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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 (p0.001), 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.

Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy.A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20.Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment).The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered.German Federal Ministry of Education and Research.

Background Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions. Methods Using data from the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia. Results 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found. Conclusion These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period.

Background Chronic tinnitus is a frequent, difficult to treat disease with high morbidity. Objective This multicenter randomized, sham-controlled trial investigated the efficacy and safety of 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal cortex in patients with chronic tinnitus. Methods Tinnitus patients were randomized to receive 10 sessions of either real or sham 1-Hz-rTMS (2000 stimuli, 110% motor threshold) to the left temporal cortex. The primary outcome was the change in the sum score of the tinnitus questionnaire (TQ) of Goebel and Hiller from baseline to end of treatment. Results A total of 163 patients were enrolled in the study (real rTMS: 75; sham rTMS: 78). At day 12, the baseline mean of 43.1 TQ points in 71 patients assigned to real rTMS changed by −0.5 points; it changed by 0.5 points from a baseline of 42.1 in 75 patients randomized to sham rTMS (adjusted mean difference between groups: −1.0; 95.19% confidence interval: −3.2 to 1.2; p = 0.36). All secondary outcome measures including measures of depression and quality of life showed no significant differences either (p > 0.11). The number of participants with side-effects or adverse events did not differ between groups. Conclusion Real 1-Hz-rTMS over the left temporal cortex was well tolerated but not superior compared with sham rTMS in improving tinnitus severity. These findings are in contrast to results from studies with smaller sample sizes and put the efficacy of this rTMS protocol for treatment of chronic tinnitus into question. Trial Registration Controlled Trials: http://www.isrctn.com/ISRCTN89848288 .

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

Repetitive transcranial magnetic stimulation (rTMS) 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.

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

Rationale 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. Objectives 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. Methods 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. Results 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. Conclusions 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.

Tinnitus is a frequent symptom of traumatic brain injury, which is difficult to treat. Repetitive transcranial magnetic stimulation has shown beneficial effects in some forms of tinnitus. However, traumatic brain injury in the past has been considered as a relative contraindication for repetitive transcranial magnetic stimulation because of the increased risk of seizures. Here we present the case of a 53-year-old male patient suffering from severe tinnitus after traumatic brain injury with comorbid depression and alcohol abuse, who received 5 treatment series of repetitive transcranial magnetic stimulation (1 Hz stimulation protocol over left primary auditory cortex, 10 sessions of 2000 stimuli each, stimulation intensity 110% resting motor threshold). Repetitive transcranial magnetic stimulation was tolerated without any side effects and tinnitus complaints (measured by a validated tinnitus questionnaire and numeric rating scales) were improved in a replicable way throughout 5 courses of transcranial magnetic stimulation up to now.

Neuroimaging studies of tinnitus suggest the involvement of wide-spread neural networks for perceptual, attentional, memory, and emotional processes encompassing auditory, frontal, parietal, and limbic areas. Despite sparse findings for tinnitus duration and laterality, tinnitus distress has been shown to be related to changes in non-auditory cortical areas. The aim of this study was to correlate tinnitus characteristics with grey matter volume in two large samples of tinnitus patients. High-resolution brain images were obtained using a 1.5 T magnetic resonance imaging scanner and analysed by means of voxel-based morphometry. In sample one (n = 257), tinnitus distress correlated negatively with grey matter volume in bilateral auditory areas including the Heschl's gyrus and insula, that is, the higher the tinnitus distress the lower the grey matter volume. The effects of this correlation were small, but stable after correction for potential confounders such as age, gender, and audiometric parameters. This negative correlation was replicated in a second independent sample (n = 78). Our results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects. The distress observed was dependent on grey matter alterations in the auditory cortex, which could reflect reverberations between perceptual and distress networks.

Tinnitus is the perception of sound in the absence of an environmental sound source. Abnormal activity in central auditory pathways is considered as the neuronal correlate of tinnitus. However, there is increasing evidence from neuroimaging studies for an additional involvement of the frontal cortex in the pathophysiology of tinnitus, especially concerning its attentional and emotional aspects. Recently, in a subgroup of tinnitus patients, temporary reduction of tinnitus intensity and tinnitus-related distress has been reported after bifrontal tDCS with the anode over the right and the cathode over the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate whether repeated application of bifrontal tDCS results in longer-lasting reduction of tinnitus and may represent a potential treatment approach. Thirty-two patients with chronic and treatment-resistant tinnitus received six sessions of bifrontal tDCS (1.5 mA, 30 min, two sessions per week) with the anode over the right and the cathode over the left DLPFC. Treatment outcome was assessed with several standardized tinnitus questionnaires, numeric rating scales, and a depression scale. In the entire group, beneficial effects of bifrontal tDCS on tinnitus were found for numeric rating scores of loudness, unpleasantness, and discomfort, but not in tinnitus or depression scales. Exploratory analysis revealed an effect of gender on treatment effects with female patients demonstrating a better response in several scores. Our open-label pilot study suggests some beneficial effect of bifrontal tDCS (anode right and cathode left) in the treatment of severe tinnitus, warranting further controlled studies.

Sleep deprivation has multiple effects on brain function. It increases the risk for epileptic seizures both in healthy individuals and in patients with epilepsy. Furthermore it represents an effective antidepressive intervention with rapid onset. However, the mechanisms underlying these effects are still largely unknown. Transcranial magnetic stimulation (TMS) can be used as a non-invasive method for the measurement of motor cortex excitability. Here we used TMS for assessing sleep deprivation effects on cortical excitability in healthy individuals. Before and after 24 h of sleep deprivation, parameters of cortical excitability (resting motor threshold, short intracortical inhibition, intracortical facilitation, cortical silent period) were measured in a sample of 15 healthy volunteers (11 women, 4 men, aged between 21 and 30 years with a mean of 24.3±2.7 years). We detected a significant (p=0.042) reduction of short intracortical inhibition (SICI) after sleep deprivation. Motor threshold, intracortical facilitation and contralateral silent period remained unchanged. Our results confirm previous studies which have demonstrated changes of SICI after sleep deprivation. Our findings further suggest that the increased risk for epileptic seizures after sleep deprivation is mediated by a reduction of intracortical inhibition. Whether this mechanism is also involved in mediating the antidepressant effect of sleep deprivation has to be addressed by further studies in depressive patients.

Valproate is widely used in the treatment of epilepsy, bipolar disorder, and chronic pain disorders, but its exact mechanisms of action is still incompletely understood.Here we used transcranial magnetic stimulation to explore effects of a single dose of 800 mg valproate on motor cortex excitability in healthy volunteers.Motor threshold, peripheral maximum M-wave, cortical silent period short intracortical inhibition, intracortical facilitation, and motor evoked potential recruitment were assessed before and 1.5 h after the administration of valproate in 15 (eight male, seven female) healthy volunteers.None of the measures of cortical excitability were found to be altered significantly after valproate.These results are in line with previous findings of unaffected intracortical excitability after a single dose of valproate, suggesting that valproate's immediate in vivo actions do not resemble the effects of classic GABAergic compounds.

An increasing number of controlled studies strongly support an antidepressant effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex. However, these data come from highly selected study populations. Whether rTMS is a feasible therapeutic tool for the treatment of depression under naturalistic condition has not yet been addressed. Here, we report results from 232 depressive patients [aged 20-76 years, baseline Hamilton Depression Rating Score (HDRS-21) 24.0 ± 7.3] treated with rTMS add-on to continued psychopharmacological treatment in a naturalistic clinical setting. Two thousand stimuli of 20-Hz rTMS were applied daily over the left dorsolateral prefrontal cortex with an intensity of 110% of motor threshold. Treatment duration was individually planned and varied between 10 and 20 sessions. In average, patients received 13 ± 6.1 rTMS sessions. In 90% of the cases, treatment was terminated regularly. No severe side effects were observed. Only four patients stopped rTMS treatment because of side effects. Ratings with the HDRS-21 before and after treatment were available in 130 patients. The average improvement of the HDRS-21 in this subsample was 9.0 ± 9.2 points. Fifty-three patients had an improvement of 50% or more. These results document that rTMS is feasible, safe and well tolerated under naturalistic conditions.

Background: There is increasing evidence that repetitive transcranial magnetic stimulation (rTMS) can reduce chronic tinnitus. However, treatment results are characterized by high interindividual variability. Therefore, the identification of predictors for treatment response is of high clinical relevance. Methods: Clinical data of 194 patients with tinnitus were evaluated. All patients were treated with a standardized rTMS procedure (1 Hz, 10 days, 2000 stimuli/day, over the left temporal cortex). A potential influence on the outcome was analysed for the following parameters: age, gender, depression scores in Beck Depression Inventory (BDI) and tinnitus severity (TQ) before rTMS, lateralization, frequency and duration of tinnitus and extent of hearing loss. Results: An effect of tinnitus laterality was observed. In patients with left-sided or bilateral tinnitus, rTMS resulted in a statistically significant reduction of TQ scores, whereas patients with right-sided tinnitus did not show a significant improvement after rTMS treatment. However, in correlation analyses, we found a trend which did not reach statistical significance that in the subgroup of treatment responders tinnitus duration influenced rTMS outcome. In addition, a multiple regression analysis identified the TQ score at baseline as a significant predictor for treatment outcome. For all other investigated parameters, no statistically significant effects were found. Conclusions: This study suggests that left temporal low-frequency rTMS has beneficial effects in left-sided and bilateral tinnitus, but not in right-sided tinnitus. In line with the results from earlier studies involving smaller samples, tinnitus duration was found to influence rTMS outcome.

Background Transcranial magnetic stimulation (TMS) is a noninvasive procedure that may be used to study individual differences in motor cortex excitability. Such differences are assumed to reflect serotonergic and other inputs to the motor cortex. Methods Here we investigate the impact of a functional polymorphism in the promoter region of the 5-hydroxytryptamine transporter gene (5-HTTLPR) on measures of motor cortex excitability. Results Sixty healthy subjects carrying one or two copies of the short 5-HTTLPR allele (s/s and s/l) showed a significant reduction in short intracortical inhibition (SICI, p = .012) and an increased cortical silent period (p = .042) compared with 60 age- and sex-matched individuals homozygous for the long allele (l/l). In contrast, motor threshold and intracortical facilitation did not differ significantly between groups. Conclusions These results provide further evidence of a role for serotonergic transmission in the modulation of cortical excitability. Differential effects on the measures under study suggest a pattern of prioritization in bioamine regulation of cortical inhibition.

Objective Low-frequency repetitive transcranial magnetic stimulation (rTMS) has shown promise for the treatment of tinnitus. Experimental data from motor cortex stimulation in healthy subjects indicate that the suppressing effect of low-frequency rTMS can be enhanced by dopaminergic receptor activation. Here we investigated whether administration of the dopamine precursor levodopa before low-frequency rTMS enhances its efficacy in tinnitus treatment. Study Design Sixteen patients with chronic tinnitus received 100 mg of levodopa before each session of low-frequency rTMS. Results were compared with a matched control group of 16 patients who received the same treatment, but without levodopa. Treatment outcome was assessed with a standardized tinnitus questionnaire. Results Both stimulation protocols resulted in a significant reduction of tinnitus scores after 10 days of stimulation; however, there was no significant difference between the two groups. Conclusion Our data suggest that 100 mg of levodopa does not enhance the effect of rTMS in the treatment of tinnitus.

Background Investigators 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. Methods A 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. Results There 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. Conclusions Application 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.

Background. Repetitive transcranial magnetic stimulation (rTMS) has shown promising effects in the treatment of chronic subjective tinnitus. However, little is known about maintenance treatment in order to achieve long-lasting improvements. Objective. This study addresses the questions whether the repeated application of rTMS treatment can contribute to the maintenance or enhancement of treatment effects and if so in which cases repetitive treatment courses are beneficial. Methods. 55 patients with chronic tinnitus were treated with two rTMS treatment courses with ten treatment sessions each. The mean intertreatment interval was 20.65 ± 18.56 months. Tinnitus severity was assessed before and after each treatment course. Results. Both treatments were well tolerated and caused significant improvement of tinnitus severity. The main predictor for the outcome of the second treatment was the development of tinnitus distress in the phase between both treatment courses: the more patients worsened in this interval, the more they improved during the second treatment course. Conclusion. Repeated application of rTMS seems to be useful in tinnitus management and should preferentially be offered to patients who experience a worsening of their tinnitus during the intertreatment interval, irrespective of their response to the first treatment course.

Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression.Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz + leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli + leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N = 17, sham coil with the TBS protocol).There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group.This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies.

BackgroundStudies suggest that symptoms of traumatic grief constitute a distinct syndrome worthy of diagnosis.AimsA consensus conference aimed to develop and test a criteria set for traumatic grief.MethodThe expert panel proposed consensus criteria for traumatic grief. Receiver operator characteristic (ROC) analyses tested the performance of the proposed criteria on 306 widowed respondents at seven months post-loss.ResultsROC analyses indicated that three of four separation distress symptoms (e.g. yearning, searching, loneliness) had to be endorsed as at least ‘sometimes true’ and four of the final eight traumatic distress symptoms (e.g. numbness, disbelief, distrust, anger, sense of futility about the future) had to be endorsed as at least ‘mostly true’ to yield a sensitivity of 0.93 and a specificity of 0.93 for a diagnosis of traumatic grief.ConclusionsPreliminary analyses suggest the consensus criteria for traumatic grief have satisfactory operating characteristics, and point to directions for further refinement of the criteria set.

Schizophrenia is a severe, debilitating, chronic disease that is accompanied by morphologic changes within the brain. However, it is unclear to what extent alterations of grey and white matter in schizophrenia are linked to the disease itself, or whether they are a consequence of neuroleptic treatment. Typical and atypical antipsychotics exert differential effects on brain structure. Moreover, atypical antipsychotics may have distinct profiles with respect to grey matter in schizophrenic patients. Findings on drug-induced grey matter changes are heterogeneous due to variation in stage of illness, duration of treatment and use of multiple antipsychotics. Using voxel-based morphometry applied to high-resolution magnetic resonance images, we show that monotherapy with the atypical agent quetiapine (mean daily dose = 445 mg ± 200 s.d.) may induce structural brain changes in first-episode schizophrenia patients (N = 20) within 21 d of treatment. Specifically, we demonstrate longitudinal macroscopic changes (i.e. grey matter increases) in the left amygdalohippocampal region that were predicted by drug plasma levels but not daily doses. These structural alterations were accompanied by a clinical improvement of schizophrenic symptoms. Comparison with healthy controls (n = 30) showed that grey matter amount in the respective amygdalar region was significantly reduced in unmedicated first-episode schizophrenia patients. These findings suggest that drug-induced neuroplastic changes in schizophrenia can occur quickly and are dependent on pharmacokinetics.

Tinnitus is related to alterations in neuronal activity of auditory and nonauditory brain areas. Targeted modulation of these areas by repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new therapeutic approach for chronic tinnitus.Two randomized, double-blind, parallel-group, controlled clinical trials were performed subsequently and pooled for analysis. A total of 192 tinnitus patients were randomly allocated to receive 10 stimulation sessions of either sham rTMS, PET-based neuronavigated 1 Hz rTMS, 1Hz r TMS over the left auditory cortex, or combined 20 Hz rTMS over the left frontal cortex, followed by 1 Hz rTMS over the left auditory cortex.rTMS treatment was well tolerated and no severe side effects were observed. All active rTMS treatments resulted in significant reduction of the TQ as compared to baseline. The comparison between treatment groups failed to reach significant differences. The number of treatment responders was higher for temporal rTMS(38%) and combined frontal and temporal rTMS (43%), as compared to sham (6%).This large study demonstrates the safety and tolerability of rTMS treatment in patients with chronic tinnitus. While the overall effect did not prove superior to placebo, secondary outcome parameters argue in favour of the active stimulation groups, and specifically the combined frontal and temporal rTMS protocol.

Tinnitus, the phantom perception of sounds, is a highly prevalent disorder. Although a wide variety of drugs have been investigated off label for the treatment of tinnitus, there is no approved pharmacotherapy. We report an open-label exploratory pilot study to assess the effect of muscle relaxants acting on the central nervous system on tinnitus patients. Cyclobenzaprine at high (30 mg) and low doses (10 mg), orphenadrine (100 mg), tizanidine (24 mg) and eperisone (50 mg) were administered to a maximum of 20 patients per group over a 12-week period. High-dose cyclobenzaprine resulted in a significant reduction in the Tinnitus Handicap Inventory (THI) score between baseline and week 12 in the intention-to-treat sample. On the other hand, other treatments were not effective. These results were confirmed in an explorative analysis where baseline corrected THI and Clinical Global Impression scores at week 12 were compared between groups. The present open trial presents a new promising pharmacotherapy for tinnitus that should be validated in placebo-controlled double-blind trials., OA-Komponente aus Allianzlizenz

Background Repetitive transcranial magnetic stimulation (rTMS) over the temporal cortex has been proposed as a new approach for the treatment of tinnitus. Even if most studies have shown beneficial effects, there is only limited knowledge about clinical predictors for treatment response and about the duration of treatment effects. Objective In this study, we compared clinical characteristics of rTMS responders and nonresponders and assessed long-term outcome in the responder group. Method Results from 235 patients, who were treated with rTMS because of chronic tinnitus were analysed. Patients received either a standard protocol of low-frequency rTMS (n = 188; 110% motor threshold, 1 Hz, 2000 stimuli/day) over the left temporal cortex or combined frontal and temporal rTMS (n = 47; 110% motor threshold, 1000 stimuli at 20 Hz, left dorsolateral prefrontal cortex plus 1000 stimuli at 1 Hz left temporal cortex). Response criterion was defined as an improvement of at least 10 points in the tinnitus questionnaire (TQ) score between baseline and the follow-up assessment 90 days after treatment. Results For the entire study group there was a highly significant effect of treatment on the TQ score. Fifty patients (21.3%) were responders according to the above mentioned definition. The response criterion was fulfilled by 19.7% of the patients receiving left temporal rTMS and by 26% of the patients receiving combined rTMS. The only significant difference between responders and nonresponders was a higher baseline score of the TQ in the responder group. There were no significant differences in all other assessed patient parameters (gender, age, tinnitus duration, tinnitus laterality, motor threshold, handedness). Ninety days after treatment the average TQ reduction in the responder group was 18.2 points as compared with baseline. At the two long-term follow-up assessments (2.12 ± 1.17 years and 3.9 ± 1.17 years after treatment) the improvement in the responder group was still 14.2, respective 14.4 points. Conclusions These data underscore the clinical relevance of rTMS in the treatment of tinnitus. A potential explanation for the observed long-lasting clinical effects is that rTMS interferes with tinnitus related neuronal activity and thus facilitates the intrinsic ability of the brain to restore normal function.

Background Repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has shown beneficial effects in patients with chronic tinnitus. Recent preclinical data in healthy controls suggest that the effects of low-frequency rTMS can be enhanced by dopaminergic drugs. Objective We investigated whether application of the dopamine reuptake inhibitor bupropion increases the clinical effects of low-frequency rTMS over the auditory cortex in tinnitus patients. Subjects and Methods Eighteen subjects with chronic tinnitus received 10 sessions of 1 Hz rTMS (2000 pulses/day, 110% motor threshold) applied to the left temporal cortex. In addition, these subjects received one dosage of 150 mg bupropion (Wellbutrin XL/Elontril) 4 hours before each TMS session. Treatment outcome was assessed with a tinnitus questionnaire over a 3-month period. Treatment effects were compared with a control group of 100 tinnitus patients matched for age, tinnitus duration, and tinnitus questionnaire baseline scores, who received the same rTMS treatment without prior bupropion application. Results For the whole sample, there was a significant effect of rTMS treatment over time. There were no significant differences between the bupropion and the control group. Conclusions Our data suggest that 150 mg bupropion administration does not enhance the effect of rTMS in the treatment of tinnitus.

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

Transcranial magnetic stimulation (TMS) is a noninvasive procedure that may be used to study individual differences in motor cortex excitability. Such differences are assumed to reflect serotonergic and other inputs to the motor cortex.Here we investigate the impact of a functional polymorphism in the promoter region of the 5-hydroxytryptamine transporter gene (5-HTTLPR) on measures of motor cortex excitability.Sixty healthy subjects carrying one or two copies of the short 5-HTTLPR allele (s/s and s/l) showed a significant reduction in short intracortical inhibition (SICI, p = .012) and an increased cortical silent period (p = .042) compared with 60 age- and sex-matched individuals homozygous for the long allele (l/l). In contrast, motor threshold and intracortical facilitation did not differ significantly between groups.These results provide further evidence of a role for serotonergic transmission in the modulation of cortical excitability. Differential effects on the measures under study suggest a pattern of prioritization in bioamine regulation of cortical inhibition.

It is well known that colour exposure can influence emotions, behaviour and perception. To get further insight into these complex synesthetic phenomena, the effect of colour stimulation on auditory and somatosensory perception was systematically investigated.14 healthy male volunteers with normal colour vision rated the loudness of auditory stimuli with a standardized scale during exposure to white, red and green light. Furthermore temperature perception was assessed during exposure of the different colours using a thermal sensory analyser.Colour exposure significantly altered auditory and somatosensory perception. Red light enhanced loudness perception and decreased cold pain thresholds, while green light stimulation reduced loudness perception and increased detection and pain thresholds for warm stimuli.This data give further evidence for cross-modal plasticity in human perception. Colour stimulation influences auditory and somatosensory perception and may therefore have potential as a new treatment strategy of phantom perceptions such as tinnitus or chronic pain.

Based on its ability to reduce the excitability of the cortex locally, low-frequency repetitive transcranial magnetic stimulation (rTMS) has been investigated for the treatment of hyperexcitability disorders such as auditory hallucinations and tinnitus. Results are promising, but characterized by only moderate improvement and a high inter-individual variability. Experimental data from motor cortex stimulation in healthy subjects indicates that the depressant effect of low-frequency rTMS can be enhanced by high-frequency priming stimulation. Here we will investigate whether high-frequency priming also improves the therapeutic efficacy of low-frequency rTMS in a clinical application. 32 patients with chronic tinnitus were randomly assigned to either a standard protocol of low-frequency rTMS (110% motor threshold, 1 Hz, 2000 stimuli/day) or a stimulation protocol in which priming stimulation with 6 Hz (90% motor threshold, 960 stimuli) preceded low-frequency rTMS (110% motor threshold, 1 Hz, 1040 stimuli/day). Stimulation was applied over the left auditory cortex by using MRI-guided coil positioning. The treatment outcome was assessed with a standardized tinnitus questionnaire. There was no significant difference between the standard protocol and the protocol involving priming stimulation. Both stimulation protocols resulted in significant clinical improvement after 10 days of stimulation, as compared to baseline. Our data does not support an enhancing effect of higher frequency priming on low-frequency rTMS in the treatment of tinnitus.

Aims: Colour affects not only the emotional state, but also cognitive performance and perception of other sensory modalities such as tone or smell. However, very little is known about the neuronal mechanisms which account for these cross-modal interactions. To explore neurobiological mechanisms of these synaesthetic phenomena, we used transcranial magnetic stimulation (TMS) to assess the impact of colour perception on motor cortex excitability. Material and Methods: Transcranial magnetic stimulation allows to assess non-invasively the integrity and excitability patterns of cortical and subcortical networks. Using this method we studied ten healthy volunteers under three different conditions (no visual stimulation, stimulation with red light, stimulation with green light). Red and green light was matched for colour intensity and brightness. The colours were presented in a randomized order by video goggles. Measurements of cortical excitability started after 5 minutes adaptation and included the assessment of motor threshold (MT), cortical silent period (CSP), paired-pulse inhibition (PPI) and paired-pulse facilitation (PPF). Results: Intracortical inhibition (PPI) was significantly increased during green light stimulation as compared with the baseline condition, while red light had no significant effect on PPI. All other parameters of cortical excitability (PPF, MT, CSP) remained unchanged during red and green light stimulation. Conclusions: These data give first evidence that colour perception may lead to changes in motor cortex excitability as a direct hint for cross modal plasticity.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to exert antidepressant effects superior to placebo treatment, though effect sizes are moderate. However, data from a randomised multicentre trial cast doubt on an augmenting or accelerating antidepressant effect of continuous rTMS and substantiate the need for exploration of new stimulation protocols. Theta burst stimulation (TBS) provides controllable, consistent, long-lasting, and powerful effects on the cortex physiology and might serve as a rather effective tool than continuous rTMS. Its efficacy has not yet been evaluated though. 61 (minus 7 drop outs) patients suffering from a moderate to severe depressive episode (unipolar, bipolar, or major depression) without psychotic symptoms and scoring at least 18 points on the Hamilton rating scale for depression (HAMD) were included. Patients received 15 sessions (one per day) of either tonic or theta burst or sham rTMS over the dorsolateral prefrontal cortex (DLPFC) as an add-onto regular pharmacotherapy in a randomized, double-blind controlled trial. In detail, we investigated the combination of high frequency (10 Hz) left frontal and low frequency (1 Hz) right frontal versus the combination of intermittent theta burst (iTBS) left frontal and continuous theta burst (cTBS) right frontal and versus placebo treatment. 20 patients were assigned to the theta burst, 17 to the tonic and 17 to the sham rTMS group. Groups were comparable with respect to age and sex. The primary outcome analysis indicates a significant effect of treatment, i.e., all patients exhibited a significant amelioration of symptoms as assessed by HAMD scores. There was no significant difference between the three interventions. However, power analyses indicate an advantage of TBS over tonic and sham rTMS with small effect sizes with negligible effect size between tonic and sham rTMS. Secondary analysis showed that eight weeks after treatment differences between groups get bigger with a linear increase of amelioration of symptoms from sham over tonic to theta burst rTMS. Further analysis with the global assessment of functioning scale and the clinical global impression scale affirmed these findings. For the Beck depression inventory no effects could be found. In conclusion, we found firstly superiority of combined left and right prefrontal rTMS over sham rTMS in depressive patients as an add-onto regular pharmacotherapy. Secondly, we also could demonstrate a superiority of TBS over tonic rTMS for the treatment of depression. Thirdly, effects were small and were highest at the last follow up visit.