Chronic Outcome Monitoring for DBS in Dystonia

Official title

Chronic Neurophyhsiological and Kinematic Biomarker Monitoring in Patients With Dystonia and Pallidal Deep Brain Stimulation

Overview

Dystonia is a severe movement disorder involving increased muscular activity and can be very variable. To date, the treatment of dystonia is challenging. One effective therapy is deep brain stimulation (DBS), an invasive therapy, where stimulation electrodes are inserted in deep brain regions and a continuous electrical therapy is delivered via a pacemaker. However, the optimization of the therapy is a long process, up to months and there is no immediate adaptation to different disease states. This project aims to improve DBS therapy: The first aim is to learn more about electrical brain activity that could be the feedback signal for individualized therapy. Secondly, the investigators want to gather information about the long-term development of the signal and potential hints for optimal therapy locations that could be acutely used to accelerate therapy optimization. To date, recordings mainly in lab settings, have suggested low-frequency activity as a biomarker for dystonia. Biomarkers are signals that are changed with therapy and that reflect symptom severity. Further understanding of the low-frequency biomarker for dystonia and its applicability in everyday life is one of the objectives in this study. Therefore, using a pacemaker that can also record brain activity, biomarker activity will be recorded for 12 months. At the same time, development of clinical symptoms will be assessed using an application with weekly questionnaires on symptoms and a video diary. At monthly appointments for data saving, resting state as well as motor activity during a finger tapping task will be recorded to also assess the development of side-effects, such as stimulation-induced slowing, and their biomarkers.

Detailed description

Dystonia is a hyperkinetic movement disorder that can have various clinical phenotypes, from isolated cervical dystonia to severe generalized dystonia. Deep brain stimulation (DBS) is an effective therapy for dystonic symptoms and has been successfully used for more than 20 years. However, clinical optimization can be a complicated and lengthy process, and to date there is no closed-loop stimulation paradigm automatically adapting to current disease states.

Previous electrophysiological research using intracranial local field potential (LFP) recordings from DBS electrodes in the internal pallidal globe (GPi) has identified low-frequency activity in the theta/alpha band (7-12 Hz) as a physiomarker for symptom severity, although stimulation effects on the neurophysiology have only been investigated indirectly to date. Interestingly, stimulation-induced bradykinesia was correlated with increased beta-band activity, pointing towards transdiagnostic biomarkers. With the Percept neurostimulator (Medtronic Inc., Minnesota, USA) high resolution electrophysiological recordings, also during stimulation, and chronic biomarker tracking have become more accessible, also allowing for investigation of long-term dynamics such as circadian variations. To date, in dystonia, only case-reports have been published using this device.

Here, the development of electrophysiological biomarkers are systematically investigated during the first post-operative year. The aim is to, firstly, characterize the potential of low-frequency activity as a biomarker for adaptive algorithms. Secondly, neurophysiological signatures (e.g. low-frequency, gamma band activity) that are predictive of symptom improvement will be characterized, which might lead to electrophysiology-guided acceleration of therapy optimization.

All patients with dystonia, regardless of the dystonia type, between the age of 5-80 years, receiving surgery for pallidal deep brain stimulation electrode implantation and the Percept device are screened to participate in the study. Participants, and if applicable the legal guardians, will provide informed consent according to the ethics approval (EA1/164/23 and EA2/163/25). The aim is to include 20-30 patients with various types of dystonia.

The first dataset will be continuously recorded biomarker activity in the low-frequency range and beta band, to also assess development of stimulation-induced beta increases. Recordings will be done using the Percept Chronic BrainSense feature that allows for continuous assessment of peak biomarker activity at an investigator-selected peak at a 5 Hz window and a temporal resolution of one mean value/10min. For symptomatic correlation, subjective (patient reported outcome (PRO) questionnaire) and objective (video-based kinematic analysis) will be collected. The PRO will cover motor symptoms as well as non-motor symptoms such as mood and pain.

The second data set will be high-resolution local-field potential recordings at monthly lab visits. Here, different therapy states (ON/OFF DBS) will be recorded during rest (comfortably seated with open eyes) and a movement task (finger tapping). Additionally, standardized clinical scales such as the Burke-Fahn-Marsden-Dystonia-Rating Scale (BFMDRS) and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) will be assessed by clinicians.

Primary outcome measures

• Amount of low-frequency band oscillatory suppression [Time frame: monthly recordings for 12 months]
• Proportion of pathological increase in beta band oscillatory activity [Time frame: monthly recordings for 12 months]

Secondary outcome measures (7)

• Proportion of dystonic symptom improvement in patient reported outcomes [Time frame: weekly, through study completion, up to 12 months]
• Proportion of dystonic symptom improvement in kinematic video-based analysis [Time frame: weekly, through study completion, for up to 12 months]
• Proportion of dystonic symptom improvement based on validated scales - Burke Fahn Marsden Dystonia Rating Scale [Time frame: monthly, through study completion, for up to 12 months]
• Proportion of dystonic symptom improvement based on validated scales - Toronto Western Spasmodic Torticollis Rating Scale [Time frame: monthly, through study completion, for up to 12 months]
• Proportion of non-motor symptom improvement [Time frame: weekly, through study completion, for up to 12 months]
• Rate of bradykinesia with velocity decrease [Time frame: weekly, through study completion, for up to 12 months]
• Rate of bradykinesia with decreased acceleration [Time frame: monthly, through study completion, for up to 12 months]

Eligibility criteria

Inclusion criteria

• Ability to give informed consent for the study, or in pediatric patients, legal guardian or parent willing to give informed consent
• Diagnosis of dystonia, which may be isolated or generalized
• Wish to receive surgical intervention with DBS to the internal pallidal globe (GPi)
• Decision to receive the sensing-enabled neurostimulator (Percept neurostimulator) PC/RC
• Age 5-80 years

Exclusion criteria

• Severe psychiatric disorders (BDI>20)
• Other severe medical conditions, that may interfere with the successful paritcipation in the study protocol
• No consent given

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Germany · 3 centers

• Medizinische Hochschule Hannover — Hanover
• Heinrich Heine University — Düsseldorf
• Charité Universitätsmedizin Berlin — Berlin

Publications

• Feldmann LK, Lofredi R, Neumann WJ, Al-Fatly B, Roediger J, Bahners BH, Nikolov P, Denison T, Saryyeva A, Krauss JK, Faust K, Florin E, Schnitzler A, Schneider GH, Kuhn AA. Toward therapeutic electrophysiology: beta-band suppression as a biomarker in chronic local field potential recordings. NPJ Parkinsons Dis. 2022 Apr 19;8(1):44. doi: 10.1038/s41531-022-00301-2. PMID 35440571
• Krause P, Mahlknecht P, Skogseid IM, Steigerwald F, Deuschl G, Erasmi R, Schnitzler A, Warnecke T, Muller J, Poewe W, Schneider GH, Vesper J, Warneke N, Eisner W, Prokop T, Muller JU, Volkmann J, Kuhn AA; Deep-Brain Stimulation for Dystonia Study Group. Long-Term Outcomes on Pallidal Neurostimulation for Dystonia: A Controlled, Prospective 10-Year Follow-Up. Mov Disord. 2025 Jun;40(6):1098-1111. d PMID 39907392
• Kupsch A, Benecke R, Muller J, Trottenberg T, Schneider GH, Poewe W, Eisner W, Wolters A, Muller JU, Deuschl G, Pinsker MO, Skogseid IM, Roeste GK, Vollmer-Haase J, Brentrup A, Krause M, Tronnier V, Schnitzler A, Voges J, Nikkhah G, Vesper J, Naumann M, Volkmann J; Deep-Brain Stimulation for Dystonia Study Group. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl PMID 17093249
• Ledingham D, Gibbs M, Mills R, Jenkins A, Nicholson C, Hussain MA, Baker M, Pavese N. Decoding Cervical Dystonia: Insights from Local Field Potentials in a Case Study Utilizing Open-Source Toolboxes. Mov Disord Clin Pract. 2025 Oct;12(10):1675-1678. doi: 10.1002/mdc3.70164. Epub 2025 Jun 5. No abstract available. PMID 40470846
• Neumann WJ, Horn A, Ewert S, Huebl J, Brucke C, Slentz C, Schneider GH, Kuhn AA. A localized pallidal physiomarker in cervical dystonia. Ann Neurol. 2017 Dec;82(6):912-924. doi: 10.1002/ana.25095. Epub 2017 Dec 5. PMID 29130551
• Peach R, Friedrich M, Fronemann L, Muthuraman M, Schreglmann SR, Zeller D, Schrader C, Krauss JK, Schnitzler A, Wittstock M, Helmers AK, Paschen S, Kuhn A, Skogseid IM, Eisner W, Mueller J, Matthies C, Reich M, Volkmann J, Ip CW. Head movement dynamics in dystonia: a multi-centre retrospective study using visual perceptive deep learning. NPJ Digit Med. 2024 Jun 18;7(1):160. doi: 10.1038/s41746-024 PMID 38890413
• Scheller U, Lofredi R, van Wijk BCM, Saryyeva A, Krauss JK, Schneider GH, Kroneberg D, Krause P, Neumann WJ, Kuhn AA. Pallidal low-frequency activity in dystonia after cessation of long-term deep brain stimulation. Mov Disord. 2019 Nov;34(11):1734-1739. doi: 10.1002/mds.27838. Epub 2019 Sep 4. PMID 31483903
• van Rheede JJ, Feldmann LK, Busch JL, Fleming JE, Mathiopoulou V, Denison T, Sharott A, Kuhn AA. Diurnal modulation of subthalamic beta oscillatory power in Parkinson's disease patients during deep brain stimulation. NPJ Parkinsons Dis. 2022 Jul 8;8(1):88. doi: 10.1038/s41531-022-00350-7. PMID 35804160

Identifiers

NCT: NCT07244549 · CCM_MDNS_COMMED-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗