The candidate's research career is directed toward developing original brain imaging methods to better characterize neurochemical alterations associated with schizophrenia, the clinical correlates of these alterations, and their relevance to treatment strategies. The candidate's previous research experience included postmortem analysis of neurochemical markers in schizophrenic brains (Clinical Brain Disorders Branch at NIMH) and neuroreceptor imaging using single photon computerized tomography (SPECT) (Department of Psychiatry, Yale University). The candidate has developed original methods for in vivo neuroreceptors quantification and evaluation of neurotransmitter release with SPECT. These developments allowed measuring dopamine (DA) synaptic transmission in the living human brain. Using this technique, the candidate and his collaborators demonstrated a dysregulation of DA transmission in the striatum of patients with schizophrenia, a finding which has been independently replicated and may constitute an important step in the elucidation of the pathophysiology of schizophrenia. The long-term goals of the candidate are to integrate multiple neurochemical imaging modalities to expand beyond static measures of neurochemicals toward testing models involving neuronal networks dysfunction implicated in schizophrenia. To achieve this objective, the candidate will continue to use SPECT neuroreceptor imaging, and will develop expertise in two brain neurochemical imaging modalities that are new to him, positron emission tomography (PET), and magnetic resonance spectroscopy (MRS). Columbia University provides a unique environment to achieve this purpose. The research plan proposes to integrate these imaging modalities to test the overall hypothesis that, in schizophrenia, a failure of development of the cortical connectivity results in dysregulation of DA subcortical systems. Functional mapping of nigrostriatal, mesolimbic and mesocortical DA synaptic activities will be achieved by combining imaging with several new radiotracers and pharmacological challenges. Correlation between scan and clinical data will be assessed, to test the hypotheses that mesolimbic hyperactivity at the D2 and D3 receptors is associated with positive symptoms, and that mesocortical hypoactivity at the D1 receptors is associated with negative symptoms. The possible role of glutamatergic transmission in these dysregulations will also be assessed. Ultimately, better understanding of these dysregulations and their role in symptomatology will lead to improved treatment strategies.
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