Exploring the Possible Beneficial Impact of Non-invasive and Invasive Neuromodulation on Freezing of Gait in Parkinson's Disease During Different Ambulatory Complexities: An Electrophysiological and fMRI Study

Freezing of gait (FOG) stands out as a devastating symptom of Parkinson's disease (PD), where patients may become momentarily glued to the ground, rendering them incapable of walking efficiently. The pathogenesis of FOG remains uncertain but is likely attributed to functional perturbations in superficial cortical and deep locomotion regions. FOG tends to manifest more prominently during complex walking, such as turning, than during simple straight forward walking, and the reasons for this phenomenon remain unclear. Unfortunately, effective methods for overcoming this ambulatory issue has yet to be identified, and quantifying paroxysmal gait spells proves challenging with clinical rating alone; thus, a scientific tool is warranted. In this 3-year proposal, the investigators plan to address these challenges comprehensively.

First, the investigators aim to develop an artificial intelligence algorithm for the identification and quantification of FOG episodes using Red-Green-Blue (RGB) and walkway pressure data. PD patients experiencing FOG will undergo a standardized walking protocol on the PKMAS System, acquiring simultaneous data from two angles of video recording and foot pressure. Labeled videos of FOG incidents will be inputted into an algorithm, Adaptive Fusion Algorithm for Spam Detection (AFSD), utilizing raw RGB data, optical flow data (DualTVL), and their combination for temporal segmentation.

Second, the investigators intend to pinpoint sources of FOG in PD patients through electrophysiological methods during unconstrained walking, employing a high-density 64-channel electroencephalographic ambulatory recording and motor imagery fMRI to delve into the pathophysiology of FOG under different ambulatory conditions. Effective connectivity among higher neural regions, including the basal ganglia, cerebellum, and cortical regions, will be explored. The resulting connectivity map will be overlaid with electric recording data to examine neurovascular coupling or uncoupling.

Third, the investigators plan to conduct non-invasive interventions (transcranial direct current stimulation: tDCS, magnetic resonance-guided focused ultrasound: MRgFUS) and Deep Brain Stimulation (DBS) to assess their impact on gait and FOG in PD patients. Motor imagery fMRI and electrophysiological investigations will be performed before and after treatment using the mentioned methods. Our multi-modal approach aims to unravel the complexities of FOG in PD patients, providing valuable insights and potentially benefiting those enduring the challenges posed by this debilitating symptom.

Eligibility Criteria:
Inclusion Criteria:

1. Patients meet the diagnosis of PD based on the established consensus criteria
2. Age above 20 years old and below 90 years
3. For MRgFUS patients: a. At least one of the 3 cardinal symptoms (akinesia, tremor, rigidity) reaches an intensity of at least 2/4. b. Parkinsonian symptoms cannot be satisfactorily controlled by optimal pharmacological treatment including L-dopa and other antiparkinsonian drugs. c. stable medication for PD ≥ 30 days.
4. DBS patients must meet Taiwan Health Insurance criteria: PD duration exceeding 5 years, positive response to levodopa (≥33% UPDRS motor score improvement), and presence of motor complications (e.g., wearing off, on-off, levodopa-related dyskinesia, or medically intractable tremor).

Exclusion Criteria:

1. Congestive heart failure (Functional III or above) or advanced cancer with distant metastasis.
2. PD at Hoehn and Yahr Stage 5.
3. DBS exclusion criteria: overt dementia or major depression.