Neurofunctional Characterization of the At-Risk Mental State for Psychosis

Schizophrenia is a complex and debilitating psychiatric illness characterized by positive symptoms like hallucinations and delusions and negative symptoms like blunting of affect, avolition, and poverty of thought. This constellation of symptoms is hypothesized to result from dopaminergic dysfunction, glutamatergic dysfunction, and dysfunctional stress-reactivity. Prior to the onset of schizophrenia there is a prodromal period when individuals begin to experience sub-clinical symptoms and decreased functioning. This period is important to study not only to help elucidate biologic mechanisms of the illness but also to potentially alter the course of the illness through early treatment. The difficulty of studying this period lies in its recognizing it prospectively. To address this researchers have begun to study the at-risk mental state, a state that is associated with a high but not inevitable risk of conversion to psychosis. The studies described in this dissertation are aimed at a neurofunctional characterization of the at-risk mental state in three primary domains: reward-anticipation, hippocampus-dependent learning, and stress-reactivity. Individuals at-risk for psychosis and age-matched healthy volunteers underwent functional magnetic resonance imaging while performing tasks targeting these domains. In the reward-anticipation task, at-risk individuals showed decreased ventral tegmental area (VTA) and dorsolateral prefrontal cortex (DLPFC) responses to reward anticipation. In the hippocampus-dependent learning task, at-risk individuals showed deficits in hippocampus-dependent memory, decreased VTA engagement, and increased DLPFC activation during learning of associations between items. In the stress-reactivity task, at-risk individuals showed increased activation in the bed nucleus of the stria terminalis/basal forebrain (BNST), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in response to neutral faces. Collectively, these experiments show that neurofunctional deficits in reward-anticipation, hippocampus-dependent learning, and stress-reactivity are present in the putative prodrome, prior to the onset of psychosis. Regions implicated are those that would be expected based on current models of schizophrenia and neurofunctional studies in those with frank psychosis.