Neural and cognitive response to emotional faces in dizygotic twins at familial risk of depression



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Face processing in twins at risk of depression


Title: Differences in neural and cognitive response to emotional faces in middle-aged dizygotic twins at familial risk of depression

Short title: Face processing in twins at risk of depression

Authors: Miskowiak, KW, Svendsen, AMB, Harmer, CJ, Elliott, R, Macoveanu, J, Siebner, HR, Kessing, LV, Vinberg, M.



Affiliations:

KWM, AMBS, JM, LVK, MV: Department of Psychiatry, Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Emails: kamilla@miskowiak.dk, anne.marie.bejerholm.svendsen@regionh.dk, Julian.macoveanu@regionh.dk, lars.vedel.kessing@regionh.dk, maj.vinberg@regionh.dk

CJH: Department of Psychiatry, University of Oxford, Email: Catherine.harmer@psych.ox.ac.uk

RE: Institute of Brain, Behaviour and Mental Health, University of Manchester, Email: rebecca.elliott@manchester.ac.uk

HRS, JM, KWM: Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark, Email: hartwig.siebner@drcmr.dk

HRS: Department of Neurology, Copenhagen University Hospital Bispebjerg



Word count abstract: 200

Word count article: 4,568

Number of tables/figures: 2/3

Corresponding author:

Kamilla Woznica Miskowiak

Psychiatric Centre Copenhagen, Rigshospitalet

Copenhagen University Hospital, Blegdamsvej 9

DK-2100 Copenhagen

Email: Kamilla@miskowiak.dk



Key words: Depression, emotional processing, twins, endophenotype, fMRI

Abstract

Background

Negative bias and aberrant neural processing of emotional faces are trait-marks of depression but findings in healthy high-risk groups are conflicting.  



Methods

Healthy middle-aged dizygotic twins (N=42) underwent functional magnetic resonance imaging (fMRI): 22 twins had a co-twin history of depression (high-risk) and 20 were without co-twin history of depression (low-risk). 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. 



Results

Unexpectedly, high-risk twins showed reduced fear vigilance and lower recognition of fear and happiness relative to low-risk twins. During face processing in the scanner, high-risk twins displayed distinct negative functional coupling between the amygdala and ventral prefrontal cortex and pregenual anterior cingulate. This was accompanied by greater fear-specific fronto-temporal response and reduced fronto-occipital response to all emotional faces relative to baseline. The risk groups showed no differences in mood, subjective state or coping.



Conclusions

Less susceptibility to fearful faces and negative cortico-limbic coupling during emotional face processing may reflect neurocognitive compensatory mechanisms in middle-aged dizygotic twins who remain healthy despite their familial risk for depression.


Key words: Twins, high-risk, resilience, fMRI, emotional faces Introduction

Major depressive disorder (MDD) is a chronic, recurring and severe mental illness. Identification of endophenotypes – illness biomarkers that are independent of the clinical state, heritable and follow a familial association – is therefore pivotal for deeper insights into the etiology of MDD and early prevention strategies (Hasler et al. 2004).

Emerging evidence highlights aberrant neurocognitive processing of emotional faces as a candidate endophenotype for MDD. Patients with MDD show greater attention to and recognition of negative (fearful and/or sad) relative to positive (happy) facial expressions (for review, see Bourke et al. 2010). This is accompanied by hyper-activity to negative faces in limbic regions including amygdala, fusiform gyrus, insula, and subgenual anterior cingulate cortex (sgACC) as well as hypo-activity in the medial, inferior and dorsolateral prefrontal cortex (PFC), supragenual ACC, insula and superior temporal cortex (Fitzgerald, Laird, Maller & Daskalakis, 2008; Stuhrmann et al. 2011). Patients also show hypo-activity to happy faces in limbic regions, fusiform gyrus and insula (Stuhrmann et al. 2011). This imbalance in neural activity is accompanied by reduced functional coupling (i.e, correlation of regional neural activity over time) between nodes of a cortico-limbic network including amygdala, medial PFC (mPFC) and pregenual ACC (pgACC) during negative face processing (Anand et al. 2005; Chen et al. 2008; Dannlowski et al. 2009; Erk et al. 2010; Kong et al. 2013; Matthews et al. 2008). This disruption of cortico-limbic FC is associated with greater depression severity (Dannlowski et al. 2009; Matthews et al. 2008) and longer illness course (Dannlowski et al. 2009). Limbic over-responsiveness and defective prefrontal top-down control of emotional reactivity to negative faces have therefore been hypothesised to constitute a pathophysiological mechanism in MDD (Phillips et al. 2008).

Negative face processing bias can be observed after clinical remission of depression. Remitted patients show greater attention to and recognition of negative facial expressions (Bhagwagar et al. 2004; Joormann & Gotlib, 2007; LeMoult et al. 2009) and hyper-activity to negative faces in the amygdala (Neumeister et al. 2006; Victor et al. 2010), dorsolateral PFC (dlPFC) and caudate (Norbury et al. 2009; Thomas et al. 2011). They also display more negative FC (i.e, anticorrelations) between amygdala and ventral frontal regions including the orbitofrontal cortex during negative face processing (Goulden et al. 2012).  However, studies in healthy first-degree relatives of patients with MDD are scarce and yielded conflicting results. While one study reported faster recognition of fearful expressions in healthy relatives (Le et al. 2007), other studies - including a study by our group in healthy monozygotic (MZ) twins at familial risk for MDD - found no such facial expression recognition bias (Mannie et al. 2007; Miskowiak et al. 2015). Nevertheless, our high-risk MZ twins did show increased attentional vigilance towards subliminally processed fearful faces and general facial expression recognition difficulties (Miskowiak et al. 2015). Functional MRI investigations of first-degree relatives have also produced equivocal results; fearful faces produced dlPFC hypo-activity but no aberrant amygdala reactivity in a study of young off-spring of MDD patients (Mannie et al. 2011), while amygdala hyper-activity to negative faces was reported in another study (Monk et al. 2008). Our MZ high-risk twins showed increased fronto-parietal reactivity and stronger anticorrelations between nodes of a distributed fronto-limbic-parietal network during emotional face processing (Miskowiak et al. 2015). This suggests that aberrant neural response to emotional faces in individuals at familiar risk for MDD represents compensatory mechanisms for heightened sensitivity to negative faces. However, given the scarcity of studies there is a need for additional studies in healthy individuals at familial risk.



Complementing our previous study in 30 MZ twins (Miskowiak et al. 2015), we conducted an independent study with a similar design in 42 healthy, never-depressed dizygotic (DZ) twins with or without co-twin history of depression (high-risk vs. low-risk groups). This enables insight into neurocognitive markers of familial risk in an ‘intermediate high-risk group’ with more shared environment than singletons but less similar genetic makeup than MZ twins. We hypothesized that the DZ high-risk twins compared with DZ low-risk twins would display negative bias in behavioural and neural response to emotional faces, as reflected by: (i) greater vigilance to and/or recognition of fearful faces, (ii) greater neural response to fearful faces in prefrontal and parietal regions without changes in amygdala activity and (iii) stronger negative FC between amygdala and the PFC and ACC during emotional face processing. Given the lower genetic load in the DZ high-risk twins, we hypothesized that the magnitude of differences in neural and behavioural response to emotional faces between high-risk and low-risk DZ twins would be smaller than those observed in MZ twins (Miskowiak et al. 2015).


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