Neural substrates underlying psychological activation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis are not well understood in humans. Trauma recall (using autobiographical script-driven imagery) may provide a model to study neural circuitry involved in LHPA axis activation to personally threatening psychological stimuli. This study sought to identify brain activation patterns that differentiated combat veterans who mounted an LHPA response to trauma recall from those who did not. Twenty-five Vietnam combat veterans (14 with current PTSD, 11 with no PTSD history) experienced autobiographic script-driven imagery in an [(15)O] H(2)O positron emission tomography (PET) paradigm with recurrent blood sampling. Trauma recall elicited acute ACTH responses in some but not all veterans, regardless of the PTSD status and independent of emotional responses. ACTH responders (mean ACTH increase of 24+/-7 pg/ml, n=13) were compared to non-responders (mean decrease of -0.6+/-0.6 pg/ml, n=12) in regional cerebral blood flow (rCBF). Both groups activated right insula (BA13) in response to trauma recall. However, ACTH responders deactivated rostral mPFC (BA10)/rostral ACC (BA32), whereas non-responders activated this same mPFC region, and deactivated amygdala, hippocampus, and temporal pole. In group contrasts comparing ACTH responders to non-responders, the responders had significantly higher rCBF in right insula and right temporal pole, whereas non-responders had higher rCBF in rostral mPFC and dorsal ACC. These results support the hypotheses that right insula is involved in psychological activation of the LHPA axis and that rostral mPFC may negatively modulate LHPA axis responses.