The relationship between cardiovascular regulation and brain activation was investigated during attempted foot lifting in paraplegic subjects and during rhythmic handgrip exercise at one-third of maximum voluntary contraction force. Brain areas of interest were the primary sensory-motor area and the insula, a hypothesized center for a central nervous feed-forward mechanism involved in cardiovascular control (“central command”). This mechanism is complementary to the usual known feedback pathways such as skeletal muscle afferent signals. Regional cerebral blood flow (rCBF) was measured in eight normal and three paraplegic subjects using positron emission tomography (PET) and oxygen-15-labeled water. Statistical parametric maps were calculated from the images comparing rest and handgrip. Paraplegics were also scanned during attempted foot lifting, a condition without sensory feedback. During activation tasks, heart rate and mean arterial pressure increased. PET activation responses (P < 0.05, corrected for multiple comparisons) were found in the contralateral primary sensory-motor area, the supplementary motor area, ipsilateral cerebellum, and bilaterally in the insula. A conjunction analysis showing responses common to handgrip and attempted foot lifting revealed activation in the right central insula (P < 0.05, corrected) in concordance with the concept of a central command feed-forward hypothesis. Hum Brain Mapp 25:259–265, 2005. © 2005 Wiley-Liss, Inc.