ABSTRACT Abnormally regulated fear and threat perception are widely regarded as the core patho- physiological process in posttraumatic stress disorder (PTSD). As a result, associative fear learning models have dominated research on the neuroscience of PTSD. However, shame, guilt, and moral injury, rather than fear, are dominant cognitive processes among individuals with PTSD, which often develops following military combat trauma. Very little is known about how PTSD affects the brain circuits associated with shame and guilt, in part due to the lack of animal models. The first goal of this proposal is to develop experimental paradigms that are suitable to the fMRI setting for investigating shame and guilt neurocircuits in PTSD. We will begin by developing a library of short vignettes highlighting dominant themes of trauma-related shame and guilt. Creating a trauma-relevant stimulus set to study shame and guilt will greatly enhance our ability, and that of the broader scientific community, to investigate the neuroscience of shame and guilt in PTSD from combat trauma. Three groups (1) patients with PTSD having prominent shame and guilt symptoms, (2) patients with PTSD without shame or guilt, and (3) combat-trauma exposed control subjects will be presented vignettes evocative of shame and guilt along with matched neutral vignettes in the fMRI environment. We hypothesize that the shame and guilt prominent PTSD group will exhibit greater activation than the other groups in canonical shame and guilt processing brain regions (self-referential) consistent with greater negative self-attribution. In addition, the functional organization of the brain will be characterized from temporally correlated activity between anatomically distinct brain regions obtained from task-related fMRI activity. We predict that self-reported shame or guilt in patients with PTSD will be associated with a disruption of functional brain networks in prominent self- referential brain regions. Behavioral measures of guilt and shame will be used to study whether PTSD modulates the association between brain activity/organization and the subjective experience of shame/guilt. The knowledge gained from the proposed research will advance the neurobiology of PTSD, and in the future with more research, shed light on treatments that engage neural targets implicated in shame and guilt. Transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and real-time fMRI neurofeedback are potential interventions that could be applied in the future to directly modulate these newly discovered targets.