Emotional cognition subgroups in unaffected first-degree relatives of patients with mood disorders.

BACKGROUND: Patients with major depressive disorder (MDD) or bipolar disorder (BD) exhibit difficulties with emotional cognition even during remission. There is evidence for aberrant emotional cognition in unaffected relatives of patients with these mood disorders, but studies are conflicting. We aimed to investigate whether emotional cognition in unaffected first-degree relatives of patients with mood disorders is characterised by heterogeneity using a data-driven approach. METHODS: Data from 94 unaffected relatives (33 of MDD patients; 61 of BD patients) and 203 healthy controls were pooled from two cohort studies. Emotional cognition was assessed with the Social Scenarios Test, Facial Expression Recognition Test and Faces Dot-Probe Test. Hierarchical cluster analysis was conducted using emotional cognition data from the 94 unaffected relatives. The resulting emotional cognition clusters and controls were compared for emotional and non-emotional cognition, demographic characteristics and functioning. RESULTS: Two distinct clusters of unaffected relatives were identified: a relatively 'emotionally preserved' cluster (55%; 40% relatives of MDD probands) and an 'emotionally blunted' cluster (45%; 29% relatives of MDD probands). 'Emotionally blunted' relatives presented with poorer neurocognitive performance (global cognition p = 0.010), heightened subsyndromal mania symptoms (p = 0.004), lower years of education (p = 0.004) and difficulties with interpersonal functioning (p = 0.005) than controls, whereas 'emotionally preserved' relatives were comparable to controls on these measures. CONCLUSIONS: Our findings show discrete emotional cognition profiles that occur across healthy first-degree relatives of patients with MDD and BD. These emotional cognition clusters may provide insight into emotional cognitive markers of genetically distinct subgroups of individuals at familial risk of mood disorders.

Reduced frontostriatal response to expected value and reward prediction error in remitted monozygotic twins with mood disorders and their unaffected high-risk co-twins.

BACKGROUND: Depressive episodes experienced in unipolar (UD) and bipolar (BD) disorders are characterized by anhedonia and have been associated with abnormalities in reward processes related to reward valuation and error prediction. It remains however unclear whether these deficits are associated with familial vulnerability to mood disorders. METHODS: In a functional magnetic resonance imaging study, we evaluated differences in the expected value (EV) and reward prediction error (RPE) signals in ventral striatum (VS) and prefrontal cortex between three groups of monozygotic twins: affected twins in remission for either UD or BD (n = 53), their high-risk unaffected co-twins (n = 34), and low-risk twins with no family history of mood disorders (n = 25). RESULTS: Compared to low-risk twins, affected twins showed lower EV signal bilaterally in the frontal poles and lower RPE signal bilaterally in the VS, left frontal pole and superior frontal gyrus. The high-risk group did not show a significant change in the EV or RPE signals in frontostriatal regions, yet both reward signals were consistently lower compared with low-risk twins in all regions where the affected twins showed significant reductions. CONCLUSION: Our findings strengthen the notion that reduced valuation of expected rewards and reduced error-dependent reward learning may underpin core symptom of depression such as loss of interest in rewarding activities. The trend reduction in reward-related signals in unaffected co-twins warrants further investigation of this effect in larger samples and prospective follow-up to confirm possible association with increased familial vulnerability to mood disorders.

Are remitted affective disorders and familial risk of affective disorders associated with metabolic syndrome, inflammation and oxidative stress? - a monozygotic twin study.

BACKGROUND: Metabolic syndrome (MetS) is associated with reduced life expectancy in patients with affective disorders, however, whether MetS also plays a role before the onset of affective disorder is unknown. We aimed to investigate whether MetS, inflammatory markers or oxidative stress act as risk factors for affective disorders, and whether MetS is associated with increased inflammation and oxidative stress. METHODS: We conducted a high-risk study including 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). Metabolic Syndrome was ascertained according to the International Diabetes Federation (IDF) criteria. Inflammatory markers and markers of oxidative stress were analyzed from fasting blood and urine samples, respectively. RESULTS: The affected and the high-risk group had a significantly higher prevalence of MetS compared to the low-risk group (20% v. 15% v. 2.5%, p = 0.0006), even after adjusting for sex, age, smoking and alcohol consumption. No differences in inflammatory and oxidative markers were seen between the three groups. Further, MetS was associated with alterations in inflammatory markers, and oxidative stress was modestly correlated with inflammation. CONCLUSION: Metabolic syndrome is associated with low-grade inflammation and may act as a risk factor and a trait marker for affective disorders. If confirmed in longitudinal studies, this suggests the importance of early intervention and preventive approaches targeted towards unhealthy lifestyle factors that may contribute to later psychopathology.

Neural response to emotional faces in monozygotic twins: association with familial risk of affective disorders

Background: Aberrant neural and cognitive response to emotional faces has been observed in people at familial risk of an affective disorder. In this functional MRI study of monozygotic twins, we explored neural correlates of the attentional avoidance of emotional faces that we had previously observed in high-risk versus affected twins, and whether an abnormal neural response to emotional faces represents a risk endophenotype. Methods: We recruited unaffected monozygotic twins with a co-twin history of mood episodes (high-risk), monozygotic twins with previous mood episodes (affected) and monozygotic twins with no personal or first-degree history of mood episodes (low-risk) between December 2014 and January 2017 based on a nationwide register linkage. Participants viewed fearful and happy faces while performing a gender discrimination task during functional MRI (fMRI) and performed emotional faces dot-probe and facial expression recognition tasks outside the scanner. Results: A total of 129 monozygotic twins underwent whole-brain fMRI. Highrisk twins (n = 38) displayed greater medial and superior prefrontal response to emotional faces than affected twins (n = 62). This greater activity correlated with stronger attentional avoidance of emotional faces in high-risk twins. In contrast, high-risk and affected twins showed no aberrant neural activity to emotional faces compared with low-risk twins (n = 29). Limitations: A limitation of this study was its cross-sectional design. Conclusion: Greater recruitment of the medial and superior prefrontal cortex during implicit emotion processing in high-risk versus affected twins may represent a compensatory or resilience mechanism. In contrast, aberrant neural response to emotional faces does not seem to be a risk endophenotype for affective disorders.

Hippocampal subfield morphology in monozygotic twins discordant for affective disorders.

Unipolar and bipolar disorders aggregate in families and have been associated with a reduced gray-matter volume in hippocampal and prefrontal cortex. Here we used structural MRI to clarify whether abnormalities in hippocampal subfield and prefrontal cortical morphology are associated with familial vulnerability (i.e., changes present both in patients and unaffected relatives compared to healthy individuals), resilience (i.e., changes differentiating unaffected relatives and patients), or sequalae of illness in a sample of monozygotic twins. We investigated regional differences in gray-matter volume extracted using FreeSurfer 6.0 between remitted affected twins (AT) with either unipolar or bipolar disorder (n = 67), unaffected discordant co-twins (UT, n = 39), and low-risk twins (LT, n = 31) with no personal or first-degree family history of affective disorders. The UT showed greater bilateral hippocampal volumes compared to AT. Between group differences in left hippocampal volume were driven by greater cornu ammonis 1-3 and 4, subiculum and subfield of dentate gyrus. For the right hippocampus, differences were driven by greater hippocampal tail and subiculum. There was a trend for UT having a larger left hippocampus than LT, but no significant differences in hippocampal volumes between AT and LT. Outside the hippocampus, AT showed a smaller volume of left dorsomedial prefrontal cortex compared to LT. Our results suggest that larger volume of specific hippocampal subfields may be associated with resilience in healthy relatives of patients with an affective illness. Moreover, a smaller volume of left dorsomedial prefrontal cortex may reflect a sequalae of illness.

Emotional cognition subgroups in mood disorders: Associations with familial risk.

Patients with mood disorders show heterogeneity in non-emotional cognition. However, it is unclear whether emotional cognition (EC) is characterised by similar heterogeneity. We aimed to investigate the heterogeneity in EC among remitted patients with mood disorders and explore its association with familial risk. Data from 269 partially or fully remitted patients with mood disorders, 87 of their unaffected relatives (UR) and 203 healthy controls (HC) were pooled from two cohort studies. Hierarchical cluster analysis was conducted using the EC data from patients. UR were categorised into groups consistent with their affected relatives' cluster assignment. Clusters were compared to HC on EC, non-emotional cognition, clinical characteristics and functioning.  We identified three clusters: an 'emotionally preserved' (57%), an 'emotionally blunted' (26%) and an 'emotionally volatile' cluster (17%). 'Emotionally blunted' and 'emotionally volatile' patients also presented more deficits in non-emotional cognition (global cognition read z=-0.3 and -0.5 respectively). Relatives of 'emotionally preserved' patients were more successful at dampening negative emotions (p=.01, d=0.39, 95% CI [-0.76,-0.09]), whereas UR of 'emotionally impaired' patients underperformed in verbal fluency (p=.03, d=0.46, 95% CI [.03, 0.68]) compared to HC. The existence of impaired EC groups in remitted mood disorder highlights a need to screen for and treat EC in mood disorders. Improved ability to dampen emotions in UR of 'emotionally preserved' patients may reflect a resilience marker while impaired verbal fluency in UR of 'emotionally impaired' patients may reflect distinct genetic risk profiles in these EC subgroups.

S100B and brain derived neurotrophic factor in monozygotic twins with, at risk of and without affective disorders.

BACKGROUND: The calcium binding protein S100B and brain derived neurotrophic factor (BDNF) are both biomarkers implicated in neuronal processes in the central nervous system and seem to be associated with affective disorders. Here we investigated both markers in a sample of monozygotic (MZ) twins with, at risk of and without affective disorders, aiming to evaluate whether these markers have a role as causal factors- or trait markers for affective disorders. METHOD: We measured serum S100B and plasma BDNF levels in 204 monozygotic twins (MZ) with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). RESULTS: No significant group differences in S100B and BDNF levels were found between the three groups. Exploratory analysis revealed that higher S100B levels were correlated with lower cognitive performance. LIMITATIONS: The cross-sectional design cannot elucidate the two neuronal biomarkers role as causal factors. We would have preferred a higher sample size in the high- and low-risk groups. CONCLUSION: The present result did not support a role for S100B and BDNF as neither causal factors nor trait markers for affective disorders. Elevated S100B levels may associate with impaired cognition, but further studies are warranted.

Emotional Mental Imagery Abnormalities in Monozygotic Twins With, at High-Risk of, and Without Affective Disorders: Present in Affected Twins in Remission but Absent in High-Risk Twins.

Background: Mental imagery abnormalities feature across affective disorders including bipolar disorder (BD) and unipolar depression (UD). Maladaptive emotional imagery has been proposed as a maintenance factor for affective symptomatology and a target for mechanism-driven psychological treatment developments. Where imagery abnormalities feature beyond acute affective episodes, further opportunities for innovation arise beyond treatments, such as for tertiary/relapse prevention (e.g., in remitted individuals) or primary prevention (e.g., in non-affected but at-risk individuals). The aim of our study was to investigate for the first time the presence of possible mental imagery abnormalities in affected individuals in remission and at-risk individuals for affective disorders using a familial risk design. Methods: A population-based cohort of monozygotic twins was recruited through linkage between the Danish national registries (N=204). Participants were grouped as: affected (remitted BD/UD; n = 115); high-risk (co-twin with history of BD/UD; n = 49), or low-risk (no co-twin history of BD/UD; n = 40). Twins completed mental imagery measures spanning key subjective domains (spontaneous imagery use and emotional imagery) and cognitive domains (imagery inspection and imagery manipulation). Results: Affected twins in remission reported enhanced emotional mental imagery compared to both low- and high-risk twins. This was characterized by greater impact of i) intrusive prospective imagery (Impact of Future Events Scale) and ii) deliberately-generated prospective imagery of negative scenarios (Prospective Imagery Task). There were no significant differences in these key measures between affected BD and UD twins in remission. Additionally, low- and high-risk twins did not significantly differ on these emotional imagery measures. There were also no significant differences between the three groups on non-emotional measures including spontaneous imagery use and cognitive stages of imagery. Conclusions: Abnormalities in emotional prospective imagery are present in monozygotic twins with affective disorders in remission-despite preserved cognitive stages of imagery-but absent in unaffected high-risk twins, and thus do not appear to index familial risk (i.e., unlikely to qualify as "endophenotypes"). Elevated emotional prospective imagery represents a promising treatment/prevention target in affective disorders.

Neural response during emotion regulation in monozygotic twins at high familial risk of affective disorders.

PURPOSE: We investigated the neural correlates of emotion regulation and -reactivity in adult unaffected monozygotic twins with a co-twin history of unipolar or bipolar disorder (high-risk), remitted or partially remitted twins with a personal history of unipolar or bipolar disorder (affected) and twins with no personal or first-degree family history of unipolar or bipolar disorder (low-risk). METHODS: We assessed 37 high-risk, 56 affected and 28 low-risk participants. Participants viewed unpleasant and neutral pictures during functional magnetic resonance imaging and were instructed to down-regulate their emotional response through reappraisal or mental imagery, as well as to maintain the elicited emotion. RESULTS: After adjusting for subsyndromal depressive symptoms, bilateral supplementary motor areas, posterior dorsal anterior cingulate cortices and the left frontal eye field showed less activity during reappraisal of unpleasant pictures in high-risk than low-risk participants. Notably, affected participants did not differ from high-risk or low-risk participants in neural response during reappraisal. There were no group differences in ventrolateral prefrontal cortex seed based functional connectivity during reappraisal or neural response during mental imagery or emotional reactivity. CONCLUSION: Lesser response in dorsal midline areas might reflect familial risk related abnormalities during down regulation of emotional reactivity through reappraisal.

Clinical Characteristics, Life Adversities and Personality Traits in Monozygotic Twins With, at Risk of and Without Affective Disorders.

Background: Affective disorders have a long-term impact on psychiatric health and are caused by multiple interacting factors including familial risk, childhood adversity, life events and personality traits. Methods: In this study, monozygotic twins (MZ) at familial risk (indexed by affective disorder in their co-twin; high-risk group), affected MZ twins (indexed by a diagnosis with affective disorder) and MZ twins with no family history of affective disorder (low-risk group) were identified through cross-linking of nation-wide Danish registers. In total, 204 MZ twins were included and psychopathology, personality traits and life adversity were evaluated by semi-structured interviews and questionnaires. Results: Affected MZ twins presented with more subclinical affective symptoms and were functionally impaired as evidenced by higher unemployment rates and reduced functional status. The affected and the high-risk groups reported more childhood adversity and had experienced more stressful life events than the low-risk group. A direct comparison within the discordant twin pairs showed that the high-risk twins presented fewer affective symptoms, better functional status, more extraversion and lower neuroticism scores than their affected co-twins although they had equal levels of life adversity as their affected co-twins. Conclusion: These findings add to the evidence indicating that patients experience higher neuroticism, persistent subclinical symptoms and reduced socio-occupational function after affective episodes. Additionally, neuroticism and extraversion seem capable of moderating the sensitivity to exposure from the environment.

The search for neuroimaging and cognitive endophenotypes: A critical systematic review of studies involving unaffected first-degree relatives of individuals with bipolar disorder.

The phenomenology and underlying pathophysiology of bipolar disorder (BD) are heterogeneous. The identification of putative endophenotypes for BD can aid in the investigation of unique patho-etiological pathways, which may lead to the development of personalised preventative and therapeutic approaches for this multi-faceted disorder. We included original studies involving unaffected first-degree relatives of BD patients (URs) and a healthy control (HC) comparison group with no first-degree family history of mental disorders, investigating: 'cold' and 'hot' cognition and functional and structural neuroimaging. Seventy-seven cross-sectional studies met the inclusion criteria. The present review revealed that URs in comparison with HCs showed: (i) widespread deficits in verbal memory, sustained attention, and executive function; (ii) abnormalities in the reactivity to and regulation of emotional information along with aberrant reward processing, and heightened attentional interference by emotional stimuli; and (iii) less consistency in the findings regarding structural and resting state neuroimaging, and electrophysiological measures.