Biomarkers of Neurodegeneration and Neuroplasticity in Parkinson's Disease Patients Treated by Bilateral M1-iTBS

NCT ID: NCT06840145

Last Updated: 2025-02-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-01
• Study Completion Date: 2024-04-12

Brief Summary

Intermittent theta-burst stimulation (iTBS) is a promising therapeutic option for Parkinson's disease patients. A study involving 24 patients will assess its effectiveness in alleviating clinical deficits. Patients will undergo 5 sessions of iTBS over the bilateral M1 and a 3-month washout period. Motor evaluation, neurocognitive assessment, serum biomarkers of neurodegeneration and neuroplasticity, and structural and functional MRI evaluations will be conducted at follow-up visits.

Detailed Description

Background and objectives:

Intermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson's disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent cortico-striatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induce clinical enhancement. Here, the primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective at reducing both scoring motor functioning and non-motor symptoms in PD. The investigators hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striatal-cortical-cerebellar functional connectivity, and positively impacting neuroglia and neuroplasticity modification.

Methods:

A total of 24 PD patients will be assessed in a crossover, randomized, double-blind, sham-controlled protocol study involving application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 sessions (1 week) of iTBS over the bilateral M1 (1 week), a 3-month washout period, and then 5 sessions (1 week) of sham stimulation. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment, evaluation of M1 excitability, combined structural magnetic resonance imaging (MRI) and resting-state electroencephalography and functional MRI, and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS.

Discussion:

The findings of this study will help to update the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate structural and functional mechanisms of M1 iTBS-induced plasticity in cortico-basal ganglia circuitry. The current approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Conditions

Parkinson's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

real iTBS

Intermittent theta burst stimulation (iTBS) will be performed using a 3 pulse bursts at 50 Hz repeated every 200 ms and delivered as short trains of 10 bursts lasting 2 s and an intertrain silence period of 8 s, for a total of 600 pulses (20 cycles of trains) and a total duration of 190 s. Intensity of iTBS will be administered to the bilateral M1 at 80% of the active motor threshold (aMT) of each patient.

Group Type: ACTIVE_COMPARATOR

repetitive transcranial magnetic stimulation

Intervention Type: DEVICE

Intermittent theta Burst stimulation will be performed as detailed in the Real arm description

sham iTBS

The repetitive transcranial magnetic stimulation (rTMS) coil stimulation will be applied in the same position of the real stimulation. Sham stimulation during treatment will follow the same procedure and both coils are identical in appearance and produce a similar sound and sensation, although the sham coil delivers no stimulation. The patient will hear the same sound of real stimulation, which will be only functionally inactive but will be completely performed (for the whole time of duration of stimulation)

Group Type: SHAM_COMPARATOR

repetitive transcranial magnetic stimulation

Intervention Type: DEVICE

Intermittent theta Burst stimulation will be performed as detailed in the Real arm description

Interventions

repetitive transcranial magnetic stimulation

Intermittent theta Burst stimulation will be performed as detailed in the Real arm description

Intervention Type: DEVICE

Other Intervention Names

rTMS; intermittent theta-burst stimulation; iTBS

Eligibility Criteria

Inclusion Criteria

• Diagnosed with PD according to the UK Parkinson's Disease Society Brain Bank diagnostic criteria (UK PDSBB) diagnostic criteria
• Disease duration of at least 5 years to reduce the risk of including levodopa-responsive atypical Parkinsonism patients;
• Disease symptomatology in the ON medication state at a H&Y scale of II-III;
• Clinical and therapeutic stability in the last 2 months previous to the recruitment period; and
• Aged 45-75 years.

Exclusion Criteria

• Lack of a PD diagnosis that meets the UK PDSBB diagnostic criteria
• Presence of a serious systemic disease
• Presence of severe or moderate cognitive impairment comparable to dementia, as revealed by an MMP score of ≤ 24
• Any incapacitating psychiatric or other clinical condition that might affect the correct performance of this protocol, such as any dystonia and/or dyskinesia
• Patients who received amantadine within the previous 60 days
• Any sign of atypical parkinsonism, neurological comorbidities, or history of cranioencephalic traumatism or epilepsy or any other contraindication for receiving neurostimulation with TMS (e.g., intracranial magnetic implant, cardiac pacemaker)

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Science and Innovation, Spain

OTHER_GOV

Sponsor Role: collaborator

Andalusian Ministry of Health and Families

UNKNOWN

Sponsor Role: collaborator

Andalusian Ministry of University, Research and Innovation

UNKNOWN

Sponsor Role: collaborator

University of Cadiz

OTHER

Sponsor Role: collaborator

Hospital Universitario Puerta del Mar

OTHER

Sponsor Role: collaborator

Instituto de investigación e innovación biomédica de Cádiz

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Javier J. Gonzalez-Rosa, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Cadiz & Institute of Biomedical Research Cadiz (INiBICA)

Locations

Hospital Universitario Puerta del Mar

Cadiz, Cadiz, Spain

Countries

Spain

Other Identifiers

PD-iTBS-2169-N-19

Identifier Type: -

Identifier Source: org_study_id