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The Neuroscientist Comments

Volume 27, Number 1, 2021 © The Author(s) 2020 10.1177/1073858420974344 Methods that enable the characterization of human brain morphometry from magnetic resonance imaging (MRI) data are demonstrating important applications in neuroscience. With the advent of modern neuroimaging technologies in the early 1990s, the proliferation of MRI scanners in research institutes around the world has made it possible to investigate different pathophysiological mechanisms in a variety of populations, including, but not limited to, normal and pathological development, neurodegeneration, traumatic brain injury, cerebrovascular diseases, autism, mood disorders, obsessive-compulsive disorder, epilepsy, and schizophrenia. However, the problem of sample size in neuroimaging studies carried out at individual institutions may be difficult to solve, also because they are expensive and timeconsuming. Although studies using less than 20 to 30 subjects are still quite common, it has become recognized that researchers from different centers can pool efforts by combining data acquisition and analyses toward large-scale collaborative projects with the aim of investigating brain structural alterations in diseases characterized by great clinical heterogeneity. Within this framework, The ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium is a collaboration of more than 1400 scientists from 43 countries studying the human brain. ENIGMA started 10 years ago, in 2009, with the initial aim of performing a large-scale neuroimaging genetic study and has since diversified into 50 working groups (WGs), pooling worldwide data, resources, and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. The approach adopted is different from other collaborative studies, since in the ENIGMA consortium datasets are not acquired using an harmonized protocol but have rather been obtained independently are analyzed individually using standardized processing pipelines and statistical models. The obtained individual results are then pooled together and analyzed through the same approach used for post hoc meta-analyses. One of the goals of ENIGMA is to compare different disorders (sharing similar mechanisms or symptoms) in terms of brain morphometrical alterations. In a recent study published in the American Journal of Psychiatry, Boedhoe and others (2020) of the ENIGMA consortium compared brain morphometrical alterations (subcortical brain volume, regional cortical thickness and cortical surface area) of patients with attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Although the three disorders are each characterized by their specific core symptoms, they frequently co-occur, and share substantial phenomenological, pathophysiological, and etiological processes, including a partly overlapping genetic liability. Boedhoe and colleagues analyzed structural MRI data from a very large sample containing thousands of individuals with ADHD (n = 2271), ASD (1777), or OCD (2323), and an extremely large number of typically developing control subjects (5827) from 151 cohorts worldwide. The samples included pediatric, adolescent, and adult samples in order to examine whether the structural alterations associated with each disorder were observed consistently across the lifespan. Results revealed a lack of shared alterations in brain structure across the disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD showed reduced hippocampal volumes, possibly related to IQ. Children and adolescents (but not adults) with ADHD also showed reduced intracranial volume with respect to control subjects, OCD or ASD. OCD was linked to greater striatal and lower limbic volumes (amygdala and hippocampus) in adulthood, but not in childhood or adolescence, while no disorder-specific effects on cortical thickness or surface area in the pediatric sample were found, and just a single region (medial orbitofrontal cortex) showed surface area differences in the adolescent sample. Finally, adult ASD patients showed increased cortical thickness in several frontal regions relative to adults with ADHD or OCD, but there were no surface area differences in this age group. Overall, these new findings challenge the idea that alterations in brain structure are stable over time in the neurodevelopmental conditions studied by Boedhoe and colleagues. One possible explanation for the lack of shared alterations (or their dependency on developmental age) could be attributed to the considerable clinical and pathophysiological heterogeneity within each disorder that may have weakened the strength of the associations. The authors did not have overlapping behavioral measures to look at the shared underlying behaviors, such as impulsivity, response inhibition, rigidity, compulsivity, and so on, and future studies may provide a broader view on the symptom level of disease groups. Another important aspect that should be considered is that the working group was not able to study the issue of comorbidity, since it would be reasonable to expect more overlap in patients who have both ADHD and OCD, or ASD and OCD, and so on. However, the study provides a useful model for future cross-disorder analyses comparing illnesses that are difficult to distinguish clinically and etiologically. The most important lesson from this project (and from the overall ENIGMA consortium activity) is that scientists worldwide are willing and able to collaborate at this scale, but at the moment the decryption of the specific or shared relationships between brain alterations and mental disorders is still far from being reached.