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Amongst reduced gravity simulators, the lower body positive pressure (LBPP) treadmill is emerging as an innovative tool for both rehabilitation and fundamental research purposes as it allows running while experiencing reduced vertical ground reaction forces. The appropriate use of such a treadmill requires an improved understanding of the associated neuromechanical changes. This study concentrates on the runner’s adjustments to LBPP-induced unweighting and reloading during running. Nine healthy males performed two running series of nine minutes at natural speed. Each series comprised three sequences of three minutes at: 100% bodyweight (BW), 60 or 80% BW, and 100% BW. The progressive unweighting and reloading transitions lasted 10 to 15 s. The LBPP-induced unweighting level, vertical ground reaction force and center of mass accelerations were analyzed together with surface electromyographic activity from 6 major lower limb muscles. The analyses of stride-to-stride adjustments during each transition established highly linear relationships between the LBPP-induced progressive changes of BW and most mechanical parameters. However, the impact peak force and the loading rate systematically presented an initial 10% increase with unweighting which could result from a passive mechanism of leg retraction. Another major insight lies in the distinct neural adjustments found amongst the recorded lower-limb muscles during the pre- and post-contact phases. The preactivation phase was characterized by an overall EMG stability, the braking phase by decreased quadriceps and soleus muscle activities, and the push-off phase by decreased activities of the shank muscles. These neural changes were mirrored during reloading. These neural adjustments can be attributed in part to the lack of visual cues on the foot touchdown. These findings highlight both the rapidity and the complexity of the neuromechanical changes associated with LBPP-induced unweighting and reloading during running. This in turn emphasizes the need for further investigation of the evolution over time of these neuromechanical changes. [ABSTRACT FROM AUTHOR]