The concept of psychosis has shifted in recent decades, as evidenced by an intensive international effort aimed at identifying and treating youth at high risk of psychosis and emerging data that subclinical psychotic symptoms appear in the general population. Individuals with an 'attenuated psychosis syndrome'(APS) present with low levels of reality distortion (unusual thought content, perceptual aberrations, suspiciousness/paranoia), in addition to disorganized speech/behavior, subjective distress and clinical help- seeking. The syndrome is phenotypically continuous with schizophrenia and a critical opportunity in which to study pathophysiological mechanisms that may be common to both APS and schizophrenia. One important potential mechanism may be found in inhibitory GABAergic and excitatory glutamatergic systems. Magnetic resonance spectroscopy (MRS) has enabled the regional measurement of GABA and glutamate/glutamine concentrations, permitting the in vivo assay of these neurotransmitters. Unmedicated patients with schizophrenia have shown elevations of Glx (glutamate/glutamine concentration) and GABA levels in the medial prefrontal cortex (mPFC), a region of the brain implicated in functional and structural imaging studies in schizophrenia and APS. We found the mPFC to exhibit greater sensitivity to benzodiazepine challenge in chronic psychotic patients, suggesting that GABAergic abnormalities. A critical question is whether these abnormalities may be detected in the APS state, which this exploratory R21 proposal will address by measuring cortical GABA and Glx in young persons with APS, compared to matched healthy control subjects and first episode psychosis (FEP) patients.
In Aim 1, we will examine GABA and Glx levels in APS individuals in the mPFC and occipital cortex, testing the prediction that GABA and Glx levels will be elevated in APS subjects in the mPFC, relative to healthy controls and medicated FEP patients. In contrast, GABA and Glx are predicted to be reduced in the occipital cortex of both APS and FEP subjects.
In Aim 2, we will assess mPFC function in APS individuals and test correlations with GABAergic and Glx signal from this same region. We predict that GABAergic and Glx signals will be inversely correlated with mPFC BOLD signal in the APS patients (but not medicated FEP patients). The anticipated impact of this R21 is three-fold: 1) An essential first step required before an R01-level proposal can examine baseline GABA and Glx as predictors of outcome (conversion to psychosis as well as clinical improvement), 2) An essential first step for a longitudinal study that will examine change in GABA and Glu and associations with outcome;and 3) A mechanistic rationale for designing therapeutic interventions that target GABA/Glx systems in APS.
Young adults with an attenuated psychosis syndrome (APS) have been a recent focus of research, as approximately 1/3 go on to develop a full-blown psychosis, and most have an Axis I disorder of some type. This study will use magnetic resonance spectroscopy and functional magnetic resonance imaging, examining GABAergic and glutamatergic function in the medial prefrontal cortex in APS individuals. A better understanding of brain disturbances associated with APS will enable design of treatment interventions, with an eventual goal of preventing the emergence of devastating disorders such as schizophrenia.
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