A maximal inspiratory breath hold (inspiratory capacity apnea) against a closed glottis evokes a large and sustained increase in muscle sympathetic nerve activity (MSNA). Because of its dependence on a high intrathoracic pressure, it has been suggested that this maneuver causes unloading of the low-pressure baroreceptors, known to increase MSNA. To determine the central origins of this sympathoexcitation, we used functional magnetic resonance imaging to define the loci and time course of activation of different brain areas. We hypothesized that, as previously shown for the Valsalvsa maneuver, discrete but widespread regions of the brain would be involved. In 15 healthy human subjects, a series of 90 gradient echo echo-planar image sets was collected during three consecutive 40-s inspiratory capacity apneas using a 3-T scanner. Global signal intensity changes were calculated and subsequently removed by using a detrending technique, which eliminates the global signal component from each voxel's signal intensity change. Whole brain correlations between changes in signal intensity and the known pattern of MSNA during the maneuver were performed on a voxel-by-voxel basis, and significant changes were determined by using a random-effects analysis procedure (P < 0.01, uncorrected). Significant signal increases emerged in multiple areas, including the rostral lateral medulla, cerebellar nuclei, anterior insula, dorsomedial hypothalamus, anterior cingulate, and lateral prefrontal cortexes. Decreases in signal intensity occurred in the dorsomedial and caudal lateral medulla, cerebellar cortex, hippocampus, and posterior cingulate cortex. Given that many of these sites have roles in cardiovascular control, the sustained increase in MSNA during an inspiratory capacity apnea is likely to originate from a distributed set of discrete areas.