Posttraumatic stress disorder (PTSD) is a highly prevalent and debilitating disorder that is broadly distributed in the US population. It is defined by a fearful response to traumatic events, and involves reexperiencing, arousal, and avoidance of reminders of the traumatic exposure. Despite efforts to characterize the pathophysiology of PTSD, no biomarkers currently exist to facilitate diagnosis, treatment development, or prediction of treatment response. Yet several lines of evidence suggest that PTSD symptoms are mediated by dysfunctional processes involving the brain's fear-circuitry network. It is not known, however, whether failure to recover from PTSD is governed by functional deficits in this circuitry. The proposed five year interdisciplinary project will clarify circuits underlying PTSD psychopathology and probe, for the first time, neural circuitry of symptomatic improvement in response to prolonged exposure (PE) treatment of PTSD. Our goals are congruent with NIMH strategic plan strategy 1.3 to """"""""identify and integrate biological markers and behavioral indicators associated with mental disorders"""""""". The project builds directly on our preliminary work in assessing deficits in extinction learning and recall by applying a basic science fear extinction paradigm to trauma-exposed healthy controls and patients with PTSD. The proposed study will employ an established extinction paradigm with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) assessments in a large and well characterized sample of patients with PTSD and trauma exposed healthy control (TE-HC) subjects. One hundred subjects including 60 individuals with PTSD and 40 trauma exposed healthy controls will be assessed by fMRI and SCR to characterize neural circuitry activation to the fear extinction task. fMRI and SCR data will be acquired simultaneously during this two-day emotional learning task. All 60 PTSD and 20 randomly assigned TE-HC participants will repeat these procedures after PTSD patients have completed 10 weeks of intensive PE treatment. Clinical ratings of PTSD severity will be conducted three months after treatment completion to permit analysis of neural predictors of longer-term treatment durability. The project will yield new insights and information concerning the neural circuitry that underlies identified extinction deficiencies that characterize PTSD. It will also provide vitally important new information concerning the neural effects of PE treatment, a first line treatment for PTSD. Together these lines of research will not only advance the identification of biomarkers for PTSD, but also facilitate identification of biomarkers of clinical response to this empirically-supported treatment that may guide future treatment development of pharmacological adjuncts to PE and novel methods for enhancing extinction processes among patients with PTSD.

Public Health Relevance

The goal of the proposed study is to use a functional magnetic resonance imaging (fMRI), and extinction learning and recall paradigm with skin conductance response (SCR) assessment, in order to examine differences in neural circuitry activation between subjects with PTSD and those exposed to trauma and didn't develop PTSD, and to probe neural mechanisms of symptomatic improvement during a treatment of Prolonged Exposure (PE) treatment. Together these lines of research will facilitate identification of brain based biomarkers for PTSD and for clinical response to an empirically supported treatment of the disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH072833-05
Application #
8118781
Study Section
Interventions Committee for Adult Disorders (ITVA)
Program Officer
Tuma, Farris K
Project Start
2005-03-02
Project End
2014-02-28
Budget Start
2011-05-01
Budget End
2012-02-29
Support Year
5
Fiscal Year
2011
Total Cost
$699,253
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Zhu, Xi; Suarez-Jimenez, Benjamin; Lazarov, Amit et al. (2018) Exposure-based therapy changes amygdala and hippocampus resting-state functional connectivity in patients with posttraumatic stress disorder. Depress Anxiety 35:974-984
Lowell, A; Suarez-Jimenez, B; Helpman, L et al. (2018) 9/11-related PTSD among highly exposed populations: a systematic review 15 years after the attack. Psychol Med 48:537-553
Zhu, Xi; Helpman, Liat; Papini, Santiago et al. (2017) Altered resting state functional connectivity of fear and reward circuitry in comorbid PTSD and major depression. Depress Anxiety 34:641-650
Lazarov, Amit; Zhu, Xi; Suarez-Jimenez, Benjamin et al. (2017) Resting-state functional connectivity of anterior and posterior hippocampus in posttraumatic stress disorder. J Psychiatr Res 94:15-22
Helpman, Liat; Zhu, Xi; Suarez-Jimenez, Benjamin et al. (2017) Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014-2017). Curr Psychiatry Rep 19:104
Helpman, Liat; Papini, Santiago; Chhetry, Binod T et al. (2016) PTSD REMISSION AFTER PROLONGED EXPOSURE TREATMENT IS ASSOCIATED WITH ANTERIOR CINGULATE CORTEX THINNING AND VOLUME REDUCTION. Depress Anxiety 33:384-91
Helpman, Liat; Marin, Marie-France; Papini, Santiago et al. (2016) Neural changes in extinction recall following prolonged exposure treatment for PTSD: A longitudinal fMRI study. Neuroimage Clin 12:715-723
Rubin, Mikael; Shvil, Erel; Papini, Santiago et al. (2016) Greater hippocampal volume is associated with PTSD treatment response. Psychiatry Res Neuroimaging 252:36-39
Papini, Santiago; Sullivan, Gregory M; Hien, Denise A et al. (2015) Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: a critical review of preclinical research. Biol Psychol 104:8-18
Shvil, Erel; Sullivan, Gregory M; Schafer, Scott et al. (2014) Sex differences in extinction recall in posttraumatic stress disorder: a pilot fMRI study. Neurobiol Learn Mem 113:101-8

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