Clinical trial NCT06570824: rTMS as an Intervention for Levodopa-induced Dyskinesia
Official title: Network Based Repetitive Transcranial Magnetic Stimulation (rTMS) as an Intervention for Levodopa-induced Dyskinesia (LID) in Parkinson's Disease (PD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Dyskinesia, Drug-Induced
Parkinson Disease
Keywords: Basal Ganglia Diseases
Parkinson's Disease
Central Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Dyskinesias
LID
Levodopa induced dyskinesia
Pre-SMA
Lead sponsor: Danish Research Centre for Magnetic Resonance
Sponsor class: OTHER
First posted: 2024-08-26
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study has a double-blinded crossover design. The research participants will, in two separate stimulation sessions, receive either real rTMS treatment or a sham-TMS stimulation. The session order (real rTMS first or sham first) will be randomised between research participants. The research participant will be blinded to which treatment (real or sham) they receive at any session. There will be two sequential groups of patients. First group will receive gamma burst rTMS stimulation and sham and the other group will receive beta burst rTMS and sham.
Primary purpose: TREATMENT

Brief summary: The proposed study investigates the use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for levodopa-induced dyskinesia (LID) in Parkinson's Disease (PD). Specifically, the study aims to determine whether patterned stimulation of the pre-supplementary motor area (pre-SMA) can delay the onset of LID after levodopa intake and reduce LID severity in PD patients. This study will provide critical insights into potential targets for rTMS treatment, optimal rTMS parameters, and the mechanisms underlying LID in Parkinson's disease.

Detailed description: Long-term use of levodopa in Parkinson's Disease (PD) often leads to motor complications, such as Levodopa-Induced Dyskinesia, which significantly impacts patients' daily lives. Various brain regions have been targeted for treatment with Transcranial Magnetic Stimulation (TMS), including the supplementary motor area (SMA), primary motor cortex, cerebellum, and prefrontal cortex. Specifically, targeting the pre-SMA with 1-Hz rTMS has been shown to delay and reduce dyskinesia severity in PD patients following levodopa administration. These findings suggest that the pre-supplementary motor area is a promising target for brain stimulation therapy, as it plays a causal role in the pathophysiology of peak-of-dose dyskinesia.

The current study aims to build on previous research by optimizing the stimulation intensity and location based on individual neuroanatomy and simulated electric fields. Additionally, the study will explore the impact of rTMS delivered in short high-frequency bursts, differing from the single rTMS pulses used in previous studies. In the context of LID, Deep Brain Stimulation (DBS) typically targets the subthalamic nucleus (STN) using gamma frequencies (40-200 Hz, most commonly 130 Hz). Drawing from this principle, the study posits that delivering rTMS bursts at gamma frequencies to the pre-SMA will effectively mitigate LID symptoms. Moreover, evidence from cortical brain rhythm recordings highlights that beta frequencies (12-30 Hz), which are crucial for movement control and are disrupted in PD, may also hold therapeutic potential. Therefore, the study will investigate whether rTMS bursts at beta frequencies could similarly reduce LID symptoms. Given the absence of prior research directly comparing the effects of different burst frequencies on LID, the study will systematically apply two distinct burst frequencies, in separate patient groups, to determine which, if either, produces a meaningful reduction in LID symptoms.

Dyskinesia onset time and severity will be measured using the Unified Dyskinesia Rating Scale (UDysRS) and assessed by a clinician rater who is blinded to the treatment condition. The results will be compared between the active and sham stimulation conditions.

Eligibility criteria: Inclusion Criteria:

* Clinically established or probable PD
* Clinical Diagnostic Criteria for Parkinson's Disease
* Peak-of-dose levodopa-induced dyskinesia.
* Stable antiparkinsonian medicine for at least four weeks.
* Signed informed consent.

Exclusion Criteria:

* Psychiatric disorders.
* Usage of antipsychotic medication, Donepezil, and GABAergic medications (such as pregabalin and gabapentin).
* Regular usage of benzodiazepines and opioids (more than once per week).
* History of neurological disease other than Parkinson's disease.
* History of epilepsy/conditions associated with increased risk to seizure-induction through TMS.
* Close relatives suffering from epilepsy/conditions associated with increased risk to seizure-induction through TMS.
* Contraindications for MRI scan
* Female participants of childbearing age must not be pregnant and that they must use contraception during the trial.
* Refuse to be informed about new health related information and accidental health related findings that might appear through participation in the study.

Primary outcomes:
measure: Unified Dyskinesia Rating Scale (UDysRS)
timeFrame: Baseline (usual medication intake) and up to 40 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick
measure: Dyskinesia onset time
timeFrame: Baseline (usual medication intake) and up to 40 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick
Secondary outcomes:
measure: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)
timeFrame: Baseline (usual medication intake) and up to 40 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick
Other outcomes:
measure: TMS adverse events and associated sensations questionnaire (TMSens_Q)
timeFrame: Immediately after the TMS intervention (sham and active)
measure: Transcranial evoked potentials (TEPs)
timeFrame: Before and immediately after the TMS intervention (sham and active), up to 20 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick
measure: Event related potentials (ERPs)
timeFrame: Immediately after taking 150 % of normal morning levodopa dose as Madopar Quick
measure: Non-Motor Symptoms Scale for Parkinson's Disease (NMSS)
timeFrame: Baseline, 4-8 weeks after inclusion
measure: Non-Motor Fluctuation Assessment (NoMoFA) Questionnaire
timeFrame: Baseline, 4-8 weeks after inclusion
measure: CANTAB battery
timeFrame: Baseline, 4-8 weeks after inclusion
measure: The Parkinson's Disease Questionnaire (PDQ-39)
timeFrame: Baseline, 4-8 weeks after inclusion
measure: The World Health Organization Quality of Life (WHOQOL)
timeFrame: Baseline, 4-8 weeks after inclusion
measure: Movement dynamics
timeFrame: Continuous up to 8 weeks after inclusion
Locations:
city: Hvidovre
country: Denmark
facility: DRCMR
Study officials:
affiliation: Head of Research, Prof, DMSc
name: Hartwig R. Siebner, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lohse A, Meder D, Nielsen S, Lund AE, Herz DM, Lokkegaard A, Siebner HR. Low-frequency transcranial stimulation of pre-supplementary motor area alleviates levodopa-induced dyskinesia in Parkinson's disease: a randomized cross-over trial. Brain Commun. 2020 Sep 18;2(2):fcaa147. doi: 10.1093/braincomms/fcaa147. eCollection 2020.
citation: Herz DM, Haagensen BN, Christensen MS, Madsen KH, Rowe JB, Lokkegaard A, Siebner HR. The acute brain response to levodopa heralds dyskinesias in Parkinson disease. Ann Neurol. 2014 Jun;75(6):829-36. doi: 10.1002/ana.24138. Epub 2014 May 28.