Publications by authors named "Thomas Frodl"

165 Publications

Altered resting-state functional connectome in major depressive disorder: a mega-analysis from the PsyMRI consortium.

Transl Psychiatry 2021 Oct 7;11(1):511. Epub 2021 Oct 7.

Department of Psychology, Friedrich Schiller University Jena, Jena, Germany.

Major depressive disorder (MDD) is associated with abnormal neural circuitry. It can be measured by assessing functional connectivity (FC) at resting-state functional MRI, that may help identifying neural markers of MDD and provide further efficient diagnosis and monitor treatment outcomes. The main aim of the present study is to investigate, in an unbiased way, functional alterations in patients with MDD using a large multi-center dataset from the PsyMRI consortium including 1546 participants from 19 centers ( www.psymri.com ). After applying strict exclusion criteria, the final sample consisted of 606 MDD patients (age: 35.8 ± 11.9 y.o.; females: 60.7%) and 476 healthy participants (age: 33.3 ± 11.0 y.o.; females: 56.7%). We found significant relative hypoconnectivity within somatosensory motor (SMN), salience (SN) networks and between SMN, SN, dorsal attention (DAN), and visual (VN) networks in MDD patients. No significant differences were detected within the default mode (DMN) and frontoparietal networks (FPN). In addition, alterations in network organization were observed in terms of significantly lower network segregation of SMN in MDD patients. Although medicated patients showed significantly lower FC within DMN, FPN, and SN than unmedicated patients, there were no differences between medicated and unmedicated groups in terms of network organization in SMN. We conclude that the network organization of cortical networks, involved in processing of sensory information, might be a more stable neuroimaging marker for MDD than previously assumed alterations in higher-order neural networks like DMN and FPN.
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http://dx.doi.org/10.1038/s41398-021-01619-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497531PMC
October 2021

Dementia-associated changes of immune cell composition within the cerebrospinal fluid.

Brain Behav Immun Health 2021 Jul 20;14:100218. Epub 2021 Apr 20.

Department of Psychiatry, University of Magdeburg, Magdeburg, Germany.

Inflammation and alterations in essential protein structures in the brain might also change the cellular distribution in the cerebrospinal fluid (CSF). Using flow cytometry, we analyzed cell populations of the innate and adaptive immune system associated with the most frequent forms of dementias. We included patients with mild cognitive impairment (MCI; N ​= ​33), Alzheimer's disease (AD; N ​= ​90), vascular dementia (VD; N ​= ​35) and frontotemporal dementia (FTD; N ​= ​17) at the time of diagnosis, before onset of treatment and 11 elderly non-demented individuals. Dependent on the form of dementia, an increased frequency of CD14 monocytes, NK cells and NKT cells was measured. Within the T cell population, a dementia-associated shift from central memory towards (late-stage) effector cells was detected. T cells and NKT cells were correlated with MMSE, NK and NKT cells were correlated with ptau, CD14 monocytes and NK cells were correlated with Amyloid-β 1-40. Our data suggest that each investigated immune cell type is involved in dementia-associated alterations within the CSF, possibly having distinct functions in their pathogenesis.
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http://dx.doi.org/10.1016/j.bbih.2021.100218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474581PMC
July 2021

Armed Conflict and Early Childhood Development in 12 Low- and Middle-Income Countries.

Pediatrics 2021 09 17;148(3). Epub 2021 Aug 17.

Regional Centre for Child and Youth Mental Health and Child Welfare - Central Norway, IPH, Norwegian University of Science and Technology, Trondheim, Norway

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.
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http://dx.doi.org/10.1542/peds.2021-050332DOI Listing
September 2021

Amygdala substructure volumes in Major Depressive Disorder.

Neuroimage Clin 2021 8;31:102781. Epub 2021 Aug 8.

Trinity College Institute of Neuroscience, Lloyd Building, Trinity College Dublin, Dublin 2, Ireland.

The role of the amygdala in the experience of emotional states and stress is well established. Connections from the amygdala to the hypothalamus activate the hypothalamic-pituitaryadrenal (HPA) axis and the cortisol response. Previous studies have failed to find consistent whole amygdala volume changes in Major Depressive Disorder (MDD), but differences may exist at the smaller substructural level of the amygdala nuclei. High-resolution T1 and T2-weighted-fluid-attenuated inversion recovery MRIs were compared between 80 patients with MDD and 83 healthy controls (HC) using the automated amygdala substructure module in FreeSurfer 6.0. Volumetric assessments were performed for individual nuclei and three anatomico-functional composite groups of nuclei. Salivary cortisol awakening response (CAR), as a measure of HPA responsivity, was measured in a subset of patients. The right medial nucleus volume was larger in MDD compared to HC (p = 0.002). Increased right-left volume ratios were found in MDD for the whole amygdala (p = 0.004), the laterobasal composite (p = 0.009) and in the central (p = 0.003) and medial (p = 0.014) nuclei. The CAR was not significantly different between MDD and HC. Within the MDD group the left corticoamygdaloid transition area was inversely correlated with the CAR, as measured by area under the curve (AUCg) (p ≤ 0.0001). In conclusion, our study found larger right medial nuclei volumes in MDD compared to HC and relatively increased right compared to left whole and substructure volume ratios in MDD. The results suggest that amygdala substructure volumes may be involved in the pathophysiology of depression.
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http://dx.doi.org/10.1016/j.nicl.2021.102781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361319PMC
September 2021

Association Between Homocysteine and Vitamin Levels in Demented Patients.

J Alzheimers Dis 2021 ;81(4):1781-1792

Department of Psychiatry and Psychotherapy, Medical Faculty, University of Magdeburg, Magdeburg, Germany.

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.
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http://dx.doi.org/10.3233/JAD-201481DOI Listing
September 2021

[Medical education in psychosocial disciplines in times of the COVID-19 pandemic - first experiences].

Fortschr Neurol Psychiatr 2021 May 4. Epub 2021 May 4.

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medizinische Fakultät, Klinik für Psychiatrie und Psychotherapie.

Aim: In specialties that heavily rely on communication skills such as psychiatry, psychotherapy and psychosomatic medicine, teaching in times of the COVID-19 pandemic is especially challenging. In this overview, educators and course directors report their experiences in eteaching and share their innovative solutions.

Methods: We present a collection of methods that relate to teaching and assessment as well as student activation.

Results: A range of helpful tools for teaching were compiled. This includes instructional videos with simulated patients, structured homework to document a mental status examination, structured hand-offs, and practical examinations in video format. Motivational techniques include podcasts with interviews with clinicians and patients and teaching with the use of cinematic material.

Discussion: Switching to online formats creates opportunities and advantages for the advancement of time- and location-independent learning. A fast conversion in this direction might also pose some disadvantages. A direct patient-student interaction is critical for engaging with transference, countertransference and situational aspects for teaching in psychosocial disciplines. Empirical studies of the effectiveness of these newly developed formats and faculty development for digital teaching are necessary.
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http://dx.doi.org/10.1055/a-1480-7258DOI Listing
May 2021

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

J Child Psychol Psychiatry 2021 Oct 22;62(10):1202-1219. Epub 2021 Mar 22.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.

Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
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http://dx.doi.org/10.1111/jcpp.13396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455726PMC
October 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

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.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

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.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Brain structural correlates of insomnia severity in 1053 individuals with major depressive disorder: results from the ENIGMA MDD Working Group.

Transl Psychiatry 2020 12 8;10(1):425. Epub 2020 Dec 8.

Department of Psychiatry, University of Münster, Münster, Germany.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.
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http://dx.doi.org/10.1038/s41398-020-01109-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723989PMC
December 2020

Reduced habenular volumes and neuron numbers in male heroin addicts: a post-mortem study.

Eur Arch Psychiatry Clin Neurosci 2021 Aug 1;271(5):835-845. Epub 2020 Oct 1.

Department of Psychiatry and Psychotherapy, University of Magdeburg, 39120, Magdeburg, Germany.

The Habenula is increasingly being investigated in addiction. Reduced volumes of other relevant brain regions in addiction, such as nucleus accumbens, globus pallidus and hypothalamus have been reported. Reduced volumes of the habenula as well as reduced neuronal cell count in the habenula have also been reported in mood disorders and an overlap between mood disorders and addiction is clinically widely recognized. Thus, our aim was to investigate possible volume and neuronal cell count differences in heroin addicts compared to healthy controls. Volumes of the medial (MHB) and lateral habenula (LHB) in heroin addicts (n = 12) and healthy controls (n = 12) were assessed by morphometry of 20 µm serial whole brain sections. Total brain volume was larger in the heroin group (mean 1466.6 ± 58.5 cm vs. mean 1331.5 ± 98.8 cm), possibly because the heroin group was about 15 years younger (p = 0.001). Despite larger mean whole brain volume, the mean relative volume of the MHB was smaller than in healthy non-addicted controls (6.94 ± 2.38 × 10 vs.10.64 ± 3.22 × 10; p = 0.004). A similar finding was observed regarding relative volumes of the LHB (46.62 ± 10.90 × 10 vs. 63.05 ± 16.42 × 10 p = 0.009). In parallel, neuronal cell numbers were reduced in the MHB of heroin-addicted subjects (395,966 ± 184,178 vs. 644,149 ± 131,140; p < 0.001). These findings were not significantly confounded by age and duration of autolysis. Our results provide further evidence for brain-structural deficits in heroin addiction.
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http://dx.doi.org/10.1007/s00406-020-01195-yDOI Listing
August 2021

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

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.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Association of thyroid peroxidase antibodies with anti-neuronal surface antibodies in health, depression and schizophrenia - Complementary linkage with somatic symptoms of major depression.

Brain Behav Immun 2020 11 1;90:47-54. Epub 2020 Aug 1.

Laboratory of Translational Psychiatry, University of Magdeburg, Magdeburg, Germany; Department of Psychiatry and Psychotherapy, University of Magdeburg, Magdeburg, Germany.

Hashimoto's thyroiditis has been associated with major depression (MD) and schizophrenia (Sz) in epidemiological studies. However, diagnostically relevant antibodies (Abs) against thyroid peroxidase (TPO) and thyroglobulin (Tg) do not act directly on neurons. We hypothesized that an increased prevalence of anti-brain-Abs in thyroid-Ab-carriers could be linked with MD and Sz even without clinically manifest Hashimoto's thyroiditis. Serum samples from 638 acutely-ill patients with MD, Sz or matched controls were systematically screened for TPO- and Tg-Abs, other endocrine-Abs and a spectrum of specific anti-brain-Abs (directed against neuronal cell surface, synaptic, other neuronal or glial proteins). Analyses were based on indirect immunofluorescence in biochip mosaics of frozen tissue sections and transfected HEK293 cells expressing respective recombinant target antigens. Psychopathology was assessed on admission and after 6 weeks treatment by HAMD-21 (in MD) or PANSS (in Sz). Seroprevalence of TPO- and/or Tg-Abs was comparable in ill and healthy individuals (MD ~10%, Sz ~7%, controls ~9%) but thyroid-Abs were associated with neuronal cell surface/synaptic-Abs (p = 0.005), particularly in schizophrenia. Thyroid Ab-positive MD patients showed higher HAMD-21 scores (particularly somatic symptoms) at baseline (p = 0.026) and better reduction of symptoms after 6 weeks (p = 0.049) than thyroid-Ab-negative patients. This was unrelated to antidepressant drug dosage, thyroid hormonal-, inflammation- and anti-brain-Ab-status. No link with PANSS scores was observed in Sz. In conclusion, the co-occurrence of thyroid-Abs and neuronal surface/synaptic-Abs may be associated with Sz. Future cerebrospinal fluid research may be promising to clarify if thyroid-Ab-associated neuronal-Abs reach the brain in Sz patients. Thyroid-Ab-related differences regarding disease-severity and -course in MD are currently unexplained, but may be caused by un-identified anti-brain-Abs or a direct action of TPO-Abs on astrocytes.
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http://dx.doi.org/10.1016/j.bbi.2020.07.039DOI Listing
November 2020

Multiple Network Dysconnectivity in Adolescents with Psychotic Experiences: A Longitudinal Population-Based Study.

Schizophr Bull 2020 12;46(6):1608-1618

Department of Psychiatry, Smurfit Building, Royal College of Surgeons Ireland at Beaumont Hospital, Dublin, Ireland.

Abnormal functional connectivity (FC, the temporal synchronization of activation across distinct brain regions) of the default mode (DMN), salience (SN), central executive (CEN), and motor (MN) networks is well established in psychosis. However, little is known about FC in individuals, particularly adolescents, reporting subthreshold psychotic experiences (PE) and their trajectory over time. Thus, the aim of this study was to investigate the FC of these networks in adolescents with PE. In this population-based case-control study, 24 adolescents (mean age = 13.58) meeting the criteria for PE were drawn from a sample of 211 young people recruited and scanned for a neuroimaging study, with a follow-up scan 2 years later (n = 18, mean age = 15.78) and compared to matched controls drawn from the same sample. We compared FC of DMN, SN, CEN, and MN regions between PE and controls using whole-brain FC analyses. At both timepoints, the PE group displayed significant hypoconnectivity compared to controls. At baseline, FC in the PE group was decreased between MN and DMN regions. At follow-up, dysconnectivity in the PE group was more widespread. Over time, controls displayed greater FC changes than the PE group, with FC generally increasing between MN, DMN, and SN regions. Adolescents with PE exhibit hypoconnectivity across several functional networks also found to be hypoconnected in established psychosis. Our findings highlight the potential for studies of adolescents reporting PE to reveal early neural correlates of psychosis and support further investigation of the role of the MN in PE and psychotic disorders.
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http://dx.doi.org/10.1093/schbul/sbaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846103PMC
December 2020

Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.

Am J Psychiatry 2020 09 16;177(9):834-843. Epub 2020 Jun 16.

The full list of authors in the ENIGMA working groups, author affiliations, author disclosures, and acknowledgments are provided in online supplements.

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data.

Methods: Structural T-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from 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. The authors examined subcortical volume, cortical thickness, and cortical 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 intracranial volume for subcortical and surface area measures).

Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood.

Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.
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http://dx.doi.org/10.1176/appi.ajp.2020.19030331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296070PMC
September 2020

Reduced hippocampal volume in adolescents with psychotic experiences: A longitudinal population-based study.

PLoS One 2020 3;15(6):e0233670. Epub 2020 Jun 3.

Dept. of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269246PMC
August 2020

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

J Affect Disord 2020 06 6;271:160-168. Epub 2020 Apr 6.

Department of Psychology, Concordia University, Montreal, Canada; CHU Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Canada; Department of Psychology, Queen's University, Kingston, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jad.2020.03.062DOI Listing
June 2020

ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing.

Transl Psychiatry 2020 05 29;10(1):172. Epub 2020 May 29.

Illinois Institute of Technology, Chicago, IL, USA.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.
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http://dx.doi.org/10.1038/s41398-020-0842-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260219PMC
May 2020

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.

Mol Psychiatry 2020 May 28. Epub 2020 May 28.

Department of Psychiatry, University of Texas Health Science Center at Houston, Houston, TX, USA.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.
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http://dx.doi.org/10.1038/s41380-020-0774-9DOI Listing
May 2020

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Mol Psychiatry 2020 May 18. Epub 2020 May 18.

Department of Psychiatry, University of Münster, Münster, Germany.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 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). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities 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 clinical value of these brain-PAD estimates.
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http://dx.doi.org/10.1038/s41380-020-0754-0DOI Listing
May 2020

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Hum Brain Mapp 2020 May 18. Epub 2020 May 18.

Division of Psychological & Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technischen Universität Dresden, Dresden, Germany.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
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http://dx.doi.org/10.1002/hbm.25029DOI Listing
May 2020

Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients.

Brain Behav Immun 2020 08 10;88:497-506. Epub 2020 Apr 10.

Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences, Magdeburg, Germany; Salus Institute, Magdeburg, Germany.

An increasing number of clinical, epidemiological and genetic studies as well as investigations of CSF and blood suggests that neuroinflammation plays an essential role in the etiology of schizophrenia and mood disorders. However, direct neuropathological evidence of inflammation within the brain tissue remains sparse and the regional distribution of lymphocytes as surrogate markers of blood-brain barrier (BBB) impairment has not yet been investigated in this context. Densities of T and B lymphocytes were assessed in coronal whole brain sections of 22 patients with schizophrenia and 20 patients suffering from major depression or bipolar disorder, compared to 20 individuals without neuropsychiatric disorders from the Magdeburg Brain Collection. Cell densities were determined by immunohistochemical staining (anti-CD3 for T cells, anti-CD20 for B cells), followed by automated microscopic image acquisition and analysis. Hierarchical clustering and detailed cluster analysis were performed to detect possible subgroups of patients. Regional distribution was assessed by analysis of color coded mappings based on microsopic scans. Elevated lymphocyte density was found in 7 out of 20 mood disorder patients (adj. p = 0.022; Fisher's exact test, FET), 9 out of 22 schizophrenic patients (adj. p = 0.014; FET) and in 1 of 20 controls (p < 0.005; FET). Several cases showed different patterns of infiltration affecting cortical regions or subcortical white matter, while some presented diffuse infiltration. In two thirds of patients, no increased lymphocyte density could be found. The current findings indicate that lymphocyte infiltration occurs in a greater proportion of schizophrenia and mood disorder patients as compared to healthy controls. Under healthy conditions lymphocytes rarely cross the BBB. Thus, higher densities are considered indicators of neuroinflammation associated with an impairment of the BBB.
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http://dx.doi.org/10.1016/j.bbi.2020.04.021DOI Listing
August 2020

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

Transl Psychiatry 2020 03 20;10(1):100. Epub 2020 Mar 20.

Department of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
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http://dx.doi.org/10.1038/s41398-020-0705-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083923PMC
March 2020

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.

Lancet Psychiatry 2020 01 24;7(1):93-108. Epub 2019 Oct 24.

Department of Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.

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.
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http://dx.doi.org/10.1016/S2215-0366(19)30290-1DOI Listing
January 2020

Insulin-signaling abnormalities in drug-naïve first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin.

Eur Psychiatry 2019 10 4;62:124-129. Epub 2019 Oct 4.

Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.eurpsy.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941668PMC
October 2019

Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment.

Schizophr Bull 2020 02;46(2):363-373

Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.

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.
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http://dx.doi.org/10.1093/schbul/sbz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442383PMC
February 2020

Psychotic experiences in childhood are associated with increased structural integrity of the left arcuate fasciculus - A population-based case-control study.

Schizophr Res 2020 01 5;215:378-384. Epub 2019 Sep 5.

Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.schres.2019.08.022DOI Listing
January 2020

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

Mol Psychiatry 2020 07 30;25(7):1511-1525. Epub 2019 Aug 30.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

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.
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http://dx.doi.org/10.1038/s41380-019-0477-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055351PMC
July 2020

No Alterations of Brain Structural Asymmetry in Major Depressive Disorder: An ENIGMA Consortium Analysis.

Am J Psychiatry 2019 12 29;176(12):1039-1049. Epub 2019 Jul 29.

The Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands (de Kovel, Francks); Orygen, the National Centre of Excellence in Youth Mental Health, Melbourne, Australia (Davey); the Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam (Veltman); the Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey (Jahanshad, Thompson); the Laboratory of Affective, Cognitive, and Translational Neuroscience, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russian Federation (Aftanas, Brack, Osipov); the Department of Neuroscience, Neuroimaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Aleman); the Department of Psychiatry, University of Melbourne, Melbourne (Baune); the Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany (Bülow); the Laboratory of Psychiatric Neuroimaging (LIM-21), Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil (Busatto Filho, Rosa); the Department of Psychiatry, Trinity College Dublin (Carballedo, Frodl); the Department of Psychiatry and the Weill Institute for Neurosciences, Division of Child and Adolescent Psychiatry, University of California, San Francisco (Connolly, Ho, Yang); the Department of Psychiatry, University of Minnesota Medical School, Minneapolis (Cullen, Mueller, Ubani, Schreiner); the Department of Psychiatry, University of Münster, Münster, Germany (Dannlowski, Dohm, Grotegerd, Leehr, Sindermann, Winter, Zaremba); the Department of Psychology, School of Arts and Social Sciences, City, University of London, London (Dima); the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany (Erwin-Grabner; Goya-Maldonado, Schnell, Singh); the Department of Psychiatry and Psychotherapy, Otto von Guericke University Magdeburg, Magdeburg, Germany (Frodl); the Centre for Affective Disorders, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Fu); the Department of Psychology, Neuroscience, and Behaviour, McMaster University, Hamilton, Canada (Hall); the Department of Psychiatry, Yale School of Medicine, New Haven, Conn. (Alexander-Bloch, Glahn); the Psychopharmacology Research Unit, Department of Psychiatry, University of Oxford, Oxford, U.K. (Godlewska); the Department of Psychology, Stanford University, Stanford, Calif. (Gotlib, Ho); the Department of Psychiatry and Psychotherapy, University Medicine Greifswald (Grabe, Wittfeld); the Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation, University Medical Center Groningen (Groenewold); the Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany (Gruber, Krämer, Simulionyte); the Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, and Melbourne Health, Melbourne (Harrison); the Youth Mental Health Team, Brain and Mind Centre, University of Sydney, Sydney, Australia (Hatton, Hickie, Lagopoulos); the Department of Psychiatry and Psychotherapy, Philipps University Marburg, Marburg, Germany (Kircher, Krug, Nenadic, Yüksel); the Department of Neurology, University of Magdeburg, Magdeburg (Li); the Departments of Psychiatry and Paediatrics, University of Calgary, Calgary, Canada (MacMaster, McLellan); the Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary (MacQueen); the Division of Psychiatry, University of Edinburgh, Edinburgh (Harris, McIntosh, Papmeyer, Whalley); Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia (Medland); the Department. of Psychiatry, Institute of Biomedical Research Sant Pau, Barcelona, Spain (Portella); the Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam (Reneman, Schrantee); the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford (Sacchet); West Region and Research Division, Institute of Mental Health, Singapore (Sim); Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town, South Africa (Groenewold, Stein); Brain Function and Dysfunction, Leids Universitair Medisch Centrum, Leiden, the Netherlands (Van der Wee); the Department of Psychiatry, Leiden University Medical Center, Leiden (Van der Werff); the Division of Mind and Brain Research, Department of Psychiatry and Psychotherapy CCM, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin (Veer, H. Walter); the Institute of Information and Communication Technologies (Instituto ITACA), Universitat Politècnica de València, València, Spain (Gilabert); the Institute for Community Medicine, University Medicine Greifswald, Greifswald (Völzke); the Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany (M. Walter); the Department of Psychology, University of Minnesota, Minneapolis (Schreiner); the German Center for Neurodegenerative Diseases, Site Rostock/Greifswald (Grabe, Wittfeld); the Department of Neuroscience, Novosibirsk State University, Novosibirsk (Aftanas); the Department of Psychology, University of Groningen, Groningen (Aleman); the Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, São Paulo (Busatto Filho, Rosa); the Department of Biomedical Sciences, Florida State University, Tallahassee (Connolly); the Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Dima); the Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen (Francks); the School of Psychology, University of East London, London (Fu); the Sunshine Coast Mind and Neuroscience Thompson Institute, Queensland, Australia (Lagopoulos); Strategic Clinical Network for Addictions and Mental Health, Alberta, Canada (MacMaster); the Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh (McIntosh); the Rehabilitation Services and Care Unit, Swiss Paraplegic Research, Nottwil, Switzerland (Papmeyer); CIBERSAM, Madrid (Portella); the Centre for Youth Mental Health, University of Melbourne, Melbourne (Davey, Schmaal); the Spinoza Center for Neuroimaging, Royal Netherlands Academy of Arts and Sciences, Amsterdam (Schrantee); Yong Loo Lin School of Medicine, National University of Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (Sim); the School of Public Health, Boston University, Boston (Ubani); the Leiden Institute for Brain and Cognition, Leiden (Van der Werff); the German Center for Cardiovascular Research, partner site Greifswald, Greifswald (Völzke).

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-weighted MRI data were processed with 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.
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http://dx.doi.org/10.1176/appi.ajp.2019.18101144DOI Listing
December 2019
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