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 critical neurotransmitter systems role in supporting cognitive functions in health and in psychiatric disorders. Interim achievements have been wide-ranging but fall in two main categories: 1. elaboration on dopaminergic mechanisms underlying emotional salience processing;and 2. endocrinological, genetic, and dopaminergic regulation of basal and mnemonic related cortical activity. With respect to the first category, notable advances have included discovery of specific links between dopamine system operations and the neurophysiology of facial expression processing, as reported this year in Molecular Psychiatry (1). 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 critical 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. With respect to the second category, we have continued to refine our knowledge about the impact of gonadal steroid hormones on higher order cognitive processes through ongoing blood flow PET studies collected strategically throughout a hormone manipulation protocol. This year, these studies have yielded remarkable new data demonstrating gene-by-sex interactions on basal regional brain activity. Prompted by past research suggesting not only involvement of brain-derived neurotrophic factor (BDNF) function in the pathophysiology and treatment of neuropsychiatric illnesses showing sexually dimorphic expression, but also in vitro interactions between BDNF and sex hormones, we examined resting limbic neurophysiology in a large cohort of healthy volunteers, genotyped for the functional BDNF Val66Met genetic variant, and demonstrated not only BDNF genotype-driven differences in prefrontal and hippocampal activity, but also a difference between men and women in these effects. We further demonstrated an interaction effect on interregional relationships, suggesting that this sex-by-genotype effect predicts not only basal activity in these regions, but also how these regions couple with other brain network nodes (2). Furthermore, inspired by recent developments in neurocognitive risk genetics, SoIN efforts to uncover the combined impact of age and APOE genotype two of the best-known risk factors for Alzheimers dementia, but also two important predictors of cognitive function in healthy individuals (3) on neural activity during memory encoding and retrieval have also been successful. In our report, published this year in the Archives of General Psychiatry, we show that disparities in the literature to date, in which APOE-hippocampal activation associations have been of opposing directions depending on the cohort studied, are explained by a fascinating interaction between APOE genotype and age. These data not only clarify past findings, but also hold promise for identification of a compensatory neurobiological mechanism in older asymptomatic risk allele carriers (4). Additionally, accomplishments in expanding current knowledge of mnemonic processing in the human brain have been a particularly promising aspect of the Sections research activities. For instance, by employing verbal working memory fMRI techniques in conjunction with clinical lesion data collected by Section collaborators, Buchsbaum et al (5) demonstrated that lesions producing conduction aphasia include the left posterior planum temporale region, a structure that is a reliable component of verbal working memory processing likely underlying sensory-motor integration. This work complements results published in Journal of Cognitive Neuroscience by the Section detailing another critical aspect of mnemonic processing, namely, the poorly understood neural mechanisms underlying the transition between short- and long-term memory (6). That study identified a shift in the distribution of memory-related activity from posterior temporo-parietal cortical networks in the first ten seconds after stimulus presentation to inferior frontal regions thereafter, indicating that as time advances, the burden of recognition memory is increasingly placed on top-down retrieval mechanisms mediated by inferior frontal cortex. 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 accelerated productivity in the coming year.

Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2012
Total Cost
$809,007
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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Trampush, J W; Yang, M L Z; Yu, J et al. (2017) GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol Psychiatry 22:336-345
van der Veen, Jan Willem; Marenco, Stefano; Berman, Karen F et al. (2017) Retrospective correction of frequency drift in spectral editing: The GABA editing example. NMR Biomed 30:
Reed, Jessica L; Gallagher, Natalie M; Sullivan, Marie et al. (2017) Sex differences in verbal working memory performance emerge at very high loads of common neuroimaging tasks. Brain Cogn 113:56-64
Wei, S-M; Baller, E B; Kohn, P D et al. (2017) Brain-derived neurotrophic factor Val(66)Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study. Mol Psychiatry :
Gregory, Michael D; Kippenhan, J Shane; Eisenberg, Daniel P et al. (2017) Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain. Sci Rep 7:6308
Marenco, Stefano; Meyer, Christian; Kuo, Susan et al. (2016) Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings. Am J Psychiatry 173:527-34
Wei, Shau-Ming; Eisenberg, Daniel P; Nabel, Katherine G et al. (2016) Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects the Relationship Between an Anxiety-Related Personality Trait and Resting Regional Cerebral Blood Flow. Cereb Cortex :
Gregory, Michael D; Kippenhan, J Shane; Dickinson, Dwight et al. (2016) Regional Variations in Brain Gyrification Are Associated with General Cognitive Ability in Humans. Curr Biol 26:1301-5
Ihne, Jessica L; Gallagher, Natalie M; Sullivan, Marie et al. (2016) Is less really more: Does a prefrontal efficiency genotype actually confer better performance when working memory becomes difficult? Cortex 74:79-95
Tong, Yunxia; Chen, Qiang; Nichols, Thomas E et al. (2016) Seeking Optimal Region-Of-Interest (ROI) Single-Value Summary Measures for fMRI Studies in Imaging Genetics. PLoS One 11:e0151391

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