BACKGROUND Neuroimaging studies show structural alterations in several brain regions in children and adults with attention-deficit/hyperactivity disorder (ADHD). Through the formation of the worldwide ENIGMA ADHD Working Group, we addressed weaknesses of prior imaging studies and meta-analyses in sample size and methodological heterogeneity. METHODS Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites (age range: 4–63 years; 66% males). Individual sites analyzed magnetic resonance imaging brain scans with harmonized protocols. Case-control differences in subcortical structures and intracranial volume (ICV) were assessed through mega-and meta-analysis. FINDINGS The volumes of the accumbens (Cohen’s d=−0.15), amygdala (d=−0.19), caudate (d=−0.11), hippocampus (d=−0.11), putamen (d=−0.14), and ICV (d=−0.10) were found to be smaller in cases relative to controls. Effect sizes were highest in children, case-control differences were not present in adults. Explorative lifespan modeling suggested a delay of maturation and a delay of degeneration. Psychostimulant medication use or presence of comorbid psychiatric disorders did not influence results, nor did symptom scores correlate with brain volume. INTERPRETATION Using the largest data set to date, we extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. We add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD, and provide unprecedented precision in effect size estimates. Lifespan analyses suggest that, in the absence of well-powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of life provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING National Institutes of Health

Humans are endowed with a natural sense of fairness that permeates social perceptions and interactions. This moral stance is so ubiquitous that we may not notice it as a fundamental component of daily decision making and in the workings of many legal, political, and social systems. Emotion plays a pivotal role in moral experience by assigning human values to events, objects, and actions. Although the brain correlates of basic emotions have been explored, the neural organization of "moral emotions" in the human brain remains poorly understood. Using functional magnetic resonance imaging and a passive visual task, we show that both basic and moral emotions activate the amygdala, thalamus, and upper midbrain. The orbital and medial prefrontal cortex and the superior temporal sulcus are also recruited by viewing scenes evocative of moral emotions. Our results indicate that the orbital and medial sectors of the prefrontal cortex and the superior temporal sulcus region, which are critical regions for social behavior and perception, play a central role in moral appraisals. We suggest that the automatic tagging of ordinary social events with moral values may be an important mechanism for implicit social behaviors in humans.

Sunovian. He is/has been involved in clinical trials conducted by Lilly & Shire. The present work is unrelated to the above grants and relationships. Jonna Kuntsi has given talks at educational events sponsored by Medice; all funds are received by King's College London and used for studies of ADHD. Theo Van Erp consulted for Roche Pharmaceuticals and has a contract with Otsuka Pharmaceutical, Ltd. Anders Dale is a Founder of CorTechs Labs, Inc. He serves on the Scientific Advisory Boards of CorTechs Labs and Human Longevity, Inc., and receives research funding through a Research Agreement with General Electric Healhcare. Paulo Mattos was on the speakers' bureau and/or acted as consultant for Janssen-Cilag, Novartis, and Shire in the previous five years; he also received travel awards to participate in scientific meetings from those companies. The ADHD outpatient program (Grupo de Estudos do Déficit de Atenção/Institute of Psychiatry) chaired by Dr. Mattos has also received research support from Novartis and Shire.The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Tobias Banaschewski served in an advisory or consultancy role for Actelion,

Recent investigations in cognitive neuroscience haveshown that ordinary human behavior is guided by emotions that are uniquely human in their experiential and interpersonal aspects. These ''moral emotions'' contribute importantly to human social behavior and derive from the neurobehavioral reorganization of the basic plan of emotions that pervade mammalian life. Disgust is one prototypic emotion with multiple domains that include viscerosomatic reaction patterns and subjective experiences linked to (a) the sensory properties of a class of natural stimuli, (b) a set of aversive experiences and (c) a unique mode of experiencing morality. In the current investigation, we tested the hypotheses that (a) the experience of disgust devoid of moral connotations (''pure disgust'') can be subjectively and behaviorally differentiated from the experience of disgust disguised in the moral emotion of ''indignation'' and that (b) pure disgust and indignation may have partially overlapping neural substrates. Thirteen normal adult volunteers were investigated with functional magnetic resonance imaging as they read a series of statements depicting scenarios of pure disgust, indignation, and neutral emotion. After the scanning procedure, they assigned one basic and one moral emotion to each stimulus from an array of six basic and seven moral emotions. Results indicated that (a) emotional stimuli may evoke pure disgust with or without indignation, (b) these different aspects of the experience of disgust could be elicited by a set of written statements, and (c) pure disgust and indignation recruited both overlapping and distinct brain regions, mainly in the frontal and temporal lobes. This work underscores the importance of the prefrontal and orbitofrontal cortices in moral judgment and in the automatic attribution of morality to social events. Human disgust encompasses a variety of emotional experiences that are ingrained in frontal, temporal, and limbic networks.

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-The trail making test (TMT) pertains to a family of tests that tap the ability to alternate between cognitive categories. However, the value of the TMT as a localizing instrument remains elusive. Here we report the results of a functional magnetic resonance imaging (fMRI) study of a verbal adaptation of the TMT (vTMT). The vTMT takes advantage of the set-shifting properties of the TMT and, at the same time, minimizes the visuospatial and visuomotor components of the written TMT. Whole brain BOLD fMRI was performed during the alternating execution of vTMTA and vTMTB in seven normal adults with more than 12 years of formal education. Brain activation related to the set-shifting component of vTMTB was investigated by comparing performance on vTMTB with vTMTA, a simple counting task. There was a marked asymmetry of activation in favor of the left hemisphere, most notably in dorsolateral prefrontal cortex (BA 6 lateral, 44 and 46) and supplementary motor area/cingulate sulcus (BA 6 medial and 32). The intraparietal sulcus (BA 7 and 39) was bilaterally activated. These findings are in line with clinico-anatomic and functional neuroimaging data that point to a critical role of the dorsolateral and medial prefrontal cortices as well as the intraparietal sulci in the regulation of cognitive flexibility, intention, and the covert execution of saccades/anti-saccades. Many commonly used neuropsychological paradigms, such as the Stroop, Wisconsin Card Sorting, and go -no go tasks, share some patterns of cerebral activation with the TMT.KEY WORDS: trail making, functional MRI, executive function, prefrontal cortex, intraparietal sulcus, cognitive switching. Correlatos cerebrais da flexibilidade cognitiva: RM funcional do teste das trilhasRESUMO -O Teste de trilhas (TT) pertence a uma família de testes que aferem a capacidade de alternar entre categorias cognitivas. Não obstante, o valor de localização do TT permanece obscuro. Neste estudo, relatamos a análise de um estudo de uma adaptação verbal do TT (TTv) com ressonância magnética funcional (RMf). O TTv realça a propriedade de mudança de categorias do TT convencional (escrito) ao mesmo tempo em que minimiza seus componentes visuoespaciais e visuomotores. O cérebro inteiro foi estudado pela técnica BOLD durante a execução alternante do TTvA e TTvB em sete adultos normais com mais de 12 anos de escolaridade. A ativação cerebral relacionada ao componente de alternância cognitiva da Parte B foi investigada comparandose o desempenho no TTvB e no TTvA. Observamos acentuada assimetria de ativação a favor do hemisfério esquerdo, especificamente no córtex frontal dorsolateral (áreas 6 lateral, 44 e 46) e área motora suplementar/ sulco do cíngulo (área 6 medial e 32). O sulco intraparietal (áreas 7 e 39) foi ativado bilateralmente. Esses achados estão de acordo com dados clínico-anatômicos e de imagem funcional que apontam para o papel crítico do córtex prefrontal dorsolateral e medial, bem como do sulco intraparietal, na regulação da flexibilidade cognitiva, dos mecanismos...

The human brain is inherently able to understand the world in moral ways, endowing most of us with an intuitive sense of fairness, concern for others, and observance of cultural norms. We have argued that this moral sensitivity ability depends on a sophisticated integration of cognitive, emotional, and motivational mechanisms, which are modulated by individual experience in different cultural milieus. Different lines of investigation on agency and morality have pointed to overlapping neural systems. Therefore, understanding the relationships between morality and agency may provide key insights into the mechanisms underlying human behavior in several clinical and societal settings. We used functional MRI to investigate the contribution of agency and of specific moral emotions to brain activation using action scripts. Results showed that emotionally neutral agency recruited neural networks previously associated with agency, intentionality and moral cognition, encompassing ventral and subgenual sectors of the medial prefrontal cortex (PFC), insula, anterior temporal cortex and superior temporal sulcus (STS). Compared to emotionally neutral agency, different categories of moral emotions led to distinct activation patterns: (1) prosocial emotions (guilt, embarrassment, compassion) activated the anterior medial PFC and STS, with (2) empathic emotions (guilt and compassion) additionally recruiting the mesolimbic pathway; (3) other-critical emotions (disgust and indignation) were associated with activation of the amygdala-parahippocampal and fusiform areas. These findings indicate that agency related to norm-abiding social behaviors of emotionally neutral scripts share neural substrates both with the "default mode" of brain function and with the moral sensitivity network. Additional activation in specific components of this network is elicited by different classes of moral emotions, in agreement with recent integrative models of moral cognition and emotion.