Background Individuals at clinical high-risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with those without symptomatic progression and with healthy controls. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 who converted to psychosis, and 135 healthy comparison subjects were scanned with MRI at baseline, 12-month follow-up, and/or the point of conversion for those who developed fully psychotic symptoms. Results In a traveling subjects sub-study, we observed excellent reliability for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR converters showed a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions, as well as a greater rate of expansion of the third ventricle, compared with CHR non-converters and healthy controls. Differential tissue loss was present among cases who had not received antipsychotic medications during the inter-scan interval and was predicted by baseline levels of an aggregate measure of pro-inflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs, but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced among cases with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

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, attentiondeficit/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.

Background-Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in 'at risk' populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.Methods-35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up ('converters'), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.Results-Significantly greater brain contraction was found in the right prefrontal region in the 'converters' compared with UHR cases who did not develop psychosis ('non-converters').Conclusions-These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.Send correspondence and reprint requests to: