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Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder.An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., "dizziness") were primed by panic triggers (e.g., "elevator") compared with neutral words (e.g., "bottle"), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment.At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs.The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.

Fibromyalgia syndrome (FMS) is a chronic pain syndrome. Neuroimaging studies provided evidence of altered gray matter volume (GMV) in FMS but, similarly, in chronic pain of other origin as well. Therefore, the purpose of this study was to evaluate the disease specificity of GMV alterations in FMS by direct comparison. Structural MRI data of the brain were acquired in 25 females with FMS and two different control groups: 21 healthy subjects and 23 patients with osteoarthritis. Regional GMVs were compared by voxel-based morphometry and additional ROI-analyses. In conclusion, we did not identify significant GMV alterations in either FMS or OA patients compared to healthy controls when adopting a conservative statistical approach with multiple comparison correction. However, even under a more liberal approach no FMS-specific GMV changes were found because both pain groups presented increased gray matter volumes in the precentral gyrus and decreased GMV in the angular gyrus/middle occipital gyrus and middle temporal gyrus in comparison with healthy controls. Since no differences between both pain groups could be detected cortical GMV changes in FMS should not be interpreted as FMS-specific but might rather reflect changes in chronic pain in general. This previously held notion is confirmed in this study by direct comparison with a control group consisting of another pain disorder.

Background Chronic itch is the most common skin-related condition, associated with a high psychosocial and economic burden. In recent years, increasing evidence of sex differences in the perception, clinical presentation and treatment requirements of itch points towards potential benefits when using sex-adapted therapies. It is well-known that body composition, absorption, metabolism, elimination and adverse drug reactions (ADRs) differ between sexes, but only little is known about the impact of sex in the pharmacology of itch treatments, which could help to rationalise sex-adapted treatment strategies. Aim To evaluate and review sex effects in the pharmacokinetics and /-dynamics of drugs used to treat itch. Methods In this narrative review we performed a PubMed and MEDLINE (Ovid) search using the terms (itch OR pruritus) AND (gender OR sex) AND (drug OR medication OR pharmacokinetics OR pharmacodynamics). Additional searches were performed for the topical and systemic drugs recommended by the European Guideline on Chronic Pruritus. Results We found numerous reports with variable levels of evidence of sex effects with respect to the pharmacokinetics and/or pharmacodynamics of 14 drug classes used for the treatment of itch, including a total of 19 systemic and 3 topical drugs. Women seem to present higher plasma levels of several drugs used in itch treatment, including tri- and tetracyclic antidepressants (e.g. doxepin, amitriptyline, mirtazapine), serotonin reuptake inhibitors (e.g. paroxetine, sertraline, fluoxetine), immunosuppressive drugs (e.g. cyclosporine, mycophenolate mofetil), serotonin receptor antagonists (e.g. ondansetron) and betablockers (e.g. propranolol). Adverse drug reactions (ADRs) were generally more common in women. Being female was reported to be an independent risk factor for QTc-prolongation associated with antihistamines and tetracyclic antidepressants. Additionally, women seem to be more prone to sedative effects of antihistamines, and to suffer from a higher frequency as well as severity of side effects with systemic calcineurin inhibitors, opioid agonists, and opioid antagonists. Women were also sensitised more often to topically applied drugs. Of note, apart from only one experimental study with capsaicin, none of these reports were designed specifically to assess the effect of sex (and gender) in the treatment of itch. Discussion/conclusion Our review supports previous reports that sex is of importance in the pharmacokinetics and /-dynamics of several drugs used to treat itch although those drugs were mostly evaluated for non-itch indications. However, the results are limited by methodological limitations evident in most studies such as underrepresentation of women in clinical trials. This emphasises the need to study the impact of sex (and gender) in future itch trials to yield better outcomes and prevent ADRs in both sexes.

The hippocampus plays a key role for episodic memory. In addition, a small but growing number of studies has shown that it also contributes to the resolution of response conflicts. It is less clear how these two functions are related, and how they are affected by hippocampal lesions in patients with mesial temporal lobe epilepsy (MTLE). Previous studies suggested that conflict stimuli might be better remembered, but whether the hippocampus is critical for supporting this interaction between conflict processing and memory formation is unknown. Here, we tested 19 patients with MTLE due to hippocampal sclerosis and 19 matched healthy controls. Participants performed a face-word Stroop task during functional magnetic resonance imaging (fMRI) followed by a recognition task for the faces. We tested whether memory performance and activity in brain regions implicated in long-term memory were modulated by conflict during encoding, and whether this differed between MTLE patients and controls. In controls, we largely replicated previous findings of improved memory for conflict stimuli. While MTLE patients showed response time slowing during conflict trials as well, they did not exhibit a memory benefit. In controls, neural activity of conflict resolution and memory encoding interacted within a hippocampal region of interest. Here, left hippocampal recruitment was less efficient for memory performance in incongruent trials than in congruent trials, suggesting an intrahippocampal competition for limited resources. They also showed an involvement of precuneus and posterior cingulate cortex during conflict resolution. Both effects were not observed in MTLE patients, where activation of the precuneus and posterior cingulate cortex instead predicted later memory. Further research is needed to find out whether our findings reflect widespread functional reorganization of the episodic memory network due to hippocampal dysfunction.

Objectives Combinations of resting-state fMRI and machine-learning techniques are increasingly employed to develop diagnostic models for mental disorders. However, little is known about the neurobiological heterogeneity of depression and diagnostic machine learning has mainly been tested in homogeneous samples. Our main objective was to explore the inherent structure of a diverse unipolar depression sample. The secondary objective was to assess, if such information can improve diagnostic classification. Materials and methods We analyzed data from 360 patients with unipolar depression and 360 non-depressed population controls, who were subdivided into two independent subsets. Cluster analyses (unsupervised learning) of functional connectivity were used to generate hypotheses about potential patient subgroups from the first subset. The relationship of clusters with demographical and clinical measures was assessed. Subsequently, diagnostic classifiers (supervised learning), which incorporated information about these putative depression subgroups, were trained. Results Exploratory cluster analyses revealed two weakly separable subgroups of depressed patients. These subgroups differed in the average duration of depression and in the proportion of patients with concurrently severe depression and anxiety symptoms. The diagnostic classification models performed at chance level. Limitations It remains unresolved, if subgroups represent distinct biological subtypes, variability of continuous clinical variables or in part an overfitting of sparsely structured data. Conclusions Functional connectivity in unipolar depression is associated with general disease effects. Cluster analyses provide hypotheses about potential depression subtypes. Diagnostic models did not benefit from this additional information regarding heterogeneity.

Objective Anxiety disorders are among the most frequent psychiatric disorders. Current treatment guidelines recommend antidepressants, the calcium modulator gabapentin, and benzodiazepines as pharmacological treatments. However, delayed onset of action precludes the use of antidepressants as an acute treatment, while benzodiazepines can be recommended only as an emergency treatment due to their inherent risk of dependence. Therefore, an alternative pharmacological agent with acute efficacy is needed. Preliminary evidence points towards possible anxiolytic properties of the atypical antipsychotic quetiapine. The goals of this study were to test the acute anxiolytic properties of quetiapine in patients suffering from arachnophobia in a challenge paradigm, and to assess the effects of quetiapine on the central nervous fear network. Methods In a randomized, double-blind, placebo-controlled proof-of-concept study, n = 58 arachnophobic patients underwent an fMRI scan while looking at phobia-related and neutral stimuli. Subjective anxiety was evaluated retrospectively in questionnaires. Results The functional imaging data revealed that patients showed stronger amygdala activation to phobia-related than to neutral stimuli. However, no effect of quetiapine on fear network activity was detected. Further, on questionnaire measures, quetiapine significantly reduced somatic anxiety symptoms, but had no effect on general psychological anxiety. Conclusion Viewing phobic pictures resulted in a robust amygdala activation in arachnophobic patients. Quetiapine seems to have no influence on activation in anxiety-related brain areas but appears to reduce acute somatic anxiety symptoms in patients with specific phobia. The central nervous correlates of the anxiolytic effects of quetiapine remain to be clarified in future studies.

In small, selected samples, an approach combining resting-state functional connectivity MRI and multivariate pattern analysis has been able to successfully classify patients diagnosed with unipolar depression. Purposes of this investigation were to assess the generalizability of this approach to a large clinically more realistic sample and secondarily to assess the replicability of previously reported methodological feasibility in a more homogeneous subgroup with pronounced depressive symptoms. Two independent subsets were drawn from the depression and control cohorts of the BiDirect study, each with 180 patients with and 180 controls without depression. Functional connectivity either among regions covering the gray matter or selected regions with known alterations in depression was assessed by resting-state fMRI. Support vector machines with and without automated feature selection were used to train classifiers differentiating between individual patients and controls in the entire first subset as well as in the subgroup. Model parameters were explored systematically. The second independent subset was used for validation of successful models. Classification accuracies in the large, heterogeneous sample ranged from 45.0 to 56.1% (chance level 50.0%). In the subgroup with higher depression severity, three out of 90 models performed significantly above chance (60.8-61.7% at independent validation). In conclusion, common classification methods previously successful in small homogenous depression samples do not immediately translate to a more realistic population. Future research to develop diagnostic classification approaches in depression should focus on more specific clinical questions and consider heterogeneity, including symptom severity as an important factor.

A secure attachment relationship is facilitated by a mother´s ability to perceive her child´s emotions, especially her child´s fear. Prior studies showed that maternal perception of an own child activated a neural network including amygdala, insula and nucleus accumbens (NAcc). Results for different emotions were inconsistent and there are no reports on children´s fear. The goal of this study was to investigate neural responses of 17 mothers to photos of their own and an unknown preschool child with happy and fearful expressions by functional magnetic resonance imaging (fMRI). Whole brain analyses showed that a fearful (vs. happy) own child elicited larger activity in the visual cortex. Region of interest (ROI) analyses (amygdala, insula, NAcc) revealed stronger responses to a happy (vs. fearful) unknown child, but equally strong responses to one´s own child´s expressions. Moreover, an own (vs. unknown) fearful child elicited larger activity in the insula and NAcc. This suggests that mothers allocated more visual attention towards their own child´s fear, but showed consistent emotional involvement with their own child across expressions. Mothers might respond with stronger empathy and approach motivation towards an own (vs. unknown) fearful child, in line with a key role of fear in the attachment relationship.

Studies on cross-modal interaction have demonstrated attenuated as well as facilitated effects for both neural responses as well as behavioral performance. The goals of this pilot study were to investigate possible cross-modal interactions of tactile stimulation on visual working memory and to identify possible neuronal correlates by using functional magnetic resonance imaging (fMRI). During fMRI, participants (n = 12 females, n = 12 males) performed a verbal n-back task (0-back and 2-back tasks) while tactile pressure to the left thumbnail was delivered. Participants presented significantly lower behavioral performances (increased error rates, and reaction times) during the 2-back task as compared to the 0-back task. Task performance was independent of pressure in both tasks. This means that working memory performance was not impacted by a low salient tactile stimulus. Also in the fMRI data, no significant interactions of n-back x pressure were observed. In conclusion, the current study found no influence of tactile pressure on task-related brain activity during n-back (0-back and 2-back) tasks.

Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear-triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders.

Depression has been associated with various alterations in magnetic resonance imaging (MRI) derived resting‐state functional connectivity. Recently, homotopic connectivity, defined as functional connectivity between homotopic regions across hemispheres, has been reported to be reduced in patients with major depressive disorder (MDD). However, little is known about structural factors underlying alterations of homotopic connectivity, which would contribute to the understanding of the altered neurophysiological architecture in patients with MDD. We compared 368 patients with MDD and 461 never‐depressed controls regarding voxel‐mirrored homotopic connectivity (VMHC) and potential underlying mechanisms such as the structural connectivity of the corpus callosum, measured by DTI‐derived fractional anisotropy (FA), and left–right symmetries in homotopic gray matter volumes. Compared to controls, patients with MDD exhibited reduced VMHC in the cuneus, putamen, superior temporal gyrus, insula, and precuneus. Within these regions, no differences in left–right symmetries in homotopic gray matter volumes were evident across cohorts. FA of the corpus callosum correlated with VMHC in the entire sample. However, patients with MDD and controls did not differ with regard to callosal FA. The findings indicate that MDD is associated with a loss of interhemispheric synchrony in regions known to be implicated in self‐referential and reward processing. They also suggest that additional mechanisms are implicated in altered homotopic connectivity of patients with MDD, other than direct callosal fiber pathways or asymmetries in homotopic gray matter volumes. Hum Brain Mapp 37:1209–1217, 2016. © 2015 Wiley Periodicals, Inc.

Recent evidence suggests that the human hippocampus (HC) is not only involved in the processing of motivationally relevant approach-avoidance conflicts but is also engaged in the resolution of more general response conflicts as measured in the Stroop paradigm. Here we investigated whether neural activity in the HC is necessary for successful response conflict resolution. We compared hippocampal recruitment during an auditory Stroop paradigm in 20 patients with mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis and 20 age-matched healthy controls using functional magnetic resonance imaging (fMRI). We analyzed hippocampal activation and behavioral performance in conflict trials relative to non-conflict trials. Moreover, functional connectivity (FC) analyses with left and right HCs as seeds were performed. Subjects’ regional gray matter volumes were analyzed based on high-resolution T2-weighted MRI scans. The current study replicated previous results showing increased activation in left HC during the processing of conflict trials in healthy subjects. By contrast, MTLE patients showed higher behavioral costs of response conflict resolution and reduced conflict-related HC activation. In patients with left MTLE, left HC activation was predictive of faster conflict-related response times (RTs). By contrast, right HC activation was related to RT slowing, suggestive of a maladaptive compensation attempt in MTLE patients. Our results provide evidence that left hippocampal activation is required for the successful resolution of response conflicts.

Highlights • NOS1 ex1f-VNTR is associated with neural correlates during fear extinction learning. • Differential effects are prominent in amygdala and hippocampus. • Patients with panic disorder and agoraphobia differ from healthy controls. • Genotype associated effects were not altered after cognitive behavioral therapy., Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

Background: Patients suffering from panic disorder and agoraphobia are significantly impaired in daily life due to anxiety about getting into a situation due to apprehension about experiencing a panic attack, especially if escape may be difficult. Dysfunctional beliefs and behavior can be changed with cognitive behavioral therapy; however, the neurobiological effects of such an intervention on the anticipation and observation of agoraphobia-specific stimuli are unknown. Methods: We compared changes in neural activation by measuring the blood oxygen level-dependent signal of 51 patients and 51 healthy controls between scans before and those after treatment (group by time interaction) during anticipation and observation of agoraphobia-specific compared to neutral pictures using 3-T fMRI. Results: A significant group by time interaction was observed in the ventral striatum during anticipation and in the right amygdala during observation of agoraphobia-specific pictures; the patients displayed a decrease in ventral striatal activation during anticipation from pre- to posttreatment scans, which correlated with clinical improvement measured with the Mobility Inventory. During observation, the patients displayed decreased activation in the amygdala. These activational changes were not observed in the matched healthy controls. Conclusions: For the first time, neural effects of cognitive behavioral therapy were shown in patients suffering from panic disorder and agoraphobia using disorder-specific stimuli. The decrease in activation in the ventral striatum indicates that cognitive behavioral therapy modifies anticipatory anxiety and may ameliorate abnormally heightened salience attribution to expected threatening stimuli. The decreased amygdala activation in response to agoraphobia-specific stimuli indicates that cognitive behavioral therapy can alter the basal processing of agoraphobia-specific stimuli in a core region of the fear network.

Background : Depressive disorders are a frequent comorbidity of panic disorder with agoraphobia (PD/AG). Cognitive-behavioral therapy (CBT) for PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbidities. However, as depressive comorbidities can confound fear circuitry activation (i.e. amygdalae, insulae, anterior cingulate cortex) in PD/AG, we investigated whether comorbid depressive disorders alter neural plasticity following CBT. Methods : Within a randomized, controlled clinical trial on exposure-based CBT, forty-two PD/AG patients including fifteen (35.7%) with a comorbid depressive disorder (PD/AG + DEP) participated in a longitudinal functional magnetic resonance imaging (fMRI) study. A differential fear conditioning task was used as probe of interest. A generalized psycho-physiological interaction analysis (gPPI) served to study functional connectivity patterns. Results : After CBT, only PD/AG patients without comorbid depressive disorders (PD/AG-DEP) showed reduced activation in the left inferior frontal gyrus (IFG) extending to the insula. While PD/AG-DEP patients showed enhanced functional connectivity (FC) between the left IFG and subcortical structures (anterior cingulate cortex, thalamus and midbrain), PD/AG + DEP patients exhibited increased FC between the left IFG and cortical structures (prefrontal, parietal regions). In both groups, FC decreased following CBT. Limitations : Primary depressed and medicated patients were excluded. Major depression and dysthymia were collapsed. Conclusions : Reduced activation in the left IFG, as previously shown in PD/AG, appears to be a specific substrate of CBT effects in PD/AG-DEP patients only. Differential patterns of FC pertaining to fear circuitry networks in patients without depression vs. cognitive networks in patients with comorbid depression may point towards different pathways recruited by CBT as a function of comorbidity.

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene ( NPSR1 ) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected ( p =.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5 min after injection ( p =.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.

This work is part of the German multicenter trial ‘Mechanisms of Action in CBT (MAC)’. The MAC study is funded by the German Federal Ministry of Education and Research (BMBF; project no. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The study was further supported by the DFG (Grant RE1632/5-1 and KFO 125 to AR; SFB TRR 58 Z02 to JD, PP and AR; C02 to JD and KD; DE357/4-1 to JD, AR, JR and AH; RTG 1256 to AR, JD and PP; IZKF-Würzburg Z-6 to HW). Corticotropin releasing hormone (CRH) is a major regulator of the hypothalamicpituitary-adrenal (HPA) axis. Binding to its receptor CRHR1 triggers the downstream release of cortisol, a hormone needed for regulation of stress responses. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here, we aimed to evaluate CRHR1 as a candidate molecule in panic disorder (PD). Allelic variation throughout the CRHR1 gene was captured by 9 selected single nucleotide polymorphisms (SNPs); these were genotyped in 531 matched case/control pairs (discovery sample (n=239); replication sample (n=292)). Four SNPs were found to be associated with PD, in at least one sub-sample. The minor alleles of rs17689918 and rs17689966 were found to significantly increase risk for PD in females of the discovery, the replication and the combined sample, both withstanding correction for multiple testing (prs17689918=1.3*10-4; prs17689966=0.042). Expressional analysis demonstrated that both minor alleles of rs17689918 and rs17689966 significantly decreased CRHR1 mRNA in the forebrain and amygdala. Bioinformatical analysis revealed a high proportion of differential neuro-relevant transcription factor binding possibly underlying expression changes. When investigating the neural correlates underlying this association, risk allele carriers of rs17689918 and rs17689966 showed aberrant differential conditioning and safety signal processing arguing for predominant generalization of fear and hence anxious apprehension. Furthermore, the minor risk (A) allele of rs17689918 led to less flight behavior during fear provoking situations, but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus, reduced CRHR1 expression driven by CRHR1 risk allele leads to a phenotype characterized by a fear bias and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder. Postprint

Background: It is unknown if health-related quality of life (HRQoL) differs between diseases associated with chronic pruritus (CP). Objective: To analyze HRQoL in relation to age, gender, skin lesions (primary vs. scratch-induced secondary) and itch intensity. Methods: Consecutive patients of our itch clinic were assessed with the Dermatology Life Quality Index (DLQI) and visual analogue scale (VAS). Results: In 510 CP patients (282 females; median age, 61.4 years), DLQI scores and VAS values were highly correlated, irrespective of the type of skin lesion. Overall, women had a lower HRQoL compared to men (females: 10.7 ± 6.7, males: 8.9 ± 6.7), but female gender was only associated with worse quality of life in patients Conclusion: HRQoL impairment in CP is highly influenced by pruritus intensity but not to the visible skin lesion or underlying cause. With limitations to item bias, DLQI is a suitable instrument for estimating quality of life impairment by CP.

Highlights • Higher amygdala activation in T risk allele carriers during the perception of agoraphobia-specific stimuli • Amygdala activation correlated negatively trendwise with the trait neuroticism in healthy controls carrying A/A genotype • A diagnosis x genotype interaction as a trend in the inferior orbitofrontal cortex during the perception of agoraphobia-specific stimuli, Introduction The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural “fear network”. We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. Method 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific “Westphal-Paradigm”. It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. Results Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). Discussion The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

Summary Background Although sex and gender are increasingly perceived as important factors in medicine, there is only very little knowledge on these issues in patients with chronic pruritus (CP). Objectives The aim of this retrospective study was to compare multiple parameters of CP in a large representative group of patients and to assess any sex and gender differences. Methods Patients (n = 1037, 54·8% women) with CP (> 6 weeks' duration) were analysed concerning gender differences in multiple parameters, including quality of life, CP-underlying diseases, co-morbidities and clinics. We used McNemar tests for dependent variables, and χ2 tests and t-tests for independent variables, to evaluate gender-specific differences. Results Men were significantly older (P

BackgroundAlthough 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.MethodThe 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.ResultsDifferential 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.ConclusionsThe 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.

The availability of an accurate genetic test to identify Huntington's Disease (HD) in the pre-symptomatic stage makes HD an important model to develop biomarkers for other neurodegenerative diseases, such as pre-clinical Alzheimer's Disease. We reasoned that functional changes, measured by functional MRI (fMRI), would precede gray matter changes and that performing a task specifically affected by the disease would carry the clearest signature. Separate cohorts of HD gene mutations carriers and controls performed four different fMRI tasks, probing functions either primarly affected by the disease (i.e. motor control), higher cognitive functions (i.e. working memory and irritability), or basic sensory functions (i.e. auditory system). With the aim to compare fMRI and structural MRI biomarkers, all subjects underwent an additional high-resolution T1-weighted MRI. Best classification performance was achived from fMRI-based activations with motor sequence tapping and task-induced irritation. Classification performance based on gray matter probability maps was also significantly above chance and similar to that of fMRI. Both were sufficiently informative to separate gene mutation carriers that were on average 17 years before predicted disease onset from controls with up to 80% accuracy. Further analyses showed that classification accuracy was best in regions of interest with low within-group heterogeneity in relation to disease specific changes. Our study indicates that structural and some functional markers can accurately detect pre-clinical neurodegeneration. However, the lower variability and easier processing of the strucutral MRI data make latter the more useful tool for disease detection in a clinical setting.

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.

This study investigated sex-specific differences in itch perception and skin reactions, as modulated by verbal suggestions, and the role of the investigator's sex. Healthy volunteers (50 males, 50 females), divided into 4 groups, were tested by male and female investigators. Itch was induced via prick testing with sodium chloride and histamine in 4 runs; 2 control conditions (with no exaggerated verbal comments about expected itch) and 2 experimental conditions (with exaggerated verbal comments). After 5 min, wheal and flare reactions were measured and itch intensity was rated by subjects on a numerical rating scale. Exaggerated verbal suggestions resulted in higher itch intensity ratings in the sodium chloride and histamine condition, and higher unpleasantness ratings and a wheal of greater extent in the sodium chloride condition, as well as a flare of greater extent in the histamine condition. The magnitude of the differences between the exaggerated verbal suggestion conditions and respective control conditions was only significantly different between male and female investigators concerning flare size in the histamine condition. There were no differences between male and female participants. Therefore, sex differences may play only a minor role in nocebo-induced itch perception.

Profound mental retardation in phenylketonuria (PKU) can be prevented by a low phenylalanine (Phe) diet. However, even patients treated early have inconsistently shown deficits in several frontal lobe–related neuropsychological tasks such as the widely accepted Stroop task. The goal of this study was to investigate whether adult patients exhibit altered brain activation in Stroop-related locations in comparison to healthy controls and if an acute increase in blood Phe levels in patients has an effect on activation patterns. Seventeen male, early-treated patients with classic PKU (mean ± SD age: 31.0 ± 5.2 years) and 15 male healthy controls (32.1 ± 6.4 years) were compared using a color-word matching Stroop task in a functional magnetic resonance imaging (fMRI) study at 3T. Participants were scanned twice, and an oral Phe load (100 mg/kg body weight) was administered to patients prior to one of the fMRI sessions (placebo-controlled). Activity in brain regions that are known to be involved in Stroop tasks was assessed. PKU patients exhibited poorer accuracy in incongruent trials. Reaction times were not significantly different. There were no consistent differences in BOLD activations in Stroop-associated brain regions. The oral Phe administration had no significant effect on brain activity. Neither a generally slower task performance nor distinctively altered functioning of brain networks involved in a task representing a subset of dopamine-dependent executive functions could be proven. Decreased accuracy and inconsistent findings in posterior areas necessitate further study of frontal-lobe functioning in PKU patients in larger study samples.

Our goal was to assess treatment effects of electroconvulsive therapy (ECT) on acoustic processing in major depression. We hypothesized that (1) depression is related to functional alterations in auditory networks, and that (2) pre-treatment alterations in auditory networks are reversible through treatment with ECT. Acoustic perception of 20 severely depressed and 20 age and gender matched healthy controls was investigated by 3 T functional magnetic resonance imaging employing repeated stimulation by sine tones. Prior to ECT, depressed patients presented a multimodal recruitment of additional brain areas including regions of the secondary visual system (cuneus, lingualis) and the medial frontal cortex. During ECT, signal intensities were reduced compared to pre-ECT values and controls. Activation of several regions increased after ECT. Our data suggest that depression is accompanied by cortical dysfunction including impaired auditory processing of non-speech stimuli. This might be based on overall alterations of brain metabolism indicating functional impairment.

Huntington's Disease (HD) is a neurogenetic disorder accompanied by an atrophy of the striatum and hence of the dopaminergic (DA) system. Neural processes subserving error processing presumably depend on the DA system. We assessed error processing in manifest HD and in presymptomatic HD‐gene‐mutation‐carriers (pHD) with event‐related potentials reflecting error processing (the error negativity or error‐related negativity and the error positivity derived from a flanker‐task. We found a reduction of the Ne in the case of HD compared to pHD reflecting dopamine system pathology. Despite the Ne being reduced in HD, behavioral adaptation was possible. In addition, the error‐rates did not differ between the groups. Optimized voxel‐based morphometry revealed that grey matter volume in the medial frontal gyrus is correlated with the Ne amplitude in symptomatic patients. In addition, the effect of a Ne‐reduction was related to the grey matter underneath the medial frontal gyrus, which is in line with two theories of the Ne. In contrast, the Pe did not differ between the groups, suggesting that the Pe is decoupled from the DA system. Interestingly we found a reduction of a late slow negativity on correct responses, which possibly reflects decreased preparatory processes in HD compared to pHD as induced by the DA alterations in HD. In conclusion a deterioration in error processing in HD compared to pHD is mainly reflected by the Ne. The deterioration might rely on two factors: a neurofunctional and a neuroanatomical. Hum Brain Mapp 2008. © 2007 Wiley‐Liss, Inc.

Involvement of the prefrontal cortex in schizophrenia has been implicated by neuropsychological, as well as neuropathological and imaging studies. Reductions of N-acetylaspartate (NAA), an in vivo marker of neuronal integrity, have repeatedly been detected in the frontal lobes of patients with schizophrenia by proton magnetic resonance spectroscopy (1H-MRS). In chronic medicated patients, a positive correlation between NAA levels of the prefrontal cortex and cognitive functioning has been observed, but to date, there have been no studies in first-episode neuroleptic-naive patients. In this study, single-voxel 1H-MRS was used to investigate neuronal function of the dorsolateral prefrontal cortex in 15 first-episode and 20 chronic schizophrenic patients. Outcomes were compared to 20 age-matched healthy controls to assess the relationship between prefrontal metabolism and neuropsychological performance. Patients with chronic schizophrenia had significant reductions of NAA, glutamate/glutamine, and choline levels compared to first-episode patients and healthy controls. Furthermore, creatine and phosphocreatine were significantly reduced in both patient groups compared to healthy controls. In the neuropsychological tests, chronic schizophrenic patients performed significantly poorer in the Auditory Verbal Learning Task (AVLT) compared to first-episode patients. In both patient groups, NAA levels of the left frontal lobe significantly correlated with performances in verbal learning and memory. These results corroborate data from recent structural and spectroscopic imaging studies of the frontal lobes in schizophrenia, in which cortical gray matter reductions after onset of symptoms as well as reduced levels of NAA in chronic, but not in first-episode schizophrenic patients have been reported.

There are an increasing number of neuroimaging studies that allow a better understanding of symptoms, neural correlates and associated conditions of fibromyalgia. However, the results of these studies are difficult to compare, as they include a heterogeneous group of patients, use different stimulation paradigms, tasks, and the statistical evaluation of neuroimaging data shows high variability. Therefore, this meta‐analytic approach aimed at evaluating potential alterations in neuronal brain activity or structure related to pain processing in fibromyalgia syndrome (FMS) patients, using quantitative coordinate‐based “activation likelihood estimation” (ALE) meta‐analysis. 37 FMS papers met the inclusion criteria for an ALE analysis (1,264 subjects, 274 activation foci). A pooled ALE analysis of different modalities of neuroimaging and additional analyses according functional and structural changes indicated differences between FMS patients and controls in the insula, amygdala, anterior/mid cingulate cortex, superior temporal gyrus, the primary and secondary somatosensory cortex, and lingual gyrus. Our analysis showed consistent results across FMS studies with potential abnormalities especially in pain‐related brain areas. Given that similar alterations have already been demonstrated in patients with other chronic pain conditions and the lack of adequate control groups of chronic pain subjects in most FMS studies, it is not clear however, whether these findings are associated with chronic pain in general or are unique features of patients with FMS. Hum Brain Mapp 37:1749–1758, 2016. © 2016 Wiley Periodicals, Inc.

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.

Introduction: Cognitive behavioural therapy (CBT) and pharmacological treatment with selective serotonin or serotonin-noradrenalin reuptake inhibitors (SSRI/SSNRI) are regarded as efficacious treatments for panic disorder with agoraphobia (PD/AG). However, little is known about treatment-specific effects on symptoms and neurofunctional correlates. Experimental procedures: We used a comparative design with PD/AG patients receiving either two types of CBT (therapist-guided (n=29) or non-guided exposure (n=22)) or pharmacological treatment (SSRI/SSNRI; n=28) as well as a wait-list control group (WL; n=15) to investigate differential treatment effects in general aspects of fear and depression (Hamilton Anxiety Rating Scale HAM-A and Beck Depression Inventory BDI), disorder-specific symptoms (Mobility Inventory MI, Panic and Agoraphobia Scale subscale panic attacks PAS-panic, Anxiety Sensitivity Index ASI, rating of agoraphobic stimuli) and neurofunctional substrates during symptom provocation (Westphal-Paradigm) using functional magnetic resonance imaging (fMRI). Comparisons of neural activation patterns also included healthy controls (n=29). Results: Both treatments led to a significantly greater reduction in panic attacks, depression and general anxiety than the WL group. The CBT groups, in particular, the therapist-guided arm, had a significantly greater decrease in avoidance, fear of phobic situations and anxiety symptoms and reduction in bilateral amygdala activation while the processing of agoraphobia-related pictures compared to the SSRI/SSNRI and WL groups. Discussion: This study demonstrates that therapist-guided CBT leads to a more pronounced short-term impact on agoraphobic psychopathology and supports the assumption of the amygdala as a central structure in a complex fear processing system as well as the amygdala׳s involvement in the fear system׳s sensitivity to treatment.

Summary Capsule fibrosis and other complications around various filled breast implants were evaluated in a rat radiation model after 12 months of implantation. Model implants, one per rat, were implanted subcutaneously. One month after subcutaneous implantation, high voltage radiation followed one half each group. A higher rate of capsule fibrosis occurred in radiated animals. Malignant tumors at the implantation site developed in 40% of radiated and 24% of non-radiated animals, with a much higher rate of mitosis in the radiated group (Mann–Whitney, P = 0.008 ). The presence of an implant is a cofactor for tumor development in rats ( χ 2 -test, χ 2 = 6.927 ; P = 0.008 ) as well as radiation, since none of the control animals developed tumors. Applied to humans, capsule contracture (fibrosis) is a common complication of radiation, while development of radiation-induced sarcoma is a rare complication after postoperative radiotherapy by all account. Still further long-term follow-up human studies are necessary.

To assess habituation effects in relation to field strength by fMRI at 1.5 vs. 3.0 T within the auditory cortex of healthy subjects.fMRI experiments were performed on 19 healthy subjects at 1.5 T (N = 12) and 3 T (N = 12). The auditory cortex was stimulated binaurally by digitally generated pulsed (nu = 5 Hz) 800 Hz sine tones with three alternating on and off periods.The mean activation after stimulation (4.4% +/- 1.2% (1.5 T) and 5.3% +/- 2.3% (3 T)) and number of activated pixels (96.7 +/- 49.8 (1.5 T) and 139.9 +/- 101 (3 T)) were higher at 3 T compared to 1.5 T; however, that difference did not reach statistical significance. A characteristic signal decay with repeated stimuli was revealed at both 1.5 and 3 T, and the response to the second and third stimulation blocks was significantly lower compared to the first. The habituation pattern was the same, independently of field strength and age.The mean activation and number of pixels were only modestly higher at 3 T, probably due to higher physiologic noise and higher local macroscopic susceptibility gradients within the temporal lobes at 3 T. Our data reveal that measured auditory habituation is independent of field strength, and data obtained at two different field strengths do not differ fundamentally in this context.

Based upon pharmacological challenge and postmortem studies, schizophrenia has been hypothesized to be caused by decreased glutamatergic neurotransmission. We investigated the glutamatergic neuronal metabolism of the dorsolateral prefrontal cortex with localized 1H magnetic resonance spectroscopy in 18 first-episode patients, 21 chronic patients with schizophrenia, and 21 age-matched controls. Chronic patients had significantly lower levels of glutamate/glutamine (Glx) and N-acetylaspartate (NAA) compared to healthy controls and first-episode patients. Reduced metabolite levels were not correlated with duration of illness or medication. Our results indicate glutamatergic dysfunction in chronic schizophrenia that could be evidence of a progressive brain disorder.

The increasing availability of high-field (3 T) MR scanners requires adapting and optimizing clinical imaging protocols to exploit the theoretically higher signal-to-noise ratio (SNR) of the higher field strength. Our aim was to establish reliable and stable protocols meeting the clinical demands for imaging the neurocranium at 3 T. Two hundred patients with a broad range of indications received an examination of the neurocranium with an appropriate assortment of imaging techniques at 3 T. Several imaging parameters were optimized. Keeping scan times comparable to those at 1.5 T we increased spatial resolution. Contrast-enhanced and non-enhanced T1-weighted imaging was best applying gradient-echo and inversion recovery (rather than spin-echo) techniques, respectively. For fluid-attenuated inversion recovery (FLAIR) imaging a TE of 120 ms yielded optimum contrast-to-noise ratio (CNR). High-resolution isotropic 3D data sets were acquired within reasonable scan times. Some artifacts were pronounced, but generally imaging profited from the higher SNR. We present a set of optimized examination protocols for neuroimaging at 3 T, which proved to be reliable in a clinical routine setting.

The aim of this study was to measure and quantify habituation phenomena within the auditory cortex of 18 healthy subjects by means of fMRI. Auditory stimulation was done by digitally generated pulsed (ν = 5 Hz) 800-Hz sine tones with three alternating ON (duration 2 min) and OFF (1 min) periods. Binaural stimulation resulted in symmetrical bihemispheric activation of the auditory cortex. Our data revealed a characteristic signal decay to repeated acoustic stimulation: the response to the second was even more pronounced, and the third stimulation block significantly lower compared to the first. Thus, our data clearly demonstrate habituation phenomena, probably due to reduced neuronal activity with increased duration and/or frequency of stimuli.

Negatively balanced neurotrophic factors may be important in precipitating clinical depression. Recently, it has been reported that antidepressant therapy may exert positive neurotrophic effects. The aim of this study was to detect probable neurotrophic changes during electroconvulsive therapy (ECT). For this purpose, N-acetylaspartate (NAA), an amino acid exclusively located in neurons, and other brain metabolites such as glutamine/glutamate (Glx), choline (Cho), and creatine (Cr) were measured in patients by localized proton magnetic resonance spectroscopy. A total of 28 severely depressed patients (DSM-IV) were enrolled, and the left amygdalar region was investigated by proton STEAM spectroscopy before and after unilateral ECT. The results were compared with 28 age- and gender-matched controls using nonparametric paired and unpaired tests. A significant increase in NAA was observed only in ECT responders (n=14; p=0.019). Five out of 14 nonresponders to ECT monotherapy were remeasured following a clinical improvement after continued ECT combined with antidepressants and were then found also to present a significant increase in NAA. In all successfully treated patients, parallel observations, that is, increased levels, were made for Glx, whereas Cho and Cr were unchanged. In conclusion, our preliminary finding of increased NAA concentrations after successful ECT may indicate a probable neurotrophic effect of ECT.

Summary Background Although sex and gender are becoming more important in diagnostics and therapy, there is still little knowledge about sex-specific differences in chronic pruritus (CP). Objectives To compare, taking into consideration the characteristics of pruritus, sex-specific differences in psychological symptoms in patients with CP. Methods Sociodemographic data, data on the clinical characteristics of the skin and CP were documented over a 1-year period in all patients attending the Competence Center Chronic Pruritus of the University Hospital Munster for the first time. All patients completed the Hospital Anxiety and Depression Scale. Student's t-tests for independent study groups and linear regression analyses were applied. Results A total of 619 patients (278 men, 341 women) were included in the analysis. Women were more anxious than men, but were not more depressed. A linear regression analysis indicated that depression and anxiety scores in women were related to the average intensity of pruritus during the previous 4 weeks and to a more generalized pruritus at the beginning of CP; older age in women also correlated with the scores on the depression subscale. Interestingly, the associations were different in men: scores on the depression scale were associated with the diagnosis of CP pruritus with multiple scratch lesions. Conclusions There are sex-specific differences in the relationship between the psychological symptoms and clinical characteristics of CP; higher anxiety scores were achieved by women. Whether psychological symptoms can be reversed when CP and scratch lesions improve is an issue that needs further exploration.

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.

BackgroundEven though itch is a common syndrome of many diseases there is only little knowledge about sex and gender differences in pruritus, especially in central itch perception and modulation. To our knowledge, this is the first fMRI study examining sex differences in perception and its modulation by distraction.MethodsExperimental itch was induced by application of histamine (0.1 mM) via microdialysis fibers twice at the left forearm and twice at the left lower leg in 33 healthy volunteers (17 females, 16 males). The brain activation patterns were assessed by fMRI during itch without and with distraction (Stroop task). Between the various conditions, subjects were asked to rate itch intensity, desire to scratch and pain intensity. In a second experiment in 10 of the 33 volunteers histamine was replaced by saline solution to serve as control for the 'Stroop' condition.ResultsWomen generally presented higher itch intensities compared to men during itch over the course of the experiment. A more specific analysis revealed higher itch intensities and desire to scratch in women during experimental induced itch that can be reduced by distraction at the lower legs when itch is followed by 'Stroop'. In contrast, men depicted significant reduction of 'itch' by 'Stroop' at the forearms. Women depicted higher brain activation of structures responsible for integration of sensory, affective information and motor integration/planning during 'itch' and 'Stroop' condition when compared to men. No sex differences were seen in the saline control condition.ConclusionWomen and men exhibited localisation dependent differences in their itch perception with women presenting higher itch intensities and desire to scratch. Our findings parallel clinical observations of women reporting higher itch intensities depending on itch localisation and suffering more from itch as compared to men.

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.

Background: Cognitive behavioral therapy (CBT) is an effective treatment for panic disorder with agoraphobia (PD/AG). It is unknown, how variants of CBT differentially modulate brain networks involved in PD/AG. This study was aimed to evaluate the effects of therapist-guided (T+) versus self-guided (T-) exposure on the neural correlates of fear conditioning in PD/AG. Method: In a randomized, controlled multicenter clinical trial in medication-free patients with PD/AG who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before (t1) and after CBT (t2). Quality-controlled fMRI data from 42 patients and 42 healthy subjects (HS) were obtained. Patients were randomized to two variants of CBT (T+, n = 22, and T-, n = 20). Results: The interaction of diagnosis (PD/AG, HS), treatment group (T+, T-), time point (t1, t2) and stimulus type (conditioned stimulus: yes, no) revealed activation in the left hippocampus and the occipitotemporal cortex. The T+ group demonstrated increased activation of the hippocampus at t2 (t2 > t1), which was positively correlated with treatment outcome, and a decreased connectivity between the left inferior frontal gyrus and the left hippocampus across time (t1 > t2). Conclusion: After T+ exposure, contingency-encoding processes related to the posterior hippocampus are augmented and more decoupled from processes of the left inferior frontal gyrus, previously shown to be dysfunctionally activated in PD/AG. Linking single procedural variants to neural substrates offers the potential to inform about the optimization of targeted psychotherapeutic interventions.

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.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.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.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.

BackgroundIn chronic PTSD, a preattentive neural alarm system responds rapidly to emotional information, leading to increased prefrontal cortex (PFC) activation at early processing stages (MethodologyThe present study investigates early fear network activity in acutely traumatized patients with PTSD. It focuses on the question whether dysfunctions previously observed in chronic PTSD patients are already present shortly after trauma exposure. We recorded neuromagnetic activity towards emotional pictures in seven acutely traumatized PTSD patients between one and seven weeks after trauma exposure and compared brain responses to a balanced healthy control sample. Inverse modelling served for mapping sources of differential activation in the brain.Principal findingsCompared to the control group, acutely traumatized PTSD patients showed an enhanced PFC response to high-arousing pictures between 60 to 80 ms. This rapid prefrontal hypervigilance towards arousing pictorial stimuli was sustained during 120-300 ms, where it was accompanied by a reduced affective modulation of occipito-temporal neural processing.ConclusionsOur findings indicate that the hypervigilance-avoidance pattern seen in chronic PTSD is not necessarily a product of an endured mental disorder, but arises as an almost immediate result of severe traumatisation. Thus, traumatic experiences can influence emotion processing strongly, leading to long-lasting changes in trauma network activation and expediting a chronic manifestation of maladaptive cognitive and behavioral symptoms.

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.

Major depression is accompanied by cortical dysfunction including impaired auditory processing of non-speech stimuli. In a previous study, we could show that potent antidepressant treatment with electroconvulsive therapy (ECT) did not lead to full functional normalization of altered fMRI activation patterns in response to sine tones although depressive symptoms improved and remission was achieved in the majority of patients. In a next step, a longitudinal follow-up investigation was conducted looking on neuronal activation over time along with full remission in a subgroup of patients of the previous study in order to address the question whether changes in neuronal activation patterns reflect a more state- or trait-dependent characteristic. Results showed that although clinically remitted, patients still exhibited an increased activity of the secondary auditory cortex and multimodal recruitment of the left cuneus, an area of the visual system. However, activity of recruited secondary visual network had decreased over time. A positive correlation was observed between the number of hospital admissions during the follow-up period and activity of the secondary visual area of the left cuneus at baseline prior to ECT. Thus, although the persistence of differences in activation patterns after sine tone presentation in this follow-up investigation could argue for a potential trait marker of depression characterized by alterations in auditory processing, attenuation of neuronal activation in some areas over time suggests that changes might in part also be state-dependent.

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.

Hypnotic paralysis has been used since the times of Charcot to study altered states of consciousness; however, the underlying neurobiological correlates are poorly understood. We investigated human brain function during hypnotic paralysis using resting-state functional magnetic resonance imaging (fMRI), focussing on two core regions of the default mode network and the representation of the paralysed hand in the primary motor cortex. Hypnotic suggestion induced an observable left-hand paralysis in 19 participants. Resting-state fMRI at 3T was performed in pseudo-randomised order awake and in the hypnotic condition. Functional connectivity analyses revealed increased connectivity of the precuneus with the right dorsolateral prefrontal cortex, angular gyrus, and a dorsal part of the precuneus. Functional connectivity of the medial frontal cortex and the primary motor cortex remained unchanged. Our results reveal that the precuneus plays a pivotal role during maintenance of an altered state of consciousness. The increased coupling of selective cortical areas with the precuneus supports the concept that hypnotic paralysis may be mediated by a modified representation of the self which impacts motor abilities.