Microstructural Correlates of Resilience against Major Depressive Disorder: Epigenetic Mechanisms?

Mental disorders are a major cause of long-term disability and are a direct cause of mortality, with approximately 800.000 individuals dying from suicide every year worldwide - a high proportion of them related to major depressive disorder (MDD)^1^. Healthy relatives of patients with major depressive disorder (MDD) are at risk to develop the disease. This higher vulnerability is associated with structural^2-4^ and functional brain changes^5^. However, we found using high angular resolution diffusion imaging (HARDI) with 61 diffusion directions that neuron tracts between frontal cortices and limbic as well as temporal and parietal brain regions are characterized by better diffusion coefficients in unaffected relatives (UHR), who managed to stay healthy, compared to healthy volunteers without any family history for a psychiatric disease (HC). Moreover, those UHR with stronger fibre connections better managed incidences of adversity in early life without later developing depression, while in HC axonal connections were found to be decreased when they had early-life adversity. Altogether these findings indicate the presence of stronger neural fibre connections in UHR, which seem to be associated with resilience against environmental stressors, which we suggest occur through epigenetic mechanisms

BDNF Val66Met polymorphism in patterns of neural activation in individuals with MDD and healthy controls.

BACKGROUND: Rs6265 single nucleotide polymorphism, which influences brain-derived neurotrophic factor (BDNF) levels in the cortical and subcortical brain structures, may result in distinguished patterns of neural activation during a major depressive disorder (MDD) episode. Valine homozygotes with high levels of BDNF and methionine carriers with lower levels of BDNF may present specific neural correlates of MDD. In our study we have tested differences in blood oxygen level dependant (BOLD) signal between individuals with MDD and healthy controls for both allelic variants. METHODS: Individuals with MDD (N = 37) and healthy controls (N = 39) were genotyped for rs6265 and compared separately in each allelic variant for BOLD response in a functional magnetic resonance imaging experiment examining appraisal of emotional scenes. The two allelic variants were also compared separately for both individuals with MDD and healthy controls. RESULTS: In the homozygous valine group MDD was associated with decreased neural activation in areas responsible for cognitive appraisal of emotional scenes. In the methionine group MDD was related to increased activation in subcortical regions responsible for visceral reaction to emotional stimuli. During an MDD episode methionine carriers showed more activation in areas associated with cognitive appraisal of emotional information in comparison to valine homozygotes. LIMITATIONS: Small sample size of healthy controls carrying methionine (N=8). CONCLUSION: Our results suggest that allelic variations in the rs6265 gene lead to specific neural correlates of MDD which may be associated with different mechanisms of MDD in the two allelic groups. This may have potential importance for screening and treatment of patients.Funding for this study was provided by the Science Foundation Ireland (Grant Number: SFI/07SK/B1214C). Health Research Board (HRB) Ireland provided funding for magnetic resonance imaging infrastructure at the Centre of Advanced Medical Imaging (CAMI) at St. James’s Hospital in Dublin.This is the author accepted manuscript. The final version is available from Elsevier at http://www.jad-journal.com/article/S0165-0327%2815%2900383-3/abstract

White matter disturbances in major depressive disorder : a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline.Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD

Effect of childhood maltreatment on brain structure in adult patients with major depressive disorder and healthy participants.

BACKGROUND: Childhood maltreatment has been found to play a crucial role in the development of psychiatric disorders. However, whether childhood maltreatment is associated with structural brain changes described for major depressive disorder (MDD) is still a matter of debate. The aim of this study was to investigate whether patients with MDD and a history of childhood maltreatment display more structural changes than patients without childhood maltreatment or healthy controls. METHODS: Patients with MDD and healthy controls with and without childhood maltreatment experience were investigated using high-resolution magnetic resonance imaging (MRI), and data were analyzed using voxel-based morphometry. RESULTS: We studied 37 patients with MDD and 46 controls. Grey matter volume was significantly decreased in the hippocampus and significantly increased in the dorsomedial prefrontal cortex (DMPFC) and the orbitofrontal cortex (OFC) in participants who had experienced childhood maltreatment compared with those who had not. Patients displayed smaller left OFC and left DMPFC volumes than controls. No significant difference in hippocampal volume was evident between patients with MDD and healthy controls. In regression analyses, despite effects from depression, age and sex on the DMPFC, OFC and hippocampus, childhood maltreatment was found to independently affect these regions. LIMITATIONS: The retrospective assessment of childhood maltreatment; the natural problem that patients experienced more childhood maltreatment than controls; and the restrictions, owing to sample size, to investigating higher order interactions among factors are discussed as limitations. CONCLUSION: These results suggest that early childhood maltreatment is associated with brain structural changes irrespective of sex, age and a history of depression.Thus, the study highlights the importance of childhood maltreatment when investigating brain structures

Dysregulation between emotion and theory of mind networks in borderline personality disorder

Individuals with borderline personality disorder (BPD) commonly display deficits in emotion regulation, but findings in the area of social cognitive (e.g., theory of mind, ToM) capacities have been heterogeneous. The aims of the current study were to investigate differences between patients with BPD and controls in functional connectivity (1) between the emotion and ToM network and (2) in the default mode network (DMN). Functional magnetic resonance imaging was used to investigate 19 healthy controls and 17 patients with BPD at rest and during ToM processing. Functional coupling was analysed. Significantly decreased functional connectivity was found for patients compared with controls between anterior cingulate cortex and three brain areas involved in ToM processes: the left superior temporal lobe, right supramarginal/inferior parietal lobes, and right middle cingulate cortex. Increased functional connectivity was found in patients compared with controls between the precuneus as the DMN seed and the left inferior frontal lobe, left precentral/middle frontal, and left middle occipital/superior parietal lobes during rest. Reduced functional coupling between the emotional and the ToM network during ToM processing is in line with emotion-regulation dysfunctions in BPD. The increased connectivity between precuneus and frontal regions during rest might be related to extensive processing of internal thoughts and self-referential information in BPD

Aerobic exercise increases hippocampal subfield volumes in younger adults and prevents volume decline in the elderly

Exercise improves both physical and mental health and increases neurogenesis in the dendate gyrus (DG) of the hippocampus. The aim of this study was to examine whether exercising, as compared to no change in regular physical activity, would impact on hippocampal volume, and in particular the core hippocampal structures, DG and cornu ammonis (CA) subfields, and whether any changes would be moderated by age. Thirty nine previously sedentary healthy participants were randomized to either a standardized progressive aerobic exercise program or to "no change" for 16 weeks. Mental health including profile of mood states (POMS), was assessed before and every 4 weeks during the program. Magnetic resonance imaging to examine hippocampal subfields was carried out before and after the program. Aerobic exercise resulted in a significant improvement of the POMS item 'vigour' compared to those in the control group. Overall left hippocampal and left CA4-DG volumes increased significantly in the exercise group while no significant changes were seen in the control group. Older adults in the control group demonstrated significant reductions in CA4-DG subfields over the study, whereas older adults in the exercise group did not show volume decline. These findings reinforce the literature that exercise has a beneficial effect on mental health and can prevent age-related volume decline. Exercise to Improve Resilience,, NCT02541136, Rec Ref 2011/45/13