prTMS as an Intervention for Bradykinesia in Parkinson's Disease

Bradykinesia is one of the core symptoms of Parkinson's Disease (PD) and has multiple facets. Movements become slower and decrease in amplitude. Speed and amplitude of movements decline gradually during repetitive movements, referred to as sequence effect. Spontaneous movements are also reduced, and movement initiation is impaired. These symptoms arise from dysfunction within the brain's motor network, particularly involving the basal ganglia-thalamo-cortical loop. The consequences of bradykinesia are far-reaching, severely affecting the patient's daily life and well-being.

Bradykinesia is primarily treated successfully with pharmacologically dopamine precursor levodopa and/or dopamine agonists. However, not all facets of bradykinesia response to dopamine such as the sequence effect and in addition as disease progresses adverse side effects emerge from medication such as dyskinesia which is involuntary choreiform or dystonic movements. These adverse effects require advanced therapies such as invasive treatment with deep brain stimulation (DBS). However, DBS is highly invasive, expensive, and may come with serious side effects.

Transcranial magnetic stimulation (TMS) has emerged as a promising non-invasive and cost-effective intervention for alleviating bradykinesia. In particular, patterned repetitive TMS (prTMS) over several brain regions including the supplementary motor area (SMA) has shown potential in modulating dysfunctional neural circuits and improving motor symptoms in patients with PD. Recent evidence suggests that the efficacy of prTMS may be enhanced by aligning stimulation with specific brain states, as the brain is most responsive to plasticity-inducing protocols right before a movement.

The current study aims to develop and validate a novel burst-based prTMS protocol called quadri-pulse stimulation (QPS), which consist of high-frequency burst with four pulses in each burst. An excitatory 200 hertz (Hz) QPS protocol has already shown to induce long-lasting plasticity changes and by incorporating the state of the brain the study aim to further enhance the effect of this QPS protocol.

Through a cross-over study design the study will apply active QPS right before a movement, active QPS between movement and sham condition before a movement in patients with PD to determine which produces a meaningful reduction in bradykinesia severity measured by Movement Disorder Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) and Modified Bradykinesia Rating Scale (MBRS).

Inclusion criteria

Above 18 years of age. Clinically established or probable Parkinson's Disease (PD), according to the Movement Disorder Society.

Clinical Diagnostic Criteria for PD. Stable antiparkinsonian medicine for at least four weeks. Signed informed consent.

Exclusion criteria

Psychiatric disorders. Current use of antipsychotic medication, Donepezil, or GABAergic agents (e.g., pregabalin, gabapentin).

Frequent benzodiazepine or opioid use defined as more than once per week on a regular basis.

History of neurological disease other than PD. Past or present mental illness. History of epilepsy/conditions associated with increased risk of seizure induction through transcranial magnetic stimulation (TMS).

Close relatives suffering from epilepsy/conditions associated with increased risk of seizures.

Contraindications for magnetic resonance imaging (MRI) Contraindications for TMS Female participants of childbearing age must not be pregnant and 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.