Nils Opel

Brain Morphometric Biomarkers Distinguishing Unipolar and Bipolar Depression A Voxel-Based Morphometry-Pattern Classification Approach

IMPORTANCE The structural abnormalities in the brain that accurately differentiate unipolar depression (UD) and bipolar depression (BD) remain unidentified. OBJECTIVES First, to investigate and compare morphometric changes in UD and BD, and to replicate the findings at 2 independent neuroimaging sites; second, to differentiate UD and BD using multivariate pattern classification techniques. DESIGN, SETTING, AND PARTICIPANTS In a 2-center cross-sectional study, structural gray matter data were obtained at 2 independent sites (Pittsburgh, Pennsylvania, and Münster, Germany) using 3-T magnetic resonance imaging. Voxel-based morphometry was used to compare local gray and white matter volumes, and a novel pattern classification approach was used to discriminate between UD and BD, while training the classifier at one imaging site and testing in an independent sample at the other site. The Pittsburgh sample of participants was recruited from the Western Psychiatric Institute and Clinic at the University of Pittsburgh from 2008 to 2012. The Münster sample was recruited from the Department of Psychiatry at the University of Münster from 2010 to 2012. Equally divided between the 2 sites were 58 currently depressed patients with bipolar I disorder, 58 age- and sex-matched unipolar depressed patients, and 58 matched healthy controls. MAIN OUTCOMES AND MEASURES Magnetic resonance imaging was used to detect structural differences between groups. Morphometric analyses were applied using voxel-based morphometry. Pattern classification techniques were used for a multivariate approach. RESULTS At both sites, individuals with BD showed reduced gray matter volumes in the hippocampal formation and the amygdala relative to individuals with UD (Montreal Neurological Institute coordinates x = -22, y = -1, z = 20; k = 1938 voxels; t = 4.75), whereas individuals with UD showed reduced gray matter volumes in the anterior cingulate gyrus compared with individuals with BD (Montreal Neurological Institute coordinates x = -8, y = 32, z = 3; k = 979 voxels; t = 6.37; all corrected P < .05). Reductions in white matter volume within the cerebellum and hippocampus were found in individuals with BD. Pattern classification yielded up to 79.3% accuracy (P < .001) by differentiating the 2 depressed groups, training and testing the classifier at one site, and up to 69.0% accuracy (P < .001), training the classifier at one imaging site (Pittsburgh) and testing it at the other independent sample (Münster). Medication load did not alter the pattern of results. CONCLUSIONS AND RELEVANCE Individuals with UD and those with BD are differentiated by structural abnormalities in neural regions supporting emotion processing. Neuroimaging and multivariate pattern classification techniques are promising tools to differentiate UD from BD and show promise as future diagnostic aids.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Hippocampal Atrophy in Major Depression: a Function of Childhood Maltreatment Rather than Diagnosis?

Reduced hippocampal volumes are probably the most frequently reported structural neuroimaging finding associated with major depressive disorder (MDD). However, it remains unclear whether altered hippocampal structure represents a risk factor for or a consequence of MDD. Reduced hippocampal volumes were consistently reported in subjects affected by childhood maltreatment. As the prevalence of childhood maltreatment is highly elevated in MDD populations, previous morphometric findings regarding hippocampal atrophy in MDD therefore might have been confounded by maltreatment experiences. The aim of this study was to differentiate the impact of childhood maltreatment from the influence of MDD diagnosis on hippocampal morphometry. Depressed patients (85) as well as 85 age- and sex-matched healthy controls underwent structural MRI. The Childhood Trauma Questionnaire was administered to estimate experiences of childhood maltreatment. Hippocampal volume and surface structure was examined by the use of two independent methods, automated segmentation (FSL-FIRST) and voxel-based morphometry (VBM8). In line with existing studies, MDD patients showed reduced hippocampal volumes, and childhood maltreatment was consistently associated with hippocampal volume loss in both, patients and healthy controls. However, no analysis revealed significant morphological differences between patients and controls if maltreatment experience was regressed out. Our results suggest that hippocampal alterations in MDD patients may at least partly be traced back to higher occurrence of early-life adverse experiences. Regarding the strong morphometric impact of childhood maltreatment and its distinctly elevated prevalence in MDD populations, this study provides an alternative explanation for frequently observed limbic structural abnormalities in depressed patients.

Prediction of Individual Response to Electroconvulsive Therapy via Machine Learning on Structural Magnetic Resonance Imaging Data

IMPORTANCE Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, biomarkers that accurately predict a response to ECT remain unidentified. OBJECTIVE To investigate whether certain factors identified by structural magnetic resonance imaging (MRI) techniques are able to predict ECT response. DESIGN, SETTING, AND PARTICIPANTS In this nonrandomized prospective study, gray matter structure was assessed twice at approximately 6 weeks apart using 3-T MRI and voxel-based morphometry. Patients were recruited through the inpatient service of the Department of Psychiatry, University of Muenster, from March 11, 2010, to March 27, 2015. Two patient groups with acute major depressive disorder were included. One group received an ECT series in addition to antidepressants (n = 24); a comparison sample was treated solely with antidepressants (n = 23). Both groups were compared with a sample of healthy control participants (n = 21). MAIN OUTCOMES AND MEASURES Binary pattern classification was used to predict ECT response by structural MRI that was performed before treatment. In addition, univariate analysis was conducted to predict reduction of the Hamilton Depression Rating Scale score by pretreatment gray matter volumes and to investigate ECT-related structural changes. RESULTS One participant in the ECT sample was excluded from the analysis, leaving 67 participants (27 men and 40 women; mean [SD] age, 43.7 [10.6] years). The binary pattern classification yielded a successful prediction of ECT response, with accuracy rates of 78.3% (18 of 23 patients in the ECT sample) and sensitivity rates of 100% (13 of 13 who responded to ECT). Furthermore, a support vector regression yielded a significant prediction of relative reduction in the Hamilton Depression Rating Scale score. The principal findings of the univariate model indicated a positive association between pretreatment subgenual cingulate volume and individual ECT response (Montreal Neurological Institute [MNI] coordinates x = 8, y = 21, z = -18; Z score, 4.00; P < .001; peak voxel r = 0.73). Furthermore, the analysis of treatment effects revealed a increase in hippocampal volume in the ECT sample (MNI coordinates x = -28, y = -9, z = -18; Z score, 7.81; P < .001) that was missing in the medication-only sample. CONCLUSIONS AND RELEVANCE A relatively small degree of structural impairment in the subgenual cingulate cortex before therapy seems to be associated with successful treatment with ECT. In the future, neuroimaging techniques could prove to be promising tools for predicting the individual therapeutic effectiveness of ECT.

Reward Processing in Unipolar and Bipolar Depression: A Functional MRI Study

Differentiating bipolar disorders (BD) from unipolar depression (UD) remains a major clinical challenge. The identification of neurobiological markers may help to differentiate these disorders, particularly during depressive episodes. This cross-sectional study, including 33 patients with UD, 33 patients with BD, and 34 healthy controls, is one of the first to directly compare UD and BD with respect to reward processing. A card-guessing paradigm was employed and brain activity associated with reward processing was investigated by means of fMRI. A 3 (group) × 2 (condition: reward>control, loss>control) ANOVA was conducted using the nucleus accumbens (NAcc) as ROI. Furthermore, a whole-brain approach was applied. A functional connectivity analysis was performed to characterize diagnosis-related alterations in the functional coupling between the NAcc and other brain areas. The ANOVA revealed higher activity for healthy controls (HCs) than for BD and UD in the NAcc during reward processing. Moreover, UD showed a higher functional connectivity between the NAcc and the VTA than HC. The patients groups could be differentiated in that BD showed a decreased activation, in the reward condition, of the NAcc, caudate nucleus, thalamus, putamen, insula, and prefrontal areas compared with UD. These results may help to refine the understanding of neural correlates of reward processing in both disorders, and to understand the neural underpinnings of anhedonia, a core symptom of depressive episodes.

Serotonin transporter gene methylation is associated with hippocampal gray matter volume

The serotonin transporter (5‐HTT) and the 5‐HTTLPR/rs25531 polymorphisms in its gene (SLC6A4) have been associated with depression, increased stress‐response, and brain structural alterations such as reduced hippocampal volumes. Recently, epigenetic processes including SLC6A4 promoter methylation were shown to be affected by stress, trauma, or maltreatment and are regarded to be involved in the etiology of affective disorders. However, neurobiological correlates of SLC6A4 promoter methylation have never been studied or compared to genotype effects by means of human neuroimaging hitherto

Obesity and major depression: Body-mass index (BMI) is associated with a severe course of disease and specific neurostructural alterations

Obesity is one of the most prevalent somatic comorbidities of major depressive disorder (MDD). Both disorders rank among the leading challenges in public health and have been independently characterized by gray matter alterations in partly overlapping brain structures. Hence, it appears crucial to investigate the possibility of a shared neurostructural correlate of this frequent comorbidity as well as its clinical implications. One hundred and fourty-four patients suffering from acute MDD and 141 healthy control subjects underwent structural MRI. Imaging data were analyzed using voxel-based morphometry (VBM). Body-mass-index (BMI) as well as state and course of disease were assessed. Higher BMI was associated with a highly comparable pattern of gray matter reductions in the medial prefrontal cortex, the orbitofrontal cortex, the caudate nucleus and the thalamus in MDD patients and healthy controls alike. In MDD-patients, BMI was associated with a more chronic course of disease and both BMI and chronicity of disorder were related to similar morphometric anomalies in medial prefrontal areas. In MDD, obese subjects might be characterized by a more chronic course of disease. Moreover, obesity and chronicity of disorder seem to share overlapping neurostructural anomalies in prefrontal areas involved in emotion regulation and impulse control. Hence, our data provide evidence for specific morphological alterations underlying this prevalent comorbidity. It further underlines the clinical importance of preventive measures against obesity accompanying MDD treatment.

Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure

In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

Are you gonna leave me? Separation Anxiety is associated with increased amygdala responsiveness and volume

The core feature of separation anxiety is excessive distress when faced with actual or perceived separation from people to whom the individual has a strong emotional attachment. So far little is known about the neurobiological underpinnings of separation anxiety. Therefore, we investigated functional (amygdala responsiveness and functional connectivity during threat-related emotion processing) and structural (grey matter volume) imaging markers associated with separation anxiety as measured with the Relationship Scale Questionnaire in a large sample of healthy adults from the Münster Neuroimaging Cohort (N = 320). We used a robust emotional face-matching task and acquired high-resolution structural images for morphometric analyses using voxel-based morphometry. The main results were positive associations of separation anxiety scores with amygdala reactivity to emotional faces as well as increased amygdala grey matter volumes. A functional connectivity analysis revealed positive associations between separation anxiety and functional coupling of the amygdala with areas involved in visual processes and attention, including several occipital and somatosensory areas. Taken together, the results suggest a higher emotional involvement in subjects with separation anxiety while watching negative facial expressions, and potentially secondary neuro-structural adaptive processes. These results could help to understand and treat (adult) separation anxiety.

Enhanced neural responsiveness to reward associated with obesity in the absence of food-related stimuli.

Obesity has been characterized by alterations in brain structure and function associated with emotion processing and regulation. Particularly, aberrations in food‐related reward processing have been frequently demonstrated in obese subjects. However, it remains unclear whether reward‐associated functional aberrations in obesity are specific for food‐related stimuli or represent a general deficit in reward processing, extending to other stimulus domains. Given the crucial role of rewarding effects in the development of obesity and the ongoing discussion on overlapping neurobiological traits of obesity and psychiatric disorders such as depression and substance‐related disorders, this study aimed to investigate the possibility of altered reward processing in obese subjects to occur in the absence of food‐related stimuli during a monetary reward condition.