In spite of relative success in the treatment of psychotic disorders, we know very little about the underlying processes which, when disrupted, lead to psychosis. This lack of understanding is particularly evident in the fact that current pharmacologic therapies still leave approximately 50 % of schizophrenic/schizoaffective patients with persistent symptoms. Better understanding of the pathophysiological processes underlying psychosis, and particularly those in patients who remain symptomatic despite treatment, will be critical to improving treatment outcomes. This in turn requires an improved understanding of the functions normally carried out by relevant brain networks. Significant findings have begun to point to a neurobiology relevant to psychosis. Examining this work, it appears that psychosis may involve a dysfunction in limbic brain regions that normally evaluate the emotional salience of stimuli, and this dysfunction likely entails abnormal interaction of limbic/emotional areas with prefrontal/cognitive areas. The establishment of emotional salience and the further processing it generates appear to involve sublenticular/basal forebrain areas, amygda.la, medial prefrontal cortex and orbitofrontal cortex. These regions receive rich doparninergic innervation and appear critical to the treatment of schizophrenia and schizoaffective disorder. We hypothesize that positive symptoms of psychosis involve the inappropriate attribution of salience, such as delusions of reference, while negative symptoms involve a failure to respond to emotional stimuli. We propose to use functional magnetic resonance imaging (fMRT) to map responses to emotionally salient stimuli in treated patients with schizophrenia/schizoaffective disorder who remain actively symptomatic, and we will test the following hypotheses:
(Aim 1) Patients with treatment-resistant positive symptoms will exhibit abnormal activation of the amygdala and medial prefrontal cortex;
(Aim 2) Patients with defict/primary negative symptoms will fail to activate the orbitofrontal cortex. Establishing the involvement of these regions in treatment resistant symptoms should provide an important piece of the much larger puzzle of psychosis, eventually leading us to new and better treatment strategies for psychotic disorders.
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