Amygdala functional connectivity in major depression - disentangling markers of pathology, risk and resilience.

BACKGROUND: Limbic-cortical imbalance is an established model for the neurobiology of major depressive disorder (MDD), but imaging genetics studies have been contradicting regarding potential risk and resilience mechanisms. Here, we re-assessed previously reported limbic-cortical alterations between MDD relatives and controls in combination with a newly acquired sample of MDD patients and controls, to disentangle pathology, risk, and resilience. METHODS: We analyzed functional magnetic resonance imaging data and negative affectivity (NA) of MDD patients (n = 48), unaffected first-degree relatives of MDD patients (n = 49) and controls (n = 109) who performed a faces matching task. Brain response and task-dependent amygdala functional connectivity (FC) were compared between groups and assessed for associations with NA. RESULTS: Groups did not differ in task-related brain activation but activation in the superior frontal gyrus (SFG) was inversely correlated with NA in patients and controls. Pathology was associated with task-independent decreases of amygdala FC with regions of the default mode network (DMN) and decreased amygdala FC with the medial frontal gyrus during faces matching, potentially reflecting a task-independent DMN predominance and a limbic-cortical disintegration during faces processing in MDD. Risk was associated with task-independent decreases of amygdala-FC with fronto-parietal regions and reduced faces-associated amygdala-fusiform gyrus FC. Resilience corresponded to task-independent increases in amygdala FC with the perigenual anterior cingulate cortex (pgACC) and increased FC between amygdala, pgACC, and SFG during faces matching. CONCLUSION: Our results encourage a refinement of the limbic-cortical imbalance model of depression. The validity of proposed risk and resilience markers needs to be tested in prospective studies. Further limitations are discussed.

The interaction of working memory and emotion in persons clinically at risk for psychosis: an fMRI pilot study.

Subtle emotional and cognitive dysfunctions may already be apparent in individuals at risk for psychosis. However, there is a paucity of research on the neural correlates of the interaction of both domains. It remains unclear whether those correlates are already dysfunctional before a transition to psychosis. We used functional magnetic resonance imaging to examine the interaction of working memory and emotion in 12 persons clinically at high risk for psychosis (CHR) and 12 healthy subjects individually matched for age, gender and parental education. Participants performed an n-back task while negative or neutral emotion was induced by olfactory stimulation. Although healthy and psychosis-prone subjects did not differ in their working memory performance or the evaluation of the induced emotion, decreased activations were found in CHR subjects in the superior parietal lobe and the precuneus during working memory and in the insula during emotion induction. Looking at the interaction, CHR subjects, showed decreased activation in the right superior temporal gyrus, which correlated negatively with psychopathological scores. Decreased activation was also found in the thalamus. However, an increase of activation emerged in several cerebellar regions. Dysfunctions in areas associated with controlling whether incoming information is linked to emotional content and in the integration of multimodal information might lead to compensatory activations of cerebellar regions known to be involved in olfactory and working memory processes. Our study underlines that cerebral dysfunctions related to cognitive and emotional processes, as well as their interaction, can emerge in persons with CHR, even in absence of behavioral differences.

Neuronal correlates of facial emotion discrimination in early onset schizophrenia.

Emotion discrimination deficits represent a well-established finding in schizophrenia. Although imaging studies addressed the cerebral dysfunctions underlying emotion perception in adult patients, the question of trait vs state characteristics is still unresolved. The investigation of juvenile patients offers the advantage of studying schizophrenia at an age where influences of illness course and long-term medication are minimized. This may enable a more detailed characterization of emotion discrimination impairments and their cerebral correlates with respect to their appearance and exact nature. A total of 12 juvenile patients with early onset schizophrenia and matched healthy juveniles participated in this study. fMRI data were acquired during an emotion discrimination task consisting of standardized photographs of faces displaying happy, sad, angry, fearful, or neutral facial expression. Similar to findings in adult patients, juvenile patients exhibited reduced performance specificity whereas sensitivity was unaffected. Independent of the valence, their processing of emotional faces was associated with hypoactivations in both fusiform gyri and in the left inferior occipital gyrus. In addition, hyperactivations in patients were found in the right cuneus common to happy, angry, and fearful faces. Further, most distinct changes were present in juvenile patients when processing sad faces. These results point to a dysfunction in cerebral circuits relevant for emotion processing already prominent in adolescent schizophrenia patients. Regions affected by a decrease in activation are related to visual and face processing, similar to deficits reported in adult patients. These changes are accompanied by hyperactivations in areas related to emotion regulation and attribution, possibly reflecting compensatory mechanisms.

Cerebral dysfunctions of emotion-cognition interactions in adolescent-onset schizophrenia.

OBJECTIVE: Schizophrenia is among the most severe of psychiatric disorders, leading to impairments of affective and cognitive abilities. These dysfunctions affect each other mutually. Adolescent-onset schizophrenia (AOS) constitutes a particularly severe form of the disorder. In this study, possible dysfunctions of the neural correlates underlying the interaction of negative emotion and working memory in AOS were investigated. METHOD: During functional magnetic resonance imaging, 12 patients with AOS and 12 non-AOS adolescents performed a verbal n-back task. Intermittently, negative and neutral emotions were induced by olfactory stimulation. Group differences in working memory, emotion, and their interaction were evaluated. RESULTS: In patients with AOS, lower performance sensitivity was observed, along with dorsolateral prefrontal, anterior cingulate, and inferior parietal hypoactivation during working memory demands. For negative versus neutral emotion induction, patients with AOS mainly showed increased brain activation compared with control subjects in widespread brain regions including the left orbitofrontal cortex and the medial frontal gyrus. Finally, during the interaction of emotion and cognition, altered patterns of activation in patients with AOS were found in the thalamocortical network, including the angular and the middle cingulate gyri extending to the precuneus. These activation differences were further decomposed by parameter estimates. CONCLUSIONS: Our results provide new insights into the neural correlates underlying the mutual influence of affective and cognitive symptoms in AOS. During the n-back task, areas typically associated with working memory performance were found hypoactivated in patients relative to the control subjects, including the dorsolateral prefrontal and parietal cortex and the anterior cingulate. However, patients with AOS mainly demonstrated increased activation in key areas of emotion processing, such as the left orbitofrontal cortex and medial frontal areas, during negative emotion induction. A dysfunctional thalamocortical network during the interaction mainly included regions involved in the integration of converging information--either on the subcortical (thalamus) or on a higher-order cortical level (comprising the angular gyrus). These findings point to dysfunctional emotion-cognition interactions in AOS, which may explain its poor prognosis.

Increased neural response related to neutral faces in individuals at risk for psychosis.

OBJECTIVE: The reliable discrimination of emotional expressions in faces is essential for adequate social interaction. Deficits in facial emotion processing are an important impairment in schizophrenia with major consequences for social functioning and subjective well-being. Whether neural circuits underlying emotion processing are already altered before illness onset is yet unclear. Investigating neural correlates of emotion processing in individuals clinically at risk for psychosis offers the possibility to examine neural processes unchanged by the manifest disorder and to study trait aspects of emotion dysfunctions. MATERIAL AND METHODS: Twelve subjects clinically at risk for psychosis and 12 matched control subjects participated in this study. fMRI data were acquired during an emotion discrimination task consisting of standardized photographs of faces displaying different emotions (happiness, sadness, anger, fear) as well as faces with neutral facial expression. RESULTS: There were no group differences in behavioral performance. Emotion discrimination was associated with hyperactivations in high-risk subjects in the right lingual and fusiform gyrus as well as the left middle occipital gyrus. Further, high-risk compared to control subjects exhibited stronger activation related to neutral faces relative to emotional faces in the inferior and superior frontal gyri, the cuneus, the thalamus and the hippocampus. CONCLUSIONS: The present study indicates that individuals clinically at risk for psychosis show differences in brain activation associated with processing of emotional and--more pronounced--neutral facial expressions despite an adequate behavioral performance. The proneness to attribute salience to neutral stimuli might indicate a biological risk marker for psychosis.

Self-face recognition in schizophrenia.

OBJECTIVE: Altered self-awareness might be a core feature of schizophrenia. Facial self-recognition in children and non-human primates has been linked to the emergence of self-awareness. In this study, the ability to recognize the own face as an indicator of certain aspects of self-awareness was investigated in patients with schizophrenia. METHODS: Standardized facial pictures of the participants (20 patients with DSM-IV schizophrenia and 20 healthy controls), of close same-sex relatives of the participants and of unknown persons were taken. These stimuli were presented on a computer screen serially in three forced choice identity recognition experiments: facial identities were presented (I) for 5 s centrally on the screen; (II) in the participants' left and right visual hemifields for 100 ms; (III) as morphed blendings between the identities, centrally for 5 s. RESULTS: There was no interaction between group and facial identity in experiments I and III. However, in experiment II an interaction between hemifield and identity emerged in the patients (p=.002). They exhibited higher error rates for their own face presented to the right hemifield (p=.003), whereas there was no effect for the control subjects. Additionally, self-face recognition (reaction time in experiment I; p=.0009 and error rates in II; p=.0006) was related to hallucinations in the patients. CONCLUSIONS: These results support the notion of a specific self-face processing dysfunction in schizophrenia. This might be related to altered self-awareness in schizophrenia.

Gender differences in the cognitive control of emotion: An fMRI study.

The interaction of emotion and cognition has become a topic of major interest. However, the influence of gender on the interplay between the two processes, along with its neural correlates have not been fully analysed so far. In this functional magnetic resonance imaging (fMRI) study we induced negative emotion using negative olfactory stimulation while male (n=21) and female (n=19) participants performed an n-back verbal working memory task. Based on findings indicating increased emotional reactivity in women, we expected the female participants to exhibit stronger activation in characteristically emotion-associated areas during the interaction of emotional and cognitive processing in comparison to the male participants. Both groups were found to be significantly impaired in their working memory performance by negative emotion induction. However, fMRI analysis revealed distinct differences in neuronal activation between groups. In men, cognitive performance under negative emotion induction was associated with extended activation patterns in mainly prefrontal and superior parietal regions. In women, the interaction between emotion and working memory yielded a significantly stronger response in the amygdala and the orbitofrontal cortex (OFC) compared to their male counterparts. Our data suggest that in women the interaction of verbal working memory and negative emotion is associated with relative hyperactivation in more emotion-associated areas whereas in men regions commonly regarded as important for cognition and cognitive control are activated. These results provide new insights in gender-specific cerebral mechanisms.

The influence of olfactory-induced negative emotion on verbal working memory: individual differences in neurobehavioral findings.

The influence of emotion on cognition plays an important role in people's everyday life as well as in psychiatric and neurological disorders. The present study used fMRI to examine the neural correlates of cognitive-emotional interactions and its inter-individual differences. Twenty-one healthy males performed a 0-back/2-back task while negative or neutral emotion was induced by negative/neutral olfactory stimulation. Subjects revealed a differential effect of emotion on cognition; in 9 subjects, negative odor had a deteriorating influence on verbal working memory ("affected group", AG) while in 12 subjects, performance was not affected in a negative way ("unaffected group", UAG). Although no brain activation differences emerged during the working memory task, the interaction of working memory and emotion yielded significant differences between the AG and the UAG. The latter showed greater activation in the fronto-parieto-cerebellar working memory (WM) network including the precuneus while the AG demonstrated stronger activation in more "emotional" areas (mainly the temporal and medial frontal cortex) as well as compensatory activations in prefrontal regions known to be essential for the cognitive down-regulation of emotions. Hence, the UAG may have been better able to counteract the detrimental influence of negative stimulation during the 2-back task and to effectively sustain or even increase activation in the task-relevant WM network. Correlation analyses for the whole group supported this interpretation; reduced working memory performance during negative stimulation was accompanied by higher activation in the inferior frontal gyrus whereas less performance impairment was related to higher activation in the precuneus. Results confirm the importance of incorporating individual differences in emotion processing and its interaction with cognitive functions in neuroimaging.