Background:

Olfactory and gustatory impairments are common clinical manifestations in patients with neurodegenerative conditions like Parkinson's disease. These chemosensory deficits significantly impact the quality of life, often preceding motor symptoms. Currently, there is a need for effective non-invasive interventions to improve sensory recovery.

Objective:

The primary objective of this study is to evaluate the therapeutic efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) combined with olfactory training in restoring chemosensory function. We aim to determine whether this combined approach provides superior outcomes compared to individual therapies or standard care.

Methods:

This clinical trial involves 120 patients diagnosed with Parkinson's disease. Participants will be randomized into four groups to receive either combined rTMS and olfactory training, isolated rTMS, isolated olfactory training, or a control intervention. The recovery of olfactory function will be measured using validated sensory testing tools (such as Sniffin' Sticks) and Electrogustometry (EGM) to assess neural pathway improvement.

Conclusion/Significance:

This study aims to provide evidence-based insights into non-invasive neurological rehabilitation for chemosensory dysfunction. The findings may help optimize personalized treatment protocols for patients suffering from sensory impairment, potentially enhancing their overall cognitive and sensory quality of life.

Study Design and Patient Selection:

This is a prospective, randomized, four-arm clinical study. A total of 120 patients meeting the inclusion criteria for Parkinson's disease-related chemosensory dysfunction are enrolled. Subjects are randomized using a 1:1:1:1 ratio.

Intervention Protocols:

rTMS Protocol: The intervention group receives high-frequency (10 Hz) stimulation targeted at the cortical regions associated with olfactory processing. The protocol consists of 2000 pulses per session.

Olfactory Training: Participants perform structured olfactory training utilizing standardized odorant sets, conducted twice daily over the 12-week study period.

Methodological Blinding: To ensure task compliance and methodological rigor, distilled water is utilized as a sensory blind check during testing procedures.

Measurements: Sensory assessments are focused on the lateral margins of the tongue using Electrogustometry (EGM) and standardized smell sensitivity tests. Changes in function are recorded using the Visual Analog Scale (VAS) at baseline and 12-week follow-up intervals.

Statistical Analysis:

Data is analyzed to compare the mean sensory threshold changes between the four groups. Baseline characteristics and longitudinal improvements are evaluated using ANOVA followed by post-hoc analysis to determine the statistical significance of the combined therapy versus monotherapy and control groups.

Inclusion Criteria:

• Patients aged between 40 and 75 years.
• Confirmed diagnosis of idiopathic Parkinson's disease (PD) according to the Movement Disorder Society (MDS) clinical diagnostic criteria.
• Confirmed olfactory dysfunction validated by the Sniffin' Sticks test at baseline (defined as a composite TDI score ≤ 30.5 for hyposmia and < 16.0 for functional anosmia).

Exclusion Criteria:

• Presence of cranial metal implants or cardiac pacemakers (absolute contraindications for rTMS).
• Pregnancy.
• Severe psychiatric disorders.
• Advanced dementia.
• History of nasal polyps or active sinusitis that could mechanically obstruct olfactory pathways.

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

The datasets will be available upon publication of the study results and will remain accessible for a period of 5 years following the publication date.

Qualified researchers who wish to access the IPD and supporting information (study protocol, statistical analysis plan, clinical study report) may submit a formal request to the corresponding author via email. The request must include a description of the intended research and evidence of institutional ethics committee approval. Data will be shared for valid scientific purposes, subject to a signed data sharing agreement to ensure participant confidentiality.

Participants are blinded to their assigned intervention arm, as they receive either active rTMS or sham stimulation, which are delivered using an identical setup. Outcome assessors, who perform the chemosensory evaluations (e.g., Sniffin' Sticks test), are also blinded to the group assignment of each participant to minimize assessment bias. Investigators involved in the analysis are masked to the group identities until the data collection phase is finalized.