The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

Empathy, defending, and functional connectivity while witnessing social exclusion.

Peers are present for most bullying episodes. Peers who witness bullying can play an important role in either stopping or perpetuating the behavior. Defending can greatly benefit victimized peers. Empathy is strongly associated with defending. Yet, less is known about defenders' neural response to witnessing social distress, and how this response may relate to the link between empathy and defending. Forty-six first-year undergraduate students (Mage = 17.7; 37 women), with varied history of peer defending, underwent fMRI scanning while witnessing a depiction of social exclusion. Functional connectivity analysis was performed across brain regions that are involved in cognitive empathy, empathetic distress, and compassion. History of defending was positively associated with functional connectivity (Exclusion > Inclusion) between the left orbitofrontal cortex (OFC) - medial prefrontal cortex (MPFC), and right OFC - left and right amygdalae. Defending was negatively associated with functional connectivity between the left OFC - anterior cingulate cortex. The relationship between history of defending and empathy (specifically, empathetic perspective taking) was moderated by functional connectivity of the right OFC - left amygdala. These findings suggest that coactivation of brain regions involved in compassionate emotion regulation and empathetic distress play a role in the relationship between empathy and peer defending.

DNA methylation differences in stress-related genes, functional connectivity and gray matter volume in depressed and healthy adolescents.

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.

The neuroscience of sadness: A multidisciplinary synthesis and collaborative review.

Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target. Neuroimaging studies - including meta-analyses - indicate that sadness is associated with reduced cortical activation, which may contribute to reduced parasympathetic inhibitory control over medullary cardioacceleratory circuits. Reduced cardiac control may - in part - contribute to epidemiological reports of reduced life expectancy in affective disorders, effects equivalent to heavy smoking. We suggest that the field may be moving toward a theoretical consensus, in which different models relating to basic emotion theory and psychological constructionism may be considered as complementary, working at different levels of the phylogenetic hierarchy.

Functional connectivity across social inclusion and exclusion is related to peer victimization and depressive symptoms in young adults.

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.

Epigenetic Changes of FKBP5 as a Link Connecting Genetic and Environmental Risk Factors with Structural and Functional Brain Changes in Major Depression.

The gene for the glucocorticoid receptor regulator FK506 binding protein 5 (FKBP5) plays a role for risk, response to treatment, and changes in brain areas in major depressive disorder (MDD). Chronic stress is associated with lower methylation of FKBP5. Our aim was to investigate whether methylation of FKBP5 reflected exposure to childhood adversity in MDD and controls and whether it was associated with structure and function of emotional processing regions. FKBP5 intron 7 GR response element region methylation and rs1360780 allelic status were assessed from whole blood in 56 MDD adults and 50 controls. Using magnetic resonance imaging, we assessed gray matter concentration of selected areas and their function during valence recognition of emotional images. Childhood adversity was investigated using the Childhood Trauma Questionnaire. In MDD patients carrying the high-risk T allele of rs1360780, lower methylation of FKBP5 was predicted by childhood adversity (F=4.95, p=0.04). In all participants, lower FKBP5 intron methylation levels were associated with reduced gray matter concentration in the inferior frontal orbital gyrus bilaterally (Wald chi-square=11.93, pFDR<0.01) and, in MDD, with its bilaterally higher activation during valence recognition (Wald chi-square=5.58, p=0.02). Activation of this region, regardless of side, was found to be lower in MDD compared to controls (Wald chi-square=3.88, p=0.049) and to be inversely correlated with depression severity (Wald chi-square=4.65, p=0.03). Our findings support the hypothesis that, in genetically predisposed individuals carrying a high-risk variant of the gene, childhood maltreatment might induce demethylation of FKBP5. This is in turn associated with structural and functional changes in the inferior frontal orbital gyrus, a relevant area for the clinical symptoms of MDD.

Impact of Early Environment on Children's Mental Health: Lessons From DNA Methylation Studies With Monozygotic Twins.

Over the past decade, epigenetic analyses have made important contributions to our understanding of healthy development and a wide variety of adverse conditions such as cancer and psychopathology. There is increasing evidence that DNA methylation is a mechanism by which environmental factors influence gene transcription and, ultimately, phenotype. However, differentiating the effects of the environment from those of genetics on DNA methylation profiles remains a significant challenge. Monozygotic (MZ) twin study designs are unique in their ability to control for genetic differences because each pair of MZ twins shares essentially the same genetic sequence with the exception of a small number of de novo mutations and copy number variations. Thus, differences within twin pairs in gene expression and phenotype, including behavior, can be attributed in the majority of cases to environmental effects rather than genetic influence. In this article, we review the literature showing how MZ twin designs can be used to study basic epigenetic principles, contributing to understanding the role of early in utero and postnatal environmental factors on the development of psychopathology. We also highlight the importance of initiating longitudinal and experimental studies with MZ twins during pregnancy. This approach is especially important to identify: (1) critical time periods during which the early environment can impact brain and mental health development, and (2) the specific mechanisms through which early environmental effects may be mediated. These studies may inform the optimum timing and design for early preventive interventions aimed at reducing risk for psychopathology.