Using fNIRS in 28 PD-FOG patients and 28 controls, the study shows rhythmic visual or auditory cues (but not their combination) acutely improve gait, increase oxyhemoglobin in PFC and S1, and strengthen functional connectivity among PFC, S1, M1, PMC and temporal/visual areas.

Findings clarify cortical hemodynamic and connectivity mechanisms by which external cueing alleviates freezing of gait, supporting non-pharmacological therapies and potential cortical targets/biomarkers for neuromodulation, but provide limited direct molecular targets for drug discovery.

INTRODUCTION: External cue interventions can effectively improve gait disturbances in patients with Parkinson's Disease (PD) and Freezing of Gait (FOG). However, the cortical mechanisms underlying cueing modulation of gait have rarely been investigated. OBJECTIVES: We aimed to compare gait performance and cerebral hemodynamic responses in patients with PD and FOG (PD-FOG) under different cueing interventions, and to further elucidate the neural mechanisms underlying the effects of different cues on gait by contrasting these findings with those of Healthy Controls (HCs). METHODS: Twenty-eight PD-FOG patients and 28 HCs were enrolled. Gait parameters were measured during the walking experiment under Rhythmic Visual Cue (RVC) and Rhythmic Auditory Cue (RAC) to compare how these cues affect gait. Functional Near-infrared Spectroscopy (fNIRS) was employed to measure changes in oxyhemoglobin concentration (∆HbO2). Additionally, inter-channel connectivity strength was calculated to evaluate Functional Connectivity (FC) across various Regions of Interest (ROIs). RESULTS: PD-FOG patients exhibit features including decreased gait velocity and stride length during freezing episodes. Both RVC and RAC enhance gait velocity and stride length. Conversely, the combined RVC and RAC (RVC + RAC) intervention did not produce meaningful changes in gait. Compared to HCs, PD-FOG patients show significantly lower ∆HbO2 in the Prefrontal Cortex (PFC) and Primary Somatosensory Cortex (S1). Both RVC and RAC interventions increase ∆HbO2 in the PFC and S1 in PD-FOG patients, whereas the RVC + RAC intervention decreases ∆HbO2 in the Premotor Cortex (PMC). Furthermore, compared with HCs, PD-FOG patients show increased FC between the S1-PFC and Primary Motor Cortex (M1)-PFC. The RVC intervention enhances FC within the PFC and between the PMC and the Visual Association Cortex (V2). The RAC intervention strengthens FC within the PFC and the PFC-Middle Temporal Gyrus (MTG). The RVC + RAC intervention increases FC within the PFC-MTG and PFC-PMC, partially compensating for functional deficits associated with cortical hypoactivation by enhancing connectivity among these ROIs. CONCLUSION: Single visual or auditory cues can improve FOG symptoms. RVC and RAC alleviate FOG by modulating cortical activation and enhancing FC between key ROIs. The heightened connectivity among these ROIs may represent the underlying neural pathway that mediates the cue-induced alleviation of FOG.