Neural and cognitive response to emotional faces in dizygotic twins at familial risk of depression
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Exploratory correlations between stressful LEs and the behavioral and fMRI changes There was no collinearity between recent stressful life events and risk status (variation inflation factor=1.1). Given the strong trend towards more recent stressful LEs in high-risk twins, we therefore conducted post-hoc exploratory Pearson’s correlations to investigate whether observed neurocognitive differences in high-risk vs. low-risk groups were associated with the degree of adversity. More LEs correlated weakly with decreased fear vigilance across the entire sample (r(40)=-0.3, p=0.046) but not in the high-risk group alone (p≥0.1). In contrast, no correlation occurred between LEs and the recognition of fearful or happy expressions (p≥0.3). Notably, entering LEs as a covariate in the statistical models did not alter the observed effects of risk status on fear vigilance or emotion recognition (p≤0.046) and revealed no additional effects of LEs (p≥0.13). More LEs also correlated with increased fear-specific activity in the identified STG (but not mPFC) clusters across the entire cohort (left STG: r(34)= 0.4, p=0.04; right STG: r(34)=0.4, p=0.03), which was reduced to a trend-level in high-risk twins (r(15)=0.5, p=0.059 and r(15)=0.4, p=0.10, respectively). Finally, more LEs were associated with stronger amygdala-mPFC anticorrelations across the entire cohort (r(34)=-0.3, p=0.04; for amygdala-pgACC: p=0.09), which was reduced to a trend-level in high-risk twins (r(15)=-0.4, p=0.09).
DiscussionThis study investigated cognitive and neural response to emotional faces in healthy, never-depressed DZ twins at high vs. low familial risk for depression. In contrast with our hypothesis, high-risk twins showed less fear vigilance and reduced recognition of fearful and happy facial expressions than low-risk twins. This was accompanied by reduced neural response within fronto-occipital regions to emotional faces and greater response to fearful vs. happy faces in medial prefrontal and superior temporal regions. While low-risk twins showed co-activation between the left amygdala and the mPFC and pgACC, high-risk twins displayed anticorrelations between these regions, which correlated with their decreased recognition of fear. These effects occurred in the absence of differences between groups in mood, neuroticism, subjective state or coping styles. Our finding of less fear vigilance and lower sensitivity to emotional – particularly fearful – faces in DZ high-risk twins contrasts with the increased attention to and recognition of negative facial expressions in MDD (for review, see Bourke et al. 2010) and no or subtle negative face bias in other healthy individuals at familial risk (Le et al. 2007; Mannie et al. 2007; Miskowiak et al. 2015). Several studies report a bias away from threat (i.e, attention avoidance of threat) in post-traumatic stress disorder (PTSD) in the presence of imminent threat or stress (e.g. Bar-Haim et al. 2010; Wald et al. 2011) and in anxious children (for review, see Pine et al. 2015). Our DZ high-risk twins showed no sign of attention avoidance of threat but rather more indifference or possibly greater attention control than low-risk twins (i.e. no bias toward or away from fear). Given the correlation between a higher number of recent stressful LEs and more attention control across the entire cohort and a strong trend toward more stressful LEs in the high-risk group, it could be speculated that that high-risk twins’ greater attention control was acquired partially through their recent life stress. Such attention control may confer resilience – a positive adaptation to stress or adversity that makes these individuals less vulnerable to depression (Haglund et al. 2007; Rutter, 2012). Consistent with this assumption, strengthened attention control after attention control training seems to contribute to symptom reduction in PTSD (Badura-Brack et al. 2015). The pattern of neural activity that confers resilience to depression is still unclear. Disruption of FC between amygdala and ventral PFC during negative emotional processing is hypothesized to play a central role in the pathophysiology of MDD (Kong et al. 2013). Therefore, our DZ high-risk twins’ distinct cortico-limbic anticorrelations during emotional face processing –which correlated with greater attention control in the presence of fearful faces– may be a compensatory mechanism or marker of resilience that keeps them from getting depressed despite their familial vulnerability. This is similar to the greater amygdala-pgACC anti-correlations during emotional face processing in MZ twins at familial risk for depression (Miskowiak et al. 2015). In keeping with this, combat-exposed resilient individuals who did not develop post-traumatic stress showed increased medial prefrontal top-down regulation of amygdala response to emotional faces (Shin et al. 2005). We found in an exploratory posthoc analysis that more stressful LEs were associated with stronger cortico-limbic anti-correlations, suggesting that prefrontal top-down control may be strengthened through adversity. Together, these findings point to greater cortico-limbic top-down regulation of emotional reactivity as a common compensatory mechanism across distinct at-risk populations. The decreased fronto-occipital response to emotional faces in our DZ high-risk twins contrasts with exaggerated response in these regions to negative faces in MDD (Surguladze et al. 2005; Suslow et al. 2010) and to emotional faces in MZ high-risk twins (Miskowiak et al. 2015). Further, the increased fear-specific activity in our DZ high-risk twins within the mPFC, STG and insula is opposite to reduced superior temporal and insula activity to negative faces in MDD patients (Fitzgerald et al. 2008). The correlation between greater fear-related mPFC-STG activity and more LEs suggests that this compensatory mechanism may be strengthened by exposure to stress in twins who remained healthy despite their familial risk. A strength of the study was the thorough longitudinal assessments of participants over several years prior to this study, which enabled inclusion of only healthy, never-depressed twins. A limitation was the modest sample size (N=42) and hence possibly limited generalizability. Another potential limitation is the relatively high age (50 years) of our high-risk twins. The participants had thus passed the major risk periods for MD onset despite their familial vulnerability and stressful LEs, suggesting that they exhibited resilience rather than vulnerability to depression. We could not conduct direct comparisons of neural activity between MZ and DZ high-risk twins to disentangle genetic makeup from shared environment because of differences in the scanning parameters between the studies. It was a limitation that we did not assess alexithymia since alexithymia is associated with decreased neural activity in a broad emotion processing network to emotional stimuli (e.g., Kret and Ploeger, 2015) and could have influenced our results. Another limitation was that we did not assess childhood trauma since early life stress influences neural activity and functional connectivity in the emotion processing network (Grant et al 2015). The study is merely associative in nature given the cross-sectional design, thus highlighting a need for prospective studies to clarify whether the neurocognitive differences in DZ high-risk twins indeed confer resilience. Functional connectivity is also merely a correlational measure which precludes a strong inference regarding the causal direction in the connectivity. Finally, cluster-extent based thresholding in fMRI analysis has limited spatial informativeness when clusters span multiple anatomical regions due to liberal statistical thresholds (Woo et al. 2014). Despite the relatively liberal cluster-extent based statistical threshold in our exploratory whole-brain analysis (Z=2.0, p<0.05), the identified clusters with differential activity between groups were spatially specific. Nevertheless, our results should be regarded as exploratory in nature. In conclusion, this exploratory study delineates neural and cognitive changes in DZ twins at familial risk for depression. We observed less fear vigilance and reduced recognition of negative and positive facial expressions, which was accompanied by cortico-limbic anti-correlations and decreased fronto-occipital activity to emotional faces. These findings contribute to the understanding of the neural and cognitive mechanisms of depression and resilience. Financial support The study was funded by the Danish Council for Independent Research and the Lundbeck Foundation. KWM’s salary is partially funded by the Lundbeck Foundation (R93-A8635) and the Weimann Stipend. HRS is supported by a Grant of Excellence on the control of actions “ContAct” from the Lundbeck Foundation (R59-A5399). The Simon Spies Foundation is acknowledged for donation of the Siemens Trio Scanner. Conflict of interest KWM has received consultancy fees within the last three years from Lundbeck and Allergan; MV has been a consultant for Eli Lilly, Lundbeck; Servier and Astra Zeneca; CJH has received consultancy fees from P1vital ltd, Servier, Eli-Lilly, is a company director of Oxford Psychologists ltd. and has also received grant income from GSK, Lundbeck, Servier and Astra Zeneca; HRS was within the past 3 years received honoraria as reviewing editor for Neuroimage, as speaker for Biogen Idec Denmark A/S, and scientific Advisor for Lundbeck; LVK has within the last three years been a consultant for Lundbeck, AstraZeneca and Servier. All other authors report no biomedical financial interests or potential conflicts of interest. 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