Ming Hsu - US grants

DESCRIPTION (provided by applicant): The current proposal aims to study neural mechanisms of social learning in healthy adults as a precursor to understanding the impact of mental illnesses on social functioning. Changes in social behavior are often the first symptoms of a striking array of neuropsychiatric disorders. However, whereas disruptions in memory, motor, or emotional functioning are readily recognized as symptoms of more serious underlying conditions, decision-making deficits are often overlooked, particularly in the social domain. Furthermore, there exist few behavioral measures or biomarkers to quantify such deficits, due in part to our limited knowledge of the underlying neural mechanisms and their relation to mental disorders. We do so via a tight integration of computational modeling of goal-directed social behavior, and testing the predictions generated using complementary experimental techniques with both fMRI and focal lesion patients. In particular, we focus on the role of dopamine and interactions between the basal ganglia and frontal cortices, which are together critical for goal-directed behavior and known to be affected in a variety of disorders. First, we will use the model, calibrated on observed behavior, to derive trial-by-trial regressors for use in functional neuroimaging experiments. Second, the estimated parameters of the model themselves can be used to compare across health and diseased groups, or find subtypes of the diseased groups. Finally, the neural correlates and the behavioral estimates can be combined in order to find novel brain-behavior markers of diseases. In this way, we seek to provide a unifying account of goal-directed behavior in both social and non- social settings, which has the potential to lead to development of new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.

Project summary/abstract The research proposal focuses on studying the electrophysiological and oscillatory mechanisms underlying decision-making involving risk-reward tradeoffs. Specifically, we will record electrophysiological data from patients with extensive prefrontal cortex ECoG coverage (tens to hundreds of electrodes in lateral PFC, orbitofrontal cortex, and other PFC areas) while they carry out a gambling task. Using this data, we will test the hypotheses that oscillatory mechanisms reflect local valuation and global top-down control processes in decision-making. Decision-making is disturbed in numerous psychiatric disorders including schizophrenia, major depression, and a variety of personality disorders. As such, a deeper understanding of the cortical mechanisms supporting decision-making capacity has the promise to shed new light in a host of disorders relevant to the mission of the NIMH.

The research proposal focuses on studying how objects come to acquire value. In particular, we focus on the fact that humans have an unparalleled capacity come to value objects, including those like money which have no intrinsic value. Specifically, we seek elucidate the set of cognitive processes that have made money-emergence possible, as well as investigate their neural underpinnings. We will do so using a game-theoretic model of money emergence and carry out experiments using complementary methodologies -functional neuroimaging (fMRI) and focal lesion patients studies. Our hypothesis is that the neural circuitry involved in strategic learning in our money emergence environments builds upon those underlying learning about rewards, but engages additional computations related to belief-formation and mentalization. Disturbances in reward processing and decision-making are a hallmark of drug abuse and addiction. As such, a deeper understanding of the neural mechanisms supporting decision-making capacity has the promise to shed new light on questions of relevance to the mission of NIDA. RELEVANCE (See instructions): Disturbances in reward processing and decision-making are a hallmark of drug abuse and addiction. By studying how people come to value objects, we aim to provide a deeper understanding of the behavioral and neural processes that are affected in drug abuse and addiction.

PROJECT SUMMARY A significant challenge for understanding social dysfunctions observed in mental illness is to link high-level theories of social behavior and cognition with the computations performed by brain circuits. Specifically, how does the brain translate social perception into social valuation, and how does such valuation influence social actions? We propose to leverage recent developments in economic theory and cognitive neuroscience to bridge this divide using a computational, model-based approach. In this proposal, we hypothesize that social behavior is underpinned by brain mechanisms that are influenced by the neurotransmitter dopamine, and that these mechanisms can be captured by computational models that integrate internal representations of social experience, and parameters relevant to dopamine tone, to inform social actions. Social valuation thus critically, and quantitatively, depends upon both internal social representations and the neurochemistry of the actor within the social environment. To assess this hypothesis, we pursue two approaches to evaluate dopamine tone: one in which we use an FDA-approved medication, tolcapone, to influence dopamine metabolism, and one in which we perform PET imaging to measure dopamine release and baseline dopamine receptor D2/D3 occupancy. We then apply a model of social valuation to subjects' behavior, and search for neural correlates of this valuation using functional MRI (fMRI). To this end, we bring together a group of experts in (1) the neuroeconomics and modeling of social and non-social decision-making, (2) cognitive neuroscience, (3) the pharmacology of frontostriatal circuits, and (4) neuroimaging. We thus seek to broaden our understanding of the computations and circuits underlying social behavior. Moreover, we believe that a model-based understanding of these behaviors and neural circuits may guide more robust predictions of the effects of pharmacological manipulations on social valuation, and provide quantitative tools to assess the effects of such manipulations in patient populations, with possible therapeutic implications.