Increased transdiaphragmatic pressure, reduced muscle blood flow, and increased duty cycle have all been associated with a reduction in the center frequency (CFdi) of the diaphragm's electrical activity (EAdi). However, the specific influence of diaphragm activation on CFdi is unknown. We evaluated whether increased diaphragm activation would result in a greater decline in the CFdi when pressure-time product (PTPdi) was kept constant. Five healthy subjects performed periods of intermittent quasi-static diaphragmatic contractions with a fixed duty cycle. In separate runs, subjects targeted transdiaphragmatic pressures (Pdi) by performing end-inspiratory holds with the glottis open and expulsive maneuvers at end-expiratory lung volume (EELV). Diaphragm activation and pressures were measured with an electrode array and balloons mounted on an esophago-gastric catheter, respectively. The EAdi, which was 25+/-8%(S.D.) of maximum at EELV, increased to 61+/-8% (P<0.001) when an identical Pdi (averaging 31+/-13 cmH2O) was generated at a higher lung volume (77% of inspiratory capacity). The latter was associated with a 17% greater decline in CFdi (P=0.012). In order to reproduce at EELV, the decrease in CFdi observed at the increased lung volume, a two-fold increase in PTPdi was required. We conclude that CFdi responds specifically to increased diaphragm activation when pressure-time product remains constant.