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.
Background Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the ...neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. Methods One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). Results We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. Conclusions Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.
Fear conditioning and extinction are basic forms of associative learning that have gained considerable clinical relevance in enhancing our understanding of anxiety disorders and facilitating their ...treatment. Modern neuroimaging techniques have significantly aided the identification of anatomical structures and networks involved in fear conditioning. On closer inspection, there is considerable variation in methodology and results between studies. This systematic review provides an overview of the current neuroimaging literature on fear conditioning and extinction on healthy subjects, taking into account methodological issues such as the conditioning paradigm. A Pubmed search, as of December 2008, was performed and supplemented by manual searches of bibliographies of key articles. Two independent reviewers made the final study selection and data extraction. A total of 46 studies on cued fear conditioning and/or extinction on healthy volunteers using positron emission tomography or functional magnetic resonance imaging were reviewed. The influence of specific experimental factors, such as contingency and timing parameters, assessment of conditioned responses, and characteristics of conditioned and unconditioned stimuli, on cerebral activation patterns was examined. Results were summarized descriptively. A network consisting of fear-related brain areas, such as amygdala, insula, and anterior cingulate cortex, is activated independently of design parameters. However, some neuroimaging studies do not report these findings in the presence of methodological heterogeneities. Furthermore, other brain areas are differentially activated, depending on specific design parameters. These include stronger hippocampal activation in trace conditioning and tactile stimulation. Furthermore, tactile unconditioned stimuli enhance activation of pain related, motor, and somatosensory areas. Differences concerning experimental factors may partly explain the variance between neuroimaging investigations on human fear conditioning and extinction and should, therefore, be taken into serious consideration in the planning and the interpretation of research projects.
Conflict and inhibition are considered to exert strong influences on the neurophysiological N200 and P300 brain responses as evoked in go/nogo and stop-signal tasks. In order to separate their ...underlying neural and functional mechanisms, the current experiment manipulated both conflict and inhibition. To do so, the go/nogo and stop-signal tasks were merged into one paradigm. Conflict was manipulated by varying go-trial frequencies across blocks (75% vs. 25%). Motor inhibition was manipulated by using go, nogo and stop trials each representing a different load of inhibition. Event-related potentials (ERPs) as well as current density reconstructions (CDRs) of fifteen healthy participants were analyzed. Overall, infrequent trials evoked significantly more pronounced N200s than frequent trials. The P300 predominantly revealed significant variations between trial types (go, nogo, stop). Estimated source activations of the MCC and the IFC supported the ERP results; N200-related effects were revealed in both regions, whereas the condition-specific variations of the P300 were only observed in the IFC. The results indicate that the N200 primarily reflects conflict-related effects whereas the P300 predominantly represents motor inhibition.
Patients suffering from major depressive disorder (MDD) show deficits in working memory (WM) performance accompanied by bilateral fronto-parietal BOLD signal changes. It is unclear whether patients ...with a first depressive episode (FDE) exhibit the same signal changes as patients with recurrent depressive episodes (RDE).
We investigated seventy-four MDD inpatients (48 RDE, 26 FDE) and 74 healthy control (HC) subjects performing an n-back WM task (0-back, 2-back, 3-back condition) in a 3T-fMRI.
FMRI analyses revealed deviating BOLD signal in MDD in the thalamus (0-back vs. 2-back), the angular gyrus (0-back vs. 3-back), and the superior frontal gyrus (2-back vs. 3-back). Further effects were observed between RDE vs. FDE. Thus, RDE displayed differing neural activation in the middle frontal gyrus (2-back vs. 3-back), the inferior frontal gyrus, and the precentral gyrus (0-back vs. 2-back). In addition, both HC and FDE indicated a linear activation trend depending on task complexity.
Although we failed to find behavioral differences between the groups, results suggest differing BOLD signal in fronto-parietal brain regions in MDD vs. HC, and in RDE vs. FDE. Moreover, both HC and FDE show similar trends in activation shapes. This indicates a link between levels of complexity-dependent activation in fronto-parietal brain regions and the stage of MDD. We therefore assume that load-dependent BOLD signal during WM is impaired in MDD, and that it is particularly affected in RDE. We also suspect neurobiological compensatory mechanisms of the reported brain regions in (working) memory functioning.
•WM-load is accompanied by bilateral fronto-parietal signal changes.•MDD patients exhibit altered BOLD signal in regions comprising the SFG, AG, and thalamus.•RDE patients exhibit altered BOLD signal in the MFG, PCG, and IFG as compared to FDE.•Both HC and FDE indicate a linear activation trend depending on task complexity.•We conclude a link between impaired signal changes and the course/stage of depression.
Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of ...morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder.
For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes.
Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala.
The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.
Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced ...schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.
Automated gray matter segmentation of magnetic resonance imaging data is essential for morphometric analyses of the brain, particularly when large sample sizes are investigated. However, although ...detection of small structural brain differences may fundamentally depend on the method used, both accuracy and reliability of different automated segmentation algorithms have rarely been compared. Here, performance of the segmentation algorithms provided by SPM8, VBM8, FSL and FreeSurfer was quantified on simulated and real magnetic resonance imaging data. First, accuracy was assessed by comparing segmentations of twenty simulated and 18 real T1 images with corresponding ground truth images. Second, reliability was determined in ten T1 images from the same subject and in ten T1 images of different subjects scanned twice. Third, the impact of preprocessing steps on segmentation accuracy was investigated. VBM8 showed a very high accuracy and a very high reliability. FSL achieved the highest accuracy but demonstrated poor reliability and FreeSurfer showed the lowest accuracy, but high reliability. An universally valid recommendation on how to implement morphometric analyses is not warranted due to the vast number of scanning and analysis parameters. However, our analysis suggests that researchers can optimize their individual processing procedures with respect to final segmentation quality and exemplifies adequate performance criteria.
Emotion regulation ability (ERA) enables individuals to disengage from negative stimuli. In this study, we investigated the role of ERA in the depression-related negativity bias. Seventy-four ...individuals with major depressive disorder and eighty-three nonclinical individuals were screened for depressiveness using the Beck Depression Inventory. ERA was assessed using the Action Orientation After Failure Subscale of the Action Control Scale. We used a classical Stroop task variant, wherein the color words were preceded by either a self-relevant positive (success-related), negative (failure-related), or neutral word prime. The expected depressiveness × emotional prime interaction did not reach significance but the expected ERA × emotional prime interaction did. The latter effect was qualified by a three-way interaction between ERA, depressiveness, and emotional prime. Specifically, ERA predicted the negativity bias in individuals with high depressiveness scores. Using the Johnson–Neyman technique, we found that this effect was significant at the level of mild to moderate depression and beyond. Thus, poor ERA in individuals with depression may cause the depression-related negativity bias, whereas (at least) moderate ERA may protect individuals with depression from this bias. Future studies should assess ERA in individuals with depressive symptomatology and investigate how it influences their everyday functioning and treatment outcomes.
•Emotion regulation ability moderates depression effects.•High emotion regulation ability reduces depression-related negativity bias.•This effect emerges at mild to moderate depression scores.
Abstract Background Depression is frequent in panic disorder (PD); yet, little is known about its influence on the neural substrates of PD. Difficulties in fear inhibition during safety signal ...processing have been reported as a pathophysiological feature of PD that is attenuated by depression. We investigated the impact of comorbid depression in PD with agoraphobia (AG) on the neural correlates of fear conditioning and the potential of machine learning to predict comorbidity status on the individual patient level based on neural characteristics. Methods Fifty-nine PD/AG patients including 26 (44%) with a comorbid depressive disorder (PD/AG+DEP) underwent functional magnetic resonance imaging (fMRI). Comorbidity status was predicted using a random undersampling tree ensemble in a leave-one-out cross-validation framework. Results PD/AG−DEP patients showed altered neural activation during safety signal processing, while +DEP patients exhibited generally decreased dorsolateral prefrontal and insular activation. Comorbidity status was correctly predicted in 79% of patients (sensitivity: 73%; specificity: 85%) based on brain activation during fear conditioning (corrected for potential confounders: accuracy: 73%; sensitivity: 77%; specificity: 70%). Limitations No primary depressed patients were available; only medication-free patients were included. Major depression and dysthymia were collapsed (power considerations). Conclusions Neurofunctional activation during safety signal processing differed between patients with or without comorbid depression, a finding which may explain heterogeneous results across previous studies. These findings demonstrate the relevance of comorbidity when investigating neurofunctional substrates of anxiety disorders. Predicting individual comorbidity status may translate neurofunctional data into clinically relevant information which might aid in planning individualized treatment. The study was registered with the ISRCTN: ISRCTN80046034.
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