Recent studies have shown that dopamine neurons respond selectively to unexpected rewards and cues predicting rewards. These data led to the hypothesis that dopamine activity encodes a reward prediction error signal that is used to learn the value of events in the world. This work has been extended to humans using functional magnetic resonance imaging (fMRI) studies that focused on blood oxygenation level dependent (BOLD) responses in brain areas targeted by dopamine neurons as indirect measures of dopamine function. These studies demonstrated that brain areas innervated by dopamine exhibit BOLD responses displaying similar properties observed for dopamine cell firing. However, these studies are limited in their utility from the standpoint of understanding dopamine function since dopamine neurons provide only one of a diversity of inputs to these brain areas.

In this dissertation we recorded directly from dopaminergic regions in the human brainstem with fMRI. Recording from the brainstem poses several methodological challenges. Therefore, a principal advance that this work represents is the establishment of methods specifically addressing challenges inherent to brainstem imaging. Using these imaging methods allows for precise measurement from brainstem dopamine nuclei, particularly the ventral tegmental area (VTA) and substantia nigra (SN).

These methods are validated in three experiments. The first experiment employs primary rewards and finds that VTA BOLD responses reflect positive reward prediction errors while the ventral striatum encodes positive and negative reward prediction errors. The second experiment generalizes this finding, showing that monetary gains also evoke VTA BOLD responses reflecting only positive reward prediction errors.

The final experiment tests dopamine’s proposed role in mediating switching between behavioral goals. According to the gating hypothesis, the reward prediction error signal emitted by dopamine neurons also serves as a signal to the prefrontal cortex to update the contents of working memory. Using a task shown previously to activate regions of prefrontal cortex thought to be involved in the maintenance of task-relevant information, we find that regions of the VTA and SN show BOLD responses consistent with this proposed gating signal.

The findings presented in this thesis constitute a significantly improved method for studying dopamine function in the human brain. This work also implies that BOLD-fMRI can be used to study other brainstem monoamine neuromodulator systems.