Udo Dannlowski

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.

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

BackgroundCognitive 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.MethodsA 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.ResultsThe 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.ConclusionsFurther studies in remitted patients and high-risk samples are required to discern whether the described abnormalities represent state or trait characteristics of depression.

Reduced amygdala–prefrontal coupling in major depression: association with MAOA genotype and illness severity

The amygdala plays a pivotal role in a cortico-limbic circuitry implicated in emotion processing and regulation. In the present study, functional connectivity of the amygdala with prefrontal areas involved in emotion regulation was investigated during a facial expression processing task in a sample of 34 depressed inpatients and 31 healthy controls. All patients were genotyped for a common functional variable number tandem repeat (VNTR) polymorphism in the promoter region of the monoamine oxidase A gene (MAOA u-VNTR) which has been previously associated with major depression as well as reduced cortico-limbic connectivity in healthy subjects. In our control group, we observed tight coupling of the amygdala and dorsal prefrontal areas comprising the dorsolateral prefrontal cortex (DLPFC), dorsal parts of the anterior cingulate cortex (dACC), and lateral orbitofrontal cortex. Amygdala-prefrontal connectivity was significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H). Hence, depressed MAOA-H carriers showed the weakest amygdala-prefrontal coupling of the investigated subgroups. Furthermore, reduced coupling of this circuitry predicted more than 40% variance of clinical variables characterizing a longer and more severe course of disease. We conclude that genetic variation in the MAOA gene may affect the course of major depression by disrupting cortico-limbic connectivity.

5-HTTLPR Biases Amygdala Activity in Response to Masked Facial Expressions in Major Depression

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. Increased amygdala reactivity has been discussed in the context of major depression. Recent studies reported that amygdala activity during conscious emotion processing is modulated by a functional polymorphism in the serotonin transporter gene (5-HTTLPR) in healthy subjects. In the present study, amygdala reactivity to displays of emotional faces was measured by means of fMRI at 3T in 35 patients with major depression and 32 healthy controls. Conscious awareness of the emotional stimuli was prevented via backward-masking to investigate automatic emotion processing. All subjects were genotyped for the 5-HTTLPR polymorphism. Risk allele carriers (S or LG) demonstrated increased amygdala reactivity to masked emotional faces, which in turn was significantly correlated with life-time psychiatric hospitalization as an index of chronicity. This might indicate that genetic variations of the serotonin transporter could increase the risk for depression chronification via altering limbic neural activity on a preattentive level of emotion processing.

The Interleukin 1 Beta (IL1B) Gene Is Associated with Failure to Achieve Remission and Impaired Emotion Processing in Major Depression

BACKGROUND Accumulating evidence suggests the involvement of inflammatory processes and cytokines in particular in the pathophysiology of major depression (MDD) and resistance to antidepressant treatment. Furthermore, amygdala and anterior cingulate cortex (ACC) responsiveness to emotional stimuli has been suggested as a predictor of treatment response. This study investigated the association between genetic variants of the interleukin 1 beta (IL1B) gene and amygdala and ACC responsiveness to emotional stimuli and response to antidepressant treatment. METHODS In this analysis, 256 Caucasian patients with MDD (145 women, 111 men) were genotyped for variants rs16944, rs1143643, and rs1143634 in the IL1B gene (2q14). Response to antidepressant treatment over 6 weeks was defined as remission (< or = 7 on the Hamilton Rating Scale for Depression-21-question) and response (>50% decrease on Hamilton Rating Scale for Depression-21-question). Brain activity under visual presentation of emotional faces was assessed in a subsample of 32 depressed patients by means of functional magnetic resonance imaging at 3 T. RESULTS Pharmacogenetic analyses show significant associations of the GG genotypes of single nucleotide polymorphisms (SNPs) rs16944 (odds ratio = 1.74; 95% confidence interval 1.2-4.3) and rs1143643 (odds ratio = 3.1; 95% confidence interval 1.3-7.8) (compared with the AA genotype) with nonremission after 6 weeks. The imaging analyses show that the number of G-alleles in both SNPs (rs16944 and rs1143643) was associated with reduced responsiveness of the amygdala and ACC to emotional stimulation. CONCLUSIONS The present study suggests a negative effect of the IL1B gene on pharmacological response and amygdala and ACC function involving the same genotypes of two SNPs (rs16944, rs116343), which taken together increase the risk of nonremission over 6 weeks of antidepressant treatment in MDD.

Serotonergic genes modulate amygdala activity in major depression

Serotonergic genes have been implicated in the pathogenesis of depression probably via their influence on neural activity during emotion processing. This study used an imaging genomics approach to investigate amygdala activity in major depression as a function of common functional polymorphisms in the serotonin transporter gene (5‐HTTLPR) and the serotonin receptor 1A gene (5‐HT1A‐1019C/G). In 27 medicated patients with major depression, amygdala responses to happy, sad and angry faces were assessed using functional magnetic resonance imaging at 3 Tesla. Patients were genotyped for the 5‐HT1A‐1019C/G and the 5‐HTTLPR polymorphism, including the newly described 5‐HTT‐rs25531 single nucleotide polymorphism. Risk allele carriers for either gene showed significantly increased bilateral amygdala activation in response to emotional stimuli, implicating an additive effect of both genotypes. Our data suggest that the genetic susceptibility for major depression might be transported via dysfunctional neural activity in brain regions critical for emotion processing.

Cannabinoid receptor 1 (CNR1) gene: Impact on antidepressant treatment response and emotion processing in Major Depression.

The endocannabinoid system has been implicated in the pathogenesis of depression and anxiety, the mediation of antidepressant drug effects in animal models and the neurobiology of emotion processing in healthy volunteers. Therefore, the impact of cannabinoid receptor 1 gene (CNR1) variants rs1049353 and rs12720071 on antidepressant treatment response was evaluated in 256 Caucasian patients with Major Depression. A subsample of 33 depressed patients was additionally scanned by fMRI under visual presentation of emotional faces. The CNR1 rs1049353 G allele conferred an increased risk of antidepressant treatment resistance, particularly in female patients with high comorbid anxiety. CNR1 rs1049353 G allele carriers also demonstrated weaker bilateral amygdala, putamen and pallidum activity as well as left lateralized caudate and thalamus activity in response to masked happy faces. This analysis provides preliminary support for a role of CNR1 gene variation in depression and anxiety, potentially mediated by subcortical hypo-responsiveness to social reward stimuli.

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

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. Hum Brain Mapp 34:2899–2909, 2013.

Individual differences in alexithymia and brain response to masked emotion faces.

Alexithymia is considered a dimensional personality trait that refers to a cluster of deficits in the recognition, differentiation, and verbalization of emotions. Research on the neurobiology of alexithymia has focused hitherto on impairments in the controlled processing of emotional information. In the present study automatic brain reactivity to facial emotion was investigated as a function of alexithymia (as assessed by the 20-Item Toronto Alexithymia Scale - TAS-20). During 3T fMRI scanning, pictures of sad, happy, and neutral facial expression masked by neutral faces were presented to 33 healthy women. A priori regions of interest in the whole brain analysis were cerebral structures that are known to be crucially involved in the emotion perception from the face. Independently from trait anxiety and depression TAS-20 alexithymia was negatively correlated with activation to masked sad and happy faces in several regions of interest (in particular, insula, superior temporal gyrus, middle occipital and parahippocampal gyrus). In addition, the TAS-20 score was negatively correlated with response of the left amygdala to masked sad faces. A reduced automatic reactivity of the amygdala and visual occipito-temporal areas could implicate less automated engagement in the encoding of emotional stimuli in high alexithymia. In addition, a low spontaneous insular and amygdalar responsivity in high alexithymia individuals could be related to an attenuation of basic emotional experiences which may contribute to problems in identifying and differentiating ones feelings.

Neural correlates of trait anxiety in fear extinction

BACKGROUND Fear conditioning involves the amygdala as the main neural structure for learning fear responses whereas fear extinction mainly activates the inhibitory prefrontal cortex (PFC). In this study we investigated whether individual differences in trait anxiety affect amygdala and dorsal anterior cingulate cortex (dACC) activation during fear conditioning and extinction. METHOD Thirty-two healthy subjects were investigated by functional magnetic resonance imaging (fMRI) at 3 T while performing a cued fear-conditioning task. All participants completed the trait version of the State-Trait Anxiety Inventory (STAI-T). Activations of the amygdala and the dACC were examined with respect to the effects of trait anxiety. RESULTS Analysis of the fMRI data demonstrated enhanced activation in fear-related brain areas, such as the insula and the ACC, during both fear conditioning and extinction. Activation of the amygdala appeared only during the late acquisition phase whereas deactivation was observed during extinction. Regression analyses revealed that highly trait-anxious subjects exhibited sustained amygdala activation and reduced dACC involvement during the extinction of conditioned responses. CONCLUSIONS This study reveals that high levels of trait anxiety are associated with both increased amygdala activation and reduced dACC recruitment during the extinction of conditioned fear. This hyper-responsivity of the amygdala and the deficient cognitive control during the extinction of conditioned fear in anxious subjects reflect an increased resistance to extinct fear responses and may thereby enhance the vulnerability to developing anxiety disorders.