Clinical trial NCT06840145: Biomarkers of Neurodegeneration and Neuroplasticity in Parkinson's Disease Patients Treated by Bilateral M1-iTBS
Official title: Biomarkers of Neurodegeneration and Neuroplasticity in Parkinson's Disease Patients Treated by Intermittent Theta-burst Stimulation Over the Bilateral Primary Motor Area: A Randomized, Double-blind, Sham-controlled, Crossover Trial Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Parkinson's Disease
Lead sponsor: Instituto de investigación e innovación biomédica de Cádiz
Sponsor class: OTHER
Collaborators: name: Ministry of Science and Innovation, Spain
name: Andalusian Ministry of Health and Families
name: Andalusian Ministry of University, Research and Innovation
name: University of Cadiz
name: Hospital Universitario Puerta del Mar
First posted: 2025-02-21
Enrollment: 24
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Each patient received both active and sham iTBS in randomized order in two different sessions, separated by at least 3 months. All patients will be tested four times: at baseline (pre-stimulation) and after iTBS (post-stimulation), both for active and sham iTBS. In each session, motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment, evaluation of M1 excitability, combined structural MRI and resting-state EEG and fMRI, and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS.
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Clinical motor improvement
timeFrame: Changes from baseline to immediately after stimulation, after 1 week, after 2 weeks, and after 4 weeks.
measure: Changes on quality of life and motor complications
timeFrame: Changes from baseline to after stimulation.
Secondary outcomes:
measure: Change in levodopa equivalent daily dose (LEDD)
timeFrame: Changes from baseline to after stimulation
measure: Change in the Parkinson's Fatigue Scale (PFS-16)
timeFrame: Changes from baseline to after stimulation
measure: Change in quality of life measured with the Parkinson Disease Questionnaire-39 (PDQ-39)
timeFrame: Changes from baseline to after stimulation
measure: Screening of cognitive function by MMP
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Screening of frontal lobe function related activities by Frontal Assessment Battery (FAB)
timeFrame: Changes from baseline to after stimulation
measure: Screening of visuospatial memory by Benton Visual Retention Test (BVRT)
timeFrame: Changes from baseline to after stimulation
measure: Beck Depression Inventory-II (BDI-II)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Hamilton Rating Scale for Anxiety (HAM-A)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Starkstein Apathy Scale (SAS)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Scale for the Evaluation of Neuropsychiatric Disorders in Parkinson's Disease (SEND-PD)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Parkinson's Psychosis Questionnaire (PPQ)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Frontal Systems Behavior Scale (FrSBe)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Center for Neurologic Study-Lability Scale (CNS-LS)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Cortical excitability TMS-EMG measures
timeFrame: Changes from baseline to immediately after stimulation
Other outcomes:
measure: Resting-state EEG activity
timeFrame: Changes from baseline to 3 days after stimulation
measure: Structural MRI - T1-weighted (T13D)
timeFrame: Changes from baseline to 1 week after stimulation
measure: Resting-state functional fMRI
timeFrame: Changes from baseline to 1 week after stimulation
measure: Serum protein quantification of Neurofilament light (NfL) protein
timeFrame: Changes from baseline to 1 week after stimulation
measure: Serum protein quantification of Glial Fibrillary Acid Protein (GFAP)
timeFrame: Changes from baseline to 2 weeks after stimulation
measure: Serum protein quantification of Brain-Derived Neurotrophic Factor (BDNF)
timeFrame: Changes from baseline to 2 weeks after stimulation
Locations:
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
Study officials:
affiliation: University of Cadiz & Institute of Biomedical Research Cadiz (INiBICA)
name: Javier J. Gonzalez-Rosa, PhD
role: PRINCIPAL_INVESTIGATOR
References: