Birth Weight and Adult IQ, but Not Anxious-Depressive Psychopathology, Are Associated with Cortical Surface Area: A Study in Twins

BACKGROUND: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles. AIMS: We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects. RESULTS: Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders. CONCLUSION: The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.This work was supported by the Spanish SAF2008-05674, European Twins Study Network on Schizophrenia Research Training Network (grant number EUTwinsS; MRTN-CT-2006-035987), the Catalan 2014SGR1636 and the PIM2010-ERN- 00642 in frame of ERA-NET NEURON. A. Córdova- Palomera was funded by The National Council for Science and Technology (CONACyT, Mexico). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Early Neurodevelopment, adult human cognition and depressive psychopathology: analysis of neuroimaging brain correlates and epigenetic mediators

[eng] In the behavioral sciences, the concept of phenotypic plasticity can be roughly categorized into two classes: developmental and activational plasticity. Developmental plasticity denotes the capacity of an individual carrying a specific genetic background to adopt different developmental trajectories under distinct settings. Complementarily, activational plasticity refers to the differential activation of adaptation mechanisms: an individual with high activational plasticity would be able to detect a wide range of environments, and to respond to it using a psychobiological phenotype from a relatively large catalogue. In this context, it is feasible postulating that several etiopathogenic mechanisms of depression-related phenotypes can be clarified by expanding on processes of biobehavioral plasticity in response to the experience. This expansion can be elaborated on the basis of both neurodevelopmental phenomena (developmental plasticity) and novel biological mechanisms detectable through neuroimaging and epigenetics approaches (activational plasticity). The present work expands on two specific hypotheses. First, depression-related psychopathological phenotypes are induced by factors altering the early neurodevelopment, and these long-lasting changes can be assessed in adulthood (depression and developmental plasticity). Secondly, the clinical manifestation of depression-related psychopathological phenotypes can be understood as activational plasticity deficits; these deficits can be assessed as neurobiological disease traits using novel epigenetic and neuroimaging techniques (depression and activational plasticity). The results of this work provide support to the neuroplasticity hypothesis of depression, from both developmental and activational perspectives. Developmentally, they suggest putative etiopathogenic pathways leading from an altered early neurodevelopment to an increased risk for depression-related phenotypes. By exploring and combining genetic, environmental and psychopathologic concepts, the feasibility of these results has been explained by combining the popular genetic pleiotropy hypothesis in psychiatry with a notion of disease-specificity liability driven by the environment. With regards to activational plasticity, this work has proposed novel genetic and epigenetic signatures potentially underlying the clinical manifestation of neuropsychiatric and neurocognitive features of depression (i.e., the genetics of DNMT3B and the epigenetics of DEPDC7); additionally, it has proposed new putative neurobiological mechanisms to explain depressive traits (i.e., a combination of differential and variable methylation, a genetically-mediated hippocampal communication deficit, and a new amygdalar synchrony failure driven by the genes)

Epigenetic outlier profiles in depression. A genome-wide DNA Methylation analysis of MZ twins

Recent discoveries highlight the importance of stochastic epigenetic changes, as indexed by epigenetic outlier DNA methylation signatures, as a valuable tool to understand aberrant cell function and subsequent human pathology. There is evidence of such changes in different complex disorders as diverse as cancer, obesity and, to a lesser extent, depression. The current study was aimed at identifying outlying DNA methylation signatures of depressive psychopathology. Here, genome-wide DNA methylation levels were measured (by means of Illumina Infinium HumanMethylation450 Beadchip) in peripheral blood of thirty-four monozygotic twins informative for depressive psychopathology (lifetime DSM-IV diagnoses). This dataset was explored to identify outlying epigenetic signatures of depression, operationalized as extreme hyper- or hypo-methylation in affected co-twins from discordant pairs that is not observed across the rest of the study sample. After adjusting for blood cell count, there were thirteen CpG sites across which depressed co-twins from the discordant pairs exhibited outlying DNA methylation signatures. None of them exhibited a methylation outlier profile in the concordant and healthy pairs, and some of these loci spanned genes previously associated with neuropsychiatric phenotypes, such as GHSR and KCNQ1. This exploratory study provides preliminary proof-of-concept validation that epigenetic outlier profiles derived from genome-wide DNA methylation data may be related to depression risk

Letter to editor: Low Birth Weight And Adult Depression: Eliciting Their Association

Theories supporting fetal origins of adult health and disease are nowadays widely accepted regarding some psychiatric conditions. However, whether genetic or environmental factors disrupting fetal growth might constitute a rick factor for depressive and/or anxious psychopathology remains still controversial

Season of birth and subclinical psychosis: systematic review and meta-analysis of new and existing data (Review)

Season of birth (SOB) has been shown to modify the risk of several health outcomes, including a number of neuropsychiatric disorders. Empirical evidence indicates that subclinical forms of psychosis in the general population share some risk factors with categorical diagnoses of psychosis. Hence, by systematically reviewing and meta-analyzing new and existing data, the current work aimed to determine whether there is evidence of an association between winter SOB and subclinical psychosis in the general population. Our meta-analytic results do not indicate an association between winter SOB and schizotypy in adult populations, although they indicate winter SOB may be a risk factor for psychotic experiences or symptoms in children around 12–15 years (OR=1.12, 95%CI:1.03–1.21). In the whole new dataset for adults (n=481, mean age=22.8 years) no association was detected in either an unadjusted model or adjusting for gender and age. Overall, our results indicate that the association between winter SOB and increased subclinical psychosis may hold in children, but does not in the broad general adult population. Nevertheless, the epidemiological and clinicopathological significance of winter SOB as a risk factor for subclinical psychosis would probably be slight due to the small effect sizes indicated by the reports available to date.Spanish Ministry of Science and Innovation SAF2008-05674-C03-00; 03; PNSD2008-I090; PNSD2009-I019; IT2009-0016 Institute of Health Carlos III (CIBERSAM, research group 08) Comissionat per a Universitats i Recerca DIUE Generalitat de Catalunya, Spain, 2014SGR1636 Fundacio Caixa Castello-Bancaixa P1-1B2010-40; P1-1B2011-47. Ministero dell'Istruzione, dell'Universita e della Ricerca, Italy IT107CB8DC. CONACyT, Mexico 31076

FKBP5 modulates the hippocampal connectivity deficits in depression: a study in twins

The hippocampus is a key modulator of stress responses underlying depressive behavior. While FKBP5 has been found associated with a large number of stress-related outcomes and hippocampal features, its potential role in modifying the hippocampal communication transfer mechanisms with other brain regions remains largely unexplored. The putative genetic or environmental roots of the association between depression and structural connectivity alterations of the hippocampus were evaluated combining diffusion weighted imaging with both a quantitative genetics approach and molecular information on the rs1360780 single nucleotide polymorphism, in a sample of 54 informative monozygotic twins (27 pairs). Three main results were derived from the present analyses. First, graph-theoretical measures of hippocampal connectivity were altered in depression. Specifically, decreased connectivity strength and increased network centrality of the right hippocampus were found in depressed individuals. Second, these hippocampal alterations are potentially driven by familial factors (genes plus shared environment). Third, there is an additive interaction effect between FKBP5’s rs1360780 variant and the graph-theoretical metrics of hippocampal connectivity to influence depression risk. Our data reveals alterations of the communication patterns between the hippocampus and the rest of the brain in depression, effects potentially driven by overall familial factors (genes plus shared twin environment) and modified by the FKBP5 gene

FKBP5 modulates the hippocampal connectivity deficits in depression : a study in twins

The hippocampus is a key modulator of stress responses underlying depressive behavior. While FKBP5 has been found associated with a large number of stress-related outcomes and hippocampal features, its potential role in modifying the hippocampal communication transfer mechanisms with other brain regions remains largely unexplored. The putative genetic or environmental roots of the association between depression and structural connectivity alterations of the hippocampus were evaluated combining diffusion weighted imaging with both a quantitative genetics approach and molecular information on the rs1360780 single nucleotide polymorphism, in a sample of 54 informative monozygotic twins (27 pairs). Three main results were derived from the present analyses. First, graph-theoretical measures of hippocampal connectivity were altered in depression. Specifically, decreased connectivity strength and increased network centrality of the right hippocampus were found in depressed individuals. Second, these hippocampal alterations are potentially driven by familial factors (genes plus shared environment). Third, there is an additive interaction effect between FKBP5’s rs1360780 variant and the graph-theoretical metrics of hippocampal connectivity to influence depression risk. Our data reveals alterations of the communication patterns between the hippocampus and the rest of the brain in depression, effects potentially driven by overall familial factors (genes plus shared twin environment) and modified by the FKBP5 gene

Environmental factors inducing depression alter the cerebellar resting-state synchronization.

Hosting nearly eighty percent of all human neurons, the cerebellum is functionally connected to large regions of the brain. Accumulating data suggest that some cerebellar resting-state alterations may constitute a key candidate mechanism for depressive psychopathology. While there is some evidence linking cerebellar function and depression, two topics remain largely unexplored. First, the genetic or environmental roots of this putative association have not been elicited. Secondly, while different mathematical representations of resting-state fMRI patterns can embed diverse information of relevance for health and disease, many of them have not been studied in detail regarding the cerebellum and depression. Here, high-resolution fMRI scans were examined to estimate functional connectivity patterns across twenty-six cerebellar regions in a sample of 48 identical twins (24 pairs) informative for depression liability. A network-based statistic approach was employed to analyze cerebellar functional networks built using three methods: the conventional approach of filtered BOLD fMRI time-series, and two analytic components of this oscillatory activity (amplitude envelope and instantaneous phase). The findings indicate that some environmental factors may lead to depression vulnerability through alterations of the neural oscillatory activity of the cerebellum during resting-state. These effects may be observed particularly when exploring the amplitude envelope of fMRI oscillations