Peter Eichhammer

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Activation-dependent brain plasticity in humans on a structural level has been demonstrated in adults after 3 months of training a visio-motor skill. The exact timescale of usage-dependent structural changes, whether days, months, or years, is, however, still debated. A better understanding of the temporal parameters may help elucidate to what extent this type of cortical plasticity contributes to fast adapting cortical processes that may be relevant to learning and effects of treatments. Using voxel-based morphometry, we are able to show that repetitive transcranial magnetic stimulation delivered to the superior temporal cortex causes macroscopic cortical changes in gray matter (GM) in the auditory cortex as early as within 5 days of continuous intervention. These structural alterations are mirrored by changes in cortical evoked potentials attributed to the GM changes and demonstrate the rapid dynamics of these processes, which occur within a time range characteristic for the onset of behavioral effects induced by a variety of treatment methods for neuropsychiatric diseases. Our finding suggests that cortical plasticity on a structural level in adult humans is already detectable after 1 week, which provides support for fast adjusting neuronal systems, such as spine and synapse turnover, and contradicts slow evolving mechanisms, such as neuronal or glial cell genesis.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap. Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Recent preclinical work strongly suggests that vagus nerve stimulation efficiently modulates nociception and pain processing in humans. Most recently, a medical device has offered a transcutaneous electrical stimulation of the auricular branch of the vagus nerve (t-VNS) without any surgery.Our study investigates whether t-VNS may have the potential to alter pain processing using a controlled design.Different submodalities of the somatosensory system were assessed with quantitative sensory testing (QST) including a tonic heat pain paradigm in 48 healthy volunteers. Each subject participated in two experimental sessions with active t-VNS (stimulation) or sham t-VNS (no stimulation) on different days in a randomized order (crossed-over). One session consisted of two QST measurements on the ipsi- and contralateral hand, each before and during 1 h of a continuous t-VNS on the left ear using rectangular pulses (250 μS, 25 Hz).We found an increase of mechanical and pressure pain threshold and a reduction of mechanical pain sensitivity. Moreover, active t-VNS significantly reduced pain ratings during sustained application of painful heat for 5 min compared to sham condition. No relevant alterations of cardiac or breathing activity or clinical relevant side effects were observed during t-VNS.Our findings of a reduced sensitivity of mechanically evoked pain and an inhibition of temporal summation of noxious tonic heat in healthy volunteers may pave the way for future studies on patients with chronic pain addressing the potential analgesic effects of t-VNS under clinical conditions.

Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition.The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04).In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Recent studies demonstrated focal brain activation in the auditory cortex of patients with chronic tinnitus. Low-frequency repetitive transcranial magnetic stimulation (rTMS) is able to reduce cortical hyperexcitability.Fusing of the individual PET-scan with the structural MRI-scan (T1, MPRAGE) allowed us to identify exactly the area of increased metabolic activity in the auditory cortex of patients with chronic tinnitus. With the use of a neuronavigational system, this target area was exactly stimulated by the figure 8-shaped magnetic coil. In a prospective study, rTMS (110% motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design. Patients were blinded regarding the stimulus condition. For the sham stimulation a specific sham-coil system was used. Fourteen patients were followed for 6 months. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller).Tertiary referral medical center.Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of verum rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score.These preliminary results demonstrate that neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.

The mesolimbic dopaminergic reward system seems to play a crucial role in reinforcing effects of nicotine. Recently, acute high-frequency repetitive transcranial magnetic stimulation (rTMS) of frontal brain regions has been shown to efficiently modulate the mesostriatal and mesolimbic dopaminergic system in both animals and humans. For this reason, we investigated whether high-frequency rTMS would be able to influence nicotine-related behavior by studying rTMS effects on craving and cigarette smoking.Fourteen treatment-seeking smokers were included in a double-blind crossover trial, conducted in 2002, comparing single days of active versus sham stimulation. Outcome measures were rTMS effects on number of cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence.High-frequency (20-Hz) rTMS of left dorsolateral prefrontal cortex reduced cigarette smoking significantly (p <.01) in an active stimulation compared with sham stimulation. Levels of craving did not change significantly.High-frequency rTMS may be useful for treatment in smoking cessation.

Deep and slow breathing (DSB) techniques, as a component of various relaxation techniques, have been reported as complementary approaches in the treatment of chronic pain syndromes, but the relevance of relaxation for alleviating pain during a breathing intervention was not evaluated so far.In order to disentangle the effects of relaxation and respiration, we investigated two different DSB techniques at the same respiration rates and depths on pain perception, autonomic activity, and mood in 16 healthy subjects. In the attentive DSB intervention, subjects were asked to breathe guided by a respiratory feedback task requiring a high degree of concentration and constant attention. In the relaxing DSB intervention, the subjects relaxed during the breathing training. The skin conductance levels, indicating sympathetic tone, were measured during the breathing maneuvers. Thermal detection and pain thresholds for cold and hot stimuli and profile of mood states were examined before and after the breathing sessions.The mean detection and pain thresholds showed a significant increase resulting from the relaxing DSB, whereas no significant changes of these thresholds were found associated with the attentive DSB. The mean skin conductance levels indicating sympathetic activity decreased significantly during the relaxing DSB intervention but not during the attentive DSB. Both breathing interventions showed similar reductions in negative feelings (tension, anger, and depression).Our results suggest that the way of breathing decisively influences autonomic and pain processing, thereby identifying DSB in concert with relaxation as the essential feature in the modulation of sympathetic arousal and pain perception.

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.

A growing number of self-report measures for the evaluation of tinnitus severity has become available to research and clinical practice. This has led to an increased awareness of depression and personality as predictors of tinnitus severity in addition to loudness and other psychoacoustic measures. However, the net impact of personality dimensions on tinnitus ratings has not been investigated when the effect of depressed mood is controlled. In the present study, we demonstrate the role of the big five personality traits, 'Neuroticism', 'Extraversion', 'Openness', 'Agreeableness', and 'Conscientiousness', in affecting scores on two standard instruments for grading tinnitus-related complaints, the tinnitus handicap inventory (THI), and the tinnitus questionnaire (TQ). When 72 individuals with chronic tinnitus were examined, 'Agreeableness' negatively correlated with THI scores (p=.003), whereas the anxiety trait 'Neuroticism' correlated both with depressive symptomatology (p<.001) and TQ scores (p=.028), but not with THI ratings (n.s.). In addition to confirming the established roles of trait anxiety and depression, low 'Agreeableness' was thus identified as a novel predictor of tinnitus severity on the THI.

Objectives Low‐frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a new treatment strategy for patients with chronic tinnitus. However, functional abnormalities in tinnitus patients also involve brain structures used for attentional and emotional processing, such as the dorsolateral prefrontal cortex. Therefore, we have developed a new rTMS treatment strategy for tinnitus patients that consists of a combination of high‐frequency prefrontal and low‐frequency temporal rTMS. Study Design A total of 32 patients received either low‐frequency temporal rTMS or a combination of high‐frequency prefrontal and low‐frequency temporal rTMS. Treatment effects were assessed with a standardized tinnitus questionnaire (TQ). Results Directly after therapy there was an improvement of the TQ‐score for both groups, but no differences between groups. An evaluation after 3 months revealed a remarkable benefit from the use of combined prefrontal and temporal rTMS treatment. Conclusion These results support recent data that suggest that auditory and nonauditory brain areas are involved in tinnitus pathophysiology.

BackgroundInvestigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia.MethodsA multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007–2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly.ResultsThere was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21.ConclusionsApplication of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases.1Mehta D. Tropf F.C. Gratten J. Bakshi A. Zhu Z. Bacanu S.-A. Hemani G. Magnusson P.K.E. Barban N. Esko T. et al.Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUKEvidence for genetic overlap between schizophrenia and age at first birth in women.JAMA Psychiatry. 2016; 73: 497-505Crossref PubMed Scopus (30) Google Scholar, 2Lee S.H. Byrne E.M. Hultman C.M. Kähler A. Vinkhuyzen A.A.E. Ripke S. Andreassen O.A. Frisell T. Gusev A. Hu X. et al.Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium InternationalSchizophrenia Working Group of the Psychiatric Genomics Consortium AuthorsSchizophrenia Working Group of the Psychiatric Genomics Consortium CollaboratorsRheumatoid Arthritis Consortium International AuthorsRheumatoid Arthritis Consortium International CollaboratorsNew data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.Int. J. Epidemiol. 2015; 44: 1706-1721Crossref PubMed Scopus (49) Google Scholar, 3Lee S.H. DeCandia T.R. Ripke S. Yang J. Sullivan P.F. Goddard M.E. Keller M.C. Visscher P.M. Wray N.R. Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ)International Schizophrenia Consortium (ISC)Molecular Genetics of Schizophrenia Collaboration (MGS)Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs.Nat. Genet. 2012; 44: 247-250Crossref PubMed Scopus (439) Google Scholar The genetic correlation is the additive genetic covariance between two traits scaled by the square root of the product of the genetic variance for each trait (i.e., the geometric mean of the trait variances). The sign of the correlation shows the direction of sharing, and the parameter definition is based on genetic variants across the allelic spectrum. Methods to estimate genetic correlation based on genetic covariance structure are well established for both quantitative and disease traits, e.g., (restricted) maximum likelihood for linear mixed models (LMM).4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 5Harville D.A. Maximum likelihood approaches to variance component estimation and to related problems.J. Am. Stat. Assoc. 1977; 72: 320-338Crossref Scopus (1543) Google Scholar, 6Patterson H.D. Thompson R. Recovery of inter-block information when block sizes are unequal.Biometrika. 1971; 58: 545-554Crossref Scopus (2718) Google Scholar Genetic covariance structure can be derived from phenotypic records using pedigree information in twin or family-based designs.7Neale M. Cardon L. Methodology for Genetic Studies of Twins and Families. Springer Science & Business Media, 2013Google Scholar Recently, genome-wide single-nucleotide polymorphism (SNP) data have been used to construct a genomic relationship matrix for the genetic covariance structure in LMM that captures the contribution of causal variants that are in linkage disequilibrium (LD) with the genotyped SNPs.4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 8VanRaden P.M. Efficient methods to compute genomic predictions.J. Dairy Sci. 2008; 91: 4414-4423Abstract Full Text Full Text PDF PubMed Scopus (3096) Google Scholar, 9Yang J. Lee S.H. Goddard M.E. Visscher P.M. GCTA: a tool for genome-wide complex trait analysis.Am. J. Hum. Genet. 2011; 88: 76-82Abstract Full Text Full Text PDF PubMed Scopus (3814) Google Scholar Such estimates assume that the genetic correlation estimated from common SNPs is representative of the parameter that depends on all genetic variants; this seems like a reasonable assumption. In contrast to the genomic restricted maximum likelihood (GREML) approach, a linkage disequilibrium score regression (LDSC)10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar method does not require individual-level genotype data but instead uses GWAS summary statistics, regressing association test statistics of SNPs on their LD scores. The LD score of a SNP is the sum of LD r2 measured with all other SNPs and can be calculated in a reference sample of the same ethnicity when individual genotype data are not available for the GWAS sample, under the assumption that the GWAS sample has been drawn from the same ethnic population as the reference sample used to calculate the LD scores. The method exploits the relationship between association test statistic and LD score expected under polygenicity. Because of this simplicity, and the massively reduced computing burden in terms of memory and time, it is feasible for LDSC to be applied to a large number of multiple traits, e.g., Bulik-Sullivan et al.,11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar Zheng et al.,12Zheng J. Erzurumluoglu A.M. Elsworth B.L. Kemp J.P. Howe L. Haycock P.C. Hemani G. Tansey K. Laurin C. Pourcain B.S. et al.Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema ConsortiumLD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.Bioinformatics. 2017; 33: 272-279Crossref PubMed Scopus (484) Google Scholar Finucane et al.13Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. et al.ReproGen ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumRACI ConsortiumPartitioning heritability by functional annotation using genome-wide association summary statistics.Nat. Genet. 2015; 47: 1228-1235Crossref PubMed Scopus (980) Google Scholar Given the attractiveness of LDSC for a massive analysis of many sets of GWAS summary statistics, it has been widely used in the community. However, genetic correlations estimated by LDSC are often reported without caution although the approach is known to be less accurate, compared to GREML.11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar In fact, the accuracies of LDSC estimates have not been thoroughly studied. In this report, we compare both the bias (difference between the simulated true value and estimated value) and accuracy (magnitude of the standard error of an estimate [SE]) between GREML and LDSC for estimation of genetic correlation. We find that both methods show little evidence of bias. However, LDSC is less accurate as reported in Bulik Sullivan et al.,11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar with SE at least more than 1.5-fold higher than that of GREML regardless of the number of samples in data used to estimate the genetic correlation. When decreasing the number of SNPs, the accuracy of LDSC decreases further. When increasing the degree of genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the SE of LDSC estimates are up to 3-fold larger than those of the GREML estimates. We also show that GREML is more accurate in genomic partitioning analyses over LDSC or stratified LDSC (sLDSC). In genomic partitioning analyses, the genetic parameters are estimated for genomic subsets defined by user-specified annotations. In analyses of real data, we show that GREML is more accurate and powerful, e.g., GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on 400,000 individuals in estimating genetic correlation between schizophrenia (SCZ) and body mass index (BMI) (−0.136 [SE = 0.017] and p value = 4.54E−15 for GREML versus −0.087 [SE = 0.019] and p value = 4.91E−06 for LDSC). In these analyses, the GREML estimate is based on UK sample only whereas the LDSC estimate is based on combined meta-datasets among which there is uncertainty about homogeneity. Furthermore, a GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which is less obvious by LDSC when using both whole-genome and partitioned estimates of genetic correlation. In the main methods, we used GREML14Lee S.H. van der Werf J.H. MTG2: an efficient algorithm for multivariate linear mixed model analysis based on genomic information.Bioinformatics. 2016; 32: 1420-1422Crossref PubMed Scopus (90) Google Scholar, 15Maier R. Moser G. Chen G.-B. Ripke S. Coryell W. Potash J.B. Scheftner W.A. Shi J. Weissman M.M. Hultman C.M. et al.Cross-Disorder Working Group of the Psychiatric Genomics ConsortiumJoint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.Am. J. Hum. Genet. 2015; 96: 283-294Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar and LDSC10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar to compare their estimates of genetic correlation using simulated as well as real data. Simulations were based on UK Biobank imputed genotype data (UKBB16Collins R. What makes UK Biobank special?.Lancet. 2012; 379: 1173-1174Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar) after stringent quality control (QC) (see Supplemental Methods). We calculated a ratio of empirical SE and its 95% confidence interval (CI) to assess the accuracy of the methods for each set of simulated data. The 95% CIs of SE were estimated based on the delta method.17Lynch M. Walsh B. Genetics and Analysis of Quantitative Traits. Sinauer Sunderland, MA1998Google Scholar When estimating genetic correlation using simulated phenotypes based on UKBB genotype data, we found that the estimates were unbiased for both GREML and LDSC (Figure S1), but the SE of GREML was at least 1.5 times smaller than that of LDSC (Figure 1). The ratio of the empirical SE from LDSC to GREML was increased up to 3.5-fold when using a smaller number of SNPs (Figure 1). All values of the ratio were significantly different from 1. It is notable that the SE of GREML estimates showed almost no difference across different numbers of SNPs whereas that of LDSC estimates gradually increased with a smaller number of SNPs (Figure S2). The ratio was invariant to sample size (Figure S3). As expected, when using the intercept constrained to zero, LDSC estimates were substantially biased when there were overlapping samples (Figure S4). We also explored alternative genetic architectures (Figure S5), which consistently showed that GREML gives a smaller SE than LDSC in any scenario. To explore the stability of the accuracy for both methods, we used two additional genotype datasets without imputation, Wellcome Trust Case Control Consortium 2 (WTCCC218Sawcer S. Hellenthal G. Pirinen M. Spencer C.C. Patsopoulos N.A. Moutsianas L. Dilthey A. Su Z. Freeman C. 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Goddard M.E. van der Werf J.H.J. Using information of relatives in genomic prediction to apply effective stratified medicine.Sci. Rep. 2017; 7: 42091Crossref PubMed Scopus (29) Google Scholar), which are publicly available (see Supplemental Methods for detailed data descriptions). We also used UKBB raw (non-imputed) genotype data (UKBBr). We calculated the correlation between the LD scores for the HapMap3 SNPs estimated based on the 1KG CEU reference sample (see Web Resources) and those based on in-sample genotype data, i.e., UKBB, WTCCC2, GERA, and UKBBr dataset (Table 1). We found that the WTCCC2, GERA, and UKBBr (raw) genotypes were less similar to the 1KG reference genotypes, compared to the UKBB (imputed) genotypes (noting that UKBB samples had been imputed to the combined data of 1KG reference and UK10K data). Table 2 shows that the SE ratio of LDSC estimate to GREML estimate was higher for WTCCC2, GERA, and UKBBr than that for UKBB. Figure 2 shows that the accuracy of GREML was consistent across different datasets, whereas that of LDSC was decreased for WTCCC2, GERA, or UKBBr, compared to UKBB dataset. This was probably due to higher (or lower) correlation between LD scores based on the 1KG reference and the in-sample genotype datasets (Table 1) which might positively or (negatively) affect the accuracy of LDSC estimates. For WTCCC2, GERA, and UKBBr data, the SE ratio of LDSC to GREML based on different number of individuals is shown in Figures S6–S8.Table 1Correlation between LD Scores Estimated Based on the HapMap3 SNPs using the 1KG CEU Reference Sample and that from Different Target PopulationsCorrelationNr.SNPsUKBBaUKBB was imputed to the combined data of the 1KG reference and UK10K data.0.946858,991UKBBrbUKBBr was based on the raw genotype data of UK Biobank data.0.720123,615cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.WTCCC20.899421,035cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.GERA0.661238,089cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.a UKBB was imputed to the combined data of the 1KG reference and UK10K data.b UKBBr was based on the raw genotype data of UK Biobank data.c The number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores. Open table in a new tab Table 2The Ratio of SE of LDSC Estimate to That of GREML Estimate using Simulated Phenotypes Based on UKBB, WTCCC2, GERA, and UKBBr Genotypes in the Scenarios without Overlapping Individuals800k400k200k100kUKBB1.60 (0.15)1.70 (0.18)1.85 (0.25)2.04 (0.33)WTCCC2NA2.15 (0.31)2.35 (0.43)2.68 (0.61)GERANANA2.87 (0.56)3.31 (1.17)UKBBrNANANA3.74 (0.79) Open table in a new tab Genome partitioning analyses are an emerging tool to estimate the genetic variance and covariance explained by functional categories (e.g., DNase I hypersensitive sites [DHS] and non-DHS24Gusev A. Lee S.H. Trynka G. Finucane H. Vilhjálmsson B.J. Xu H. Zang C. Ripke S. Bulik-Sullivan B. Stahl E. et al.Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumPartitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.Am. J. Hum. Genet. 2014; 95: 535-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar). Currently, genomic partitioning analyses focus on SNP-heritability enrichment analyses, formally testing for enrichment of signal compared to the expectation that the estimates are proportional to the number of SNPs allocated to each annotation. Considering genomic partitioning in cross-disorder analyses is a natural extension to identify regions where genetic correlations between disorders are highest and lowest. Here, we assessed the performance of the methods in the context of genome partitioning analyses using simulated phenotypes based on UKBB genotype data. A better LDSC approach to estimate genetic correlation for each category might be sLDSC, stratifying by genomic annotation; however, this method is currently under development (i.e., there is software [see Web Resources], but there is no published document or paper verifying the method). Nonetheless, since the sLDSC is available to the research community, we applied both LDSC and sLDSC to estimate partitioned genetic correlations for the simulated data (Supplemental Methods). For genome partitioning analyses, we showed that LDSC estimates of genetic correlation were biased whether using LD scores estimated from the 1KG reference or in-sample data (UKBB) while GREML estimates gave unbiased estimates for each functional category (Figure 3). sLDSC estimates were unbiased only when using LD scores from the in-sample data, and their SEs are relatively larger than those of GREML or LDSC (Figure 3). This was probably due to the fact that the different distribution of causal variants and their effects between DHS and non-DHS regions were better captured by an explicit covariance structure fitted in GREML. We also applied the methods to a range of simulation scenarios and found similar results in that GREML performed better than LDSC or sLDSC (Figure S9 and Table S1), which was consistent with the previous results (Figures 1 and 2). It is notable that in a deliberately severe scenario (e.g., causal variants are simulated only within few kb of a boundary), GREML could give biased estimation of genetic correlation.13Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. et al.ReproGen ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumRACI ConsortiumPartitioning heritability by functional annotation using genome-wide association summary statistics.Nat. Genet. 2015; 47: 1228-1235Crossref PubMed Scopus (980) Google Scholar, 24Gusev A. Lee S.H. Trynka G. Finucane H. Vilhjálmsson B.J. Xu H. Zang C. Ripke S. Bulik-Sullivan B. Stahl E. et al.Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumPartitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.Am. J. Hum. Genet. 2014; 95: 535-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar While focusing on the accuracy of genetic correlation estimates, there is an important implication for the bias in SNP-heritability estimates for both GREML and LDSC (Figure S10). When using the WTCCC2, GERA, and UKBBr data, which were less similar to the 1KG reference genotypes, compared to the UKBB data, LDSC estimates were substantially biased whereas GREML estimates were close to the true value in estimation of SNP heritability (Figure S10). However, this result is well known and LDSC was not recommended for SNP heritability by the original authors,10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar but rather only for relative enrichment analysis. Despite this, LDSC is widely used for SNP-heritability estimation (because it is quick and simple). Thus, for completeness we include analyses for different scenarios to quantify the properties of the methods. When reducing the number of SNPs, estimated SNP heritabilities from LDSC were consistently unbiased; however, those from GREML were proportionally underestimated (Figure S11). When using non-HapMap3 SNPs, LDSC estimates were consistently biased (Figure S12) and less accurate, compared to GREML estimates (Figures S13 and S14), which probably explains why LDSC is implemented using only HapMap3 SNPs. Although the genetic correlation is robust to such biasedness,4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar SNP heritability itself should be carefully interpreted for both GREML and LDSC. We also noted that LDSC and sLDSC estimates for SNP heritability were biased in the genome partitioning analysis (Figure S15) although the estimated enrichment was close to the true value when using sLDSC and in-sample LD scores (Figure S15). We used real phenotype and individual genotype data from the Psychiatric Genomics Consortium (PGC) and UKBB to estimate genetic variance and covariance between SCZ and BMI using LDSC and GREML (Table 3 and Figure S16). We also used publicly available GWAS summary statistics for LDSC to see how much the SE of estimates could be reduced by increasing the number of samples and number of SNPs. For real data analyses, we obtained theoretical SE to assess the accuracy of the methods. GREML and LDSC estimates for the SNP heritability were 0.192 (SE 0.004) and 0.280 (SE 0.016) for SCZ and 0.184 (SE 0.004) and 0.255 (SE 0.014) for BMI. The notable difference between GREML and LDSC was probably because of a relatively small number of SNPs (500K) that might result in underestimated GREML SNP heritability (see Figure S11). This is one of the caveats of using GREML with real data that usually comprise multiple cohorts genotyped on different platforms, such that, even with imputation, the overlapping set of SNPs imputed with high confidence may be limited. The estimated genetic correlation for GREML and LDSC was −0.136 (SE 0.017) and −0.173 (SE 0.031). This indicated that the GREML estimate was 3.5 and 1.8 times more precise than LDSC estimates for the SNP heritability and genetic correlation, respectively. For LDSC, we also considered using additional GWAS summary statistics from publicly available resources.25Schizophrenia Working Group of the Psychiatric Genomics ConsortiumBiological insights from 108 schizophrenia-associated genetic loci.Nature. 2014; 511: 421-427Crossref PubMed Scopus (5068) Google Scholar, 26Locke A.E. Kahali B. Berndt S.I. Justice A.E. Pers T.H. Day F.R. Powell C. Vedantam S. Buchkovich M.L. Yang J. et al.LifeLines Cohort StudyADIPOGen ConsortiumAGEN-BMI Working GroupCARDIOGRAMplusC

Background Clinical as well as neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterized by focal brain activation. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders by reducing cortical excitability. Methods In three patients suffering from chronic tinnitus, the effect of magnetic resonance imaging and positron emission tomography guided neuronavigated 1 Hz rTMS on auditory cortex activity was evaluated, using a sham controlled double-blind crossover design. Results Two of three patients revealed clearly increased metabolic activity in circumscript areas of the primary auditory cortex (PAC), allowing a selective stimulation of these cortical areas with low-frequency rTMS. Considerable improvement in tinnitus was achieved in these patients. Conclusions Neuronavigated rTMS of increased PAC activity may help to better understand the neuronal basis of chronic tinnitus and might offer a new option for treating auditory phantom perceptions like chronic tinnitus.

Unilaterally increased metabolic activity within the primary auditory cortex (PAC) represents a robust finding in tinnitus patients. Targeting these hyperactive areas with image-guided low frequency repetitive transcranial magnetic stimulation (rTMS) results in subjective tinnitus reduction. More pronounced activation of the PAC predicted higher resistance to rTMS.[18F]deoxyglucose (FDG)-positron emission tomography (PET) was used to assess metabolic activity within the central auditory system in tinnitus. The study investigated whether patterns of neuronal activity correlate with clinical features or may be used for the prediction of treatment outcome.Twenty patients with chronic tinnitus underwent PET imaging followed by low frequency rTMS treatment. Neuroimaging data were compared with clinical parameters and treatment outcome.PET data demonstrated an asymmetric activation of the central auditory system. Seventeen patients revealed increased activity of the primary auditory cortex on the left side, three on the right side. The extent of hypermetabolic activity prior to treatment correlated significantly with tinnitus reduction after rTMS, but not with clinical characteristics such as tinnitus severity, tinnitus laterality or tinnitus duration.

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.

Chronic tinnitus is associated with hyperactivity of the central auditory system. Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a treatment for chronic tinnitus. This study determined the factors that predict a beneficial outcome with rTMS treatment.Forty-five patients with chronic tinnitus underwent 10 sessions of low-frequency rTMS to their left auditory cortex. The treatment outcome was assessed with a tinnitus questionnaire. Therapeutic success was related to the patients' clinical characteristics.A significant reduction in tinnitus complaints occurred after rTMS. In the questionnaire, 40% of the patients improved by five points or more. Treatment responders were characterized by shorter duration of tinnitus complaints and no hearing impairment.Tinnitus-related neuroplastic changes might be less pronounced in patients with normal hearing and a short history of complaints. This could explain why those patients benefitted more from rTMS treatment.

Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation.

The etiology of somatization is incompletely understood, but could be elucidated by models of psychosocial stress. Academic exam stress has effectively been applied as a naturalistic stress model, however its effect on somatization symptoms according to ICD-10 and DSM-IV criteria has not been reported so far. Baseline associations between somatization and personality traits, such as alexithymia, have been studied exhaustively. Nevertheless, it is largely unknown if personality traits have an explanatory value for stress induced somatization.This longitudinal, quasi-experimental study assessed the effects of university exams on somatization - and the reversal of effects after an exam-free period. Repeated-observations were obtained within 150 students, measuring symptom intensity before, during and after an exam period, according to the Screening for Somatoform Symptoms 7-day (SOMS-7d). Additionally, self-reports on health status were used to differentiate between medically explained and medically unexplained symptoms. Alexithymia, neuroticism, trait-anxiety and baseline depression were surveyed using the Toronto-Alexithymia Scale (TAS-20), the Big-Five Personality Interview (NEO-FFI), the State Trait Anxiety Inventory (STAI) and Beck's Depression Inventory (BDI-II). These traits were competitively tested for their ability to explain somatization increases under exam stress.Somatization significantly increased across a wide range of symptoms under exam stress, while health reports pointed towards a reduction in acute infections and injuries. Neuroticism, alexithymia, trait anxiety and depression explained variance in somatization at baseline, but only neuroticism was associated with symptom increases under exam stress.Exam stress is an effective psychosocial stress model inducing somatization. A comprehensive quantitative description of bodily symptoms under exam stress is supplied. The results do not support the stress-alexithymia hypothesis, but favor neuroticism as a personality trait of importance for somatization.

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.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.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.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.

Academic exam stress is known to compromise sleep quality and alter drug consumption in university students. Here we evaluated if sleeping problems and changes in legal drug consumption during exam stress are interrelated. We used the Pittsburgh Sleep Quality Index (PSQI) to survey sleep quality before, during, and after an academic exam period in 150 university students in a longitudinal questionnaire study. Self-reports of alcohol, caffeine, and nicotine consumption were obtained. The Perceived Stress Questionnaire (PSQ-20) was used as a measure of stress. Sleep quality and alcohol consumption significantly decreased, while perceived stress and caffeine consumption significantly increased during the exam period. No significant change in nicotine consumption was observed. In particular, students shortened their time in bed and showed symptoms of insomnia. Mixed model analysis indicated that sex, age, health status, as well as the amounts of alcohol and caffeine consumed had no significant influence on global sleep quality. The amount of nicotine consumed and perceived stress were identified as significant predictors of diminished sleep quality. Nicotine consumption had a small-to-very-small effect on sleep quality; perceived stress had a small-to-moderate effect. In conclusion, diminished sleep quality during exam periods was mainly predicted by perceived stress, while legal drug consumption played a minor role. Exam periods may pose an interesting model for the study of stress-induced sleeping problems and their mechanisms.

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.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.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.Beneficial effects of high-frequency rTMS on negative and depressive symptoms were found, together with a trend for worsening positive symptoms in schizophrenic patients.

Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterised by focal brain activation. Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders. In one patient suffering from chronic tinnitus, [18F]deoxyglucose PET revealed increased metabolic activity in a circumscript area of the left primary auditory cortex (PAC). The effect of MRI and PET guided neuronavigated IHz rTMS of this area was evaluated in a single-blind, sham-controlled, cross-over manner, followed by a 4-week open treatment. Following active stimulation there was a remarkable effect, enduring several weeks, on tinnitus sensation, which was paralleled by altered cortical excitability. These findings suggest that neuronavigated rTMS of increased PAC activity might offer a new option for treating auditory phantom perceptions like chronic tinnitus. NeuroReport 14:977–980 © 2003 Lippincott Williams & Wilkins.

Clinical, neurophysiological and neuroimaging data suggest that chronic tinnitus resembles neuropsychiatric syndromes characterised by focal brain activation. Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an efficient method in treating brain hyperexcitability disorders. In one patient suffering from chronic tinnitus, [18F]deoxyglucose PET revealed increased metabolic activity in a circumscript area of the left primary auditory cortex (PAC). The effect of MRI and PET guided neuronavigated IHz rTMS of this area was evaluated in a single-blind, sham-controlled, cross-over manner, followed by a 4-week open treatment. Following active stimulation there was a remarkable effect, enduring several weeks, on tinnitus sensation, which was paralleled by altered cortical excitability. These findings suggest that neuronavigated rTMS of increased PAC activity might offer a new option for treating auditory phantom perceptions like chronic tinnitus. NeuroReport 14:977–980 © 2003 Lippincott Williams & Wilkins.

Functional somatic syndromes are characterized by high morbidity due to various, fluctuating symptoms without objective somatic findings. There is increasing evidence for the contribution of emotional and cognitive functions to symptom formation, which has been well established in the perception of pain. In addition to their involvement in various other cognitive and emotional processes, the anterior cingulate and insular cortex are thought to contribute to the so-called “pain neuromatrix”. Recent data suggest that these areas appear also to be involved in symptom manifestation in multiple chemical sensitivity. Here we used functional Magnetic Resonance Imaging (fMRI) to test whether this network is also involved in the induction of unpleasant perceptions by sham mobile phone radiation in subjectively electrosensitive patients. This design enabled us to completely dissociate the unpleasant subjective perception from any real physical stimulus. Fifteen subjectively electrosensitive patients and 15 age- and gender-matched healthy controls were exposed to sham mobile phone radiation and heat as a control condition. The perceived stimulus intensities were rated on a five-point scale. During anticipation of and exposure to sham mobile phone radiation increased activations in anterior cingulate and insular cortex as well as fusiform gyrus were seen in the electrosensitive group compared to controls, while heat stimulation led to similar activations in both groups. Symptom manifestation during sham exposure to mobile phone radiation was accompanied by specific alterations of cortical activity in anterior cingulate and insular cortex in subjectively electrosensitive patients further supporting the involvement of these areas in the perception of unpleasantness and generation of functional somatic syndromes.

Tinnitus affects 10% of the population, its pathophysiology remains incompletely understood, and treatment is elusive. Functional imaging has demonstrated a relationship between the intensity of tinnitus and the degree of reorganization in the auditory cortex. Experimental studies have further shown that tinnitus is associated with synchronized hyperactivity in the auditory cortex. Therefore, targeted modulation of auditory cortex has been proposed as a new therapeutic approach for chronic tinnitus.Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive methods that can modulate cortical activity. These techniques have been applied in different ways in patients with chronic tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been successful in reducing the intensity of tinnitus during the time of stimulation and could be predictive for treatment outcome of chronic epidural stimulation using implanted electrodes.Another approach that uses rTMS as a treatment for tinnitus is application of low-frequency rTMS in repeated sessions, to induce a lasting change of neuronal activity in the auditory cortex beyond the duration of stimulation. Beneficial effects of this treatment have been consistently demonstrated in several small controlled studies. However, results are characterized by high interindividual variability and only a moderate decrease of the tinnitus. The role of patient-related (for example, hearing loss, tinnitus duration, age) and stimulation-related (for example, stimulation site, stimulation protocols) factors still remains to be elucidated.Even in this early stage of investigation, there is a convincing body of evidence that rTMS represents a promising tool for pathophysiological assessment and therapeutic management of tinnitus. Further development of this technique will depend on a more detailed understanding of the neurobiological effects mediating the benefit of TMS on tinnitus perception. Moreover clinical studies with larger sample sizes and longer follow-up periods are needed.

Hintergrund Tinnitus zählt zu den gesundheitlichen Beeinträchtigungen mit häufiger psychiatrischer Komorbidität, zur Symptomerfassung stehen dennoch nur wenige Selbstbeurteilungsinstrumente in deutscher Sprache zur Verfügung. Methoden Die vorliegende Validierung des ins Deutsche übersetzten Tinnitus Handicap Inventory (THI) wurde an 74 Patienten mit chronischem Tinnitus durchgeführt. Als Referenzskala diente der Tinnitusfragebogen von Goebel u. Hiller. Ergebnisse und Diskussion Durchschnittliche Item-Trennschärfe und interne Skalenkonsistenz des deutschen THI entsprachen der THI-Originalversion, Die Korrelation des THI mit dem Tinnitusfragebogen betrug 0,70, und mit dem Beck-Depressions-Inventar 0,64. Die Ergebnisse sprechen für die Validität des deutschsprachigen THI.

The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs.No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families.Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

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.

Neuroleptic induced akathisia is a common and distressful extrapyramidal side effect of antipsychotic treatment. A significant proportion of the variability of its development has been left unexplained and has to be attributed to individual susceptibility. Since hereditary factors have been discussed in the etiology of acute akathisia (AA), part of the individual susceptibility might be of genetic origin. Moreover, AA is regarded as a forerunner of tardive dyskinesia, a drug-induced chronic movement disorder, which may be associated with homozygosity for the Ser9Gly variant of the DRD3 gene. Considering expression studies, which demonstrated functional variants of DRD3 polymorphisms, we investigated whether homozygosity for the Ser9Gly variant of the DRD3 gene is associated with AA. Homozygosity for the Ser9Gly variant of the DRD3 gene was connected to an 88% incidence of AA as compared with a considerably lower 46.9% incidence of AA in schizophrenic patients nonhomozygous for the 2-2 allele (exact P = 0.0223). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:187-191, 2000.

Objective Intranasal oxytocin has been shown to affect human social and emotional processing, but its potential to affect pain remains elusive. This randomized, placebo-controlled, double-blind, crossover trial investigated the effect of intranasal oxytocin on the perception and processing of noxious experimental heat in 36 healthy male volunteers. Methods Thermal thresholds were determined according to the Quantitative Sensory Testing protocol. A functional magnetic resonance imaging experiment including intensity and unpleasantness ratings of tonic heat was used to investigate the effects of oxytocin within the brain. Results Thirty men (aged 18–50 years) were included in the study. Intranasal oxytocin had no significant effect on thermal thresholds, but significantly (t = −2.06, p = .046) reduced heat intensity ratings during functional magnetic resonance imaging. The effect on intensity ratings was small (−3.46 points on a 100-point visual analog scale [95% confidence interval {CI} = −6.86 to −0.07] and independent of temperature. No effects of oxytocin on stimulus- or temperature-related processing were found at the whole-brain level at a robust statistical threshold. A region of interest analysis indicated that oxytocin caused small but significant decreases in left (−0.045%, 95% CI = −0.087 to −0.003, t = −2.19, p = .037) and right (−0.051%, 95% CI = −0.088 to −0.014], t = −2.82, p = .008) amygdala activity across all temperatures. Conclusions The present study provides evidence for a significant but subtle inhibitory effect of oxytocin on thermal stimulus ratings and concurrent amygdala activity. Neither of the two effects significantly depended of temperature; therefore, the hypothesis of a pain-specific effect of oxytocin could not be confirmed. Trial Registration: EUDRA-CT 2009-015115-40

The present study aimed at investigating whether chronic pain patients are impaired in Theory of Mind (ToM), or Emotional Awareness.Thirty inpatients suffering from chronic somatoform pain, as well as thirty healthy controls matched for age, sex, and education were recruited. ToM abilities were measured using the Frith-Happé animation task, in which participants interpret video-clips depicting moving geometric forms that mimic social interactions. The responses given were scored for appropriateness and the degree of inferred intentionality according to established protocols. Emotional awareness was measured using the Levels of Emotional Awareness Scale (LEAS), for which participants provide written descriptions of feelings in imaginary emotional situations. Standardized scoring was performed to capture the number and quality of emotional terms used.Responses lengths were similar in both groups and for both tasks. Patients attained significantly lower intentionality but not appropriateness scores when interpreting ToM interactions. No significant group differences were found when interpreting goal directed interactions. Emotional awareness scores were significantly lower in patients compared to healthy controls.Our results suggest that chronic pain patients are impaired in mentalizing and emotional awareness. Future studies are needed to determine whether these ToM and emotional awareness deficits contribute to the etiology of somatoform pain and whether addressing these deficits in therapeutic interventions can improve polymodal pain therapy.

Transcranial magnetic stimulation (TMS) provides an intriguing in vivo method to investigate motor cortex excitability in men. This offers new insights into the neurophysiological basis of neuropsychiatric diseases. Earlier TMS studies in patients with schizophrenia revealed inconsistent results, probably due to major confounding variables like state of medication and stage of illness. To control for these effects, we studied two TMS paradigms in 21 drug-naive first-episode schizophrenic patients and 21 age- and sex-matched healthy controls. The patient group demonstrated a significant lower resting motor threshold as compared with healthy controls, whereas TMS paradigms of intracortical inhibition and intracortical facilitation failed to show significant differences between patients and controls. This pattern of TMS parameters is similar to that obtained in healthy volunteers investigated under increasing doses of ketamine, a central acting drug known to produce psychosis-like effects. In agreement with recent results of functional imaging, our neurophysiological findings suggest that drug-induced and naturally occurring psychosis may share a common pathway, which may base on dysfunctional glutamatergic mechanisms.

Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an innovative treatment for chronic tinnitus. The aim of the present study was to elucidate the underlying mechanism and to evaluate the relationship between clinical outcome and changes in cortical excitability. We investigated ten patients with chronic tinnitus who participated in a sham-controlled crossover treatment trial. Magnetic-resonance-imaging and positron-emission-tomography guided 1 Hz rTMS were performed over the auditory cortex on 5 consecutive days. Active and sham treatments were separated by one week. Parameters of cortical excitability (motor thresholds, intracortical inhibition, intracortical facilitation, cortical silent period) were measured serially before and after rTMS treatment by using single- and paired-pulse transcranial magnetic stimulation. Clinical improvement was assessed with a standardized tinnitus-questionnaire.We noted a significant interaction between treatment response and changes in motor cortex excitability during active rTMS. Specifically, clinical improvement was associated with an increase in intracortical inhibition, intracortical facilitation and a prolongation of the cortical silent period. These results indicate that intraindividual changes in cortical excitability may serve as a correlate of response to rTMS treatment.The observed alterations of cortical excitability suggest that low frequency rTMS may evoke long-term-depression like effects resulting in an improvement of subcortical inhibitory function.

Repetitive transcranial magnetic stimulation (rTMS) is a brain stimulation technique which has received increasing attention as an antidepressant treatment. However available studies are characterized by a substantial variability in response. We hypothesized that individual patients' characteristics might contribute to such heterogeneity. Therefore we investigated whether either alterations of regional cerebral blood flow (rCBF) or clinical characteristics may predict antidepressant response to rTMS.24 patients with major depression and stable medication received high frequency (10 Hz) rTMS over the left dorsolateral prefrontal cortex (DLPFC) for two weeks as add-on treatment. ECD-Single photon emission computed tomographay (SPECT) imaging was performed 1 to 2 days before rTMS.Tertial referral centerAfter two weeks of rTMS a mean reduction of 30% of the initial Hamilton Depression Rating Score (HAMD) was observed. Using a multivariate regression model with simultaneous evaluation of the relative impact of a-priori chosen potential factors influencing treatment outcome, two variables, the pretreatment anterior cingulate rCBF and the former response to antidepressant agents proved significant. High pretreatment anterior cingulate activity and low treatment resistance to pharmacologic therapy were positive predictors for treatment response to rTMS.Pretreatment anterior cingulate activity seems to be a useful prognostic marker of rTMS treatment response, which is in line with other treatment strategies, like sleep deprivation, electroconvulsive therapy or antidepressant medication.

Recent advances in functional imaging have opened new possibilities for understanding tinnitus. Especially, positron emission tomography (PET) has been increasingly used in the last two decades to identify cortical networks, which are involved in the generation of various forms of chronic tinnitus. PET studies have confirmed that the anatomical location of the anomalies that cause many forms of tinnitus are regions of the brain that are normally involved in auditory processing as well as regions engaged in emotional processing. These findings have contributed to the development of new more causally oriented treatment strategies. In particular, identification of increased activity of the auditory cortex by PET has prompted the use of focal brain stimulation techniques such as electrical or transcranial magnetic stimulation in treatment of tinnitus. PET studies that map distinct neurochemical pathways and receptors by the use of specific ligands may in the future provide new possibilities for pharmacologically based treatment of some forms of tinnitus.

Dysfunctional thinking about sleep is a central aspect in the perpetuation of primary insomnia and a target symptom of cognitive behavioral therapy for insomnia (CBT-I). Insomnia symptoms also occur in other sleep disorders, but it is not known to what extent it is related to dysfunctional thinking about sleep.The Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS) was administered to inpatients at a sleep center. The following groups were included: 34 patients with primary insomnia (PI), 30 patients with sleep apnea syndrome (SAS), 31 patients with restless legs syndrome (RLS), 26 patients with SAS comorbid with RLS (SAS + RLS), and 24 patients with idiopathic hypersomnia or narcolepsy. Eighty-four healthy subjects served as a control group. The DBAS scores were compared across the different sleep disorders and correlated with polysomnographic (PSG) variables, subjective sleep parameters, scores of the Beck Depression Inventory (BDI), and the Regensburg Insomnia Scale (RIS; measuring psychological symptoms of insomnia).Compared to healthy controls, DBAS scores were increased in PI, RLS and RLS + SAS. There was a low correlation between DBAS scores and PSG variables, moderate correlations between DBAS and subjective sleep parameters and BDI scores (r = 0.528), and a high correlation between DBAS and the RIS score (r = 0.603).The observation of increased DBAS scores in other sleep disorders besides primary insomnia underscores the usefulness of a broadened diagnostic procedure and suggests that CBT-I modules may be a complementary treatment tool for these disorders.

Recently it has been shown that acute sleep loss has a direct impact on emotional processing in healthy individuals. Here we studied the effect of chronically disturbed sleep on emotional processing by investigating two samples of patients with sleep disorders.25 patients with psychophysiologic insomnia (23 women and 2 men, mean age: 51.6 SD; 10.9 years), 19 patients with sleep apnea syndrome (4 women and 15 men, mean age: 51.9; SD 11.1) and a control sample of 24 subjects with normal sleep (15 women and 9 men, mean age 45.3; SD 8.8) completed a Facial Expressed Emotion Labelling (FEEL) task, requiring participants to categorize and rate the intensity of six emotional expression categories: anger, anxiety, fear, happiness, disgust and sadness. Differences in FEEL score and its subscales among the three samples were analysed using ANOVA with gender as a covariate.Both patients with psychophysiologic insomnia and patients with sleep apnea showed significantly lower performance in the FEEL test as compared to the control group. Differences were seen in the scales happiness and sadness. Patient groups did not differ from each other.By demonstrating that previously known effects of acute sleep deprivation on emotional processing can be extended to persons experiencing chronically disturbed sleep, our data contribute to a deeper understanding of the relationship between sleep loss and emotions.

Exposure to electromagnetic fields (EMF) as well as EMF-related complaints has increased over the past decades. However, it is unclear whether these complaints are related to the electromagnetic or other physical properties of these fields per se, to salience of EMF in media, or to both. What is the prevalence of EMF-related complaints in the general population? What are the influencing factors on this prevalence? Does reporting of EMF-related symptoms depend on cognitive factors? To answer these questions, a survey with random variation of three cognitive factors was performed. As expected, EMF-related complaints were reported more by females and people with higher somatization tendency. Age had no significant linear effect on EMF-related complaints. The cognitive condition of threat produced a significant contrast effect among people with high somatization tendency on EMF-related complaints. Cognition can influence reporting of EMF-related effects. Thus, in future research of such effects, psychologically influencing factors should be included. Also risk communication should incorporate knowledge about social cognition.

Several lines of evidence indicate an involvement of the dopaminergic system in alcoholism, withdrawal, suicidality, and attention-deficit hyperactivity disorder (ADHD). The functionally relevant -141C Ins/Del polymorphism located upstream to exon 1 in the 5'-region of the dopamine D2 receptor (DRD2) gene might be an interesting candidate gene. We investigated a sample of 1,126 well-characterized, primary chronic alcoholics of German descent according to a phenotype-genotype strategy, i.e., alcoholics suffering from severe withdrawal complications such as seizure or delirium, family history positive (FH+) alcoholics, alcoholics with an antisocial personality disorder (ASPD), alcoholics with an ADHD, and type 1 or type 2 alcoholics according to Cloninger's typology. Compared to the control subjects, there was a significant excess of the -141C Del allele in alcoholics with a paternal and grandpaternal history of alcoholism and in alcoholic subgroups with suicidality or without a history of withdrawal symptoms. There were no significant differences in allele frequency between the entire group or subgroups of alcoholics and healthy controls. Therefore, the -141C Del variant of the DRD2 might be a protective factor against the development of withdrawal symptoms. However, it might also be a risk factor in a highly burdened subgroup of alcoholics with a paternal and grandpaternal history of alcoholism and it might contribute to the substantially higher likelihood of suicide in alcoholics.

Abstract Background: Despite a broad clinical use, the mechanism of action of SCS is poorly understood. Current information suggests that the effects of SCS are mediated by a complex set of interactions at several levels of the nervous system including spinal and supraspinal mechanisms. Aims: The study was undertaken to investigate the influence of SCS on distinct parameters of cortical excitability using single‐ and paired‐pulse transcranial magnetic stimulation (TMS). Methods: Five patients with chronic neuropathic pain were examined with the SCS stimulator on and off by means of TMS. Pain was assessed using a visual‐analogue scale. Electrophysiological and pain parameters of patients during this procedure were compared by means of a linear mixed effect model. Results: SCS induced a significant modulation of cortical excitability, especially by influencing the parameter “intracortical facilitation” ( t =−2.657; df=8; p =0.029). A significant relationship between this parameter and “perceived pain” could be obtained ( t =−4.798; df=8; p =0.002). Conclusions: These results suggest that SCS is able to influence neurobiological processes at the supraspinal level and that clinical effects of SCS may be at least in part of cortical origin.

There is a good theoretical basis and early research evidence suggesting that transcranial magnetic stimulation (TMS) may have treatment potential in tinnitus. Further studies with larger sample sizes and additional assessment of neurobiological effects are necessary.Tinnitus is a common and often severely disabling disorder for which there is no satisfactory treatment. TMS is a new, non-invasive method of modifying the excitability of the cerebral cortex, which has proven effective in auditory hallucinations and other disorders. Some early studies have been published in which TMS has been used in the treatment of tinnitus. The objective of this paper is to examine the literature and consider the potential for TMS as a therapy in tinnitus.A thorough search of the tinnitus and TMS literature was conducted, and all available relevant material was examined.Tinnitus is common, with a prevalence of 8.2% in subjects aged 50 years and over, and may be associated with great distress (tinnitus sufferers). There are no effective treatments. Tinnitus is frequently associated with deafness, and may be the result of a pathological plasticity process. Neuroimaging studies demonstrate increased activity within the central auditory system. TMS is a non-invasive method of modulating excitability in cerebral cortex. It uses electromagnetic principles and has been successfully employed in the treatment of other conditions associated with increased activity of the cerebral cortex. Meanwhile, a growing number of studies suggest that repetitive TMS may be effective in the treatment of chronic tinnitus.

Background 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. Method 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. Results 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. Conclusions These results demonstrate significant cognitive and neurobiological alterations pointing to a higher genuine individual vulnerability of electromagnetic hypersensitive patients.

Chronic tinnitus is a frequent condition, which can have enormous impact on patient's life and which is very difficult to treat. Accumulating data indicate that chronic tinnitus is related to dysfunctional neuronal activity in the central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method which allows to focally modulate neuronal activity. An increasing amount of studies demonstrate reduction of tinnitus after repeated sessions of low-frequency rTMS and indicate that rTMS might represent a new promising approach for the treatment of tinnitus. However available studies have been mono-centric and are characterized by small sample sizes. Therefore, this multi-center trial will test the efficacy of rTMS treatment in a large sample of chronic tinnitus patients.This is a randomized, placebo-controlled, double-blind multi-center trial of two weeks 1 Hz rTMS-treatment in chronic tinnitus patients. Eligible patients will be randomized to either 2 weeks real or sham rTMS treatment. Main eligibility criteria: male or female individuals aged 18-70 years with chronic tinnitus (duration > 6 months), tinnitus-handicap-inventory-score > or = 38, age-adjusted normal sensorineural hearing (i.e. not more than 5 dB below the 10% percentile of the appropriate age and gender group (DIN EN ISO 7029), conductive hearing loss < or = 15dB. The primary endpoint is a change of tinnitus severity according to the tinnitus questionnaire of Goebel and Hiller (baseline vs. end of treatment period). A total of 138 patients are needed to detect a clinical relevant change of tinnitus severity (i.e. 5 points on the questionnaire of Goebel and Hiller; alpha = 0.05; 1-beta = 0.80). Assuming a drop-out rate of less than 5% until the primary endpoint, 150 patients have to be randomized to guarantee the target number of 138 evaluable patients. The study will be conducted by otorhinolaryngologists and psychiatrists of 7 university hospitals and 1 municipal hospital in Germany.This study will provide important information about the efficacy of rTMS in the treatment of chronic tinnitus.Current Controlled Trials ISRCTN89848288.

Increasing evidence suggests that dysfunctions of the cortico-cerebello-thalamocortical circuit are involved in the pathophysiology of neuropsychiatric disorders. This study explores the effects of cerebellar repetitive transcranial magnetic stimulation (rTMS) on cerebello-thalamocortical pathways. Ten healthy volunteers received MRI-guided rTMS in four separate sessions (120% motor threshold, 1000 stimuli) over either the medial or the right lateral cerebellum using frequencies of 1 and 10 Hz. Motor cortex excitability was assessed before and after the intervention by paired-pulse transcranial magnetic stimulation. Depending on stimulation frequency, cerebellar rTMS differentially modified intracortical inhibition. Low frequency rTMS increased short intracortical inhibition (SICI), whereas high frequency rTMS had no significant effect on SICI. These results suggest that rTMS over the cerebellum can modulate cerebello-thalamocortical pathways in a frequency-specific manner. De nombreuses observations suggèrent que des dysfonctionnements du circuit cortico-cérébello-thalamocortical sont impliqués dans la physiopathologie de désordres neuropsychiatriques. Cette étude explore les effets de la stimulation magnétique transcrânienne répétitive (SMTr) cérébelleuse sur des voies cérébello-thalamocorticales. Dix volontaires sains ont été traités en quatre sessions séparées par SMTr couplée à la neuronavigation IRM. Des trains de stimulations à 1 et 10 Hz (120 % du seuil moteur, 1000 stimuli) ont été appliqués en regard de la partie médiale ou latérale droite du cervelet. L’excitabilité du cortex moteur a été mesurée avant et après l’intervention par SMT en doubles chocs pairés. La SMTr cérébelleuse a modifié l’inhibition intracorticale de manière différente en fonction de la fréquence de stimulation. La SMTr de basse fréquence a augmenté l’inhibition intracorticale, tandis que les stimulations de hautes fréquences n’ont eu aucun effet significatif sur l’inhibition intracorticale.

Sleep deprivation was found to exert complex effects on affective dimensions and modalities of pain perception both in healthy volunteers and patients with major depression. Considering multifaceted links between mood and pain regulation in patients with chronic somatoform pain, it is intriguing to study sleep deprivation effects for the first time in this group of patients. Twenty patients with a somatoform pain disorder according to ICD-10 diagnostic criteria were sleep-deprived for one night, followed by one recovery night. Clinical pain complaints (visual analog scale), detection- and pain thresholds (temperature and pressure) as well as mood states (Profile of Mood States) were assessed on the day prior to the experiment, on the day after sleep deprivation and on the day after recovery sleep. We found a discrepancy between significantly increased clinical pain complaints and unaltered experimental pain perception after sleep deprivation. Only the clinical pain complaints, but not the experimental pain thresholds were correlated with tiredness-associated symptoms. Total mood disturbances decreased and feelings of depression and anger improved significantly after sleep deprivation. However, these changes were not correlated with a change in clinical pain perception. We conclude that sleep deprivation may generally change the reagibility of the limbic system, but mood processing and pain processing may be affected in an opposite way reflecting neurobiological differences between emotional regulation and interoceptive pain processing.

Deep and slow breathing (DSB) is a central part of behavioral exercises used for acute and chronic pain management. Its mechanisms of action are incompletely understood. 1) To test the effects of breathing frequency on experimental pain perception in a dose dependent fashion. 2) To test the effects of breathing frequency on cardiorespiratory variables hypothesized to mediate DSB analgesia. 3) To determine the potential of the cardiorespiratory variables to mediate antinociceptive DSB effects by regression analysis. Single-blind, randomized, crossover trial. Twenty healthy participants. Visually paced breathing at 0.14 Hz, 0.10 Hz, 0.06 Hz, and resting frequency. Cardiorespiratory variables: RR-interval (= 60 seconds/heart rate), standard deviation of the RR-interval (SDRR), and respiratory CO2. Experimental pain measures: heat pain thresholds, cold pain thresholds, pain intensity ratings, and pain unpleasantness ratings. 1) There was no effect of DSB frequency on experimental pain perception. 2) SDRR and respiratory CO2 were significantly modulated by DSB frequency, while RR-interval was not. 3) Baseline-to-DSB and session-to-session differences in RR-interval significantly predicted pain perception within participants: Prolonged RR-intervals predicted lower pain ratings, while shortened RR-intervals predicted higher pain ratings. SDRR and respiratory CO2 were not found to predict pain perception. The present study could not confirm hypotheses that the antinociceptive effects of DSB are related to changes in breathing frequency, heart rate variability, or hypoventilation/hyperventilation when applied as a short-term intervention. It could confirm the notion that increased cardiac parasympathetic activity is associated with reduced pain perception.

Abstract 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.

Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine. Using data from the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS. 26 participants from the RESIS trial were on clozapine, receiving active (N = 12) or sham (N = 14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time × group interactions were significant in the PANSS positive subscale (p = 0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p < 0.001), the PANSS total scale (p = 0.015), but not the PANSS negative subscale (p = 0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group. In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants.

Results of neurophysiological and neuroimaging studies suggest that some forms of chronic tinnitus can be regarded to be “hyperexcitability syndromes”, caused by abnormal focal brain activity. Low frequency repetitive magnetic stimulation (rTMS) is an efficient method to selectively reduce the abnormally increased activity in distinct cortical areas. An increasing amount of clinical data suggest that low frequency rTMS might be an effective therapy that is directed at the cause of some forms of chronic tinnitus. To further explore the underlying neurobiological mechanisms we investigated the effect of rTMS on cortical excitability in healthy human subjects using the protocol, which has been successfully used for the treatment of tinnitus. We determined different parameters of motor cortex excitability (resting motor threshold, RMT; active motor threshold, AMT; short intracortical inhibition, ICI; short intracortical facilitation, ICF; and the duration of the cortical silent period, CSP) before and after 5 days of low frequency rTMS (2000 stimuli/day at 110% of RMT) over the left auditory cortex. Five sessions of low frequency rTMS resulted in a significant prolongation of the CSP. All other signs of cortical excitability that we studied remained unchanged. These findings suggest, that low frequency rTMS may evoke long-term depression (LTD)-like effects resulting in enhancement of subcortical inhibition.

Abstract Background Recent research has suggested that oxytocin receptor gene ( OXTR ) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p ≤ 0.01). Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant. Conclusions Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.

To investigate the relationship between alexithymia and depression and their influence on the subjective versus experimental pain perception in somatoform pain disorder.Three groups consisting of 40 patients with somatoform pain disorder, 40 patients with depression, and 40 healthy controls were matched. They completed questionnaires regarding alexithymia (TAS26) and depressive feelings (BDI-II). In addition, pain patients rated their subjective pain intensity (NRS). Quantitative sensory testings were conducted in all participants examining temperature (CPT, HPT) and mechanical (MPT, PPT) thresholds.Analysis of variance showed that alexithymia was significantly increased in both patient groups compared to healthy controls, but with the highest amount in somatoform pain. Regression analyses confirmed that this finding was in part due to a high comorbidity of depressive feelings in both patient groups. We found a discrepancy between increased clinical pain ratings and elevated pressure pain thresholds, indicating a less intense mechanical pain perception in somatoform pain. Correlation analyses demonstrated a significant connection of subjective pain ratings and pressure pain thresholds with depressive feelings.Contrary to the results of other experimental pain studies on chronic muskuloskeletal pain syndromes, we could not confirm central sensitization in somatoform pain disorder. Our findings place the somatoform pain disorder more in the direction of affective disorder such as depression. These findings may improve a better understanding of the disease and also have direct therapeutic implications. The high occurrence of alexithymia and depressive feelings in somatoform pain should be considered in diagnostic and therapeutic regimens of these patients.

Susceptibility to chronic tinnitus is highly variable and of particular interest when it comes to defining strategies for prevention and treatment. While several rare monogenic disorders have been described that are associated with tinnitus, the genetic underpinnings of the more common forms of the syndrome are still poorly understood. The present article incorporates recent advancements in the field, including the epidemiology of tinnitus in subjects with neuropsychiatric illness, and highlights pilot studies of candidate genes.

Summary Current studies suggest dysfunctional emotional processing as a key factor in the aetiology of temporomandibular disorder ( TMD ). Investigating facial emotion recognition ( FER ) may offer an elegant and reliable way to study emotional processing in patients with TMD . Twenty patients with TMD and the same number of age‐, sex‐ and education‐matched controls were measured with the F acially E xpressed E motion L abelling ( FEEL ) test, the 26‐item Toronto A lexithymia S cale ( TAS ‐26), the S creening for S omatoform S ymptoms ( SOMS ‐2a), the G erman P ain Q uestionnaire and the 21‐item H amilton D epression R ating S cale ( HAMD ). The patients had significantly lower Total FEEL Scores ( P = 0·021) as compared to the controls, indicating a lower accuracy of FER . Furthermore, we were able to demonstrate significant group differences with respect to the following issues: patients were more alexithymic ( P = 0·006), stated more somatoform symptoms ( P &lt; 0·004) and had higher depressive scores in the HAMD ( P &lt; 0·003). The factors alexithymia and somatisation could explain 31% (adjusted 27%) of the variance of the FEEL Scores in the sample. The estimation of the standardised regression coefficients suggests an equivalent influence of TAS ‐26 and SOMS ‐2a on the FEEL Scores, whereas ‘group’ (patients versus healthy controls) and depressive symptoms did not contribute significantly to the model. Our findings highlight FER deficits in patients with TMD , which are partially explained by concomitant alexithymia and somatisation. As suggested previously, impaired FER in patients with TMD may further point to probable aetiological proximities between TMD and somatoform disorders.

Measurement of motor cortex excitability with single and paired pulse transcranial magnetic stimulation has become an established method for in vivo characterization of the effects of central-acting drugs. The comparison of drug-free and medicated patients with schizophrenia suggests an association of neuroleptics intake and prolongation of the cortical silent period (CSP). However all available data come from cross-sectional non-randomized studies. Thus it is not clear whether the observed difference is an effect of medication or reflects differences in disease severity or both. We aimed to investigate whether the CSP or other parameters of cortical excitability change, when cortical excitability is measured in drug-free patients with acute psychosis before and after 3 week intake of the atypical neuroleptic quetiapine. Different parameters of cortical excitability were studied in 24 drug-free patients with acute psychosis before and after 3 weeks of treatment with a mean dose of 352 ± 199 mg quetiapine. We observed a significant prolongation of the cortical silent period (CSP) after three week treatment with quetiapine. Other parameters of cortical excitability such as motor threshold (MT), short intracortical inhibition (SICI) and intracortical facilitation (ICF) remained unaffected. There was a significant improvement in clinical parameters (PANS, GAF) but no significant correlation between clinical improvement and changes in cortical excitability. These longitudinal data are in line with previous reports from cross-sectional studies. The excitability changes induced by three-week intake of quetiapine in acute psychotic patients confirm the notion that neuroleptic treatment is associated with an increase in CSP.

Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.

Background: The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce.

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep - is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p < 0.001) the antidepressant effect of PSD up to 4 days. This finding indicates that rTMS is an efficacious method to prevent relapse after PSD.

70-80% of regular smokers fulfill the ICD-10-criteria of dependence. In Germany, approximately 120,000 deaths per year are caused by tobacco-associated diseases. In contrast, therapeutic interventions, such as nicotine substitution or bupropione, yield poor abstinence rates of 30% after 12 months, at best. In animal experiments, repetitive transcranial magnetic stimulation (rTMS) exhibited modulatory effects on dopaminergic neurotransmission in regions of the so-called reward system. This pilot study should evaluate, if rTMS could modulate subjective craving for tobacco, which quite often leads to relapse to smoking. Therefore, 11 tobacco-dependent cigarette smokers were randomly assigned to a course of verum- and placebo-rTMS on consecutive days. Craving, as measured by a visual analogue scale, is significantly decreased after Verumstimulation compared to placebo-stimulation intra-individually. This encourages further studies to clarify, if rTMS might be helpful in achieving higher tobacco abstinence rates in smokers willing to quits.

Transcranial magnetic stimulation of the dorsolateral prefrontal cortex by single pulses of varying field intensities was used to measure thresholds of individual perception and motor response in three groups of subjects: subjectively electrosensitive people, general population controls with a high burden of complaints related to electromagnetic field (EMF) exposure in the literature (highest decile in complaint burden), and general population controls with a low burden of complaints (lowest decile in complaint burden). The major study endpoint was the ability of the subjects to differentiate between real magnetic stimulation and a sham condition. There were no significant differences between groups in the thresholds, neither of detecting the real magnetic stimulus nor in motor response. But the three groups differed significantly in differentiating between stimulation and sham condition, with the subjectively electrosensitive people having the lowest ability to differentiate and the control group with high level of EMF-related complaints having the best ability to differentiate. Differences between groups were mostly due to false alarm reactions in the sham condition reported by subjectively electrosensitives (SES). We found no objective correlate of the self perception of being “electrosensitive.” Overall, our experiment does not support the hypothesis that subjectively electrosensitive patients suffer from a physiological hypersensitivity to EMFs or stimuli. Further research should focus on disposing factors explaining the unspecific sensory hyperresponsiveness of subjectively electrosensitive subjects. Bioelectromagnetics 26:287–298, 2005. © 2005 Wiley-Liss, Inc.

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.

Idiopathic tinnitus is a frequent and often debilitating auditory phantom perception of largely unknown pathological conditions. In electrophysiological and functional neuroimaging studies, affected subjects have shown excessive spontaneous activity in the central auditory system. To further investigate the underlying central nervous component, we assessed motor cortex excitability in 19 patients with chronic tinnitus by means of transcranial magnetic stimulation (TMS). When results were compared with data from 19 healthy controls matched for age and sex, we found significantly enhanced intracortical facilitation in tinnitus patients. These findings parallel excitability changes after limb amputation and experimental deafferentation. Our results give further support to crossmodal interactions involving neuroplastic changes in some forms of tinnitus and may help to better understand mechanisms of maladaptive cortical reorganisation involved in phantom perceptions.

Hypersensitivity to electromagnetic fields is frequently claimed to be linked to a variety of unspecific somatic and/or neuropsychological complaints. Whereas provocation studies often failed to demonstrate a causal relationship between electromagnetic field exposure and symptom formation, neurophysiological examinations highlight baseline deviations in people claiming to be electrosensitive. To elucidate a potential role of dysfunctional cortical regulations in mediating hypersensitivity to electromagnetic fields, cortical excitability parameters were measured by transcranial magnetic stimulation in subjectively electrosensitive patients (n=23) and two control groups (n=49) differing in their level of unspecific health complaints. Electrosensitive patients showed reduced intracortical facilitation as compared to both control groups, while motor thresholds and intracortical inhibition were unaffected. This pilot study gives additional evidence that altered central nervous system function may account for symptom manifestation in subjectively electrosensitive patients as has been postulated for several chronic multisymptom illnesses sharing a similar clustering of symptoms.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed for stabilizing the antidepressant effect of sleep deprivation (SD) by preventing the relapse after a night of recovery sleep. In this study, we aimed to replicate these data coming from a small pilot study in a larger patient sample.Thirty-seven patients were randomly assigned to receive either active or sham rTMS on four consecutive days after one night of SD. The majority of the participants had experienced an antidepressant effect of SD in the past. At each rTMS session 1000 stimuli were applied over the left dorsolateral prefrontal cortex at 10 Hz with an intensity of 110% resting motor threshold. For sham stimulation, a sham-coil system was used. Treatment effects were assessed with a modified version of the Hamilton Depression Rating Scale and a self-report well-being scale (BfS) before SD, after SD, during rTMS and 3 days after rTMS.SD led to a highly significant reduction of depressive symptoms in the whole group as reflected by a mean Hamilton Depression Rating Scales score reduction of 56% (with omission of sleep items). In both the active and the sham-stimulated group, the symptom reduction remained stable for the whole observation period. No difference between active and sham rTMS was observed.SD is capable of inducing pronounced antidepressant effects. In contrast to a previous study, active rTMS was not superior to sham rTMS in stabilizing the antidepressant effects of SD, which was mainly due to a pronounced effect in the sham group in this study population.

Transcranial magnetic stimulation (TMS) studies reported changes in motor evoked potential amplitude after acupuncture needling both at traditional acupoints and non-acupoints. However, the effects of needle penetration per se have not yet been investigated with TMS. The present study aimed at exploring effects of deep manual acupuncture needling compared to a state-of-the-art, non-penetrating control condition on several standard TMS measures of motor system excitability. Twenty healthy volunteers received both verum and sham acupuncture applied at the acupoint GB 34 near the right knee, using a crossover design. A needle with a retractable tip (“Streitberger needle”) was used as sham condition to minimize non-specific effects. TMS parameters (resting motor threshold, active motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation) were calculated from the abductor digiti minimi (ADM) of both hands 15 min before and after needling by a researcher blind to the treatment condition. Verum compared to sham acupuncture significantly increased resting motor threshold. No significant treatment effect was found for any other measure, though cortical silent period and intracortical facilitation showed trends to increase in the hemisphere contralateral to the needling site after verum acupuncture. These results suggest a subtle but specific inhibitory effect of acupuncture needle penetration at acupoint GB 34 on motor system excitability. Further investigations should be performed with a particular emphasis on the measurements of resting motor threshold, cortical silent periods and intracortical facilitation. Des études utilisant la stimulation magnétique transcrânienne (SMT) ont montré des modifications d’amplitude des potentiels évoqués moteurs après implantation d’aiguilles d’acupuncture, aussi bien dans les points d’acupuncture traditionnels qu’en d’autres endroits. On n’a cependant jamais investigué par SMT les effets spécifiques de la pénétration de l’aiguille. Le but de cette étude est de comparer, au moyen de différentes mesures d’excitabilité corticale réalisées au moyen de la SMT, les effets de l’application réelle d’une aiguille d’acupuncture à une condition contrôle où, toutes conditions étant égales par ailleurs, aucune insertion n’a lieu. Des aiguilles d’acupuncture réelles et « placebo » ont été successivement appliquées sur le point d’acupuncture GB34 (voisin du genou droit) chez 20 sujets volontaires sains, selon un paradigme de type « crossover ». Afin de minimiser les effets non spécifiques, une aiguille à extrémité rétractile (aiguille de Streitberger) fut utilisée pour la condition placebo. Les réponses aux SMT ont été recueillies au niveau des abducteurs du cinquième doigt des deux mains. Les paramètres suivants ont été mesurés : seuil d’obtention des réponses motrices au repos et sous activation volontaire, la période de silence corticale, la facilitation intracorticale. L’examinateur ignorait dans quelle condition les enregistrements étaient réalisés. Une augmentation significative du seuil moteur au repos fut observée en conditions réelles par rapport au placebo. Aucun autre effet significatif ne fut constaté, mais bien une tendance non significative de la période de silence corticale et de la facilitation intracorticale uniquement dans l’hémisphère cérébral controlatéral par rapport au site d’insertion de l’aiguille réelle. Nos résultats suggèrent que l’insertion d’une aiguille d’acupuncture dans le point GB34 exerce un effet inhibiteur discret, mais spécifique sur l’excitabilité du cortex moteur. Ils démontrent l’intérêt potentiel d’études menées sur de plus grands groupes, avec une attention particulière portée sur les mesures du seuil moteur au repos, des périodes de silence cortical et d’inhibition intracorticale.

Motor cortex excitability was found to be changed after repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex highlighting the occurrence of cross-modal plasticity in non-invasive brain stimulation. Here, we investigated the effects of temporal low-frequency rTMS on motor cortex plasticity in a large sample of tinnitus patients. In 116 patients with chronic tinnitus different parameters of cortical excitability were assessed before and after ten rTMS treatment sessions. Patients received one of three different protocols all including 1 Hz rTMS over the left temporal cortex. Treatment response was defined as improvement by at least five points in the tinnitus questionnaire (TQ). Variables of interest were resting motor threshold (RMT), short-interval intra-cortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). After rTMS treatment RMT was decreased by about 1% of stimulator output near-significantly in the whole group of patients. SICI was associated with significant changes with respect to treatment response. The group of treatment responders showed a decrease of SICI over the course of treatment, the group of non-responders the reverse pattern. Minor RMT changes during rTMS treatment do not necessarily suggest the need for systematic re-examination of the RMT for safety and efficacy issues. Treatment response to rTMS was shown to be related to changes in SICI that might reflect modulation of GABAergic mechanisms directly or indirectly related to rTMS treatment effects.

We performed a systematic review of the studies employing repetitive transcranial magnetic stimulation (rTMS) in subjects with smoking addiction. High-frequency (HF) rTMS over the prefrontal cortex (PFC), in particular the left dorsolateral PFC (DLPFC), might represent a save and innovative treatment tool for tobacco consumption and craving in nicotine-dependent otherwise healthy people. rTMS can be effective for this indication also in patients with schizophrenia, but the results are conflicting and sufficient evidence from large-scale trials is still lacking. Promising results have been obtained using particular techniques for brain stimulation, such as deep rTMS and theta burst stimulation. Multiple-target HF rTMS can also have a potential in smoking cessation. fMRI and EEG recordings have proven to be useful for objectively assessing the treatment effects. TMS is likely to be most effective when paired with an evidence-based self-help intervention, cognitive-behavioral interventions and nicotine replacement therapy. However, the most recent studies employed different protocols and yielded heterogeneous results, which should be replicated in further controlled studies with larger sample sizes and rigorous standards of randomization. To date, no recommendation other than that a possible efficacy of HF-rTMS of the left DLPFC can be made for alternative rTMS procedures in nicotine craving and consumption.

High-frequency transcranial random noise stimulation (hf-tRNS) is a non-invasive neuromodulatory technique capable of increasing human cortex excitability. There were only published case reports on the use of hf-tRNS targeting the lateral prefrontal cortex in treating negative symptoms of schizophrenia, thus necessitating systematic investigation. We designed a randomized, double-blind, sham-controlled trial in a cohort of stabilized schizophrenia patients to examine the efficacy of add-on hf-tRNS (100–640 Hz; 2 mA; 20 min) using a high definition 4 × 1 electrode montage (anode AF3, cathodes AF4, F2, F6, and FC4) in treating negative symptoms (ClinicalTrials.gov ID: NCT04038788). Participants received either active hf-tRNS or sham twice daily for 5 consecutive weekdays. Primary outcome measure was the change over time in the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), which was measured at baseline, after 10-session stimulation, and at one-week and one-month follow-ups. Among 36 randomized patients, 35 (97.2%) completed the trial. Intention-to-treat analysis showed a significantly greater decrease in PANSS-FSNS score after active (−17.11%) than after sham stimulation (−1.68%), with a large effect size (Cohen's d = 2.16, p < 0.001). The beneficial effect lasted for up to one month. In secondary-outcome analyses, the authors observed improvements with hf-tRNS of disorganization symptoms, unawareness of negative symptoms, subjective response to taking antipsychotics, and antipsychotic-induced extrapyramidal symptoms. No effects were observed on the neurocognitive performance and other outcome measures. Overall, hf-tRNS was safe and efficacious in improving negative symptoms. Our promising findings should be confirmed in a larger sample of patients with predominant negative symptoms.

The functions of autism-associated Neuroligins (Nlgs) are modulated by their post-translational modifications, such as proteolytic cleavage. A previous study has shown that there are different endogenous forms of DNlg3 in Drosophila, indicating it may undergo proteolytic processing. However, the molecular mechanism underlying DNlg3 proteolytic processing is unknown. Here, we report a novel proteolytic mechanism that is essential for DNlg3 maturation and function in the nervous system.Molecular cloning, cell culture, immunohistochemistry, western blotting and genetic studies were employed to map the DNlg3 cleavage region, identify the protease and characterize the cleavage manner. Behavior analysis, immunohistochemistry and genetic manipulations were employed to study the functions of different DNlg3 forms in the nervous system and neuromuscular junction (NMJs).Tumor necrosis factor α-converting enzyme (TACE) cleaved DNlg3 exclusively at its extracellular acetylcholinesterase-like domain to generate the N-terminal fragment and the short membrane-anchored fragment (sDNlg3). DNlg3 was constitutively processed in an activity-independent manner. Interestingly, DNlg3 was cleaved intracellularly in the Golgi apparatus before it arrived at the cell surface, a unique cleavage mechanism that is distinct from ‘conventional’ ectodomain shedding of membrane proteins, including rodent Nlg1. Genetic studies showed that sDNlg3 was essential for maintaining proper locomotor activity in Drosophila.Our results revealed a unique cleavage mechanism of DNlg3 and a neuron-specific role for DNlg3 maturation which is important in locomotor activity.Our study provides a new insight into a cleavage mechanism of Nlgs maturation in the nervous system.

Despite the introduction of atypical antipsychotic drugs, treatment-resistant symptoms still represent a serious problem in schizophrenia. Currently, there is evidence from clinical studies suggesting that treatment with repetitive transcranial magnetic stimulation (rTMS) may improve schizophrenia symptoms. Our review provides an overview of clinical rTMS studies in schizophrenic patients. A systematic search of the literature (Cochrane and Medline databases up to December 2005) was conducted. Most studies showed methodological problems due to their explorative character and small sample sizes. In some studies, a treatment effect of high-frequency rTMS applied over the prefrontal cortex was seen with respect to negative symptoms. On the other hand, low-frequency rTMS in the temporal lobe area might lead to a suppression of auditory hallucinations. It is concluded that larger sham-controlled studies are required to allow an adequate assessment of the clinical and neurobiological effects of rTMS in schizophrenic patients. The currently available data provide insufficient evidence to support the use of rTMS as an adjuvant treatment for schizophrenic psychopathology, but encourage further investigation of rTMS as a novel treatment approach.

Tinnitus is a common and often severely disabling disorder for which there is no satisfactory treatment. Transcranial magnetic stimulation (TMS) is a new, non-invasive method of modifying the excitability of the cerebral cortex, which has proven effective in auditory hallucinations and other disorders. Some early studies have been published in which TMS has been trialed in the treatment of tinnitus. The aim of the present paper was to examine the literature and consider the potential for TMS as a therapy in tinnitus. A thorough search of the tinnitus and TMS literature was conducted, and all available relevant material was examined. Discussions were held with leaders in both fields. Tinnitus is common and there are no effective treatments. It is frequently associated with deafness, and may be the result of a pathological plastic process, secondary to loss of innervation of the outer hair cells of the cochlea. Neuroimaging studies demonstrate increase blood flow to the primary and secondary auditory cortices, particularly on the left side. Transcranial magnetic stimulation is a non-invasive method of perturbing and inducing change in the cerebral cortex. It uses electromagnetic principles and has been successfully employed in the treatment of other conditions associated with increased activity of the cerebral cortex. A small number of studies have suggested that TMS may be effective in the treatment of tinnitus. There is a good theoretical basis and early research evidence suggesting that TMS may have treatment potential in tinnitus. Further, larger studies are necessary.

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Anliegen: Klinische, neurophysiologische und funktionell bildgebende Daten belegen, dass Tinnitus mit umschriebener kortikaler Überaktivität assoziiert ist. Niedrigfrequente rTMS ist eine neuartige nicht-invasive Methode zur Reduktion kortikaler Aktivität. Methode: Patienten mit chronischem Tinnitus wurden im Rahmen einer plazebokontrollierten Pilotstudie mit niedrigfrequenter rTMS behandelt (110 % Motorschwelle; 1 Hz; 2000 Stimuli/Tag über fünf Tage). Mithilfe eines Neuronavigationssystems konnte auf der Basis struktureller und funktioneller Bilddaten das hyperaktive Areal im primärakustischen Kortex individuell gezielt stimuliert werden. Ergebnisse: Nach Behandlung mit aktiver TMS kam es zu einer Verminderung der Tinnituswahrnehmung, Behandlungeffekte hielten bei einem Teil der Patienten über mehrere Monate an. Schlussfolgerungen: Neuronavigierte rTMS eröffnet neue Möglichkeiten im Verständnis und in der Behandlung von chronischem Tinnitus.

Illumination science has long established effects of coloured light on emotional state, cognitive performance, plus tactile, gustatory and olfactory perception. To explore the neurobiological mechanisms underlying these crossmodal phenomena, cortical excitability was addressed by single and paired-pulse transcranial magnetic stimulation (TMS) in 23 men with normal colour vision, and in 10 subjects with red–green blindness. Using a sequential challenge, excitability measures were recorded at baseline and during exposure to either red or green light. Dichromacy did not predict any of the electrophysiological parameters under study regardless of the spectral paradigm. In both dichromats and trichromats, red and green illumination did not induce any significant effects on resting motor threshold, short intracortical inhibition, intracortical facilitation and cortical silent periods. Our results suggest that motor cortex excitability as assessed by TMS is not sensitive to the modulatory effects of context-independent red and green light.

Acetylcholine exerts strong neuromodulating action at cortical and subcortical neurons and networks. Alterations of cortical excitability, induced by acute and repeated administration of the acetylcholinesterase inhibitor rivastigmine were investigated with transcranial magnetic stimulation in healthy volunteers. It was found that rivastigmine had an overall significant effect on the stimulus-response curve with mean values suggesting an enhancement 1.5 and 3 h after a single loading dose of 3 mg rivastigmine and a reduction after 7 days of daily administration of 3 mg rivastigmine. Motor threshold, intracortical inhibition, intracortical facilitation, cortical silent period, M-wave, F-wave and peripheral silent period remained unaffected either by acute or repeated administration of rivastigmine. Our results demonstrate that effects of acetylcholine on motor cortex excitability in healthy subjects are reflected by alterations of the stimulus-response curve. The differential effect between acute and chronic administration of rivastigmine may reflect dynamic properties of different receptor subtypes.

In a previous study an association has been reported between motor cortex excitability, as measured by paired-pulse transcranial magnetic stimulation (TMS) and neuroticism of the NEO personality inventory; this correlation was carried by the men. The aim of the present study was to replicate these findings in a larger sample and with additional measures of motor cortex excitability. Eighty-nine healthy volunteers filled in the NEO-FFI and underwent several measures of motor cortex excitability (resting and active motor thresholds, double-pulse TMS with interstimulus intervals of 1-20ms, and cortical silent period). We did not find any systematic significant correlations of personality factors with motor cortex excitability. Dividing the samples by sex or controlling for confounders such as age, sex and education level by partial correlations did not reveal any significant associations either. Reasons for the failure of replication may include differences in sample characteristics, personality measures, and TMS methodology. However, synopsis of literature indicates that association of personality and motor cortex excitability might be mediated rather by state than by trait factors.

Chronic tinnitus is a brain network disorder with involvement of auditory and non-auditory areas. Repetitive transcranial magnetic stimulation (rTMS) over the temporal cortex has been investigated for the treatment of tinnitus. Several small studies suggest that motor cortex excitability is altered in people with tinnitus. We retrospectively analysed data from 231 patients with chronic tinnitus and 120 healthy controls by pooling data from different studies. Variables of interest were resting motor threshold (RMT), short-interval intra-cortical inhibition (SICI), intra-cortical facilitation (ICF), and cortical silent period (CSP). 118 patients were tested twice - before and after ten rTMS treatment sessions over the left temporal cortex. In tinnitus patients SICI and ICF were increased and CSP was shortened as compared to healthy controls. There was no group difference in RMT. Treatment related amelioration of tinnitus symptoms were correlated with normalisations in SICI. These findings confirm earlier studies of abnormal motor cortex excitability in tinnitus patients. Moreover our longitudinal data suggest that altered SICI may reflect a state parameter, whereas CSP and ICF may rather mirror a trait-like predisposing factor of tinnitus. These findings are new and innovative as they enlarge the knowledge about basic physiologic and neuroplastic processes in tinnitus.

hSKCa3 is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. Since an association between longer alleles of this CAG repeat and bipolar disorder or schizophrenia has been reported, we genotyped the polymorphic CAG repeat in 91 German family trios of patients with bipolar disorder I and used the transmission disequilibrium test (TDT) to test for association. Applying a dichotomized model (≤19 or >19 CAG triplets), we found no evidence for an association of longer alleles with bipolar disorder (TDT = 0.75, P = 0.386). Regarding the whole range of alleles, there was no preference in transmitting the larger of the two observed alleles from parents to the affected offspring. In parallel we performed an independent case-control study on German patients with bipolar disorder and schizophrenia. Again we did not detect an overrepresentation of longer CAG repeats in patients. Thus, our data do not support the hypothesis that longer CAG repeats in the hSkCa3 gene contribute to the susceptibility for bipolar disorder and schizophrenia.

Disturbed GABA-B mediated inhibitory cortical processes are discussed to be involved both in schizophrenia as well as in chronic tinnitus. Transcranial magnetic stimulation (TMS) provides an intriguing in vivo method to investigate GABA-B associated aspects of cortical inhibition, thus allowing to detect disease-related cortical inhibitory processes.Parameters of cortical excitability were measured by TMS in drug-naive first-episode schizophrenic patients and in patients suffering from chronic tinnitus.The cortical silent period as measured by TMS indicated a dysfunctional GABA-B mediated cortical inhibition in both groups of patients.TMS offers new insights into the pathophysiology of neuropsychiatric disorders. Parameters of this technique point to changes in GABA-B associated inhibitory processes within thalamocortial circuits both in schizophrenia and chronic tinnitus. These data are in line with current models of disturbed thalamic gating in phantom perceptions like auditory hallucinations, chronic tinnitus and central pain.