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

Abstract Freezing of gait (FOG) in Parkinson’s disease (PD) is a major cause of disability, often resistant to dopaminergic therapy and deep brain stimulation (DBS). Its underlying neural mechanisms remain unclear. The mesencephalic locomotor region (MLR) is a critical hub for gait control and a therapeutic target for DBS, but the respective functional roles of its two main nuclei, i.e. the cuneiform nucleus (CuN) and the pedunculopontine nucleus (PPN), remain unclear in human gait. Here, we combined local field potential recordings from both the CuN and PPN with detailed biomechanical analyses of gait initiation in four PD patients suffering from dopa-resistant FOG. Neural activity was aligned to anticipatory postural adjustments (APA) and step execution to characterize the temporal organization of MLR dynamics during gait initiation and to identify alterations preceding freezing episodes. We also examined the effects of CuN, PPN and sham stimulation on gait initiation. During gait initiation, the CuN and PPN exhibited distinct temporal and spectral neuronal activity patterns associated with different phases of gait initiation. Alpha-band activity in the CuN increased prior to APA and correlated with stepping rhythm, whereas the PPN showed prominent beta-band desynchronization during postural adjustments followed by alpha modulation during step execution. When FOG occurred after gait initiation (FOG + trials, n = 38), we observed a breakdown of this spatiotemporal organization. Specifically, freezing was preceded by exaggerated and mistimed alpha-band synchronization across the MLR and abnormal modulation of PPN beta activity compared with non-freezing trials (FOG− trials, n = 115, p < 0.05). CuN stimulation selectively improved gait rhythm, whereas PPN stimulation worsened forward propulsion. Across patients, excessive mesencephalic alpha activity predicted impaired gait initiation and reduced responsiveness to stimulation. Together, these findings reveal a functional dissociation within the human MLR, with CuN activity linked to rhythmic step preparation and PPN activity associated with postural and execution-related processes, and subsequent FOG was associated with disruption of MLR dynamics during gait initiation, rather than a uniform loss of locomotor drive. By clarifying the distinct roles of the CuN and PPN and identifying frequency-specific biomarkers associated with gait failure, this study provides a mechanistic framework for understanding variable outcomes of MLR-DBS and supports the development of spatially and temporally adaptive neuromodulation strategies for gait disorders.