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Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active ( n= 34) or sham ( n= 39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r ⩽−0.441, all P ⩽0.009), but not the sham rTMS group (all r ⩽0.211, all P ⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group ( F (9, 207) =2.72, P= 0.005, partial η 2 =0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new treatment option for depression. Previous studies were performed with low sample sizes in single centres and reported heterogeneous results. To investigate the efficacy of rTMS as augmentative treatment in depression. In a randomised, double-blind, sham-controlled multicentre trial 127 patients with moderate to severe depressive episodes were randomly assigned to real or sham stimulation for 3 weeks in addition to simultaneously initiated antidepressant medication. We found no difference in the responder rates of the real and the sham treatment groups (31% in each) or in the decrease of the scores on the depression rating scales. The data do not support previous reports from smaller samples indicating an augmenting or accelerating antidepressant effect of rTMS. Further exploration of the possible efficacy of other stimulation protocols or within selected sub-populations of patients is necessary.

Background. Repetitive transcranial magnetic stimulation (rTMS) of frontal brain regions is under study as a non-invasive method in the treatment of affective disorders. Recent publications provide increasing evidence that rTMS may be useful in treating schizophrenia. Results are most intriguing, demonstrating a reduction of negative symptoms following high-frequency rTMS. In this context, disentangling of negative and depressive symptoms is of the utmost importance when understanding specific rTMS effects on schizophrenic symptoms. Method. Using a sham-controlled parallel design, 20 patients with schizophrenia were included in the study. Patients were treated with high-frequency 10 Hz rTMS over 10 days. Besides clinical ratings, ECD-SPECT (technetium-99 bicisate single photon emission computed tomography) imaging was performed before and after termination of rTMS treatment. Results. High-frequency rTMS leads to a significant reduction of negative symptoms combined with a trend for non-significant improvement of depressive symptoms in the active stimulated group as compared with the sham stimulated group. Additionally, a trend for worsening of positive symptoms was observed in the actively treated schizophrenic patients. In both groups no changes in regional cerebral blood flow could be detected by ECD-SPECT. Conclusions. Beneficial effects of high-frequency rTMS on negative and depressive symptoms were found, together with a trend for worsening positive symptoms in schizophrenic patients.

We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. This finding was supported by meta-analysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P=0.00062-0.048), GABRP (P=0.0024-0.042), and GABRA6 (P=0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P=0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABAA receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

Hypersensitivity to electromagnetic fields (EMF) is frequently claimed to be linked to a variety of non-specific somatic and neuropsychological complaints. Whereas provocation studies often failed to demonstrate a causal relationship between EMF exposure and symptom formation, recent studies point to a complex interplay of neurophysiological and cognitive alterations contributing to symptom manifestation in electromagnetic hypersensitive patients (EHS). However, these studies have examined only small sample sizes or have focused on selected aspects. Therefore this study examined in the largest sample of EHS EMF-specific cognitive correlates, discrimination ability and neurobiological parameters in order to get further insight into the pathophysiology of electromagnetic hypersensitivity. In a case-control design 89 EHS and 107 age- and gender-matched controls were included in the study. Health status and EMF-specific cognitions were evaluated using standardized questionnaires. Perception thresholds following single transcranial magnetic stimulation (TMS) pulses to the dorsolateral prefrontal cortex were determined using a standardized blinded measurement protocol. Cortical excitability parameters were measured by TMS. Discrimination ability was significantly reduced in EHS (only 40% of the EHS but 60% of the controls felt no sensation under sham stimulation during the complete series), whereas the perception thresholds for real magnetic pulses were comparable in both groups (median 21% versus 24% of maximum pulse intensity). Intra-cortical facilitation was decreased in younger and increased in older EHS. In addition, typical EMF-related cognitions (aspects of rumination, symptom intolerance, vulnerability and stabilizing self-esteem) specifically differentiated EHS from their controls. These results demonstrate significant cognitive and neurobiological alterations pointing to a higher genuine individual vulnerability of electromagnetic hypersensitive patients.

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

Abstract Background The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients’ response to rTMS. Methods We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction. Results Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern. Conclusions Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.

[...] an unspecific individual 'guessing tendency' β, which is dependent on subjects' gender (women guess more often), age (older subjects guess more often), sequence of the experiment (subjects starting with verum coils guess more often) and a remarkable effect for hypersensitivity: EHS [odds ratio (OR) 2.24] clearly feel more often exposed to a magnetic pulse of recognizable intensity than their controls. * [...] during series 3 and 4 (approximately equivalent to the second half of an individual's experimental session), subjects showed a greater tendency to report a sensory perception.

The hormone oxytocin has been hypothesized to influence the emotional dimension of pain. This randomized, placebo-controlled, double-blind, crossover study explored whether intranasal oxytocin and emotional context can affect heat pain perception in 30 healthy male volunteers. After receiving 36 IU oxytocin or placebo, participants underwent functional Magnetic Resonance Imaging (fMRI) during which noxious and non-noxious thermode heat stimuli were applied. Simultaneously, scenes from the International Affective Pictures System (IAPS) with positive, neutral and negative emotional valence were shown. Heat intensity and unpleasantness ratings were obtained. The activity of whole-brain correlates of heat processing was quantified via multi-voxel pattern analysis. We observed no appreciable main effects of oxytocin on ratings or neural pain correlates. Effects of emotional picture valence on ratings were smaller than reported in previous studies. Nevertheless, oxytocin was found to significantly enhance the influence of picture valence on unpleasantness ratings at noxious heat levels. No corresponding changes in whole-brain correlates of heat intensity processing were found. Our study provides evidence that intranasal oxytocin increases the effects of emotional context on the subjective unpleasantness of experimental heat pain. Future studies are needed to determine whether this effect can be utilized in clinical settings.