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Background: Studies in adult depressed patients have indicated that altered DNA methylation patterns at genes related to serotonin and HPA axis functioning (e.g., SLC6A4, FKBP5) are associated with changes in frontolimbic functional connectivity and structure. Here, we examined whether these associations can be generalized to adolescents.Methods: 25 adolescents with depression (Mean age = 15.72 ± 0.94 SD; 20 girls) and 20 healthy controls (Mean age = 16.05 ± 1.5 SD; 16 girls) underwent a functional and structural magnetic resonance imaging protocol, which included a resting-state assessment and measures of brain morphometry. DNA was obtained from saliva. Levels of SLC6A4 and FKBP5 methylation were determined using pyrosequencing.Results: SLC6A4 methylation was linked to amygdala-frontal operculum resting-state functional connectivity (rs-FC), regardless of diagnosis, and was differentially associated with inferior orbitofrontal gyrus (IFOG) gray matter (GM) volume in adolescents with depression and controls. Replicating and extending previous findings in adults, FKBP5 methylation was associated with IFOG GM volume in depressed and healthy adolescents, as well as orbitofrontal cortex (OFC)-rostral prefrontal cortex (RPFC) connectivity in healthy adolescents only.Limitations: Effects of medication use or genotype cannot be ruled out. Further, the relatively small sample size and predominately female sample may limit generalizability.Conclusions: These findings suggest that previously observed associations between SLC6A4 and FKBP5 methylation and frontolimbic processes in adult depressed patients can be in part generalized to adolescent patients. Further, findings suggest that measuring peripheral methylation at these genes deserves further attention as potential markers of typical and atypical development. [ABSTRACT FROM AUTHOR]

Background: Peer victimization is associated with increased risk for depression, as well as increased neural response to social exclusion in the anterior cingulate cortex (ACC) and the amygdala. Altered functional connectivity (FxC) of fronto-limbic circuitry is associated with risk for various affective disorders. The present study examined the relationship between fronto-limbic FxC during social exclusion, prior peer victimization experience and depressive symptoms.Methods: Three mutually exclusive groups were formed: peer victimized (with a history of peer victimization), defenders (history of defending peers), and controls (no prior peer victimization experience) (n = 15/group; Mage = 17.7 years). Functional Magnetic Resonance Imaging data were collected while participants completed the Cyberball paradigm (simulating the experience of social exclusion). FxC between the Medial Prefrontal Cortex (MPFC), ACC, right insula and left amygdala, was compared between groups and examined in relation to depressive symptoms.Results: Prior peer victimization experience was associated with differences in fronto-limbic FxC across social inclusion and exclusion. Defenders displayed distinct shifts in FxC across the transition from being included to excluded. Peer victimized individuals exhibited a unique pattern of amygdala-specific FxC during inclusive interaction with peers, and in the continuous FxC across inclusion and exclusion. FxC of the MPFC-amygdala across inclusion and exclusion moderated the relationship between peer victimization and depressive symptoms.Limitations: Small sample size and cross-sectional design limit interpretation of the findings.Conclusions: Peer victimized individuals who exhibit continuous positive FxC of the MPFC-left amygdala across inclusion and exclusion may be at greater risk for depressive symptoms. [ABSTRACT FROM AUTHOR]

Early adversity can influence gene expression via epigenetic mechanisms, including DNA methylation. Peripheral tissues are essential in psychiatric epigenetics, as methylation generally cannot be assessed in the living human brain. Several magnetic resonance imaging (MRI) studies show associations of peripheral serotonin transporter gene (SLC6A4) methylation with function and/or structure of frontal-limbic circuits and brain's resting-state. Commonly used samples are derived from blood, saliva or buccal cells. However, little is known regarding which peripheral tissue is most strongly associated with human brain processes. The aim of the current study was to compare the extent of the association between peripheral SLC6A4 promoter methylation and frontal-limbic function, structure and resting-state in healthy individuals across peripheral tissues. Forty healthy prospectively-followed adults underwent anatomical, resting-state and functional MRI. Saliva-, blood- and buccal-derived DNA methylation was assessed by pyrosequencing. Blood-derived SLC6A4 methylation was positively associated with superior frontal gray matter (GM) volume and with right lateral parietal area (RLP)-frontal pole regional resting-state functional connectivity (rsFC). Saliva-derived SLC6A4 methylation was positively associated with superior frontal GM volume. Buccal-derived SLC6A4 methylation was positively associated with superior and inferior frontal and anterior cingulate cortical (ACC) GM volumes, and with RLP-ACC, frontal pole and medial prefrontal regional rsFC. Current results confirmed the relevance of peripheral methylation for frontal-limbic processes in humans. Buccal cells may be the most sensitive cell type when studying SLC6A4 promoter methylation and its associated risk for neural vulnerability and resilience for psychopathologies in which serotonin is implicated. These data should be further validated in clinical populations. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of sadness, the prevailing mood in major depression (MD), in a prospective, well-documented community sample followed since birth. Methods: The children, comprising 136 children (65 boys and 71 girls) of mothers with varying levels of depressive symptomatology, were scanned – using a 1.5-Tesla system – while they watched 5 blocks of both sad and neutral film excerpts. Following scanning, they rated the emotions they experienced, and if they identified sadness, they were also asked to rate its intensity. Results: In children whose mothers exhibited higher depressive symptomatology, compared to children whose mothers displayed lower depressive symptomatology, altered neural responses to sad film excerpts were noted in brain regions known to be involved in sadness and MD, notably the insula, anterior cingulate cortex and caudate nucleus, even though the children did not differ in current mood. Limitations: Whether this represents genetic vulnerability or a consequence of exposure to maternal depressive symptoms at a young age is unknown. Discussion: The results are consistent with the results of studies in healthy adults and MD patients. The present study suggests that an altered pattern of regional brain responses to sad stimuli, is already present in childhood and might represent vulnerability for MD later in life. [Copyright &y& Elsevier]