Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

Task-generic and task-specific connectivity modulations in the ADHD brain:an integrated analysis across multiple tasks

Contains fulltext : 231786.pdf (publisher's version ) (Open Access)Attention-deficit/hyperactivity disorder (ADHD) is associated with altered functioning in multiple cognitive domains and neural networks. This paper offers an overarching biological perspective across these. We applied a novel strategy that extracts functional connectivity modulations in the brain across one (P(single)), two (P(mix)) or three (P(all)) cognitive tasks and compared the pattern of modulations between participants with ADHD (n-89), unaffected siblings (n = 93) and controls (n = 84; total N = 266; age range = 8-27 years). Participants with ADHD had significantly fewer P(all) connections (modulated regardless of task), but significantly more task-specific (P(single)) connectivity modulations than the other groups. The amplitude of these P(single) modulations was significantly higher in ADHD. Unaffected siblings showed a similar degree of P(all) connectivity modulation as controls but a similar degree of P(single) connectivity modulation as ADHD probands. P(all) connections were strongly reproducible at the individual level in controls, but showed marked heterogeneity in both participants with ADHD and unaffected siblings. The pattern of reduced task-generic and increased task-specific connectivity modulations in ADHD may be interpreted as reflecting a less efficient functional brain architecture due to a reduction in the ability to generalise processing pathways across multiple cognitive domains. The higher amplitude of unique task-specific connectivity modulations in ADHD may index a more "effortful" coping strategy. Unaffected siblings displayed a task connectivity profile in between that of controls and ADHD probands, supporting an endophenotype view. Our approach provides a new perspective on the core neural underpinnings of ADHD

Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD

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Depth-dependent intracortical myelin organization in the living human brain determined by in vivo ultra-high field magnetic resonance imaging

Background: Intracortical myelin is a key determinant of neuronal synchrony and plasticity that underpin optimal brain function. Magnetic resonance imaging (MRI) facilitates the examination of intracortical myelin but presents with methodological challenges. Here we describe a whole-brain approach for the in vivo investigation of intracortical myelin in the human brain using ultra-high field MRI. Methods: Twenty-five healthy adults were imaged in a 7 Tesla MRI scanner using diffusion-weighted imaging and a T 1 -weighted sequence optimized for intracortical myelin contrast. Using an automated pipeline, T 1 values were extracted at 20 depth-levels from each of 148 cortical regions. In each cortical region, T 1 values were used to infer myelin concentration and to construct a non-linearity index as a measure the spatial distribution of myelin across the cortical ribbon. The relationship of myelin concentration and the non-linearity index with other neuroanatomical properties were investigated. Five patients with multiple sclerosis were also assessed using the same protocol as positive controls. Results: Intracortical T 1 values decreased between the outer brain surface and the gray-white matter boundary following a slope that showed a slight leveling between 50% and 75% of cortical depth. Higher-order regions in the prefrontal, cingulate and insular cortices, displayed higher non-linearity indices than sensorimotor regions. Across all regions, there was a positive association between T 1 values and non-linearity indices (P < 10 125 ). Both T 1 values (P < 10 125 ) and non-linearity indices (P < 10 1215 ) were associated with cortical thickness. Higher myelin concentration but only in the deepest cortical levels was associated with increased subcortical fractional anisotropy (P = 0.05). Conclusions: We demonstrate the usefulness of an automatic, whole-brain method to perform depth-dependent examination of intracortical myelin organization. The extracted metrics, T 1 values and the non-linearity index, have characteristic patterns across cortical regions, and are associated with thickness and underlying white matter microstructure

Social responsiveness to inanimate entities: Altered white matter in a ‘social synaesthesia’

Judgments about personalities and social traits can be made by relatively brief exposure to animate living things. Here we show that unusual architecture in the microstructure of the human brain is related to atypical mental projections of personality and social structure onto things that are neither living nor animate. Our participants experience automatic, life-long and consistent crossmodal associations between language sequences (e.g., letters, numbers and days) and complex personifications (e.g., A is a businessman; 7 a good-natured woman). Participants with this 'Ordinal Linguistic Personification' (Simner and Hubbard, 2006) which we describe here as a form of social synaesthesia, showed lower fractional anisotropy (FA) values in five clusters at whole-brain significance, compared with non-synaesthetes (in the pre-postcentral gyrus/dorsal corticospinal tract, left superior corona radiata, and the genu, body and left side of the corpus callosum). We found no regions of the brain with increased FA in synaesthetes. A number of these regions with reduced FA play a role in social responsiveness, and our study is the first to show that unusual differences in white matter microstructure in these regions is associated with compelling feelings of social cohesion and personality towards non-animate entities. We show too that altered patterns of connectivity known to typify synaesthesia are not limited to variants involving a 'merging of the senses', but also extend to what might be thought of as a cogno-social variant of synaesthesia, linking language and personality attributes in this surprising way

Discrepancies of polygenic effects on symptom dimensions between adolescents and adults with ADHD

A significant proportion of individuals with attention-deficit/hyperactivity disorder (ADHD) show persistence into adulthood. The genetic and neural correlates of ADHD in adolescents versus adults remain poorly characterized. We investigated ADHD polygenic risk score (PRS) in relation to previously identified gray matter (GM) patterns, neurocognitive, and symptom findings in the same ADHD sample (462 adolescents & 422 adults from the NeuroIMAGE and IMpACT cohorts). Significant effects of ADHD PRS were found on hyperactivity and impulsivity symptoms in adolescents, hyperactivity symptom in adults, but not GM volume components. A distinct PRS effect between adolescents and adults on individual ADHD symptoms is suggested

Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity

Objective Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). Method Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). Results We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. Conclusions We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity

Reduced fronto-striatal volume in attention-deficit/hyperactivity disorder in two cohorts across the lifespan

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting white-matter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings

Personality, Health, and Brain Integrity:The Lothian Birth Cohort Study 1936

Objective: To explore associations between the 5-factor model (FFM; neuroticism, extraversion, openness/intellect, agreeableness, and conscientiousness), personality traits, and measures of whole-brain integrity in a large sample of older people, and to test whether these associations are mediated by health-related behaviors. Method: Participants from the Lothian Birth Cohort 1936 completed the International Personality Item Pool measure, a 5-factor public-domain personality measure (http://ipip.ori.org), and underwent a structural magnetic resonance brain scan at the mean age of 73 years, yielding 3 measures of whole brain integrity: average white matter fractional anisotropy (FA), brain-tissue loss, and white matter hyperintensities (N = 529 to 565). Correlational and mediation analyses were used to test the potential mediating effects of health-related behaviors on the associations between personality and integrity. Results: Lower conscientiousness was consistently associated with brain-tissue loss (β = −0.11, p < 0.01), lower FA (β = 0.16, p < 0.001) and white matter hyperintensities (β = −0.10, p < 0.05). Smoking, alcohol consumption, diet, physical activity, body mass index and a composite health-behavior variable displayed significant associations with measures of brain integrity (range of r = 0.10 to 0.25). The direct effects of conscientiousness on brain integrity were mediated to some degree by health behaviors, with the proportions of explained direct effects ranging from 0.1% to 13.7%. Conclusion: Conscientiousness was associated with all 3 measures of brain integrity, which we tentatively interpret as the effects of personality on brain aging. Small proportions of the direct effects were mediated by individual health behaviors. Results provide initial indications that lifetime stable personality traits may influence brain health in later life through health-promoting behaviors. (PsycINFO Database Record (c) 2016 APA, all rights reserved