Healthy co-twins of patients with affective disorders show reduced risk-related activation of the insula during a monetary gambling task

Macoveanu J, Miskowiak KW, Kessing LV, Siebner HR, Vinberg M

J Psychiatry Neuroscience (in press)


Background: Healthy first-degree relatives to patients with affective disorders are at increased risk for affective disorders and express discrete structural and functional abnormalities in the brain reward system. However, the value-based decision-making is not well understood in these at-risk individuals.

Methods: We investigated healthy monozygotic (n = 30) and dizygotic (n = 37) twins with or without a co-twin history of affective disorders (high-risk and low-risk groups, respectively) using functional MRI while performing a gambling task. We assessed group differences in activity related to gambling risk over the entire brain.

Results: Neural activity in 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 ventral striatum to increasing gambling risk and negatively correlated with individual risk-taking behavior. Compared with low-risk twins, the high-risk twins showed a bilateral reduction of risk-related activity in the middle insula extending into temporal cortex with increasing gambling risk. Post-hoc analyses revealed that this effect was strongest in dizygotic twins.

Limitations: The higher average age of the twin cohort (49.2 years) may indicate an increased resilience to affective disorders. The size of the monozygotic high-risk group was relatively small (n=13).

Conclusion: The reduced processing of risk magnitude in the middle insula may indicate a deficient integration of exteroceptive information related to risk-related cues with interoceptive states in individuals at familial risk for affective disorders. Impaired risk processing might contribute to increased vulnerability to affective disorders.

Different neural and cognitive response to emotional faces in healthy monozygotic twins at risk of depression

Miskowiak KW, Glerup L, Vestbo C, Harmer CJ, Reinecke A, Macoveanu J, Siebner HR, Kessing LV, Vinberg M

Psychol Med. 2015 May;45(7):1447-58.


BACKGROUND: Negative cognitive bias and aberrant neural processing of emotional faces are trait-marks of depression. Yet it is unclear whether these changes constitute an endophenotype for depression and are also present in healthy individuals with hereditary risk for depression.

METHOD: Thirty healthy, never-depressed monozygotic (MZ) twins with a co-twin history of depression (high risk group: n = 13) or without co-twin history of depression (low-risk group: n = 17) were enrolled in a functional magnetic resonance imaging (fMRI) study. During fMRI, participants viewed fearful and happy faces while performing a gender discrimination task. After the scan, they were given a faces dot-probe task, a facial expression recognition task and questionnaires assessing mood, personality traits and coping strategies.

RESULTS: High-risk twins showed increased neural response to happy and fearful faces in dorsal anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), pre-supplementary motor area and occipito-parietal regions compared to low-risk twins. They also displayed stronger negative coupling between amygdala and pregenual ACC, dmPFC and temporo-parietal regions during emotional face processing. These task-related changes in neural responses in high-risk twins were accompanied by impaired gender discrimination performance during face processing. They also displayed increased attention vigilance for fearful faces and were slower at recognizing facial expressions relative to low-risk controls. These effects occurred in the absence of differences between groups in mood, subjective state or coping.

CONCLUSIONS: Different neural response and functional connectivity within fronto-limbic and occipito-parietal regions during emotional face processing and enhanced fear vigilance may be key endophenotypes for depression

Serotonin transporter genotype, salivary cortisol, neuroticism and life events: impact on subsequent psychopathology in healthy twins at high and low risk for affective disorder

Vinberg M, Miskowiak K, Kessing LV

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jan 3;48:193-8.


OBJECTIVE: To investigate if cortisol alone or in interaction with other risk factors (familial risk, the serotonin transporter genotype, neuroticism and life events (LEs)) predicts onset of psychiatric disorder in healthy individuals at heritable risk.

MATRIAL AND METHODS: In a high-risk study, 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high and low risk twins) were baseline assessed. Participants were followed up for seven years and then reassessed with a personal interview revealing whether they had developed psychiatric illness.

RESULTS: 36 participants (15.4%) developed psychiatric disorder. Using Cox proportional hazards ratio (HR) estimates neither morning nor evening salivary cortisol at baseline did predict illness onset. In multivariate Cox models, the two-way interaction between morning cortisol and LEs lifetime before baseline was significantly associated with onset. Further, the HR of onset was higher concerning individuals carrying the short allele of the 5-HTTPLR and having experienced more LEs lifetime. Familial risk for affective disorder predicted illness and the risk of onset was further increased in individuals at familial risk carrying the short allele of the 5-HTTPLR.

CONCLUSIONS: Cortisol levels alone do not increase the risk of onset of psychiatric illness but the interaction of a lower cortisol level and the experience of more LEs do. The 5-HTTLPR genotype seems to interact and contribute to increased stress vulnerability in combination with other stress indicators of illness thereby adding to the risk of subsequent psychopathology.