Search

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Background: Although it is known that the nutritional status among elderly persons and, in particular, patients with dementia, is compromised, malnutrition that results in insufficient uptake of several vitamins is often not diagnosed. Objective: An elevated homocysteine level is a known strong risk factor for vascular dementia (VaD) and Alzheimer’s disease (AD). Several B vitamins are involved in the metabolism of homocysteine. Therefore, we investigated the serum levels of vitamin B1, vitamin B6, folate, and vitamin B12 in 97 patients with mild cognitive impairment (MCI) or different forms of dementia and 54 elderly control persons without dementia. Results: Compared to aged non-demented people, vitamins B1, B6, B12, and folate were decreased in serum of patients with AD, and patients with Lewy body dementia had reduced vitamin B12 level. Vitamin B6 was diminished in VaD. Patients with frontotemporal dementia showed no alterations in vitamin levels. Age was identified as an important factor contributing to the concentrations of vitamin B1 and B6 in serum, but not vitamin B12 and folate. Increased levels of total homocysteine were detected especially in MCI and AD. Homocysteine correlated negatively with levels of vitamins B6, B12, and folate and positively with Q Albumin. Conclusion: Our data suggest that despite increased homocysteine already present in MCI, vitamin levels are decreased only in dementia. We propose to determine the vitamin levels in patients with cognitive decline, but also elderly people in general, and recommend supplementing these nutrients if needed.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

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.

Translational Psychiatry 11(1), 511 (2021). doi:10.1038/s41398-021-01619-w, Published by Nature Publishing Group, London

[Importance] Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., [Objective] To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., [Design, Setting, and Participants] Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., [Main Outcomes and Measures] Interregional profiles of group difference in cortical thickness between cases and controls., [Results] A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., [Conclusions and Relevance] In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Several studies in major depressive disorder (MDD) have found inflammation, especially C-reactive protein (CRP), to be consistently associated with MDD and network dysfunction. The aim was to investigate whether CRP is linked to a distinct set of resting-state functional connectivity (RSFC) alterations.For this reason, we investigated the effects of diagnosis and elevated blood plasma CRP levels on the RSFC in 63 participants (40 females, mean age 31.4 years) of which were 27 patients with a primary diagnosis of MDD and 36 healthy control-subjects (HC), utilizing a seed-based approach within five well-established RSFC networks obtained using fMRI.Of the ten network pairs examined, five showed increased between-network RSFC-values unambiguously connected either to a diagnosis of MDD or elevated CRP levels. For elevated CRP levels, increased RSFC between DMN and AN was found. Patients showed increased RSFC within DMN areas and between the DMN and ECN and VAN, ECN and AN and AN and DAN.The results of this study show dysregulated neural circuits specifically connected to elevated plasma CRP levels and independent of other alterations of RSFC in MDD. This dysfunction in neural circuits might in turn result in a certain immune-inflammatory subtype of MDD.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

OBJECTIVES Despite 1 in 10 children being affected by armed conflicts, there is limited evidence on the effects of conflicts on early childhood development (ECD), an important Sustainable Development Goals indicator. We aimed to elucidate the relationship between exposure to conflicts and ECD. METHODS We conducted a multinational observational study using population-based data on 27 538 children 36 to 59 months old from Demographic and Health Surveys from 12 low- and middle-income countries merged with prospective data on conflicts from Uppsala Conflict Data Program. We estimated the association between 1 to 5 consecutive years of exposure to conflicts within 50 km and ECD after inverse probability of treatment weighting. Mediators of the relationship between conflicts and ECD were identified. We also estimated the association between conflicts and individual domains of ECD. RESULTS Exposure to conflicts was associated with a 5.9% decrease (95% confidence interval −7.5% to −4.3%) in the probability of a child being developmentally on track from the first year of exposure. This was compounded after the second year, with 5 consecutive years of exposure associated with a 10.4% decrease in the probability of a child being developmentally on track (95% confidence interval −13.7% to −7.2%). A lack of access to early childhood education was a significant mediator into the fifth year of exposure. Among individual ECD domains, socioemotional development was disproportionately impaired. CONCLUSIONS Exposure to nearby conflicts is associated with an increased probability of delayed ECD, especially with chronic exposure. Children in affected areas should be provided psychosocial support and early childhood education from an early stage.

Background Smaller hippocampus volume represents a consistent finding in major depression (MDD). Hippocampal neuroplasticity due to chronic stress might have differential effect on hippocampal subfields. We investigated the effects of the rs1360780 polymorphism of the hypothalamic-pituitary-axis related gene FKBP5 in combination with early life stress (ELA) on the structure of hippocampal subfields in MDD. Methods We assessed the hippocampal subfields volumes in 85/67 MDD/healthy controls. We investigated the effects of diagnosis, FKBP5 allelic status and their interaction as predictors of hippocampal subfield volumes as well as the effect of ELA and its interaction with FKBP5. Results MDD patients had smaller hippocampal volumes, in particular within the cornu ammonis (CA) and dentate gyrus (DG) regions. Patients exposed to ELA had larger hippocampi, in particular within the CA and DG. Among the patients exposed to ELA, the T allele carriers displayed lower volumes within the hippocampus-amygdala-transition-area (HATA) as those subjects homozygous for the C allele. Limitations We pooled the subjects from 2 centers in order to increase the sample size. We did not include the cumulative lifetime exposure to medication. Conclusions Hippocampal volume reductions in MDD were present particularly in the CA and DG. MDD with ELA display differential volume changes compared to MDD without ELA. The significant interaction between ELA and the rs1360780 polymorphism in HATA suggests a role of FKBP5 in the pathophysiology of structural alterations in depression.

Special Issue: The ENIGMA Consortium: the first 10 years.-- Karolinska Schizophrenia Project (KaSP)., Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., National Institute of Mental Health, Grant/Award Numbers: MH104284, MH116147, R01MH113619, R01 MH090553, R01MH117014, R01MH042191; Karolinska Institutet; Stockholm County Council; Southern and Eastern Norway Regional Health Authority; German Centre for Cardiovascular Research; DZHK; Siemens Healthineers; University of Queensland; US National Institute of Child Health and Human Development, Grant/Award Number: RO1HD050735; Australian National Health and Medical Research Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Institute on Drug Abuse, Grant/Award Numbers: UL1 TR000153, 1 U24 RR025736-01, 1 U24 RR021992; Brain Injury Fund Research Grant Program; Indiana State Department of Health Spinal Cord; Parents Against Childhood Epilepsy; Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures; Epilepsy Foundation; American Epilepsy Society; Knut and Alice Wallenberg Foundation; European Community's Horizon 2020 Programme; Vici Innovation Program; NWO Brain & Cognition Excellence Program; Netherlands Organization for Scientific Research; Hersenstichting Nederland; Netherlands Organization for Health Research and Development; Geestkracht Programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; Universiteit Utrecht; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; National Center for Advancing Translational Sciences; National Institutes of Health; National Center for Research Resources; Consortium grant, Grant/Award Number: U54 EB020403; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Number: G0500092; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; the Research Council, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Swedish Research Council; European Community's Seventh Framework Programme, Grant/Award Number: 602450; King's College London; South London and Maudsley NHS Foundation Trust; Biomedical Research Centre; National Institute for Health Research.

Journal of affective disorders 283, 115-122 (2021). doi:10.1016/j.jad.2020.11.124, Published by Elsevier Science, Amsterdam [u.a.]

BackgroundChildhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

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, p(FDR)

Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology.

N-Methyl-D-aspartate glutamate receptor (NMDA-R) antibodies (Abs) could play a role in neurodegenerative disorders. Since, in these diseases, NMDA-R Abs were detected in serum, but only sporadic in cerebrospinal fluid (CSF), the origin and impact of the Abs are still unresolved. We examined the presence of NMDA-R Abs in serum and CSF using a cell-based immunofluorescence assay as well as the function of the blood-CSF-barrier (B-CSF-B) by determination of Q albumin (ratio of albumin in CSF and serum) in patients with mild cognitive impairment (MCI; N = 59) and different types of dementia, Alzheimer's disease (AD; N = 156), subcortical ischemic vascular dementia (SIVD; N = 61), and frontotemporal dementia (FTD; N = 34). Serum IgA/IgM NMDA-R Abs and/or a disturbed B-CSF-B were sporadically present in all investigated patients' groups. In AD, these Abs often developed during the disease course. Patients with either no hippocampal atrophy and/or no AD-related characteristic changes in CSF, referred to "non-classical" AD, were characterized by seropositivity at diagnosis and loss of function of the B-CSF-B showed a progressive decline in cognitive functions and a poor prognosis. Our data indicate that NMDA-R Abs are present in different types of dementia and elderly healthy individuals. In combination with disturbed B-CSF-B integrity, they seem to promote their pathological potential on cognitive decline, and thus, a subgroup of dementia patients with these unique characteristics might inform clinicians.

Background Major depression is characterized by an impaired ability to evaluate and modify emotional responses as well as attention deficits, however the neural origins of these features are unresolved. The aim of the study was to investigate activation and functional connectivity changes during recognition and voluntary attentional regulation of emotion in 34 patients with major depressive disorder (MDD) compared to 35 controls. Methods We employed an fMRI task in which participants assessed the valence or the shape of emotional stimuli. Then we analysed BOLD responses and functional connectivity using psycho-physiological interaction during the two conditions. Results Patients showed more incorrect responses across both trial types. Recognition trials recruited areas belonging to the ventral system, which is involved in the generation and automatic processing of emotion. Shift of attention away from the emotional content activated areas belonging to the dorsal emotion regulation system. Patients showed hyper-connectivity between and within the default mode and task positive networks. While shifting attention away from emotion, patients had a reduced response of the anterior insula and increased connectivity across areas involved in emotion generation and regulation. Connectivity between the amygdala and visual areas was also altered in patients compared to controls during evaluation of negative and positive pictures, which might be related to biased valence processing. Finally, during regulation of negative trials and recognition of positive trials patients showed decreased coupling in areas involved in attention allocation and emotional regulation. Limitations Most of the patients were medicated, although potential effects of treatment were investigated. Conclusions Overall, our findings are compatible with abnormal functional coupling in MDD of regions involved in perception, recognition and attention allocation, especially during regulation of negative images and valence evaluation of positive images.

Schizophrenia is a severe neuropsychiatric disorder with impairments in social cognition. Several brain regions have been implicated in social cognition, including the nucleus caudatus, prefrontal and temporal cortex, and cerebellum. Oxytocin is a critical modulator of social cognition and the formation and maintenance of social relationships and was shown to improve symptoms and social cognition in schizophrenia patients. However, it is unknown whether the oxytocin receptor is altered in the brain. Therefore, we used qRT-PCR and Ornithine Vasotocin Analog ([125I]OVTA)-based receptor autoradiography to investigate oxytocin receptor expression at both the mRNA and protein level in the left prefrontal and middle temporal cortex, left nucleus caudatus, and right posterior superior vermis in 10 schizophrenia patients and 6 healthy controls. Furthermore, to investigate confounding effects of long-term antipsychotic medication we treated rats with clozapine or haloperidol for 12weeks and assessed expression of the oxytocin receptor in cortical and subcortical brain regions. In schizophrenia patients, we found a downregulation of oxytocin receptor mRNA in the temporal cortex and a decrease in receptor binding in the vermis. In the other regions, the results showed trends in the same direction, without reaching statistical significance. We found no differences between antipsychotic-treated rats and controls. Downregulated expression and binding of the oxytocin receptor in brain regions involved in social cognition may lead to a dysfunction of oxytocin signaling. Our results support a dysfunction of the oxytocin receptor in schizophrenia, which may contribute to deficits of social cognition.

Background: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES. Methods: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting. Results: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3β (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. Conclusion: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.

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.

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T-1-weighted MRI data were processedwith a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1.Results: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Aims: Smaller hippocampal volumes are among the most consistently reported neuroimaging findings in schizophrenia. However, little is known about hippocampal volumes in people who report psychotic experiences. This study investigated differences in hippocampal volume between young people without formal diagnoses who report psychotic experiences (PEs) and those who do not report such experiences. This study also investigated if any differences persisted over two years. Methods: A nested case-control study of 25 adolescents (mean age 13.5 years) with reported PEs and 25 matched controls (mean age 13.36 years) without PEs were drawn from a sample of 100 local schoolchildren. High-resolution T1-weighted anatomical imaging and subsequent automated cortical segmentation (Freesurfer 6.0) was undertaken to determine total hippocampal volumes. Comprehensive semi-structured clinical interviews were also performed including information on PEs, mental diagnoses and early life stress (bullying). Participants were invited for a second scan at two years. Results: 19 adolescents with PEs and 19 controls completed both scans. Hippocampal volumes were bilaterally lower in the PE group compared to the controls with moderate effects sizes both at baseline [left hippocampus p = 0.024 d = 0.736, right hippocampus p = 0.018, d = 0.738] and at 2 year follow up [left hippocampus p = 0.027 d = 0.702, right = 0.048 d = 0.659] throughout. These differences survived adjustment for co-morbid mental disorders and early life stress. Conclusions: Psychotic experiences are associated with total hippocampal volume loss in young people and this volume loss appears to be independent of possible confounders such as co-morbid disorders and early life stress.

Innate immunity has been linked to initiation of Alzheimer’s disease and multiple sclerosis. Moreover, risk of first-episode psychosis (FEP) and schizophrenia (Sz) is increased after various infections in predisposed individuals. Thus, we hypothesized an analogous role of innate immunity with increased C-reactive protein (CRP) in non-affective psychosis. Differential blood count, CRP, neutrophil and monocyte–macrophage activation markers, cortisol and psychotic symptoms (Positive and Negative Syndrome Scale [PANSS]) were assessed in controls (n = 294) and acutely ill unmedicated FEP (n = 129) and Sz (n = 124) patients at baseline and after 6 weeks treatment. Neutrophils, monocytes, and CRP were increased in patients vs controls at baseline (P < .001), and neutrophil and monocyte counts correlated positively with activation markers. Eosinophils were lower at baseline in FEP (P < .001) and Sz (P = .021) vs controls. Differences in neutrophils (P = .023), eosinophils (P < .001), and CRP (P < .001) were also present when controlling for smoking and cortisol, and partially remitted after antipsychotic treatment. FEP patients with high neutrophils (P = .048) or monocytes (P = .021) had higher PANSS-P scores at baseline but similar disease course. CRP correlated with PANSS-P at baseline (ρ = 0.204, P = .012). Improvement of positive symptoms after treatment correlated with declining neutrophils (ρ = 0.186, P = .015) or CRP (ρ = 0.237, P = .002) and rising eosinophils (ρ = −0.161, P = .036). In FEP, normalization of neutrophils (ρ = −0.231, P = .029) and eosinophils (ρ = 0.209, P = .048) correlated with drug dosage. In conclusion, innate immune system activation correlated with PANSS-P, supporting the immune hypothesis of psychosis. Neutrophil and monocyte counts and CRP levels may be useful markers of disease acuity, severity, and treatment response.

Contains fulltext : 204879pub.pdf (Publisher’s version ) (Open Access) Contains fulltext : 204879pos.pdf (Author’s version postprint ) (Open Access) OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Introduction: Despite the fact, that symptom-triggered alcohol withdrawal treatment is recommended by German guidelines on alcoholism, many hospitals continue to use fixed-schedule protocols, as they have been successfully applied for many years. Methods: This retrospective study compared all patients' records of alcohol withdrawal treatment from October 2010 to November 2011 at Magdeburg's University Department of Psychiatry (n=120). A symptom-triggered protocol with clomethiazole (AESB, n=46) was used in parallel with the existing fixed-schedule protocol with diazepam (n=74). Results: The symptom-triggered group showed less need of pharmacological treatment duration (p

Around 1 in 5 children under 13 years old experience sub-clinical psychotic experiences (PEs) like hallucinations and delusions. While PEs in childhood are a significant risk factor for adult psychotic disorders, the majority of those experiencing childhood PEs do not develop a psychotic disorder. Individual differences in regional brain maturation rates may be responsible for this age-related and often transient emergence of PEs. Fronto-temporal association tracts undergo extensive maturation and myelination throughout childhood and adolescence, thus we focus on individual differences in one such tract, the arcuate fasciculus. A normative population-based sample of children (aged 11–13) attended a clinical interview and MRI (n = 100), 25 of whom were identified as reporting strong PEs. This group had reduced mean and radial diffusivity in the arcuate fasciculus compared with a group of matched controls (n = 25) who reported no PEs. The group difference was greater in the left hemisphere than the right. Mediation analyses showed that this group difference was driven predominantly by perceptual disturbances and an along-tract analysis showed that the group difference was greatest approximately halfway between the frontal and temporal termination points of the tract (adjacent to the left lateral ventricle). This study is the first to investigate links between arcuate fasciculus diffusivity and psychotic experiences in a population sample of children.

The objective of this study was to determine the effect of major depressive disorder (MDD) on white matter microstructures after a 6-year period compared to healthy controls (HC). This study included a small sample size of 26 participants, including 14 patients with MDD clinically diagnosed at baseline, and 12 HCs. MRI brain scans were conducted at baseline and follow-up, 75.32 (±2.25) months after the initial scan. Tractography of 7 regions including the fornix, cingulum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and uncinate fasciculus were conducted using ExploreDTI software. Both groups showed significant reduction in tract integrity between time points. MDD diagnosis was shown to have an effect on longitudinal FA of the left dorsal cingulum and the left parahippocampal cingulum. A significant inverse relationship was found between ΔFA [baseline FA - follow-up FA] of the right uncinate fasciculus and the left rostral cingulum with ΔHAM-D [baseline HAM-D - follow-up HAM-D] within the MDD group. These preliminary findings support the hypothesis that limbic structures including the cingulum are involved in MDD pathophysiology and may be affected even after remission. Moreover, they indicate that recovery from depression symptoms may slow the rate of WM degradation associated with aging in these regions of interest.

Background Tryptophan depletion is a well-replicated biological finding in Major Depressive Disorder (MDD). The kynurenine pathway (KP) and its rate-limiting tryptophan degrading enzyme, indolamine 2,3 dioxygenase (IDO), have been implicated in the pathogenesis of depression. IDO expression is driven by inflammatory cytokines, providing a putative link between inflammation and neuropathology. This study examined circulating concentrations of C-reactive protein (CRP), plasma tryptophan, kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) and whole blood mRNA expression of IDO in patients with major depressive disorder (MDD) compared with healthy controls (HC). Methods A diagnosis of major depression was made according to DSM-IV. Depression severity was assessed using the Hamilton depression (HAM-D) rating scale. 74 MDD patients, 39 with a first presentation of MDD (fpMDD) and 35 with chronic or recurrent episodes (rMDD), and 37 HC were recruited to the study. Whole blood and plasma samples were collected. Expression of markers in whole blood were measured by PCR, circulating CRP by ELISA and KP metabolites by LC–MS/MS. Hippocampal cornu ammonis (CA) and subiculum volumes were determined by MRI and calculated using FreeSurfer. Results Tryptophan concentrations were significantly reduced in MDD compared to HC. There was a positive correlation between QUIN and both CRP concentrations and whole blood IDO1 in MDD. KYNA concentrations were reduced in MDD patients presenting with a first episode (fpMDD) compared to those presenting with recurrent depression (rMDD) and HC. By contrast QUIN concentrations were elevated in rMDD compared to fpMDD and HC. KYNA/QUIN was reduced in MDD and rMDD but not fpMDD compared to HC. Hippocampal subfield volumes were smaller in MDD patients than HC for CA1 (left only), CA2/3 (left and right) and CA4 (right only). CRP and CA1 volumes were negatively correlated bilaterally in MDD patients. KYNA and subiculum volume were positively correlated bilaterally. Discussion This study found evidence of KP metabolism imbalance in MDD patients in addition to tryptophan reduction and mild immune activation. Relationships between CRP and KYNA with some hippocampal subfield volumes in MDD patients suggest that this inflammatory signature may be associated with reduced hippocampal subfield volumes in depression.

Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance.

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.

Background: The aim of the present study was to investigate the association of fMRI blood oxygen–level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

Background: At present there is a substantial uncertainty regarding the extent and nature of autism spectrum disorder (ASD) and bipolar affective disorder (BPAD) co-occurrence due to disparate findings in previous studies. This paper aimed to find and review original studies on co-occurrence rates of ASD with BPAD, assess them, synthesize the findings in a systematic way, present an overview and make recommendations for future research. Methods: Systematic literature searches were performed using several databases. Selected articles had to describe an original study that provided prevalence and/or incidence analysis on ASD co-occurring together with BPAD. Results and Conclusion: A significant minority of patients (7%) with ASD suffers from BPAD. An accurate detection of co-occurring ASD and BPAD can lead to a more targeted treatment and improve the patients' functioning and quality of life.

Alterations of the glucocorticoid system and of hippocampal volumes have consistently been reported in patients with major depressive disorders (MDD). The aim of the present study was to investigate whether the messenger RNA (mRNA) expression of glucocorticoid inducible genes is associated with changes in the cornu ammonis (CA) and dentate gyrus subfields. Forty-three patients with MDD and 43 healthy controls were recruited and investigated with high resolution magnetic resonance imaging. Hippocampal subfields were measured using freesurfer. Measurement of whole blood mRNA expression of glucocorticoid inducible genes serum and glucocorticoid-regulated kinase 1 (SGK1), FK506 binding protein 5 (FKBP5), and glucocorticoid induced leucine zipper (GILZ) was performed. Patients with MDD had significantly smaller volumes of CA1, CA2/3, CA4/DG, and subiculum compared to healthy controls. In the regression analysis, the factor diagnosis had a significant moderating effect on the association of SGK1 and hippocampal volumes. Patients with low expression of SGK1 had significantly smaller CA2/3 and CA4/DG volumes compared to patients with high expression of SGK1 mRNA and to healthy controls with low/high expression of SGK1, respectively. Therefore, a lack of mRNA expression of glucocorticoid inducible genes in patients with MDD that seems to correspond to a blunted cortisol response is associated with smaller hippocampal CA and dentate gyrus volumes. SGK1 seems to be particularly relevant for stress-related mental disorders.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.72.

Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state‐of‐the‐art voxel‐based morphometry (VBM) to investigate whether transcranial magnetic stimulation‐induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole‐brain analyses (P