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Principal Investigator: Matthew Nassar
Organization: BROWN UNIVERSITY
Fiscal Year: 2024
Award: $85,484
Funding agency: National Institute of Mental Health
Project Abstract
Humans display tremendous flexibility in their everyday behavior, adjusting it rapidly when appropriate (i.e.
adopting mask wearing after onset of Covid-19), but not when inappropriate (i.e. continuing to drive after
involvement in an unavoidable car accident). Recent work has highlighted the role that transient fluctuations in
arousal, thought to be mediated by activation of the locus coeruleus norepinephrine (LC/NE) system, play in
behavioral adjustments. Increasing NE pharmacologically promotes behavioral updating in rodents and
peripheral measures of arousal, such as pupil diameter and P300 orienting response, provide a window into
the dynamics that underlie these behavioral adjustments in humans. A mechanistic understanding of these
processes could provide a valuable therapeutic target for a wide range of psychiatric disorders in which
behavioral flexibility is impaired. However, current theory falls short, in part because it fails to account for the
contextual nature of arousal: that heightened arousal reflects more behavioral adjustment in some settings or
individuals, but less in others. We believe that previous computational accounts of NE have likely failed to
explain heterogenous effects on behavior because they have ignored the neural representations on which NE
acts. Recent advances in computational neuroscience have highlighted the importance of neural
representations for efficient learning in complex environments, and provided tools to measure them. Building
on this work, we developed a computational model in which NE drives transitions in neural representation that
lead to behavioral adjustment when new representations persist in time (ie. after Covid), but reduce behavioral
adjustment when they do not (after a freak accident). We propose that representational dynamics evoked by
NE are not random, but instead are governed by assumptions about environmental structure, which differ
across settings and individuals, to produce heterogeneous effects of arousal on behavior. This idea could
facilitate personalized predictions for how NE manipulations would alter behavior, potentially enabling better
treatment of attention deficit and anxiety disorders. Achieving this goal would first require basic research
experiments to better characterize how and why arousal differentially relates to behavior across task contexts,
individuals, and learning. Here we conduct these basic research studies, first measuring arousal by proxy in
adversarial task structures (i.e. post-covid versus post-accident) to dissect the computational mechanisms
through which it modulates behavior. Next, we examine internal representations directly, using fMRI in a task
with ambiguous structure, to understand whether and how inter-individual differences in representational
structure give rise to inter-individual differences in behavior and its sensitivity to arousal. Finally, we extend our
existing computational model such that it can learn structure through experience and make individualized
predictions for behavior across a wide range of possible environments. We test these predictions, as well as
their relevance to various mental health constructs, in a large-scale online validation study.
Terms: <AD/HD><ADHD><Accidents><Adopted><Affect><Algorithms><Anxiety Disorders><Arousal><Attention deficit hyperactivity disorder><Attentional deficit><Basic Research><Basic Science><Behavior><Behavioral><Brain><Brain Nervous System><COVID-19><CV-19><Causality><Cell Communication and Signaling><Cell Signaling><Cognitive><Complex><Computer Models><Computerized Models><Coronavirus Infectious Disease 2019><Cues><Data><Dependence><Diameter><Drugs><E1A Binding Protein p300><EEG><EP300><EP300 gene><Effectiveness><Electroencephalogram><Electroencephalography><Encephalon><Environment><Etiology><Failure><Functional MRI><Functional Magnetic Resonance Imaging><Future><Goals><Human><Impairment><Individual><Individual Differences><Instruction><Intracellular Communication and Signaling><KAT3B><Learning><Levarterenol><Levonorepinephrine><Life><Link><Locus Coeruleus><Masks><Measures><Mediating><Medication><Mental Health><Mental Hygiene><Mental disorders><Mental health disorders><Modeling><Modern Man><NE system><Nature><Noradrenaline><Norepinephrine><Nucleus Pigmentosus Pontis><Participant><Pattern><Peripheral><Persons><Pharmaceutical Preparations><Play><Policies><Predominantly Hyperactive-Impulsive Type Attention-Deficit Disorder><Predominantly Hyperactive-Impulsive Type Hyperactivity Disorder><Process><Proxy><Psychiatric Disease><Psychiatric Disorder><Psychological Health><Pupil><Reversal Learning><Rodent><Rodentia><Rodents Mammals><Role><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Testing><Time><Update><Work><attentive deficit><automobile accident><behavior influence><behavior prediction><behavioral influence><behavioral prediction><biological signal transduction><blue nucleus><car accident><causation><computational framework><computational modeling><computational models><computational neuroscience><computer based models><computer based prediction><computer framework><computerized modeling><coping><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><disease causation><drug/agent><experience><experiment><experimental research><experimental study><experiments><fMRI><flexibility><flexible><histone acetyltransferase p300><individualized predictions><inter-individual variability><inter-individual variation><interindividual variability><interindividual variation><learning algorithm><locus ceruleus structure><mental illness><neural><neural mechanism><neuromechanism><norepinephrine system><novel><p300><personalized predictions><pharmacologic><post-COVID><post-COVID-19><post-coronavirus disease 2019><predictive modeling><psychiatric illness><psychological disorder><research study><response><social role><theories><therapeutic target><tool><validation studies>