ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults?

Objective: To assess changes in cannabis use in young adults as a function of psychotic-like experiences. Method: Participants were initially recruited at age 14 in high schools for the longitudinal IMAGEN study. All measures presented here were assessed at follow-ups at age 19 and at age 22, respectively. Perceived stress was only assessed once at age 22. Ever users of cannabis (N = 552) gave qualitative and quantitative information on cannabis use and psychotic-like experiences using the Community Assessment of Psychic Experiences (CAPE). Of those, nearly all n = 549 reported to have experienced at least one psychotic experience of any form at age 19. Results: Mean cannabis use increased from age 19 to 22 and age of first use of cannabis was positively associated with a change in cannabis use between the two time points. Change in cannabis use was not significantly associated with psychotic-like experiences at age 19 or 22. In exploratory analysis, we observed a positive association between perceived stress and the experience of psychotic experiences at age 22. Conclusion: Age of first use of cannabis influenced trajectories of young cannabis users with later onset leading to higher increase, whereas the frequency of psychotic-like experiences was not associated with a change in cannabis use. The observed association between perceived stress and psychotic-like experiences at age 22 emphasizes the importance of stress experiences in developing psychosis independent of cannabis use

Expression of yeast lipid phosphatase Sac1p is regulated by phosphatidylinositol-4-phosphate

<p>Abstract</p> <p>Background</p> <p>Phosphoinositides play a central role in regulating processes at intracellular membranes. In yeast, a large number of phospholipid biosynthetic enzymes use a common mechanism for transcriptional regulation. Yet, how the expression of genes encoding lipid kinases and phosphatases is regulated remains unknown.</p> <p>Results</p> <p>Here we show that the expression of lipid phosphatase Sac1p in the yeast <it>Saccharomyces cerevisiae </it>is regulated in response to changes in phosphatidylinositol-4-phosphate (PI(4)P) concentrations. Unlike genes encoding enzymes involved in phospholipid biosynthesis, expression of the <it>SAC1 </it>gene is independent of inositol levels. We identified a novel 9-bp motif within the 5' untranslated region (5'-UTR) of <it>SAC1 </it>that is responsible for PI(4)P-mediated regulation. Upregulation of <it>SAC1 </it>promoter activity correlates with elevated levels of Sac1 protein levels.</p> <p>Conclusion</p> <p>Regulation of Sac1p expression via the concentration of its major substrate PI(4)P ensures proper maintenance of compartment-specific pools of PI(4)P.</p

Psychosocial stress and brain function in adolescent psychopathology

Objective: To explore how conduct, hyperactivity/inattention, and emotional symptoms are associated with neural reactivity to social-emotional stimuli, and the extent to which psychosocial stress modulates these relationships. Method: Participants were community adolescents recruited as part of the European IMAGEN study. Bilateral amygdala regions of interest were used to assess the relationship between the three symptom domains with fMRI neural reactivity during passive viewing of dynamic angry and neutral facial expressions. Exploratory functional connectivity and whole-brain multiple regression approaches were used to analyze how the symptoms and psychosocial stress relate to other brain regions. Results: In response to the social-emotional stimuli, adolescents with high levels of conduct or hyperactivity/inattention symptoms showed hyperactivity of the amygdala, and several regions across the brain, when they experienced a greater number of stressful life events. This effect was not observed with emotional symptoms. A cluster in the mid-cingulate was found to be common to both conduct problems and hyperactivity symptoms. Exploratory functional connectivity analyses suggested amygdala-precuneus connectivity is associated with hyperactivity/inattention symptoms. Conclusions: The results link hyperactive amygdala responses, and regions critical for top-down emotional processing, with high levels of psychosocial stress in individuals with greater conduct and hyperactivity/inattention symptoms. This work highlights the importance of studying how psychosocial stress impacts functional brain responses to social-emotional stimuli, particularly in adolescents with externalizing symptoms

Role of human tissue kallikrein in gastrointestinal stromal tumour invasion

Background: Human tissue kallikrein (hK1) generates vasodilator kinins from kininogen and promotes angiogenesis by kinin-dependent and kinin-independent mechanisms. Here, we investigate the expression and functional relevance of hK1 in human gastrointestinal stromal tumour (GIST).&lt;p&gt;&lt;/p&gt; Methods: Vascularisation and hK1 expression of GIST samples were assessed by immunohistochemistry. In two GIST cell lines, hK1 expression was assessed by PCR, and hK1 protein levels and activity were measured by ELISA and an amidolytic assay, respectively. The effect of hK1 silencing, inhibition or overexpression on GIST cell proliferation, migration and paracrine induction of angiogenesis was studied. Finally, local and systemic levels of hK1 were assessed in mice injected with GIST cells.&lt;p&gt;&lt;/p&gt; Results: Human tissue kallikrein was detected in 19 out of 22 human GIST samples. Moreover, GIST cells express and secrete active hK1. Titration of hK1 demonstrated its involvement in GIST invasive behaviour, but not proliferation. Furthermore, hK1 released by GIST cells promoted endothelial cell migration and network formation through kinin-dependent mechanisms. Gastrointestinal stromal tumour implantation in nude mice resulted in local and systemic hK1 expression proportional to tumour dimension.&lt;p&gt;&lt;/p&gt; Conclusions: Human tissue kallikrein is produced and released by GIST and participates in tumour invasion. Further studies are needed to validate hK1 as a diagnostic biomarker and therapeutic target in GIST

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30-0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|rho| = 0.31-0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|rho = 0.24-0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|rho| = 0.10-0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives