Neuroimaging of Brain Circuits and Neurogenetic Mechanisms in Normal Cognition

在其核心科学议程的服务中，综合神经影像科（SoIN）继续其长期致力于描述与精神疾病相关的神经系统的神经化学，神经遗传学和神经心理学贡献。该部门在开发前所未有的多模态正电子发射断层扫描数据集方面取得了特别进展，该数据集将很快能够以比以前更全面的方式回答有关多巴胺突触前和突触后功能的基本问题。在过去的一年里，对数据采集的巨大努力已经导致d1样多巴胺受体，d2样多巴胺受体和突触前多巴胺合成的全脑测量数据在同一时间收集，精心筛选的健康个体，直到现在才开始允许新的分析合成这些不同但相互关联的多巴胺功能指标。我们期望从这些实验中获得的见解将使我们对迄今为止收集到的零碎线索有更大的了解，这些线索是关于这种关键的神经递质系统在支持健康和精神疾病的认知功能方面的作用。

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.