PROJECT SUMMARY Schizophrenia is an exceedingly prevalent and burdensome illness that affects ~26 million individuals world-wide and accounts for ~16 million years of life lost due to disability per year. A characteristic symptom of schizophrenia is auditory hallucinations, occurring in ~80% of patients with ~30% of sufferers unresponsive to available treatments. Despite their impact, the neural mechanisms of auditory hallucinations are poorly understood. Auditory hallucinations are thought to arise from greater bias towards prior knowledge when forming perceptions (prior bias). Prior bias is the incorporation of prior knowledge into percepts that biases perception towards more likely sensory events. Previous studies using single-unit recordings during perceptual decision-making tasks have probed the neural manifestation of prior bias. A major finding of this work is that behavioral bias for a stimulus feature (e.g. leftward motion vs rightward motion) is associated with greater activity in neurons with receptive fields tuned to that stimulus feature. To probe the neural mechanisms of prior bias it is thus critical to define the tuning of receptive fields and design experiments that capitalize on this tuning (Aim 1). Population receptive field (pRF) mapping is a novel fMRI method that allows definition of neural tuning in auditory and visual regions with tonotopic and retinotopic organization, respectively. For example, tonotopic pRF mapping can define regions that are macroscopically organized with ensembles of neurons tuned to a specific tone frequency. By combining tonotopic pRF with a behavioral task to probe perceptual biases in tone frequency a direct measurement of the neural mechanisms of prior bias in auditory hallucinations can be developed (Aim 2). In Aim 1 we will use pRF tonotopic mapping to define the tonotopic organization of the auditory cortex in unmedicated patients with schizophrenia (N=30) and investigate differences compared to matched healthy controls (N=30). We hypothesize that the severity of auditory hallucinations will be correlated with broader pRF tuning in the associative auditory cortex. In Aim 2 we will determine the neural representation of prior bias in auditory hallucinations by acquiring fMRI during a two-tone frequency discrimination task in the same unmedicated schizophrenia patients and matched healthy controls from Aim 1. This task elicits prior bias that will be directly measured by using the tonotopic maps acquired in Aim 1 to localize activation to specific frequencies. We hypothesize that prior bias will manifest in the fMRI signal as an over-activation of the pRF's tuned to the prior information and that the degree of over-activation will correlate with the severity of auditory hallucinations.