[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; · 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 (Vienna, Austria : 1996). 06/2014;
[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 (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.Molecular Psychiatry advance online publication, 29 April 2014; doi:10.1038/mp.2014.39.
[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; · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.Molecular Psychiatry advance online publication, 15 January 2013; doi:10.1038/mp.2012.172.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. Method The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. RESULTS: Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. CONCLUSIONS: The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.
Psychological Medicine 01/2014; 44(2):381–394. · 5.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 01/2014; 9(7):e102692. · 3.73 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 01/2014; · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia. Method: Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rating Scale scores. Results: At baseline, nonresponders exhibited enhanced activation in the right pregenual anterior cingulate cortex, the hippocampus, and the amygdala in response to a safety signal. While this activation pattern partly resolved in nonresponders after CBT, successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies. Treatment response was associated with an inhibitory functional coupling between the anterior cingulate cortex and the amygdala that did not change over time. Conclusions: This study identified brain activation patterns associated with treatment response in patients with panic disorder with agoraphobia. Altered safety signal processing and anterior cingulate cortex-amygdala coupling may indicate individual differences among these patients that determine the effectiveness of exposure-based CBT and associated neuroplastic changes. Findings point to brain networks by which successful CBT in this patient population is mediated.
American Journal of Psychiatry 08/2013; 170(11):1345-1355. · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE:Kennedy disease is a rare X-linked neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the androgen-receptor gene. Apart from neurologic signs, this mutation can cause a partial androgen insensitivity syndrome with typical alterations of gonadotropic hormones produced by the pituitary gland. The aim of the present study was therefore to evaluate the impact of Kennedy disease on pituitary gland volume under the hypothesis that endocrinologic changes caused by partial androgen insensitivity may lead to morphologic changes (ie, hypertrophy) of the pituitary gland.MATERIALS AND METHODS:Pituitary gland volume was measured in sagittal sections of 3D T1-weighted 3T-MR imaging data of 8 patients with genetically proven Kennedy disease and compared with 16 healthy age-matched control subjects by use of Multitracer by a blinded, experienced radiologist. The results were analyzed by a univariant ANOVA with total brain volume as a covariant. Furthermore, correlation and linear regression analyses were performed for pituitary volume, patient age, disease duration, and CAG repeat expansion length. Intraobserver reliability was evaluated by means of the Pearson correlation coefficient.RESULTS:Pituitary volume was significantly larger in patients with Kennedy disease (636 [±90] mm(3)) than in healthy control subjects (534 [±91] mm(3)) (P = .041). There was no significant difference in total brain volume (P = .379). Control subjects showed a significant decrease in volume with age (r = -0.712, P = .002), whereas there was a trend to increasing gland volume in patients with Kennedy disease (r = 0.443, P = .272). Gland volume correlated with CAG repeat expansion length in patients (r = 0.630, P = .047). The correlation coefficient for intraobserver reliability was 0.94 (P < .001).CONCLUSIONS:Patients with Kennedy disease showed a significantly higher pituitary volume that correlated with the CAG repeat expansion length. This could reflect hypertrophy as the result of elevated gonadotropic hormone secretion caused by the androgen receptor mutation with partial androgen insensitivity.
American Journal of Neuroradiology 06/2013; · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.
European Archives of Psychiatry and Clinical Neuroscience 04/2013; · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. METHODS: In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. RESULTS: After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS-) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the "fear network" (amygdalae, insulae, anterior cingulate cortex) across time. CONCLUSIONS: This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional ("fear network") processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.
[Show abstract][Hide abstract] ABSTRACT: The neuropeptide S (NPS) system has been suggested to contribute to the pathogenesis of anxiety. In order to further characterize the cognitive-neurophysiological relevance of neuropeptide S in the etiology of anxiety, the influence of a functional neuropeptide S receptor gene (NPSR1) variant on response inhibition and error monitoring was investigated under consideration of the dimensional phenotype of anxiety sensitivity (AS). In a sample of N=97 healthy probands, event-related potential (ERP) measurement using a modified Flanker task was applied allowing for a distinct neurophysiological examination of processes related to response inhibition (Nogo-N2, Nogo-P3) and error monitoring (Ne/ERN). All subjects were genotyped for the functional NPSR1 A/T (Asn(107)Ile) variant (rs324981) and characterized for anxiety sensitivity using the anxiety sensitivity index (ASI). Carriers of the NPSR1 T allele displayed intensified response inhibition (Nogo-P3) and error monitoring (Ne/ERN), which was in both cases paralleled by the behavioural data. Furthermore, anxiety sensitivity was found to be higher in NPSR1 T allele carriers and to correlate with Nogo-P3 and Ne/ERN. A mediation analysis revealed the ERN to mediate the effect between NPSR1 genotype and anxiety sensitivity. In summary, the more active NPSR1 T allele may confer enhanced response inhibition and increased error monitoring and might drive particularly error monitoring as a neurophysiological endophenotype of anxiety as reflected by increased anxiety sensitivity. These findings further corroborate a major role of the neuropeptide S system in the pathogenesis of anxiety and suggest a potentially beneficial use of therapeutic agents targeting the NPS system in anxiety disorders.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: Spinobulbar muscular atrophy [Kennedy's disease (KD)] is a rare X-linked neurodegenerative disorder of mainly spinal and bulbar motoneurons. Recent studies suggest a multisystem character of this disease. The aim of this study was to identify and characterize structural changes of gray (GM) and white matter (WM) in the central nervous system. MATERIAL AND METHODS: Whole-brain-based voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analyses were applied to MRI data of eight genetically proven patients with KD and compared with 16 healthy age-matched controls. RESULTS: Diffusion tensor imaging analysis showed not only decreased fractional anisotropy (FA) values in the brainstem, but also widespread changes in central WM tracts, whereas VBM analysis of the WM showed alterations primarily in the brainstem and cerebellum. There were no changes in GM volume. The FA value decrease in the brainstem correlated with the disease duration. CONCLUSION: Diffusion tensor imaging analysis revealed subtle changes of central WM tract integrity, while GM and WM volume remained unaffected. In our patient sample, KD had more extended effects than previously reported. These changes could either be attributed primarily to neurodegeneration or reflect secondary plastic changes due to atrophy of lower motor neurons and reorganization of cortical structures.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: The neurobiological basis of non-organic movement impairments is still unknown. As conversion disorder and hypnotic states share many characteristics, we applied an experimental design established in conversion disorder to investigate hypnotic paralysis. METHODS: Movement imitation and observation were investigated by functional magnetic resonance imaging (fMRI) in 19 healthy subjects with and without hypnotically induced paralysis of their left hand. Paralysis-specific activation changes were explored in a multivariate model and functional interdependencies of brain regions by connectivity analysis. RESULTS: Hypnotic paralysis during movement imitation induced hypoactivation of the contralateral sensorimotor cortex (SMC) and ipsilateral cerebellum and increased activation of anterior cingulate cortex (ACC), frontal gyrus and insula. No paralysis-specific effects were revealed during movement observation. CONCLUSIONS: Hyperactivation of ACC, middle frontal gyrus (MFG), and insula might reflect attention (MFG), conflict-detection (ACC) and self-representation processes (insula) during hypnotic paralysis. The lack of effects in movement observation suggests that early motor processes are not disturbed due to the transient nature of the hypnotic impairment.