Elsevier

NeuroImage

Volume 53, Issue 1, 15 October 2010, Pages 58-64
NeuroImage

Exaggerated neural response to emotional faces in patients with bipolar disorder and their first-degree relatives

https://doi.org/10.1016/j.neuroimage.2010.05.069Get rights and content

Abstract

Neuroimaging studies have demonstrated abnormalities in patients with bipolar disorder, including overactivity in anterior limbic structures in response to fearful or happy facial expressions. We investigated whether such anomalies might constitute heritable deviations underlying bipolar disorder, by virtue of being detectable in unaffected relatives carrying genetic liability for illness. Twenty patients with bipolar I disorder, twenty of their unaffected 1st degree relatives and twenty healthy volunteers participated in functional magnetic resonance imaging experiments of facial emotion processing. In one of these experiments, the participants watched faces expressing fear of varying intensities (moderate and high), intermixed with the non-emotional faces, and in another experiment — faces expressing moderate or high degrees of happiness intermixed with non-emotional faces. Repeated measures 2 × 3 × 3 ANOVA with emotion (fear and happy), intensity (neutral, moderate, and high) as within-subjects variables and group (patients, relatives, and controls) as between-subjects variable produced two clusters of differential activation, located in medial prefrontal cortex and left putamen. Activity in medial prefrontal cortex was greater in patients and in relatives compared with healthy volunteers in response to both fearful and happy faces. Activity in left putamen in response to moderate fear was greater in patients and in relatives compared with controls. Patients (but not relatives) showed also a greater activation in response to high intensity happy faces, compared with controls. Region of Interest analysis of amygdala activation showed increased activity in left amygdala in both patients and relatives groups in response to intensively happy faces. Exaggerated medial prefrontal cortical and subcortical (putamen and amygdala) responses to emotional signals may represent heritable neurobiological abnormalities underlying bipolar disorder.

Research Highlights

►bipolar disorder is associated with exaggerated MPFC response to emotional faces. ►this is also true for relatives of our patients independently of emotion valence. ►left putamen is differentially activated in patients, relatives and controls. ►left amygdala response to happy faces is exaggerated in patients and relatives. ►the results indicate a dysregulation of emotional processing in bipolar disorder.

Introduction

Bipolar disorder (BD) has a strong genetic contribution with heritability estimates varying from 85% to 89% (McGuffin et al., 2003). The identification of neurobiological abnormalities in unaffected first-degree relatives of patients is a core approach in the search for possible heritable markers of the illness. Unaffected first-degree relatives are free from any medication effects and variations in mood state which may confound true picture of the mechanism of disorder. However given the probable polygenic nature of BD, they are likely to share some of the genotypic variants underlying neurobiological abnormalities associated with vulnerability for the disorder (Hasler et al., 2006). There is evidence that genetically liable but unaffected relatives of patients with BD share with affected individuals' grey and white matter deficits (McDonald et al., 2004, van der Schot et al., 2009, Chaddock et al., 2009), neuropsychological dysfunction in facial emotion labeling (Brotman et al., 2008), response inhibition, set shifting, executive function, verbal memory and sustained attention (Bora et al., 2009).

Facial emotion recognition is an important function that impacts on socio-emotional functioning and is consistently abnormal in patients with BD (McClure-Tone, 2009). Functional neuroimaging studies of facial emotion processing in BD have reported decreased dorso-lateral prefrontal cortex and increased left amygdala or striatal activation in response to fearful and happy facial expressions (Lawrence et al., 2004, Yurgelun-Todd et al., 2000, Hassel et al., 2008). Lennox et al. (2004) reported that bipolar patients with mania had negative bias during sad facial affect recognition, which was associated with an attenuation of activation in the subgenual anterior cingulate and bilateral amygdala, and increased activation in the posterior cingulate and posterior insula. Both manic and depressed bipolar patients overactivated multiple brain regions during processing of mood-incongruent facial expressions (Chen et al., 2006b).

Although inconsistencies exist in the functional neuroimaging literature, these studies in general agree with a model of BD in which dysfunctional neural circuitry manifests in a disbalance between cortical and subcortical activity, whereby reduced dorsal prefrontal performance is associated with the disinhibition of subcortical structures, e.g., amygdala, striatum, and thalamus (Sheline, 2003, Strakowski et al., 2004, Phillips et al., 2008).

It is unclear whether such abnormalities are associated with the illness state, or represent stable or heritable traits. Recent functional neuroimaging evidence indicates that patients with BD and their unaffected relatives share hyperactivation in certain brain structures to cognitive tasks (Drapier et al., 2008, Thermenos et al., 2009). However there are no studies to our knowledge addressing whether heritable mechanisms may drive the abnormalities of cerebral activation underlying emotional processing in BD. In the present study we used fMRI to examine the regional neural correlates of processing happy and fearful facial expressions in remitted patients with BD and their unaffected 1st degree relatives.

Based on the evidence reviewed as above, we hypothesized that the patients with BD and their 1st degree relatives will demonstrate similar patterns of activation in response to emotional faces, in particular — overactivation in limbic subcortical structures (striatum, amygdala).

Section snippets

Participants

Sixty participants underwent fMRI scanning for the study. Twenty remitted patients with familial Bipolar I Disorder and twenty of their unaffected first-degree relatives were recruited via voluntary support groups, the study website or by direct referral from their mental health services. Twenty healthy volunteers were recruited by newspaper advertisements. The groups were matched for age, gender, years of education and parental social class. These subjects had previously participated in the

Experimental design

Study subjects participated in two 6-minute experiments employing event-related fMRI. In each experiment, subjects were presented with facial identities depicting morphed expressions of one emotion (either happiness or fear), and with faces expressing no emotion (neutral faces). The facial expression stimuli were chosen from the standard set of pictures “Facial expressions of emotion: stimuli and tests” (Young et al., 2002). In the experiment with fearful faces, there were 20 neutral faces, 20

fMRI data analysis

The fMRI data were analyzed with software developed at the Institute of Psychiatry (XBAM), using a nonparametric approach to minimize assumptions (Brammer et al., 1997). For more details, also see http://brainmap.it. The XBAM software uses median statistics to control outlier effects and employs permutation rather than normal theory based inference. Furthermore its most common test statistic is computed by standardizing for individual difference in residual noise before embarking on second

Results

Sociodemographic and performance data for each group are provided in Table 1.

The details of brain activation per emotion/group and the coordinates of significant clusters are presented in Supplemental material — Tables S1 and S2. To neutral faces all groups activated bilateral areas of visual primary and association cortices, cerebellum, postcentral/parietal cortex and thalamus. To expressions of moderate and intensive fear or happiness the participants activated areas of visual association

Discussion

In this study we have identified exaggerated regional cerebral activation in response to facial emotional expressions of fear and happiness both in patients with BD and their unaffected first-degree relatives. The area of medial prefrontal cortex identified by our analysis is located in the medial wall of prefrontal cortex, dorsal to the anterior cingulate cortex. A recent meta-analysis of neuroimaging studies of emotion (Kober et al., 2008) showed that medial prefrontal cortex has a key role

Acknowledgments

The authors report no competing interests. This study was supported by a Medical Research Council (UK) Pathfinder Award (Colm McDonald). Katja Schulze was supported by Guy's & St Thomas' Charitable Foundation Research Studentship. We are grateful to the Manic Depression Fellowship for help with recruitment of participants and to all the families who participated in the research. We thank M. Andiappan for help with statistical analysis.

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