Simultaneous PET MR is a new imaging modality that offers clear advantages over previous technologies for the mapping of neurotransmitter release. Theoretical analyses, as well as preliminary studies in nonhuman primates, support the hypothesis that sensitivity for detection and quantitative measurement will be can be significantly improved allowing us to extend the range of research questions which can be asked and answered. In this application we propose further development of the methodology, experimental validation, and proof-of-principal studies in depressed patients. In our currently funded R21 application, we proposed that changes in MR measurements blood volume elicited by specific pharmacological challenges were functions of time-varying neurotransmitter levels. Preliminary work with amphetamine and dopamine receptor blockade supports and extends that idea. The dopamine system is but one example of what we postulate is a more general approach, which in this application includes the serotonergic system. We hypothesize that concurrent PET and fMRI will yield synergistic data that, combined with our kinetic analysis methods, can dramatically improve our ability to detect and quantify the spatiotemporal patterns of serotonergic and dopaminergic neurotransmission in the brain. Our interdisciplinary team puts forth an application encompassing technical development and psychiatric investigation in which we propose to refine our kinetic modeling methods, develop methods to quantitatively integrate fMRI and PET data, and assess the translational value of these methods to study dopamine and serotonin transmission in clinical depression.
The goals of the proposed research program are to extend methods for mapping neurochemical signaling in the brain and to apply these imaging techniques toward the study of the neurobiological underpinnings of depression. Approaches will be refined and validated to integrate the molecular specificity of positron emission tomography (PET) with the sensitivity and temporal resolution of functional magnetic resonance imaging (fMRI) with an eye toward use in the burgeoning generation of hybrid PET/MR scanners. Our new neuroimaging procedures and analysis routines will be used to investigate deficits in dopamine and serotonin signaling in subpopulations of depressed patients.
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