The Silvio O. Conte center dopamine dysfunction in Schizophrenia

nyspifacadefaded The Silvio O. Conte Center
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Participate in a brain imaging study

Project 2
Functional Correlates of Cortical and Subcortical Dopamine Dysregulation in Schizophrenia

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The central hypothesis of the Center is that striatal dopamine (DA) hyperactivity leads to prefrontal cortical DA dysfunction and deficits in prefrontal cortex-mediated cognitive processes. P2 will test this hypothesis by characterizing the correlations between working memory (WM)-related neural activation in the dorsolateral prefrontal cortex (DLPFC) (and related behavioral performance) and presynaptic measures of DA function in the striatum and DLPFC. In P1, indices of presynaptic DA function in the striatum ([18F]-DOPA uptake) and in DLPFC ([11C]FLB457 displacement) will be obtained in 33 unmedicated patients with schizophrenia and 33 demographically matched, healthy control subjects (HC). To test the primary hypothesis of P2, we will assess WM capacity, as measured by behavioral performance, and WM-related regional activation patterns in the DLPFC, as assessed with Functional Magnetic Resonance Imaging (fMRI), on all subjects participating in P1. To do this, in the first year, P2 will characterize the self-ordering task and compare it to the more widely-used n-back task in terms of its neurocognitive properties in patients with schizophrenia. The self ordering task is designed to manipulate WM load with more resolution and control than other tasks, such as the n-back, that are widely used in clinical neurocognitive studies in schizophrenia. The task features up to 11 different levels of WM load and, similar to the n-back task, activates the DLPFC in healthy subjects.

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Self-ordered Working Memory task

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Brain regions activated during the self-ordered working memory task.

Our preliminary data indicate that patients with schizophrenia perform the self-ordering task through at least 8 steps and show reliable deficits that depend on WM load. Thus, P2 will obtain, within subjects, the full function characterizing the relationship between DLPFC activation and WM load, and determine whether patients with schizophrenia show "inefficiency" and/or "reduced capacity" in their ability to recruit the DLPFC to perform WM tasks. This task will subsequently be used to test for correlations among WM-related DLPFC function, striatal DA, and DLPFC DA. Together these studies will establish to what extent there are relationships between the capacity to release DA in the striatum or DLPFC (data obtained from P1) and the efficiency or capacity of the DLPFC to respond to changes in WM demands. These data will ultimately increase our understanding of the neural mechanisms, and, in particular, dopaminergic mechanisms, that regulate WM in humans and the contribution of striatal and prefrontal cortical DA transmission to WM deficits in schizophrenia.

The researchers involved with project 2 are: PI Daphna Shohamy Co-PI's Anissa Abi-Dargham and Jeffrey Lieberman, Co-Investigator Holly Moore, Collaborator Jared Van Snellenberg and Consultant Tor Wager.

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