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Principal Investigator: JULIAN F. THAYER
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $58,647
Funding agency: National Institute of Mental Health
Contact PD/PI: YASSA, MICHAEL
PROJECT SUMMARY
Anhedonia—the diminished capacity to experience pleasure from normally pleasurable stimuli—is a
transdiagnostic symptom of multiple psychiatric disorders, including depression, schizophrenia and post-
traumatic stress disorder. The recent and rapid growth of anhedonia research is fueled by its alarming clinical
presentation: anhedonia is independently associated with increased risk of suicide, treatment resistance, and
reduced quality of life. Major depressive disorder and schizophrenia—disorders of which anhedonia is a cardinal
symptom—are linked with increasingly high levels of economic burden related to substantial health care costs
and unemployment. There is currently no clear biological definition of anhedonia. As a result, clinicians rely on
self-report measures with no clear established connection to its underlying neurobiology. While behavioral
reward processing deficits and dysfunctional reward circuitry have been observed in anhedonia, in-the-moment
reward responding is frequently preserved, suggesting that memory for the value of the experience may be
compromised. This prompts the central question of this proposal: to what extent is anhedonia a memory
problem? We propose to test a memory-based account for anhedonia as part of our goal to biologically define
the construct. We note that while it is unlikely that memory is the only basis for anhedonia (certainly there are
clear experiential aspects), it may be an understudied and underappreciated player. Critically, a well-defined
memory contribution can help identify novel treatment targets and pave the path to improving clinical practice
with biologically informed decision-making. We use a computational psychiatry approach, combining
mathematical modeling of behavior in novel paradigms with advanced neuroimaging and AI tools to identify and
validate biomarkers relevant to the prevention and treatment of anhedonia. We unite computational models of
value, reinforcement learning, and episodic memory, bridging across the RDoC domains of Positive Valence and
Cognitive Systems. Our aims are to: (1) Test the impact of anhedonia on value-modulated episodic memory and
its neural mechanisms using high-resolution whole brain fMRI; (2) Test the impact of anhedonia on memory-
guided decisions for reward and the associated neural mechanisms using high-resolution whole brain fMRI; and
(3) Test the impact of anhedonia on structural and functional connectivity measures as well as autonomic
regulation. We will also use AI/ML tools to create a multimodal library of predictive biomarkers for anhedonia.
Our ultimate goal is to develop a comprehensive, mechanistic, and actionable memory-based account for
anhedonia using new paradigms, computational models, high-resolution neuroimaging, as well as artificial
intelligence approaches to develop novel interventions and improve clinical practice.
Project Summary/Abstract
Terms: <AI system><Anhedonia><Artificial Intelligence><Behavior><Behavioral><Biological><Brain><Brain Nervous System><Clinical><Computer Models><Computer Reasoning><Computerized Models><Decision Making><Diagnostic><Disease><Disorder><Economic Burden><Encephalon><Episodic memory><Functional MRI><Functional Magnetic Resonance Imaging><Goals><Health Care Costs><Health Costs><Healthcare Costs><Intervention><Intervention Strategies><Learning><Libraries><Link><Machine Intelligence><Major Depressive Disorder><Math Models><Measures><Memory><Mental Depression><Mental disorders><Mental health disorders><Neurobiology><PTSD><Patient Self-Report><Positive Valence><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Prevention><Psychiatric Disease><Psychiatric Disorder><Psychiatry><Psychological reinforcement><Public Health><QOL><Quality of life><RDoC><Regulation><Reinforcement><Research><Research Domain Criteria><Resolution><Rewards><Schizophrenia><Schizophrenic Disorders><Self-Report><Stimulus><Symptoms><Techniques><Testing><Unemployment><biologic><biomarker validation><clinical decision-making><clinical depression><clinical practice><cognitive system><computational modeling><computational models><computer based models><computerized modeling><dementia praecox><depression><experience><fMRI><improved><interventional strategy><jobless><joblessness><major depression><major depression disorder><marker validation><mathematic model><mathematical model><mathematical modeling><mental illness><multi-modality><multimodality><neural imaging><neural mechanism><neuro-imaging><neurobiological><neuroimaging><neurological imaging><neuromechanism><novel><out of work><pleasure><post-trauma stress disorder><posttrauma stress disorder><predictive biomarkers><predictive marker><predictive molecular biomarker><preservation><psychiatric illness><psychological disorder><rapid growth><resistance to therapy><resistant to therapy><resolutions><reward circuitry><reward processing><schizophrenic><suicidal risk><suicide risk><therapeutic resistance><therapy resistant><tool><traumatic neurosis><treatment resistance><unemployed>