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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.

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.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.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.

Brain communications 4(4), fcac190 (2022). doi:10.1093/braincomms/fcac190, Published by Oxford University Press, [Oxford]

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.

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.

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.

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.

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.

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.

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., Graphical Abstract Graphical Abstract

Depressive Storungen gehoren zu den haufigsten Erkrankungen weltweit. Trotz vielfaltiger Therapieoptionen stellt die effektive Behandlung noch eine Herausforderung dar. Neben einer Psychotherapie und Psychopharmakotherapie haben sich in den letzten Jahren die „nicht invasiven Stimulationsverfahren“ zu einer weiteren, erfolgsversprechenden Behandlungsalternative entwickelt. Hierzu gehoren die repetitive transkranielle Magnetstimulation (rTMS) und die transkranielle Gleichstromstimulation (tDCS). rTMS und tDCS konnten in klinischen Studien ihre antidepressive Wirksamkeit und gute Vertraglichkeit nachweisen. Die rTMS kann aufgrund der breiten Datenlage als etabliertes Verfahren zur Depressionsbehandlung angesehen werden. Fur den Einsatz der tDCS in der Depressionsbehandlung liegen erste vielversprechende Ergebnisse vor, jedoch ist die Datenbasis noch deutlich geringer als fur die rTMS, sodass weitere Studien abgewartet werden mussen, bevor eine endgultige Empfehlung gegeben werden kann. Depressive disorders belong to the most frequent health diseases in the world. Despite a broad variety of therapeutic options, treatment stills remains challenging. In the last years, “non-invasive brain stimulation techniques” have been developed as new, promising treatment options. Among them, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been shown antidepressant efficacy and safety in clinical studies. Especially, rTMS has been established as an accepted treatment due to the broad evidence of efficacy. In contrast, tDCS has shown some promising results, but further studies are needed before recommendations for use in clinical routine can be made.

ZusammenfassungDie Entstehung depressiver Erkrankungen wird im Allgemeinen als multifaktorielles Geschehen verstanden. In den letzten Jahren konnten vielfältige neurobiologische Veränderungen beschrieben werden, die mit der Entstehung und dem Verlauf von depressiven Erkrankungen in Zusammenhang gebracht werden. Das ursprüngliche Paradigma der Monoanminomangelhypothese wird dabei immer weiter relativiert, es resultiert somit mittlerweile ein komplexes, aber immer noch nicht vollständiges Verständnis der Genese dieser Erkrankungen. Dabei greifen die verschiedenen physiologischen Erkrankungsmodelle mit wachsendem Wissensstand zunehmend ineinander über.

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 .

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

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.

Treatment of patients with tinnitus is mainly pursued on the basis of screening data, encompassing answers to questionnaires or audiological examinations. Since tinnitus affects the quality of life of patients and is associated with comorbidities like depression, the screening step involves the acquisition of extensive amounts of information, which may contribute to the design of a personalized treatment. Often times, it can be observed that patients give up their treatment before completion (i.e., they constitute “dropout” cases). In this study, we investigate how multi-target classification on the screening data can contribute to characterize patients that will drop out of the study. For our analysis, we base or considerations on the target variable “tinnitus loudness”, i.e. the subjectively perceived loudness of the phantom signal. Following this, we attempt to identify variables that explain the tinnitus loudness together with the likelihood of interrupting the treatment. To be more precise, we report on results from gathered data of 1419 tinnitus patients from the University Hospital of Regensburg.

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.Die Entstehung depressiver Erkrankungen wird im Allgemeinen als multifaktorielles Geschehen verstanden. In den letzten Jahren konnten vielfältige neurobiologische Veränderungen beschrieben werden, die mit der Entstehung und dem Verlauf von depressiven Erkrankungen in Zusammenhang gebracht werden. Das ursprüngliche Paradigma der Monoanminomangelhypothese wird dabei immer weiter relativiert, es resultiert somit mittlerweile ein komplexes, aber immer noch nicht vollständiges Verständnis der Genese dieser Erkrankungen. Dabei greifen die verschiedenen physiologischen Erkrankungsmodelle mit wachsendem Wissensstand zunehmend ineinander über.

Zusammenfassung. Depressive Erkrankungen gehören zu den häufigsten Erkrankungen weltweit und verursachen aufgrund ihrer Schwere und Dauer beträchtliches Leid für die betroffenen Patienten und bedeutende gesundheitsökonomische Kosten. Zwar stehen mittlerweile eine Vielzahl therapeutischer Methoden zur Verfügung, nichtsdestotrotz erweist sich die Behandlung im Einzelfall im klinischen Alltag häufig als sehr schwierig. Bei einer Behandlung mit Antidepressiva lassen sich selten Response- und Remissionsraten von mehr als 60–70 % erreichen. D. h. mehr als ein Drittel der behandelten Patienten spricht nicht auf die Therapie an bei hoher interindividueller Schwankung. Hinzukommt die Verträglichkeit, die in vielen Fällen beispielweise aufgrund einer Psychopharmaka-induzierten Gewichtszunahme oder sexuellen Dysfunktion limitierend sein kann. Zwar haben alle Antidepressiva in randomisierten-kontrollierten Studien ihre Wirksamkeit nachweisen können. Jedoch entspricht das Patientengut einer klinischen Studie selten dem klinischen Alltag und der Wirksamkeitsnachweis erfolgt über Gruppenvergleiche. Vor diesem Hintergrund kann ein individuelles Vorgehen, dass die Bedürfnisse des einzelnen Patienten berücksichtigt die Akzeptanz, Verträglichkeit und damit auch die Wirksamkeit der antidepressiven Therapie verbessern. Mit zunehmender Erforschung von individuellen Prädiktoren für eine Response auf ein bestimmtes Verfahren kann dieses Vorgehen weiter verbessert werden.

Antidepressiva stellen neben der Psychotherapie eine wesentliche Saule der Depressionsbehandlung dar. Die Vertraglichkeit ist sehr wichtig, da Nebenwirkungen der haufigste Grund sind, warum Medikamente wieder abgesetzt werden. So kristallisiert sich zunehmend heraus, dass bestimmte Antidepressiva auch unerwunschte Nebenwirkungen auf das emotionale Erleben des Patienten haben konnen, die in der Praxis haufig ubersehen werden.

Background Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral-prefrontal cortex (DLPFC) with conventional figure-of-8 (=butterfly) coils has been used as an antidepressant therapeutic tool for almost twenty years. Very recently, an innovative rTMS coil, the so-called double cone coil (DC), was introduced allowing the modulation of the anterior cingulate cortex (AC). We investigated safety and therapeutic effectiveness of this stimulation in a naturalistic clinical setting. Method Forty-five patients suffering a moderate to severe depressive episode were randomized to receive 15 sessions of either conventional rTMS of the left DLPFC (" butterfly -rTMS"; 10 Hz; 2000 stimuli/day, RMT 110%), mediofrontal double cone coil stimulation of the anterior cingulate cortex (" ACDC -rTMS" with equal parameters), or sham-stimulation. The primary outcome was the change in the 21-items Hamilton Rating Scale for Depression (HAMD) from baseline to the end of treatment. Secondary outcome measures were changes over the course of the trial regarding the HAMD, the Beck Depression Inventory (BDI), the Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF) scales. Results There was a significant group × time interaction effect regarding the primary outcome ( F = 3.269; df = 2,37; P = 0.049). Post-hoc t-testing revealed a significant effect for the comparison ACDC vs. butterfly at week 3/end of treatment ( T = 2.646; df = 26; P = 0.014). No severe adverse events occurred during the study. ACDC -stimulation was well tolerated by the majority of patients similar like butterfly -rTMS and sham-stimulation. Conclusion This pilot study demonstrated the feasibility of ACDC -rTMS-stimulation as an add-on-treatment for depression. Its clinical effects warrant further investigation in the future.

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.

ZusammenfassungAls transkranielle Magnetstimulation (TMS) wird ein Verfahren bezeichnet, bei dem ein Stimulator über eine Spule kurze elektromagnetische Pulse mit einer Flussdichte von bis zu 2 Tesla induziert, welche die Schädelkalotte mit wenig Abschwächung durchdringen und zu einer Depolarisierung neuronaler Zellverbände führen. Die Stromdichte am Stimulationsort wird von einer Vielzahl physikalischer und biologischer Parametern bestimmt: Spulengeometrie sowie -positionierung, der Abstand der Spule zum Kortex, die Pulsform, die Intensität, Frequenz und das Muster der Stimulation sowie die dreidimensionale Orientierung der stimulierten neuronalen Strukturen im Verhältnis zur Geometrie des Magnetfeldes. Bei der repetitiven transkraniellen Magnetstimulation (rTMS) werden mehrere elektromagnetische Einzelstimuli als Reizserien mit konstanter Wiederholungsrate appliziert. Mithilfe dieser repetitiven TMS können Veränderungen der neuronalen Aktivität induziert werden, die über die eigentliche Stimulationsdauer hinweg andauern. Im vorliegenden Themenheft wird die Datenlage zu etablierten und potenziellen therapeutischen Anwendungen der repetitiven transkraniellen Magnetstimulation in psychiatrischen Indikationsgebieten zusammengefasst. Eine Empfehlung mit Evidenzgrad A kann für die hochfrequente rTMS-Behandlung des linken dorsolateralen präfrontalen Kortex (DLPFC) bei depressiven Störungen ausgesprochen werden. Empfehlungen mit dem Evidenzgrad B bestehen für niederfrequente rTMS des rechten DLPFC bei der Behandlung depressiver Störungen und für hochfrequente rTMS des linken DLPFC bei depressiver Symptomatik von Patienten mit Parkinson-Syndrom. Wahrscheinlich besteht ein additiver Effekt von rTMS des DLPFC zu einer antidepressiven Pharmakotherapie. Eine Empfehlung mit dem Evidenzgrad C kann folgenden rTMS-Paradigmen zugesprochen werden: hochfrequente rTMS des linken DLPFC bei Patienten mit schizophrener Negativsymptomatik (trotz einer großen negativen Multicenterstudie), niederfrequente rTMS des linken TPC bei chronischem Tinnitus und akustischen Halluzinationen (trotz vieler Publikationen eher niedriges Evidenzniveau), hochfrequente rTMS des rechten DLPFC bei Patienten mit posttraumatischer Belastungsstörung und hochfrequente rTMS des linken DLPFC bei Nikotinabhängigkeit. Gerade bei der Behandlung von Patienten mit chronischem und therapieresistentem Erkrankungsverlauf ist zu erwarten, dass dem gesamten Bereich neurostimulatorischer Methoden eine steigende Bedeutung zukommen wird. Es bleibt zu hoffen, dass vor dem Hintergrund innovativer technischer Entwicklungen und verbesserter Studienmethodologie die transkranielle Magnetstimulation in der nahen Zukunft ihr volles therapeutisches Potenzial entfalten wird.

ZusammenfassungZum Einsatz der repetitiven transkraniellen Magnetstimulation (rTMS) in der Behandlung des chronischen Tinnitus liegen 20 randomisierte placebokontrollierte Studien vor. In der Mehrzahl der Studien erfolgte die Behandlung mit niederfrequenter (1 Hz) rTMS über dem temporalen oder temporoparietalen Kortex. Die Spulenlokalisation erfolgte in den meisten Studien entweder linksseitig oder kontralateral zur Tinnituslateralität. Bei der Betrachtung ergibt sich kein eindeutiges Bild. Die Unterschiede in den Ergebnissen der einzelnen Studien könnten bedingt sein durch die Heterogenität der Stimulationsprotokollen und der Studiendesigns. Die Mehrzahl der Studien zeigte einen Nutzen der aktiven Stimulation im Vergleich zur Sham-Stimulation. Die Effektstärke war jedoch klein, der Effekt war in einzelnen (auch methodisch hochwertigen) Studien nicht nachweisbar und die Dauer des Behandlungseffektes bleibt ungewiss. Mehrere Studien legen nahe, dass die Behandlungseffekte durch die zusätzliche hochfrequente rTMS des linken frontalen Kortex verstärkt werden können. Aufgrund der nicht ganz eindeutigen Studienlage kann für den Einsatz der rTMS in der Behandlung des chronischen Tinnitus lediglich die Empfehlung mit Level C (mögliche Effekte wiederholter niederfrequenter rTMS-Sitzungen des temporalen/temporoparietalen Kortex) ausgesprochen werden.

ZusammenfassungDepressive Störungen treten mit einer jährlichen Prävalenz zwischen 5 und 15% in der Gesamtbevölkerung auf. Der Einsatz der repetitiven transkraniellen Magnetstimulation (rTMS) zur Behandlung depressiver Störungen stellt das Indikationsgebiet mit der umfassendsten Datengrundlage und den vielversprechendsten Ergebnissen dar. Bei der Anwendung von rTMS bei depressiven Störungen handelt es sich um ein akzeptiertes, evidenzbasiertes Therapieverfahren, welches durch die Amerikanische Psychiatrische Vereinigung, das kanadische Network for Mood and Anxiety Treatments und die World Federation of Societies of Biological Psychiatry anerkannt wird. Basierend auf der Hypothese einer Lateralisation der Emotionsverarbeitung bei depressiven Patienten wurden zwei Hauptlinien in der rTMS-Behandlung depressiver Störungen entwickelt: einerseits niederfrequente inhibierende Stimulation des rechten DLPFC (mutmaßlich hyperaktiv bei depressiven Patienten) und hochfrequente (exzitatorische) rTMS des linken DLPFC (mutmaßlich hypoaktiv bei depressiven Patienten) bzw. eine Kombination beider Ansätze. Für beide Ansätze steht eine überzeugende Evidenz zur Verfügung, welche auf den antidepressiven Effekt von rTMS insbesondere bei der Behandlung akuter unipolar-depressiver Episoden verweist. Generell ist davon auszugehen, dass die Erfolgswahrscheinlichkeit einer Behandlung mit rTMS bei einer Anwendung im akuten Stadium, relativ jungen Patienten (< 65 Jahre) und geringer Therapieresistenz oder mit nur teilweiser therapeutischer Response am höchsten ist. Die durch Therapiestudien gemessene Stärke der antidepressiven Wirkung gilt als moderat und unterliegt dem antidepressiven Effekt einer Elektrokonvulsionstherapie. Um rTMS aber als therapeutische Option in Deutschland für die Behandlung depressiver Störungen in der Zukunft attraktiv zu gestalten, wird es von entscheidender Bedeutung sein, den genauen Stellenwert der rTMS in einem gestuften Behandlungsschema zu definieren sowie klinisch effektive “Erhaltungsprotokolle” zu definieren, um einen erreichten Therapieerfolg zeitlich überdauernd zu sichern. Zudem sollte die rTMS an geeigneter Stelle in den Behandlungsleitlinien Eingang finden. Es kann unter Berücksichtigung dieser Kritikpunkte rTMS des DLPFC als klinisch relevante therapeutische Technik zur Behandlung pharmakoresistenter, mittelgradiger bis schwerer depressiver Episoden empfohlen werden.

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.

The identification of subpopulations with particular characteristics with respect to a disease is important for personalized diagnostics and therapy design. For some diseases, the outcome is described by more than one target variable. An example is tinnitus: the perceived loudness of the phantom signal and the level of distress caused by it are both relevant targets for diagnosis and therapy. In this work, we study the potential of multi-target classification for the identification of those screening variables, which separate best among the different subpopulations of patients, paying particular attention to subpopulations with discordant value combinations of loudness and distress. We analyse the screening data of 1344 tinnitus patients from the University Hospital Regensburg, including questions from 7 questionnaires, and report on the performance of our workflow in target separation and in ranking the questionnaires variables on their discriminative power.