Neurogenetics of emotion processing in major depression

Die vorliegende Arbeit charakterisiert neurogenetische Mechanismen der Depression. In einer ersten Studie wurden neurobiologische Korrelate der automatischen Emotionsverarbeitung bei Depressiven mittels fMRT untersucht. Es zeigte sich, dass Depressive im Vergleich mit Gesunden eine Hyperresponsivität der Amygdala auf negative Reize zeigen, jedoch eine Hyporesponsivität auf positive Reize. In einer zweiten Studie konnte gezeigt werden, dass ein derartiges Muster mit einer genetischen Variante im Serotonintransportergen (5-HTTLPR) assoziiert ist. In einem dritten Experiment wurde eine genetische Variante im Neuropeptid Y Gen untersucht. Die depressiven Träger von Risikoallelen, die mit einem schlechten Ansprechen auf Pharmakotherapie assoziiert sind, zeigten ebenfalls ein Muster von gesteigerter Amygdalaresponsivität auf bedrohliche Gesichter. Dieser Forschungsansatz schlägt eine Brücke zwischen kleinen Effekten einzelner genetischer Varianten und komplexen psychiatrischen Phänotypen

Long-Term Neuroanatomical Consequences of Childhood Maltreatment: Reduced Amygdala Inhibition by Medial Prefrontal Cortex

Similar to patients with Major depressive disorder (MDD), healthy subjects at risk for depression show hyperactivation of the amygdala as a response to negative emotional expressions. The medial prefrontal cortex is responsible for amygdala control. Analyzing a large cohort of healthy subjects, we aimed to delineate malfunction in amygdala regulation by the medial prefrontal cortex in subjects at increased risk for depression, i.e., with a family history of affective disorders or a personal history of childhood maltreatment. We included a total of 342 healthy subjects from the FOR2107 cohort (www.for2107.de). An emotional face-matching task was used to identify the medial prefrontal cortex and right amygdala. Dynamic Causal Modeling (DCM) was conducted and neural coupling parameters were obtained for healthy controls with and without particular risk factors for depression. We assigned a genetic risk if subjects had a first-degree relative with an affective disorder and an environmental risk if subjects experienced childhood maltreatment. We then compared amygdala inhibition during emotion processing between groups. Amygdala inhibition by the medial prefrontal cortex was present in subjects without those two risk factors, as indicated by negative model parameter estimates. Having a genetic risk (i.e., a family history) did not result in changes in amygdala inhibition compared to no risk subjects. In contrast, childhood maltreatment as environmental risk has led to a significant reduction of amygdala inhibition by the medial prefrontal cortex. We propose a mechanistic explanation for the amygdala hyperactivity in subjects with particular risk for depression, in particular childhood maltreatment, caused by a malfunctioned amygdala downregulation via the medial prefrontal cortex. As childhood maltreatment is a major environmental risk factor for depression, we emphasize the importance of this potential early biomarker

A Longitudinal Study

Adverse experiences interact with individual vulnerability in the etiology of mental disorders, but due to the paucity of longitudinal studies, their precise interplay remains unclear. Here, we investigated how individual differences in threat responsiveness modulated adjustments in negative affect during the COVID-19 pandemic. Participants (N = 441) underwent a fear conditioning and generalization experiment between 2013 and 2020 and were reassessed regarding anxiety and depression symptoms after the pandemic outbreak. Participants showed increased levels of negative affect following pandemic onset, which were partly modulated by laboratory measures of threat responsiveness. Decreased differentiation of threat and safety signals in participants with higher prepandemic depression and anxiety scores in the laboratory assessment were most predictive of increased symptom levels after the onset of the pandemic. However, effects were small and should be replicated in independent samples to further characterize how individual differences in threat processing interact with adverse experiences in the development of psychopathology.Peer Reviewe

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk