Ronny Redlich

Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala

Major depression has been repeatedly associated with amygdala hyper‐responsiveness to negative (but not positive) facial expressions at early, automatic stages of emotion processing using subliminally presented stimuli. However, it is not clear whether this “limbic bias” is a correlate of depression or represents a vulnerability marker preceding the onset of the disease. Because childhood maltreatment is a potent risk factor for the development of major depression in later life, we explored whether childhood maltreatment is associated with amygdalar emotion processing bias in maltreated but healthy subjects. Amygdala responsiveness to subliminally presented sad and happy faces was measured by means of fMRI at 3 T in N = 150 healthy subjects carefully screened for psychiatric disorders. Childhood maltreatment was assessed by the 25‐item childhood trauma questionnaire (CTQ). A strong association of CTQ‐scores with amygdala responsiveness to sad, but not happy facial expressions emerged. This result was further qualified by an interaction of emotional valence and CTQ‐scores and was not confounded by trait anxiety, current depression level, age, gender, intelligence, education level, and more recent stressful life‐events. Childhood maltreatment is apparently associated with detectable changes in amygdala function during early stages of emotion processing which resemble findings described in major depression. Limbic hyper‐responsiveness to negative facial cues could be a consequence of the experience of maltreatment during childhood increasing the risk of depression in later life. Limitation: the present association of limbic bias and maltreatment was demonstrated in the absence of psychopathological abnormalities, thereby limiting strong conclusions. Hum Brain Mapp 34:2899–2909, 2013.

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.

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.

Amygdala excitability to subliminally presented emotional faces distinguishes unipolar and bipolar depression: an fMRI and pattern classification study.

Bipolar disorder and Major depressive disorder are difficult to differentiate during depressive episodes, motivating research for differentiating neurobiological markers. Dysfunctional amygdala responsiveness during emotion processing has been implicated in both disorders, but the important rapid and automatic stages of emotion processing in the amygdala have so far never been investigated in bipolar 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

Neural correlates of affective priming effects based on masked facial emotion: an fMRI study.

Affective priming refers to the phenomenon that subliminal presentation of facial emotion biases subsequent evaluation of a neutral object in the direction of the prime. The aim of the present study was to specify the neural correlates of evaluative shifts elicited by facial emotion shown below the threshold of conscious perception. We tested the hypotheses whether the amygdala is involved in negative priming, whereas the nucleus accumbens participates in positive priming. In addition, exploratory whole brain correlation analyses were conducted. During 3T fMRI scanning, pictures of sad, happy, and neutral facial expression masked by neutral faces were presented to 110 healthy adults who had to judge valence of masks on a four-point scale. There was evidence for significant negative priming based on sad faces. A correlation was observed between amygdala activation and negative priming. Activation in medial, middle, and superior frontal and middle temporo-occipital areas, and insula was also associated with negative priming. No significant priming based on happy faces was found. However, nucleus accumbens activation to happy faces correlated with the positive priming score. The present findings confirm that the amygdala but also other brain regions, especially the medial frontal cortex, appear involved in automatically elicited negative evaluative shifts.

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.