BACKGROUND: Mechanical ventilation is delivered to sedated patients during anesthesia, but also to nonsedated patients (ventilator weaning, noninvasive ventilation). In these circumstances, patient-ventilator asynchrony may occur, provoking discomfort and unduly increasing work of breathing. In certain cases, it is associated with an increased inspiratory load. Inspiratory loading in awake humans activates the premotor cortical regions, as illustrated by the occurrence of electroencephalographic premotor potentials. In normal humans during noninvasive ventilation, the authors used an experimental model of patient-ventilator asynchrony to determine whether premotor cortical activation occurs in this setting. METHODS: Noninvasive pressure support ventilation was administered to seven healthy volunteers aged 22-27 yr with continuous electroencephalographic recordings in Cz. The ventilator settings were first adjusted to make the subjects feel comfortable ("comfort"), and then modified to induce respiratory "discomfort" (evaluated on a 10-cm visual analog scale). This was achieved by setting the ventilator to a higher trigger level, reducing the slope of the pressure support rise, and reducing the level of pressure support. The settings were finally brought back to their initial values. To identify a respiratory-related premotor activity, a minimum of 80 preinspiratory electroencephalographic epochs were averaged. RESULTS: Altering ventilator settings induced respiratory discomfort (average visual scale 4 [1.5-6.0] vs. 0 [0-1.0] cm during "comfort"; P < 0.0001). This was associated with premotor potentials in all cases, which disappeared upon return to "comfort." CONCLUSIONS: This study indicates that "ventilator fighting" in healthy humans is associated with an activation of higher cerebral areas. Premotor potentials could thus be markers of patient-ventilator asynchrony at the brain level. Both corroboration in patients and the elucidation of the causative or reactive nature of the association are needed before determining clinical implications.