Direct sub-second measurement of neuromodulator signaling during risky decision-making

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PROJECT SUMMARY Much work in decision neuroscience has been predicated on the hypothesis that dopaminergic signaling plays a critical role in value representations and their updating, and recent work has linked abnormalities in such value representations to specific features of psychiatric illness (e.g., anhedonia in major depression). However, despite the fundamental role that risk plays in evaluating choice options as well as the role sensitivity to risk plays in psychiatric illness, including anxiety disorders at one extreme and health risk behaviors like substance use at another other, an understanding of the neurobiology of risk remains elusive. Indirect evidence from pharmacological studies have suggested both serotoninergic and noradrengergic signaling may play roles in representations of risk; however, direct measurement of serotonin or norepinephrine signaling during risky choice has yet to be examined in humans. Recent advances by MPI Montague’s group allow the unprecedented ability to track neuromodulator responses with high temporal resolution and chemical specificity. Specifically, MPI Montague’s team is able to directly and simultaneously measure dopamine and serotonin responses in awake humans with the temporal resolution (~ 1 ms) required to examine the relationship of neuromodulator release with decision-making processes. For signal identification and extraction, the recording method uses machine-learning algorithms (elastic net regression) combined with electrochemistry using only off-the shelf hardware and software. The product of this ‘elastic net electrochemistry’ is recordings of in vivo neuromodulator fluctuations at sub-second resolution. This application merges the decision neuroscience expertise of MPI King-Casas with these advances of MPI Montague to directly examine serotonergic, noradrenergic, and dopaminergic functioning during risky choice. To achieve this goal, we will record neuromodulator responses in participants with medication-resistant epilepsy who already have intracranial depth electrodes in place for phase-II monitoring. Depth electrodes will be implanted by our neurosurgery colleagues at Virginia Tech’s medical affiliate Carilion Clinic (Carilion Clinic PI: Witcher). During recording, participants will perform i) a risk elicitation task (Holt & Laury type task) and ii) a reward learning task (multi-arm bandit task) that have been shown by our group and others both to reliably evoke neural responses associated with risk and representations as they are monitored in a standard (i.e., non-surgical) hospital suite. Depth recordings will be made using a standard montage that includes multiple contacts along the dorsal-rostral axis of the medial prefrontal cortex.