Paranoid ideation—the mistaken belief that intentional harm is likely to occur—spans a continuum, from mild suspicion to persecutory delusions. Among patients with schizophrenia and other psychosis disorders, elevated levels of paranoia are common, debilitating, and challenging to treat. The cues (public environments, strangers) and processes (anxiety) that promote paranoia have grown increasingly clear, but the brain bases of these pathways are unknown, thwarting the development of mechanistic models and, ultimately, the development of more effective or tolerable biological interventions. Leveraging our team’s unique multidisciplinary expertise and productive track record of NIH-sponsored research, this project will use an innovative combination of paranoia assessments, advanced neuroimaging techniques, and smartphone-based experience sampling to clarify the factors governing paranoia. We will enroll the full spectrum of paranoia without gaps or discontinuities—including psychosis patients with frank persecutory delusions and matched community controls. These data will allow us to rigorously examine the hypothesized contribution of brain circuits responsible for triggering anxiety and evaluating the threat potential of everyday social cues, such as faces. Integrating neuroimaging measures with experience-sampling data will enable us to extend these insights to the real world—a key step to establishing therapeutic relevance—for the first time. It has become increasingly clear that categorical psychiatric diagnoses (e.g. schizophrenia) present significant barriers to understanding pathophysiology. Our focus on dimensional measures of paranoia overcomes many of these barriers and dovetails with the National Institute of Mental Health’s Strategic Objectives and Research Domain Criteria (RDoC) initiative. This work would provide a potentially transformative opportunity to test and refine theory, deepen our understanding of etiology, guide the development of new translational models, discover new treatment targets, and provide an integrative biopsychosocial framework for unifying research across investigators, approaches, and scholarly guilds.

PUBLIC HEALTH RELEVANCE STATEMENT A key challenge for psychiatry and clinical psychology is to discover, understand, and ultimately to treat the root causes of the most serious and debilitating mental illness, including schizophrenia and other psychotic disorders. This project will harness an innovative combination of state-of-the-art technologies — including brain imaging and smartphone-based mobile surveys— to objectively identify and prioritize the pathways that promote paranoia, a common, debilitating, and treatment-resistant symptom of psychosis. This project will provide a potentially transformative opportunity to identify new treatment targets and to accelerate the development of digital interventions that are scalable, customizable, and inexpensive.