A key step in the development of more effective treatments for mood and anxiety disorders is to identify the brain circuits critically involved in the regulation of emotion. A predominant neurobiological model of emotion regulation, supported by animal and functional imaging data, is that ventromedial prefrontal cortex (vmPFC) mediates the regulation of negative affect through top-down inhibition of the amygdala. A corollary prediction of this model is that the loss of vmPFC function would result in disinhibition of the amygdala, and consequently greater negative affect. However, the candidate's preliminary studies of brain-injured humans demonstrate that focal damage to vmPFC actually reduces the experience of negative emotion. These preliminary data raise important follow-up questions about the role of vmPFC in regulating negative emotion in humans. The immediate overall aim of the research and training plan is to test whether vmPFC is indeed critically involved in the regulation of negative emotion through inhibition of the amygdala. In four studies of brain-injured humans, the candidate will examine how vmPFC damage affects 1) the cortisol response to psychosocial stress, 2) the acquisition and extinction of conditioned fear responses, as measured with skin conductance and startle reflex, 3) the structural integrity of white matter pathways between PFC and amygdala, as measured with diffusion tensor imaging (DTI) and 4) the functional activation of the amygdala in response to emotional facial expressions, as measured with fMRI. Results from these studies will help illuminate the role of vmPFC in the regulation of emotion. Through completion of these projects and other training activities, the candidate will acquire expertise in DTI, fMRI, and several physiological measures related to emotion. Learning these experimental techniques will allow the candidate to significantly advance the methods used to study brain lesion patients, and establish a framework for innovative long-term research into the neural substrates of emotional processing. The proposed program of training and research will be conducted at the University of Wisconsin-Madison, which is a leading institution in the neuroscientific study of emotion, featuring state-of-the art neuroimaging facilities and distinguished faculty. PUBLIC HEALTH RELEVANCE: Depression and anxiety disorders afflict millions of Americans, yet the standard treatments, such as antidepressant drugs and counseling, have had limited success. A better understanding of the brain circuits underlying human emotion is an important step in developing more effective treatments. The proposed research will provide new information about how the brain functions to regulate negative emotion.