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)

Abstract

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.

Abstract

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

Risk markers for affective disorder, a seven-years follow up study of a twin cohort at low and high risk for affective disorder

Vinberg M, Miskowiak K, Kessing LV

J Psychiatr Res. 2013 May;47(5):565-71

Abstract

This study aims to investigate whether: familial history of affective disorder, subclinical depressive symptoms and life events (LEs) are predictive of a later development of mood disorder (onset). In a high-risk study, 234 healthy monozygotic and dizygotic twins with and without a co-twin history of affective disorder (high and low risk twins, respectively) were identified through nationwide registers and assessed from 2002 to 2005. Participants were followed longitudinally at 6-months intervals for up to nine years and finally reassessed with a personal interview to obtain information on whether they had an onset. During the follow-up period (mean time 7.0 years), 36 participants (15.4%) developed onset. Onset was significantly associated with risk status (Hazard ratio (HR) = 1.38, 95% CI 1.08-1.76), female sex, HR = 2.70, 95% CI 1.19-6.97, age HR = 0.97, 95% CI 0.93-0.99), and also with baseline Hamilton 17 score (HR = 1.30, 95% CI 1.13-1.48), Becks Depression Inventory 21 (HR = 1.14, 95% CI, 1.05-1.24) and neuroticism (HR = 1.08, 95% 1.02-1.12). Finally, the experience of LEs lifetime before baseline predicted onset (HR = 1.20, 95% CI 1.01-1.46) and the experience of LEs during follow-up also predicted onset (HR = 1.06, 95% CI 1.01-1.11). These findings suggest that young individuals at familial risk of affective disorders are at enhanced risk of onset and at further risk when having female sex and more subclinical depressive symptoms at baseline. Further, they seem to experience more LEs and to be more vulnerable to these.

Brain Derived Neurotrophic Factor (BDNF) levels as a possible predictor of psychopathology in healthy twins at high and low risk for affective disorder

Vinberg M, Miskowiak K, Kessing LV

Psychoneuroendocrinology. 2014 Jan;39:179-83

Abstract

Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction with the BDNF Val66Met polymorphism predict onset of affective disorder in healthy individuals at heritable risk for affective disorder. In a high-risk study, we assessed whole blood levels of BDNF in 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high and low risk twins, respectively). Participants were followed up longitudinally with questionnaires at 6-month intervals for mean seven years and then reassessed with a personal interview to obtain information about whether they had developed psychiatric illness. At follow-up 36 participants (15.4%) had developed psychiatric disorder. Cox regression analysis revealed that BDNF levels at baseline were not associated with onset of illness in this explorative study. Further, two-way interactions between BDNF levels and the Val66Met polymorphism or between familial risk and the Val66Met polymorphism did not predict illness onset.

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.

Abstract

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.

Impairment of executive function and attention predicts onset of affective disorder in healthy high-risk twins

Vinberg M, Miskowiak KW, Kessing LV

J Clin Psychiatry. 2013 Aug;74(8):e747-53.

Abstract

OBJECTIVE: To investigate whether measures of cognitive function can predict onset of affective disorder in individuals at heritable risk.

METHOD: In a high-risk study, 234 healthy monozygotic and dizygotic twins with and without a co-twin history of affective disorder (high- and low-risk twins, respectively) were identified through nationwide registers and assessed at baseline using the Schedules for Clinical Assessment in Neuropsychiatry, the 17-item Hamilton Depression Rating Scale (HDRS), and the cognitive tests Trail Making Test Parts A and B, the Stroop test, and the Cambridge Cognitive Examination-Revised (CAMCOR). Participants were followed longitudinally at 6-month intervals for up to 9 years and finally reassessed with a personal interview to obtain information on whether they had developed psychiatric illness. The study was conducted between 2003 and 2012.

RESULTS: 36 participants (15.4%) developed psychiatric disorder, mainly affective and anxiety disorders (31 diagnoses) (ICD-10). Onset was predicted by decreased executive function as reflected by performance on the Trail Making Test A – B (hazard ratio [HR] = 1.02; 95% CI, 1.00-1.03) when adjusted for sex, age, years of education and HDRS score at baseline. Reduced global cognitive function as indicated by a lower CAMCOR score at baseline showed a trend toward an association with subsequent illness onset (P = .08). With regard to the 5 CAMCOR subscales, lower scores on attention (HR = 0.71; 95%, CI, 0.54-0.94) and language (HR = 0.76; 95% CI, 0.58-0.99) were significantly associated with subsequent illness onset.

CONCLUSIONS: Among healthy individuals at heritable risk for affective disorder, discrete cognitive deficits, especially within executive function and attention, seem to predict subsequent onset of affective illness.