Anatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson’s Disease (ALIGN-PD): Study Protocol for a Randomized Double-blind Crossover Trial

Anatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson’s Disease (ALIGN-PD): 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 Anatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson’s Disease (ALIGN-PD): Study Protocol for a Randomized Double-blind Crossover Trial Simon Herstell, Charlotte Schedlich-Teufer, Christina van der Linden, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7851313/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Parkinson’s disease (PD) motor symptoms are effectively treated with subthalamic deep brain stimulation (STN-DBS). LFP guided, adaptive deep brain stimulation (LFP-adaptive-DBS) is a novel strategy which adjusts stimulation current based on measured neuronal activity. This trial is the first to compare anatomically informed continuous DBS (Anatomy-continuous-DBS) to LFP-adaptive-DBS. Methods We conduct a monocentric, randomized and double-blind crossover trial with 30 PD patients enrolled. Patients receive two different programs (Anatomy-continuous-DBS and LFP-adaptive-DBS), each program is tested for two weeks after an initial optimization phase. In the LFP-adaptive-DBS program, the contact selection is based on LFP measurements, while contact selection in the Anatomy-continuous-DBS program is based on individual anatomy targeting the dorsolateral STN. The primary outcome is patient preference after completion of both phases. Secondary outcomes comprise motor symptoms, electrophysiological assessments, accelerometric monitoring and questionnaire-based measurements of non-motor symptoms, treatment expectation, and quality of life. Discussion To date both approaches have not been evaluated in a head-to-head comparison, and it remains unclear whether any offers superior treatment effects. This trial aims to provide insights into clinical utility of LFP-adaptive-DBS in comparison to anatomy-informed continuous DBS. We hope to provide further insights into the question which patients might benefit most from LFP-adaptive-DBS. Trial registration https//drks.de/register/de/trial/DRKS00037920/preview Number DRKS00037920, Date 20250916 Neurology Parkinson’s Disease Deep Brain Stimulation Subthalamic Nucleus Imaging-guided Programming Clinical Trials adaptive deep brain stimulation Figures Figure 1 Figure 2 Figure 3 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} Anatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson’s Disease (ALIGN-PD): Study Protocol for a Randomized Double-blind Crossover Trial Trial registration {2a and 2b}. Deutsches Register für Klinische Studien (DRKS00037920, September 16th, 2025) Protocol version {3} ALIGN Prüfplan 1.0 (11.02.2025) Funding {4} This study was funded through internal institution resources. No external funding was received. Author details {5a} Herstell S,¹* Schedlich-Teufer C,¹* Van der Linden C,¹ Jergas H,¹ Prümm B,¹ Visser-Vandewalle V,² Strelow J,¹ Thies T,¹ Petry-Schmelzer JN,¹ Dembek TA,¹ Brandt GA, 3 Barbe MT¹ 1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany 2 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Stereotactic and Functional Neurosurgery, Cologne, Germany 3 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Neurology with Experimental Neurology, Berlin, Germany * both authors contributed equally to this work Name and contact information for the trial sponsor {5b} Universität zu Köln Albertus-Magnus-Platz 50923 Köln D - Germany Role of sponsor {5c} No outside party was involved in the study’s design, data acquisition, analysis, interpretation, manuscript preparation, or the decision to submit it for publication. Responsibility for all aspects of the research rests exclusively with the investigator team, without external oversight or influence. Introduction Background and rationale {6a} Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for advanced Parkinson’s Disease. 1,2 Conventional continuous DBS (cDBS) provides stimulation with fixed parameters (frequency, pulse width, and amplitude), that are usually set by the treating physicians during clinical visits. Patients can typically adjust the amplitude on-demand within predefined limits using a handheld device. Recently two novel approaches to DBS programming have been introduced and are transforming clinical care. On the one hand, imaging guided DBS programming, which we refer to as anatomically informed continuous DBS (Anatomy-continuous-DBS), builds on the finding, that optimal motor symptom control is achieved with stimulation in the dorsolateral STN. 3 Inspecting each patient’s preoperative magnetic resonance imaging (MRI) and postoperative lead position relative to STN subregions (“anatomy-informed” DBS) clinicians can pre-identify effective contacts and improve suboptimal outcomes, when clinical programming achieved unsatisfactory results. 4,5 On the other hand, sensing enabled devices (e.g., Percept™ with BrainSense™) open up new possibilities for contact selection and current delivery. Electrophysiological recordings of local field potentials (LFPs) within the STN consistently demonstrate elevated β-power (13–35 Hz) activity as a reliable biomarker of symptom severity and dopaminergic state. 6,7 The “Electrode Identifier”™ as a built-in function of Medtronic Percept™ devices (Medtronic, Minneapolis, Minnesota, USA), enables clinicians to select contacts with strong β-signal, which have been shown to be clinically effective. 8 Beyond LFP-based contact selection, continuous monitoring of the β signal enables adaptive stimulation, where stimulation amplitude is adjusted depending on β-power. 9 Previous research suggests LFP-adaptive-DBS could improve motor symptoms and fluctuations, reduce dopaminergic requirements, enhance quality of life, and potentially lower energy use compared with cDBS. 10,11 To date both approaches have not been evaluated in a head-to-head comparison, and it remains unclear whether any offers superior treatment effects. Objectives {7} The primary aim is to assess patient preference versus anatomy-informed continuous DBS (Anatomy-continuous-DBS) and potential advantages in symptom control and side-effect reduction. Trial design {8} The design follows a randomized, controlled, double-blind, crossover trial with a comparison of anatomically informed continuous DBS (Anatomy-continuous-DBS) and LFP-adaptive-DBS. The randomized allocation ratio is 1:1 with each participant receiving both interventions. The trial follows a superiority framework with the primary outcome being patient preference. Secondary outcomes are exploratory. Methods: Participants, interventions and outcomes Study setting {9} The study will be conducted as a single-center trial at the University Hospital of Cologne. Eligibility criteria {10} Inclusion criteria: Clinically established diagnosis of Parkinson’s disease Bilateral implantation of directional leads for deep brain stimulation in the subthalamic nucleus at least 10 weeks prior to study initiation Stimulation system allowing adaptive stimulation (Medtronic Percept™ RC/PC) Age > 18 years Oral and written informed consent Exclusion criteria: Relevant cognitive deficit Levodopa dysregulation syndrome Severe affective disorder Inability or unwillingness to independently switch stimulation programs using the patient controller Insufficient image quality of perioperative clinical imaging (cMRI/cCT) for reconstruction of the individual lead position for Anatomy-continuous-DBS 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. The informed consent process addresses only the data collection and uses for this current trial. Interventions Explanation for the choice of comparators {6b} The two DBS programming methods were chosen as comparators based on their clinical relevance. Both programming strategies have evolved in parallel in recent years, departing from the classic monopolar contact review (systematic contact-by-contact testing). Anatomy-continuous-DBS strategies are implemented at many centers and can be applied in a time-efficient, standardized manner, reducing time-investment for initial as well as re-programming. 12 LFP-adaptive-DBS combines two new aspects – contact selection based on the most pronounced β-peak as well as adaptive stimulation, with potential improvement over some aspects of continuous DBS, allowing for a neuromodulation potentially closer to physiological brain circuit mechanisms. However, first clinical applications show that LFP-adaptive-DBS typically requires more refinement of stimulation settings over a longer period. 2,13 To date, no blinded trial has demonstrated superiority in patient preference for LFP-adaptive-DBS over Anatomy-continuous-DBS that would justify the additional programming burden. Further, evidence is needed, identifying which patients benefit from LFP-adaptive-DBS versus Anatomy-continuous-DBS, and vice versa. Intervention description {11a} The study intervention is an LFP-adaptive-DBS program using β-band LFP sensing with Medtronic Percept™/BrainSense™. A1: First, during a prolonged end-of-dose “OFF” state, the contact(s) with the highest alpha-β-band peak are identified (on either left or right side, 8 to 30 Hz, amplitude ≥ 1.2 µVp); a stimulation program is then created that activates the β-maximal contact while enabling passive chronic β-signal recording at home for 5–7 days to capture day-to-day variability. If several contacts show suitable β-signals, contacts may be combined; if no β-peak is detected, the clinically active contact is maintained, and chronic sensing is activated on the adjacent contacts. S1: Inpatient programming follows with overnight dopaminergic withdrawal (≥12 h), a motor exam (MDS-UPDRS III) with stimulation OFF, and configuration of the LFP-adaptive-DBS algorithm by setting β-based thresholds and patient-tolerated amplitude bounds. Thresholds will be implemented based on the LFP timeline data with the upper threshold being set to 75 th percentile of daytime timeline LFP-power and lower threshold to 25 th percentile of daytime timeline LFP power. Adjustment of LFP-adaptive-DBS settings will then occur based on clinical findings, e.g. adjustment of amplitude or thresholds. LFP-adaptive-DBS will first be setup to follow the dual-threshold stimulation mode. If clinically satisfactory outcome cannot be achieved using dual-threshold mode, single-threshold settings can be tested and applied. The control intervention is anatomy-informed continuous DBS (Anatomy-continuous-DBS). Lead locations in relation to the STN are visualized with a CE-marked clinical software (SureTune™, Medtronic) to select contacts that place the electric field in the dorsolateral STN (the motor territory). Contact selection will be performed following the protocol described in Brandt et al. 2024. 5 Stimulation amplitude is then fine-tuned during the same inpatient stay. Pulse widths and stimulation frequency will be kept constant at 60 µs and 130 Hz. At discharge, three programs are stored on the handheld patient controller: LFP-adaptive-DBS, Anatomy-continuous-DBS, and the pre-study clinical program. Anatomy-continuous-DBS is initially activated for 2 days; on these days patients are encouraged to further titrate stimulation amplitudes within the Anatomy-continuous-DBS program using the patients’ handheld controller. After titration, patients switch into LFP-adaptive-DBS. A2: A visit follows where LFP-adaptive-DBS settings are controlled for signs of adaptation (e.g. amplitude adaptation) regarding the LFP-measurements and can be refined (e.g. adjustment of thresholds). We will check LFP timeline for plausibility and artifacts. If LFP-adaptive-DBS settings lead to satisfactory results for the patient the study team may find the patient eligible for allocation to the blinded weeks. If side effects occur, LFP timeline yields implausible results or adaptation seems faulty (e.g. due to artifacts), visits can be repeated as often as needed for satisfactory results, prior to A3 and A4. Reasons for further refinements and number of visits will be noted. Anatomy-continuous-DBS may be modified during these visits, too. Contact selection will not be modified. A3 and A4: Thereafter, in a randomized, blinded crossover, LFP-adaptive-DBS and Anatomy-continuous-DBS are each applied for two weeks (order block-randomized). To preserve blinding, patients keep the handheld patient controller in a sealed container which can be accessed in case of emergency. A wrist-worn accelerometer is worn throughout each treatment phase for minimum three days. Patients are asked to fill out movement diaries for three days, starting on the fourth day after reprogramming of DBS settings. Follow-up ambulatory visits at the end of each two-week period include motor assessment, adverse-event review, and questionnaires; patient and investigator are later asked to guess allocation to assess blinding quality. At completion of the two blinded two-week periods patients are asked in a forced choice design which program they preferred over the other. N1: A telephone follow-up at three months documents ongoing program use and outcomes. Criteria for discontinuing or modifying allocated interventions {11b} Participants may withdraw at any point without providing a reason. If a participant stops one of the treatment weeks early, they may still enter the next treatment phase provided the discontinued week was their first assignment. Preference for treatment will be recorded irrespective of whether both weeks were completed. For safety, each participant’s pre-existing, pre-trial DBS program will remain available as a rescue setting via the handheld patient controller. Strategies to improve adherence to interventions {11c} To promote protocol adherence, participants will be provided with a precise timetable for the intervention phases, clear guidance on when to adjust amplitude, and a motor diary for daily entries during each stable-treatment week. Between visits, study staff will perform scheduled telephone follow-ups to monitor adherence and address issues. At in-person visits, the team will check the device settings to verify that the assigned DBS program is active. Relevant concomitant care permitted or prohibited during the trial {11d} Participants should maintain their regular medication regimen and routine care throughout the trial period. Participants must not participate in other interventional clinical trials during the study period. Provisions for post-trial care {30} This clinical study will be conducted in compliance with ICH-GCP (E6[R2]) and Regulation (EU) No. 536/2014 (Clinical Trials Regulation). All Adverse Events (AEs) and Serious Adverse Events (SAEs) will be documented and assessed by the investigator throughout the study period. The investigator will evaluate each event for seriousness, intensity, outcome, and potential causal relationship to the investigational procedure or product. In accordance with the applicable ethical and professional standards (e.g., Berufsordnung für Ärzte), all serious or unexpected adverse events that might affect the safety of study participants must be promptly reported to the responsible Ethics Committee. After completion of the trial, participants return to routine care at our hospital. Outcomes {12} The primary endpoint is patient preference between Anatomy-continuous-DBS and LFP-adaptive-DBS. A Likert-scale assessment of preference will be assessed exploratively. Secondary endpoints comprise motor assessments, clinical (MDS-UPDRS III) and objective (accelerometry), alongside patient-reported measures (FOG-Q, PDQ-39, MDS-UPDRS I/II/IV, VHI), treatment expectation, total electric energy delivered, LFP recordings, and motor diaries. Participant timeline {13} Sample size {14} The sample size calculation is based on the primary outcome, which is the proportion of patients preferring LFP-adaptive-DBS over Anatomy-continuous-DBS in a forced-choice comparison following a randomized, double-blind, two-period crossover design. The null hypothesis assumes no difference in preference between the two treatments (i.e. 50% of patients prefer LFP-adaptive-DBS), and the alternative hypothesis posits a superiority of LFP-adaptive-DBS with a true preference rate of 75 to 80%. This estimate is supported by clinical trials showing a large preference of LFP-adaptive-DBS over continuous DBS. 10,11 We assume a one-sided exact binomial test at a significance level of α = 0.05, with a target power of 80%. To account for potential dropouts, we conservatively estimate a 10-15% dropout rate. Under these assumptions, a total sample size of 30 patients was determined to be appropriate to achieve 80% power to detect a preference rate of 75% against the null of 50%. A power curve illustrating the relationship between sample size and power under the assumed effect size is shown in Figure 2. This analysis is powered to detect relatively large treatment effects. A negative trial does not exclude smaller effects of the study intervention on patient preferences. The preference ratio will be reported descriptively. The analysis follows an intention-to-treat approach. Recruitment {15} Participants will be recruited from the Neurology Department’s patient cohort at University Hospital Cologne. Eligibility will first be prescreened using existing medical records; candidates who pass this step will undergo a confirmatory examination by a study physician to verify inclusion and exclusion criteria. Assignment of interventions: allocation Sequence generation {16a} Randomization will be performed in R (R Core Team, 2021) using the randomizeR package (Uschner et al., 2018) with a fixed seed, applying permuted block sizes of 4, 6, and 8 to ensure balanced AB/BA sequences. Concealment mechanism {16b} Allocation is concealed using sequentially numbered, opaque and sealed envelopes. The seed used to generate the randomization list is kept in a password-protected file on site on one designated computer. After confirming eligibility, an unblinded investigator opens the assigned envelope and programs the device according to the indicated sequence. The handheld patient controller is stored in a sealed envelope but will be given inside the envelope to the patient, in case emergency unblinding is required e.g. for medical reasons. The treatment order remains undisclosed to blinded study personnel. Implementation {16c} A single designated team member will open the prepared envelopes to determine treatment order and manage the programming devices. This individual will enroll participants and assign the intervention sequence. Assignment of interventions: Blinding Who will be blinded {17a} This is a double-blind trial. Participants, clinical raters, and all study staff—except one unblinded programmer—are blinded to treatment allocation (LFP-adaptive-DBS vs. Anatomy-continuous-DBS). The unblinded programmer draws the sequence from sealed envelopes and operates the programming devices, while safeguarding allocation secrecy. Outcome assessments are performed by blinded personnel with no access to allocation. Motor examinations (MDS-UPDRS III) are video-recorded and rated later in random order to maintain blinded evaluation. Procedure for unblinding if needed {17b} Unblinding is allowed if patients cannot tolerate the program they have been assigned to. In case of a medical emergency or adverse event deemed requiring knowledge of the active DBS program for safe and appropriate clinical management, the unblinded programmer will handle medical care of the patient to secure blinding of the remaining members of the study team. Each unblinding of patient or further study team members will be logged, noting the justification and the individuals involved. Data collection and management Plans for assessment and collection of outcomes {18a} All outcomes will be assessed by trained clinical investigators. To ensure data quality, standardized case report forms (CRFs) will be used throughout; any changes will be clearly annotated and signed by the responsible investigator. Plans to promote participant retention and complete follow-up {18b} Participants will receive clear scheduling at enrollment. The brief treatment phases (two weeks per intervention) reduce burden. If a participant stops the first treatment week, they may still proceed to the next phase. For discontinuing participants, we will obtain the primary endpoint (treatment preference) whenever feasible, irrespective of completion of both treatment arms, and collect secondary outcomes at the time of discontinuation for partial analyses. All participants exposed to at least one intervention enter the safety set. Data management {19} Data will be captured on paper CRFs with checklists and tables to ensure completeness. Participants will be pseudonymized. Any changes to CRFs will be clearly annotated and signed by the investigator. Subsequently, data will be transferred to a dedicated digital spreadsheet. This spreadsheet will be password-protected and routinely backed up to a secure network drive. LFP data will be imported after pseudonymizing and off-setting time-stamp to a hospital computer. Confidentiality {27} Participant identities will be safeguarded via coded identifiers. Each participant receives a unique pseudonymized code (e.g., ALIGN01) used on all study documents and datasets. The key linking identities to codes is stored separately from study data in two secure locations: an access-restricted electronic file on the hospital IT system and a hard copy in the investigator site file kept in a locked cabinet. Only authorized study staff may access the linkage file. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} There will be no collection of biological specimen. Statistical methods Statistical methods for primary and secondary outcomes {20a} The primary outcome is a patient preference between Anatomy-continuous-DBS and LFP-adaptive-DBS treatments. Preference is recorded as a forced binary choice (LFP-adaptive-DBS vs. Anatomy-continuous-DBS) at the end of the second treatment phase (A4). Patient preference will be coded as 0 (Anatomy-continuous-DBS preference) or 1 (LFP-adaptive-DBS preference). The statistical analysis of the primary outcome follows an intention to treat approach, where patient preference will be evaluated notwithstanding completion of treatment phases. The primary hypothesis is that LFP-adaptive-DBS is preferred over Anatomy-continuous-DBS by a proportion of patients significantly greater than 50%. The null hypothesis (H₀) assumes no preference difference (proportion = 0.5), while the alternative hypothesis (H₁) posits a superiority of LFP-adaptive-DBS preference (proportion > 0.5). An exact one-sided binomial test will be used to evaluate the proportion of patients preferring LFP-adaptive-DBS under the null hypothesis of 50%. A one-sided significance level of α = 0.05 will be used. Missing preference data due to completed dropout without preference will not be imputed. These patients will be excluded from the primary analysis but included in descriptive reporting and a secondary sensitivity analysis. In the latter, a conservative imputation strategy will be applied, treating such patients as not preferring LFP-adaptive-DBS (i.e., counted against the alternative hypothesis) to assess robustness of the findings. If a patient does not complete one or two treatment phases but still gives a preference their choice will be evaluated for the primary endpoint. To assess potential order effects, the distribution of treatment preferences will be examined by treatment sequence. A Fisher’s exact test will be used to evaluate whether preference is associated with the order in which treatments were received. This analysis is exploratory and intended to detect potential biases due to sequence effects. In the case of a non-significant result in the superiority analysis, a non-inferiority analysis with a margin δ = 0.10 will be conducted; this is pre-specified as exploratory, intended to support clinical interpretation, and is not used as the basis for sample size determination. The choice of δ = 0.10 is guided by the fact that (a) patient preference is a subjective endpoint and (b) LFP-adaptive-DBS may provide advantages for patients with advanced Parkinson’s disease (e.g., better control of fluctuations). A sensitivity analysis with smaller δ values will be conducted exploratorily; however, the non-inferiority criterion is considered met if the original δ = 0.10 threshold is satisfied. Secondary outcomes include changes in clinical symptom scores (e.g., MDS-UPDRS III), adverse events, and patient-reported outcomes measured at the end of each treatment phase. Exploratory analysis will assess potential treatment effects and variability. For quantitative secondary outcomes measured after each treatment, data will be analyzed as repeated measures within subjects. Depending on data completeness and distribution, either paired analyses (paired t-test or Wilcoxon signed-rank test) or linear mixed-effects models will be applied to compare the LFP-adaptive-DBS and Anatomy-continuous-DBS conditions. Clinically relevant baseline covariates (e.g., age, sex, disease duration) may be included in exploratory models to improve precision and account for individual variability. No correction for multiplicity will be applied due to the exploratory nature of these analyses, but exact p -values and 95% confidence intervals will be reported. Interim analyses {21b} An interim analysis has been added to the study design and submitted to the local ethics committee as a protocol amendment prior to first patient in. The interim analysis will be conducted only after formal approval has been obtained prior to the planned interim time point. Interim would proceed after 18 evaluable preference assessments. The O’Brien-Fleming alpha-spending approach would be applied so that early termination in favor of superiority is only possible if at least 15 out of 18 patients prefer LFP-adaptive-DBS. A non-binding futility recommendation would be issued if fewer than 11 out of 18 patients favor LFP-adaptive-DBS. In all other cases, recruitment will continue up to the full target of 30 patients. This protocol will be updated timely, once ethics approval has been granted. Methods for additional analyses (e.g., subgroup analyses) {20b} Exploratory subgroup analyses will examine whether clinical characteristics such as disease subtype, disease duration, age, levodopa equivalent daily dose (LEDD) 14 , and electrophysiological phenotype based on the LFP patterns influence treatment effects. Composite sub scores from clinical rating scales (e.g., dyskinesia or off‑period scores from MDS-UPDRS IV, dyskinesia, and off-time) may also be evaluated. Given the limited sample size, models will be kept simple and variables chosen based on clinical relevance. All additional analyses will be exploratory and clearly identified as such. No formal adjustment for multiple comparisons will be applied but exact p ‑values and 95% confidence intervals will be reported. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} All randomized participants who receive at least one intervention will be analyzed. For the primary endpoint (patient preference), a stated preference will be included even if both treatment periods were not completed. The primary analysis will include patients who completed no treatment period but provide a valid preference rating (modified intention to treat design). Exposure will be reported. A missing preference rating will not be included in the primary analysis. Envelope opening, changing of program or rescue unblinding will be reported. However, preference given will be evaluated as planned. For multi-item scales (e.g., MDS-UPDRS III), if up to two items are missing, those items will be imputed with the group mode at that time point. If an entire score is missing, the participant will be excluded from the primary analysis of that endpoint. A blinded review will be done before unblinding to verify analysis readiness. Decisions arising from this review will be recorded and, if relevant, aligned with the study analysis plan (SAP) prior to unblinding. No treatment allocation will be revealed. Plans to give access to the full protocol, participant level-data and statistical code {31c} The complete study protocol can be obtained from the corresponding author upon reasonable request. After study completion, participant-level data may be shared for academic use, provided suitable data-sharing agreements are in place and required ethical approvals have been obtained. Oversight and monitoring Composition of the coordinating center 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. Composition of the data monitoring committee, its role and reporting structure {21a} Both interventions reflect routine clinical practice with well-characterized safety. Safety oversight will be maintained by the study team throughout. Any decision to stop early will be taken by the principal investigator in accordance with these criteria. Trial monitoring is planned to be performed by the ZKS Köln – Center for Clinical Trials Cologne. Adverse event reporting and harms {22} All emerging or worsening Adverse Events (AEs) and Serious Adverse Events (SAEs) will be documented and evaluated by the investigator throughout the study period. Each event will be assessed for seriousness, intensity, outcome, and its potential causal relationship to the investigational procedure or product. In accordance with applicable regulatory, ethical, and professional requirements (e.g., ICH GCP, ISO 14155, and the Berufsordnung für Ärzte), any serious or unexpected adverse events that may affect the safety of study participants will be reported promptly to the responsible ethics Committee. Frequency and plans for auditing trial conduct {23} No dedicated auditing is planned beyond routine monitoring by the Center for Clinical Trials Cologne (ZKS Köln). ZKS Köln will review protocol adherence, data accuracy, and regulatory compliance. Should issues be identified, the principal investigator will institute corrective measures. The institutional ethics committee may audit the study at its discretion, independently of the investigators. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Any protocol changes that could influence study conduct, participant safety or benefit, or materially alter procedures, aims, or design will require a formal amendment. All amendments must be approved by the IRB/ethics committee before they are enacted. After approval, relevant revisions influencing trial procedures affecting patients (e.g. different visits, change in consent form) will be communicated to all relevant stakeholders, patients and study team. Dissemination plans {31a} Results will be shared through peer-reviewed journal publications and presentations at relevant scientific meetings, irrespective of study outcome. Findings will also be posted to the trial’s registration record. Participants may request a lay summary of the results. The protocol was prepared in line with the SPIRIT guidelines. Discussion We will compare LFP-adaptive-DBS with Anatomy-continuous-DBS using a randomized, double-blinded cross-over with patient-preference as primary endpoint. A head-to-head comparison is necessary to assess the clinical relevance of these approaches. Anatomy-continuous-DBS only emerged recently. A growing body of studies indicates positive outcomes. 4,5,15,16 With commercial software for imaging guided programming readily available, over recent years Anatomy-continuous-DBS is increasingly adopted in clinical centers. 5 4,15 In contrast to LFP-adaptive-DBS, Anatomy-continuous-DBS can be programmed time-efficiently in most cases and typically achieves satisfactory symptom control, after some clinical refinement if needed; new tools allow more precise spatial delivery of current reducing overstimulation side effects. 4 Yet the continuous nature of stimulation might resemble physiological fluctuations of the affected circuits less closely. 17 LFP-adaptive-DBS is a novel stimulation mode allowing for a contact selection based on ß-Power and delivering electric current contingent on it; it may therefore provide a more physiological intervention. 10,18 Whereas contact selection in LFP-adaptive-DBS is time-efficient, programming the chronic adaptive stimulation is relatively time-consuming, requires experience, and patients cannot adjust stimulation amplitude themselves. 10,13 Both programming strategies represent distinct approaches to contact selection as the imaging guided contact selection might not coincide with the LFP-adaptive-DBS selection. Further, the mode of delivery of stimulation differs. As such, both stimulation modes represent diverging, competing paradigms of “individualized” DBS. As both approaches are now available in routine care, further indicators are needed to determine whether the time-intensive implementation of LFP-adaptive-DBS is justified. While the MDS-UPDRS Part III captures motor outcomes reliably, it may underrepresent relevant adverse effects and fluctuations for patients —e.g., stimulation-induced dysarthria, motor variability, and non-motor symptoms. 19–21 Accelerometers offer a more granular insight into motor symptoms but do not capture well non-motor domains. 22 Psychometric assessments allow for a more nuanced perspective on subjective aspects of wellbeing, many of which are subject to substantial fluctuation in PD. 23 Ultimately, all beneficial and disadvantageous effects of a therapy are synthesized in the patient's choices. Hence, we propose to consider a sustained patient preference for a blinded stimulation mode over time as an integrated measure of stimulation efficacy and tolerability. 24 To date, no blinded head-to-head comparison has been conducted. By centering around patient preference, this trial will help understand the importance of LFP-adaptive-DBS in the clinical context in relation to imaging-guided programming strategies. Preference will be elicited via a blinded forced choice. This sacrifices gradations of preference in favor of interpretability and feasibility in a crossover design; as all participants experience both conditions, we consider the compromise acceptable. To control for potential confounders like treatment expectation, we chose a blinded study design. A two-week exposition was chosen as it is long enough to allow an evaluation on everyday life. 11 Given the duration of exposure, we do not consider washout effects to be relevant for the primary endpoint. Exposure days will be reported for all patients. Nonetheless exposition is short enough to be tolerable if one condition proves less satisfactory. We will report on sequence effects. To assess stability of patient preference the preference choice and active program will be elicited again three months after the primary endpoint and findings will be reported exploratively. We expect our results to inform both, patients and DBS programmers alike about the relevance of LFP-adaptive-DBS for patient satisfaction. There are some limitations to consider regarding our trial design. As per manufacturer, LFP-adaptive-DBS, allows for a range of different programming strategies. 18 In this trial, dual-threshold LFP-adaptive-DBS will be configured as the default. Where clinically indicated by the study physician, single threshold LFP-adaptive-DBS may be substituted. We will report the distribution of LFP-adaptive-DBS modes, deviation from LFP-adaptive-DBS settings like ramp-up time, used and report the clinical reasons for deviating from default settings. The study is exploratory with respect to secondary outcomes like motor control (MDS UPDRS Part III) and psychometric measures and not powered to detect small or moderate effects in patient preference. This circumstance is in part due to the small patient sample at hand. Single-center conduct was chosen to permit rapid initiation and rigorously standardized delivery of a complex stimulation protocol. Although this constrains generalizability, internal validity is strengthened by uniform programming, randomized double-blind crossover, pre-registration, and prospective deviation logging. The design enabled full financial independence from industry in which major manufacturers have a direct stake. Trial status Protocol Version: ALIGN Prüfplan 1.0. (Dat: 11.02.2025), Recruitment is set to begin on the 15 th of October 2025. The anticipated completion date for recruitment is 30th September 2026. Abbreviations Anatomy-continuous-DBS – anatomically informed continuous deep brain stimulation DBS – deep brain stimulation FOG-Q – Freezing of Gait Questionnaires LEDD – Levodopa Equivalent Dose LFP-adaptive-DBS – LFP-guided adaptive deep brain stimulation MDS-UPDRS – Movement Disorder Society Universal Parkinson Disease Rating Scale PDQ-39 – Parkinsons Disease Questionnaire STN – subthalamic nucleus TEX – Treatment Expectation Questionnaire VHI – Voice Handicap Index Declarations Acknowledgements We thank the patients and their families for their participation and commitment. We are equally grateful to the healthcare professionals who make complex care possible—especially Study Nurses Max Pohl and Justus Rewolle, and Parkinson Nurse Susanne Hoffmann. Authors’ contributions {31b} SH and CST contributed equally as co-first authors. SH conceived the protocol, conducts imaging-guided contact selection and adaptive stimulation settings, performs data collection, and drafted the manuscript. CST conceived the study, designed the protocol and drafted the manuscript. HJ conceived the study, designed the protocol and drafted the manuscript. Both authors revised and approved the final manuscript. CVDL contributed to study design, performs data collection, conducts imaging-guided contact selection and adaptive stimulation settings, contributed to study design and revised the manuscript. VVV provided supervision and revised the manuscript. TT provided supervision and revised the manuscript. JS provided supervision and revised the manuscript. TAD contributed to the study design, performs data collection, supports analysis of imaging and accelerometer data, and revised the manuscript. BP performs data collection and revised the manuscript. GB conceived the study, designed the protocol and drafted 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 internally funded by the Neurology Department, University Hospital Cologne. No external funders or sponsors are involved. All personnel, infrastructure, and materials are provided by the department. No outside entity contributed to the study design, data collection, analysis, interpretation, manuscript preparation, or the decision to submit. All authority and responsibility rest solely with the investigator team. Availability of data and materials {29} The final dataset will be available to the principal investigator and trial co-investigators, with no contractual limits on access. After completion, de-identified data may be shared on reasonable request under data-sharing agreements and ethics approval. All statistical analyses will be conducted by the study team, with unrestricted investigator access to the results. Ethics approval and consent to participate {24} Approval for this study was granted by the ethics committee of the Medical Faculty, University of Cologne (Ref. 25-1053). All participants will provide oral and written informed consent before being enrolled in the trial. Consent for publication {32} Not applicable. Competing interests {28} SH received travel recompensation from Boston Scientific. BP has no competing interests to declare. TT is affiliated with ki:elements GmbH, her work is unrelated with this project, however. GAB received honoraria for advisory board participation unrelated to this work and travel expenses for educational activities from Boston Scientific and Medtronic GmbH. CST received travel funding from Medtronic GmbH for an educational program. CVDL was funded by the CCSP Cologne Clinician Scientist Program (CCSP, Faculty of Medicine, University of Cologne) and received travel recompensations from Boston Scientific and Medtronic GmbH for educational activities. HJ received travel recompensations from Boston Scientific .JNPS was given financial support by the CCSP and received funding by the German Research Foundation (DFG, FI 773/15-1) unrelated to this project. VVV received honoraria for advisory board participation and speaker fees from Boston Scientific, Medtronic and LivaNova. TAD's work was supported by the CCSP and will receive funding by Boston Scientific. 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 Page 14 of 18 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 Schuepbach, W. M. M. et al. Neurostimulation for Parkinson’s disease with early motor complications. N. Engl. J. Med. 368 , 610–622 (2013). Deuschl, G. et al. A Randomized Trial of Deep-Brain Stimulation for Parkinson’s Disease. N. Engl. J. Med. 355 , 896–908 (2006). Dembek, T. A. et al. Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease. Ann. Neurol. 86 , 527–538 (2019). Torres, V. et al. Image-guided programming deep brain stimulation improves clinical outcomes in patients with Parkinson’s disease. Npj Park. Dis. 10 , 29 (2024). Brandt, G. A. 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. 14 , 575–587 (2024). Oswal, A. et al. Neural signatures of hyperdirect pathway activity in Parkinson’s disease. Nat. Commun. 12 , 5185 (2021). Kuhn, A. A. et al. High-Frequency Stimulation of the Subthalamic Nucleus Suppresses Oscillatory Activity in Patients with Parkinson’s Disease in Parallel with Improvement in Motor Performance. J. Neurosci. 28 , 6165–6173 (2008). Binder, T. et al. Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson’s disease: A comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial. Brain Stimul. Basic Transl. Clin. Res. Neuromodulation 16 , 1243–1251 (2023). Jimenez-Shahed, J. Device profile of the percept PC deep brain stimulation system for the treatment of Parkinson’s disease and related disorders. Expert Rev. Med. Devices 18 , 319–332 (2021). Bronte-Stewart, H. M. et al. Long-Term Personalized Adaptive Deep Brain Stimulation in Parkinson Disease: A Nonrandomized Clinical Trial. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2025.2781 (2025) doi:10.1001/jamaneurol.2025.2781. Busch, J. L. et al. Chronic adaptive deep brain stimulation for Parkinson’s disease: clinical outcomes and programming strategies. Npj Park. Dis. 11 , 264 (2025). Brandt, G. A. et al. Moving beyond trial and error: a strategy for anatomically informed contact selection in subthalamic deep brain stimulation for Parkinson’s disease. Mov. Disord. 38 , (2023). Stanslaski, S. et al. Sensing data and methodology from the Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease (ADAPT-PD) clinical trial. Npj Park. Dis. 10 , 174 (2024). Jost, S. T. et al. Levodopa Dose Equivalency in Parkinson’s Disease: Updated Systematic Review and Proposals. Mov. Disord. 38 , 1236–1252 (2023). Rigon, L. et al. Concordance between imaging and clinical based STN-DBS programming improves motor outcomes of directional stimulation in Parkinson’s disease. J. Park. Dis. 15 , 409–420 (2025). Roediger, J. et al. Automated deep brain stimulation programming based on electrode location: a randomised, crossover trial using a data-driven algorithm. Lancet Digit. Health 5 , e59–e70 (2023). Little, S. et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann. Neurol. 74 , 449–457 (2013). Medtronic. Percept TM PC Neurostimulator with BrainSense TM Technology: White Paper . https://www.medtronic.com/content/dam/medtronic-wide/public/western-europe/products/neurological/percept-pc-neurostimulator-whitepaper.pdf (2023). Aldridge, D., Theodoros, D., Angwin, A. & Vogel, A. P. Speech outcomes in Parkinson’s disease after subthalamic nucleus deep brain stimulation: A systematic review. Parkinsonism Relat. Disord. 33 , 3–11 (2016). Jergas, H. et al. One side effect: two networks? Lateral and posteromedial stimulation spreads induce dysarthria in subthalamic deep brain stimulation for Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 96 , 280–286 (2025). Barbe, M. T. et al. Deep Brain Stimulation for Freezing of Gait in Parkinson’s Disease With Early Motor Complications. Mov. Disord. 35 , 82–90 (2020). Moreau, C. et al. Overview on wearable sensors for the management of Parkinson’s disease. Npj Park. Dis. 9 , 153 (2023). Franke, C. & Storch, A. Nonmotor Fluctuations in Parkinson’s Disease. in International Review of Neurobiology vol. 134 947–971 (Elsevier, 2017). Brandt, G. A. et al. Comparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson’s Disease (CONECT) . https://drks.de/search/en/trial/DRKS00034229 (2025). Additional Declarations The authors declare potential competing interests as follows: SH received travel recompensation from Boston Scientific. BP has no competing interests to declare. TT is affiliated with ki:elements GmbH, her work is unrelated with this project, however. GAB received honoraria for advisory board participation unrelated to this work and travel expenses for educational activities from Boston Scientific and Medtronic GmbH. CST received travel funding from Medtronic GmbH for an educational program. CVDL was funded by the CCSP Cologne Clinician Scientist Program (CCSP, Faculty of Medicine, University of Cologne) and received travel recompensations from Boston Scientific and Medtronic GmbH for educational activities. HJ received travel recompensations from Boston Scientific .JNPS was given financial support by the CCSP and received funding by the German Research Foundation (DFG, FI 773/15-1) unrelated to this project. VVV received honoraria for advisory board participation and speaker fees from Boston Scientific, Medtronic and LivaNova. TAD's work was supported by the CCSP and will receive funding by Boston Scientific. 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 Page 14 of 18 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. 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Questionnaires: FOGQ, PDQ-39, MDS-UPDRS I/II/IV, VHI, TEX (LFP-adaptive-DBS, Anatomy-continuous-DBS)\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7851313/v1/05fc571d0c344ff54aa49a6c.jpg"},{"id":93777900,"identity":"b25a19f7-8519-4312-9efa-52c358c2c4fc","added_by":"auto","created_at":"2025-10-17 12:44:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55344,"visible":true,"origin":"","legend":"\u003cp\u003eExact binomial power curve for detecting a preference rate of 75% versus the null hypothesis of 50%, using a one-sided test at α = 0.05. The curve shows the statistical power (\u003cem\u003ey\u003c/em\u003e-axis) as a function of total sample size (\u003cem\u003ex\u003c/em\u003e-axis). Accounting for an anticipated dropout rate of 10-15%, a total sample size of 30 patients was selected to ensure adequate power in the final analysis.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7851313/v1/c5e2d8e544644fe1c85fe415.jpg"},{"id":93779174,"identity":"98619494-95f3-49ef-9af0-85b205d3489b","added_by":"auto","created_at":"2025-10-17 12:52:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":66794,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Method section.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7851313/v1/9db88f367953564e609ffc94.png"},{"id":93780525,"identity":"38a39945-46cb-4cf5-be08-12d5dce7900d","added_by":"auto","created_at":"2025-10-17 13:08:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1875281,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7851313/v1/26b6590b-53b9-4fbc-b385-eb11c309f715.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: SH received travel recompensation from Boston Scientific. BP has no competing interests to declare. TT is affiliated with ki:elements GmbH, her work is unrelated with this project, however. GAB received honoraria for advisory board participation unrelated to this work and travel expenses for educational activities from Boston Scientific and Medtronic GmbH. CST received travel funding from Medtronic GmbH for an educational program. CVDL was funded by the CCSP Cologne Clinician Scientist Program (CCSP, Faculty of Medicine, University of Cologne) and received travel recompensations from Boston Scientific and Medtronic GmbH for educational activities. HJ received travel recompensations from Boston Scientific .JNPS was given financial support by the CCSP and received funding by the German Research Foundation (DFG, FI 773/15-1) unrelated to this project. VVV received honoraria for advisory board participation and speaker fees from Boston Scientific, Medtronic and LivaNova. TAD's work was supported by the CCSP and will receive funding by Boston Scientific. 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 Page 14 of 18 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.","formattedTitle":"\u003cp\u003eAnatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson’s Disease (ALIGN-PD): Study Protocol for a Randomized Double-blind Crossover Trial\u003c/p\u003e","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: 34.1158%;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson\u0026rsquo;s Disease (ALIGN-PD):\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eStudy Protocol for a Randomized Double-blind Crossover Trial\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\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: 34.1158%;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eDeutsches Register f\u0026uuml;r Klinische Studien (DRKS00037920, September 16th, \u0026nbsp;2025)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eALIGN Pr\u0026uuml;fplan 1.0 (11.02.2025)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eThis study was funded through internal institution resources. No external funding was received.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eHerstell S,\u0026sup1;* Schedlich-Teufer C,\u0026sup1;* Van der Linden C,\u0026sup1; Jergas H,\u0026sup1; Pr\u0026uuml;mm B,\u0026sup1; Visser-Vandewalle V,\u0026sup2; Strelow J,\u0026sup1; Thies T,\u0026sup1; Petry-Schmelzer JN,\u0026sup1; Dembek TA,\u0026sup1; Brandt GA,\u003csup\u003e3\u003c/sup\u003e Barbe MT\u0026sup1;\u003c/p\u003e\n \u003cp\u003e1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Stereotactic and Functional Neurosurgery, Cologne, Germany\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 Charit\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, Berlin, Germany\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e* both authors contributed equally to this work\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\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: 65.8842%;\"\u003e\n \u003cp\u003eUniversit\u0026auml;t zu K\u0026ouml;ln\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAlbertus-Magnus-Platz\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50923 K\u0026ouml;ln\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eD - Germany\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: 34.1158%;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eNo outside party was involved in the study\u0026rsquo;s design, data acquisition, analysis, interpretation, manuscript preparation, or the decision to submit it for publication. Responsibility for all aspects of the research rests exclusively with the investigator team, without external 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\u003eDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for advanced Parkinson’s Disease.\u003csup\u003e1,2\u003c/sup\u003e Conventional continuous DBS (cDBS) provides stimulation with fixed parameters (frequency, pulse width, and amplitude), that are usually set by the treating physicians during clinical visits. Patients can typically adjust the amplitude on-demand within predefined limits using a handheld device. Recently two novel approaches to DBS programming have been introduced and are transforming clinical care.\u003c/p\u003e\n\u003cp\u003eOn the one hand, imaging guided DBS programming, which we refer to as anatomically informed continuous DBS (Anatomy-continuous-DBS), builds on the finding, that optimal motor symptom control is achieved with stimulation in the dorsolateral STN.\u003csup\u003e3\u003c/sup\u003e Inspecting\u0026nbsp;each patient’s\u0026nbsp;preoperative\u0026nbsp;magnetic resonance imaging\u0026nbsp;(MRI)\u0026nbsp;and\u0026nbsp;postoperative lead position relative to STN subregions (“anatomy-informed” DBS)\u0026nbsp;clinicians\u0026nbsp;can pre-identify effective contacts\u0026nbsp;and improve suboptimal outcomes, when clinical programming achieved unsatisfactory results.\u003csup\u003e4,5\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn the other hand, sensing enabled devices (e.g., Percept™ with BrainSense™) open up new possibilities for contact selection and current delivery. Electrophysiological recordings of local field potentials (LFPs) within the STN consistently demonstrate elevated β-power (13–35 Hz) activity as a reliable biomarker of symptom severity and dopaminergic state.\u003csup\u003e6,7\u003c/sup\u003e The “Electrode Identifier”™\u0026nbsp;as a built-in function of Medtronic Percept™\u0026nbsp;devices (Medtronic,\u0026nbsp;Minneapolis, Minnesota, USA), enables\u0026nbsp;clinicians to select contacts with strong β-signal, which have been shown to be clinically effective.\u003csup\u003e8\u003c/sup\u003e Beyond LFP-based contact selection, continuous monitoring of the β signal enables adaptive stimulation, where stimulation amplitude is \u0026nbsp;adjusted depending on β-power.\u003csup\u003e9\u003c/sup\u003e Previous research\u0026nbsp;suggests\u0026nbsp;LFP-adaptive-DBS\u0026nbsp;could\u0026nbsp;improve motor symptoms and fluctuations, reduce dopaminergic requirements, enhance quality of life, and potentially lower energy use compared with cDBS.\u003csup\u003e10,11\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo date both approaches have not been evaluated in a head-to-head comparison, and it remains unclear whether any offers superior treatment effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary aim is to assess patient preference versus anatomy-informed continuous DBS (Anatomy-continuous-DBS) and potential advantages in symptom control and side-effect reduction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe design follows a randomized, controlled, double-blind, crossover trial with a comparison of anatomically informed continuous DBS (Anatomy-continuous-DBS) and LFP-adaptive-DBS. The randomized allocation ratio is 1:1 with each participant receiving both interventions. The trial follows a superiority framework with the primary outcome being patient preference. Secondary outcomes are exploratory.\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will be conducted as a single-center trial at the University Hospital of Cologne. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eClinically established diagnosis of Parkinson\u0026rsquo;s disease\u003c/li\u003e\n \u003cli\u003eBilateral implantation of directional leads for deep brain stimulation in the subthalamic nucleus at least 10 weeks prior to study initiation\u003c/li\u003e\n \u003cli\u003eStimulation system allowing adaptive stimulation (Medtronic Percept\u0026trade; RC/PC)\u003c/li\u003e\n \u003cli\u003eAge \u0026gt; 18 years\u003c/li\u003e\n \u003cli\u003eOral and written informed consent\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cbr\u003e\u0026nbsp;Exclusion criteria:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eRelevant cognitive deficit\u003c/li\u003e\n \u003cli\u003eLevodopa dysregulation syndrome\u003c/li\u003e\n \u003cli\u003eSevere affective disorder\u003c/li\u003e\n \u003cli\u003eInability or unwillingness to independently switch stimulation programs using the patient controller\u003c/li\u003e\n \u003cli\u003eInsufficient image quality of perioperative clinical imaging (cMRI/cCT) for reconstruction of the individual lead position for Anatomy-continuous-DBS\u003c/li\u003e\n\u003c/ul\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.\u0026nbsp;\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. The informed consent process addresses only the data collection and uses for this 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 methods were chosen as comparators based on their clinical relevance. Both programming strategies have evolved in parallel in recent years, departing from the classic monopolar contact review (systematic contact-by-contact testing). Anatomy-continuous-DBS strategies are implemented at many centers and can be applied in a time-efficient, standardized manner, reducing time-investment for initial as well as re-programming.\u003csup\u003e12\u003c/sup\u003e LFP-adaptive-DBS\u0026nbsp;combines two new aspects \u0026ndash; contact selection based on the most pronounced \u0026beta;-peak as well as adaptive stimulation,\u0026nbsp;with potential improvement over some aspects of\u0026nbsp;continuous\u0026nbsp;DBS, allowing for a neuromodulation potentially closer to physiological brain circuit mechanisms. However, first clinical applications show that LFP-adaptive-DBS typically requires more refinement of stimulation settings over a longer period.\u003csup\u003e2,13\u003c/sup\u003e To date, no blinded trial\u0026nbsp;has demonstrated\u0026nbsp;superiority in patient preference for\u0026nbsp;LFP-adaptive-DBS over Anatomy-continuous-DBS that would justify the additional programming burden.\u0026nbsp;Further, evidence is needed, identifying which patients benefit from LFP-adaptive-DBS versus Anatomy-continuous-DBS, and vice versa.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u0026nbsp;The study intervention is an LFP-adaptive-DBS program using \u0026beta;-band LFP sensing with Medtronic Percept\u0026trade;/BrainSense\u0026trade;. A1: First, during a prolonged end-of-dose \u0026ldquo;OFF\u0026rdquo; state, the contact(s) with the highest alpha-\u0026beta;-band peak are identified (on either left or right side, 8 to 30 Hz, amplitude \u0026ge; 1.2 \u0026micro;Vp); a stimulation program is then created that activates the \u0026beta;-maximal contact while enabling passive chronic \u0026beta;-signal recording at home for 5\u0026ndash;7 days to capture day-to-day variability. If several contacts show suitable \u0026beta;-signals, contacts may be combined; if no \u0026beta;-peak is detected, the clinically active contact is maintained, and chronic sensing is activated on the adjacent contacts.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eS1: Inpatient programming follows with overnight dopaminergic withdrawal (\u0026ge;12 h), a motor exam (MDS-UPDRS III) with stimulation OFF, and configuration of the LFP-adaptive-DBS algorithm by setting \u0026beta;-based thresholds and patient-tolerated amplitude bounds. Thresholds will be implemented based on the LFP timeline data with the upper threshold being set to 75\u003csup\u003eth\u003c/sup\u003e percentile\u0026nbsp;of\u0026nbsp;daytime\u0026nbsp;timeline LFP-power and lower threshold to\u0026nbsp;25\u003csup\u003eth\u003c/sup\u003e percentile\u0026nbsp;of\u0026nbsp;daytime\u0026nbsp;timeline LFP power.\u0026nbsp;Adjustment of\u0026nbsp;LFP-adaptive-DBS\u0026nbsp;settings will then occur based on clinical findings, e.g. adjustment of amplitude or thresholds.\u0026nbsp;LFP-adaptive-DBS\u0026nbsp;will first be setup to follow the dual-threshold stimulation mode. If clinically satisfactory outcome cannot be achieved using dual-threshold mode, single-threshold\u0026nbsp;settings can be tested and applied.\u003c/p\u003e\n\u003cp\u003eThe control intervention is anatomy-informed continuous DBS (Anatomy-continuous-DBS). Lead locations in relation to the STN are visualized with a CE-marked clinical software (SureTune\u0026trade;, Medtronic) to select contacts that place the electric field in the dorsolateral STN (the motor territory). Contact selection will be performed following the protocol described in Brandt et al. 2024.\u003csup\u003e5\u003c/sup\u003e \u0026nbsp;\u0026nbsp;Stimulation\u0026nbsp;amplitude is then fine-tuned during the same inpatient stay.\u0026nbsp;Pulse\u0026nbsp;widths and stimulation frequency will be kept constant at 60 \u0026micro;s\u0026nbsp;and 130 Hz.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt discharge, three programs are stored on the handheld patient controller: LFP-adaptive-DBS, Anatomy-continuous-DBS, and the pre-study clinical program. Anatomy-continuous-DBS is initially activated for 2 days; on these days patients are encouraged to further titrate stimulation amplitudes within the Anatomy-continuous-DBS program using the patients\u0026rsquo; handheld controller. After titration, patients switch into LFP-adaptive-DBS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA2: A visit follows where LFP-adaptive-DBS settings are controlled for signs of adaptation (e.g. amplitude adaptation) regarding the LFP-measurements and can be refined (e.g. adjustment of thresholds). We will check LFP timeline for plausibility and artifacts. If LFP-adaptive-DBS settings lead to satisfactory results for the patient the study team may find the patient eligible for allocation to the blinded weeks. If side effects occur, LFP timeline yields implausible results or adaptation seems faulty (e.g. due to artifacts), visits can be repeated as often as needed for satisfactory results, prior to A3 and A4. Reasons for further refinements and number of visits will be noted.\u003cbr\u003e\u0026nbsp;Anatomy-continuous-DBS may be modified during these visits, too. Contact selection will not be modified.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u0026nbsp;A3 and A4: Thereafter, in a randomized, blinded crossover, LFP-adaptive-DBS and Anatomy-continuous-DBS are each applied for two weeks (order block-randomized). To preserve blinding, patients keep the handheld patient controller in a sealed container which can be accessed in case of emergency. A wrist-worn accelerometer is worn throughout each treatment phase for minimum three days. Patients are asked to fill out movement diaries for three days, starting on the fourth day after reprogramming of DBS settings.\u003c/p\u003e\n\u003cp\u003eFollow-up ambulatory visits at the end of each two-week period include motor assessment, adverse-event review, and questionnaires; patient and investigator are later asked to guess allocation to assess blinding quality. At completion of the two blinded two-week periods patients are asked in a forced choice design which program they preferred over the other.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; N1: A telephone follow-up at three months documents ongoing program use and outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants may withdraw at any point without providing a reason. If a participant stops one of the treatment weeks early, they may still enter the next treatment phase provided the discontinued week was their first assignment. Preference for treatment will be recorded irrespective of whether both weeks were completed. For safety, each participant\u0026rsquo;s pre-existing, pre-trial DBS program will remain available as a rescue setting via the handheld patient controller.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo promote protocol adherence, participants will be provided with a precise timetable for the intervention phases, clear guidance on when to adjust amplitude, and a motor diary for daily entries during each stable-treatment week. Between visits, study staff will perform scheduled telephone follow-ups to monitor adherence and address issues. At in-person visits, the team will check the device settings to verify that the assigned DBS program is active.\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 should maintain their regular medication regimen and routine care throughout the trial period. Participants must not participate in other interventional clinical trials during the study period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Provisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u0026nbsp;This clinical study will be conducted in compliance with ICH-GCP (E6[R2]) and Regulation (EU) No. 536/2014 (Clinical Trials Regulation).\u003c/p\u003e\n\u003cp\u003eAll Adverse Events (AEs) and Serious Adverse Events (SAEs) will be documented and assessed by the investigator throughout the study period. The investigator will evaluate each event for seriousness, intensity, outcome, and potential causal relationship to the investigational procedure or product. In accordance with the applicable ethical and professional standards (e.g., Berufsordnung f\u0026uuml;r \u0026Auml;rzte), all serious or unexpected adverse events that might affect the safety of study participants must be promptly reported to the responsible Ethics Committee.\u003c/p\u003e\n\u003cp\u003eAfter completion of the trial, participants return to routine care at our hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is patient preference between Anatomy-continuous-DBS and LFP-adaptive-DBS. A Likert-scale assessment of preference will be assessed exploratively. Secondary endpoints comprise motor assessments, clinical (MDS-UPDRS III) and objective (accelerometry), alongside patient-reported measures (FOG-Q, PDQ-39, MDS-UPDRS I/II/IV, VHI), treatment expectation, total electric energy delivered, LFP recordings, and motor diaries.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\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\u003eThe sample size calculation is based on the primary outcome, which is the proportion of patients preferring LFP-adaptive-DBS over Anatomy-continuous-DBS in a forced-choice comparison following a randomized, double-blind, two-period crossover design. The null hypothesis assumes no difference in preference between the two treatments (i.e. 50% of patients prefer LFP-adaptive-DBS), and the alternative hypothesis posits a superiority of LFP-adaptive-DBS with a true preference rate of 75 to 80%. This estimate is supported by clinical trials showing a large preference of LFP-adaptive-DBS over continuous DBS.\u003csup\u003e10,11\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe assume a one-sided exact binomial test at a significance level of \u0026alpha; = 0.05, with a target power of 80%. To account for potential dropouts, we conservatively estimate a 10-15% dropout rate. Under these assumptions, a total sample size of 30 patients was determined to be appropriate to achieve 80% power to detect a preference rate of 75% against the null of 50%. A power curve illustrating the relationship between sample size and power under the assumed effect size is shown in Figure\u0026nbsp;2.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u0026nbsp;This analysis is powered to detect relatively large treatment effects. A negative trial does not exclude smaller effects of the study intervention on patient preferences. The preference ratio will be reported descriptively. The analysis follows an intention-to-treat approach.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be recruited from the Neurology Department\u0026rsquo;s patient cohort at University Hospital Cologne. Eligibility will first be prescreened using existing medical records; candidates who pass this step will undergo a confirmatory examination by a study physician to verify 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\u003eRandomization will be performed in R (R Core Team, 2021) using the randomizeR package (Uschner et al., 2018) with a fixed seed, applying permuted block sizes of 4, 6, and 8 to ensure balanced AB/BA sequences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAllocation is concealed using sequentially numbered, opaque and sealed envelopes. The seed used to generate the randomization list is kept in a password-protected file on site on one designated computer. After confirming eligibility, an unblinded investigator opens the assigned envelope and programs the device according to the indicated sequence. The handheld patient controller is stored in a sealed envelope but will be given inside the envelope to the patient, in case emergency unblinding is required e.g. for medical reasons. The treatment order remains undisclosed to blinded study personnel.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA single designated team member will open the prepared envelopes to determine treatment order and manage the programming devices. This individual will enroll participants and assign the intervention sequence.\u0026nbsp;\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 is a double-blind trial. Participants, clinical raters, and all study staff\u0026mdash;except one unblinded programmer\u0026mdash;are blinded to treatment allocation (LFP-adaptive-DBS vs. Anatomy-continuous-DBS). The unblinded programmer draws the sequence from sealed envelopes and operates the programming devices, while safeguarding allocation secrecy. Outcome assessments are performed by blinded personnel with no access to allocation. Motor examinations (MDS-UPDRS III) are video-recorded and rated later in random order to maintain blinded evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Procedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnblinding is allowed if patients cannot tolerate the program they have been assigned to. In case of a medical emergency or adverse event deemed requiring knowledge of the active DBS program for safe and appropriate clinical management, the unblinded programmer will handle medical care of the patient to secure blinding of the remaining members of the study team. Each unblinding of patient or further study team members will be logged, noting the justification and the individuals 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 outcomes will be assessed by trained clinical investigators. To ensure data quality, standardized case report forms (CRFs) will be used throughout; any changes will be clearly annotated and signed by the responsible 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\u003eParticipants will receive clear scheduling at enrollment. The brief treatment phases (two weeks per intervention) reduce burden. If a participant stops the first treatment week, they may still proceed to the next phase. For discontinuing participants, we will obtain the primary endpoint (treatment preference) whenever feasible, irrespective of completion of both treatment arms, and collect secondary outcomes at the time of discontinuation for partial analyses. All participants exposed to at least one intervention enter the safety set.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be captured on paper CRFs with checklists and tables to ensure completeness. Participants will be pseudonymized. Any changes to CRFs will be clearly annotated and signed by the investigator. Subsequently, data will be transferred to a dedicated digital spreadsheet. This spreadsheet will be password-protected and routinely backed up to a secure network drive. LFP data will be imported after pseudonymizing and off-setting time-stamp to a hospital computer.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipant identities will be safeguarded via coded identifiers. Each participant receives a unique pseudonymized code (e.g., ALIGN01) used on all study documents and datasets. The key linking identities to codes is stored separately from study data in two secure locations: an access-restricted electronic file on the hospital IT system and a hard copy in the investigator site file kept in a locked cabinet. Only authorized study staff may access the linkage file.\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\u003eThere will be no collection of biological specimen.\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 primary outcome is a patient preference between Anatomy-continuous-DBS and LFP-adaptive-DBS treatments. Preference is recorded as a forced binary choice (LFP-adaptive-DBS vs. Anatomy-continuous-DBS) at the end of the second treatment phase (A4). Patient preference will be coded as 0 (Anatomy-continuous-DBS preference) or 1 (LFP-adaptive-DBS preference). The statistical analysis of the primary outcome follows an intention to treat approach, where patient preference will be evaluated notwithstanding completion of treatment phases.\u003c/p\u003e\n\u003cp\u003eThe primary hypothesis is that LFP-adaptive-DBS is preferred over Anatomy-continuous-DBS by a proportion of patients significantly greater than 50%. The null hypothesis (H₀) assumes no preference difference (proportion = 0.5), while the alternative\u0026nbsp;hypothesis (H₁) posits a superiority of\u0026nbsp;LFP-adaptive-DBS\u0026nbsp;preference\u0026nbsp;(proportion \u0026gt; 0.5).\u003cbr\u003e\u0026nbsp;An exact one-sided binomial test will be used to evaluate the proportion of patients preferring\u0026nbsp;LFP-adaptive-DBS\u0026nbsp;under the null hypothesis of 50%. A one-sided significance\u0026nbsp;level of \u0026alpha; = 0.05 will\u0026nbsp;be used.\u003c/p\u003e\n\u003cp\u003eMissing preference data due to completed dropout without preference will not be imputed. These patients will be excluded from the primary analysis but included in descriptive reporting and a secondary sensitivity analysis. In the latter, a conservative imputation strategy will be applied, treating such patients as not preferring LFP-adaptive-DBS (i.e., counted against the alternative hypothesis) to assess robustness of the findings. If a patient does not complete one or two treatment phases but still gives a preference their choice will be evaluated for the primary endpoint.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo assess potential order effects, the distribution of treatment preferences will be examined by treatment sequence. A Fisher\u0026rsquo;s exact test will be used to evaluate whether preference is associated with the order in which treatments were received. This analysis is exploratory and intended to detect potential biases due to sequence effects.\u003c/p\u003e\n\u003cp\u003eIn the case of a non-significant result in the superiority analysis, a non-inferiority analysis with a margin \u0026delta; = 0.10 will be conducted; this is pre-specified as exploratory, intended to support clinical interpretation, and is not used as the basis for sample size determination. The choice of \u0026delta; = 0.10 is guided by the fact that (a) patient preference is a subjective endpoint and (b) LFP-adaptive-DBS may provide advantages for patients with advanced Parkinson\u0026rsquo;s disease (e.g., better control of fluctuations). A sensitivity analysis with smaller \u0026delta; values will be conducted exploratorily; however, the non-inferiority criterion is considered met if the original \u0026delta; = 0.10 threshold is satisfied.\u003c/p\u003e\n\u003cp\u003eSecondary outcomes include changes in clinical symptom scores (e.g., MDS-UPDRS III), adverse events, and patient-reported outcomes measured at the end of each treatment phase. Exploratory analysis will assess potential treatment effects and variability.\u003c/p\u003e\n\u003cp\u003eFor quantitative secondary outcomes measured after each treatment, data will be analyzed as repeated measures within subjects. Depending on data completeness and distribution, either paired analyses (paired t-test or Wilcoxon signed-rank test) or linear mixed-effects models will be applied to compare the\u0026nbsp;LFP-adaptive-DBS and Anatomy-continuous-DBS conditions.\u0026nbsp;Clinically relevant baseline covariates (e.g., age, sex, disease duration) may be included in exploratory models to improve precision and account for individual variability. No correction for multiplicity will be applied due to the exploratory nature of these analyses, but exact\u0026nbsp;\u003cem\u003ep\u003c/em\u003e-values and 95% confidence intervals will be reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn interim analysis has been added to the study design and submitted to the local ethics committee as a protocol amendment prior to first patient in. The interim analysis will be conducted only after formal approval has been obtained prior to the planned interim time point.\u003cbr\u003eInterim would proceed after 18 evaluable preference assessments. The O\u0026rsquo;Brien-Fleming alpha-spending approach would be applied so that early termination in favor of superiority is only possible if at least 15 out of 18 patients prefer LFP-adaptive-DBS. A non-binding futility recommendation would be issued if fewer than 11 out of 18 patients favor LFP-adaptive-DBS. In all other cases, recruitment will continue up to the full target of 30 patients. This protocol will be updated timely, once ethics approval has been granted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g., subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExploratory subgroup analyses will examine whether clinical characteristics such as disease subtype, disease duration, age, levodopa equivalent daily dose (LEDD)\u003csup\u003e14\u003c/sup\u003e,\u0026nbsp;and electrophysiological phenotype based on the LFP patterns influence treatment effects. Composite sub scores from clinical rating scales (e.g., dyskinesia or off‑period scores from MDS-UPDRS IV, dyskinesia,\u0026nbsp;and off-time) may also be evaluated. Given the limited sample size, models will be kept simple and variables chosen based on clinical relevance. All additional analyses will be exploratory and clearly identified as such. No formal adjustment for multiple comparisons will be applied but exact \u003cem\u003ep\u003c/em\u003e‑values and 95% confidence intervals will be reported.\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\u003eAll randomized participants who receive at least one intervention will be analyzed. For the primary endpoint (patient preference), a stated preference will be included even if both treatment periods were not completed. The primary analysis will include patients who completed no treatment period but provide a valid preference rating (modified intention to treat design). Exposure will be reported. A missing preference rating will not be included in the primary analysis.\u0026nbsp;\u003cbr\u003e\u0026nbsp;Envelope opening, changing of program or rescue unblinding will be reported. However, preference given will be evaluated as planned.\u0026nbsp;\u003cbr\u003e\u0026nbsp;For multi-item scales (e.g., MDS-UPDRS III), if up to two items are missing, those items will be imputed with the group mode at that time point. If an entire score is missing, the participant will be excluded from the primary analysis of that endpoint.\u0026nbsp;A blinded review will be done before unblinding to verify analysis readiness. Decisions arising from this review will be recorded and, if relevant, aligned with the study analysis plan (SAP) prior to unblinding. No treatment allocation will be revealed.\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 complete study protocol can be obtained from the corresponding author upon reasonable request. After study completion, participant-level data may be shared for academic use, provided suitable data-sharing agreements are in place and required ethical approvals have been obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating center 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.\u0026nbsp;\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\u003eBoth interventions reflect routine clinical practice with well-characterized safety. Safety oversight will be maintained by the study team throughout. Any decision to stop early will be taken by the principal investigator in accordance with these criteria. Trial monitoring is planned to be performed by\u0026nbsp;the ZKS K\u0026ouml;ln \u0026ndash; Center for Clinical Trials Cologne.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll emerging or worsening Adverse Events (AEs) and Serious Adverse Events (SAEs) will be documented and evaluated by the investigator throughout the study period. Each event will be assessed for seriousness, intensity, outcome, and its potential causal relationship to the investigational procedure or product. In accordance with applicable regulatory, ethical, and professional requirements (e.g., ICH GCP, ISO 14155, and the Berufsordnung f\u0026uuml;r \u0026Auml;rzte), any serious or unexpected adverse events that may affect the safety of study participants will be reported promptly to the responsible ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo dedicated auditing is planned beyond routine monitoring by the Center for Clinical Trials Cologne (ZKS K\u0026ouml;ln). ZKS K\u0026ouml;ln will review protocol adherence, data accuracy, and regulatory compliance. Should issues be identified, the principal investigator will institute corrective measures. The institutional ethics committee may audit the study at its discretion, independently of 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 protocol changes that could influence study conduct, participant safety or benefit, or materially alter procedures, aims, or design will require a formal amendment. All amendments must be approved by the IRB/ethics committee before they are enacted. After approval, relevant revisions influencing trial procedures affecting patients (e.g. different visits, change in consent form) will be communicated to all relevant stakeholders, patients and study team.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResults will be shared through peer-reviewed journal publications and presentations at relevant scientific meetings, irrespective of study outcome. Findings will also be posted to the trial\u0026rsquo;s registration record. Participants may request a lay summary of the results. The protocol was prepared in line with the SPIRIT guidelines.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe will compare LFP-adaptive-DBS with Anatomy-continuous-DBS using a randomized, double-blinded cross-over with patient-preference as primary endpoint. A head-to-head comparison is necessary to assess the clinical relevance of these approaches.\u003c/p\u003e\n\u003cp\u003eAnatomy-continuous-DBS only emerged recently. A growing body of studies indicates positive outcomes.\u003csup\u003e4,5,15,16\u003c/sup\u003e With commercial software for imaging guided programming readily available, over recent years Anatomy-continuous-DBS is increasingly adopted in clinical centers.\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e4,15\u003c/sup\u003e In contrast to LFP-adaptive-DBS, Anatomy-continuous-DBS can be programmed time-efficiently in most cases and typically achieves satisfactory symptom control, after some clinical refinement if needed; new tools allow more precise spatial delivery of current reducing overstimulation side effects.\u003csup\u003e4\u003c/sup\u003e Yet the continuous nature of stimulation might resemble physiological fluctuations of the affected circuits less closely.\u003csup\u003e17\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLFP-adaptive-DBS is a novel stimulation mode allowing for a contact selection based on \u0026szlig;-Power and delivering electric current contingent on it; it may therefore provide a more physiological intervention.\u003csup\u003e10,18\u003c/sup\u003e Whereas contact selection in LFP-adaptive-DBS is time-efficient, programming the chronic adaptive stimulation is relatively time-consuming, requires experience, and patients cannot adjust stimulation amplitude themselves.\u003csup\u003e10,13\u003c/sup\u003e Both programming strategies represent distinct approaches to contact selection as the imaging guided contact selection might not coincide with the LFP-adaptive-DBS selection. Further, the mode of delivery of stimulation differs. As such, both stimulation modes represent diverging, competing paradigms of \u0026ldquo;individualized\u0026rdquo; DBS. As both approaches are now available in routine care, further indicators are needed to determine whether the time-intensive implementation of LFP-adaptive-DBS is justified.\u003cbr\u003eWhile the MDS-UPDRS Part III captures motor outcomes reliably, it may underrepresent relevant adverse effects and fluctuations for patients \u0026mdash;e.g., stimulation-induced dysarthria, motor variability, and non-motor symptoms.\u003csup\u003e19\u0026ndash;21\u003c/sup\u003e Accelerometers offer a more granular insight into motor symptoms but do not capture well non-motor domains.\u003csup\u003e22\u003c/sup\u003e Psychometric assessments allow for a more nuanced perspective on subjective aspects of wellbeing, many of which are subject to substantial fluctuation in PD.\u003csup\u003e23\u003c/sup\u003e Ultimately, all beneficial and disadvantageous effects of a therapy are synthesized in the patient\u0026apos;s choices. Hence, we propose to consider a sustained patient preference for a blinded stimulation mode over time as an integrated measure of stimulation efficacy and tolerability.\u003csup\u003e24\u003c/sup\u003e To date, no blinded head-to-head comparison has been conducted. By centering around patient preference, this trial will help understand the importance of LFP-adaptive-DBS in the clinical context in relation to imaging-guided programming strategies.\u003c/p\u003e\n\u003cp\u003ePreference will be elicited via a blinded forced choice. This sacrifices gradations of preference in favor of interpretability and feasibility in a crossover design; as all participants experience both conditions, we consider the compromise acceptable. To control for potential confounders like treatment expectation, we chose a blinded study design. A two-week exposition was chosen as it is long enough to allow an evaluation on everyday life.\u003csup\u003e11\u003c/sup\u003e Given the duration of exposure, we do not consider washout effects to be relevant for the primary endpoint. Exposure days will be reported for all patients. Nonetheless exposition is short enough to be tolerable if one condition proves less satisfactory. We will report on sequence effects. To assess stability of patient preference the preference choice and active program will be elicited again three months after the primary endpoint and findings will be reported exploratively. We expect our results to inform both, patients and DBS programmers alike about the relevance of LFP-adaptive-DBS for patient satisfaction.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are some limitations to consider regarding our trial design. As per manufacturer, LFP-adaptive-DBS, allows for a range of different programming strategies.\u003csup\u003e18\u003c/sup\u003e In this trial, dual-threshold LFP-adaptive-DBS will be configured as the default. Where clinically indicated by the study physician, single threshold LFP-adaptive-DBS may be substituted. We will report the distribution of LFP-adaptive-DBS modes, deviation from LFP-adaptive-DBS settings like ramp-up time, used and report the clinical reasons for deviating from default settings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study is exploratory with respect to secondary outcomes like motor control (MDS UPDRS Part III) and psychometric measures and not powered to detect small or moderate effects in patient preference. This circumstance is in part due to the small patient sample at hand. Single-center conduct was chosen to permit rapid initiation and rigorously standardized delivery of a complex stimulation protocol. Although this constrains generalizability, internal validity is strengthened by uniform programming, randomized double-blind crossover, pre-registration, and prospective deviation logging. The design enabled full financial independence from industry in which major manufacturers have a direct stake.\u0026nbsp;\u003c/p\u003e"},{"header":"Trial status","content":"\u003cp\u003eProtocol Version: ALIGN Pr\u0026uuml;fplan 1.0. (Dat: 11.02.2025), Recruitment is set to begin on the 15\u003csup\u003eth\u003c/sup\u003e of October 2025. The anticipated completion date for recruitment is 30th September 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAnatomy-continuous-DBS \u0026ndash; anatomically informed continuous deep brain stimulation\u003c/p\u003e\n\u003cp\u003eDBS \u0026ndash; deep brain stimulation\u003c/p\u003e\n\u003cp\u003eFOG-Q \u0026ndash; Freezing of Gait Questionnaires\u003c/p\u003e\n\u003cp\u003eLEDD \u0026ndash; Levodopa Equivalent Dose\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLFP-adaptive-DBS \u0026ndash; LFP-guided adaptive deep brain stimulation\u003c/p\u003e\n\u003cp\u003eMDS-UPDRS \u0026ndash; Movement Disorder Society Universal Parkinson Disease Rating Scale\u003c/p\u003e\n\u003cp\u003ePDQ-39 \u0026ndash; Parkinsons Disease Questionnaire\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSTN \u0026ndash; subthalamic nucleus\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTEX \u0026ndash; Treatment Expectation Questionnaire\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVHI \u0026ndash; Voice Handicap Index\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients and their families for their participation and commitment. We are equally grateful to the healthcare professionals who make complex care possible—especially Study Nurses Max Pohl and Justus Rewolle, and Parkinson Nurse Susanne Hoffmann.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSH and CST contributed equally as co-first authors. SH conceived the protocol, conducts imaging-guided contact selection and adaptive stimulation settings, performs data collection, and drafted the manuscript. \u0026nbsp;CST conceived the study, designed the protocol and drafted the manuscript. HJ conceived the study, designed the protocol and drafted the manuscript. Both authors revised and approved the final manuscript. CVDL contributed to study design, performs data collection, conducts imaging-guided contact selection and adaptive stimulation settings, contributed to study design and revised the manuscript. VVV provided supervision and revised the manuscript. TT provided supervision and revised the manuscript. JS provided supervision and revised the manuscript. TAD contributed to the study design, performs data collection, supports analysis of imaging and accelerometer data, and revised the manuscript. BP performs data collection and revised the manuscript. GB conceived the study, designed the protocol and drafted 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 internally funded by the Neurology Department, University Hospital Cologne. No external funders or sponsors are involved. All personnel, infrastructure, and materials are provided by the department.\u003c/p\u003e\n\u003cp\u003eNo outside entity contributed to the study design, data collection, analysis, interpretation, manuscript preparation, or the decision to submit. All authority and responsibility rest 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 dataset will be available to the principal investigator and trial co-investigators, with no contractual limits on access. After completion, de-identified data may be shared on reasonable request under data-sharing agreements and ethics approval. All statistical analyses will be conducted by the study team, with unrestricted investigator access to the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproval for this study was granted by the ethics committee of the Medical Faculty, University of Cologne (Ref. 25-1053). All participants will provide oral and written informed consent before being enrolled in the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSH received travel recompensation from Boston Scientific. BP has no competing interests to declare. TT is affiliated with ki:elements GmbH, her work is unrelated with this project, however. GAB received honoraria for advisory board participation unrelated to this work and travel expenses for educational activities from Boston Scientific and Medtronic GmbH. CST received travel funding from Medtronic GmbH for an educational program. CVDL was funded by the CCSP Cologne Clinician Scientist Program (CCSP, Faculty of Medicine, University of Cologne) and received travel recompensations from Boston Scientific and Medtronic GmbH for educational activities. HJ received travel recompensations from Boston Scientific .JNPS was given financial support by the CCSP and received funding by the German Research Foundation (DFG, FI 773/15-1) unrelated to this project. VVV received honoraria for advisory board participation and speaker fees from Boston Scientific, Medtronic and LivaNova. TAD's work was supported by the CCSP and will receive funding by Boston Scientific. 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 Page 14 of 18 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.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSchuepbach, W. M. M. \u003cem\u003eet al.\u003c/em\u003e Neurostimulation for Parkinson\u0026rsquo;s disease with early motor complications. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e368\u003c/strong\u003e, 610\u0026ndash;622 (2013).\u003c/li\u003e\n\u003cli\u003eDeuschl, G. \u003cem\u003eet al.\u003c/em\u003e A Randomized Trial of Deep-Brain Stimulation for Parkinson\u0026rsquo;s Disease. \u003cem\u003eN. Engl. J. 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Lateral and posteromedial stimulation spreads induce dysarthria in subthalamic deep brain stimulation for Parkinson\u0026rsquo;s disease. \u003cem\u003eJ. Neurol. Neurosurg. Psychiatry\u003c/em\u003e \u003cstrong\u003e96\u003c/strong\u003e, 280\u0026ndash;286 (2025).\u003c/li\u003e\n\u003cli\u003eBarbe, M. T. \u003cem\u003eet al.\u003c/em\u003e Deep Brain Stimulation for Freezing of Gait in Parkinson\u0026rsquo;s Disease With Early Motor Complications. \u003cem\u003eMov. Disord.\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 82\u0026ndash;90 (2020).\u003c/li\u003e\n\u003cli\u003eMoreau, C. \u003cem\u003eet al.\u003c/em\u003e Overview on wearable sensors for the management of Parkinson\u0026rsquo;s disease. \u003cem\u003eNpj Park. Dis.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 153 (2023).\u003c/li\u003e\n\u003cli\u003eFranke, C. \u0026amp; Storch, A. Nonmotor Fluctuations in Parkinson\u0026rsquo;s Disease. in \u003cem\u003eInternational Review of Neurobiology\u003c/em\u003e vol. 134 947\u0026ndash;971 (Elsevier, 2017).\u003c/li\u003e\n\u003cli\u003eBrandt, G. A. \u003cem\u003eet al.\u003c/em\u003e \u003cem\u003eComparative Evaluation of Standardized Imaging-Guided Contact Selection for Subthalamic Deep Brain Stimulation in Parkinson\u0026rsquo;s Disease (CONECT)\u003c/em\u003e. https://drks.de/search/en/trial/DRKS00034229 (2025).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University Hospital Cologne","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s Disease, Deep Brain Stimulation, Subthalamic Nucleus, Imaging-guided Programming, Clinical Trials, adaptive deep brain stimulation","lastPublishedDoi":"10.21203/rs.3.rs-7851313/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7851313/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eParkinson\u0026rsquo;s disease (PD) motor symptoms are effectively treated with subthalamic deep brain stimulation (STN-DBS). LFP guided, adaptive deep brain stimulation (LFP-adaptive-DBS) is a novel strategy which adjusts stimulation current based on measured neuronal activity. This trial is the first to compare anatomically informed continuous DBS (Anatomy-continuous-DBS) to LFP-adaptive-DBS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conduct a monocentric, randomized and double-blind crossover trial with 30 PD patients enrolled. Patients receive two different programs (Anatomy-continuous-DBS and LFP-adaptive-DBS), each program is tested for two weeks after an initial optimization phase. In the LFP-adaptive-DBS program, the contact selection is based on LFP measurements, while contact selection in the Anatomy-continuous-DBS program is based on individual anatomy targeting the dorsolateral STN. The primary outcome is patient preference after completion of both phases. Secondary outcomes comprise motor symptoms, electrophysiological assessments, accelerometric monitoring and questionnaire-based measurements of non-motor symptoms, treatment expectation, and quality of life.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e\u003cp\u003eTo date both approaches have not been evaluated in a head-to-head comparison, and it remains unclear whether any offers superior treatment effects. This trial aims to provide insights into clinical utility of LFP-adaptive-DBS in comparison to anatomy-informed continuous DBS. We hope to provide further insights into the question which patients might benefit most from LFP-adaptive-DBS.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e\u003cp\u003ehttps//drks.de/register/de/trial/DRKS00037920/preview Number DRKS00037920, Date 20250916\u003c/p\u003e","manuscriptTitle":"Anatomically vs. eLectrophysIologically Guided Contact SelectioN in Deep Brain Stimulation for Parkinson’s Disease (ALIGN-PD): Study Protocol for a Randomized Double-blind Crossover Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 12:44:14","doi":"10.21203/rs.3.rs-7851313/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"25633bca-1129-4315-81f5-65857b19fe56","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56298963,"name":"Neurology"}],"tags":[],"updatedAt":"2026-03-25T06:46:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 12:44:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7851313","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7851313","identity":"rs-7851313","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}