Altered resting-state functional connectivity of default mode network in brachioradial pruritus.

BACKGROUND: Patients with chronic pruritus (CP) have a low quality of life, thus it is important to gain a better understanding of the underlying processes. Previous functional magnetic resonance imaging studies at rest (rsfMRI) have shown that mainly areas associated with the default mode network (DMN), sensorimotor (SMN), frontoparietal (FPN) and salience networks (SN) are involved in the processing of itch in patients with chronic pruritus (CP), as well as the cortico-striatal circuit, which is involved in the motoric preparation of scratching. rsfMRI studies on functional connectivity (FC) patterns of resting-state networks (RSNs) in patients with inflammatory atopic dermatitis (AD) or with neuropathic brachioradial pruritus (BRP) compared with healthy controls (HC) are lacking. OBJECTIVES: The main goals of this study were to investigate whether functional connectivity within networks and areas associated with itch detection and processing are altered in patients with AD and BRP compared with matched healthy controls by rsfMRI, respectively. METHODS: Patients with AD (n = 28) and with BRP (n = 28) were compared with corresponding matched healthy controls by rsfMRI. Group-specific RSNs were identified by independent component analysis (ICA) and between-group differences in the RSNs were analysed by dual regression technique. Seed-based functional connectivity was analysed in several itch-related brain regions belonging to the DMN, SN and FPN, respectively. RESULTS: ICA and seed-based analyses revealed decreased functional connectivity in BRP compared with HC specially within the DMN including the precuneus and cingulate cortex. For AD patients in comparison with HC, as well as when BRP and AD patients were compared directly, no significant FC differences at rest were seen. CONCLUSIONS: Our findings point towards decreased FC particularly in the DMN at rest in patients with BRP. These results seem to indicate that central connectivity patterns at rest differentially encode itch in BRP and AD.

Interaction of Developmental Venous Anomalies with Resting-State Functional MRI Measures.

BACKGROUND AND PURPOSE: Functional MR imaging of the brain, used for both clinical and neuroscientific applications, relies on measuring fluctuations in blood oxygenation. Such measurements are susceptible to noise of vascular origin. The purpose of this study was to assess whether developmental venous anomalies, which are frequently observed normal variants, can bias fMRI measures by appearing as true neural signal. MATERIALS AND METHODS: Large developmental venous anomalies (1 in each of 14 participants) were identified from a large neuroimaging cohort (n = 814). Resting-state fMRI data were decomposed using independent component analysis, a data-driven technique that creates distinct component maps representing aspects of either structured noise or true neural activity. We searched all independent components for maps that exhibited a spatial distribution of their signals following the topography of developmental venous anomalies. RESULTS: Of the 14 developmental venous anomalies identified, 10 were clearly present in 17 fMRI independent components in total. While 9 (52.9%) of these 17 independent components were dominated by venous contributions and 2 (11.8%) by motion artifacts, 2 independent components (11.8%) showed partial neural signal contributions and 5 independent components (29.4%) unambiguously exhibited typical neural signal patterns. CONCLUSIONS: Developmental venous anomalies can strongly resemble neural signal as measured by fMRI. They are thus a potential source of bias in fMRI analyses, especially when present in the cortex. This could impede interpretation of local activity in patients, such as in presurgical mapping. In scientific studies with large samples, developmental venous anomaly confounds could be mainly addressed using independent component analysis-based denoising.

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

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.

Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach.

Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain's evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.

Influence of single-dose quetiapine on fear network activity - A pharmaco-imaging study.

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.

[New treatment options for chronic pruritus]. / Neues zur Therapie des chronischen Pruritus.

Prevalent in 14-17 % of the population, chronic pruritus is among the most common and stressful symptoms in medicine. In spite of new findings regarding the origin and chronification of the symptom, therapy remains a great challenge. There is a lack of approved therapies that provide rapid and efficient reduction of pruritus. As a result, the affected patients suffer a long time (even months to years), and somatic (scratch lesions, super infections, sleep disorders) and psychosomatic disorders develop. Interdisciplinary cooperation with various specialists is important not just for these reasons, but also due to different etiologies of the symptom and common comorbidities. In addition, there remains a great need for uniformly devised, clinically controlled studies, recommendations and guidelines. New therapeutic approaches are currently being verified in clinical trials. This allows for future prospects of possible new and partially targeted therapies. This article provides a summary of current therapeutic options based on case series, individual randomized controlled trials and the current S2K guideline.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. 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 risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk 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 gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization 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.

[Gender-specific Aspects of Knowledge and Gender Sensitivity in Medical Education - An Inventory]. / Geschlechtsspezifisches Wissen und Gendersensibilität in der medizinischen Lehre - eine Bestandsaufnahme.

BACKGROUND: Gender competence is an essential prerequisite for individualized patient care. OBJECTIVES: The aim of this study is to survey the level of knowledge and attitudes towards gender-related aspects at 2 German medical schools. MATERIALS AND METHODS: An online questionnaire was used to collect data on gender competence in medicine including biological basics of sex differences, clinical aspects, socio-cultural factors as well as questions regarding gender role concepts. In total 1 671 students, 330 basic scientists, 413 physicians and 53 professors from the German Medical Schools Münster and Duisburg-Essen took part in the survey. RESULTS: The level of knowledge on gender-specific aspects in medicine is unsatisfactory at both medical schools. The average of correct answers on gender-related questions of all groups is less than 55%. Looking at gender sensitivity the existence and importance of gender disparities in medicine is agreed upon by the majority of participants. However, most of them regard only the patients' but not the physician's sex as relevant. CONCLUSIONS: The study reveals a lack of knowledge and the necessity for improvement: the integration of gender-specific aspects into medical routine is an important step towards a truly individualized medical care.

[Why medicine? Analyzing students' motives for studying medicine]. / Warum Medizin studieren?

BACKGROUND: Despite increasing numbers of physicians, shortage of doctors is a predominant problem in the German health care system. AIM: AIM of the present study is a detailed and gendered analysis of current motives to study medicine in order to deduce implications for securing medical care in the future. METHODS: Study motives of medical students from Duisburg-Essen and Muenster were assessed using an online questionnaire. 13 given motives had to be rated on a 5 point Likert-scale according to their relevance for the decision to study medicine. Descriptive analysis regarding age, gender, location and study period was performed and a dichotomization of data (agreement vs. disagreement) was undertaken for logistic regression analysis. RESULTS: 1545 medical students took part in the survey (64.5% female). "Many-faceted workspaces", "varied tasks", "helping patients", "scientific interest" and "good career prospects" - backward-sorted - were the most frequent study motives indicated by medical students. The aspect "helping patients" was more important to female than to male students, the latter rated career-associated motives e. g. income, reputation etc. as more relevant. Only for about 8% of the respondents - independently of gender - compatibility of job and family was a motive to study medicine. CONCLUSION: Perspectively, results of this study could help to shape medicine in a way that will appeal to the growing up generation of doctors: a sophisticated, demanding and fulfilling occupation compatible with family with options to carve out a career for those who want to - regardless of gender. Furthermore, coaching programs paralleling either medical studies or work as clinician should be considered to improve the matching of gender-specific study motives and careers.

Relations between the characteristics and psychological comorbidities of chronic pruritus differ between men and women: women are more anxious than men.

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 Münster 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.

The functional -1019C/G HTR1A polymorphism and mechanisms of fear.

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.

[Sex- and gender-sensitive research in epidemiology and medicine: how can this be achieved? Aims and first results of the network "Sex-/Gender-Sensitive Research in Epidemiology, Neurosciences and Genetics/Cancer Research"]. / Geschlechtersensible Forschung in Epidemiologie und Medizin: Wie kann das erreicht werden? : Ziele und erste Ergebnisse des Verbundes "Geschlechtersensible Forschung in Epidemiologie, Neurowissenschaften und Genetik/Tumorforschung".

BACKGROUND: It is considered general knowledge among physicians and epidemiologists that biological and social aspects associated with being male or female have a strong influence on health and disease. Integrating these aspects into research is necessary to counteract the problems--including ethical problems--resulting from a different evidence basis for men and women. From January 2011 to June 2014 the Federal Ministry of Education and Research supported the network "Sex-/Gender-Sensitive Research in Epidemiology, Neuroscience and Genetics/Cancer Research" with three subprojects, which aimed to promote gender-sensitive research practices. The concepts and results are presented in this article. METHODS: The subproject gathered data (literature analyses, questionnaires) and offered programs for young scientists. Experiences and results were collected and generalized, for instance, in the form of definitions of terms. RESULTS: 50 young scientists have taken part in the training program, identifying associations and barriers in sex-/gender-sensitive research. Among others, a working definition for "sex-/gender-sensitive research" was developed, as well as definitions for the terms "sex-specific" (for biological characteristics that are specific to men or women) and "sex-/gender-dependent" or "sex-/gender-associated" (for biological and social factors, for which the extent of occurrence differs between the sexes). PRELIMINARY ASSESSMENT: The concepts realized by the network are well suited to stimulate further development and discussions. The definition of terms is an important base for a productive and high-yielding interdisciplinary collaboration.

Anticipating agoraphobic situations: the neural correlates of panic disorder with agoraphobia.

BACKGROUND: Panic disorder with agoraphobia is characterized by panic attacks and anxiety in situations where escape might be difficult. However, neuroimaging studies specifically focusing on agoraphobia are rare. Here we used functional magnetic resonance imaging (fMRI) with disorder-specific stimuli to investigate the neural substrates of agoraphobia. METHOD: We compared the neural activations of 72 patients suffering from panic disorder with agoraphobia with 72 matched healthy control subjects in a 3-T fMRI study. To isolate agoraphobia-specific alterations we tested the effects of the anticipation and perception of an agoraphobia-specific stimulus set. During fMRI, 48 agoraphobia-specific and 48 neutral pictures were randomly presented with and without anticipatory stimulus indicating the content of the subsequent pictures (Westphal paradigm). RESULTS: During the anticipation of agoraphobia-specific pictures, stronger activations were found in the bilateral ventral striatum and left insula in patients compared with controls. There were no group differences during the perception phase of agoraphobia-specific pictures. CONCLUSIONS: This study revealed stronger region-specific activations in patients suffering from panic disorder with agoraphobia in anticipation of agoraphobia-specific stimuli. Patients seem to process these stimuli more intensively based on individual salience. Hyperactivation of the ventral striatum and insula when anticipating agoraphobia-specific situations might be a central neurofunctional correlate of agoraphobia. Knowledge about the neural correlates of anticipatory and perceptual processes regarding agoraphobic situations will help to optimize and evaluate treatments, such as exposure therapy, in patients with panic disorder and agoraphobia.

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia.

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.

Multivariate classification of blood oxygen level-dependent FMRI data with diagnostic intention: a clinical perspective.

SUMMARY: There has been a recent upsurge of reports about applications of pattern-recognition techniques from the field of machine learning to functional MR imaging data as a diagnostic tool for systemic brain disease or psychiatric disorders. Entities studied include depression, schizophrenia, attention deficit hyperactivity disorder, and neurodegenerative disorders like Alzheimer dementia. We review these recent studies which-despite the optimism from some articles-predominantly constitute explorative efforts at the proof-of-concept level. There is some evidence that, in particular, support vector machines seem to be promising. However, the field is still far from real clinical application, and much work has to be done regarding data preprocessing, model optimization, and validation. Reporting standards are proposed to facilitate future meta-analyses or systematic reviews.

MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy.

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.

Gender differences in chronic pruritus: women present different morbidity, more scratch lesions and higher burden.

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 χ(2) tests and t-tests for independent variables, to evaluate gender-specific differences. RESULTS: Men were significantly older (P < 0·001) than women and had significantly more often cardiovascular (P < 0·001) and urogenital (P < 0·0001) co-morbidities, a higher number of co-medications (P = 0·041), and more often dermatological and systemic diseases leading to CP. Women had more neuropathic and psychosomatic diseases underlying the CP. They significantly more often showed a worsening of the CP by emotional (P = 0·002) and psychosomatic factors (P = 0·046). Women reported more often on localized itching occurring in attacks, with stinging, warmth and painful qualities (P < 0·05). Women significantly more often showed chronic scratch lesions and prurigo nodularis (P = 0·001), in contrast to men who significantly more frequently had CP on noninflamed skin (P = 0·004). In addition, women obtained higher visual analogue scale scores (P = 0·031) and reported a higher impact on quality of life (P = 0·033) than men. CONCLUSIONS: There are gender-specific differences not only in the quality, localization and triggering of CP but also in the underlying disease and scratching behaviour. These facts must be taken into account in the medical care of patients with CP and when conducting any kind of clinical research on itch. Further research is needed to achieve a gender-specific and gender-adapted diagnostics and treatment of CP.

Auditory processing in remitted major depression: a long-term follow-up investigation using 3T-fMRI.

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.

Cerebral mechanisms of experimental hyperalgesia in fibromyalgia.

The present study examined the hyperresponsiveness of the central nervous system in patients with fibromyalgia syndrome (FMS) related to mechanical hyperalgesia. The goals were to differentiate between increased pain ratings and hyperalgesia related either to peripheral or to central sensitization and to correlate with cerebral activation pattern. Seventeen patients and 17 healthy controls were examined, placing an experimental incision in the right volar forearm and causing tonic pain. Experimental pain, primary and secondary hyperalgesia were assessed during the time course of the experimental pain, and the changes in hyperalgesia were correlated to brain activation (functional magnetic resonance imaging). Patients with FMS experienced the experimental pain during the time course as more painful than healthy controls (F(score) = 3.93, p(score) = 0.008). While they did not present a different course of primary hyperalgesia (F(score) = 1.01, p(score) = 0.40), they did show greater secondary hyperalgesia (F(score) = 5.45, p(score) = 0.004). In patients with FMS, the cerebral pattern corresponding to secondary hyperalgesia was altered. The activity in the dorsolateral prefrontal cortex was inversely correlated with secondary hyperalgesia in healthy controls (R = -0.34 p = 0.005); in patients, this correlation was disrupted (R = 0.19 p = 0.12). These findings point to an alteration of pain transmission at the central level in FMS (e.g., loss of inhibition) and might be related to changes in cerebral-midbrain-spinal mechanisms of pain inhibition.

Brain correlates of hypnotic paralysis-a resting-state fMRI study.

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.