To investigate brain mechanisms whereby electrical stimulation of the motor cortex (MCS) may induce pain relief in patients with neuropathic pain, cerebral blood flow (CBF) changes were studied using H 2 O PET in 19 consecutive patients treated with MCS for refractory neuropathic pain. Patients were studied in three conditions, (a) before MCS (Baseline, stimulator stopped 4 weeks before), (b) during a 35-min period of MCS and (c) during a 75-min period after MCS had been discontinued (OFF). Compared to Baseline, turning on the stimulator was associated with CBF increase in the contralateral (anterior) midcingulate cortex (aMCC, BA24 and 32) and in the dorso-lateral prefrontal (BA10) cortices. The most important changes of CBF were observed in the 75 min after discontinuation of MCS (OFF). This post-stimulation period was associated with CBF increases in a large set of cortical and subcortical regions (from posterior MCC (pMCC) to pregenual (pg) ACC, orbitofrontal cortex, putamen, thalami, posterior cingulate and prefrontal areas) and in the brainstem (mesencephalon/periaqueductal grey (PAG) and pons). CBF changes in the post-stimulation period correlated with pain relief. Functional connectivity analysis showed significant correlation between pgACC and PAG, basal ganglia, and lower pons activities, supporting the activation of descending ACC-to-PAG connections. MCS may act in part through descending (top-down) inhibitory controls that involve prefrontal, orbitofrontal and ACC as well as basal ganglia, thalamus and brainstem. These hemodynamic changes are lengthened and might therefore underlie the long-lasting clinical effects that largely outlast the actual stimulation periods.