rTMS as an Intervention for Levodopa-induced Dyskinesia (ADAPT-LIDI)

Network Based Repetitive Transcranial Magnetic Stimulation (rTMS) as an Intervention for Levodopa-induced Dyskinesia (LID) in Parkinson's Disease (PD)

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.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; Dyskinesia, Drug-Induced
• Intervention / Treatment: Device: active TMS; Device: sham TMS

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.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laura Sakalauskaite, MD; Phone Number: +45 38621184; Email: laura.sakalauskaite.01@regionh.dk

Study Locations

• Denmark
  • Hvidovre, Denmark, 2650
    • Recruiting
    • DRCMR
    • Contact: Hartwig Siebner, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gamma burst rTMS; Real stimulation with 4 pulses at the frequency of 130Hz repeating at 1 Hz will be delivered on the pre-SMA using the active side of the coil for 30 minutes	Device: active TMS; Transcranial magnetic stimulation using MagVenture XP Orange Stimulator using active side of MagVenture Cool-B70 coil
Sham Comparator: Sham gamma burts rTMS; Sham stimulation with 4 pulses at the frequency of 130Hz repeating at 1Hz will be delivered on the pre-SMA with a non-active side of the coil for 30 minutes	Device: sham TMS; Sham transcranial magnetic stimulation using MagVenture XP Orange Stimulator, flipping the active side of the MagVenture Cool-B70 coil
Active Comparator: Beta burst rTMS; Real stimulation with 4 pulses at the frequency of 20Hz repeating at 1 Hz be delivered on the pre-SMA using the active side of the coil for 30 minutes	Device: active TMS; Transcranial magnetic stimulation using MagVenture XP Orange Stimulator using active side of MagVenture Cool-B70 coil
Sham Comparator: Sham beta burst rTMS; Sham stimulation with 4 pulses at the frequency of 20Hz repeating at 1Hz will be delivered on the pre-SMA with a non-active side of the coil for 30 minutes	Device: sham TMS; Sham transcranial magnetic stimulation using MagVenture XP Orange Stimulator, flipping the active side of the MagVenture Cool-B70 coil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Unified Dyskinesia Rating Scale (UDysRS)	UDysRS utilizes rater information, patient self-report and objective measures of dyskinesia to provide assessments of impairment and disability due to dyskinesia.The UDysRS total score ranges from 0 to 104 with a lower score indicating less dyskinesia.	Baseline (usual medication intake) and up to 40 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick
Dyskinesia onset time	The onset time of dyskinesia in minutes after levodopa administration	Baseline (usual medication intake) and up to 40 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)	Measure the changes of scores of United Parkinson's Disease Rating Scale Part III in active stimulation compared to sham. The total scores range from 0 (good health) to 132 (poor health).	Baseline (usual medication intake) and up to 40 minutes after taking 150 % of normal morning levodopa dose as Madopar Quick

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
TMS adverse events and associated sensations questionnaire (TMSens_Q)	Questionnaire for assessing any side effects and sensations associated with TMS stimulation, including the assessment of masking (sham or active treatment) of participants.	Immediately after the TMS intervention (sham and active)
Transcranial evoked potentials (TEPs)	Change in cortical excitability pre-post stimulation and OFF-ON states after levodopa administration	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
Non-Motor Symptoms Scale for Parkinson's Disease (NMSS)	The Non-Motor Symptoms Scale (NMSS) is a 30-item rater-based scale to assess a wide range of non-motor symptoms in patients with Parkinson's disease (PD). The scores on the NMSS range from 0 to 360, with higher scores implying a higher severity and frequency of nonmotor symptoms.	Baseline, 4-8 weeks after inclusion
CANTAB battery	Measures of response inhibition, spatial planning and working memory and reaction time	Baseline, 4-8 weeks after inclusion
Movement dynamics	Duration of dyskinesia per day in minutes, OFF/ON periods per day in minutes	Continuous up to 8 weeks after inclusion
Event related potentials (ERPs)	Dynamics of EEG during a Go/Nogo task: movement related potentials, spectral features	Immediately after taking 150 % of normal morning levodopa dose as Madopar Quick
Non-Motor Fluctuation Assessment (NoMoFA) Questionnaire	27-item self-administered questionnaire that is used for capturing both static and fluctuating non-motor symptoms in PD. Possible score for the NoMoFA ranges from 0 to 81 points, with higher scores implying a higher severity and frequency of nonmotor symptoms.	Baseline, 4-8 weeks after inclusion
The Parkinson's Disease Questionnaire (PDQ-39)	39 item self-administered questionnaire that assesses how often people with Parkinson's experience difficulties across 8 dimensions of daily living including relationships, social situations and communication. Each dimension total score range from 0 (never have difficulty) to 100 (always have difficulty). Lower scores reflect better quality of life.	Baseline, 4-8 weeks after inclusion
The World Health Organization Quality of Life (WHOQOL)	General quality of life assessment as a part of patient reported outcome assessment. The possible score ranges in each case from 0 to 100 points. Higher scores indicate better quality of life.	Baseline, 4-8 weeks after inclusion

Collaborators and Investigators

• Sponsor: Danish Research Centre for Magnetic Resonance
• Investigators: Principal Investigator: Hartwig R. Siebner, Prof., Head of Research, Prof, DMSc

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Institutional website

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: May 3, 2024
• First Submitted That Met QC Criteria: August 22, 2024
• First Posted (Actual): August 26, 2024

Study Record Updates

• Last Update Posted (Actual): August 28, 2024
• Last Update Submitted That Met QC Criteria: August 26, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Parkinson's Disease; Movement Disorders; Central Nervous System Diseases; Neurodegenerative Diseases; Synucleinopathies; Dyskinesias; Basal Ganglia Diseases; Levodopa induced dyskinesia; LID; Pre-SMA
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Drug-Related Side Effects and Adverse Reactions; Poisoning; Neurotoxicity Syndromes; Parkinson Disease; Dyskinesias; Dyskinesia, Drug-Induced
• Other Study ID Numbers: ADAPT-LIDI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sharing of anonymised data
• IPD Sharing Time Frame: After study completion
• IPD Sharing Access Criteria: Anonymised data, reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No