Existing models emphasize enhanced threat processing, poor extinction and inhibition of fear, and atypical function in prefrontal-limbic circuitry in response to threat as central mechanisms in PTSD. Strong evidence supports these models and the exposure therapies developed to target these mechanisms. But as many as half of children and adults with PTSD fail to respond to these therapies and exhibit a chronic course that lasts for many years. I propose a novel conceptual model that identifies broad impairment in hippocampus- dependent associative learning as a vulnerability factor for PTSD beyond threat pathways. Associating contextual, temporal, and sensory details together is essential to form an integrated representation of an event. Difficulty remembering the place, sequence of events, or specific sights, sounds, and smells present during a traumatic event may contribute to hallmark symptoms of PTSD: overgeneralized and incomplete trauma memories, hyperarousal to trauma cues in safe contexts, generalization of fear to cues resembling those present during the trauma, and re-experiencing aspects of the trauma at other times and places. Prior research has found that smaller hippocampal volume before trauma increases risk of developing chronic PTSD. But we have yet to identify the precise hippocampal functions that contribute to PTSD risk. The present study will test the links between associative learning of multi-sensory information, hippocampal function and connectivity, and PTSD chronicity and severity. I will determine the predictive utility of my Associative Learning Model of PTSD by examining whether associative learning and function in hippocampal circuits predict PTSD beyond established threat pathways. These hypotheses will be tested in an ongoing longitudinal study including 3 groups (N=90; 30/group): adolescents with PTSD, adolescents with trauma exposure and no PTSD, and adolescents with no trauma exposure. I hypothesize that adolescents with PTSD will perform worse on tasks assessing associative learning of contextual, visual, auditory, and temporal information and will have less hippocampal activation and altered connectivity during associative learning than the trauma-only and healthy control groups. I expect that poor associative learning and atypical hippocampal recruitment will predict PTSD over and above behavioral and neural responses to threat. The proposed research addresses NIMH Strategic Plan Objective 3 by identifying a distinct neurobiological and cognitive mechanism underlying PTSD and by expanding existing mechanistic models to account for heterogeneity in PTSD symptom expression, severity, and chronicity. Such knowledge is required to tailor interventions to the most relevant mechanisms in different subtypes of PTSD, particularly treatment-resistant PTSD. This fellowship will provide training in neuroimaging methods, translational approaches to PTSD, and the neurobiology of learning and memory that will be critical to evaluate this novel conceptual model and to foster my transition to an independent research career.

Public Health Relevance

Enhanced threat processing and difficulty regulating fear responses are core features of PTSD and are targeted with most evidence-based treatments; yet as many as half of people with PTSD fail to respond to these treatments and exhibit a chronic course that lasts for many years. My proposal seeks to identify a novel mechanism underlying PTSD that could provide novel treatment targets. I examine disruptions in associative learning and associated hippocampal circuitry as vulnerability factors for PTSD that have predictive value over and above established pathways involving threat processing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH116559-02
Application #
9717106
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bechtholt, Anita J
Project Start
2018-06-16
Project End
2021-06-15
Budget Start
2019-06-16
Budget End
2020-06-15
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195