Distinct roles of the human cuneiform and pedunculopontine nuclei in gait initiation and freezing of gait

Abstract Freezing of gait in Parkinson’s disease (PD) is a major cause of disability, often resistant to dopaminergic therapy and deep brain stimulation (DBS). Its underlying mechanisms remain unclear, mainly because the roles of the human mesencephalic locomotor region (MLR) nuclei are not well understood. Here, we combined rare local field potentials (LFP) recordings from the cuneiform (CuN) and pedunculopontine nuclei (PPN) with biomechanical markers of gait initiation (GI) in four PD patients. We identified functional differences: increases in CuN alpha-band activity precede anticipatory postural adjustments (APA) and correlate with the rhythm of upcoming steps, whereas decreases in PPN beta-band activity occur during APA just before the lead foot lifts off. Imminent freezing is characterized by a breakdown of this organization, marked by mistimed alpha-band surges across the MLR and abnormal PPN beta-band modulation. CuN stimulation selectively improved the stepping rhythm, while PPN stimulation worsened pace or forward vigor. Furthermore, exaggerated mesencephalic alpha-band power was associated with poor clinical responses. These results clarify the individual roles of MLR nuclei in human locomotion and identify pathological alpha dynamics as a biomarker for advancing adaptive neurostimulation.