Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder that can occur following exposure to a traumatic event. Child abuse is one of the leading causes of PTSD. Symptoms of avoidance, hyperarousal, and intrusive recollections of the event can persist into adulthood. Although, women are more than twice as likely as men to develop PTSD, little is known about the neurobiological factors that underlie sex differences in risk and resilience to PTSD. The amygdala is a limbic brain region that plays a critical role in evaluating the salience of psychosocial stimuli. Studies using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) have found that individuals with PTSD show exaggerated amygdala responses to pictures of fearful faces. Oxytocin (OT) is a neuropeptide that promotes social bonding, trust and calmness. Intranasal administration of OT reduces amygdala responding to fearful faces. Of note, sexual dimorphisms in the interaction between the amygdala and the OT system have been found. In addition, sex differences in the sensitivity of the OT system to early life experiences have also been found and suggest that OT may be a critical neurobiological factor that underscores sex differences in risk and resilience to PTSD. The broad and long-term objectives of this proposal are to provide preliminary data that will guide an R01 application exploring 1) how interactions between neuropeptides and limbic brain activity are involved in the pathophysiology of PTSD 2) sex differences in neuropeptidergic regulation of limbic brain activity and 3) how these differences confer risk and resilience to PTSD. To meet these objectives we have proposed three specific aims.
Specific Aim 1 : To compare amygdala responding to fearful faces between men (n=15) and women (n=15) with PTSD related to childhood trauma;and resilient men (n=15) and women (n=15) without PTSD (free of other major Axis I disorders) who have experienced childhood trauma.
Specific Aim 2 : To compare intranasal OT versus placebo on amygdala responding to fearful faces between the four study groups.
Specific Aim 3 : To explore the interaction between plasma levels of oxytocin and amygdala responding between the four study groups. All subjects will have moderate to severe scores on the Childhood Trauma Questionnaire and a history of a childhood trauma that meets the Diagnostic Statistical Manual-IV Criterion A of PTSD. Amygdala responding will be measured using BOLD fMRI and all of the women will be scanned during the early to mid-follicular phase of their menstrual cycle. Intranasal OT or placebo will be administered in a double-blind, crossover design before each of two scanning sessions. Plasma OT samples will be collected prior to medication administration. Comparisons between men and women with PTSD will provide insight into sex differences in the neurobiologic correlates of risk in PTSD. Comparisons between men and women with a history of child abuse with and without PTSD will provide critical information regarding sex differences in the neural substrates of resilience.
Although sex differences in brain development, structure and function are well known, few studies have explored how these differences contribute to risk and resilience to mental illness. Therefore, biomedical research studies investigating sex differences in brain physiology may lead to more effective intervention and treatment strategies.
| Flanagan, Julianne C; Hand, Anne; Jarnecke, Amber M et al. (2018) Effects of oxytocin on working memory and executive control system connectivity in posttraumatic stress disorder. Exp Clin Psychopharmacol 26:391-402 |
