Is the wiring of the human brain genetically influenced? In this work, we used diffusion tensor imaging (DTI) to study extremely rare individuals with Williams syndrome (WS). This highly uncommon genetic disorder is caused by a microdeletion of approximately 25 genes on chromosome 7, and provided an opportunity to study genetic regulation of white matter development. We showed for the first time, fibers found in white matter are oriented differently, give origin to aberrant posterior tracts, and show altered lateralization patterns in those with WS. Overall reduction of water diffusion in the brain revealed alterations of tissue structure. Moreover, there was the presence of excess longitudinal bundles above the corpus callosum and the absence of an anterior commissure. From these data, we extend the hypothesis that one or more of the affected genes in WS control development of fibers in the final stages of development and that these fibers are deviated longitudinally. This is the first delineation of white matter structural abnormalities in WS and provides the first data showing that the abnormal axonal tracts may be critically involved in cognitive and social functions specifically affected in WS. Our observations link the deleted genes to the development of long-range connectivity in the brain. WS is also characterized by hypersocial personality and prominent visuospatial construction impairments. Another study examined neural interactions of ventral stream areas in WS using a passive face- and house-viewing fMRI paradigm. Visual stream is divided into two processing steams: a dorsal stream (processes spatial information) and a ventral stream (subserves object processing). The hallmark cognitive impairment in WS is in visuospatial construction, the ability to visualize an object or picture as a set of parts and construct a replica from those parts. During house-viewing, significant activation differences were observed between subjects with WS and a matched control group in processing aspects of the spatial environment. Abnormal functional connectivity was found between other brain areas dealing with place, face, fear processing and PFC. These results indicate that abnormal upstream visual object processing may contribute to the complex cognitive/behavioral phenotype in WS, and provide a systems-level characterization of genetically-mediated abnormalities of neural interactions.? ? As characterization of single genetic variants rapidly proceeds, the research may increasingly turn to dissecting gene-gene and gene-environment interactions. In one study we examined dopamine- and cAMP-regulated phosphoprotein (DARPP-32) encoded by PPP1R1B. In this study, we identify a common PPP1R1B haplotype which predicts mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests. Multimodal imaging revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of prefrontal cortex (PFC). Recent fMRI studies of genetic variation in COMT and GRM3 suggest that these genes influence prefrontal signal-to-noise in the dopaminergic and glutaminergic systems. Another study used fMRI to examine the combined effects of COMT and GRM3 on components of the working memory network. We observed epistatic interaction of these two genes on the engagement of PFC during working memory. The GRM3 genotype was significantly associated with inefficient prefrontal engagement and altered frontoparietal coupling on a COMT Val/Val background. Conversely, COMT Met/Met background mediated against the effect of GRM3 genotype. We found that variants in these two genes interacted to modulate the efficiency of cortical activation, frontoparietal integration and differential engagement of the ventrolateral PFC (VLPFC). We conclude that these findings extend putative brain dopaminergic and glutaminergic cross-talk to systems-level interactions in cortical circuits implicated in working memory dysfunction. These studies have led to the identification of converging molecular pathways and their neuronal and systems level targets. We expect that these results will ultimately change our view of the pathophysiology of psychiatric disease, like schizophrenia, and point the way to new treatment targets and more principled clinical management.? ? We studied genotype effect of COMT Val158Met on corticolimbic circuitry and functional connectivity during processing of stimuli and the relationship to the temperamental trait of novelty seeking. Using fMRI we found that the Met allele was associated with an increase in hippocampal formation (HF) and ventrolateral PFC (VLPFC) activation while viewing faces displaying negative emotion. In another study we examined the effect of COMT Val158Met on the function of HF and VLPFC and their functional coupling during recognition memory. The COMT Val allele was associated with: poorer performance at retrieval; reduced recruitment of neuronal resources in HF and increased recruitment in VLPFC during both encoding and retrieval; and unfavorable functional coupling between these two regions at retrieval. Our results shed new light on differences in responsivity and connectivity between HF and VLPFC related to genetic modulation of dopamine. Since little is known about neural mechanisms underlying human personality and temperament, in another study we used a combined genetic and imaging approach focused on MAOA, an enzyme for monoamine metabolism associated with temperament and antisocial behavior. Male carriers of the low-expressing variant showed dysregulated amygdala activation and increased functional coupling with ventromedial PFC. Our data implicate a neural circuit for variation in human personality under genetic control of MAOA. Again looking at the impact of genetic variation on brain circuitry, regulator of G-protein signaling 4 (RGS4) in the striatum regulates dopaminergic signaling and aids in mediating crosstalk between D1 and D2 receptors. Using multimodal neuroimaging, we demonstrated that genetic variation in RGS4, A allele, which is associated with psychosis, impacts blood oxygenation level-dependent (BOLD) response and network coupling of information processing nodes and results in regionally specific reductions in gray and white matter structural volume. ? ? We extended our knowledge of path analysis, which quantifies interactions among brain regions based on connectivity models, but is limited by lack of precise anatomical and functional constraints. To address this, we developed an automated path analysis procedure guided by known anatomical connectivity in monkey. We used a large human fMRI data set to build a """"""""nuclear model"""""""" specifying a small number of well validated connections, then used a data-driven search algorithm to add known anatomically constrained connectivity. To allow paths that might reflect noise in the sample and provide a stringent test of this model, we used randomly sampled subject data. Our results show that a well-fitting model of limbic circuitry can be derived and statistically validated from fMRI. This validated model can be used to study genetic and disease-related variation across individuals.? ? In another study, we describe the topology of frequency-specific brain functional networks using magnetoencephalographic time series followed by construction and analysis of undirected connectivity graphs and dynamical consequences for network synchronization. We showed a fractal organization of large-scale functional networks in the resting state. This work identifies order parameters for functional topology that may support adaptive self-organizing behavior of the edge of chaos and provides measures for the study of genetic, cognitive, and behavioral influences on fractal small-world architecture of
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