Subtle behavioural responses during negative emotion reactivity and down-regulation in bipolar disorder: A facial expression and eye-tracking study

Accepted Manuscript

Subtle behavioural responses during negative emotion reactivity and down-regulation in bipolar disorder: A facial expression and eye-tracking study Ingrid Broch-Due , Hanne Lie Kjærstad , Lars Vedel Kessing , Kamilla Miskowiak PII: DOI: Reference:

S0165-1781(17)31491-9 10.1016/j.psychres.2018.04.054 PSY 11383

To appear in:

Psychiatry Research

Received date: Revised date: Accepted date:

10 August 2017 1 March 2018 22 April 2018

Please cite this article as: Ingrid Broch-Due , Hanne Lie Kjærstad , Lars Vedel Kessing , Kamilla Miskowiak , Subtle behavioural responses during negative emotion reactivity and downregulation in bipolar disorder: A facial expression and eye-tracking study, Psychiatry Research (2018), doi: 10.1016/j.psychres.2018.04.054

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Highlights  BD patients show aberrant facial displays of emotion when viewing unpleasant pictures  BD patients gaze away from unpleasant and neutral pictures  Gazing away may be a possible compensatory response for heightened emotional liability  These measures provide sensitive tools of abnormal emotional reactivity in BD

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Title: Subtle behavioural responses during negative emotion reactivity and down-regulation in bipolar disorder: A facial expression and eye-tracking study

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Authors: Ingrid Broch-Due†, Hanne Lie Kjærstad†, Lars Vedel Kessing, Kamilla Miskowiak*

Affiliations: The Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen,

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Denmark.

* Corresponding author: Kamilla Woznica Miskowiak, CADIC, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Email:

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[email protected]

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Word count: 3792 words

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† Joint first authorship

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Abstract Abnormal processing of emotional information and regulation are core trait-related features of bipolar disorder (BD) but evidence from behavioural studies is conflicting. This study aimed to investigate trait-related abnormalities in emotional reactivity and regulation in BD using novel

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sensitive behavioural measures including facial expressions and eye movements. Fifteen patients with BD in full or partial remission and 16 healthy controls (HCs) were given a computerised task in which they were instructed to „react to‟ unpleasant and neutral pictures or „dampen‟ their emotional response to aversive pictures. Participants rated their emotional response after each

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picture block, and eye-movements and facial expressions were recorded. Patients generally gazed less at unpleasant and neutral pictures during emotion processing and regulation. During emotional reactivity, patients exhibited stronger facial expressions to neutral pictures, a lack of facial expressions to unpleasant pictures, and more surprised facial expressions to both neutral and

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unpleasant pictures compared to HCs. The results point to subtle abnormalities in visual gaze

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patterns and facial displays of emotion between patients with BD during emotion processing and regulation. Aberrant eye-movements and facial displays seem to could provide a more sensitive

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measure of emotional reactivity in BD than traditional behavioural measures, which could aid future diagnostic accuracy.

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Key words: hot cognition; emotion regulation; emotion processing; eye-tracking; facial expression

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1. Introduction Bipolar disorder (BD) is a chronic psychiatric disorder characterised by recurrent affective episodes of mania and depression and high rates of misdiagnosis (Goodwin and Jamison, 2007). Difficulty with emotion regulation is a key feature of BD that contributes to poor psychosocial outcomes and

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occupational functioning (Aparicio et al., 2017; Van Rheenen and Rossell, 2014). The genetic origins of BD is still unclear, partly due to patho-etiological heterogeneity (Kerner, 2015) and complex gene-environment interactions (Uher, 2014), and thus the pathophysiology of the illness remains elusive (Miskowiak et al., 2016). As such, the identification of endophenotypes (i.e.,

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intermediate phenotypes) provides a promising avenue for improved understanding of the

psychopathology of BD. Endophenotypes are highly heritable disease-associated traits, present regardless of illness phase, and found in non-affected family members to a greater extent than in the general population (Gershon and Goldin, 1986; Gottesman and Gould, 2003; Leboyer et al., 1998).

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The identification of endophenotypes of BD has the potential to enhance the development of novel

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targeted treatments and improve diagnostic accuracy (Hasler et al., 2006; Kerner, 2015; Miskowiak et al., 2016).

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Emerging evidence indicates that aberrant emotion regulation represents a putative endophenotype of BD (Miskowiak et al., 2016). That is, deficits in emotion regulation is present

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during acute episodes (de Almeida and Phillips, 2013; Phillips et al., 2008), periods of remission

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(Townsend et al., 2013), as well as in genetically predisposed unaffected relatives of patients with BD (Kanske et al., 2015). In fact, functional magnetic resonance imaging (fMRI) studies have consistently reported aberrant frontolimbic response during emotion reactivity and regulation and in patients with BD and high-risk populations (Miskowiak et al., 2016; Phillips et al., 2008; Townsend and Altshuler, 2012). While neuroimaging is a sensitive method to detect subtle neural changes, it is unfeasible for diagnostic evaluations in routine clinical practice. Moreover, subjective measures of

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emotion regulation have generally failed to show any abnormalities in patients with BD (e.g., Gruber et al., 2014; Hay et al., 2015; Kanske et al., 2015; Morris et al., 2012). This is likely due to lack of sensitivity of these self-report measures. There is therefore a need for research into improved, cost-effective measures with sensitivity to detect abnormalities in the reactivity to and

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regulation of emotions in BD. Sensitive behavioural techniques such as eye-tracking and facial expression analysis have the potential to yield more cost-efficient and detailed insight into emotion reactivity and regulation than traditional behavioural (i.e., accuracy and response times) or subjective (i.e., self-report)

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measures. Eye movements and fixations provide information about the cortical mechanisms underlying cognitive functions (Henderson and Ferreira, 2013; Hutton, 2008). Previous research has revealed unique patterns of attention in UD and anxiety (Armstrong and Olatunji, 2012), as evidenced by increased vigilance (i.e., gaze) towards threat-related stimuli and mood-congruent

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maintenance of gaze, respectively. Further, two recent eye-tracking studies found that patients with

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BD, regardless of illness phase, showed increased attention to threatening images (but not emotional faces) compared to HCs (García-Blanco et al., 2014; Peckham et al., 2016). Another

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promising behavioural tool that has received little attention in BD research is facial displays of emotion. Facial expressions are crucial for social interaction and can contribute to emotion

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regulation difficulties (Davies et al., 2016). Indeed, research using the Facial Action Coding System

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(FACS) on patients with unipolar depression (UD) has shown differential facial displays of emotions to negative and positive stimuli in the absence of self-reported emotion differences in UD (Gehricke and Shapiro, 2000; Sloan et al., 1997). Furthermore, diminished subjective emotional reactivity combined with lower frequency and intensity of facial expressions to pleasant stimuli has also been reported in UD (Sloan et al., 2001). Only three published studies have assessed facial displays of emotion in BD in response to emotional stimuli (Gruber et al., 2011; Gruber et al., 2014;

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Gruber et al., 2008). These found no group differences in facial expressions between BD and HCs. However, the studies assessed facial displays of happiness and sadness (Gruber et al., 2011), or composite positive and negative facial expressions (Gruber et al., 2014; Gruber et al., 2008). Including a wider array of display of emotions is likely to reveal greater sensitivity to more subtle

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differences in facial expressivity in BD. Taken together, there is emerging evidence to suggest that a multidisciplinary approach that combines subtle behavioural (eye-tracking and facial expressions) and subjective responses during emotion reactivity and regulation can provide sensitive and cost effective measures of aberrant

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emotion processing in BD. This exploratory study therefore aimed to investigate whether there are trait-related behavioural differences in emotional reactivity and ability to downregulate emotion in symptomatically stable patients with BD utilising a novel combination of these new techniques and subjective measures. We hypothesised that patients with BD in full or partial remission would

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exhibit aberrant eye-movement patterns and facial expressiveness during reactions to unpleasant

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stimuli to and attempts to down-regulate negative emotions in the absence of differences in (the less

2. Methods

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sensitive) self-report measures of emotion reactivity.

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2.1 Participants and Screening

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Patients with BD, in partial or full remission, and HCs, with no personal or first-degree familial history of psychiatric illness, were recruited for this study between September 2016 and January 2017. Patients with BD were recruited consecutively from Clinic for Affective Disorders, Psychiatric Centre Copenhagen, as part of a larger study of neurocognitive, brain-based biomarkers in newly diagnosed patients with BD, the Bipolar Illness Onset Study (Kessing et al., 2017). Controls were recruited through advertisements on relevant websites and through the Copenhagen

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University Hospital blood bank as in previous studies (Jacoby et al., 2016; Munkholm et al., 2014). Patients with BD were screened with Schedules for Clinical Assessment in Neuropsychiatry (SCAN) to confirm ICD-10 diagnosis. Additionally, all participants were screened with the 17-item Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960) and Young Mania Rating Scale

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(YMRS) (Young et al., 1978) to ensure full or partial remission (scores of ≤14 on both measures) (see demographics Table 1). Written informed consent was obtained prior to participation. The BIO study was approved by the regional ethics committee (H-7-2014-007) and data protection agency

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(RHP-2015-023).

2.2 Procedure

Participants who fulfilled the inclusion criteria were invited to take part in one assessment at the Psychiatric Centre Copenhagen, Copenhagen University Hospital, which lasted approximately two

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hours as part of the BIO study. At the end of this test session, they were given a set of computerised

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cognitive tests and their eye movements and facial emotion expressions were measured. First, eye movements were calibrated using a seven-point calibration at the start of the task. Participants were

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instructed to breathe normally and find a comfortable position. Due to the combination of facial expression and eye-tracking measures, they were also instructed to not look away from the

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screen during the task.

2.3 Experimental paradigm A total of 48 highly unpleasant pictures and 24 neutral pictures from the International Affective Picture System (IAPS) (Lang et al., 2008) were shown one at a time on a laptop screen for each four seconds (see Table S1 for IAPS picture numbers). The participants were instructed to either „view‟ the images or to „dampen‟ their emotional response. They were however not specifically

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instructed as to which emotion regulation strategy to use. The lack of specific instructions as to how to down-regulate emotions was chosen to increase the likelihood of participants using emotion regulation strategies that resemble how they would regulate emotions in everyday life. Hence, tThe task consisted of three conditions: View Neutral, View Negative, and Dampen

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Negative. Pictures selected for the two negative conditions were matched on valence and arousal (see Table 1).

Each condition consisted of 24 images, presented in six randomised blocks of four images. Each image was exposed individually for four seconds. Randomisation of the blocks of images was

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conducted prior to testing and the sequence of images was equal for all participants. The task was administered on a Lenovo T340 laptop computer with a 13” screen using iMotions software platform version 6.1.

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2.4 Measures

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2.4.1 Self-Report

Following each block of four images, participants were asked to rate the intensity of their subjective

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experience of negative/unpleasant emotions on a 100-point visual analogue scale (VAS) ranging

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from „none‟ to „a lot‟.

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2.4.2 Eye-tracking

Fixation count, total fixation duration, and gaze time (total time spent viewing, including fixations), were measured using a Tobii X2-30 eye-tracker with a sampling rate of 30Hz. The eye-tracker uses infrared illuminators that generate reflection patterns in the corneas of the eyes of the participants (Tobii Pro, Sweden). Eye-tracking data for fixation count, total fixation time in percentage, and gaze time in percentage was extracted from the raw data using the iMotions software. A duration

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dispersion algorithm, namely dispersion threshold identification (I-DT) (Komogortsev et al., 2010) with a A minimum fixation duration threshold of 100ms allowing 1 degree radius change with at least 50% of samples available was applied. This ensured that a fixation would be identified as valid only if 50% or more of participants gaze data was available. Eye-tracking

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data for whole-image-analysis and for areas of interest (AOI) were extracted and analysed. Areas of interest were obtained manually and used as a tool to compare gaze and fixation locations between the two groups. The AOIs were defined through generating fixation heat maps for the HC group. Heat map generation is a visual analysis tool available through the iMotions software

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that allows identification of particular AOIs for further analysis.

2.4.3 Facial Expression

Facial expressions were measured using the Affectiva Affdex algorithm. The Affdex system

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identifies and follows precise locations on the participants‟ face (action units) and maps facial

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expressions to emotions built on the EMFACS (Affectiva, USA) (Ekman and Friesen, 1978). Based on action unit activation the Affdex system classifies the following seven emotions: anger, sadness,

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disgust, fear, joy, surprise, and contempt and also computes measures for valence and engagement, a measure of facial expressiveness (Table 2) (iMotions, Denmark; Affectiva, USA). Facial

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expression data was extracted from the raw data for the following emotions: anger, sadness, disgust,

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fear, joy, and surprise. Contempt was omitted from analysis due to current limited reliability (iMotions, Denmark). Additionally, data for engagement/expressiveness and valence of facial expressions were obtained. Raw data corresponding to the six mentioned emotions and engagement/expressiveness were computed to obtain a binary result within the iMotions software platform with a threshold of 10, meaning that only facial expressions with at least a 10% probability of a human assessor rating the emotion equally to the Affdex algorithm were accepted. The

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threshold was set to capture subtle changes in facial expressions evoked by images displayed only four seconds each. Data for positive and negative facial expressions were calculated using a threshold of 30. Note that the thresholds do not refer to an absolute presence or absence of an emotion or facial expression but to a probability of the facial emotion/valence displayed by the

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participant. The thresholds were set according to software platform defaults due to a paucity of comparable previous research utilising computerised facial expression analysis. Expressions that did not reach either threshold were treated as neutral or as a lack of facial expressions. All facial expression data were calculated as the percentage of time the participants displayed the

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particular facial expression within each condition.

2.4.4 Quality assurance: Eye-tracking quality and eyelid closure

Eye-tracking quality (i.e., the amount of valid gaze data that was recorded) and time (%)

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eyelid closure were measured with the Tobii X2-30 eye-tracker and the Affdex system,

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2.5 Statistical analysis

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respectively, and extracted from the iMotions software.

Emotional reactivity was examined using repeated-measures analyses of variance (ANOVA) with

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condition (view neutral vs. view negative) as the within-subjects factor and diagnostic group (BD,

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HC) as between-subjects factor. Emotion regulation (i.e., degree to which participants were able to successfully down-regulate their emotional responses) was analysed with repeated measures ANOVAs with condition (view negative vs. dampen negative) as within-subjects factor and group as between-subjects factor. For statistically significant interactions, we conducted (i) follow-up independent samples t-tests for normally distributed data, or Mann-Whitney U test for non-normally distributed data, to examine to origin of the interaction; (ii) post-hoc analyses of covariance

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(ANCOVA) adjusting for differences in depressive and manic symptoms, respectively; and (iii) Pearson‟s correlation analyses between the relevant dependent variables and mood symptoms to assess whether the interaction was influenced by subsyndromal symptoms in the BD group. Analyses were performed with Statistical Package for Social Sciences (SPSS, version 22.0). All

reported as partial eta squared (ƞp2) and Cohen's d.

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3. Results

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effects are reported as significant at ps≤0.05 (two-tailed), and effect sizes for significant results are

3.1 Participant characteristics

A total of 18 patients and 19 HCs who fulfilled the inclusion criteria were enrolled. Four Six participants (two three HCs and threetwo patients with BD) were excluded during analysis due to

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incomplete data. Patients with BD and HCs were well-matched for age (p>0.56), gender (p>0.58),

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and years of education (p>0.30). As expected, patients with BD scored higher than HCs on

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measures of depression (p<0.001) and mania (p=0.02) symptoms (Table 1).

3.2 Emotional reactivity

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3.2.1 Main effect of task

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Unpleasant pictures evoked more negative subjective emotions than neutral pictures across all participants (F(1,27)=101.86, p<0.001, ƞp2=0.79), indicating that the affective manipulation was indeed successful (Table 2). In general, participants gazed more (F(1,29)=19.19, p<0.001, ƞp2=0.40), fixated more (F(1,29)=10.95, p=0.003, ƞp2=0.27), and exhibited a trend towards longer fixations (F(1,29)=2.88, p=0.10), when viewing negative compared to neutral images. Further, there was a trend towards unpleasant pictures evoking more sad (F(1,29)=3.48, p=0.072) and general

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negative (F(1,29)=3.58, p=0.068) facial expressions than neutral pictures. There was no effect of unpleasant vs. neutral pictures on measures of engagement, anger, disgust, joy, surprise, fear, general positive, or general neutral facial expressions (ps≥0.12).

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3.2.2 Group comparisons As expected, there were no significant differences between groups or group-by-task interaction on self-reported emotional reactions to the affective pictures (ps≥0.64).

Whole-image eye-tracking analysis revealed a group by condition interaction for gaze

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(F(1,29)=7.20, p=0.012, ƞp2=0.20), driven by patients with BD gazing significantly less at both neutral (t=2.82, df=20.42, p=0.010, Cohen‟s d=1.02) and negative (t=2.09, df=29, p=0.045, Cohen‟s d=6.86) images (Figure 2A). This interaction was reduced to a trend when controlling for depressive (F(1,28)=2.87, p=0.10) and mania (F(1,28)=3.95, p=0.057) symptoms. Moreover, more

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depressive symptoms correlated with less gaze during viewing of neutral (r=-0.36, df=31, p=0.049)

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but not negative images (p>0.15), while more mania symptoms correlated with less gaze during viewing of both neutral (r=-0.47, df=31, p=0.007) and negative images (r=-0.43, df=31, p=0.017).

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No group differences were found for fixation time or fixation count (ps≥0.21). The facial expression analysis revealed a significant main effect of group for facial

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expressions of surprise (F(1,29)=4.31, p=0.047, ƞp2=0.13), but no significant interaction (p>0.16).

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This group difference was driven by increased surprise facial expressions exhibited by patients with BD compared to HCs when viewing all pictures. Moreover, there was a significant group by condition interaction for engagement representing greater engagement in BD patients while viewing neutral than negative pictures (F(1,29)=7.91, p=0.009, ƞp2=0.21; Posthoc Mann Whitney U test Neural: U=75.5, p=0.078; Negative: p≥0.60) (Figure 3). This significant interaction prevailed when controlling for subsyndromal mania (F(1,28)=9.23, p=0.005, ƞp2=0.25) and depressive symptoms

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(F(1,28)=4.39, p=0.045, ƞp2=0.14). Exploratory post-hoc correlational analyses showed that for all participants, engaged facial expressions correlated moderately with more subsyndromal mania symptoms when viewing neutral (r=0.54, df=31, p=0.002) and negative images (r=0.54, df=31, p=0.002). Significant group by condition interaction was also found for general neutral facial

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expressions (i.e., lack of facial emotion expressivity) (F(1,29)=4.72, p=0.0038, ƞp2=0.14; Posthoc Mann Whitney U test non-significant: ps≥0.57), suggesting that patients with BD generally lacked emotional facial expressions while viewing negative vs. neutral pictures compared to HCs (Figure 3). This interaction prevailed after controlling for subsyndromal mania symptoms (F(1,28)=5.32,

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p=0.029, ƞp2=0.16), but not depressive symptoms (p>0.23). Exploratory correlational analysis showed no significant correlations with mood symptoms (ps≥0.27). There were no differences between groups in expressions of anger, sadness, disgust, fear, or for general negative facial expressions (p>0.17). Moreover, there was also a trend towards a group by condition interaction for

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general positive and joyous facial expressions, suggesting that patients with BD may exhibit more

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positive facial expressions when viewing neutral vs. negative images compared to HCs (general

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positive: F(1,29)=3.47, p=0.073; joy: F(1,29)=2.91, p=0.099).

3.3 Emotion down-regulation

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3.3.1 Main effect of task

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As expected, participants generally reported less negative emotion subsequent to dampening their emotional responses vs. simply viewing the unpleasant images (F(1,27)=38.42, p<0.001, ƞp2=0.59). Participants gazed significantly less (F(1,29)=22.22, p<0.001, ƞp2=0.43), had lower numbers of fixations (F(1,29)=12.95, p=0.001, ƞp2=0.31), and spent less time fixating (F(1,29)=9.69, p=0.004, ƞp2=0.25) at AOIs when dampening vs. viewing negative images. Whole-image analyses revealed no significant main effect of task for gaze (p>0.35), time fixating (p>0.19), or total number of

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fixations (p>0.19). Finally, dampening emotional responses to unpleasant pictures also produced statistically significantly decreased facial expressiveness (i.e., engagement) (F(1,29)=6.21, p=0.019, ƞp2=0.18) and facial expressions of sadness (F(1,29)=4.33, p=0.046, ƞp2=0.13), and a trend towards less angry facial expressions (F(1,29)=3.55, p=0.070) than in the passive viewing conditions. No

negative, and general neutral facial expressions (ps≥0.29).

3.3.2 Group comparisons

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significant change was found for disgust, joy, surprise, fear, as well as general positive, general

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There were no significant group differences on self-reported negative emotion when dampening vs. viewing negative images (ps≥0.43). However, patients with BD gazed less at all unpleasant pictures than HCs, independently of the given instruction („dampen‟ and „view‟; i.e., main effect of group) (whole image: F(1,29)=4.18, p=0.050, ƞp2=0.13; AOI: F(1,29)=3.19, p=0.084) (Figure 2B). No

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group differences were found for fixation time or total number of fixations when viewing AOIs

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(ps≥0.11) or whole images (ps≥0.19). There were also no significant group differences on facial

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expressions when dampening vs simply viewing negative images (ps≥0.12).

3.4. Data quality analysis

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3.4.1. Emotional reactivity

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3.4.1.1. Main effect of task There was a main effect of task for data quality (F(1,29)=26.16, p<0.001, ƞp2=0.47), suggesting the amount of valid gaze data recorded from participants was generally lower when viewing neutral compared to negative images. There was also a trend towards a statistically significant main effect of task for eye-lid closure (F(1,29)=3.81, p=0.061) as participants generally closed their eyes more when viewing negative compared to neutral images.

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3.4.1.2. Group differences There was a group by condition interaction for eye-tracking quality (F(1,29)=9.16, p=0.005, ƞp2=0.24), driven by poorer eye-tracking quality in patients with BD when instructed to view neutral (t=2.96, df=21.78, p=0.007, Cohen’s d=1.07) and negative (t=2.23, df=29, p=0.033,

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Cohen’s d=0.80) pictures. A group by condition interaction was also found for eyelid closure (F(1,29)=5.21, p=0.030, ƞp2=0.15): relative to HCs, patients with BD were more likely to close their eyes when instructed to view neutral images (t=2.14, df=29, p=0.041, Cohen’s d=0.76), but not negative images (p>0.44).

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3.4.2. Emotion down-regulation 3.4.2.1. Main effect of task

There was no statistically significant main effect of task for data quality (p>0.77) nor eye-lid closure (p>0.97).

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3.4.2.2. Group differences

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The data quality analysis revealed a statistically significant main effect of group (F(1,29)=4.46, p=0.044, ƞp2=0.13), but no significant interaction (p>0.80), suggesting that eye-

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tracking quality for patients with BD was overall lower than that for HCs. There were no

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differences between groups on amount of time they spent closing their eyes (ps≥0.35).

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4. Discussion

The present study examined whether remitted patients with BD show trait-related abnormalities in eye-movements and facial emotion expressions during emotional reactivity to and down-regulation of emotional response to unpleasant pictures. BD patients generally gazed less at all images (unpleasant and neutral) than HCs during the emotional reactivity and - regulation. During emotional reactivity, patients exhibited stronger facial expressions (i.e., engagement) when viewing

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neutral images, a lack of facial expressions when viewing aversive images, and generally more surprised facial expressions when viewing both neutral and aversive images compared to HCs. However, contrary to our hypothesis, we found no differences between patients with BD and HCs in facial displays of emotion during emotion down-regulation. Aberrant facial expressions and eye

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gaze occurred in the absence of any differences in self-reported emotional reactivity or success of emotion regulation.

Healthy controls showed negative facial expressions while viewing unpleasant images and lacked facial expressions during neutral picture presentations, in keeping with previous evidence for

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a modulatory effect of emotion on facial expressions (see for example Niedenthal et al., 2005). In contrast, patients lacked facial expressivity when viewing unpleasant pictures, but exhibited heightened expressivity to neutral images. Patients‟ reverse displays of emotions and particularly the lack of emotion expressivity to unpleasant pictures may in part be due to their increased gazing

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away from these pictures (García-Blanco et al., 2014). This finding is particularly interesting in the

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absence of differences in total fixation time and number of fixations. Decreased gaze time suggests that when not fixating on the image, patients more often completely disengaged their attention by

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looking elsewhere or closing their eyes rather than keeping their gaze within the boundaries of the image, despite being instructed otherwise. The amount of valid gaze time recorded was lower in

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patients compared to HCs during emotion processing. Poorer eye-tracking quality reflects

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invalid recordings due to blinking, looking away from the screen, poor calibration, etc. Patients with BD were indeed found to be more likely to blink or close their eyes when viewing neutral images. As such, patients‟ visual avoidance of neutral and unpleasant scenes could represent an automatic response to compensate for heightened emotional reactivity (Kashdan et al., 2006). Patients‟ increased facial response to neutral pictures is in accordance with evidence for heightened subjective emotional reactivity to neutral stimuli in patients with BD (Lemaire et al.,

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2015; M'Bailara et al., 2012; M‟Bailara et al., 2009). In contrast with our demonstration of decreased emotion expressivity to unpleasant pictures in BD, previous studies of the facial displays of emotion in response to affective stimuli showed no abnormalities in BD patients (Gruber et al., 2011; Gruber et al., 2009; Gruber et al., 2008). This discrepancy between the present and previous

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findings might be due to the novel approach used in the present study. Specifically, we assessed a greater number of facial expressions and the degree of facial expressivity, and these were evaluated digitally rather than by a human coder. Also, findings of decreased gaze time in patients with BD contrast with research by García-Blanco et al. (García-Blanco et al., 2015; García-Blanco et al.,

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2014) who observed increased attention (i.e., fixation time) to threatening images in BD, but no differences in gaze time. This discrepancy is likely due to paradigms employed (i.e., assessment of visual behaviour during simultaneous presentation of multiple affective pictures vs. free-viewing of a sole neutral/unpleasant image) (Carvalho et al., 2015).

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Patients‟ increased gazing away from decreased gaze at unpleasant pictures during emotion

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regulation and from at all images during emotion reactivity was demonstrated for the first time in our study. In contrast, the absence of abnormal facial displays of emotions during emotion down-

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regulation in BD patients was also observed by Gruber and colleagues (Gruber et al., 2014) during cognitive reappraisal. This supports our interpretation that patients with BD use gaze to regulate

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mood by means of avoidance of/distraction from potential aversive stimuli, resulting in less

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negative facial expressions to aversive images. Suppression or avoidance of emotional experience has been associated with

psychopathology, including depression and anxiety disorders (Aldao et al., 2010). Bipolar disorder may therefore be associated with dysregulated emotional responses rather than an absence of regulation, per se (i.e., increased avoidance resulting in more engaged facial expressions in response to neutral stimuli and decreased facial responses to negative stimuli). This may further explain

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differential patterns of neural activity during emotion regulation in patients with BD (Phillips et al., 2008). That is, whereas healthy populations utilise adaptive cognitive regulatory strategies in which prefrontal areas inhibit sub-cortical and limbic regions, patients with BD exhibit increased bottomup responses in which decreased prefrontal activation is coupled with hyper-activated limbic areas

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when regulating emotions (Townsend and Altshuler, 2012). Indeed, studies employing automatic attentional control of emotion have shown that patients with BD exhibit increased activity in subcortical areas implicated in emotion processing rather than prefrontal regions involved in automatic attentional control (Phillips et al., 2008). While neuroimaging thus provide more

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sensitive assays of aberrant emotion reactivity and regulation in BD than subjective reports, the present findings suggest that subtle differences in visual gaze and facial expressions provide similarly sensitive – albeit less costly and thus more clinically feasible – measures. The putative habitual gazing away from unpleasant emotional images is interesting in light

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of new evidence for patients‟ propensity to experience frequent vivid negative intrusive mental

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images in everyday life, which is thought to contribute to affective lability in BD (Di Simplicio et al., 2016). Since such intrusive mental images exacerbate negative emotional reactivity in everyday

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life (Holmes et al., 2008), they may explain patients‟ use of automatic attentional avoidance, whereby patients habitually gaze away from emotional images to limit their emotional impact.

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Abnormalities within emotion processing and regulation thus provide key targets for treatment

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strategies and have implications for treatment response. Patients‟ emotion regulation abilities may improve with therapies that emphasise more adaptive emotion regulation strategies than visual avoidance (e.g., cognitive reappraisal), thereby improving abilities to down-regulate negative emotion (Zilverstand et al., 2017). The modest sample size limits generalisability of the results and impedes the investigation into the effect of medication on emotion processing and emotion regulation. In fact, recent evidence

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suggests an effect of lithium and dopamine antagonists on facial emotion processing (Bilderbeck et al., 2017). Thus it is feasible that the differences in visual gaze patterns and facial displays of emotion found in the present study may be modulated by the effect of medication. Nevertheless, given the scarcity of research on subtle behavioural differences during emotion processing and

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regulation, the study was exploratory in nature and aimed to be hypothesis generating. Moreover, the group by condition interaction for gaze during emotional reactivity was reduced to a trend when controlling for subsyndromal depressive and mania symptoms. This result suggests that residual symptoms could account for the increased gazing away from neutral

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and negative stimuli seen in patients, or be due to reduction in statistical power in this

relatively small sample size when adding a covariate to the analysis. The results should therefore be interpreted with caution and warrant replication in a larger sample with greater statistical power. Another limitation was that the sampling rate of the eye tracker, which denotes

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the number of data points collected per second, was limited to 30Hz. A higher sampling rate would

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provide improved continuity of eye movements as a measure of attentional selection (Armstrong and Olatunji, 2012) and allow for more detailed analysis of fixations (Tobii Pro, Sweden). Finally,

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in order to obtain best quality facial expression data, participants were instructed not to look away from the screen. This however impedes the interpretation of gaze time, in which we are

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unable to identify whether participants spontaneously look away from the screen as an

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emotion regulation strategy. Despite these limitations, this study provides preliminary insight into the potential of multidisciplinary measures involving facial displays of emotion and eye-tracking as a tool for the identification of aberrant emotion processing and regulation in BD. Follow-up replication with a larger sample is warranted to further elucidate subtle behavioural responses during emotion processing and regulation in BD.

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In conclusion, the present study provided preliminary evidence for subtle differences in visual gaze patterns and facial displays of emotion between remitted patients with BD and HCs during emotion processing and regulation. Specifically, remitted patients with BD gazed more away when reacting to and down-regulating emotional reactivity to unpleasant pictures. They also

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showed aberrant facial expressions (lack of expressivity) during emotional reactivity to unpleasant pictures. The results warrant further larger-scale studies of eye-gaze and facial emotions during emotional reactivity and - regulation in BD. If the findings are replicated, this would highlight these relatively inexpensive subtle behavioural measures of aberrant affective cognition as putative

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endophenotype of BD that could aid future diagnostic accuracy in clinic settings.

Disclosures

LVK has within the preceding three years been a consultant for Lundbeck, AstraZeneca and

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Sunovion. KMW has acted as a consultant for and received honoraria from Lundbeck and Allergan

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in the past three years. All other authors report no potential conflicts of interest.

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Neuroimage 151, 105-116.

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Table 1. Participant demographic characteristics Bipolar Disorder Healthy Controls Statistics Mean (SD) Mean (SD) 16 17 N Age 32.7 (11.1) 35.1 (12.6) t=-0.59 χ2=0.31 Gender (% Female) 53 43 Education (yrs.) 14.5 (2.8) 15.5 (2.8) t=-1.07 HDRS 6.6 (4.4) 1.0 (1.2) t=4.95 YMRS 2.8 (2.9) 0.9 (1.2) t=2.48 Antidepressants, no (%) 2 (12.5) Antipsychotics, no (%) 8 (50.0) Anticonvulsants, no (%) 9 (56.3) Benzodiazepines, no (%) 3 (18.8) Lithium, no (%) 7 (43.8) Note. HDRS = Hamilton Depression Rating Scale; YMRS = Young Mania Rating Scale

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0.56 0.58 0.30 <0.001 0.02

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Table 2. Behavioural data View Negative

Dampen Negative

Valence, M (SD)a

5.57 (1.48)

2.59 (1.62)

2.46 (1.54)

a

3.32 (2.11)

5.68 (2.31)

5.83 (2.19)

2.17 (1.37) 2.38 (3.15)

39.44 (20.14) 43.13 (22.77)

28.27 (14.97) 28.62 (18.49)

Arousal, M (SD) Self-reported negative affect, M (SD) Bipolar Disorder Healthy Control IAPS normative data

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View Neutral

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Table 3. Facial emotion classification and corresponding EMFACS action units as measured by Affdex (Affective, USA; iMotions, Denmark) Action units 4, 5, 7, 23

Fear

1, 2, 4, 5, 7, 20, 26

Joy

6, 12

Surprise

1, 2, 5, 26

Sadness

1, 4, 15

Disgust

9, 15, 16

Positive

12, 6

Negative

1, 4, 9, 10, 15, 17, 24, 28

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Engagement/Expressivity 2, 4, 9, 15, 17, 18, 24, 25, 28, 12

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FACS Description Brow lowerer, Upper lid raiser, Lid tightener, Lip tightener Inner brow raiser, Outer brow raiser, Brow lowerer, Upper lid raiser, Lid tightener, Lip stretcher, Jaw drop Cheek raiser, Lip corner puller Inner brow raiser, Outer brow raiser, Upper lid raiser, Jaw drop Inner brow raiser, Brow lowerer, Lip corner depressor Nose wrinkler, Lip corner Depressor, Lower lip depressor Lip corner puller, cheek raiser Inner brow raiser, Brow lowerer, Nose wrinkler, Upper lip raiser, Lip corner depressor, Chin raiser, Lip pressor, Lip suck Outer brow raiser, Brow lowerer, Nose wrinkler, Lip corner depressor, Chin raiser, Lip puckerer, Lip pressor, Lips part, Lip suck, Lip corner puller.

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Emotion Anger

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Figure 3. Mean change in facial expressivity (bottom) and neutral facial expressions (top) during

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„react‟ conditions. Error bars represent standard error of the mean.

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Figure 1.

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Figure 2.

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Figure 3.

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