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Our aim was to identify the functional and structural brain changes that underlie irritability in premanifest HD (preHD). Twenty preHD carriers and 20 gene\u2010negative controls from HD families took part in the study. Although the 5\u2010year probability of disease onset was only 11%, the preHD group showed striatal atrophy and increased clinical irritability ratings. Functional MRI was performed during a mood induction experiment by means of recollection of emotional (angry, sad, and happy) and neutral autobiographical episodes. While there were no significant group differences in the subjective intensity of the emotional experience, the preHD group showed increased anger\u2010selective activation in a distributed network, including the pulvinar, cingulate cortex, and somatosensory association cortex, compared to gene\u2010negative controls. Pulvinar activation during anger experience correlated negatively with putaminal grey matter volume and positively with irritability rating<jats:bold>s<\/jats:bold> in the preHD group. In addition, the preHD group showed a decrease in anger\u2010selective activation in the amygdala, which correlated with putaminal and caudate grey matter volume. In conclusion, compared to gene\u2010negative controls, anger experience in preHD is associated with activity changes in a distributed set of regions known to be involved in emotion regulation. Increased activity is related to behavioral and volumetric measures, providing insight in the pathophysiology of early neuropsychiatric symptoms in preHD. <jats:italic>Hum Brain Mapp 36:2681\u20132690, 2015<\/jats:italic>. \u00a9 <jats:bold>2015 Wiley Periodicals, Inc<\/jats:bold>.<\/jats:p>","DOI":"10.1002\/hbm.22799","type":"journal-article","created":{"date-parts":[[2015,4,9]],"date-time":"2015-04-09T05:01:42Z","timestamp":1428555702000},"page":"2681-2690","source":"Crossref","is-referenced-by-count":35,"title":["Functional brain changes underlying irritability in premanifest <scp>H<\/scp>untington's disease"],"prefix":"10.1002","volume":"36","author":[{"given":"Jan","family":"Van den Stock","sequence":"first","affiliation":[{"name":"Department of Neurosciences KU Leuven, Psychiatry Research Group Leuven Belgium"},{"name":"Old Age Psychiatry Department University Hospitals Leuven Leuven 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