Posttraumatic Stress Disorder (PTSD) is a debilitating disorder associated with increased suicide risk, educational dropout, unemployment, relationship instability, and the development of other psychiatric disorders. An estimated 3 billion dollars are lost in workforce productivity each year to this disorder. The majority of individuals in the US will experience a traumatic event in their lifetime, yet not all develop PTSD. There is evidence that genetic and epigenetic factors account for 30 ? 70% of these individual differences, but the mechanisms by which they exert this influence are not well understood. In the long run, understanding these mechanisms will greatly inform both how to identify those at risk for certain clusters of PTSD symptoms, and how to tailor individual treatments for the best recovery outcomes. Previous research has identified negative alterations in mood and cognition, specifically negative alterations in self-cognitions (e.g., shame, perceived worthlessness, incompetence) as a strong predictor of PTSD risk, status, and severity. Negative self-processing is associated with alterations in the neural correlates of self-referential processing (e.g., midline cortical structures) and autobiographical memory systems (e.g., medial temporal lobe structures, MTL). Negative self-cognitions are also associated with altered stress response physiology in the hypothalamic?pituitary?adrenal (HPA) axis system. Previous research in the training lab has identified a candidate gene, FKBP5, that is involved in the modulation of HPA axis function and MTL memory systems. Polymorphisms in FKBP5 are also associated with increased risk for PTSD. Additionally, the DNA methylation status of promoters involved in HPA axis regulation, including those for both FKBP5 and the glucocorticoid receptor gene, NR3C1, is known to be associated with PTSD treatment outcome and response. Using functional magnetic resonance imaging approaches, the present research aims to examine the relationship between traumatic experience and the neural mechanisms of negative self-referential processing, and determine how this relationship changes during PTSD extinction. Also, this proposal aims to better understand how the epigenetic profile of both FKBP5 and NR3C1 predicts, and perhaps changes, in response to recovery from PTSD (and negative self-cognitions) along with its neural correlates. This understanding will help identify individuals who will respond most optimally to a specific empirically based PTSD treatment, Cognitive Processing Therapy, while further connecting genetic biomarkers of risk with neural intermediate phenotypes underlying PTSD symptomatology.

Public Health Relevance

Posttraumatic stress disorder (PTSD) is a significant personal and societal burden. This proposal will examine genetic, epigenetic, behavioral, and brain activity changes related to PTSD dysfunction and recovery. Results from this proposal will inform how to identify those at risk for certain PTSD symptoms, how to better identify those who will respond most optimally to a treatment, and how to tailor individual treatments for the best recovery outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32MH109274-02
Application #
9302323
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chavez, Mark
Project Start
2016-06-10
Project End
2019-06-09
Budget Start
2017-06-10
Budget End
2018-06-09
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
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Fenster, Robert J; Lebois, Lauren A M; Ressler, Kerry J et al. (2018) Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat Rev Neurosci 19:535-551
Logue, Mark W; van Rooij, Sanne J H; Dennis, Emily L et al. (2018) Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia. Biol Psychiatry 83:244-253