Suicide Mortality Risk among Patients with Lung Cancer-A Systematic Review and Meta-Analysis.

The risk for suicide in patients with cancer is higher compared to the general population. However, little is known about patients with lung cancer specifically. We therefore implemented a systematic review and random-effects meta-analysis of retrospective cohort studies on suicide in patients with lung cancer. We searched a high number of common databases up to 02/2021. For the systematic review, a total of 23 studies was included. To exclude bias due to patient sample overlap, the meta-analysis was performed on 12 studies. The pooled standardized mortality ratio (SMR) for suicide was 2.95 (95% Confidence Interval (CI) = 2.42-3.60) for patients with lung cancer as compared to the general population. Subgroups with a pronouncedly higher risk for suicide compared to the general population were found for patients living in the USA (SMR = 4.17, 95% CI = 3.88-4.48), with tumors of late stage (SMR = 4.68, 95% CI = 1.28-17.14), and within one year after diagnosis (SMR = 5.00, 95% CI = 4.11-6.08). An increased risk for suicide was found in patients with lung cancer, with subgroups at particular risk. Patients at increased risk should be monitored more closely for suicidality and should receive specialized psycho-oncological and psychiatric care. Further studies should clarify the role of smoking and depressive symptoms on suicidality among lung cancer patients.

Suicide risk and mortality among patients with cancer.

Despite substantial progress in cancer therapy in recent decades, patients with cancer remain at high suicide risk. Data from individual studies have not been comprehensively quantified and specific risk factors are ill-defined. We assessed suicide mortality risk according to cancer prognosis, stage, time since diagnosis, gender, ethnicity, marital status, year of recruitment and geographic region. We searched EMBASE, MEDLINE, PsycINFO, Web of Science, CINAHL and Google Scholar for relevant articles up to February 2021. We used a random effects model, performed meta-regression meta-analysis and assessed heterogeneity and publication bias using I², funnel plots and Egger's and Begg's tests. We performed a systematic review including 62 studies and 46,952,813 patients. To avoid patient sample overlap, the meta-analysis was performed on 28 studies, involving 22,407,690 patients with cancer. Suicide mortality was significantly increased compared with the general population (standardized mortality ratio = 1.85, 95% confidence interval = 1.55-2.20). Risk was strongly related to cancer prognosis, cancer stage, time since diagnosis and geographic region. Patients with cancer, particularly those with specific risk factors, should be closely monitored for suicidality and need specialized care to reduce short- and long-term risks of suicide.

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.

Electrophysiological evaluation of high and low-frequency transcranial random noise stimulation over the auditory cortex.

BACKGROUND: Transcranial random noise stimulation (tRNS) is a non-invasive brain stimulation technique which uses electrical alternating currents applied at random frequencies. Besides the ability to alter cortical excitability, past research demonstrated that high-frequency tRNS over the auditory cortex can modulate both spontaneous and auditory evoked oscillatory brain activity. OBJECTIVES: The aim of the present study was to examine the effects of high- and low-frequency auditory tRNS on EEG power and evoked activity. METHODS: Low-frequency (0.1-100Hz), high-frequency (100-640Hz) and sham tRNS were administered for a stimulation over the auditory cortex in 22 healthy subjects. Before and after tRNS stimulation auditory steady state responses (ASSR) of 20 and 40Hz stimuli as well as oscillatory brain activity were recorded with electroencephalography (EEG). RESULTS: Stimulation of both verum tRNS protocols revealed no significant changes either in ASSR or in resting state EEG activity. Unexpectedly, sham tRNS resulted in a significant decrease in 20Hz ASSR and an increase in the alpha frequency band (8-12.5Hz). CONCLUSION: We were not able to replicate previous findings of a modulation of resting state EEG activity and ASSR by tRNS.

The more the merrier? Preliminary results regarding treatment duration and stimulation frequency of multisite repetitive transcranial magnetic stimulation in chronic tinnitus.

The current study examines two different protocols of repetitive transcranial magnetic stimulation (rTMS) targeting three key hubs of cortical tinnitus networks. Patients chose whether they preferred to undergo rTMS treatment for 10 or 20 sessions and were randomized to the different rTMS protocols thereafter. Ninety patients were enrolled in the study with a total dropout rate of 10%. Both rTMS protocols were well tolerated by the patients without any serious adverse events. Overall treatment effects were small both for 2 weeks and 4 weeks of treatment. There was no significant interaction effect between measurement time point and treatment group for neither of the outcome measures nor any differences regarding the applied treatment regimens. The effects of this study contradict former observations suggesting multisite rTMS protocols as promising neuromodulatory strategies. This lack of effect could not be enhanced by increasing the number of treatment sessions in our study.

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.

Lidocaine injections to the otic ganglion for the treatment of tinnitus-A pilot study.

Tinnitus is defined as the perception of noise without an external acoustic stimulus. Due to the heterogeneity of tinnitus, no treatment has proven equally beneficial to every single of these patients. Previous studies have shown that trigeminal input can interfere with the perception of tinnitus. Therefore, we aimed to explore the therapeutic potential of lidocaine injections in trigeminal structures. We conducted a pilot study with 19 participants to explore feasibility and tolerability of this approach. The intervention consisted of three injections of lidocaine in the anatomical area of the trigeminal ganglion and the ganglion oticum via an oral approach corresponding to the affected side of tinnitus. We performed an assessment that included the Mini-TQ, CGII, and numeric rating scales of tinnitus loudness and severity at different time points over a follow-up period of 12 weeks. In addition to changes of subjective tinnitus complaints, potential adverse events were documented. Patients were treated at the Centre of Otorhinolaryngology in Traunstein, Germany, and data were analyzed at the University of Regensburg, Germany. We did not observe any relevant side effects. There was a significant reduction of tinnitus distress (Mini-TQ, Tinnitus severity) and loudness (measured subjectively) over time. Our pilot data suggests that lidocaine injections targeting trigeminal structures may be able to reduce tinnitus complaints. Future studies should investigate the effects of lidocaine injections in placebo-controlled trials in an extended sample size to further explore the potential benefits of this therapeutic approach on tinnitus.

Bifrontal high-frequency transcranial random noise stimulation is not effective as an add-on treatment in depression.

BACKGROUND: Depressive disorders are linked to dysfunction in prefrontal cortical areas. Hence, non-invasive neurostimulation of the prefrontal cortex has demonstrated antidepressant efficacy. In the present study, we investigated the efficacy of high frequency transcranial random noise stimulation (hf-tRNS) as an add-on treatment for depression in a sham-controlled randomized trial. METHODS: Forty in-patients with depression were randomized and treated with real or sham hf-tRNS (100-650 Hz) with 0 mA offset. The electrodes were mounted over the left and right dorsolateral prefrontal cortex. The Hamilton Depression Rating Scale (primary outcome), the Major Depression Inventory, the Clinical Global Impression scale and the Global Assessment of Functioning scale were used for assessment at baseline, after 3 weeks of intervention (end of treatment), and 9 weeks after intervention. Safety parameters included cognitive functioning and reported side-effects. RESULTS: Comparison of real and sham treatment at the planned interim analysis showed an amelioration of symptoms in both groups for all outcomes with numeric but not statistically significant superiority of the sham arm for the primary outcome. Thus, the study was terminated prematurely after an interim analysis. There were no systematic differences with respect to safety parameters. LIMITATIONS: The negative finding might be related to the specific stimulation parameters used in this study. CONCLUSIONS: Our study suggests that prefrontal hf-tRNS is safe but not effective as an add-on treatment of depression. The challenge for future studies employing transcranial electric stimulation remains to identify effective stimulation parameters for the treatment of depression.

Limited predictive value of admission time in clinical psychiatry.

BACKGROUND: A large proportion of admissions to psychiatric hospitals happen as emergency admissions and many of them occur out of core working hours (during the weekends, on public holidays and during night time). However, very little is known about what determines admission times and whether the information of admission time bears any relevance for the clinical course of the patients. In other words, do admission times correlate with diagnostic groups? Can accumulations of crises be detected regarding circadian or weekly rhythms? Can any differences between workdays and weekends/public holidays be detected? May it even be possible to use information on admission times as a predictor for clinical relevance and severity of the presented condition measured by the length of stay? METHODS: In the present manuscript we analyzed data derived from 37'705 admissions to the Psychiatric District Hospital of Regensburg located in the Southern part of Germany covering the years 2013 to 2018 with regard to ICD-10 diagnostic groups and admission times. The hospital provides 475 beds for in-patient treatment in all fields of clinical psychiatry including geriatrics and addiction medicine. RESULTS: Several core questions could be answered based on our analysis: 1st Our analysis confirms that there is a high percentage of unheralded admissions out of core time showing broad variation. 2nd In contrary to many psychiatrists' misconceptions the time of admission has no relevant impact on the length of stay in the hospital. 3rd The predictive value of admission time regarding the allocation to ICD-10 diagnostic groups is low explaining only 1% of variability. CONCLUSIONS: Taken together, our data reveal the enormous variation of admission times of psychiatric patients accounting for the need of adequate and consistent provision of personnel and spatial resources.

SARS-CoV-2 Risk Management in Clinical Psychiatry: A Few Considerations on How to Deal With an Unrivaled Threat.

The pandemic spread of the corona virus SARS-CoV-2 has even-handedly shattered national and international health systems and economies almost in an instant. As numbers of infections and COVID-19-related deaths rise from day to day, fears and uncertainties on how to deal with this unknown threat are extremely present both for individuals and societies as a whole. In this manuscript, we aim to exemplarily describe the bullet points concerning (a) the internal risk management, (b) the organizational and structural changes, and (c) the communicational strategies applied in a Psychiatric University Hospital in the Southern part of Germany. The authors are well aware about the fact that almost none of these considerations may be considered as evidence-based at the moment. However, the authors trust that these reflections and experiences may be useful as an orientation for similar risk constellations in other afflicted countries due to the temporal delay of the pandemic course.

Add-on spironolactone as antagonist of the NRG1-ERBB4 signaling pathway for the treatment of schizophrenia: Study design and methodology of a multicenter randomized, placebo-controlled trial.

BACKGROUND: Preclinical studies recently showed that the mineralocorticoid antagonist spironolactone acts also as an antagonist of the NRG1-ERBB4 signaling pathway and improves schizophrenia-like behaviour in Nrg1 transgenic mouse model. As this signaling pathway is critically linked to the pathophysiology of schizophrenia, especially in the context of working-memory dysfunction, spironolactone may be a novel treatment option for patients with schizophrenia targeting cognitive impairments. AIMS: To evaluate whether spironolactone added to an ongoing antipsychotic treatment improves cognitive functioning in schizophrenia. METHODS: The add-on spironolactone for the treatment of schizophrenia trial (SPIRO-TREAT) is a multicenter randomized, placebo-controlled trial with three arms (spironolactone 100 mg, spironolactone 200 mg and placebo). Schizophrenia patients are treated for three weeks and then followed-up for additional nine weeks. As primary outcome, we investigate changes in working memory before and at the end of the intervention phase. We will randomize 90 patients. Eighty-one patients are intended to reach the primary endpoint measure at the end of the three-week intervention period. Secondary endpoints include other measures of cognition, psychopathology, safety measures and biological measures. CONCLUSIONS: SPIRO-TREAT is the first study evaluating the efficacy of the mineralocorticoid receptor antagonist spironolactone to improve cognitive impairments in schizophrenia patients targeting the NRG1-ERBB4 signaling pathway. With SPIRO-TREAT, we intend to investigate a novel treatment option for cognitive impairments in schizophrenia that goes beyond the established concepts of interfering with dopaminergic neurotransmission as key pathway in schizophrenia treatment. CLINICAL TRIAL REGISTRATION: International Clinical Trials Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE.

Resting motor threshold and magnetic field output of the figure-of-8 and the double-cone coil.

The use of the double-cone (DC) coil in transcranial magnetic stimulation (TMS) is promoted with the notion that the DC coil enables stimulation of deeper brain areas in contrast to conventional figure-of-8 (Fo8) coils. However, systematic comparisons of these two coil types with respect to the spatial distribution of the magnetic field output and also to the induced activity in superficial and deeper brain areas are limited. Resting motor thresholds of the left and right first dorsal interosseous (FDI) and tibialis anterior (TA) were determined with the DC and the Fo8 coil in 17 healthy subjects. Coils were orientated over the corresponding motor area in an angle of 45 degrees for the hand area with the handle pointing in posterior direction and in medio-lateral direction for the leg area. Physical measurements were done with an automatic gantry table using a Gaussmeter. Resting motor threshold was higher for the leg area in contrast to the hand area and for the Fo8 in contrast to the DC coil. Muscle by coil interaction was also significant providing higher differences between leg and hand area for the Fo8 (about 27%) in contrast to the DC coil (about 15%). Magnetic field strength was higher for the DC coil in contrast to the Fo8 coil. The DC coil produces a higher magnetic field with higher depth of penetration than the figure of eight coil.

Daily high-frequency transcranial random noise stimulation of bilateral temporal cortex in chronic tinnitus - a pilot study.

Several studies emphasized the potential of single and multiple transcranial random noise stimulation (tRNS) sessions to interfere with auditory cortical activity and to reduce tinnitus loudness. It was the objective of the present study to evaluate the use of high-frequency (hf) tRNS in a one-arm pilot study in patients with chronic tinnitus. Therefore, 30 patients received 10 sessions of high frequency tRNS (100-640 Hz; 2 mA; 20 minutes) over the bilateral temporal cortex. All patients had received rTMS treatment for their tinnitus at least 3 months before tRNS. Primary outcome was treatment response (tinnitus questionnaire reduction of ≥5 points). The trial was registered at clinicaltrials.gov (NCT01965028). Eight patients (27%) responded to tRNS. Exactly the same number of patients had responded before to rTMS, but there were only two "double responders" for both treatments. None of the secondary outcomes (tinnitus numeric rating scales, depressivity, and quality of life) was significant when results were corrected for multiple comparisons. tRNS treatment was accompanied by tolerable side effects but resulted in temporal increases in tinnitus loudness in 20% of the cases (2 drop-outs). Our trial showed that hf-tRNS is feasible for daily treatment in chronic tinnitus. However, summarizing low treatment response, increase of tinnitus loudness in 20% of patients and missing of any significant secondary outcome, the use of hf-tRNS as a general treatment for chronic tinnitus cannot be recommended at this stage. Differences in treatment responders between tRNS and rTMS highlight the need for individualized treatment procedures.

A Comprehensive Review of Dorsomedial Prefrontal Cortex rTMS Utilizing a Double Cone Coil.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has become increasingly popular during the last decades mainly driven by the antidepressant effects of dorsolateral prefrontal cortex stimulation with "butterfly" coils. Only recently, alternative targets such as the dorsomedial prefrontal cortex (dmPFC) have been brought into focus and innovative coil designs such as the angled geometry of the double cone coil (DCC) have raised hope to reach even deeper located targets. OBJECTIVE: To provide a systematic and comprehensive review on the application of rTMS stimulation of the dmPFC using the DCC in neuropathological and healthy samples. METHODS: We systematically searched the MEDLINE® database (http://www.ncbi.nlm.nih.gov/pubmed/). Due to the heterogeneous naming of DCC stimulation over the dmPFC a variety of search terms was applied resulting in a numeral quantity of 340 hits. RESULTS: DCC stimulation over the dmPFC has been proven to be safe and feasible in various neuropsychiatric disorders and in healthy subjects. Clinical results are encouraging, but have to be considered as preliminary as data from sham-controlled clinical trials and knowledge about the neurobiological underpinnings are still scarce. CONCLUSION: DCC stimulation over the dmPFC represents a promising approach in the fast evolving noninvasive brain stimulation techniques aiming at the functional modulation of brain areas vitally involved in affect, sensory autonomic, cognitive, and salience regulation. This may hold potential for both neuroscientific research and clinical applications in the treatment of psychiatric disorders.

Anti-Suicidal Efficacy of Repetitive Transcranial Magnetic Stimulation in Depressive Patients: A Retrospective Analysis of a Large Sample.

Background: Suicide is a major public health problem. About 90% of suicide victims have one or more major psychiatric disorder, with a reported 20-fold increased risk for suicide in patients with affective disorders in comparison with healthy subjects. Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective alternative or adjunctive treatment option for patients with depressive disorders, but little is known about its effects on suicide risk. Objective: For the assessment of the effectiveness of rTMS on suicidal ideation and behaviors, we performed a retrospective analysis of a large sample of patients with depressive disorders, who were treated with rTMS. Methods: We analyzed the records of 711 TMS in- and out-patients with depressive affective disorders in a tertiary referral hospital between 2002 and 2017. Out of these patients we were able to collect Hamilton depression rating scale (HAMD) data of 332 patients (180 females, 152 males; age range 20 to 79 years; mean age 47.3 ± 12.3) for which we analyzed the change of suicidal ideation by using item 3 (suicidality) of HAMD. Results: Out of all 711 patients treated with rTMS for their depression, one patient (0.1%) committed suicide during the TMS treatment. In the statistical analysis of the subsample with 332 patients there was an overall amelioration of depressive symptoms accompanied by a significant decrease in the suicidality item with a medium effect size. Decrease in suicidality was not inferior to changes in other items as indicated by effect sizes. Forty-seven percent of patients showed an amelioration in suicidality, 41.3% of patients did not show a change in their suicidality's scores, and 11.7% of patients showed an increase in suicidality's scores from baseline to final rating. Correlation of item 3 (suicidality) and item 7 (drive) demonstrated a significant positive association, revealing improved drive with a parallel decreased suicidality. Conclusion: Based on the proposed data, there is no evidence that rTMS increases the risk for suicide during the course of the treatment. Conversely, rTMS tends to reduce suicidal ideation. Our findings call for further rTMS controlled studies using large sample sizes and specific suicidality assessment measures to obtain more conclusive results.

A Pilot Study of Peripheral Muscle Magnetic Stimulation as Add-on Treatment to Repetitive Transcranial Magnetic Stimulation in Chronic Tinnitus.

While brain stimulation techniques have been examined as treatment options for chronic tinnitus for many years, they have recently been extended to multimodal treatment approaches. As chronic tinnitus is often accompanied by comorbid muscular tension in the neck and back, we performed a one-arm pilot study to explore the feasibility of a new multimodal treatment approach. In detail, repetitive peripheral magnetic stimulation (rPMS) of the back was performed before and after each session of repetitive transcranial magnetic stimulation (rTMS) of the brain. Data of 41 patients were analyzed, all of which were treated with ten sessions of rTMS of the left prefrontal and left temporoparietal cortex followed by rPMS of the neck and back muscles. Tinnitus severity was measured using the tinnitus questionnaire (TQ). Neck pain was assessed using the neck pain and disability scale (NPAD). The new treatment approach was feasible and well accepted by the majority of patients. However, the overall patient group did not improve significantly in either of the questionnaires. If patients were divided in different subgroups depending on whether they were suffering from neck pain or somatosensory tinnitus, explorative post-hoc tests suggested differential effects: patients with both neck pain and somatosensory tinnitus had better outcomes than patients without those conditions or with neck pain only. This was true for both the TQ and the NPAD. This effect was of transient nature though: the TQ score went back to its baseline level after a follow-up period of 12 weeks. Based on our results we recommend that in studies that investigate tinnitus treatments targeting somatosensory afferents patients should be stratified according to somatic co-morbidities and somatosensory influence on the tinnitus percept. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT02306447.

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.