This competing continuation proposal will take advantage of a unique opportunity to further follow up on a series of investigations of the origin of biologic markers for post-traumatic stress disorder (PTSD) in a population of identical twins discordant for combat exposure in Vietnam. The main possible marker origins to be addressed are: a.) familial vulnerability for PTSD vs. b.) acquired PTSD sign. Familial vulnerability will be evaluated by examining the main effect of between-pair Diagnosis (PTSD vs. non- PTSD in the combat-exposed twin), as well as by contrasting the (high-risk) combat-unexposed co-twins of combat-exposed twins with PTSD vs. the (low-risk) combat-unexposed co-twins of combat-exposed twins without PTSD. Acquired PTSD sign will be evaluated by examining the interaction between Diagnosis and within-pair Exposure (combat vs. no combat), as well as by contrasting the PTSD combat twins vs. their own combat-unexposed co-twins. Recent pilot data suggest that the following may be familial vulnerability factors for PTSD: a.) decreased rostral anterior cingulate cortex (rACC) and increased amygdala activation during passive viewing of overt fearful facial expressions during fMRI, and b.) increased dorsal ACC activation during a multi-source interference task (MSIT) during fMRI. In contrast, pilot data suggest that c.) impaired retention of extinction of a psychophysiologic conditioned fear response may be an acquired PTSD sign. The work in this competing continuation proposal will include testing the above three pilot findings in additional twin subjects in an attempt to obtain definitive results. Finding (c) will also be pursued using fMRI. Additional experiments will include measuring d.) regional cerebral blood flow during script-driven imagery of combat and other personal stressful events during positron emission tomography, and e.) n- acetyl aspartate levels in dACC, rACC, ventromedial prefrontal cortex, and hippocampus by magnetic resonance spectroscopy. Twin subjects will be invited travel to the Massachusetts General Hospital for two days of neuroimaging protocols. Results are expected to advance our understanding of the constitutional vs. acquired nature of biologic abnormalities in PTSD and the neuroanatomy and pathogenesis of this disorder. Additionally the proposed research may identify biologic mediators of the effects of candidate genes on risk for PTSD.

Public Health Relevance

This study will attempt to further resolve the origin of biologic abnormalities in post-traumatic stress disorder (PTSD) by determining whether or not they are present in the identical twins of combat veterans with PTSD. Abnormalities that are found to be acquired could become the target of PTSD treatments, whereas abnormalities that serve as risk factors for PTSD could be used in screening for persons at risk and possible preventive interventions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Yao, Yin Y
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Massachusetts General Hospital
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Dahlgren, M K; Laifer, L M; VanElzakker, M B et al. (2018) Diminished medial prefrontal cortex activation during the recollection of stressful events is an acquired characteristic of PTSD. Psychol Med 48:1128-1138
Alexandra Kredlow, M; Pineles, Suzanne L; Inslicht, Sabra S et al. (2017) Assessment of skin conductance in African American and Non-African American participants in studies of conditioned fear. Psychophysiology 54:1741-1754
Goetz, Jared M; Pitman, Seth R; Tanev, Kaloyan S et al. (2016) Mixed-Handedness in Identical Twins Discordant for Combat Exposure in Vietnam: Relationship to Posttraumatic Stress Disorder. J Neuropsychiatry Clin Neurosci 28:45-8
VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline et al. (2014) From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders. Neurobiol Learn Mem 113:3-18
Tsai, Melyssa; Mori, Alaina M; Forsberg, Christopher W et al. (2013) The Vietnam Era Twin Registry: a quarter century of progress. Twin Res Hum Genet 16:429-36
Hayes, Jasmeet P; Vanelzakker, Michael B; Shin, Lisa M (2012) Emotion and cognition interactions in PTSD: a review of neurocognitive and neuroimaging studies. Front Integr Neurosci 6:89
Shin, Lisa M; Bush, George; Milad, Mohammed R et al. (2011) Exaggerated activation of dorsal anterior cingulate cortex during cognitive interference: a monozygotic twin study of posttraumatic stress disorder. Am J Psychiatry 168:979-85
Hughes, Katherine C; Shin, Lisa M (2011) Functional neuroimaging studies of post-traumatic stress disorder. Expert Rev Neurother 11:275-85
Gilbertson, Mark W; McFarlane, Alexander C; Weathers, Frank W et al. (2010) Is trauma a causal agent of psychopathologic symptoms in posttraumatic stress disorder? Findings from identical twins discordant for combat exposure. J Clin Psychiatry 71:1324-30
Metzger, Linda J; Clark, C Richard; McFarlane, Alexander C et al. (2009) Event-related potentials to auditory stimuli in monozygotic twins discordant for combat: association with PTSD. Psychophysiology 46:172-8

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