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Corlett et al., 2010

Theoretical model: Schematic of reward prediction error signals before learning, following learning and during extinction. Health: Right DLPFC prediction error response during causal learning in healthy subjects (Corlett et al., 2004) – V: violation of expectancy, C: confirmation of expectancy. Disease: Aberrant right frontal prediction error response in patients with first episode psychosis. The more profound the disruption, the more severe the delusions (Corlett et al., 2007b) - C: controls, P: patients with psychosis.

Our lab is located in the Connecticut Mental Health Center (CMHC), which is a collaborative effort between Yale University Department of Psychiatry and the Connecticut Department of Mental Health and Addiction Services. CMHC provides clinical services to residents of the Greater New Haven area while also providing a base for mental health research, education, and community problem solving. Our lab offices are specifically housed in the Clinical Neuroscience Research Unit (CNRU), which is a specialized coalition of research groups dedicated to the understanding, diagnosis, and treatment of neuropsychiatric disorders. The CNRU offers an inpatient facility and outpatient clinics where individuals voluntarily participate in clinical research studies. The Belief, Learning, & Memory Lab employs a variety of study techniques ranging from investigational drug treatment to neuroimaging in order to better understand the root mechanisms underlying disorders such as schizophrenia and addiction.

Corlett et al., 2007

The mismatch between expectancy and actual occurrence gives rise to a prediction error. These signals are used by organisms to guide behaviour; they drive learning and the allocation of attention to important stimuli in the environment. Noise in the system that generates prediction errors may be responsible for some of the symptoms of psychosis, notably delusions. Neurochemically these mismatch signals are coded by phasic dopamine activity in the midbrain which is under the regulatory influence of glutamate from the prefrontal cortex. We propose that ketamine provides a useful model psychosis in healthy volunteers (because of its impact upon both glutamatergic and dopaminergic function). The impact of ketamine upon prediction error processing may be assessed with sensitive neuroimaging techniques such as functional magnetic resonance imaging (fMRI). FMRI studies have identified a frontostriatal system, sensitive to prediction errors during causal learning. Investigating the impact of ketamine upon brain responses to error-driven causal learning and relating that impact to ketamine induced psychopathology ketamine provides a truer understanding of psychosis at the levels of symptoms, cognition and the brain.

The NMDA receptor hypofunction model of schizophrenia is based upon the observation of psychotic and cognitive symptoms very similar to the symptom profile of schizophrenia on administration of NMDA receptor antagonists, such as PCP and ketamine. Our work aims to evaluate the NMDA-hypofunction model of schizophrenia by characterising the role of the frontal cortex in associative learning in normal controls, subsequently, healthy volunteers administered ketamine, and in individuals with schizophrenia. The explanatory power of the ketamine model will be assessed by the extent to which the particular aspects of task performance (both behavioral and neurophysiological) that are attenuated under ketamine are congruent with the patterns of performance observed in patients with schizophrenia.