms of Parkinson’s disease (PD) (1,2). It effectively reduces motor fluctuations and decreases the required dosages of dopaminergic medication, maintaining these benefits well beyond the immediate postoperative phase (3). However, individual treatment responses remain variable, highlighting the need for further optimization to enable consistent clinical outcomes for all patients (4). A critical prerequisite for achieving optimal stimulation effects is the precise placement of the electric field (5,6). Extensive research has established that stimulation of the posterodorsal aspect of the subthalamic nucleus (STN) is most effective in reducing akinetic-rigid symptoms with minimal side effects (7–10). To further enhance the precision of stimulation beyond the initial implantation, modern DBS leads are equipped with multiple segmented contacts (11,12). These allow for vertical and horizontal current steering, thereby facilitating more targeted stimulation (13). Traditionally, optimal stimulation contacts are identified through a monopolar review, i.e. multiple test stimulations conducted during a comprehensive clinical examination by a DBS expert (14,15). While generally deemed effective, this process is cumbersome, subjective and time-consuming (16,17). In recent years, several software solutions have been introduced that enable visualization of the individual lead position in relation to the target brain structures (18,19). Multiple studies have demonstrated that expert clinicians can determine effective stimulation contacts using this imaging data in a more time-efficient manner compared to conventional approaches (20–23). However, the optimal strategy for imaging-guided DBS programming remains to be established. Comparative correlation analyses suggest that even minor differences in contact selection strategies may significantly impact treatment outcomes (24). So far, efforts to standardize imaging-guided DBS programming have been limited. Prior investigations have refrained from specifying the exact algorithms or decision-making processes used for contact selection based on visual information. To address this gap, we designed a randomized double-blind crossover trial to compare a standardized protocol for imaging-guided contact selection to conventional DBS programming. Objectives {7} Does standardized imaging-guided contact selection facilitate equal symptom control compared to conventional contact selection for STN-DBS in PD? Trial design {8} This study is a randomized, controlled, double-blind, crossover trial with an intra-individual head-to-head comparison of two deep brain stimulation (DBS) programs. The allocation ratio is 1:1, with each participant receiving both interventions in a randomized sequence. The trial follows an equivalence framework, with the primary outcome being tested for equality using the Prescott test. Methods: Participants, interventions and outcomes Study setting {9} This study will be executed as a monocentric study (University Hospital Cologne, Cologne, Germany). Eligibility criteria {10} Inclusion criteria: - Clinically confirmed diagnosis of Parkinson’s disease according to current MDS criteria (25) - Implanted DBS system with bilateral directional leads for at least 10 weeks - Availability of high-resolution cranial preoperative MRI and postoperative CT from routine clinical imaging - Stable Parkinson’s disease-specific medication regimen for at least 2 weeks - Age over 18 years Exclusion criteria: - Debilitating postural instability - Cognitive impairment meeting diagnostic criteria for dementia - Vestibular or orthopedic comorbidities with significant impact on daily functioning - Dopamine dysregulation syndrome - Inability or unwillingness to reliably operate the DBS system's remote control Who will take informed consent? {26a} Informed consent will be obtained from all potential participants both in written and oral form by study physicians prior to enrollment in the trial. Additional consent provisions for collection and use of participant data and biological specimens {26b} No biological specimens will be collected in this study. Participant data will be collected according to established guidelines, with no provisions for use in ancillary studies. The informed consent process addresses only the data collection and use for the current trial. Interventions Explanation for the choice of comparators {6b} The two DBS programming approaches were selected for comparison based on their clinical relevance and potential impact on patient care. Conventional clinical contact selection through test stimulations represents the current standard of care in most DBS centers worldwide and has established efficacy. However, this approach is time-consuming, requires specialized expertise, and may be subject to inter-examiner variability (20,21). Standardized imaging-guided contact selection has emerged as a potentially more efficient alternative that might provide more consistent outcomes across centers (23). Our specific standardized protocol targeting the dorsolateral STN is based on our clinical experience and previous research showing this approach’s association with optimal motor improvement (24). Intervention description {11a} The study intervention will be a DBS program with a contact selection based on individual imaging. The required imaging is acquired during our clinical routine: Preoperative isometric (1.0 mm³ voxel size) T1- and T2-weighted MRI (3T Ingenia, Achieva, 1.5T Ingenia, Philips Healthcare, The Netherlands) and a postoperative high resolution CT scan (IQon Spectral CT, iCT 256, Brilliance 256, Philips Healthcare, The Netherlands). Imaging will be assessed with a proprietary software (Brainlab Elements GUIDE XT, Brainlab, Munich, Germany). After automated fusion of the available images three nuclei will be segmented using the integrated segmentation function (nucleus ruber, substantia nigra, subthalamic nucleus). The dorsal, lateral and medial borders of the STN are refined based on the T2 hypointensity. The lead positions will be determined using the automated lead detection algorithm. Lead orientations will either be determined via the automatic lead orientation detection algorithm or assessed visually, if necessary. Contact selections will be determined with the 3D visualization of a representative VTA (Volume of Tissue Activated; 2 mA, 60 µs, 130 Hz), which is positioned following a predetermined strategy (24): 1) If a lead is positioned in the visual center of the posterior third of the STN, omnidirectional settings are selected. Otherwise, the maximal directional focus is applied and faced toward the posterior third of the STN. 2) Contact levels close to the dorsal border of the STN are selected to align the dorsal border of the VTA with the dorsal border of the STN, focusing on the dorsal motor STN. If a ring contact is the closest to the dorsal border of the STN with a lead positioned off-center to the posterior third of the STN, directional contacts on the neighboring level can be used to facilitate directional stimulation at the investigator’s discretion. The control intervention will be a DBS program with a contact selection determined during a physical examination after overnight cessation of dopaminergic medications with test stimulations by movement disorders experts with extensive experience in DBS treatment. During the examination the most effective level will be determined, multi-level configurations are permitted at the clinician’s discretion. Directional settings will be selected, when the clinician deems a clinical benefit during test stimulations. Both DBS programs will apply pulses with 60 µs at 130 Hz. The initial amplitudes are determined based on a subsequent blinded amplitude titration and determined as rigidity threshold + 0.5 mA. Each DBS program will be applied for a week. Study participants will be asked to autonomously titrate the optimal amplitudes during the first three days of the respective treatment weeks. During the following three days amplitudes will be kept stable. Criteria for discontinuing or modifying allocated interventions {11b} Adverse events, including stimulation-induced side effects, will be monitored and documented throughout the study duration. Participants retain the right to withdraw from the study at any time without explanation. Should a participant choose to discontinue a treatment week, they may still proceed to the subsequent treatment phase if the aborted week was their first allocation. Assessment of treatment preference will occur regardless of whether participants complete both treatment weeks. To ensure patient safety each participant will have their established DBS program available as a rescue option accessible via the patient remote. Strategies to improve adherence to interventions {11c} To ensure adherence to the intervention protocols, each participant will receive a detailed schedule of their treatment periods, instructions for indications for amplitude adjustments and a motor diary to record daily experiences with each DBS program during the stable treatment phase. Study personnel will conduct regular phone check-ins between scheduled visits to monitor protocol adherence and address any concerns. During on-site visits, the research team will verify DBS program settings to confirm participants are receiving the allocated intervention. Relevant concomitant care permitted or prohibited during the trial {11d} Participants will be advised to maintain their regular medication regimen and routine care throughout the trial period. Participants are prohibited from enrolling in other interventional clinical trials during the study period. Provisions for post-trial care {30} Upon trial completion, participants will transition to regular care at our hospital. Any adverse events related to trial participation will be treated according to standard clinical protocols within our institution. Participants are covered by insurance coverage for trial-related injuries or harm. Outcomes {12} The primary outcome will be patient preference between imaging-guided contact selection and clinical contact selection. Secondary outcome measures include clinical (MDS-UPDRS III) and objective (Accelerometer) motor symptom assessments as well as patient questionnaires (FOG-Q, PDQ-39, MDS-UPDRS I/II/IV, MDS-NMSS) and motor diaries. Participant timeline {13} Sample size {14} Our comparative power simulation (Monte Carlo method with 100,000 iterations, p(b) = 1-p(a), n = 10:1:100) evaluated four binary outcome tests across Cohen's h effect sizes. Results revealed the Prescott Test of Equality minimizes false negatives in small cohorts (n < 60) compared to McNemar, Sign-Test, and Permutation Statistics (Figure 2). This specialized test was developed in 1981 specifically for crossover designs and demonstrates superior robustness against treatment order effects [27]. Based on the simulations within the framework of Cohen’s h we determined that a study with 27 subjects would achieve 80% statistical power at α = 0.05 (two-sided) to detect a true preference difference for detecting large, i.e. a substantial and clinically significant differences (Figure 2). In the binary choice scenario of this study Cohen’s h = 0.8 corresponds to a preference distribution of 70% versus 30%. Anticipating a dropout rate of 10% we plan to recruit 30 subjects. Recruitment {15} Study participants will be recruited from the patient population of the Neurological Department of the University Hospital Cologne. Suitable candidates will be prescreened based on the available medical records. For definitive screening possible study participants will be reexamined by a study physician to assess inclusion and exclusion criteria. Assignment of interventions: allocation Sequence generation {16a} The allocation sequence will be generated through block randomization. Blocks containing six tokens (3× AB/3× BA treatment sequences) will be prepared to ensure balanced allocation of treatment order. Concealment mechanism {16b} The allocation sequence will be concealed using prepared envelopes containing the randomized treatment order tokens. The documented treatment order and interventions will be stored securely in sealed envelopes and a password-protected database. Implementation {16c} One designated study team member will determine the treatment order by drawing from the prepared envelopes, establish the imaging-guided contact selection, and handle the programming devices. This team member will enroll participants and assign them to the intervention sequences. The remaining team members will remain blinded to patient anatomy and active treatment throughout the study. Assignment of interventions: Blinding Who will be blinded {17a} This study employs a double-blind design. Trial participants, clinical assessors, and all study team members except for one designated programmer will be blinded to the treatment allocation. The designated programmer will determine treatment order, establish the imaging-guided contact selection, and handle the programming devices, while maintaining confidentiality of the allocation. Clinical DBS programming will be conducted by blinded team members who have no access to the treatment allocation information. Motor scales will be assessed based on video documentation to facilitate blinded ratings. Procedure for unblinding if needed {17b} Unblinding will only be permitted in the event of a serious adverse event (SAE) where knowledge of the active DBS program is essential for appropriate clinical management and patient safety. All instances of unblinding will be documented, including the reason and personnel involved. Data collection and management Plans for assessment and collection of outcomes {18a} All outcome assessments will be performed by trained clinical investigators. To promote data quality, standardized clinical research forms (CRFs) will be used for all assessments, and any modifications will be clearly marked and signed by the investigator. Plans to promote participant retention and complete follow-up {18b} To promote participant retention and complete follow-up, participants will receive clear scheduling information at enrollment and reminder calls prior to each study visit. The relatively short duration of each treatment phase (one week per intervention) minimizes participant burden. Should a participant choose to discontinue a treatment week, they may still proceed to the subsequent treatment phase if the aborted week was their first allocation. For participants who discontinue, we will collect the primary outcome measure (treatment preference) whenever possible, regardless of whether they complete both treatment weeks. Secondary outcome measures will be collected at the time of discontinuation to allow for partial analysis. All participants who receive at least one intervention will be included in the safety analysis. Transportation support will be offered to participants who have difficulty attending follow-up visits to minimize attrition. Data management {19} Data will be collected on physical clinical research forms (CRFs) with check lists and tables to ensure complete data entry. All CRF modifications will be clearly marked and signed by the investigator. The data will then be transferred to a dedicated spreadsheet for analysis. To ensure data quality, both source documentation and CRFs will be subject to monitoring by the Zentrum für Klinische Studien Köln (ZKS Köln). The monitors will verify 100% of inclusion and exclusion criteria as well as the primary outcome measure for all subjects. Additional random sampling of other data points will be conducted during regular monitoring visits to verify overall data integrity. The dedicated spreadsheet will be password-protected and regularly backed up to a designated secure hard drive within the hospital's network. Confidentiality {27} Personal information about participants will be protected through a coding system. Each participant will be assigned a unique anonymized code (e.g., CONECT01) that will be used on all study documentation and data. The master list linking participant identities to their assigned codes will be maintained separately from the study data in two secure locations: as an electronic file on the hospital's secured computer system with restricted access, and as a physical copy stored in the investigator site file kept in a locked cabinet with controlled access. Only authorized study personnel will have access to this decoding information. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable. This study does not involve the collection, evaluation, or storage of biological specimens. Statistical methods Statistical methods for primary and secondary outcomes {20a} The binary outcome of patient preference will be coded as 0 (clinical contact selection) or 1 (imaging-guided contact selection) and analyzed with the Prescott test (26). Based on the power simulations described above the h0-hypothesis is defined as follows: 'Based on patient preference there is not any large, i.e. substantial and clinically significant difference between treatments (Cohen’s h > 0.8)'. A p-value < 0.05 indicates a clinically relevant difference between treatments. The secondary outcomes (MDS-UPDRS, PDQ39, MDS-NMSS, FOG-Q and motor diaries) will be compared across groups and timepoints using repeated measures ANOVA for normally distributed data or Kruskal-Wallis test for non-normally distributed data. Prior to analysis, data will be tested for normality using the Shapiro-Wilk test. The accelerometric data will be collected and kept for post-hoc analysis. Interim analyses {21b} For interim safety and efficacy evaluation, a formal analysis will be conducted after completion of the third randomization block (18 subjects, representing > 50% of enrollment). The trial will be terminated early if either of two predefined stopping criteria are met: Statistical significance of the Prescott Test for the primary endpoint (p < 0.05) indicating a very large treatment effect. Treatment discontinuation exceeding 70% in either study arm indicating a safety signal. Methods for additional analyses (e.g. subgroup analyses) {20b} Additional analyses will include both subgroup analyses and mixed modeling approaches. Clinical characteristics including disease type (akinetic-rigid, tremor-dominant, mixed presentation), disease duration, levodopa equivalent daily dose (LEDD), age, and cognitive status (MoCA score) will serve as independent variables. Composite subscores from assessment scales, such as dyskinesia and off-period scores from UPDRS IV, will also be analyzed. Mixed effects models will be employed to account for the repeated measures design and individual variability, with treatment condition as fixed effect and participant as random effect. These models will allow for examination of potential moderators of treatment effects. All additional analyses will be considered exploratory and will be clearly identified as such in the reporting of results. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} The analysis will include all randomized participants who received at least one intervention. For handling missing data, if a maximum of two components of a multiple component score (such as MDS-UPDRS III) is missing, the missing item value(s) will be imputed using the most frequent (mode) response to this item in the entire group at the corresponding time point. If a score is completely missing, the patient will be excluded from the main analysis of the corresponding endpoint. For the primary outcome of patient preference, if a participant fails to complete both treatment phases but provides a preference statement, this will be included in the analysis. Plans to give access to the full protocol, participant level-data and statistical code {31c} The full study protocol will be made available upon reasonable request to the corresponding author. Participant-level data may be shared for academic purposes following study completion, subject to appropriate data sharing agreements and ethical approvals. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} This single-center study is conducted by a small study team consisting of the principal investigator and co-investigators who are responsible for day-to-day trial operations, including participant recruitment, intervention delivery, data collection, and management. The Zentrum für Klinische Studien Köln (ZKS Köln) provides institutional monitoring services and oversight to ensure compliance with Good Clinical Practice guidelines. The ZKS Köln conducts regular monitoring visits to verify source documentation, data integrity, and protocol adherence. There are no separate steering committee, endpoint adjudication committee, or external data management team for this trial. Composition of the data monitoring committee, its role and reporting structure {21a} Due to the short duration of the study, the crossover design, and the low-risk profile of the interventions (comparing two established DBS programming approaches rather than testing a novel intervention), a formal Data Monitoring Committee has not been established for this trial. Both DBS programming approaches under investigation represent variations of standard clinical care, with well-characterized safety profiles. Safety monitoring will be conducted by the study team in conjunction with the Zentrum für Klinische Studien Köln (ZKS Köln), which provides independent monitoring services. Predefined stopping rules have been established for the interim analysis, and these decisions will be made by the principal investigator in consultation with the ZKS Köln based on the predefined criteria. Adverse event reporting and harms {22} Adverse events (AEs) and serious adverse events (SAEs) will be collected, assessed, and documented throughout the study period. At each study visit, participants will be actively questioned about any experienced adverse events. Spontaneously reported adverse events will also be documented. SAEs will be reported to the principal investigator within 24 hours of detection and will be documented in detail, including onset, duration, resolution, and measures taken. SAEs that are related to the study intervention and unexpected will trigger the unblinding procedure and be reported to the Ethics Committee according to local requirements. Frequency and plans for auditing trial conduct {23} No formal auditing procedures are planned for this trial beyond the regular monitoring provided by the Zentrum für Klinische Studien Köln (ZKS Köln). The monitoring activities conducted by ZKS Köln will verify adherence to the protocol, accuracy of data collection, and compliance with regulatory requirements. If concerns arise during monitoring, the principal investigator will implement corrective actions as needed. The institutional ethics committee retains the right to audit the trial at their discretion, which would be conducted independently from the investigators. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Any modifications to the protocol that may impact the conduct of the study, participant safety, potential benefit, or that significantly affect study procedures, objectives, or design will require a formal amendment. All amendments will be submitted to the Institutional Review Board/Ethics Committee for approval before implementation. Once approved, the changes will be communicated to all relevant parties. Dissemination plans {31a} Trial results will be disseminated through publication in peer-reviewed scientific journals and presentation at relevant scientific conferences, regardless of the outcome. There are no publication restrictions. The results will also be reported in the clinical trial registry where the study was registered. Participants will receive a summary of the study findings upon request. This study protocol was written in accordance to the SPIRIT Guidelines (27). Discussion Due to the substantial clinical efficacy of subthalamic DBS, significant treatment effects can be reliably demonstrated using the motor exam of the long-established MDS-UPDRS ( 28 , 2 , 29 ). While the strengths of this measure entail a broad validation, strong correlation with disease severity and established inter- and intra-rater variabilities ( 30 , 31 ), the subtle but clinically relevant differences between two DBS programs, such as stimulation-induced dysarthria, can easily be underrepresented (1/132 points) in this measure ( 32 – 34 ). To sensitively detect treatment differences both regarding treatment efficacy and side effects we propose patient preference after a cross-over trial as a meaningful measure of perceivable and clinically meaningful differences in treatment-related quality of life. The dichotomous nature of this endpoint offers statistical advantages over the inherent variability found in semi-quantitative assessment tools such as the MDS-UPDRS. To facilitate most valid comparison, the DBS programs will be compared by the study participants after one week of treatment with each program. One week allows stimulation effects to stabilize beyond initial adjustments and to be explored in the participants’ environment, while also being brief enough for recall. As the expected difference in preference, i.e. the treatment effect cannot be determined a priori, we refrained from guessing expected distributions but employed the well-established framework of Cohen’s h ( 35 ). While a small treatment effect (h = 0.3) is considered measurable, but insignificant, a large treatment effect (h = 0.8) is considered substantial and clinically relevant. We conclude, that while the detection of modest effects requires 63 subjects, a large difference in patient preference can be excluded (with a power > 80%) after a negative trial with 27 subjects. Perspective The specialized nature of DBS care necessitates a multi-disciplinary team approach within tertiary centers, which traditionally constrains sample sizes, frequently to fewer than 20 participants per study. This limitation stands in stark contrast to the rapidly expanding technological innovations in the field and the heterogeneous presentation of the treated diseases, characterized by diverse clinical phenotypes and scenarios observed in everyday clinical practice. This dichotomy creates an urgent need for methodologically robust studies that are sufficiently powered yet practically feasible within existing clinical infrastructures. The challenge facing the field is substantial: how to generate high-quality evidence that can withstand scientific scrutiny while acknowledging the practical constraints of clinical realities. Traditional clinical trial designs often fail to accommodate these tensions, resulting in either underpowered studies or impractical protocols that cannot be implemented in real-world settings. Based on these considerations, we propose this specialized study design as a methodological bridge—combining statistical efficiency with clinical practicality. Our approach enables meaningful comparisons between DBS treatment strategies while remaining feasible within the constraints of specialized tertiary care settings. This design maximizes the information yield from necessarily limited sample sizes, potentially accelerating the translation and dissemination of technological advances into improved patient outcomes. Trial status Protocol version: CONECT Prüfplan 1.2 (April 5th, 2025). Recruitment began on July 10th, 2024. The anticipated completion date for recruitment is March 31th, 2026. Abbreviations DBS Deep Brain Stimulation STN Subthalamic Nucleus STN-DBS Subthalamic Deep Brain Stimulation PD Parkinson's Disease MDS-UPDRS Movement Disorder Society-Unified Parkinson's Disease Rating Scale FOG-Q Freezing of Gait Questionnaire PDQ-39 Parkinson's Disease Questionnaire-39 MDS-NMSS Movement Disorder Society-Non-Motor Symptom Scale CT Computed Tomography MRI Magnetic Resonance Imaging VTA Volume of Tissue Activated LEDD Levodopa Equivalent Daily Dose MoCA Montreal Cognitive Assessment SAE Serious Adverse Event AE Adverse Event CRF Clinical Research Form ZKS Köln Zentrum für Klinische Studien Köln (Center for Clinical Studies Cologne) Declarations Acknowledgements We would like to acknowledge the patients and their families for their participation and commitment to this research. We also express our gratitude to the healthcare professionals who enable the complex care for our patients, including Study Nurses Max Pohl and Justus Rewolle, and Parkinson Nurse Susanne Hoffmann. Authors’ contributions {31b} GAB conceived the study, designed the protocol, performs data collection, and drafted the manuscript. LP contributed to protocol development, conducts imaging-guided contact selection, performs data collection, and revised the manuscript. JNPS contributed to the study design and revised the manuscript. CvdL performs data collection, conducts clinical contact selection, and revised the manuscript. CST performs data collection, conducts clinical contact selection, and revised the manuscript. VVV provided supervision and revised the manuscript. TAD contributed to the study design, supports analysis of imaging and accelerometer data, and revised the manuscript. MTB is the Principal Investigator: he provided the resources, conceived the study design, conducts clinical contact selection and revised the manuscript. All authors read and approved the final manuscript. Funding {4} This study is conducted with internal institutional resources only. No external funding bodies or sponsors are involved in this research. All personnel, facilities, and materials used in this study are provided through departmental resources at the Neurology Department of the University Hospital Cologne. No external entities have any role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication. All decisions related to the research process remain solely with the investigator team. Availability of data and materials {29} The final trial dataset will be accessible to the principal investigator and co-investigators directly involved in the trial. There are no contractual agreements in place that limit access to the dataset for investigators. De-identified data may be made available to other researchers upon reasonable request following study completion, subject to appropriate data sharing agreements and ethical approvals. Statistical analyses will be performed by the study team, with no restrictions on investigator access to analyzed data. Ethics approval and consent to participate {24} Ethical approval for this study has been obtained from the Ethics Committee of the Medical Faculty of the University of Cologne (reference number 23-1367). Written, informed consent to participate will be obtained from all participants prior to enrollment in the trial. Consent for publication {32} Not applicable. This manuscript does not contain individual person's data, images, or videos. A model consent form for study participation is available upon request from the corresponding author. Competing interests {28} GAB received honoraria for advisory board participation unrelated to this work and travel expenses for educational activities from Boston Scientific and Medtronic GmbH. LP has nothing to declare. JNPS was supported by the Cologne Clinician Scientist Program (CCSP, Faculty of Medicine, University of Cologne), funded by the German Research Foundation (DFG, FI 773/15-1) unrelated to this project. CvdL was supported by the DFG (Project Number 502436811), unrelated to this project, and by the CCSP. CST received personal funding from Medtronic GmbH. VVV received honoraria for advisory board participation and speaker fees from Boston Scientific, Medtronic and LivaNova. TAD's work was supported by the CCSP. He additionally received speaker honoraria from Boston Scientific and Medtronic GmbH unrelated to this work. MTB received speaker's honoraria from Medtronic GmbH, Boston Scientific, Abbott (formerly St Jude), GE Medical, UCB, Apothekerverband Köln eV, and Bial; 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 Institut für Qualitaet und Wirtschaftlichkeit im Gesundheitswesen. References Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, et al. Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology. 1998 Sep;51(3):850–5. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006 Aug 31;355(9):896–908. Bove F, Mulas D, Cavallieri F, Castrioto A, Chabardès S, Meoni S, et al. Long-term Outcomes (15 Years) After Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease. Neurology. 2021 Jul 19;97(3):e254–62. Lachenmayer ML, Mürset M, Antih N, Debove I, Muellner J, Bompart M, et al. Subthalamic and pallidal deep brain stimulation for Parkinson’s disease-meta-analysis of outcomes. NPJ Park Dis. 2021 Sep 6;7(1):77. Ellis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, et al. Reoperation for suboptimal outcomes after deep brain stimulation surgery. Neurosurgery. 2008 Oct;63(4):754–60; discussion 760-761. Hamani C, Florence G, Heinsen H, Plantinga BR, Temel Y, Uludag K, et al. Subthalamic Nucleus Deep Brain Stimulation: Basic Concepts and Novel Perspectives. eNeuro [Internet]. 2017 Sep 1 [cited 2022 Oct 26];4(5). Available from: https://www.eneuro.org/content/4/5/ENEURO.0140-17.2017 Herzog J, Fietzek U, Hamel W, Morsnowski A, Steigerwald F, Schrader B, et al. Most effective stimulation site in subthalamic deep brain stimulation for Parkinson’s disease. Mov Disord Off J Mov Disord Soc. 2004 Sep;19(9):1050–4. Wodarg F, Herzog J, Reese R, Falk D, Pinsker MO, Steigerwald F, et al. Stimulation site within the MRI-defined STN predicts postoperative motor outcome. Mov Disord. 2012;27(7):874–9. Dembek TA, Roediger J, Horn A, Reker P, Oehrn C, Dafsari HS, et al. Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease. Ann Neurol. 2019;86(4):527–38. Akram H, Sotiropoulos SN, Jbabdi S, Georgiev D, Mahlknecht P, Hyam J, et al. Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson’s disease. NeuroImage. 2017 Sep 1;158:332–45. Steigerwald F, Müller L, Johannes S, Matthies C, Volkmann J. Directional deep brain stimulation of the subthalamic nucleus: A pilot study using a novel neurostimulation device. Mov Disord Off J Mov Disord Soc. 2016 Aug;31(8):1240–3. Dembek TA, Reker P, Visser-Vandewalle V, Wirths J, Treuer H, Klehr M, et al. Directional DBS increases side-effect thresholds-A prospective, double-blind trial. Mov Disord Off J Mov Disord Soc. 2017 Oct;32(10):1380–8. Krauss JK, Lipsman N, Aziz T, Boutet A, Brown P, Chang JW, et al. Technology of deep brain stimulation: current status and future directions. Nat Rev Neurol. 2021 Feb;17(2):75–87. Volkmann J, Herzog J, Kopper F, Deuschl G. Introduction to the programming of deep brain stimulators. Mov Disord. 2002;17(S3):S181–7. Picillo M, Lozano AM, Kou N, Puppi Munhoz R, Fasano A. Programming Deep Brain Stimulation for Parkinson’s Disease: The Toronto Western Hospital Algorithms. Brain Stimulat. 2016 Jun;9(3):425–37. Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, et al. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. Arch Neurol. 2005 Aug;62(8):1250–5. Moro E, Esselink RJA, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson’s disease of electrical parameter settings in STN stimulation. Neurology. 2002 Sep 10;59(5):706–13. Neudorfer C, Butenko K, Oxenford S, Rajamani N, Achtzehn J, Goede L, et al. Lead-DBS v3.0: Mapping deep brain stimulation effects to local anatomy and global networks. NeuroImage. 2023 Mar 1;268:119862. Pavese N, Tai YF, Yousif N, Nandi D, Bain PG. Traditional Trial and Error versus Neuroanatomic 3-Dimensional Image Software-Assisted Deep Brain Stimulation Programming in Patients with Parkinson Disease. World Neurosurg. 2020 Feb;134:e98–102. Lange F, Steigerwald F, Malzacher T, Brandt GA, Odorfer TM, Roothans J, et al. Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming. Front Neurol [Internet]. 2021 [cited 2022 Nov 14];12. Available from: https://www.frontiersin.org/articles/10.3389/fneur.2021.785529 Waldthaler J, Bopp M, Kühn N, Bacara B, Keuler M, Gjorgjevski M, et al. Imaging-based programming of subthalamic nucleus deep brain stimulation in Parkinson’s disease. Brain Stimulat. 2021 Sep;14(5):1109–17. Duffley G, Szabo A, Lutz BJ, Mahoney-Rafferty EC, Hess CW, Ramirez-Zamora A, et al. Interactive mobile application for Parkinson’s disease deep brain stimulation (MAP DBS): An open-label, multicenter, randomized, controlled clinical trial. Parkinsonism Relat Disord. 2023 Apr 1;109:105346. Aubignat M, Berro A, Tir M, Lefranc M. Imaging-Guided Subthalamic Nucleus Deep Brain Stimulation Programming for Parkinson Disease: A Real-Life Pilot Study. Neurol Clin Pract. 2024 Dec;14(6):e200326. Brandt GA, Stopic V, van der Linden C, Strelow JN, Petry-Schmelzer JN, Baldermann JC, et al. A Retrospective Comparison of Multiple Approaches to Anatomically Informed Contact Selection in Subthalamic Deep Brain Stimulation for Parkinson’s Disease. J Park Dis. 2024;14(3):575–87. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord Off J Mov Disord Soc. 2015 Oct;30(12):1591–601. Prescott RJ. The Comparison of Success Rates in Cross-Over Trials in the Presence of an Order Effect. J R Stat Soc Ser C Appl Stat. 1981;30(1):9–15. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013 Jan 8;346:e7586. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003 Nov 13;349(20):1925–34. Schuepbach WMM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013 Feb 14;368(7):610–22. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129–70. Benamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee GJ, Grosset DG. Correlation of Parkinson’s disease severity and duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord Off J Mov Disord Soc. 2000 Jul;15(4):692–8. Hauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, Schapira AH, et al. Minimal Clinically Important Difference in Parkinson’s Disease as Assessed in Pivotal Trials of Pramipexole Extended Release. Park Dis. 2014;2014:467131. Skodda S, Grönheit W, Mancinelli N, Schlegel U. Progression of voice and speech impairment in the course of Parkinson’s disease: a longitudinal study. Park Dis. 2013;2013:389195. Tripoliti E, Zrinzo L, Martinez-Torres I, Frost E, Pinto S, Foltynie T, et al. Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease. Neurology. 2011 Jan 4;76(1):80–6. Cohen J. Statistical Power Analysis for the Behavioral Sciences. Routledge; 2013. 656 p. Cite Share Download PDF Status: Published Journal Publication published 30 Dec, 2025 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 22 Jun, 2025 Reviewers invited by journal 19 Jun, 2025 Editor assigned by journal 05 Jun, 2025 First submitted to journal 04 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6542345","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":473592895,"identity":"1fe3f61c-8f24-40cf-97f2-baf96cebd4e3","order_by":0,"name":"Gregor Alexander Brandt","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIiWNgGAWjYBCDBBAhwVABYjA2ANnMRGo5cAaspbGBeC0H28AMRrxa5KMPH37xcQ9Dnnn72YO3P86zy+Offbj9wQcGazlcWgzPpaVZznjGUCxzJi/Z4uC25GKJc4mNjTMY0o1xaunhMTPmOcCQOIMhx0zi4LYDiQ1nGBubeRgOJzbg1ML/DaKF/w1Qy5wDifNBWv4wHK7HpUWeh4f5MViLBMiWhgOJG0BaGBgOJ+BymAEPmxnjjAMSxRISb4wtzhxLTtwI1DKzxyDdEKctPcyPP3w4YJMnwZ9jeKOixi5x3hn2Bx9+VFjL47TlAAObBCje0cVxaQDa0sDA/AG39CgYBaNgFIwCIAAArPhdZmbPCgMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-9984-2069","institution":"Charite Universitatsmedizin Berlin","correspondingAuthor":true,"prefix":"","firstName":"Gregor","middleName":"Alexander","lastName":"Brandt","suffix":""},{"id":473592896,"identity":"2970f2c8-d065-4b8a-b694-f3624d47a6e3","order_by":1,"name":"Lisa Piotrowsky","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Piotrowsky","suffix":""},{"id":473592897,"identity":"348a7b05-4382-419a-a563-9b76956e4f2d","order_by":2,"name":"Jan Niklas Petry-Schmelzer","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"Niklas","lastName":"Petry-Schmelzer","suffix":""},{"id":473592898,"identity":"4ff91125-0fd5-46b6-89a0-003d9b38feb7","order_by":3,"name":"Christina van der Linden","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Christina","middleName":"van der","lastName":"Linden","suffix":""},{"id":473592899,"identity":"928e1214-a254-4e4c-bac1-a09a225d194e","order_by":4,"name":"Charlotte Schedlich-Teufer","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Schedlich-Teufer","suffix":""},{"id":473592900,"identity":"82ad1b62-3f64-44bb-877f-0528ec0b2f9f","order_by":5,"name":"Veerle Visser-Vandewalle","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Veerle","middleName":"","lastName":"Visser-Vandewalle","suffix":""},{"id":473592901,"identity":"b3733f00-f379-46ec-96ab-5ee8b6a9048c","order_by":6,"name":"Till Anselm Dembek","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Till","middleName":"Anselm","lastName":"Dembek","suffix":""},{"id":473592902,"identity":"6f28df0f-0453-4f0f-93d2-ebaecd205813","order_by":7,"name":"Michael Thomas Barbe","email":"","orcid":"","institution":"Uniklinik Köln: Universitatsklinikum Koln","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"Thomas","lastName":"Barbe","suffix":""}],"badges":[],"createdAt":"2025-04-27 20:32:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6542345/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6542345/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-09396-3","type":"published","date":"2025-12-30T15:58:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86240369,"identity":"65b479e8-31fb-4fad-865b-d569a09e4827","added_by":"auto","created_at":"2025-07-08 10:33:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":570544,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic trial timeline including a schedule of enrolment, interventions, and assessments.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6542345/v1/21479edfdc42e3e262e73e64.png"},{"id":86241768,"identity":"fe87bf7a-448a-40b5-b6c7-a94f8bcae44f","added_by":"auto","created_at":"2025-07-08 10:49:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":269315,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStatistical Power by Effect and Sample Size:\u003c/strong\u003e Monte Carlo simulation with pseudorandomized probabilities for a binary choice (p(b) = 1 – p(a)) with four different test statistics. Each panel shows the analysis for probability distributions representing either a small (left), medium (middle) or large (right) treatment effect as defined by Cohen’s h. While permutation statistics (red) and the Sign test (yellow) lead to more conservative power estimations across the spectrum of sample sizes than Prescott (blue) and McNemar (green) tests. Below the sample size of 60 the Prescott Test yield the highest power among the compared tests.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6542345/v1/a0e2a8d2e7c03639a40d0e02.png"},{"id":99545314,"identity":"08d03d97-df6b-41ab-861d-eabd0cf4d214","added_by":"auto","created_at":"2026-01-05 16:05:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2348265,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6542345/v1/17c891bc-959e-497f-bde9-2901ec7cf91c.pdf"}],"financialInterests":"","formattedTitle":"Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson's Disease: Study Protocol for a Randomized Double-blind Crossover Trial","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eComparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson\u0026apos;s Disease: Study Protocol for a Randomized Double-blind Crossover Trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eDeutsches Register f\u0026uuml;r Klinische Studien (DRKS00034229, May 27\u003csup\u003eh\u003c/sup\u003e) 2024)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eProtocol version\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eCONECT Pr\u0026uuml;fplan 1.2 (April 5\u003csup\u003eth\u003c/sup\u003e, 2025)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eThis study is conducted with internal institutional resources. No external funding was received.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eBrandt GA\u003csup\u003e1,3\u003c/sup\u003e, Piotrowsky L\u003csup\u003e1\u003c/sup\u003e, Petry-Schmelzer JN\u003csup\u003e1\u003c/sup\u003e, van der Linden C\u003csup\u003e1\u003c/sup\u003e, Schedlich-Teufer C\u003csup\u003e1\u003c/sup\u003e, Visser-Vandewalle V\u003csup\u003e2\u003c/sup\u003e, Dembek TA\u003csup\u003e1\u003c/sup\u003e, Barbe MT\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eUniversity of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eUniversity of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Stereotactic and Functional Neurosurgery\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u0026nbsp;\u003c/sup\u003eCharit\u0026eacute; - Universit\u0026auml;tsmedizin Berlin, corporate member of Freie Universit\u0026auml;t Berlin and Humboldt Universit\u0026auml;t zu Berlin, Department of Neurology with Experimental Neurology\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eUniversit\u0026auml;t zu K\u0026ouml;ln\u003c/p\u003e\n \u003cp\u003eAlbertus-Magnus-Platz\u003c/p\u003e\n \u003cp\u003e50923 K\u0026ouml;ln\u003c/p\u003e\n \u003cp\u003eD - Germany\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eNo external entity had any role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication. All decisions related to the research process remained solely with the investigator team, with no external authoritative oversight or influence.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubthalamic Deep Brain Stimulation (DBS) is a well-established neuromodulation therapy used to alleviate the motor symptoms of Parkinson’s disease (PD) (1,2). It effectively reduces motor fluctuations and decreases the required dosages of dopaminergic medication, maintaining these benefits well beyond the immediate postoperative phase (3). However, individual treatment responses remain variable, highlighting the need for further optimization to enable consistent clinical outcomes for all patients (4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA critical prerequisite for achieving optimal stimulation effects is the precise placement of the electric field (5,6). Extensive research has established that stimulation of the posterodorsal aspect of the subthalamic nucleus (STN) is most effective in reducing akinetic-rigid symptoms with minimal side effects\u0026nbsp;(7–10). To further enhance the precision of stimulation beyond the initial implantation, modern DBS leads are equipped with multiple segmented contacts\u0026nbsp;(11,12). These allow for vertical and horizontal current steering, thereby facilitating more targeted stimulation\u0026nbsp;(13).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTraditionally, optimal stimulation contacts are identified through a monopolar review, i.e. multiple test stimulations conducted during a comprehensive clinical examination by a DBS expert (14,15). While generally deemed effective, this process is cumbersome, subjective and time-consuming (16,17).\u003c/p\u003e\n\u003cp\u003eIn recent years, several software solutions have been introduced that enable visualization of the individual lead position in relation to the target brain structures (18,19). Multiple studies have demonstrated that expert clinicians can determine effective stimulation contacts using this imaging data in a more time-efficient manner compared to conventional approaches\u0026nbsp;(20–23). However, the optimal strategy for imaging-guided DBS programming remains to be established. Comparative correlation analyses suggest that even minor differences in contact selection strategies may significantly impact treatment outcomes\u0026nbsp;(24).\u003c/p\u003e\n\u003cp\u003eSo far, efforts to standardize imaging-guided DBS programming have been limited. Prior investigations have refrained from specifying the exact algorithms or decision-making processes used for contact selection based on visual information. To address this gap, we designed a randomized double-blind crossover trial to compare a standardized protocol for imaging-guided contact selection to conventional DBS programming.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDoes standardized imaging-guided contact selection facilitate equal symptom control compared to conventional contact selection for STN-DBS in PD?\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a randomized, controlled, double-blind, crossover trial with an intra-individual head-to-head comparison of two deep brain stimulation (DBS) programs. The allocation ratio is 1:1, with each participant receiving both interventions in a randomized sequence. The trial follows an equivalence framework, with the primary outcome being tested for equality using the Prescott test.\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be executed as a monocentric study (University Hospital Cologne, Cologne, Germany).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eInclusion criteria:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e- Clinically confirmed diagnosis of Parkinson\u0026rsquo;s disease according to current MDS criteria (25)\u003c/p\u003e\n\u003cp\u003e- Implanted DBS system with bilateral directional leads for at least 10 weeks\u003c/p\u003e\n\u003cp\u003e- Availability of high-resolution cranial preoperative MRI and postoperative CT from routine clinical imaging\u003c/p\u003e\n\u003cp\u003e- Stable Parkinson\u0026rsquo;s disease-specific medication regimen for at least 2 weeks\u003c/p\u003e\n\u003cp\u003e- Age over 18 years\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eExclusion criteria:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e- Debilitating postural instability\u003c/p\u003e\n\u003cp\u003e- Cognitive impairment meeting diagnostic criteria for dementia\u003c/p\u003e\n\u003cp\u003e- Vestibular or orthopedic comorbidities with significant impact on daily functioning\u003c/p\u003e\n\u003cp\u003e- Dopamine dysregulation syndrome\u003c/p\u003e\n\u003cp\u003e- Inability or unwillingness to reliably operate the DBS system\u0026apos;s remote control\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent will be obtained from all potential participants both in written and oral form by study physicians prior to enrollment in the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo biological specimens will be collected in this study. Participant data will be collected according to established guidelines, with no provisions for use in ancillary studies. The informed consent process addresses only the data collection and use for the current trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe two DBS programming approaches were selected for comparison based on their clinical relevance and potential impact on patient care. Conventional clinical contact selection through test stimulations represents the current standard of care in most DBS centers worldwide and has established efficacy. However, this approach is time-consuming, requires specialized expertise, and may be subject to inter-examiner variability (20,21).\u003c/p\u003e\n\u003cp\u003eStandardized imaging-guided contact selection has emerged as a potentially more efficient alternative that might provide more consistent outcomes across centers (23). Our specific standardized protocol targeting the dorsolateral STN is based on our clinical experience and previous research showing this approach\u0026rsquo;s association with optimal motor improvement (24). \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study intervention will be a DBS program with a contact selection based on individual imaging. The required imaging is acquired during our clinical routine: Preoperative isometric (1.0 mm\u0026sup3; voxel size) T1- and T2-weighted MRI (3T Ingenia, Achieva, 1.5T Ingenia, Philips Healthcare, The Netherlands) and a postoperative high resolution CT scan (IQon Spectral CT, iCT 256, Brilliance 256, Philips Healthcare, The Netherlands). Imaging will be assessed with a proprietary software (Brainlab Elements GUIDE XT, Brainlab, Munich, Germany). After automated fusion of the available images three nuclei will be segmented using the integrated segmentation function (nucleus ruber, substantia nigra, subthalamic nucleus). The dorsal, lateral and medial borders of the STN are refined based on the T2 hypointensity. The lead positions will be determined using the automated lead detection algorithm. Lead orientations will either be determined via the automatic lead orientation detection algorithm or assessed visually, if necessary. Contact selections will be determined with the 3D visualization of a representative VTA (Volume of Tissue Activated; 2 mA, 60 \u0026micro;s, 130 Hz), which is positioned following a predetermined strategy (24):\u003c/p\u003e\n\u003cp\u003e1) If a lead is positioned in the visual center of the posterior third of the STN, omnidirectional settings are selected. Otherwise, the maximal directional focus is applied and faced toward the posterior third of the STN.\u003c/p\u003e\n\u003cp\u003e2) Contact levels close to the dorsal border of the STN are selected to align the dorsal border of the VTA with the dorsal border of the STN, focusing on the dorsal motor STN. If a ring contact is the closest to the dorsal border of the STN with a lead positioned off-center to the posterior third of the STN, directional contacts on the neighboring level can be used to facilitate directional stimulation at the investigator\u0026rsquo;s discretion.\u003c/p\u003e\n\u003cp\u003eThe control intervention will be a DBS program with a contact selection determined during a physical examination after overnight cessation of dopaminergic medications with test stimulations by movement disorders experts with extensive experience in DBS treatment. During the examination the most effective level will be determined, multi-level configurations are permitted at the clinician\u0026rsquo;s discretion. Directional settings will be selected, when the clinician deems a clinical benefit during test stimulations.\u003c/p\u003e\n\u003cp\u003eBoth DBS programs will apply pulses with 60 \u0026micro;s at 130 Hz. The initial amplitudes are determined based on a subsequent blinded amplitude titration and determined as rigidity threshold + 0.5 mA. Each DBS program will be applied for a week. Study participants will be asked to autonomously titrate the optimal amplitudes during the first three days of the respective treatment weeks. During the following three days amplitudes will be kept stable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events, including stimulation-induced side effects, will be monitored and documented throughout the study duration. Participants retain the right to withdraw from the study at any time without explanation. Should a participant choose to discontinue a treatment week, they may still proceed to the subsequent treatment phase if the aborted week was their first allocation. Assessment of treatment preference will occur regardless of whether participants complete both treatment weeks. To ensure patient safety each participant will have their established DBS program available as a rescue option accessible via the patient remote.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure adherence to the intervention protocols, each participant will receive a detailed schedule of their treatment periods, instructions for indications for amplitude adjustments and a motor diary to record daily experiences with each DBS program during the stable treatment phase. Study personnel will conduct regular phone check-ins between scheduled visits to monitor protocol adherence and address any concerns. During on-site visits, the research team will verify DBS program settings to confirm participants are receiving the allocated intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be advised to maintain their regular medication regimen and routine care throughout the trial period. Participants are prohibited from enrolling in other interventional clinical trials during the study period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e Provisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUpon trial completion, participants will transition to regular care at our hospital. Any adverse events related to trial participation will be treated according to standard clinical protocols within our institution. Participants are covered by insurance coverage for trial-related injuries or harm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome will be patient preference between imaging-guided contact selection and clinical contact selection. Secondary outcome measures include clinical (MDS-UPDRS III) and objective (Accelerometer) motor symptom assessments as well as patient questionnaires (FOG-Q, PDQ-39, MDS-UPDRS I/II/IV, MDS-NMSS) and motor diaries. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur comparative power simulation (Monte Carlo method with 100,000 iterations, p(b) = 1-p(a), n = 10:1:100) evaluated four binary outcome tests across Cohen\u0026apos;s h effect sizes. Results revealed the Prescott Test of Equality minimizes false negatives in small cohorts (n \u0026lt; 60) compared to McNemar, Sign-Test, and Permutation Statistics (Figure 2). This specialized test was developed in 1981 specifically for crossover designs and demonstrates superior robustness against treatment order effects [27].\u003c/p\u003e\n\u003cp\u003eBased on the simulations within the framework of Cohen\u0026rsquo;s h we determined that a study with 27 subjects would achieve 80% statistical power at \u0026alpha; = 0.05 (two-sided) to detect a true preference difference for detecting large, i.e. a substantial and clinically significant differences (Figure 2). In the binary choice scenario of this study Cohen\u0026rsquo;s h = 0.8 corresponds to a preference distribution of 70% versus 30%. Anticipating a dropout rate of 10% we plan to recruit 30 subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy participants will be recruited from the patient population of the Neurological Department of the University Hospital Cologne. Suitable candidates will be prescreened based on the available medical records. For definitive screening possible study participants will be reexamined by a study physician to assess inclusion and exclusion criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe allocation sequence will be generated through block randomization. Blocks containing six tokens (3\u0026times; AB/3\u0026times; BA treatment sequences) will be prepared to ensure balanced allocation of treatment order.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe allocation sequence will be concealed using prepared envelopes containing the randomized treatment order tokens. The documented treatment order and interventions will be stored securely in sealed envelopes and a password-protected database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne designated study team member will determine the treatment order by drawing from the prepared envelopes, establish the imaging-guided contact selection, and handle the programming devices. This team member will enroll participants and assign them to the intervention sequences. The remaining team members will remain blinded to patient anatomy and active treatment throughout the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study employs a double-blind design. Trial participants, clinical assessors, and all study team members except for one designated programmer will be blinded to the treatment allocation. The designated programmer will determine treatment order, establish the imaging-guided contact selection, and handle the programming devices, while maintaining confidentiality of the allocation. Clinical DBS programming will be conducted by blinded team members who have no access to the treatment allocation information. Motor scales will be assessed based on video documentation to facilitate blinded ratings.\u003cstrong\u003e\u003cbr\u003e Procedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnblinding will only be permitted in the event of a serious adverse event (SAE) where knowledge of the active DBS program is essential for appropriate clinical management and patient safety. All instances of unblinding will be documented, including the reason and personnel involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll outcome assessments will be performed by trained clinical investigators. To promote data quality, standardized clinical research forms (CRFs) will be used for all assessments, and any modifications will be clearly marked and signed by the investigator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo promote participant retention and complete follow-up, participants will receive clear scheduling information at enrollment and reminder calls prior to each study visit. The relatively short duration of each treatment phase (one week per intervention) minimizes participant burden. Should a participant choose to discontinue a treatment week, they may still proceed to the subsequent treatment phase if the aborted week was their first allocation. For participants who discontinue, we will collect the primary outcome measure (treatment preference) whenever possible, regardless of whether they complete both treatment weeks. Secondary outcome measures will be collected at the time of discontinuation to allow for partial analysis. All participants who receive at least one intervention will be included in the safety analysis. Transportation support will be offered to participants who have difficulty attending follow-up visits to minimize attrition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be collected on physical clinical research forms (CRFs) with check lists and tables to ensure complete data entry. All CRF modifications will be clearly marked and signed by the investigator. The data will then be transferred to a dedicated spreadsheet for analysis. To ensure data quality, both source documentation and CRFs will be subject to monitoring by the Zentrum f\u0026uuml;r Klinische Studien K\u0026ouml;ln (ZKS K\u0026ouml;ln). The monitors will verify 100% of inclusion and exclusion criteria as well as the primary outcome measure for all subjects. Additional random sampling of other data points will be conducted during regular monitoring visits to verify overall data integrity. The dedicated spreadsheet will be password-protected and regularly backed up to a designated secure hard drive within the hospital\u0026apos;s network.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePersonal information about participants will be protected through a coding system. Each participant will be assigned a unique anonymized code (e.g., CONECT01) that will be used on all study documentation and data. The master list linking participant identities to their assigned codes will be maintained separately from the study data in two secure locations: as an electronic file on the hospital\u0026apos;s secured computer system with restricted access, and as a physical copy stored in the investigator site file kept in a locked cabinet with controlled access. Only authorized study personnel will have access to this decoding information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study does not involve the collection, evaluation, or storage of biological specimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe binary outcome of patient preference will be coded as 0 (clinical contact selection) or 1 (imaging-guided contact selection) and analyzed with the Prescott test (26). Based on the power simulations described above the h0-hypothesis is defined as follows: \u0026apos;Based on patient preference there is not any large, i.e. substantial and clinically significant difference between treatments (Cohen\u0026rsquo;s h \u0026gt; 0.8)\u0026apos;. A p-value \u0026lt; 0.05 indicates a clinically relevant difference between treatments.\u003c/p\u003e\n\u003cp\u003eThe secondary outcomes (MDS-UPDRS, PDQ39, MDS-NMSS, FOG-Q and motor diaries) will be compared across groups and timepoints using repeated measures ANOVA for normally distributed data or Kruskal-Wallis test for non-normally distributed data. Prior to analysis, data will be tested for normality using the Shapiro-Wilk test. The accelerometric data will be collected and kept for post-hoc analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor interim safety and efficacy evaluation, a formal analysis will be conducted after completion of the third randomization block (18 subjects, representing \u0026gt; 50% of enrollment). The trial will be terminated early if either of two predefined stopping criteria are met: \u003c/p\u003e\n\u003col style=\"list-style-type: lower-roman;\"\u003e\n\u003cli\u003eStatistical significance of the Prescott Test for the primary endpoint (p \u0026lt; 0.05) indicating a very large treatment effect.\u003c/li\u003e\n\u003cli\u003eTreatment discontinuation exceeding 70% in either study arm indicating a safety signal.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional analyses will include both subgroup analyses and mixed modeling approaches. Clinical characteristics including disease type (akinetic-rigid, tremor-dominant, mixed presentation), disease duration, levodopa equivalent daily dose (LEDD), age, and cognitive status (MoCA score) will serve as independent variables. Composite subscores from assessment scales, such as dyskinesia and off-period scores from UPDRS IV, will also be analyzed. Mixed effects models will be employed to account for the repeated measures design and individual variability, with treatment condition as fixed effect and participant as random effect. These models will allow for examination of potential moderators of treatment effects. \u003c/p\u003e\n\u003cp\u003eAll additional analyses will be considered exploratory and will be clearly identified as such in the reporting of results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analysis will include all randomized participants who received at least one intervention. For handling missing data, if a maximum of two components of a multiple component score (such as MDS-UPDRS III) is missing, the missing item value(s) will be imputed using the most frequent (mode) response to this item in the entire group at the corresponding time point. If a score is completely missing, the patient will be excluded from the main analysis of the corresponding endpoint. For the primary outcome of patient preference, if a participant fails to complete both treatment phases but provides a preference statement, this will be included in the analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe full study protocol will be made available upon reasonable request to the corresponding author. Participant-level data may be shared for academic purposes following study completion, subject to appropriate data sharing agreements and ethical approvals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-center study is conducted by a small study team consisting of the principal investigator and co-investigators who are responsible for day-to-day trial operations, including participant recruitment, intervention delivery, data collection, and management. The Zentrum f\u0026uuml;r Klinische Studien K\u0026ouml;ln (ZKS K\u0026ouml;ln) provides institutional monitoring services and oversight to ensure compliance with Good Clinical Practice guidelines. The ZKS K\u0026ouml;ln conducts regular monitoring visits to verify source documentation, data integrity, and protocol adherence. There are no separate steering committee, endpoint adjudication committee, or external data management team for this trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the short duration of the study, the crossover design, and the low-risk profile of the interventions (comparing two established DBS programming approaches rather than testing a novel intervention), a formal Data Monitoring Committee has not been established for this trial. Both DBS programming approaches under investigation represent variations of standard clinical care, with well-characterized safety profiles. Safety monitoring will be conducted by the study team in conjunction with the Zentrum f\u0026uuml;r Klinische Studien K\u0026ouml;ln (ZKS K\u0026ouml;ln), which provides independent monitoring services. Predefined stopping rules have been established for the interim analysis, and these decisions will be made by the principal investigator in consultation with the ZKS K\u0026ouml;ln based on the predefined criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events (AEs) and serious adverse events (SAEs) will be collected, assessed, and documented throughout the study period. At each study visit, participants will be actively questioned about any experienced adverse events. Spontaneously reported adverse events will also be documented. SAEs will be reported to the principal investigator within 24 hours of detection and will be documented in detail, including onset, duration, resolution, and measures taken. SAEs that are related to the study intervention and unexpected will trigger the unblinding procedure and be reported to the Ethics Committee according to local requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo formal auditing procedures are planned for this trial beyond the regular monitoring provided by the Zentrum f\u0026uuml;r Klinische Studien K\u0026ouml;ln (ZKS K\u0026ouml;ln). The monitoring activities conducted by ZKS K\u0026ouml;ln will verify adherence to the protocol, accuracy of data collection, and compliance with regulatory requirements. If concerns arise during monitoring, the principal investigator will implement corrective actions as needed. The institutional ethics committee retains the right to audit the trial at their discretion, which would be conducted independently from the investigators.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny modifications to the protocol that may impact the conduct of the study, participant safety, potential benefit, or that significantly affect study procedures, objectives, or design will require a formal amendment. All amendments will be submitted to the Institutional Review Board/Ethics Committee for approval before implementation. Once approved, the changes will be communicated to all relevant parties.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrial results will be disseminated through publication in peer-reviewed scientific journals and presentation at relevant scientific conferences, regardless of the outcome. There are no publication restrictions. The results will also be reported in the clinical trial registry where the study was registered. Participants will receive a summary of the study findings upon request.\u003c/p\u003e\n\u003cp\u003eThis study protocol was written in accordance to the SPIRIT Guidelines (27).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDue to the substantial clinical efficacy of subthalamic DBS, significant treatment effects can be reliably demonstrated using the motor exam of the long-established MDS-UPDRS (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). While the strengths of this measure entail a broad validation, strong correlation with disease severity and established inter- and intra-rater variabilities (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), the subtle but clinically relevant differences between two DBS programs, such as stimulation-induced dysarthria, can easily be underrepresented (1/132 points) in this measure (\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). To sensitively detect treatment differences both regarding treatment efficacy and side effects we propose patient preference after a cross-over trial as a meaningful measure of perceivable and clinically meaningful differences in treatment-related quality of life. The dichotomous nature of this endpoint offers statistical advantages over the inherent variability found in semi-quantitative assessment tools such as the MDS-UPDRS.\u003c/p\u003e \u003cp\u003eTo facilitate most valid comparison, the DBS programs will be compared by the study participants after one week of treatment with each program. One week allows stimulation effects to stabilize beyond initial adjustments and to be explored in the participants\u0026rsquo; environment, while also being brief enough for recall.\u003c/p\u003e \u003cp\u003eAs the expected difference in preference, i.e. the treatment effect cannot be determined a priori, we refrained from guessing expected distributions but employed the well-established framework of Cohen\u0026rsquo;s h (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). While a small treatment effect (h\u0026thinsp;=\u0026thinsp;0.3) is considered measurable, but insignificant, a large treatment effect (h\u0026thinsp;=\u0026thinsp;0.8) is considered substantial and clinically relevant. We conclude, that while the detection of modest effects requires 63 subjects, a large difference in patient preference can be excluded (with a power\u0026thinsp;\u0026gt;\u0026thinsp;80%) after a negative trial with 27 subjects.\u003c/p\u003e\n\u003ch3\u003ePerspective\u003c/h3\u003e\n\u003cp\u003eThe specialized nature of DBS care necessitates a multi-disciplinary team approach within tertiary centers, which traditionally constrains sample sizes, frequently to fewer than 20 participants per study. This limitation stands in stark contrast to the rapidly expanding technological innovations in the field and the heterogeneous presentation of the treated diseases, characterized by diverse clinical phenotypes and scenarios observed in everyday clinical practice. This dichotomy creates an urgent need for methodologically robust studies that are sufficiently powered yet practically feasible within existing clinical infrastructures.\u003c/p\u003e \u003cp\u003eThe challenge facing the field is substantial: how to generate high-quality evidence that can withstand scientific scrutiny while acknowledging the practical constraints of clinical realities. Traditional clinical trial designs often fail to accommodate these tensions, resulting in either underpowered studies or impractical protocols that cannot be implemented in real-world settings.\u003c/p\u003e \u003cp\u003eBased on these considerations, we propose this specialized study design as a methodological bridge\u0026mdash;combining statistical efficiency with clinical practicality. Our approach enables meaningful comparisons between DBS treatment strategies while remaining feasible within the constraints of specialized tertiary care settings. This design maximizes the information yield from necessarily limited sample sizes, potentially accelerating the translation and dissemination of technological advances into improved patient outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTrial status\u003c/b\u003e \u003c/p\u003e \u003cp\u003eProtocol version: CONECT Pr\u0026uuml;fplan 1.2 (April 5th, 2025). Recruitment began on July 10th, 2024. The anticipated completion date for recruitment is March 31th, 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDBS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDeep Brain Stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSTN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSubthalamic Nucleus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSTN-DBS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSubthalamic Deep Brain Stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eParkinson's Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDS-UPDRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMovement Disorder Society-Unified Parkinson's Disease Rating Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFOG-Q\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFreezing of Gait Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDQ-39\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eParkinson's Disease Questionnaire-39\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDS-NMSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMovement Disorder Society-Non-Motor Symptom Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVTA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVolume of Tissue Activated\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLEDD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLevodopa Equivalent Daily Dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMoCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMontreal Cognitive Assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSerious Adverse Event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse Event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical Research Form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eZKS K\u0026ouml;ln\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eZentrum f\u0026uuml;r Klinische Studien K\u0026ouml;ln (Center for Clinical Studies Cologne)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the patients and their families for their participation and commitment to this research. We also express our gratitude to the healthcare professionals who enable the complex care for our patients, including Study Nurses Max Pohl and Justus Rewolle, and Parkinson Nurse Susanne Hoffmann.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGAB conceived the study, designed the protocol, performs data collection, and drafted the manuscript. LP contributed to protocol development, conducts imaging-guided contact selection, performs data collection, and revised the manuscript. JNPS contributed to the study design and revised the manuscript. CvdL performs data collection, conducts clinical contact selection, and revised the manuscript. CST performs data collection, conducts clinical contact selection, and revised the manuscript. VVV provided supervision and revised the manuscript. TAD contributed to the study design, supports analysis of imaging and accelerometer data, and revised the manuscript. MTB is the Principal Investigator: he provided the resources, conceived the study design, conducts clinical contact selection and revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is conducted with internal institutional resources only. No external funding bodies or sponsors are involved in this research. All personnel, facilities, and materials used in this study are provided through departmental resources at the Neurology Department of the University Hospital Cologne. No external entities have any role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication. All decisions related to the research process remain solely with the investigator team.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe final trial dataset will be accessible to the principal investigator and co-investigators directly involved in the trial. There are no contractual agreements in place that limit access to the dataset for investigators. De-identified data may be made available to other researchers upon reasonable request following study completion, subject to appropriate data sharing agreements and ethical approvals. Statistical analyses will be performed by the study team, with no restrictions on investigator access to analyzed data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study has been obtained from the Ethics Committee of the Medical Faculty of the University of Cologne (reference number 23-1367). Written, informed consent to participate will be obtained from all participants prior to enrollment in the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not contain individual person's data, images, or videos. A model consent form for study participation is available upon request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGAB received honoraria for advisory board participation unrelated to this work and travel expenses for educational activities from Boston Scientific and Medtronic GmbH. LP has nothing to declare. JNPS was supported by the Cologne Clinician Scientist Program (CCSP, Faculty of Medicine, University of Cologne), funded by the German Research Foundation (DFG, FI 773/15-1) unrelated to this project. CvdL was supported by the DFG (Project Number 502436811), unrelated to this project, and by the CCSP. CST received personal funding from Medtronic GmbH. VVV received honoraria for advisory board participation and speaker fees from Boston Scientific, Medtronic and LivaNova. TAD's work was supported by the CCSP. He additionally received speaker honoraria from Boston Scientific and Medtronic GmbH unrelated to this work. MTB received speaker's honoraria from Medtronic GmbH, Boston Scientific, Abbott (formerly St Jude), GE Medical, UCB, Apothekerverband Köln eV, and Bial; 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 Institut für Qualitaet und Wirtschaftlichkeit im Gesundheitswesen.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, et al. Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson\u0026rsquo;s disease. Neurology. 1998 Sep;51(3):850\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eDeuschl G, Schade-Brittinger C, Krack P, Volkmann J, Sch\u0026auml;fer H, B\u0026ouml;tzel K, et al. A randomized trial of deep-brain stimulation for Parkinson\u0026rsquo;s disease. N Engl J Med. 2006 Aug 31;355(9):896\u0026ndash;908.\u003c/li\u003e\n \u003cli\u003eBove F, Mulas D, Cavallieri F, Castrioto A, Chabard\u0026egrave;s S, Meoni S, et al. Long-term Outcomes (15 Years) After Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease. Neurology. 2021 Jul 19;97(3):e254\u0026ndash;62.\u003c/li\u003e\n \u003cli\u003eLachenmayer ML, M\u0026uuml;rset M, Antih N, Debove I, Muellner J, Bompart M, et al. Subthalamic and pallidal deep brain stimulation for Parkinson\u0026rsquo;s disease-meta-analysis of outcomes. NPJ Park Dis. 2021 Sep 6;7(1):77.\u003c/li\u003e\n \u003cli\u003eEllis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, et al. Reoperation for suboptimal outcomes after deep brain stimulation surgery. Neurosurgery. 2008 Oct;63(4):754\u0026ndash;60; discussion 760-761.\u003c/li\u003e\n \u003cli\u003eHamani C, Florence G, Heinsen H, Plantinga BR, Temel Y, Uludag K, et al. Subthalamic Nucleus Deep Brain Stimulation: Basic Concepts and Novel Perspectives. eNeuro [Internet]. 2017 Sep 1 [cited 2022 Oct 26];4(5). Available from: https://www.eneuro.org/content/4/5/ENEURO.0140-17.2017\u003c/li\u003e\n \u003cli\u003eHerzog J, Fietzek U, Hamel W, Morsnowski A, Steigerwald F, Schrader B, et al. Most effective stimulation site in subthalamic deep brain stimulation for Parkinson\u0026rsquo;s disease. Mov Disord Off J Mov Disord Soc. 2004 Sep;19(9):1050\u0026ndash;4.\u003c/li\u003e\n \u003cli\u003eWodarg F, Herzog J, Reese R, Falk D, Pinsker MO, Steigerwald F, et al. Stimulation site within the MRI-defined STN predicts postoperative motor outcome. Mov Disord. 2012;27(7):874\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eDembek TA, Roediger J, Horn A, Reker P, Oehrn C, Dafsari HS, et al. Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease. Ann Neurol. 2019;86(4):527\u0026ndash;38.\u003c/li\u003e\n \u003cli\u003eAkram H, Sotiropoulos SN, Jbabdi S, Georgiev D, Mahlknecht P, Hyam J, et al. Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson\u0026rsquo;s disease. NeuroImage. 2017 Sep 1;158:332\u0026ndash;45.\u003c/li\u003e\n \u003cli\u003eSteigerwald F, M\u0026uuml;ller L, Johannes S, Matthies C, Volkmann J. Directional deep brain stimulation of the subthalamic nucleus: A pilot study using a novel neurostimulation device. Mov Disord Off J Mov Disord Soc. 2016 Aug;31(8):1240\u0026ndash;3.\u003c/li\u003e\n \u003cli\u003eDembek TA, Reker P, Visser-Vandewalle V, Wirths J, Treuer H, Klehr M, et al. Directional DBS increases side-effect thresholds-A prospective, double-blind trial. Mov Disord Off J Mov Disord Soc. 2017 Oct;32(10):1380\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eKrauss JK, Lipsman N, Aziz T, Boutet A, Brown P, Chang JW, et al. Technology of deep brain stimulation: current status and future directions. Nat Rev Neurol. 2021 Feb;17(2):75\u0026ndash;87.\u003c/li\u003e\n \u003cli\u003eVolkmann J, Herzog J, Kopper F, Deuschl G. Introduction to the programming of deep brain stimulators. Mov Disord. 2002;17(S3):S181\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003ePicillo M, Lozano AM, Kou N, Puppi Munhoz R, Fasano A. Programming Deep Brain Stimulation for Parkinson\u0026rsquo;s Disease: The Toronto Western Hospital Algorithms. Brain Stimulat. 2016 Jun;9(3):425\u0026ndash;37.\u003c/li\u003e\n \u003cli\u003eOkun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, et al. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. Arch Neurol. 2005 Aug;62(8):1250\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eMoro E, Esselink RJA, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson\u0026rsquo;s disease of electrical parameter settings in STN stimulation. Neurology. 2002 Sep 10;59(5):706\u0026ndash;13.\u003c/li\u003e\n \u003cli\u003eNeudorfer C, Butenko K, Oxenford S, Rajamani N, Achtzehn J, Goede L, et al. Lead-DBS v3.0: Mapping deep brain stimulation effects to local anatomy and global networks. NeuroImage. 2023 Mar 1;268:119862.\u003c/li\u003e\n \u003cli\u003ePavese N, Tai YF, Yousif N, Nandi D, Bain PG. Traditional Trial and Error versus Neuroanatomic 3-Dimensional Image Software-Assisted Deep Brain Stimulation Programming in Patients with Parkinson Disease. World Neurosurg. 2020 Feb;134:e98\u0026ndash;102.\u003c/li\u003e\n \u003cli\u003eLange F, Steigerwald F, Malzacher T, Brandt GA, Odorfer TM, Roothans J, et al. Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming. Front Neurol [Internet]. 2021 [cited 2022 Nov 14];12. Available from: https://www.frontiersin.org/articles/10.3389/fneur.2021.785529\u003c/li\u003e\n \u003cli\u003eWaldthaler J, Bopp M, K\u0026uuml;hn N, Bacara B, Keuler M, Gjorgjevski M, et al. Imaging-based programming of subthalamic nucleus deep brain stimulation in Parkinson\u0026rsquo;s disease. Brain Stimulat. 2021 Sep;14(5):1109\u0026ndash;17.\u003c/li\u003e\n \u003cli\u003eDuffley G, Szabo A, Lutz BJ, Mahoney-Rafferty EC, Hess CW, Ramirez-Zamora A, et al. Interactive mobile application for Parkinson\u0026rsquo;s disease deep brain stimulation (MAP DBS): An open-label, multicenter, randomized, controlled clinical trial. Parkinsonism Relat Disord. 2023 Apr 1;109:105346.\u003c/li\u003e\n \u003cli\u003eAubignat M, Berro A, Tir M, Lefranc M. Imaging-Guided Subthalamic Nucleus Deep Brain Stimulation Programming for Parkinson Disease: A Real-Life Pilot Study. Neurol Clin Pract. 2024 Dec;14(6):e200326.\u003c/li\u003e\n \u003cli\u003eBrandt GA, Stopic V, van der Linden C, Strelow JN, Petry-Schmelzer JN, Baldermann JC, et al. A Retrospective Comparison of Multiple Approaches to Anatomically Informed Contact Selection in Subthalamic Deep Brain Stimulation for Parkinson\u0026rsquo;s Disease. J Park Dis. 2024;14(3):575\u0026ndash;87.\u003c/li\u003e\n \u003cli\u003ePostuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson\u0026rsquo;s disease. Mov Disord Off J Mov Disord Soc. 2015 Oct;30(12):1591\u0026ndash;601.\u003c/li\u003e\n \u003cli\u003ePrescott RJ. The Comparison of Success Rates in Cross-Over Trials in the Presence of an Order Effect. J R Stat Soc Ser C Appl Stat. 1981;30(1):9\u0026ndash;15.\u003c/li\u003e\n \u003cli\u003eChan AW, Tetzlaff JM, G\u0026oslash;tzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013 Jan 8;346:e7586.\u003c/li\u003e\n \u003cli\u003eKrack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson\u0026rsquo;s disease. N Engl J Med. 2003 Nov 13;349(20):1925\u0026ndash;34.\u003c/li\u003e\n \u003cli\u003eSchuepbach WMM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson\u0026rsquo;s disease with early motor complications. N Engl J Med. 2013 Feb 14;368(7):610\u0026ndash;22.\u003c/li\u003e\n \u003cli\u003eGoetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson\u0026rsquo;s Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129\u0026ndash;70.\u003c/li\u003e\n \u003cli\u003eBenamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee GJ, Grosset DG. Correlation of Parkinson\u0026rsquo;s disease severity and duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord Off J Mov Disord Soc. 2000 Jul;15(4):692\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eHauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, Schapira AH, et al. Minimal Clinically Important Difference in Parkinson\u0026rsquo;s Disease as Assessed in Pivotal Trials of Pramipexole Extended Release. Park Dis. 2014;2014:467131.\u003c/li\u003e\n \u003cli\u003eSkodda S, Gr\u0026ouml;nheit W, Mancinelli N, Schlegel U. Progression of voice and speech impairment in the course of Parkinson\u0026rsquo;s disease: a longitudinal study. Park Dis. 2013;2013:389195.\u003c/li\u003e\n \u003cli\u003eTripoliti E, Zrinzo L, Martinez-Torres I, Frost E, Pinto S, Foltynie T, et al. Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease. Neurology. 2011 Jan 4;76(1):80\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eCohen J. Statistical Power Analysis for the Behavioral Sciences. Routledge; 2013. 656 p.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s Disease, Deep Brain Stimulation, Subthalamic Nucleus, Imaging-guided Programming, Clinical Trials","lastPublishedDoi":"10.21203/rs.3.rs-6542345/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6542345/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Subthalamic deep brain stimulation (STN-DBS) effectively treats motor symptoms in Parkinson's disease, but individual responses vary. Despite modern directional leads allowing more precise stimulation, optimal contact selection strategies remain undefined. This study compares a standardized imaging-guided contact selection protocol to conventional clinical programming.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We designed a monocentric, randomized, double-blind crossover trial enrolling 30 people with Parkinson's Disease with bilateral directional STN-DBS. Participants will receive both programming approaches: standardized imaging-guided contact selection targeting the dorsolateral STN and conventional contact selection through clinical test stimulations. Each configuration will be applied for one week. The primary outcome is patient preference after both treatments. Secondary outcomes include motor assessments, accelerometric monitoring and questionnaire-based quality of life measures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e: This study addresses a critical gap in standardization of imaging-guided DBS programming. By using patient preference as the primary outcome, we aim to capture clinically meaningful differences that may not be detected with traditional motor scales. The crossover design balances statistical power with clinical feasibility in specialized care settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration\u003c/strong\u003e: Deutsches Register für Klinische Studien (DRKS00034229, May 27th, 2024)\u003c/p\u003e","manuscriptTitle":"Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson's Disease: Study Protocol for a Randomized Double-blind Crossover Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-08 10:33:12","doi":"10.21203/rs.3.rs-6542345/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-06-22T06:35:22+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-19T11:52:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-05T06:14:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-06-04T07:27:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2fcb0caa-ab29-4f1d-85a4-942c4ecc73f0","owner":[],"postedDate":"July 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T16:01:08+00:00","versionOfRecord":{"articleIdentity":"rs-6542345","link":"https://doi.org/10.1186/s13063-025-09396-3","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-12-30 15:58:01","publishedOnDateReadable":"December 30th, 2025"},"versionCreatedAt":"2025-07-08 10:33:12","video":"","vorDoi":"10.1186/s13063-025-09396-3","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09396-3","workflowStages":[]},"version":"v1","identity":"rs-6542345","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6542345","identity":"rs-6542345","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}