Assessing the impact of sex on high-frequency repetitive transcranial magnetic stimulation´s clinical response in schizophrenia - results from a secondary analysis.

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. METHODS: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS: 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION: In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Effects of high-frequency prefrontal rTMS on heart frequency rates and blood pressure in schizophrenia.

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.

Efficacy of high-frequency repetitive transcranial magnetic stimulation in schizophrenia patients with treatment-resistant negative symptoms treated with clozapine.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Evaluation of the symmetry of biogeneric design suggestions in Cerec/inLab.

This study evaluates the symmetry of initial proposals for anterior tooth restorations delivered by the Cerec software. By using a symmetric preparation model and a special angulation gauge for restoration axes, the study proves that the restoration proposals are symmetric with respect to the median sagittal plane.

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms - Results from an exploratory re-analysis.

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.

Predicting Response to Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia Using Structural Magnetic Resonance Imaging: A Multisite Machine Learning Analysis.

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.

1-Hz rTMS in the treatment of tinnitus: A sham-controlled, randomized multicenter trial.

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.

Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham-Controlled Trial.

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.

Psychophysiological Associations between Chronic Tinnitus and Sleep: A Cross Validation of Tinnitus and Insomnia Questionnaires.

BACKGROUND: The aim of the present study was to assess the prevalence of insomnia in chronic tinnitus and the association of tinnitus distress and sleep disturbance. METHODS: We retrospectively analysed data of 182 patients with chronic tinnitus who completed the Tinnitus Questionnaire (TQ) and the Regensburg Insomnia Scale (RIS). Descriptive comparisons with the validation sample of the RIS including exclusively patients with primary/psychophysiological insomnia, correlation analyses of the RIS with TQ scales, and principal component analyses (PCA) in the tinnitus sample were performed. TQ total score was corrected for the TQ sleep items. RESULTS: Prevalence of insomnia was high in tinnitus patients (76%) and tinnitus distress correlated with sleep disturbance (r = 0.558). TQ sleep subscore correlated with the RIS sum score (r = 0.690). PCA with all TQ and RIS items showed one sleep factor consisting of all RIS and the TQ sleep items. PCA with only TQ sleep and RIS items showed sleep- and tinnitus-specific factors. The sleep factors (only RIS items) were sleep depth and fearful focusing. The TQ sleep items represented tinnitus-related sleep problems. DISCUSSION: Chronic tinnitus and primary insomnia are highly related and might share similar psychological and neurophysiological mechanisms leading to impaired sleep quality.

Efficacy and Safety of Repeated Courses of rTMS Treatment in Patients with Chronic Subjective Tinnitus.

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.

Left prefrontal high-frequency repetitive transcranial magnetic stimulation for the treatment of schizophrenia with predominant negative symptoms: a sham-controlled, randomized multicenter trial.

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.

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Changes in motor cortex excitability associated with temporal repetitive transcranial magnetic stimulation in tinnitus: hints for cross-modal plasticity?

BACKGROUND: 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). RESULTS: 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. CONCLUSIONS: 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.

Antipsychotic treatment with quetiapine increases the cortical silent period.

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 3week 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 3weeks of treatment with a mean dose of 352±199mg 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.

Amygdalohippocampal neuroplastic changes following neuroleptic treatment with quetiapine in first-episode schizophrenia.

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.

State- and trait-related alterations of motor cortex excitability in tinnitus patients.

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.

Auditory cortex is implicated in tinnitus distress: a voxel-based morphometry study.

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.

Repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus after traumatic brain injury: a case study.

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.