In the service of its core scientific agenda, the Section on Integrative Neuroimaging (SoIN) has continued its long-standing commitment to characterizing the neurochemical, neurogenetic, and neuropsychological contributions to neural systems relevant to mental illness. The Section has made particular progress in developing an unprecedented multimodal positron emission tomography dataset that will soon be able to answer fundamental questions about dopamine pre- and post-synaptic function in a more comprehensive way than previously possible. Enormous efforts toward data acquisition in the past year have resulted in D1-like dopamine receptor, D2-like dopamine receptor, and presynaptic dopamine synthesis whole brain measurements collected in the same, painstakingly screened healthy individuals, which only now are beginning to allow for novel analyses synthesizing these disparate but interrelated indices of dopamine functioning. We expect that insights from these experiments will allow greater perspective on the piecemeal clues gathered to date about this vital neurotransmitter systems role in supporting cognitive functions in health and in psychiatric disorders. Interim achievements have been wide-ranging and include elaboration on dopaminergic mechanisms underlying attentional control and emotional salience processing as well as discovery of novel gene-gene interactions on mnemonic related activity in the hippocampus. A distinguished lineage of experimentation has established the importance of dopamine in cognitive functions that are disrupted in neuropsychiatric illness. We and others have previously shown that genetic variation in the gene for catechol-O-methyl transferase (COMT), an enzyme responsible for regulating cortical dopamine concentrations, is an important predictor of the efficient function of frontal neural systems recruited during cognitive challenge. Extending this work, we now have shown that in healthy individuals, pharmacological inhibition of COMT at doses that do not impact gross behavioral measures of attention are able to significantly decrease neural responses to an attention control task (Magalona et al., 2013). Additionally, we have discovered specific links between dopamine system operations and the neurophysiology of facial expression processing, as reported this year in Molecular Psychiatry (Jabbi et al., 2013). Using a highly multimodal, integrative neuroimaging approach that levies advantages of positron emission tomography (PET), magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), this study was able to tackle long-standing lack of knowledge about how emotional facial expressions are processed in the brain. This is a ripe area of research because the neural mechanisms contributing to altered processing of social cues in neuropsychiatric conditions such as schizophrenia, autism and Williams syndrome remain mysterious, preventing development of targeted biological therapies. In this study, we first characterized functional correlates of facial expression viewing with unprecedented detail by measuring sustained blood-oxygenation level-dependent (BOLD) signal (providing excellent spatial resolution;from fMRI) and transient gamma-band activity (GBA;providing excellent temporal resolution;from MEG) responses to environmentally valid, dynamic emotional cues. We then progressed to demonstrate for the first time that midbrain presynaptic dopamine synthesis (from PET) predicts these dynamic signals in regions known to code perceptual, mnemonic and experiential aspects of emotional stimuli. Other recent work has focused on defining the impact of dopamine-relevant gene variants associated with schizophrenia on dopamine synthesis and has generated new hypotheses about how sequelae of common genetic variation intersects with the biology of mental illness. This includes several epistatic hypotheses that, as discussed in Eisenberg et al (2013), have become increasingly critical. In fact, one of the major advances we have made this year has been to demonstrate with fMRI an interaction between SLC12A2 and DISC1 genetic markers on hippocampal activation, representing the first in vivo human experiments to confirm previously observed interactions of the same genes on hippocampal neuronal development. (Callicott et al., 2013) In summary, the Section on Integrative Neuroimaging has made remarkable progress toward advancing its long-range, central research aims, and, by virtue of these efforts particularly the crucial ongoing multimodal data collection is well poised for progress in the coming year.

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Project End
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Budget End
Support Year
19
Fiscal Year
2013
Total Cost
$879,394
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
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Jabbi, Mbemba; Kohn, Philip D; Nash, Tiffany et al. (2015) Convergent BOLD and Beta-Band Activity in Superior Temporal Sulcus and Frontolimbic Circuitry Underpins Human Emotion Cognition. Cereb Cortex 25:1878-88
Dickinson, Dwight; Straub, Richard E; Trampush, Joey W et al. (2014) Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals. JAMA Psychiatry 71:647-56
Jabbi, M; Nash, T; Kohn, P et al. (2013) Midbrain presynaptic dopamine tone predicts sustained and transient neural response to emotional salience in humans: fMRI, MEG and FDOPA PET. Mol Psychiatry 18:4-6
Baller, Erica B; Wei, Shau-Ming; Kohn, Philip D et al. (2013) Abnormalities of dorsolateral prefrontal function in women with premenstrual dysphoric disorder: a multimodal neuroimaging study. Am J Psychiatry 170:305-14
Dreher, Jean-Claude; Kohn, Philip; Kolachana, Bhaskar et al. (2009) Variation in dopamine genes influences responsivity of the human reward system. Proc Natl Acad Sci U S A 106:617-22
Dreher, Jean-Claude; Meyer-Lindenberg, Andreas; Kohn, Philip et al. (2008) Age-related changes in midbrain dopaminergic regulation of the human reward system. Proc Natl Acad Sci U S A 105:15106-11