7. Project Summary It is well-established that both childhood trauma and stressful recent life events can bring about and worsen the symptoms of mental illness. However, the underlying mechanisms by which stressors exert these effects remain unclear. The overarching goal of the proposed project is to investigate candidate neural pathways linking stressful life events to the symptoms of psychotic illness, in particular. There is strong evidence that early-life adversity can increase reactivity to acute stress later in life. This effect is believed to be mediated by “sensitization” of brain dopamine pathways projecting to critical frontal and subcortical structures. However, both early-life and acute stress have been shown to reduce responsivity to rewards and positive experiences, as well. We will investigate how specific circuits connecting frontal, limbic, and subcortical structures – especially circuits involved in the processing of rewards and other salient stimuli and events – may mediate relationships between cumulative stress exposure and both the positive and negative symptoms of psychotic illness. Another goal is to examine how brain responses to acute stressors, as well as the effects of brain changes resulting from early-life adversity, vary across the spectrum of psychotic illness. In pursing these goals, we will use clinical assessment tools, self-report measures, experimental behavioral paradigms (including those for the induction of acute stress), computational modeling, and functional Magnetic Resonance Imaging (fMRI). We will also obtain, from study participants, ecological momentary assessments (EMA) of naturalistic stressors, rewards, and symptoms, as encountered and experienced in everyday life. We will enroll a sample of 164 individuals, made up of three subsamples: 82 individuals with schizophrenia or schizoaffective disorder, 41 first-degree relatives of schizophrenia patients, and 41 healthy volunteers. It is expected that participants from such a sample will have a range positive and negative symptoms. We regard this work as important, in that it is designed to contribute to a better understanding of the mechanisms by which both lifetime and acute stress impact psychopathology, thus contributing to the NIMH's stated mission of “defining the mechanisms of complex disorders.” The proposed project is strongly aligned with the strategic plan of the NIMH, in that it seeks to link advances in biology – our increased understanding of the functional roles of specific frontal-subcortical and limbic circuits, in particular – with a major environmental factor known to influence mental disorders: stress. Finally, it is expected that the results of this work would inform our ability to develop biomarkers for prediction of psychosis risk and course, and to use pharmacological and non-pharmacological interventions in individuals with psychotic illness.