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.

Supporting return to work after psychiatric hospitalization-A cluster randomized study (RETURN-study).

BACKGROUND: If people with episodic mental-health conditions lose their job due to an episode of their mental illness, they often experience personal negative consequences. Therefore, reintegration after sick leave is critical to avoid unfavorable courses of disease, longer inability to work, long payment of sickness benefits, and unemployment. Existing return-to-work (RTW) programs have mainly focused on "common mental disorders" and often used very elaborate and costly interventions without yielding convincing effects. It was the aim of the RETURN study to evaluate an easy-to-implement RTW intervention specifically addressing persons with mental illnesses being so severe that they require inpatient treatment. METHODS: The RETURN study was a multi-center, cluster-randomized controlled trial in acute psychiatric wards addressing inpatients suffering from a psychiatric disorder. In intervention wards, case managers (RTW experts) were introduced who supported patients in their RTW process, while in control wards treatment, as usual, was continued. RESULTS: A total of 268 patients were recruited for the trial. Patients in the intervention group had more often returned to their workplace at 6 and 12 months, which was also mirrored in more days at work. These group differences were statistically significant at 6 months. However, for the main outcome (days at work at 12 months), differences were no longer statistically significant (p = 0.14). Intervention patients returned to their workplace earlier than patients in the control group (p = 0.040). CONCLUSIONS: The RETURN intervention has shown the potential of case-management interventions when addressing RTW. Further analyses, especially the qualitative ones, may help to better understand limitations and potential areas for improvement.

Disentangling dyskinesia from parkinsonism in motor structures of patients with schizophrenia.

Patients with schizophrenia frequently suffer from motor abnormalities, but underlying alterations in neuroarchitecture remain unclear. Here, we aimed to disentangle dyskinesia from parkinsonism in motor structures of patients with schizophrenia and to assess associated molecular architecture. We measured grey matter of motor regions and correlated volumetric estimates with dyskinesia and parkinsonism severity. Associations with molecular architecture were identified by cross-modal spatial correlations between ensuing maps of abnormality-related volume alterations and neurotransmitter maps from healthy populations. Both phenomena were linked to (specific) striatal and basal forebrain reductions as well as to D1 receptor density. Dyskinesia also manifested in cerebellar decrease, while parkinsonism was associated with less motor cortex volume. The parkinsonism-related brain pattern was additionally associated with 5-HT1A/2A and µ-opioid receptors distribution. Findings suggest the need to develop psychopharmacological compounds that display not only selectivity for receptor subtypes but also anatomical selectivity for alleviating dyskinesia without worsening parkinsonism and vice versa.

Changing the Antipsychotic in Early Nonimprovers to Amisulpride or Olanzapine: Randomized, Double-Blind Trial in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Meta-analyses have shown that the majority of patients with schizophrenia who have not improved after 2 weeks of treatment with an antipsychotic drug are unlikely to fully respond later. We hypothesized that switching to another antipsychotic with a different receptor binding profile is an effective strategy in such a situation. STUDY DESIGN: In total, 327 inpatients with an acute exacerbation of schizophrenia were randomized to double-blind treatment with either olanzapine (5-20 mg/day) or amisulpride (200-800 mg/day). Those patients who had not reached at least 25% Positive-and-Negative-Syndrome-Scale (PANSS) total score reduction from baseline after 2 weeks (the "non-improvers") were rerandomized double-blind to either staying on the same compound ("stayers") or to switching to the other antipsychotic ("switchers") for another 6 weeks. The primary outcome was the difference in the number of patients in symptomatic remission between the combined "switchers" and the "stayers" after 8 weeks of treatment, analyzed by logistic regression. STUDY RESULTS: A total of 142 nonimprovers were rerandomized at week two. 25 (45.5 %) of the 'stayers' compared to 41 (68.3 %) of the "switchers" reached remission at endpoint (p = .006). Differences in secondary efficacy outcomes were not significant, except for the PANSS negative subscore and the Clinical-Global-Impression-Scale. "Switchers" and "stayers" did not differ in safety outcomes. CONCLUSIONS: Switching "non-improvers" from amisulpride to olanzapine or vice-versa increased remission rates and was safe. The superiority in the primary outcome was, however, not paralleled by significant differences in most secondary efficacy outcomes and the effect was only apparent at the last visit making replications of longer duration necessary.

Evidence and expert consensus based German guidelines for the use of repetitive transcranial magnetic stimulation in depression.

INTRODUCTION: Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field. METHODS: The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations. FINDINGS: Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Prediction of response to repetitive transcranial magnetic stimulation in phantom sounds based on individual brain anatomy.

Non-invasive brain stimulation can reduce the severity of tinnitus phantom sounds beyond the time of stimulation by inducing regional neuroplastic changes. However, there are no good clinical predictors for treatment outcome. We used machine learning to investigate whether brain anatomy can predict therapeutic outcome. Sixty-one chronic tinnitus patients received repetitive transcranial magnetic stimulation of left dorsolateral prefrontal and temporal cortex. Before repetitive transcranial magnetic stimulation, a structural magnetic resonance image was obtained from all patients. To predict individual treatment response in new subjects, we employed a support vector machine ensemble for individual out-of-sample prediction. In the cross-validation, the support vector machine ensemble based on stratified sub-sampling and feature selection yielded an area under the curve of 0.87 for prediction of therapy success in new, previously unseen subjects. This corresponded to a balanced accuracy of 83.5%, sensitivity of 77.2% and specificity of 87.2%. Investigating the most selected features showed the involvement of the auditory cortex but also revealed a network of non-auditory brain areas. These findings suggest that idiosyncratic brain patterns accurately predict individual responses to repetitive transcranial magnetic stimulation treatment for tinnitus. Our findings may hence pave the way for future investigations into the precision treatment of tinnitus, involving automatic identification of the appropriate treatment method for the individual patient.

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.

Altered brain responses to emotional facial expressions in tinnitus patients.

Tinnitus, the phantom perception of sound, is a frequent disorder that can lead to severe distress and stress-related comorbidity. The pathophysiological mechanisms involved in the etiology of tinnitus are still under exploration. Electrophysiological and functional neuroimaging studies provide increasing evidence for abnormal functioning in auditory but also in non-auditory, e.g., emotional, brain areas. In order to elucidate alterations of affective processing in patients with chronic tinnitus, we used functional magnetic resonance imaging (fMRI) to measure neural responses to emotionally expressive and neutral faces. Twelve patients with chronic tinnitus and a group of 11 healthy controls, matched for age, sex, hearing loss and depressive symptoms were investigated. While viewing emotionally expressive faces compared to neutral faces brain activations in the tinnitus patients differed from those of the controls in a cluster that encompasses the amygdala, the hippocampus and the parahippocampal gyrus bilaterally. Whereas in controls affective faces induced higher brain activation in these regions than neutral faces, these regions in tinnitus patients were deactivated. Our results (1) provide evidence for alterations of affective processing of facial expressions in tinnitus patients indicating general domain-unspecific dysfunctions in emotion processing and (2) indicate the involvement of medial temporal areas in the pathophysiology of tinnitus.

Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal).

As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: "Tinnitus" for the former and "Tinnitus Disorder" for the latter. The proposed definition then becomes "Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder "when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.". In other words "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.

Cognitive Behavioral Therapy For Alleviating The Distress Caused By Tinnitus, Hyperacusis And Misophonia: Current Perspectives.

This article reviews the evidence related to the efficacy of Cognitive Behavioral Therapy (CBT) for alleviating the distress caused by tinnitus, hyperacusis and misophonia. Where available, the review was focused on meta-analyses of randomized controlled trials (RCTs) using either passive control groups (typically waiting list or education only) or active control groups (receiving some other form of treatment). Where data from RCTs were not available, case studies and retrospective studies were reviewed. Analyses were conducted separately for studies of patients with tinnitus, hyperacusis and misophonia. RCTs show that CBT is effective in alleviating the distress caused by tinnitus in comparison to passive control groups and sometimes active control groups. CBT for tinnitus can be effective both in individual and in group settings, whether delivered by psychiatrists, clinical psychologists, or specially trained audiologists. CBT for tinnitus can also be effective when delivered via the internet, when combined with help from audiologists. Usually, CBT does not reduce the loudness of tinnitus but it can improve quality of life. Case studies and some limited RCTs suggest that CBT can also be effective in alleviating the distress caused by hyperacusis and misophonia. However, RCTs with active control groups are currently lacking. There is strong evidence supporting the effectiveness of CBT in alleviating the distress caused by tinnitus. However, it is not yet clear whether CBT is more effective than some other forms of treatment. RCTs with active control groups are needed to establish more clearly the extent to which CBT is effective in alleviating the distress caused by hyperacusis and misophonia.

Parental Mental Illness in Childhood as a Risk Factor for Suicidal and Self-Harm Ideations in Adults Seeking Help for Tinnitus and/or Hyperacusis.

Purpose The aim of this study was to explore the relationship between parental mental illness in childhood with suicidal and self-harm ideations in adults seeking help for their tinnitus and/or hyperacusis. Method This was a retrospective, cross-sectional study. The data for 292 consecutive patients who attended a Tinnitus and Hyperacusis Therapy Specialist Clinic in the United Kingdom were included. Results Forty-six of 292 patients, or 15.75% of the patients, expressed that they have been bothered by suicidal and self-harm ideations within the last 2 weeks. Furthermore, 38.7% of the patients (113/292) reported that, while they were growing up during the first 18 years of life, their parent(s) were suffering from a mental illness. Logistic regression analysis showed a significant relationship between suicidal and self-harm ideations and the history of parental mental illness after adjusting the model for (a) tinnitus disability as measured via the Tinnitus Handicap Inventory (Newman, Jacobson, & Spitzer, 1996), (b) hyperacusis as measured via the Hyperacusis Questionnaire (Khalfa et al., 2002), (c) anxiety as measured via the Generalized Anxiety Disorder Questionnaire (Spitzer, Kroenke, Williams, & Löwe, 2006), (d) depression as measured via the Patient Health Questionnaire (Kroenke, Spitzer, & Williams, 2001), and (e) age and gender. Adjusted odds ratio was 2.5 (95% CI [1.14, 5.6], p = .022). The only other variable that was significantly related to the risk of suicidal and self-harm ideations was depression; adjusted odds ratio was 7.7 (95% CI [2.6, 26.3], p = .001). Conclusions Clinicians who offer tinnitus and hyperacusis rehabilitation should screen for suicidal and self-harm ideations among patients, especially for those with symptoms of depression and a childhood history of parental mental illness. Patients with suicidal and self-harm ideations should be referred to mental health services for further diagnosis and treatment.

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.

Toward a Robust, Universal Predictor of Gas Hydrate Equilibria by Means of a Deep Learning Regression.

Due to offshore reservoirs being developed in ever deeper and colder waters, gas hydrates are increasingly becoming a significant factor when considering the profitability of a reservoir due to flow disruptions, equipment, and safety hazards arising from the hydrate plug formation. Due to low-dosage hydrate inhibitors such as kinetic inhibitors competing with traditional thermodynamic inhibitors such as methanol, accurate information regarding the hydrate equilibrium conditions is required to determine the optimal hydrate control strategy. Existing thermodynamic models can prove inflexible regarding parameter adjustment and the incorporation of new data. Developing a multivariate regression model capable of generalizing hydrate equilibria over a wide range of conditions, with results competing with thermodynamic models is worthwhile. A multilayer perceptron neural network of three hidden layers has undergone supervised training means of a backpropagation to accurately predict uninhibited hydrate equilibrium pressure for a range of gas mixtures with nine input features, excluding hydrogen sulfide and electrolytes, from a dataset of 1209 equilibrium points, 670 of which are multicomponent gases, sampled in a rigorous data sampling campaign from existing experimental studies. Statistical significance of results has been emphasized, with models validated using 10-fold cross-validation and holdout validation, facilitating hyperparameter optimization without overfitting, while stratified holdout ensures testing a wide range of conditions. The developed model has proven to outperform two popular thermodynamic models. Various scoring metrics are used, with an average cross-validated R 2 of 0.987 ± (0.003). An R 2 of 0.993 and mean absolute percentage error of 5.56% are yielded for holdout validation. Auxiliary models are included to determine the multicomponent prediction capability and dependency on individual data sources. Multicomponent data prediction has proven successful; results prove that the model accurately generalizes hydrate equilibria and is well suited to predicting unseen data. Positive results are largely insensitive to exact model parameters, thus indicating a robust, replicable methodology.

[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

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.

Brain stimulation-induced neuroplasticity underlying therapeutic response in phantom sounds.

Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state-of-the-art voxel-based morphometry (VBM) to investigate whether transcranial magnetic stimulation-induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole-brain analyses (P < 0.05, FWE corrected), we assessed longitudinal gray matter changes as well as structural connectivity between the ensuing regions. We observed longitudinal mesoscopic gray matter changes of left dorsolateral prefontal (DLPFC), left operculo-insular, and right inferior temporal cortex (ITC) in responders (N = 22) but not nonresponders (N = 38), as indicated by a group × time interaction and post-hoc tests. These results were neither influenced by age, sex, hearing loss nor by tinnitus laterality, duration, and severity at baseline. Furthermore, we found robust DLPFC-insula and insula-ITC connectivity in responders, while only relatively weak DLPFC-insula connectivity and no insula-ITC connectivity could be demonstrated in nonresponders. Our results reinforce the implication of nonauditory brain regions in phantom sounds and suggest the dependence of therapeutic response on their neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554-562, 2018. © 2017 Wiley Periodicals, Inc.