Over the past year, 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 environmental and genetic determinants of dopamine functioning;and 2. endocrinological, genetic, and dopaminergic regulation of basal and mnemonic related cortical activity. With respect to the first category, notable advances have included uncovering the first in vivo evidence for a relationship between regional brain dopamine synthetic capacity and season, published this year in the Journal of Neuroscience. Clinically important circannual fluctuations in symptoms of neuropsychiatric illnesses (e.g., seasonal affective disorder, bipolar illness, schizophrenia, and drug abuse) have long been recognized and indicate that the human central nervous system is responsive to seasonal variation. Though striatal dopamine systems have been indirectly implicated in these illnesses pathophysiology, and experiments in rodents have documented circannual variation in striatal dopamine release as well as substantial interactions between melatonin a neurohormone critically involved in seasonal neuroadaptation and dopamine both in the striatum and its mesencephalic presynaptic neurons, the neurobiological foundations of seasonality in humans have remained unclear. In line with reports from small postmortem and cerebrospinal fluid investigations, we found that sex- and age-matched healthy individuals studied during the fall-winter months, relative to the spring-summer months, evidenced greater presynaptic dopamine synthesis in the dorsal putamen, which receives particular innervation from the substantia nigra. This novel result represents a major advance in our understanding of the neurochemical underpinnings of chronobiological processes in the human brain and may carry critical implications for novel treatment approaches to neuropsychiatric illnesses with cyclical phenomenology. 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. The Section has also been engaged in fruitful efforts to understand the influence of gene and gene-by-sex interactions on basal regional brain activity. Furthermore, inspired by recent developments in neurocognitive risk genetics, SoIN efforts to uncover the combined impact of age and APOE genotype on neural activity during memory encoding and retrieval are currently culminating, and provide not only clarification of disparities in the literature to date, but also promise for identification of a compensatory neurobiological mechanism in older asymptomatic risk allele carriers. 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 (Brain and Language, 2011) 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. 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
17
Fiscal Year
2011
Total Cost
$949,799
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
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