IntroductionHeritable genetic traits and environmental components both contribute to the etiology of affective disorders. While the specific contribution of these 2 factors to disorder onset remains elusive, family and twin studies have consistently identified a family history of affective disorders as a major risk factor.1 First-degree relatives of patients with depression have a 2-fold to 4-fold increased risk for depression than individuals with no psychiatric history in first-degree relatives.2 Yet the specific neurobiological correlates mediating this vulnerability to affective disorders, which are transmitted in affected families, remain to be identified.Recent studies in high-risk individuals have revealed that healthy individuals at familial risk for affective disorders show a range of neurobiological abnormalities. Two studies from our group showed lower serotonin (5-HT) transporter binding in the prefrontal cortex 3 and decreased hippocampal volume. 4 We recently observed altered neural response in the hippocampus and orbitofrontal cortex to monetary gains and losses in healthy first-degree relatives of patients with depression.5 Accordingly, other groups have shown altered frontal and subcortical reward-related neural processes in healthy individuals at familial risk for affective disorders. [6][7][8] Prospective longitudinal studies may provide valuable insights into the association between risk factors and disorder onset. By following healthy high-risk individuals for 7 years before the onset of any affective disorder, we were able to show that discrete subclinical symptoms predict subsequent disorder onset. 9 The personality trait neuroticism, which refers to emotional instability, vulnerability to stress and anxiety disorders, 10 was also found to predict subsequent disorder Background: Healthy first-degree relatives of patients with affective disorders are at increased risk for affective disorders and express discrete structural and functional abnormalities in the brain reward system. However, value-based decision making is not well understood in these at-risk individuals. Methods: We investigated healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorders (high-risk and low-risk groups, respectively) using functional MRI during a gambling task. We assessed group differences in activity related to gambling risk over the entire brain. Results: We included 30 monozygotic and 37 dizygotic twins in our analysis. Neural activity in the anterior insula and ventral striatum increased linearly with the amount of gambling risk in the entire cohort. Individual neuroticism scores were positively correlated with the neural response in the ventral striatum to increasing gambling risk and negatively correlated with individual risk-taking behaviour. Compared with low-risk twins, the high-risk twins showed a bilateral reduction of risk-related activity in the middle insula extending into the temporal cortex with increasing gambling risk. Post hoc analyses revealed that this e...