Centre for Youth Mental Health - Research Publications
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ItemPeripheral telomere length and hippocampal volume in adolescents with major depressive disorder(SPRINGERNATURE, 2015-11-10)Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.
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ItemFusiform Gyrus Dysfunction is Associated with Perceptual Processing Efficiency to Emotional Faces in Adolescent Depression: A Model-Based Approach(FRONTIERS MEDIA SA, 2016-02-01)While the extant literature has focused on major depressive disorder (MDD) as being characterized by abnormalities in processing affective stimuli (e.g., facial expressions), little is known regarding which specific aspects of cognition influence the evaluation of affective stimuli, and what are the underlying neural correlates. To investigate these issues, we assessed 26 adolescents diagnosed with MDD and 37 well-matched healthy controls (HCL) who completed an emotion identification task of dynamically morphing faces during functional magnetic resonance imaging (fMRI). We analyzed the behavioral data using a sequential sampling model of response time (RT) commonly used to elucidate aspects of cognition in binary perceptual decision making tasks: the Linear Ballistic Accumulator (LBA) model. Using a hierarchical Bayesian estimation method, we obtained group-level and individual-level estimates of LBA parameters on the facial emotion identification task. While the MDD and HCL groups did not differ in mean RT, accuracy, or group-level estimates of perceptual processing efficiency (i.e., drift rate parameter of the LBA), the MDD group showed significantly reduced responses in left fusiform gyrus compared to the HCL group during the facial emotion identification task. Furthermore, within the MDD group, fMRI signal in the left fusiform gyrus during affective face processing was significantly associated with greater individual-level estimates of perceptual processing efficiency. Our results therefore suggest that affective processing biases in adolescents with MDD are characterized by greater perceptual processing efficiency of affective visual information in sensory brain regions responsible for the early processing of visual information. The theoretical, methodological, and clinical implications of our results are discussed.
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ItemNo Preview AvailableLarge-Scale Hypoconnectivity Between Resting-State Functional Networks in Unmedicated Adolescent Major Depressive Disorder(NATURE PUBLISHING GROUP, 2016-11)Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period.
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ItemCorrecting for cell-type effects in DNA methylation studies: reference-based method outperforms latent variable approaches in empirical studies(BIOMED CENTRAL LTD, 2017-01-30)Based on an extensive simulation study, McGregor and colleagues recently recommended the use of surrogate variable analysis (SVA) to control for the confounding effects of cell-type heterogeneity in DNA methylation association studies in scenarios where no cell-type proportions are available. As their recommendation was mainly based on simulated data, we sought to replicate findings in two large-scale empirical studies. In our empirical data, SVA did not fully correct for cell-type effects, its performance was somewhat unstable, and it carried a risk of missing true signals caused by removing variation that might be linked to actual disease processes. By contrast, a reference-based correction method performed well and did not show these limitations. A disadvantage of this approach is that if reference methylomes are not (publicly) available, they will need to be generated once for a small set of samples. However, given the notable risk we observed for cell-type confounding, we argue that, to avoid introducing false-positive findings into the literature, it could be well worth making this investment.Please see related Correspondence article: https://genomebiology.biomedcentral.com/articles/10/1186/s13059-017-1149-7 and related Research article: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0935-y.
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ItemNo Preview AvailableBrain Aging in Major Depressive Disorder: Results From the ENIGMA MDD Consortium(ELSEVIER SCIENCE INC, 2018-05-01)Background: Major Depressive Disorder has been associated with accelerated biological aging. From a brain perspective, normal aging is associated with significant loss of grey matter and depression may have an accelerating effect on age-related brain atrophy. Here, data on brain aging in MDD from the ENIGMA MDD Working Group will be presented. Methods: A normative model of brain-based age was devel- oped in 4708 healthy controls by applying a Gaussian Process Regression analysis with 10-fold cross-validation to estimate chronological age from structural MRI scans, separately for males and females. This model was then applied to 2924 MDD individuals to predict their brain-based age. Accelerated brain aging was measured as the difference between predicted brain-based age and actual chronological age (brain age gap). Results: The brain age model explained 92% and 93% of the age variance in female and male healthy controls, respectively. The mean absolute error (MAE) was 6.79 years in females and 6.60 in males. Application of the model to MDD patients showed a mean brain age gap of 0.75 years in females (MAE¼6.82) and 0.64 in males (MAE¼6.68), which were significantly lower than brain age gap estimates in healthy controls in both females (F(1,4379)¼6.10,P¼0.01) and males (F(1,3166)¼4.07,P¼0.04). Our preliminary analysis also showed greater brain age gap associations with various clinical characteristics. Conclusions: We found preliminary evidence for accelerated brain aging in MDD, however, the brains of patients were estimated to be only <1 years older than healthy controls. The impact of different methods, feature selection and potential confounding effects will also be discussed.
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ItemNo Preview AvailableMETHYLOME-WIDE ASSOCIATION STUDIES FOR MAJOR DEPRESSIVE DISORDER IN BLOOD OVERLAP WITH METHYLATION RESULTS FROM BRAIN AND LARGE-SCALE GWAS(ELSEVIER SCIENCE BV, 2019-01-01)Background: Epigenetic modifications such as DNA methy- lation provide stability and diversity to the cellular phenotype and aberrant methylation has been implicated in processes underlying psychiatric disorders. Therefore, studies combining DNA methylation and genotype information provide a promis- ing approach to study disorders where genotype information alone has failed to reveal the full etiology. Methods: We applied an optimized MBD-seq protocol to assay the complete CpG methylome in cases with Major Depressive Disorder (MDD) and controls using blood samples (N=1,132) from Netherlands Study of Depression and Anxiety and brain samples (N=64) from the Victorian Brain Bank Network. Data were analyzed with RaMWAS, a novel Biocon- ductor package specifically designed for Methylome-Wide Association Studies (MWAS). To study the overlap between top MWAS findings in blood and brain, we used a permutation based enrichment test (shiftR) that accounted for the depen- dency between adjacent CpG sites. Furthermore, we utilized the methylation data in combination with existing genotype information from the same individuals in a MWAS of CpGs created or destroyed by SNPs. Next, we tested whether top results from this CpG-SNP MWAS overlapped with recent large- scale GWAS to identify robust associations with genomic loci of importance for MDD etiology Results: The MWAS in blood identified five methylome- wide significant sites (P o 5 10-8) from three distinct loci and 472 nominally significant (P o 1 10-5) CpG sites. To study the robustness of the overall MWAS signal, we used an “in-sample” replication based on k-fold cross validation. Results showed that the findings replicated (P = 4.0 10- 10). When we compared blood and brain we found that top blood MWAS findings were significantly enriched for top CpGs in the brain MWAS (P = 5.4 10-3). The MWAS of CpG-SNPs identified 32 nominally significant sites and in- sample replication showed that the signal replicated (P = 2.2 10-8). Finally, the top CpG-SNP MWAS showed a consistent trend towards enrichment in all tested large- scale GWAS, with the most significant enrichment observed for the 23andMe study (P = 4.9 10-3). This overlap involved 55 genes that were overrepresented (P o 0.01) in 12 level-5 gene ontology terms, of which a major portion was related to neuronal regulation, function and development. Discussion: This work involves the largest MWAS for MDD performed to date. Our integrated analysis with brain tissue, genotype information and GWAS results highlighted biological functions of potential value for MDD etiology. Part of the associated methylation marks in blood overlapped with MWAS finding in brain. As blood can easily be collected in a clinical setting, these loci may be of direct value as potential diagnostic biomarkers for MDD.
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ItemNo Preview AvailableDeviations From Normative Age-Brain Associations in Over 3,000 Individuals With Major Depressive Disorder(ELSEVIER SCIENCE INC, 2019-05-15)Background: Major depressive disorder (MDD) is a complex heterogeneous disorder. Identifying brain alterations as indi- vidual deviations from normative patterns of brain-age asso- ciations, instead of patient group mean differences, can provide important insights into heterogeneous patterns of brain abnormalities observed in MDD. Methods: We estimated normative models of (1) age pre- dicting individual structural brain measures, and (2) structural brain measures predicting age (Brain Age model) using ma- chine learning in healthy individuals (N¼2,515) from the ENIGMA MDD consortium. We applied model parameters to independent samples of healthy individuals (N¼2,513) and MDD patients (N¼3,433) to obtain predicted values of brain structure (model 1) and age (model 2). Z-scores quantifying differences between predictive and true values were calcu- lated, representing individual deviations from the normative range. Results: The estimated normative models showed good model fit in the training sample; e.g. a correlation of R¼0.86 between actual and predicted age for the Brain Age Model, and good generalization to independent healthy and MDD samples. We identified heterogeneous patterns of brain deviations in MDD patients (model 1). Patients with more extreme deviations showed different clinical characteristics compared to patients residing within the normative range. Additionally, patients were estimated on average w1 year older than controls (model 2), but we also observed large between-person variation in brain age gaps. Further ana- lyses showed associations between brain age gap and clinical symptoms. Conclusions: Our work shows substantial heterogeneity in deviations from normal age-related variation in brain structure in individuals with MDD. The impact of and solutions for con- founding effects of scan site will also be discussed.
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ItemNo Preview AvailableEpigenetic aging in major depressive disorder(ELSEVIER, 2019-01-01)Major depressive disorder (MDD) is associated with increased risk of mortality and aging-related diseases [1–3]. The authors examined whether MDD is associated with higher epigenetic aging (EA) [4] in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of MDD have a further impact on these patterns, and whether findings replicate in brain tissue. DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate EA. MDD diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying EA in blood and brain. Significantly higher EA was observed in MDD patients compared with control subjects, with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, EA was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent dataset of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. As compared with control subjects, MDD patients exhibited higher EA in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.
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ItemNo Preview AvailableHigh levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression(ELSEVIER SCIENCE BV, 2018-05)BACKGROUND: Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group. METHODS: The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents. RESULTS: There were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn. LIMITATIONS: Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations. CONCLUSIONS: The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.
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ItemNo Preview AvailableEpigenetic Aging in Major Depressive Disorder(AMER PSYCHIATRIC PUBLISHING, INC, 2018-08)OBJECTIVE: Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. The authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation (DNAm) patterns, whether clinical characteristics of major depression have a further impact on these patterns, and whether the findings replicate in brain tissue. METHOD: DNAm age was estimated using all methylation sites in blood of 811 depressed patients and 319 control subjects with no lifetime psychiatric disorders and low depressive symptoms from the Netherlands Study of Depression and Anxiety. The residuals of the DNAm age estimates regressed on chronological age were calculated to indicate epigenetic aging. Major depression diagnosis and clinical characteristics were assessed with questionnaires and psychiatric interviews. Analyses were adjusted for sociodemographic characteristics, lifestyle, and health status. Postmortem brain samples of 74 depressed patients and 64 control subjects were used for replication. Pathway enrichment analysis was conducted using ConsensusPathDB to gain insight into the biological processes underlying epigenetic aging in blood and brain. RESULTS: Significantly higher epigenetic aging was observed in patients with major depression compared with control subjects (Cohen's d=0.18), with a significant dose effect with increasing symptom severity in the overall sample. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score. The case-control difference was replicated in an independent data set of postmortem brain samples. The top significantly enriched Gene Ontology terms included neuronal processes. CONCLUSIONS: As compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. This effect was even more profound in the presence of childhood trauma.