Distinguishing bipolar disorder from major depressive disorder is a major challenge in psychiatric treatment. Consequently, there has been growing interest in identifying neuronal biomarkers of disorder-specific pathophysiological processes to differentiate affective disorders. Thirty-six depressed bipolar patients, 36 depressed unipolar patients, and 36 matched healthy controls (HCs) participated in an fMRI experiment. Emotional faces served as stimuli in a matching task. We investigated neural activation towards angry, fearful, and happy faces focusing on prototypical regions related to emotion processing, ie, the amygdala and the anterior cingulate gyrus (ACG). Furthermore, we employed a whole-brain and a multivariate pattern classification analysis. Unipolar patients showed abnormally reduced ACG activation toward happy and fearful faces compared with bipolar patients and HCs respectively. Furthermore, the whole-brain analysis revealed significantly increased activation in bipolar patients compared with unipolar patients in the fearful condition in the right frontal and parietal cortex. Moreover, the multivariate pattern classification analysis yielded significant classification rates of up to 72% based on ACG activation elicited by fearful faces. Our results question the rather 'amygdalocentric' neurobiological models of mood disorders. We observed patterns of abnormally reduced ventral and supragenual ACG activation, potentially indicating impaired bottom-up emotion processing and automatic emotion regulation specifically in unipolar but not in bipolar individuals.

DNA methylation profiles of the serotonin transporter gene (SLC6A4) have been shown to alter SLC6A4 expression, drive antidepressant treatment response and modify brain functions. This study investigated whether methylation of an AluJb element in the SLC6A4 promotor was associated with major depressive disorder (MDD), amygdala reactivity to emotional faces, 5-HTTLPR/rs25531 polymorphism, and recent stress. MDD patients (n=122) and healthy controls (HC, n=176) underwent fMRI during an emotional face-matching task. Individual SLC6A4 AluJb methylation profiles were ascertained and associated with MDD, amygdala reactivity, 5-HTTLPR/rs25531, and stress. SLC6A4 AluJb methylation was significantly lower in MDD compared to HC and in stressed compared to less stressed participants. Lower AluJb methylation was particularly found in 5-HTTLPR/rs25531 risk allele carriers under stress and correlated with less depressive episodes. fMRI analysis revealed a significant interaction of AluJb methylation and diagnosis in the amygdala, with MDD patients showing lower AluJb methylation associated with decreased amygdala reactivity. While no joint effect of AluJb methylation and 5-HTTLPR/rs25531 existed, risk allele carriers showed significantly increased bilateral amygdala activation. These findings suggest a role of SLC6A4 AluJb methylation in MDD, amygdala reactivity, and stress reaction, partly interwoven with 5-HTTLPR/rs25531 effects. Patients with low methylation in conjunction with a shorter MDD history and decreased amygdala reactivity might feature a more stress-adaptive epigenetic process, maybe via theoretically possible endogenous antidepressant-like effects. In contrast, patients with higher methylation might possibly suffer from impaired epigenetic adaption to chronic stress. Further, the 5-HTTLPR/rs25531 association with amygdala activation was confirmed in our large sample.

Methylation within the AluJb appears to have strong effects on hippocampal gray matter volumes, indicating that epigenetic processes can alter brain structures crucially involved in stress-related disorders. Different ways of regulating SLC6A4 expression might involve exonization or transcription factor binding as potentially underlying mechanisms, which, however, is speculative and warrants further investigation.

No abstract

Epigenetic alterations of the brain-derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF-Val 66 Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face-matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF-Val 66 Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = −26, t (166) = 3.00, TFCE = 42.39, p (FWE) = .045), whereby the BDNF-Val 66 Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = −.19, p = .015) and amygdala reactivity (r = −.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF † These authors contributed equally as joint first authors. ‡ These authors contributed equally as joint senior authors.