[Show abstract][Hide abstract] ABSTRACT: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.Molecular Psychiatry advance online publication, 30 June 2015; doi:10.1038/mp.2015.69.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and -regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI-data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. Additionally, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and -regulation. The present data suggest that NCAN forms susceptibility to neuro-structural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.Neuropsychopharmacology accepted article preview online, 24 March 2015. doi:10.1038/npp.2015.86.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2015; DOI:10.1038/npp.2015.86 · 7.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cognitive deficits are common symptom presentations in neurology and psychiatry. Cognitive symptoms during major depressive episodes cause subjective distress as well as difficulties during therapy and psychosocial reintegration. Depression-associated cognitive symptoms are characterized by a mood-congruent information processing bias as well as by cognitive performance deficits. A diagnostically relevant profile of neuropsychological impairments specific to depression has not yet been identified. Nevertheless, deficits of executive and declarative memory functions have repeatedly been reported. The time course of cognitive deficits after remission of mood is not entirely clear. Depending on the point of time of the reinvestigation, patients may still exhibit pronounced cognitive deficits. This article presents the current knowledge about cognitive symptoms in major depression, including the pathophysiology and treatment options.
Der Nervenarzt 01/2015; 86(1):99-115. DOI:10.1007/s00115-014-4219-z · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n=185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n=245; after CBT: n=171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n=39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.
[Show abstract][Hide abstract] ABSTRACT: Background: Coping plays an important role for emotion regulation in threatening situations. The model of coping modes designates repression and sensitization as two independent coping styles. Repression consists of strategies that shield the individual from arousal. Sensitization indicates increased analysis of the environment in order to reduce uncertainty. According to the discontinuity hypothesis, repressors are sensitive to threat in the early stages of information processing. While repressors do not exhibit memory disturbances early on, they manifest weak memory for these stimuli later. This study investigates the discontinuity hypothesis using functional magnetic resonance imaging (fMRI).
Methods: Healthy volunteers (20 repressors and 20 sensitizers) were selected from a sample of 150 students on the basis of the Mainz Coping Inventory. During the fMRI experiment, subjects evaluated and memorized emotional and neutral faces. Subjects performed two sessions of face recognition: immediately after the fMRI session and three days later.
Results: Repressors exhibited greater activation of frontal, parietal and temporal areas during encoding of angry faces compared to sensitizers. There were no differences in recognition of facial emotions between groups neither immediately after exposure nor after three days.
Conclusions: The fMRI findings suggest that repressors manifest an enhanced neural processing of directly threatening facial expression which confirms the assumption of hyper-responsivity to threatening information in repression in an early processing stage. A discrepancy was observed between high neural activation in encoding-relevant brain areas in response to angry faces in repressors and no advantage in subsequent memory for these faces compared to sensitizers.
PLoS ONE 12/2014; 9(12):e112398. DOI:10.1371/journal.pone.0112398 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Importance: Although neuroimaging research has made substantial progress in identifying the large-scale neural substrate of anxiety disorders, its value for clinical application lags behind expectations. Machine-learning approaches have predictive potential for individual-patient prognostic purposes and might thus aid translational efforts in psychiatric research.
Objective: To predict treatment response to cognitive behavioral therapy (CBT) on an individual-patient level based on functional magnetic resonance imaging data in patients with panic disorder with agoraphobia (PD/AG). Design, Setting, and Participants: We included 49 patients free of medication for at least 4 weeks and with a primary diagnosis of PD/AG in a longitudinal study performed at 8 clinical research institutes and outpatient centers across Germany. The functional magnetic resonance imaging study was conducted between July 2007 and March 2010.
Interventions: Twelve CBT sessions conducted 2 times a week focusing on behavioral exposure. Main Outcomes and Measures: Treatment response was defined as exceeding a 50% reduction in Hamilton Anxiety Rating Scale scores. Blood oxygenation level-dependent signal was measured during a differential fear-conditioning task. Regional and whole-brain gaussian process classifiers using a nested leave-one-out cross-validation were used to predict the treatment response from data acquired before CBT.
Results: Although no single brain region was predictive of treatment response, integrating regional classifiers based on data from the acquisition and the extinction phases of the fear-conditioning task for the whole brain yielded good predictive performance (accuracy, 82%; sensitivity, 92%; specificity, 72%; P < .001). Data from the acquisition phase enabled 73% correct individual-patient classifications (sensitivity, 80%; specificity, 67%; P < .001), whereas data from the extinction phase led to an accuracy of 74% (sensitivity, 64%; specificity, 83%; P < .001). Conservative reanalyses under consideration of potential confounders yielded nominally lower but comparable accuracy rates (acquisition phase, 70%; extinction phase, 71%; combined, 79%).
Conclusions and Relevance: Predicting treatment response to CBT based on functional neuroimaging data in PD/AG is possible with high accuracy on an individual-patient level. This novel machine-learning approach brings personalized medicine within reach, directly supporting clinical decisions for the selection of treatment options, thus helping to improve response rates.
[Show abstract][Hide abstract] ABSTRACT: Variation in the 5'-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ≥50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.
Journal of Neural Transmission 09/2014; DOI:10.1007/s00702-014-1311-2 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
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.
PLoS ONE 07/2014; 9(7):e102692. DOI:10.1371/journal.pone.0102692 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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. Since 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. 85 depressed patients as well as 85 age- and sex-matched healthy controls underwent structural MRI. The Childhood Trauma Questionnaire (CTQ) 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.Neuropsychopharmacology accepted article preview online, 13 June 2014; doi:10.1038/npp.2014.145.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.145 · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cognitive behavioral models of panic disorder (PD) stress the importance of an increased attentional focus towards bodily symptoms in the onset and maintenance of this debilitating anxiety disorder. In this fMRI mental tracking paradigm, we looked at the effects of focusing one's attention internally (interoception) vs. externally (exteroception) in a well-studied group at risk for PD-that is anxiety-sensitive females (AS-high). We hypothesized that AS-high subjects compared to control subjects will present higher arousal and decreased valence scores during interoception and parallel higher activity in brain areas which are associated with fear and interoception. 24 healthy female students with high levels of anxiety sensitivity and 24 healthy female students with normal levels of anxiety sensitivity serving as control group were investigated by 3 T fMRI. Subjects either focused their attention on their heartbeats (internal condition) or on neutral tones (external condition). Task performance was monitored by reporting the number of heartbeats or tones after each block. State of arousal and emotional valence were also assessed. The high anxiety-sensitive group reported higher arousal scores compared to controls during the course of the experiment. Simultaneously, fMRI results indicated higher activation in anxiety-sensitive participants than in controls during interoception in a network of cortical and subcortical brain regions (thalamus, amygdala, parahippocampus) that overlaps with known fear circuitry structures. In particular, the activity of the right amygdala was up-regulated. Future prospective-longitudinal studies are needed to validate the role of the amygdala for transition to disorder. Attention to internal body functions up-regulates the activity of interoceptive and fear-relevant brain regions in anxiety-sensitive females, a high-risk group for the development of anxiety disorders.
Journal of Neural Transmission 06/2014; DOI:10.1007/s00702-014-1248-5 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic studies found the A allele of the single nucleotide polymorphism rs1006737 in the CACNA1C gene, which encodes for the alpha 1C subunit of the voltage-dependent, L-type calcium ion channel Cav1.2, to be overrepresented in patients with major depressive disorder (MDD). Altered prefrontal brain functioning and impaired semantic verbal fluency (SVF) are robust findings in these patients. A recent functional magnetic resonance imaging (fMRI) study found the A allele to be associated with poorer performance and increased left inferior frontal gyrus (IFG) activation during SVF tasks in healthy subjects. In the present study, we investigated the effects of rs1006737 on neural processing during SVF in MDD. In response to semantic category cues, 40 patients with MDD and 40 matched controls overtly generated words while brain activity was measured with fMRI. As revealed by whole brain analyses, genotype significantly affected brain activity in patients. Compared to patients with GG genotype, patients with A allele demonstrated increased task-related activation in the left middle/inferior frontal gyrus and the bilateral cerebellum. Patients with A allele also showed enhanced functional coupling between left middle/inferior and right superior/middle frontal gyri. No differential effects of genotype on SVF performance or brain activation were found between diagnostic groups. The current data provide further evidence for an impact of rs1006737 on the left IFG and demonstrate that genetic variation in CACNA1C modulates neural responses in patients with MDD. The observed functional alterations in prefrontal and cerebellar areas might represent a mechanism by which rs1006737 influences susceptibility to MDD.
Journal of Psychiatric Research 06/2014; 53. DOI:10.1016/j.jpsychires.2014.02.003 · 4.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 (Mnster 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 x E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-alpha, 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 x 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.
[Show abstract][Hide abstract] ABSTRACT: Major depression is associated with impairments in semantic verbal fluency (VF). However, the neural correlates underlying dysfunctional cognitive processing in depressed subjects during the production of semantic category members still remain unclear. In the current study, an overt and continuous semantic VF paradigm was used to examine these mechanisms in a representative sample of 33 patients diagnosed with a current episode of unipolar depression and 33 statistically matched healthy controls. Subjects articulated words in response to semantic category cues while brain activity was measured with functional magnetic resonance imaging (fMRI). Compared to controls, patients showed poorer task performance. On the neural level, a group by condition interaction analysis, corrected for task performance, revealed a reduced task-related deactivation in patients in the right parahippocampal gyrus, the right fusiform gyrus, and the right supplementary motor area. An additional and an increased task-related activation in patients were observed in the right precentral gyrus and the left cerebellum, respectively. These results indicate that a failure to suppress potentially interfering activity from inferior temporal regions involved in default-mode network functions and visual imagery, accompanied by an enhanced recruitment of areas implicated in speech initiation and higher-order language processes, may underlie dysfunctional cognitive processing during semantic VF in depression. The finding that patients with depression demonstrated both decreased performance and aberrant brain activation during the current semantic VF task demonstrates that this paradigm is a sensitive tool for assessing brain dysfunctions in clinical populations.
European Archives of Psychiatry and Clinical Neuroscience 02/2014; 264(7). DOI:10.1007/s00406-014-0491-y · 3.36 Impact Factor