Publications by authors named "Edith Pomarol-Clotet"

120 Publications

A functional connectivity study to investigate the role of the right anterior insula in modulating emotional dysfunction in borderline personality disorder.

Psychosom Med 2021 Oct 4. Epub 2021 Oct 4.

Movement Disorders Unit. Neurology Department. Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Spain Department of Psychiatry. Hospital de la Santa Creu I Sant Pau, IIB-Sant Pau. Barcelona, Spain Centro de Investigación Biomédica en Red de Salud Mental. CIBERSAM, Spain. Department of Psychiatry and Legal Medicine, Autonomous University of Barcelona, UAB, Barcelona, Spain. FIDMAG Germanes Hospitalàries Research Foundation, Barcelona. Spain. Servicio de Salud Mental, Hospital de Igualada, Consorci Sanitari de l'Anoia, Igualada, Barcelona, Spain.

Objectives: Previous imaging studies in patients with borderline personality disorder (BPD) have detected functional brain dysfunctions. Mindfulness training may improve the symptoms of BPD, although the neural mechanisms involved remain poorly understood. This study had several key aims: 1) to investigate the role of right anterior insula (rAI) functional connectivity in modulating baseline emotional status in BPD; 2) to compare differences in connectivity changes after mindfulness training versus interpersonal effectiveness intervention; and 3) to explore the correlation between longitudinal changes in imaging data and clinical indicators.

Method: Thirty-eight Patients with BPD underwent resting state functional magnetic resonance imaging (rs-fMRI). Participants completed self-report clinical scales and participated in a dialectical-behavioral therapy (mindfulness versus interpersonal effectiveness modules). Changes in clinical and imaging variables were evaluated longitudinally after completion the first 10-week sessions of psychotherapeutic intervention.

Results: At baseline, the rAI was strongly connected with the other salience network nodes and anti-correlated with most core nodes of the default mode network (p < 0.05 corrected). The functional connectivity of the rAI correlated with emotional dysregulation and deficits in mindfulness capacities (p < 0.05 corrected). After completion of psychotherapeutic intervention, both groups (mindfulness and interpersonal effectiveness) showed divergent post-therapy functional connectivity changes, which were in turn associated with the clinical response.

Conclusions: The functional connectivity of the right anterior insula seems to play an important role in emotion dysregulation and deficits in mindfulness capacities in individuals with BPD. Psychotherapy appears to modulate this functional connectivity, leading to beneficial changes in clinical variables.
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http://dx.doi.org/10.1097/PSY.0000000000001019DOI Listing
October 2021

Sex differences in neurocognitive and psychosocial functioning in bipolar disorder.

J Affect Disord 2021 Sep 25;296:208-215. Epub 2021 Sep 25.

Bipolar and Depressive Disorders Unit, Hospital Clinic, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Catalonia, Spain.

Background: Sex differences influence the clinical characteristics and course of illness of bipolar disorder (BD).

Objective: Therefore, the aim of the present study was to examine the role of sex differences in neurocognitive performance and psychosocial functioning in a large sample of euthymic patients suffering from BD.

Methods: The sample included 462 individuals, 347 patients with BD (148 males and 199 females) and 115 healthy controls (HC) (45 males and 70 females). Performance on a comprehensive neuropsychological battery assessing six cognitive domains and psychosocial functioning was compared between groups using linear mixed models, with sex and group as main effects, group by sex interactions and center as a random effect.

Results: Males performed better than females in working memory (p < 0.001), whereas females outperformed males in the verbal learning (p = 0.03) and memory recognition (p = 0.03) tasks. No significant group by sex interactions were detected in cognitive performance. There were no overall sex differences or group by sex interactions in psychosocial functioning.

Limitations: Lack of assessment of visuo-spatial working memory.

Conclusions: There were no overall sex differences in neurocognition and psychosocial functioning. However, small sex differences in some measures of working memory and verbal memory were found. Individual differences of each patient, including sex perspective, should be considered in order to perform a tailored intervention plan adjusted to specific needs in the context of personalized treatment.
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http://dx.doi.org/10.1016/j.jad.2021.09.066DOI Listing
September 2021

Activation and deactivation patterns in schizophrenia during performance of an fMRI adapted version of the stroop task.

J Psychiatr Res 2021 Sep 23;144:1-7. Epub 2021 Sep 23.

CIBERSAM (Biomedical Research Networking Centre in Mental Health), Spain; Department of Psychiatry. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain; Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, (IdISSC), Madrid, Spain.

The Stroop task, which examines an aspect of executive function/cognitive control, the ability to inhibit prepotent responses, has been relatively little examined in schizophrenia, and the findings have been inconsistent. Whether performance of this task is associated with failure of de-activation in the disorder is also uncertain. We examined 42 schizophrenic patients and 61 healthy controls during performance of an fMRI-adapted version of the Stroop task, the counting Stroop task. Task-related activations (incongruent > congruent condition) and de-activations (baseline > incongruent) were examined using whole-brain, voxel-based methods. In the healthy controls, task performance was found to be associated with activations in the left dorsolateral prefrontal cortex and the dorsal anterior cingulate cortex, among other regions. De-activations were seen in the medial frontal cortex, the middle and posterior cingulate gyrus and cuneus, the parahippocampal gyrus and the hippocampus. The schizophrenic patients did not show reduced activation compared to the healthy controls. They did, however, show failure of de-activation in the medial frontal cortex. Our negative finding with respect to hypoactivation during performance of a task requiring inhibition of prepotent responses suggests that brain functional abnormality in schizophrenia may not affect all aspects of executive function/cognitive control. The finding of medial frontal cortex failure of de-activation adds to existing findings of default mode network dysfunction in the disorder.
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http://dx.doi.org/10.1016/j.jpsychires.2021.09.039DOI Listing
September 2021

Auditory hallucinations activate language and verbal short-term memory, but not auditory, brain regions.

Sci Rep 2021 Sep 23;11(1):18890. Epub 2021 Sep 23.

FIDMAG Hermanas Hospitalarias Research Foundation, C/. Dr. Antoni Pujadas 38, 08830, Sant Boi de Llobregat, Barcelona, Spain.

Auditory verbal hallucinations (AVH, 'hearing voices') are an important symptom of schizophrenia but their biological basis is not well understood. One longstanding approach proposes that they are perceptual in nature, specifically that they reflect spontaneous abnormal neuronal activity in the auditory cortex, perhaps with additional 'top down' cognitive influences. Functional imaging studies employing the symptom capture technique-where activity when patients experience AVH is compared to times when they do not-have had mixed findings as to whether the auditory cortex is activated. Here, using a novel variant of the symptom capture technique, we show that the experience of AVH does not induce auditory cortex activation, even while real speech does, something that effectively rules out all theories that propose a perceptual component to AVH. Instead, we find that the experience of AVH activates language regions and/or regions that are engaged during verbal short-term memory.
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http://dx.doi.org/10.1038/s41598-021-98269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460641PMC
September 2021

Target selection for deep brain stimulation in treatment resistant schizophrenia.

Prog Neuropsychopharmacol Biol Psychiatry 2022 Jan 10;112:110436. Epub 2021 Sep 10.

Psychiatry Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.

The use of deep brain stimulation (DBS) in treatment resistant patients with schizophrenia is of considerable current interest, but where to site the electrodes is challenging. This article reviews rationales for electrode placement in schizophrenia based on evidence for localized brain abnormality in the disorder and the targets that have been proposed and employed to date. The nucleus accumbens and the subgenual anterior cingulate cortex are of interest on the grounds that they are sites of potential pathologically increased brain activity in schizophrenia and so susceptible to the local inhibitory effects of DBS; both sites have been employed in trials of DBS in schizophrenia. Based on other lines of reasoning, the ventral tegmental area, the substantia nigra pars reticulata and the habenula have also been proposed and in some cases employed. The dorsolateral prefrontal cortex has not been suggested, probably reflecting evidence that it is underactive rather than overactive in schizophrenia. The hippocampus is also of theoretical interest but there is no clear functional imaging evidence that it shows overactivity in schizophrenia. On current evidence, the nucleus accumbens may represent the strongest candidate for DBS electrode placement in schizophrenia, with the substantia nigra pars reticulata also showing promise in a single case report; the ventral tegmental area is also of potential interest, though it remains untried.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110436DOI Listing
January 2022

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Hum Brain Mapp 2021 Sep 8. Epub 2021 Sep 8.

Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) [Georgia State University, Georgia Institute of Technology], Emory University, Atlanta, Georgia, USA.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.
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http://dx.doi.org/10.1002/hbm.25625DOI Listing
September 2021

Interindividual variability of functional connectome in schizophrenia.

Schizophr Res 2021 09 27;235:65-73. Epub 2021 Jul 27.

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Schizophrenia is a complex psychiatric disorder that displays an outstanding interindividual variability in clinical manifestation and neurobiological substrates. A better characterization and quantification of this heterogeneity could guide the search for both common abnormalities (linked to lower intersubject variability) and the presence of biological subtypes (leading to a greater heterogeneity across subjects). In the current study, we address interindividual variability in functional connectome by means of resting-state fMRI in a large sample of patients with schizophrenia and healthy controls. Among the different metrics of distance/dissimilarity used to assess variability, geodesic distance showed robust results to head motion. The main findings of the current study point to (i) a higher between subject heterogeneity in the functional connectome of patients, (ii) variable levels of heterogeneity throughout the cortex, with greater variability in frontoparietal and default mode networks, and lower variability in the salience network, and (iii) an association of whole-brain variability with levels of clinical symptom severity and with topological properties of brain networks, suggesting that the average functional connectome overrepresents those patients with lower functional integration and with more severe clinical symptoms. Moreover, after performing a graph theoretical analysis of brain networks, we found that patients with more severe clinical symptoms had decreased connectivity at both whole-brain level and within the salience network, and that patients with higher negative symptoms had large-scale functional integration deficits.
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http://dx.doi.org/10.1016/j.schres.2021.07.010DOI Listing
September 2021

Study Protocol-Coping With the Pandemics: What Works Best to Reduce Anxiety and Depressive Symptoms.

Front Psychiatry 2021 2;12:642763. Epub 2021 Jul 2.

Imaging of Mood- and Anxiety-Related Disorders (IMARD) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population. We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models. Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics.
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http://dx.doi.org/10.3389/fpsyt.2021.642763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282901PMC
July 2021

Age- and gender-related differences in brain tissue microstructure revealed by multi-component T relaxometry.

Neurobiol Aging 2021 10 10;106:68-79. Epub 2021 Jun 10.

FIDMAG Germanes Hospitalàries Research Foundation, Sant Boi de Llobregat, Barcelona, Spain; Mental Health Research Networking Center (CIBERSAM), Madrid, Spain.

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T relaxometry cross-sectional study to date in healthy adults (N = 145, 18-60 years). Five quantitative microstructure parameters derived from various segments of the estimated T spectra were evaluated, allowing a more specific interpretation of results in terms of tissue microstructure. We found similar age-related myelin water fraction (MWF) patterns in men and women but we also observed differential male related results including increased MWF content in a few white matter tracts, a faster decline with age of the intra- and extra-cellular water fraction and its T relaxation time (i.e. steeper age related negative slopes) and a faster increase in the free and quasi-free water fraction, spanning the whole grey matter. Such results point to a sexual dimorphism in brain tissue microstructure and suggest a lesser vulnerability to age-related changes in women.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.002DOI Listing
October 2021

Neural correlates of disturbance in the sense of agency in schizophrenia: An fMRI study using the 'enfacement' paradigm.

Schizophr Res 2021 Jul 1. Epub 2021 Jul 1.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.

An altered sense of self-awareness and agency has been proposed to underlie symptoms of schizophrenia. In this study, we used the enfacement illusion paradigm - in which perception of another person's face leads to changes in perception of one's own peri-personal space - to examine the brain correlates of the sense of agency and its potential disruption in schizophrenia. Thirty-three schizophrenic patients and 27 healthy controls underwent fMRI scanning during performance of a task designed to elicit the enfacement illusion. Activations were examined using whole-brain analysis and also in an a priori identified region of interest (ROI) in the temporoparietal junction (TPJ), a region that has been described as involved in self/other differentiation and sense of agency. Both groups showed a pattern of cortical activation involving the pre and postcentral cortex, Rolandic operculum, insula, parietal, temporal and occipital cortex bilaterally as well as TPJ (but only right-side in patients). Examination of the TPJ ROI revealed significantly reduced activation on the left in the patients that was associated with poorer insight. The findings suggest brain functional abnormality in schizophrenia related to the formation or maintenance of processes related to self and/or agency. Decreased function in the TPJ may have a role in the impaired insight seen in patients with the disorder.
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http://dx.doi.org/10.1016/j.schres.2021.06.031DOI Listing
July 2021

methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes.

Epigenomics 2021 Jun 4;13(11):845-858. Epub 2021 May 4.

Hospital Universitari Institut Pere Mata, Ctra. de l'Institut Pere Mata, s/n. 43206, Reus, Catalonia, Spain.

To investigate  methylation in the brains of bipolar disorder (BD) patients and its association with mRNA levels and comethylation with myelin genes. Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. 5-methylcytosine levels were increased and directly associated with b mRNA expression in the brains of BD patients. We also observed that was comethylated with a group of myelin genes. is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, comethylation with myelin genes supports the role of this receptor in myelination.
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http://dx.doi.org/10.2217/epi-2021-0006DOI Listing
June 2021

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals.

Mol Psychiatry 2021 Apr 16. Epub 2021 Apr 16.

Unit for Psychosomatics / CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.
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http://dx.doi.org/10.1038/s41380-021-01098-xDOI Listing
April 2021

Structural brain abnormalities in borderline personality disorder correlate with clinical severity and predict psychotherapy response.

Brain Imaging Behav 2021 Oct 26;15(5):2502-2512. Epub 2021 Feb 26.

Department of Psychiatry Hospital de la Santa Creu i Sant Pau, C/ Sant Antoni Mª Claret, 167.08025, Barcelona, Spain.

Although previous imaging studies in borderline personality disorder (BPD) have found brain abnormalities, the results have been inconsistent. This study aimed to investigate structural brain abnormalities using voxel-based morphometry (VBM) and cortical thickness (Cth) analyses in a large sample of patients with BPD. Additionally, we aimed to determine the correlation between structural abnormalities and clinical severity and to assess its potential value at predicting psychotherapeutic response. Sixty-one individuals with BPD and 19 healthy controls underwent magnetic resonance imaging. Participants with BPD completed several self-report clinical scales, received dialectical-behavioral therapy skills training and post-therapy changes in clinical scores were also recorded. Gray matter volume (GMV) and Cth differences between groups were compared. Within the BPD group, we further characterized the structural brain correlates of clinical severity and investigated the relationship between pre-therapy structural abnormalities and therapeutic response. As potential confounders we included age, sex, educational level, and total intracranial volume (the latter only in VBM analyses). Compared to controls, the BPD group showed a reduced GMV/Cth in prefrontal areas but increased GMV in the limbic structures (amygdala and parahippocampal regions). Prefrontal abnormalities correlated with higher baseline scores on impulsivity and general BPD severity. Increased GMV in the parahippocampal area correlated with a greater emotion dysregulation. Importantly, several baseline structural abnormalities correlated with worse response to psychotherapy. Patients with BPD showed a reduced GMV in the prefrontal areas but a greater GMV in the limbic structures. Several structural abnormalities (i.e. middle and inferior prefrontal areas, anterior insula, or parahippocampal area) correlated with clinical severity and could potentially be used as imaging biological correlates biomarkers to predict psychotherapy response.
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http://dx.doi.org/10.1007/s11682-021-00451-6DOI Listing
October 2021

Corrigendum to 'Voxel-based meta-analysis via permutation of subject images (PSI): Theory and implementation for SDM' [Neuroimage 186 (2019) 174-184/YNIMG_15396].

Neuroimage 2021 May 17;231:117859. Epub 2021 Feb 17.

FIDMAG Germanes Hospitalàries, Sant Boi de Llobregat, Barcelona, Spain; Mental Health Research Networking Center (CIBERSAM), Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centre for Psychiatric Research and Education, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.neuroimage.2021.117859DOI Listing
May 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

Comparison of non-parametric T relaxometry methods for myelin water quantification.

Med Image Anal 2021 04 8;69:101959. Epub 2021 Jan 8.

Computer Science Department, University of Verona, Verona, Italy.

Multi-component T relaxometry allows probing tissue microstructure by assessing compartment-specific T relaxation times and water fractions, including the myelin water fraction. Non-negative least squares (NNLS) with zero-order Tikhonov regularization is the conventional method for estimating smooth T distributions. Despite the improved estimation provided by this method compared to non-regularized NNLS, the solution is still sensitive to the underlying noise and the regularization weight. This is especially relevant for clinically achievable signal-to-noise ratios. In the literature of inverse problems, various well-established approaches to promote smooth solutions, including first-order and second-order Tikhonov regularization, and different criteria for estimating the regularization weight have been proposed, such as L-curve, Generalized Cross-Validation, and Chi-square residual fitting. However, quantitative comparisons between the available reconstruction methods for computing the T distribution, and between different approaches for selecting the optimal regularization weight, are lacking. In this study, we implemented and evaluated ten reconstruction algorithms, resulting from the individual combinations of three penalty terms with three criteria to estimate the regularization weight, plus non-regularized NNLS. Their performance was evaluated both in simulated data and real brain MRI data acquired from healthy volunteers through a scan-rescan repeatability analysis. Our findings demonstrate the need for regularization. As a result of this work, we provide a list of recommendations for selecting the optimal reconstruction algorithms based on the acquired data. Moreover, the implemented methods were packaged in a freely distributed toolbox to promote reproducible research, and to facilitate further research and the use of this promising quantitative technique in clinical practice.
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http://dx.doi.org/10.1016/j.media.2021.101959DOI Listing
April 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 and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder.

Sci Rep 2021 01 27;11(1):2373. Epub 2021 Jan 27.

FIDMAG Research Foundation, C/. Dr. Antoni Pujadas, 38, Sant Boi de Llobregat, 08830, Barcelona, Spain.

Previous studies have shown that the gene encoding the adhesion G protein-coupled receptor L3 (ADGRL3; formerly latrophilin 3, LPHN3) is associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Conversely, no studies have investigated the anatomical or functional brain substrates of ADGRL3 risk variants. We examined here whether individuals with different ADGRL3 haplotypes, including both patients with ADHD and healthy controls, showed differences in brain anatomy and function. We recruited and genotyped adult patients with combined type ADHD and healthy controls to achieve a sample balanced for age, sex, premorbid IQ, and three ADGRL3 haplotype groups (risk, protective, and others). The final sample (n = 128) underwent structural and functional brain imaging (voxel-based morphometry and n-back working memory fMRI). We analyzed the brain structural and functional effects of ADHD, haplotypes, and their interaction, covarying for age, sex, and medication. Individuals (patients or controls) with the protective haplotype showed strong, widespread hypo-activation in the frontal cortex extending to inferior temporal and fusiform gyri. Individuals (patients or controls) with the risk haplotype also showed hypo-activation, more focused in the right temporal cortex. Patients showed parietal hyper-activation. Disorder-haplotype interactions, as well as structural findings, were not statistically significant. To sum up, both protective and risk ADGRL3 haplotypes are associated with substantial brain hypo-activation during working memory tasks, stressing this gene's relevance in cognitive brain function. Conversely, we did not find brain effects of the interactions between adult ADHD and ADGRL3 haplotypes.
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http://dx.doi.org/10.1038/s41598-021-81915-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840726PMC
January 2021

Brain imaging of executive function with the computerised multiple elements test.

Brain Imaging Behav 2021 Oct 26;15(5):2317-2329. Epub 2021 Jan 26.

FIDMAG Germanes Hospitalàries Research Foundation, Dr Pujadas, 38, 08830, Sant Boi de Llobregat, Barcelona, Spain.

The Computerised Multiple Elements Test (CMET) is a novel executive task to assess goal management and maintenance suitable for use within the fMRI environment. Unlike classical executive paradigms, it resembles neuropsychological multi-elements tests that capture goal management in a more ecological way, by requiring the participant to switch between four simple games within a specified time period. The present study aims to evaluate an fMRI version of the CMET and examine its brain correlates. Thirty-one healthy participants performed the task during fMRI scanning. During each block, they were required to play four simple games, with the transition between games being made either voluntarily (executive condition) or automatically (control condition). The executive condition was associated with increased activity in fronto-parietal and cingulo-opercular regions, with anterior insula activity linked to better task performance. In an additional analysis, the activated regions showed to form functional networks during resting-state and to overlap the executive fronto-parietal and cingulo-opercular networks identified in resting-state with independently defined seeds. These results show the ability of the CMET to elicit activity in well-known executive networks, becoming a potential tool for the study of executive impairment in neurological and neuropsychiatric populations in a more ecological way than classical paradigms.
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http://dx.doi.org/10.1007/s11682-020-00425-0DOI Listing
October 2021

The BAT: A videotaped battery to assess theory of mind in schizophrenia.

Psychiatry Res 2021 03 4;297:113709. Epub 2021 Jan 4.

Department of Clinical Psychology and Psychobiology. Faculty of Psychology. University of Barcelona. Barcelona, Spain.

The ability of attributing mental states to oneself and to the others (theory of mind, ToM) is impaired in schizophrenia. ToM is not a monolithic function, it includes different capacities: some implies the decoding of affective states, others the reasoning about mental states. We have developed the BAT, a Battery to Assess Theory of mind abilities in adult psychotic subjects in an ecological audiovisual format. The performance on the BAT and three other test of social cognition was compared in a sample of schizophrenic patients with a control group. The samples were matched in terms of age and premorbid IQ. The BAT was sensitive to detect the ToM impairments in schizophrenia, showed good internal consistency and concurrent validity. The area under the ROC curves established a cutoff point that would correctly classify controls and patients in a 96.6% of cases. The factorial analysis isolated two factors: empathy and reasoning, with a good adjustment. Our results showed that the BAT could be a valid, ecological and usable tool to assess ToM in psychotic patients, with good psychometric properties, that would allow obtaining a more complete profile of their impairment.
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http://dx.doi.org/10.1016/j.psychres.2021.113709DOI Listing
March 2021

Multivariate Brain Functional Connectivity Through Regularized Estimators.

Front Neurosci 2020 8;14:569540. Epub 2020 Dec 8.

Campbell Family Mental Health Research Institute, Toronto, ON, Canada.

Functional connectivity analyses are typically based on matrices containing bivariate measures of covariability, such as correlations. Although this has been a fruitful approach, it may not be the optimal strategy to fully explore the complex associations underlying brain activity. Here, we propose extending connectivity to multivariate functions relating to the temporal dynamics of a region with the rest of the brain. The main technical challenges of such an approach are multidimensionality and its associated risk of overfitting or even the non-uniqueness of model solutions. To minimize these risks, and as an alternative to the more common dimensionality reduction methods, we propose using two regularized multivariate connectivity models. On the one hand, simple linear functions of all brain nodes were fitted with ridge regression. On the other hand, a more flexible approach to avoid linearity and additivity assumptions was implemented through random forest regression. Similarities and differences between both methods and with simple averages of bivariate correlations (i.e., weighted global brain connectivity) were evaluated on a resting state sample of = 173 healthy subjects. Results revealed distinct connectivity patterns from the two proposed methods, which were especially relevant in the age-related analyses where both ridge and random forest regressions showed significant patterns of age-related disconnection, almost completely absent from the much less sensitive global brain connectivity maps. On the other hand, the greater flexibility provided by the random forest algorithm allowed detecting sex-specific differences. The generic framework of multivariate connectivity implemented here may be easily extended to other types of regularized models.
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http://dx.doi.org/10.3389/fnins.2020.569540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753183PMC
December 2020

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group.

Hum Brain Mapp 2020 Oct 19. Epub 2020 Oct 19.

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

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.
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http://dx.doi.org/10.1002/hbm.25249DOI Listing
October 2020

Greater male than female variability in regional brain structure across the lifespan.

Hum Brain Mapp 2020 Oct 12. Epub 2020 Oct 12.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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http://dx.doi.org/10.1002/hbm.25204DOI Listing
October 2020

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Hum Brain Mapp 2020 Oct 7. Epub 2020 Oct 7.

Neuroscience Research Australia, Sydney, Australia.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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http://dx.doi.org/10.1002/hbm.25206DOI Listing
October 2020

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

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group.

Hum Brain Mapp 2020 Jul 29. Epub 2020 Jul 29.

Division of Mental Health and Addicition, Oslo University Hospital, Oslo, Norway.

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness.
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http://dx.doi.org/10.1002/hbm.25098DOI Listing
July 2020

Brain metabolic changes in patients with treatment resistant schizophrenia treated with deep brain stimulation: A series of cases.

J Psychiatr Res 2020 08 19;127:57-61. Epub 2020 May 19.

Psychiatry Department, Institut d'Investigació Biomèdica-Sant Pau (IIB-SANT PAU), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona (UAB), Department of Psychiatry and Forensic Medicine, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain.

Deep brain stimulation (DBS) has been found to be effective in treatment resistant neurological and psychiatric disorders. So far there has been only one completed trial in schizophrenia, in which seven treatment resistant patients received DBS in the subgenual anterior cingulate cortex (sgACC, N = 4) or the nucleus accumbens (NAc, N = 3); four met symptomatic response criteria over the trial period. Six patients underwent 18 F-FDG PET at baseline and after at least 6 months of stimulation. Individual patient analysis indicated that DBS to both the sgACC and NAc was associated with local and distant changes in glucose metabolism. Increments and decrements of brain activity were observed in regions that included the medial prefrontal cortex, the dorsolateral prefrontal cortex, the anterior cingulate cortex, the caudate nucleus, the NAc, the hippocampus and the thalamus. Increased activity appeared to be associated with clinical improvement. These preliminary findings suggest that DBS acts by modulating cerebral activity in the cortico-basal-thalamic-cortical circuit in patients with schizophrenia who show improvement in psychotic symptoms.
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http://dx.doi.org/10.1016/j.jpsychires.2020.05.016DOI Listing
August 2020

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA.

Neuroimage 2020 09 26;218:116956. Epub 2020 May 26.

CIBERSAM, Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).
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http://dx.doi.org/10.1016/j.neuroimage.2020.116956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524039PMC
September 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
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