Hippocampal volume reductions and functional impairments are reliable findings in post-traumatic stress disorder (PTSD) imaging studies. However, it is not clear if and how hippocampal dysfunction contributes to the etiology and maintenance of PTSD. Individuals with PTSD are often described as showing fear responses to trauma reminders outside of contexts in which these cues would reasonably predict danger. Animal studies suggest that the hippocampus is required to form and recall associations between contextual stimuli and aversive events. For example, the hippocampus is critical for encoding memories in which a complex configuration of multiple cues is associated with the aversive event. Conversely, the hippocampus is not required for associations with discrete cues. In animal studies, if configural memory is disrupted, learning strategies using discrete cue associations predominate. These data suggest poor hippocampal function could bias the organism towards forming multiple simple cue associations during trauma, thus increasing the chances of fear responses in multiple environments (or contexts) in which these cues may be present. Here we will examine clinical and animal literature to support a theory of hippocampal dysfunction as a primary contributory factor to the etiology of PTSD, and discuss future research required to test these hypotheses.

Rationale To improve outcomes for patients undergoing extinction-based therapies (e.g. exposure therapy) for anxiety disorders such as post-traumatic stress disorder, there has been interest in identifying pharmaceutical compounds which might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known however about the effects of OT treatment on conditioned fear responding and extinction in humans. Objectives The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. Methods A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal spray. Forty-five min after treatment, participants underwent extinction training. Twenty-four hrs later subjects were tested for extinction recall. Results Relative to placebo, the OT group showed increased fear potentiated startle responding during the earliest stage of extinction training relative to placebo, however all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later the OT group showed significantly higher recall of extinction relative to placebo. Conclusions The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.

Summary Background Posttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms. Methods The “Marine Resiliency Study II” (MRS-II; October 2011–October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n = 923, PTSD symptoms: n = 42, anxiety symptoms: n = 37, and depression symptoms: n = 12). Results Results suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS−), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom group showed normal safety signal discrimination and extinction of conditioned fear, but exhibited increased baseline startle reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The depression symptom group showed similar physiological and self-report measures as the healthy group. Discussion These data are consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD symptoms compared to general anxiety and depression symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological “domains” across anxiety disorders that may predict differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will examine whether poor learning of safety signals provides a marker of vulnerability to develop PTSD or is specific to symptom state.

Self-report studies suggest that patients with Bulimia Nervosa (BN) evidence difficulties with interoceptive awareness. Indeed, interoceptive deficits may persist after recovery of BN and may be a biological trait that predisposes symptom development in BN. However, no studies to date have directly assessed interoceptive sensitivity, or accuracy in detecting and perceiving internal body cues, in patients with or recovered from BN. Nine women who had recovered from BN and 10 healthy control women completed the Heart Beat Perception Task (HBPT) in which individuals were required to estimate the number of heartbeats between intervals of time. Accuracy scores were compared between groups. Significant differences were found between the groups on the HBPT ((F 1,19 )= 7.78, p=.013, Cohen's d= 1.16) when controlling for age. These results suggest that deficits in interoceptive sensitivity are present in individuals recovered from BN. Thus interoceptive deficits may be one factor that bridges the gap between brain dysfunction and symptom presentation in BN.