This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1,400 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.

BackgroundSocial anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to neutral faces has, as of yet, not been investigated in patients with SAD and their family members concurrently. Here, we examined whether impaired habituation to neutral faces is a putative neurobiological endophenotype of SAD by using data from the multiplex and multigenerational Leiden Family Lab study on SAD.MethodsParticipants (n = 110; age, 9.2 – 61.5 years) performed a habituation paradigm involving neutral faces, as these are strong social stimuli with an ambiguous meaning. We used functional magnetic resonance imaging data to investigate whether brain activation related to habituation was associated with the level of social anxiety within the families. Furthermore, the heritability of the neural habituation response was estimated.ResultsOur data revealed a relationship between impaired habituation to neutral faces and social anxiety in the right hippocampus and right amygdala. In addition, our data indicated that this habituation response displayed moderate ‐ to‐moderately high heritability in the right hippocampus.ConclusionThe present results provide support for altered habituation as a candidate SAD endophenotype; impaired neural habitation cosegregrated with the disorder within families and was heritable. These findings shed light on the genetic susceptibility to SAD.

Cross-sectional Diffusion Tensor Imaging (DTI) studies have reported alterations in white matter (WM) microstructure in adolescents with internalizing psychopathology. Yet, longitudinal studies investigating the course of WM microstructure are lacking. This study explored WM alterations and its relation to clinical symptoms over time in adolescents with internalizing disorders. DTI scans were acquired at baseline and after three months in 22 adolescents with clinical depression and comorbid anxiety (INT), and 21 healthy peers (HC) (age: 12-18). Tract-based spatial statistics was used for three voxelwise analyses: i) changes in WM microstructure between and within the INT and HC group; ii) associations between changes in symptom severity and changes in WM microstructure within youths with INT; and iii) associations between baseline WM parameters with changes in symptom severity within youths with INT. Data did not reveal changes in WM microstructure between or within groups over three months' time nor associations between changes in WM microstructure and changes in self-reported symptoms (analyses corrected for age, gender and puberty stage). Lower baseline levels of fractional anisotropy (FA) in the right posterior corona radiata (PCR) and right cingulum were associated with a higher decrease of depressive symptoms within the INT group. Post hoc analysis of additional WM parameters in the significant FA clusters showed that higher levels of baseline mean diffusivity and radial diffusivity in the PCR were associated with a lower decrease in depressive symptoms. Baseline WM microstructure characteristics were associated with a higher decrease in depressive symptoms over time. These findings increase our understanding of neurobiological mechanisms underlying the course of internalizing disorders in adolescents.

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IntroductionPatients with a bipolar disorder (BD) may experience one or several episodes of major depression before transitioning into a manic phase. Given that treatment with common antidepressants may exacerbate symptoms of mania in patients with BD, initial diagnosis of major depressive disorder (MDD) is a significant issue affecting BD patients. Currently, a family history of BD is used as an early identifier for BD, but as genetic factors associated with BD confer susceptibility to a wide range of psychiatric illnesses, this approach lacks specificity. Thus, there is a pressing need for a biomarker which specifically predicts development of bipolar symptoms in patients with MDD, rather than a trait vulnerability to psychiatric disorderObjectives The aim of this study is to assess alterations in fronto-limbic function that exist prior to the manifestation of the first manic episode in BD patients without familial predisposition for BD.MethodsTo identify a biomarker for conversion to BD we performed a study in a naturalistic sample of MDD patients without a familial risk for BD, which were followed for 9 years. We used a seed-based functional connectivity analysis to assess differences in resting-state fronto-limbic connectivity between MDD patients who converted to BD during the follow-up period (n = 11), and non-converting MDD patients (n = 56).ResultsClusters of significantly reduced functional connectivity were found in the fronto-limbic network of prospective converters relative to non-converters.ConclusionsFindings suggest that alterations of fronto-limbic functional connectivity during episodes of depression predate and associate with conversion to BD later in life, in the absence of familial risk. These fronto-limbic functional connectivity disturbances may be of interest for diagnosing early-stage BD, and may offer insight in the mechanisms that drive conversion in the absence of familial predisposition. Findings from this study need to be verified through large-scale longitudinal imaging studies in naturalistic cohorts of MDD patients.Disclosure of InterestNone Declared