Breathing is a complex process, which can be controlled through voluntary command or neural control. Parkinson's disease (PD) is a progressive neurological disorder. Many individuals with PD experience respiratory problems, such as coughing difficulties or shortness of breath. Changes in neural control of breathing could be part of the reason of these respiratory problems. This study will measure whether neural control of breathing is impaired in individuals with PD compared to healthy individuals.

Rationale: Parkinson's disease (PD) is a progressive neurological disorder, characterised by loss of dopaminergic neurons. Respiratory dysfunction is common in patients with PD and can lead to pneumonia, which is a common cause of death in PD. However, the exact mechanism of respiratory dysfunction in PD is unknown. The complex process of neural control of breathing may be involved, but this is understudied. This is partly caused by methodological limitations to quantify neural control of breathing. In this study, we will use respiratory neurophysiological methods to determine whether neural control of breathing is impaired in Parkinson's disease. These techniques are hypercapnic ventilatory response, respiratory related evoked potentials and transcranial magnetic stimulation. This study will test the hypothesis that the neural control of breathing is impaired in individuals with PD compared to healthy subjects.

Objective: Primary Objective: To identify disease (Parkinson's disease) specific alterations in neural control of breathing by using respiratory neurophysiological techniques.

Study design: Exploratory cross-sectional study.

Study population: Healthy subjects (n=15) and patients with Parkinson's disease (n=15) >18 years old.

Main study parameters/endpoints:

• Hypercapnic ventilatory response curve (HCVR): HCVR will be determined using the CO2-rebreathing technique.
• Respiratory related evoked potential (RREP): RREP is a measure of cerebral cortical activity elicited by a short inspiratory occlusion.
• Transcranial magnetic stimulation (TMS) diaphragm: TMS is an established tool for investigating the cortical excitability related to breathing.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risk of this study for the participants is negligible. Subjects do not directly benefit from participating in this study. The scientific benefit of this study is to achieve a better understanding of the neural control of breathing in Parkinson's disease. The outcomes of this study may give rise to future new treatments in Parkinson's disease. The burden of the separate study procedures is relatively small: there are no invasive procedures and patients continue their medication as usual. However, the total time of the visit and the collective burden of the experiments may be perceived as strenuous. Therefore, subjects will be explicitly informed about this aspect of the study, and enough breaks will be scheduled in the program.

Inclusion Criteria:

• Healthy subjects: competent adult (>18 years) volunteers
• Patients: adult (<18 years) patients with Parkinson's disease, clinically confirmed by a movement disorder specialised neurologist with Hoehn and Yahr staging 1 to 3
• Willingness and ability to understand nature and content of the study
• Ability to participate and comply with study requirements

Exclusion Criteria:

• Healthy subjects: previous or ongoing diseases of the central nervous system
• Patients: previous or ongoing diseases of the central nervous system, other than Parkinson's disease
• History of or current psychiatric treatment
• History of or current brain surgery or epilepsy, unclusing deep brain stimulation
• Neuromuscular disorders
• Pre-existing pulmonary disease, such as chronic obstructive pulmonary disease, asthma or pulmonary fibrosis
• TMS incompatibility (metal parts in head or neck, skin allergies)
• Implanted cardiac pacemaker or defibrillator, neurostimulator, cochlear implant or medical infusion device
• Large or ferromagnetic metal parts in the head (exept for a dental wire)
• Pregnancy
• Smoking

Healthy participants: volunteers. Age- and sex-matched to the participants with Parkinson's disease.

Participants with Parkinson's disease: recruited through the outpatient registry at the Radboud University Medical Center that have approved contact for research purposes.