Animal experiments have shown that descending pathways from the frontal cortex modulate the release of dopamine in the caudate nucleus and putamen and regulate the activity of subthalamic nucleus (STN). To study cortico-striatal and cortico-subthalamic connectivity in the human brain we studied normal volunteers and Parkinsonian patients undergoing stereotactic surgery for bilateral implantation of deep brain stimulators. Normal volunteers were investigated with [/sup 11/C]raclopride PET following repetitive transcranial magnetic stimulation (TMS) of dorsolateral prefrontal (DLPFC) and primary motor cortex (MC) and Parkinsonian patients were studied using intra-operative single unit recordings from STN during stereotactic surgery while stimulating the MC with single pulse TMS. In normals, repetitive TMS of the DLPFC was shown to induce release of dopamine in the ipsilateral caudate nucleus while repetitive TMS of the MC decreased significantly [/sup 11/C]raclopride binding potentials in the ipsilateral putamen. In Parkinsonian patients, TMS induced an excitation in 74.9 % of STN neurons investigated. This activation was followed by a long lasting inhibition of the STN neuronal activity which did not correlate with PD severity. These invivo studies suggest that cortico-striatal and cortico-subthalamic projections may promote a powerful modulatory control of their subcortical target regions in the human brain.