Amygdala excitability to subliminally presented emotional faces distinguishes unipolar and bipolar depression: an fMRI and pattern classification study.

BACKGROUND: Bipolar disorder and Major depressive disorder are difficult to differentiate during depressive episodes, motivating research for differentiating neurobiological markers. Dysfunctional amygdala responsiveness during emotion processing has been implicated in both disorders, but the important rapid and automatic stages of emotion processing in the amygdala have so far never been investigated in bipolar patients. METHODS: fMRI data of 22 bipolar depressed patients (BD), 22 matched unipolar depressed patients (MDD), and 22 healthy controls (HC) were obtained during processing of subliminal sad, happy and neutral faces. Amygdala responsiveness was investigated using standard univariate analyses as well as pattern-recognition techniques to differentiate the two clinical groups. Furthermore, medication effects on amygdala responsiveness were explored. RESULTS: All subjects were unaware of the emotional faces. Univariate analysis revealed a significant group × emotion interaction within the left amygdala. Amygdala responsiveness to sad>neutral faces was increased in MDD relative to BD. In contrast, responsiveness to happy>neutral faces showed the opposite pattern, with higher amygdala activity in BD than in MDD. Most of the activation patterns in both clinical groups differed significantly from activation patterns of HC--and therefore represent abnormalities. Furthermore, pattern classification on amygdala activation to sad>happy faces yielded almost 80% accuracy differentiating MDD and BD patients. Medication had no significant effect on these findings. CONCLUSIONS: Distinct amygdala excitability during automatic stages of the processing of emotional faces may reflect differential pathophysiological processes in BD versus MDD depression, potentially representing diagnosis-specific neural markers mostly unaffected by current psychotropic medication.

Discriminating unipolar and bipolar depression by means of fMRI and pattern classification: a pilot study.

Bipolar disorders rank among the most debilitating psychiatric diseases. Bipolar depression is often misdiagnosed as unipolar depression, leading to suboptimal therapy and poor outcomes. Discriminating unipolar and bipolar depression at earlier stages of illness could therefore help to facilitate efficient and specific treatment. In the present study, the neurobiological underpinnings of emotion processing were investigated in a sample of unipolar and bipolar depressed patients matched for age, gender, and depression severity by means of fMRI. A pattern-classification approach was employed to discriminate the two samples. The pattern classification yielded up to 90 % accuracy rates discriminating the two groups. According to the feature weights of the multivariate maps, medial prefrontal and orbitofrontal regions contributed to classifications specific to unipolar depression, whereas stronger feature weights in dorsolateral prefrontal areas contribute to classifications as bipolar. Strong feature weights were observed in the amygdala for the negative faces condition, which were specific to unipolar depression, whereas higher amygdala features weights during the positive faces condition were observed, specific to bipolar subjects. Standard univariate fMRI analysis supports an interpretation, where this might be related to a higher responsiveness, by yielding a significant emotion × group interaction within the bilateral amygdala. We conclude that pattern-classification techniques could be a promising tool to classify acutely depressed subjects as unipolar or bipolar. However, since the present approach deals with small sample sizes, it should be considered as a proof-of-concept study. Hence, results have to be confirmed in larger samples preferably of unmedicated subjects.

Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala.

UNLABELLED: Major depression has been repeatedly associated with amygdala hyper-responsiveness to negative (but not positive) facial expressions at early, automatic stages of emotion processing using subliminally presented stimuli. However, it is not clear whether this "limbic bias" is a correlate of depression or represents a vulnerability marker preceding the onset of the disease. Because childhood maltreatment is a potent risk factor for the development of major depression in later life, we explored whether childhood maltreatment is associated with amygdalar emotion processing bias in maltreated but healthy subjects. Amygdala responsiveness to subliminally presented sad and happy faces was measured by means of fMRI at 3 T in N = 150 healthy subjects carefully screened for psychiatric disorders. Childhood maltreatment was assessed by the 25-item childhood trauma questionnaire (CTQ). A strong association of CTQ-scores with amygdala responsiveness to sad, but not happy facial expressions emerged. This result was further qualified by an interaction of emotional valence and CTQ-scores and was not confounded by trait anxiety, current depression level, age, gender, intelligence, education level, and more recent stressful life-events. Childhood maltreatment is apparently associated with detectable changes in amygdala function during early stages of emotion processing which resemble findings described in major depression. Limbic hyper-responsiveness to negative facial cues could be a consequence of the experience of maltreatment during childhood increasing the risk of depression in later life. LIMITATION: the present association of limbic bias and maltreatment was demonstrated in the absence of psychopathological abnormalities, thereby limiting strong conclusions.

Mood-congruent amygdala responses to subliminally presented facial expressions in major depression: associations with anhedonia.

BACKGROUND: Anhedonia has long been recognized as a key feature of major depressive disorders, but little is known about the association between hedonic symptoms and neurobiological processes in depressed patients. We investigated whether amygdala mood-congruent responses to emotional stimuli in depressed patients are correlated with anhedonic symptoms at automatic levels of processing. METHODS: We measured amygdala responsiveness to subliminally presented sad and happy facial expressions in depressed patients and matched healthy controls using functional magnetic resonance imaging. Amygdala responsiveness was compared between patients and healthy controls within a 2 (group) x 2 (emotion) design. In addition, we correlated patients' amygdala responsiveness to sad and happy facial stimuli with self-report questionnaire measures of anhedonia. RESULTS: We included 35 patients and 35 controls in our study. As in previous studies, we observed a strong emotion x group interaction in the bilateral amygdala: depressed patients showed greater amygdala responses to sad than happy faces, whereas healthy controls responded more strongly to happy than sad faces. The lack of automatic right amygdala responsiveness to happy faces in depressed patients was associated with higher physical anhedonia scores. LIMITATIONS: Almost all depressed patients were taking antidepressant medications. CONCLUSION: We replicated our previous finding of depressed patients showing automatic amygdala mood-congruent biases in terms of enhanced reactivity to negative emotional stimuli and reduced activity to positive emotional stimuli. The altered amygdala processing of positive stimuli in patients was associated with anhedonia scores. The results indicate that reduced amygdala responsiveness to positive stimuli may contribute to anhedonic symptoms due to reduced/inappropriate salience attribution to positive information at very early processing levels.

Neural correlates of affective priming effects based on masked facial emotion: an fMRI study.

Affective priming refers to the phenomenon that subliminal presentation of facial emotion biases subsequent evaluation of a neutral object in the direction of the prime. The aim of the present study was to specify the neural correlates of evaluative shifts elicited by facial emotion shown below the threshold of conscious perception. We tested the hypotheses whether the amygdala is involved in negative priming, whereas the nucleus accumbens participates in positive priming. In addition, exploratory whole brain correlation analyses were conducted. During 3T fMRI scanning, pictures of sad, happy, and neutral facial expression masked by neutral faces were presented to 110 healthy adults who had to judge valence of masks on a four-point scale. There was evidence for significant negative priming based on sad faces. A correlation was observed between amygdala activation and negative priming. Activation in medial, middle, and superior frontal and middle temporo-occipital areas, and insula was also associated with negative priming. No significant priming based on happy faces was found. However, nucleus accumbens activation to happy faces correlated with the positive priming score. The present findings confirm that the amygdala but also other brain regions, especially the medial frontal cortex, appear involved in automatically elicited negative evaluative shifts.

Alexithymia is related to differences in gray matter volume: a voxel-based morphometry study.

OBJECTIVE: Alexithymia has been characterized as the inability to identify and describe feelings. Functional imaging studies have revealed that alexithymia is linked to reactivity changes in emotion- and face-processing-relevant brain areas. In this respect, anterior cingulate cortex (ACC), amygdala, anterior insula and fusiform gyrus (FFG) have been consistently reported. However, it remains to be clarified whether alexithymia is also associated with structural differences. METHODS: Voxel-based morphometry on T1-weighted magnetic resonance images was used to investigate gray matter volume in 17 high alexithymics (HA) and 17 gender-matched low alexithymics (LA), which were selected from a sample of 161 healthy volunteers on basis of the 20-item Toronto Alexithymia Scale. Data were analyzed as statistic parametric maps for the comparisons LA>HA and HA>LA in a priori determined regions of interests (ROIs), i.e., ACC, amygdala, anterior insula and FFG. Moreover, an exploratory whole brain analysis was accomplished. RESULTS: For the contrast LA>HA, significant clusters were detected in the ACC, left amygdala and left anterior insula. Additionally, the whole brain analysis revealed volume differences in the left middle temporal gyrus. No significant differences were found for the comparison HA>LA. CONCLUSION: Our findings suggest that high compared to low alexithymics show less gray matter volume in several emotion-relevant brain areas. These structural differences might contribute to the functional alterations found in previous imaging studies in alexithymia.

Adult attachment anxiety is associated with enhanced automatic neural response to positive facial expression.

According to social psychology models of adult attachment, a fundamental dimension of attachment is anxiety. Individuals who are high in attachment anxiety are motivated to achieve intimacy in relationships, but are mistrustful of others and their availability. Behavioral research has shown that anxiously attached persons are vigilant for emotional facial expression, but the neural substrates underlying this perceptual sensitivity remain largely unknown. In the present study functional magnetic resonance imaging was used to examine automatic brain reactivity to approach-related facial emotions as a function of attachment anxiety in a sample of 109 healthy adults. Pictures of sad and happy faces were presented masked by neutral faces. The Relationship Scales Questionnaire (RSQ) was used to assess attachment style. Attachment anxiety was correlated with depressivity, trait anxiety, and attachment avoidance. Controlling for these variables, attachment-related anxiety was positively related to responses in left inferior, middle, and medial prefrontal areas, globus pallidus, claustrum, and right cerebellum to masked happy facial expression. Attachment anxiety was not found to be associated with brain activation due to masked sad faces. Our findings suggest that anxiously attached adults are automatically more responsive to positive approach-related facial expression in brain areas that are involved in the perception of facial emotion, facial mimicry, or the assessment of affective value and social distance.

Catechol-O-methyltransferase gene variation: impact on amygdala response to aversive stimuli.

The functional catechol-O-methyltransferase (COMT) val158met polymorphism has been found to be associated with anxiety disorders and depression as well as with neural correlates of emotional processing, with, however, contradictory results. Thus, the aim of the present study was to re-evaluate the impact of the COMT val158met variant on neural activation correlates of emotional face processing in a sample of healthy probands. In 85 healthy subjects genotyped for the COMT val158met polymorphism, amygdala responses were assessed by means of fMRI. Participants were presented with anger- and fear-relevant faces in a robust emotion-processing paradigm. For exploratory reasons, a supplementary whole-brain analysis of the allele-dose model and a gender-stratified analysis were conducted. The COMT 158val allele showed an allele-dose effect on increased predominantly left-sided amygdala activity in response to fearful/angry facial stimuli (p(uncorrected)=.00004). This effect was independent from the distribution of the frequently studied 5-HTTLPR polymorphism for which a linear effect of S-alleles on amygdala responsiveness was replicated. The influence of COMT 158val alleles was only discerned in the female subgroup of probands. The whole-brain analysis suggested associations of the COMT 158val allele with increased activity in areas of the ventral visual stream and the lateral prefrontal cortex. The present results provide further support for a-potentially female-specific-role of the COMT val158met polymorphism in the genetic and neural underpinnings of anxiety- and depression-related intermediate phenotypes and may aid in further clarifying the differential role of COMT genotype driven dopaminergic tonus in the processing of emotionally salient stimuli.

Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging.

BACKGROUND: Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. METHODS: One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). RESULTS: We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. CONCLUSIONS: Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.

Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli.

Recent studies point to a role of neuropeptide-S (NPS) in the etiology of anxiety disorders. In animal models, NPS and its receptor (NPSR) were shown to be highly expressed in the amygdala, a central structure in the fear circuit, also known to be hyper-responsive in anxiety disorders. Recently, a functional polymorphism in the NPSR gene (rs324981 A/T) has been associated with panic disorder and anxiety sensitivity. However, the role of NPSR gene variation in the modulation of fear-related amygdala responsiveness remains to be clarified. In 79 healthy subjects genotyped for NPSR rs324981, amygdala responses were assessed by means of fMRI. The participants were presented with fear-relevant faces in a robust emotion-processing paradigm frequently used to study amygdala responsiveness. We observed a strong association of NPSR T-alleles with right amygdala responsiveness to fear-relevant faces. The association peak was located in the BLA. Furthermore, responsiveness to aversive stimuli within this BLA cluster predicted a participant's self-reported harm avoidance but not depression level. We conclude that NPSR genotype is associated with increased amygdala responsiveness to fear-relevant stimuli. Thereby, NPSR rs324981 apparently causes an indirect effect on anxiety-related traits and potentially contributes to the pathogenesis of anxiety disorders by shaping fear-related limbic activity.

Facial emotion processing in major depression: a systematic review of neuroimaging findings.

BACKGROUND: Cognitive models of depression suggest that major depression is characterized by biased facial emotion processing, making facial stimuli particularly valuable for neuroimaging research on the neurobiological correlates of depression. The present review provides an overview of functional neuroimaging studies on abnormal facial emotion processing in major depression. Our main objective was to describe neurobiological differences between depressed patients with major depressive disorder (MDD) and healthy controls (HCs) regarding brain responsiveness to facial expressions and, furthermore, to delineate altered neural activation patterns associated with mood-congruent processing bias and to integrate these data with recent functional connectivity results. We further discuss methodological aspects potentially explaining the heterogeneity of results. METHODS: A Medline search was performed up to August 2011 in order to identify studies on emotional face processing in acutely depressed patients compared with HCs. A total of 25 studies using functional magnetic resonance imaging were reviewed. RESULTS: The analysis of neural activation data showed abnormalities in MDD patients in a common face processing network, pointing to mood-congruent processing bias (hyperactivation to negative and hypoactivation to positive stimuli) particularly in the amygdala, insula, parahippocampal gyrus, fusiform face area, and putamen. Furthermore, abnormal activation patterns were repeatedly found in parts of the cingulate gyrus and the orbitofrontal cortex, which are extended by investigations implementing functional connectivity analysis. However, despite several converging findings, some inconsistencies are observed, particularly in prefrontal areas, probably caused by heterogeneities in paradigms and patient samples. CONCLUSIONS: Further studies in remitted patients and high-risk samples are required to discern whether the described abnormalities represent state or trait characteristics of depression.