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Abstract Background Tinnitus can cause considerable psychological distress among patients, particularly if comorbidities occur. Despite a strong relationship between tinnitus-related distress and depression, the underlying mechanisms represent a long-standing question. By investigating the co-development of tinnitus-related distress and depressiveness throughout therapy, we capture the dynamic interplay of both conditions and uncover underlying common features mediating their link. Methods Large datasets from two different day clinics in Germany have been analyzed using a regularization method for predictor selection (analysis 1) and latent growth curve modeling (LCM; analysis 2). Tinnitus-related distress was assessed using the Tinnitus Questionnaire (TQ). All patients have been experiencing chronic subjective tinnitus with a minimum mean severity level of TQ grade 2. Treatment at both day clinics involved tinnitus management according to clinical guidelines with minor idiosyncratic differences. Analysis 1 was performed on a dataset of 500 patients who received the Jena Interdisciplinary Treatment for Tinnitus (JITT) for 5 consecutive days between 2013 and 2017. Analysis 2 was performed on a second dataset, which included 1016 patients treated at the Tinnitus Center of the Charité Universitätsmedizin Berlin for 7 days between 2011 and 2015. Results Here, we show a substantial bidirectional relationship between tinnitus-related distress and depression severity while emphasizing the role of somatic symptoms and perceived stress in the experience and maintenance of tinnitus awareness. The LCM provides adequate model fit (CFI = 0.993, SRMR = 0.016). Conclusions Our results indicate enhanced therapy success in depression when tinnitus-related distress is addressed and vice versa. The combined treatment of tinnitus and depression is proposed for future treatment strategies.

Background: Despite the high frequency of tinnitus and its impact on wellbeing, little is known about its economic burden, and, to our knowledge, no data are available on out-of-pocket (OOP) expenses. Methods: In 2022, a survey was conducted on OOP costs of tinnitus. We enrolled 679 participants with slight, moderate, and severe tinnitus in Italy, United Kingdom, Netherlands, Germany, and Spain. We estimated annual OOP expenses for tinnitus-related healthcare visits, treatments, medications, and alternative medicine practices. Prevalence of tinnitus in the general population, obtained from a representative survey we conducted in Europe in 2017–2018, was used to generalize costs for people with any tinnitus at the national level. Results: OOP expenses were 368€ (95% confidence intervals [CI], 78€–690€), 728€ (95% CI, 316€–1,288€), and 1,492€ (95% CI, 760€–2,688€) for slight, moderate, and severe tinnitus, respectively, with annual expenditure of 565€ for people with any tinnitus: 209€ for healthcare visits; 93€ for treatments; 16€ for drugs; 64€ for hearing supporting systems; and 183€ for acupuncture, homeopathy, and osteopathy. Individuals with slight, moderate, and severe tinnitus expressed a willingness to invest 1.6, 4.3, and 7.0 times their monthly income, respectively, to achieve complete relief from tinnitus. Conclusion: This study offers for the first time insights into the OOP expenses incurred by individuals with tinnitus. OOP expenses exhibited substantial variations based on severity status, accounting for more than 17 billion € in the countries considered. In terms of financial burden, these findings align tinnitus to the recognized leading disabilities, including back pain and migraine.

Objectives. The study aimed to assess the relationship of tinnitus with hyperacusis with cognitive impairment as indicated by the Montreal Cognitive Assessment (MoCA) tool. Methods. This multicenter cross-sectional study included individuals with chronic tinnitus from the “Unification of Treatments and Interventions for Tinnitus Patients” (UNITI) database. Participants were recruited from four different tertiary clinical centers located in Athens and Granada (Mediterranean group), as well as Berlin and Regensburg (German group). In total, 380 individuals with a diagnosis of non-pulsatile chronic tinnitus (permanent and constant tinnitus lasting more than 6 months) and no evidence of severe cognitive impairment (MoCA score >22) were enrolled. The evaluation utilized the following tools: MoCA, Tinnitus Handicap Inventory (THI), Hyperacusis Questionnaire (GÜF), Patient Health Questionnaire (PHQ-9), and the European School for Interdisciplinary Tinnitus Research Screening Questionnaire. Results. MoCA scores differed between German and Mediterranean individuals (P

BackgroundGold-standard approaches for chronic tinnitus involve hearing amplification measures and psychological therapy, where applicable. Whilst schema therapy is accumulating evidence as a transdiagnostically useful treatment framework, its applicability for patients with chronic tinnitus has not yet been examined. The present study (a) explores latent dimensions of psychological distress in a sample of chronic tinnitus patients, and (b) examines whether the schema mode model might explain these dimensions – thus constituting a potentially helpful conceptualization and treatment framework.MethodsN = 696 patients with chronic tinnitus completed the Tinnitus Questionnaire, Tinnitus Handicap Inventory, Hospital Anxiety and Depression Scale, Perceived Stress Questionnaire and ICD-10 Symptom Rating. As criterion, patients further completed the Schema Mode Inventory (SMI-r) – which assesses psychological constructs linked to negative self-beliefs (“parent modes”), primary emotions resulting from unmet psychological needs (“child modes”), and secondary emotional or behavioral attempts to reinstate or maintain psychological equilibrium (“coping modes”). A varimax-rotated principal axis factor analysis grouped the primary item pool. Factor scale scores were then correlated with the SMI-r.ResultsA three-factor solution explained 37.4% of variance and represented 78% of the included items. Following item content examination, the factors represented (1) General emotional distress, (2) Tinnitus-attributed emotional distress, and (3) Socio-audiological impairment. Factors 1|2 correlated highly (r = 0.70), Factors 2|3 moderately (r = 0.62). Linked to the schema mode model, Factor 1 correlated highly with the “vulnerable child” (r = 0.78), and moderately with the “parent”, “angry child”, and “detached protector” modes (0.53 < r < 0.65). Factor 2 correlated moderately with the “vulnerable child” (r = 0.53). Factor 3 was largely uncorrelated with SMI-r scores – although a low correlation with the “detached protector” warrants further examination.Conclusion“General” and “tinnitus-attributed” emotional distress correlate highly – warranting holistic (not symptom-specific) psychological case conceptualization and treatment planning. Viewed from a schema mode perspective, the “vulnerable child” explains substantial variance across both dimensions. Consequently, autobiographically anchored, unmet emotional needs and emotional detachment constitute key treatment targets. Social-audiological impairment should be multimodally conceptualised and treated with hearing aids and psychological support measures, as applicable.

Abstract The clinical heterogeneity of chronic tinnitus poses major challenges to patient management and prompts the identification of distinct patient subgroups (or phenotypes) that respond more predictable to a particular treatment. We model heterogeneity in treatment response among phenotypes of tinnitus patients concerning their change in self-reported health burden, psychological characteristics, and tinnitus characteristics. Before and after a 7-day multimodal treatment, 989 tinnitus patients completed 14 assessment questionnaires, from which 64 variables measured general tinnitus characteristics, quality of life, pain experiences, somatic expressions, affective symptoms, tinnitus-related distress, internal resources, and perceived stress. Our approach encompasses mechanisms for patient phenotyping, visualizations of the phenotypes and their change with treatment in a projected space, and the extraction of patient subgroups based on their change with treatment. On average, all four distinct phenotypes identified at the pre-intervention baseline showed improved values for nearly all the considered variables following the intervention. However, a considerable intra-phenotype heterogeneity was noted. Five clusters of change reflected variations in the observed improvements among individuals. These patterns of treatment effects were identified to be associated with baseline phenotypes. Our exploratory approach establishes a groundwork for future studies incorporating control groups to pinpoint patient subgroups that are more likely to benefit from specific treatments. This strategy not only has the potential to advance personalized medicine but can also be extended to a broader spectrum of patients with various chronic conditions.

BackgroundAmongst “third-wave” cognitive behavioural therapies, schema therapy demonstrates encouraging efficacy across various mental health conditions. Within this field, clinical interest has begun to converge on the “schema-mode-model” – a conceptualization framework for affective, cognitive and behavioral states that guide individuals’ perceptions and behaviours at a given point in time. Schema mode expressions in patients with chronic tinnitus are as-yet unexamined.MethodsThe present study reports self-report data from N = 696 patients with chronic tinnitus who completed the Schema Mode- and Tinnitus Handicap Inventories alongside measures of perceived stress, anxiety and depression. The Schema Mode Inventory assesses so-called maladaptive “parent”, “child” and “coping” modes. Parent modes can be understood as self-states which are characterized by self-critical and hostile beliefs; child modes are characterized by biographically unmet emotional needs; and coping modes by inflexible attempts to regulate emotion and stabilize one’s sense of self. Descriptive, correlational and mediation analyses investigated schema mode expressions (1) in patients with chronic tinnitus, (2) as compared to published reference values from a healthy control sample, (3) in their relation to other psychological constructs, and (4) regarding their potential role in driving tinnitus-related distress.ResultsPatients reported mild-to-moderate levels of emotional distress. Compared to healthy controls, patients showed (1) high relative expressions of child-, detachment and compliant coping modes and (2) a conspicuously low relative expression of the ‘punitive parent’ mode. Correlational patterns suggested strong associations of (1) parent as well as angry child modes with perceived stress and anxiety, (2) the vulnerable child mode with all measured constructs and (3) emotional distress with - intrapersonally - emotional detachment as well as - interpersonally - alleged compliance. Mediation analyses demonstrated that tinnitus-related distress was driven by significant interactions between child and coping modes.ConclusionsThe study provides initial clinical evidence for the relevance and applicability of schema-mode based formulation and treatment planning in patients with chronic tinnitus.

Despite good agreement of national guidelines for the assessment and treatment of tinnitus, there is still substantial variation regarding tinnitus-related healthcare across Europe. In contrast to previous work, which has mainly focussed on the perspective of healthcare professionals, we here report the results of separate web-based surveys conducted with clinicians and researchers as well as tinnitus patients. These surveys were devised to obtain information about their respective attitudes and needs with respect to tinnitus healthcare, and to reveal possible interdisciplinary inconsistencies among clinicians and researchers. We mainly targeted participants from Germany, Cyprus, and Greece, the countries in which the institutions of the researchers involved in this project are based. Results showed, firstly, that the treatment satisfaction of the patients was overall more negative than that of the clinicians and researchers, and that the patients' treatment satisfaction did not depend on the number of different treatments they had received. Secondly, patients as well as clinicians and researchers indicated that they were interested in learning more about a variety of tinnitus-related topics, especially treatment strategies, with no marked differences between clinicians from different professional disciplines. This suggests similar tinnitus-specific educational needs in patients and healthcare professionals.

Abstract Background Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. Methods Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. Discussion The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. Trial registration ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis.

The aim of this study was to identify key proteins of synaptic transmission in the cochlear nucleus (CN) that are involved in normal hearing, acoustic stimulation, and tinnitus. A gene list was compiled from the GeneCards database using the keywords “synaptic transmission” AND “tinnitus” AND “cochlear nucleus” (Tin). For comparison, two gene lists with the keywords “auditory perception” (AP) AND “acoustic stimulation” (AcouStim) were built. The STRING protein–protein interaction (PPI) network and the Cytoscape data analyzer were used to identify the top two high-degree proteins (HDPs) and their high-score interaction proteins (HSIPs), together referred to as key proteins. The top1 key proteins of the Tin-process were BDNF, NTRK1, NTRK3, and NTF3; the top2 key proteins are FOS, JUN, CREB1, EGR1, MAPK1, and MAPK3. Highly significant GO terms in CN in tinnitus were “RNA polymerase II transcription factor complex”, “late endosome”, cellular response to cadmium ion”, “cellular response to reactive oxygen species”, and “nerve growth factor signaling pathway”, indicating changes in vesicle and cell homeostasis. In contrast to the spiral ganglion, where important changes in tinnitus are characterized by processes at the level of cells, important biological changes in the CN take place at the level of synapses and transcription.

Abstract The role of stress and its neuroendocrine mediators in tinnitus is unclear. In this study, we measure cortisol as an indicator of hypothalamus–pituitary–adrenal (HPA) axis alterations and brain-derived neurotrophic factor (BDNF) as a marker of adaptive neuroplasticity in hair of chronic tinnitus patients to investigate relationships with tinnitus-related and psychological factors. Cross-sectional data from chronic tinnitus inpatients were analyzed. Data collection included hair sampling, pure tone audiometry, tinnitus pitch and loudness matching, and psychometric questionnaires. Elastic net regressions with n-fold cross-validation were performed for cortisol (N = 91) and BDNF (N = 87). For hair-cortisol (R2 = 0.10), the strongest effects were sampling in autumn and body-mass index (BMI) (positive), followed by tinnitus loudness (positive) and smoking (negative). For hair-BDNF (R2 = 0.28), the strongest effects were hearing aid use, shift work (positive), and tinnitus loudness (negative), followed by smoking, tinnitus-related distress (Tinnitus Questionnaire), number of experienced traumatic events (negative), and physical health-related quality of life (Short Form-12 Health Survey) (positive). These findings suggest that in chronic tinnitus patients, higher perceived tinnitus loudness is associated with higher hair-cortisol and lower hair-BDNF, and higher tinnitus-related distress with lower hair-BDNF. Regarding hair-BDNF, traumatic experiences appear to have additional stress-related effects, whereas hearing aid use and high physical health-related quality of life appear beneficial. Implications include the potential use of hair-cortisol and hair-BDNF as biomarkers of tinnitus loudness or distress and the need for intensive future research into chronic stress-related HPA axis and neuroplasticity alterations in chronic tinnitus.

Abstract Background Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and assessments, or applications of interventions targeting only a single organ level. Combinatory treatment approaches, potentially targeting multiple systems as well as treatment personalization, might provide remedy and enhance treatment responses. The aim of the present study is to systematically examine established tinnitus therapies both alone and in combination in a large sample of tinnitus patients. Further, it wants to provide the basis for personalized treatment approaches by evaluating a specific decision support system developed as part of an EU-funded collaborative project (Unification of treatments and interventions for tinnitus patients; UNITI project). Methods/study design This is a multi-center parallel-arm randomized clinical trial conducted at five different clinical sites over the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counseling, hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated. Assessments and interventions are harmonized over the involved clinical sites. The primary outcome measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory. Discussion Results and conclusions from the current study might not only provide an essential contribution to combinatory and personalized treatment approaches in tinnitus but could also provide more profound insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus. Trial registration ClinicalTrials.gov NCT04663828 . Registered on 11 December 2020.

BackgroundDepression and anxiety are known to be associated with stress-induced changes in the immune system. Bothersome tinnitus can be related to stress and often co-occurs with depression and anxiety. This study investigates associations of psychological and audiological tinnitus-related factors with inflammatory parameters and immune cell subsets in chronic tinnitus patients as well as treatment-related effects.MethodsThis longitudinal study of inpatients treated with compact multimodal tinnitus-specific cognitive behavioral therapy included four repeated measurement sessions: baseline (N = 41), treatment end, 7.8-week (N = 35), and 13.8-week follow-up (N = 34). Data collection included audiometric testing, blood sampling, and psychometric questionnaires: Tinnitus Handicap Inventory (THI), Perceived Stress Questionnaire (PSQ-20), and Hospital Anxiety Depression Scale (HADS). Flow cytometry was used to analyze immune cell subsets. Statistical analyses comprised correlation and network analysis (cross-sectional), and linear mixed effect models (longitudinal).ResultsBootstrapped network analysis showed negative averaged cross-sectional associations of cytotoxic natural killer (NKc) cell frequency (CD56 + CD16+) and PSQ-20 (−0.21 [−0.48, 0]) and of regulatory natural killer (NKreg) cell frequency (CD56 + CD16dim/−) and HADS anxiety (−0.14 [−0.38, 0]). No significant treatment effects were found. A negative predictive effect of baseline PSQ-20 scores (β = −6.22 [−12.18, −0.26], p = 0.041) and a positive predictive effect of baseline ferritin levels (β = 8.90 [2.76, 15.03], p = 0.004) on NKc cell frequency across the repeated measurement sessions were observed.ConclusionWe observed negative relationships between perceived stress levels and NKc cell frequency and between anxiety levels and NKreg cell frequency in chronic tinnitus patients. These exploratory results suggest stress−/anxiety-related immune alterations in bothersome tinnitus but need to be tested in further confirmatory studies with larger sample sizes. The potential of NK cells as biomarkers of emotional distress in chronic tinnitus should be further investigated.

BackgroundChronic tinnitus is a clinically multidimensional phenomenon that entails audiological, psychological and somatosensory components. Previous research has demonstrated age and female gender as potential risk factors, although studies to this regard are heterogeneous. Moreover, whilst recent research has begun to identify clinical “phenotypes,” little is known about differences in patient population profiles at geographically separated and specialized treatment centers. Identifying such differences might prevent potential biases in joint randomized controlled trials (RCTs) and allow for population-specific treatment adaptations.MethodTwo German tinnitus treatment centers were compared regarding pre-treatment data distributions of their patient population bases. To identify overlapping as well as center-specific factors, juxtaposition-, similarity-, and meta-data-based methods were applied.ResultsBetween centers, significant differences emerged. One center demonstrated some predictive power of the patients of the other center with regard to questionnaire score after treatment, indicating similarities in treatment response across center populations. Furthermore, adherence to the completion of the questionnaires was found to be an important factor in predicting post-treatment data.DiscussionDifferential age and gender distributions per center should be considered as regards RCT design and individualized treatment planning.

BackgroundCurrently, there are no objective markers to measure treatment efficacy in chronic (distressing) tinnitus. This study explores whether stress-related biomarkers cortisol and brain-derived neurotrophic factor (BDNF) measured in hair samples of chronic tinnitus patients change after compact multimodal tinnitus-specific cognitive behavioral therapy.MethodsIn this longitudinal study, hair-cortisol and hair-BDNF levels, self-reported tinnitus-related distress (Tinnitus Questionnaire; TQ), and perceived stress (Perceived Stress Questionnaire; PSQ-20) were assessed before and 3 months after 5 days of treatment in N = 80 chronic tinnitus patients. Linear mixed-effects models with backward elimination were used to assess treatment-induced changes, and a cross-lagged panel model (structural equation model) was used for additional exploratory analysis of the temporal associations between TQ and hair-BDNF.ResultsAt follow-up, a reduction in TQ (p < 0.001) and PSQ-20 scores (p = 0.045) was observed, which was not influenced by baseline hair-cortisol or hair-BDNF levels. No changes in biomarker levels were observed after treatment. The exploratory analysis tentatively suggests that a directional effect of baseline TQ scores on hair-BDNF levels at follow-up (trend; p = 0.070) was more likely than the opposite directional effect of baseline hair-BDNF levels on TQ scores at follow-up (n.s.).DiscussionWhile the treatment effectively reduced tinnitus-related distress and perceived stress in chronic tinnitus patients, this effect was not mirrored in biological changes. However, the lack of changes in hair-cortisol and hair-BDNF levels might have been influenced by the treatment duration, follow-up interval, or confounding medical factors, and therefore must be interpreted with caution. The relationship between tinnitus-related distress and hair-BDNF levels should be explored further to obtain a better understanding of stress-related effects in chronic tinnitus.

BackgroundMeasurement of tinnitus-related distress and treatment responsiveness is key in understanding, conceptualizing and addressing this often-disabling symptom. Whilst several self-report measures exist, the heterogeneity of patient populations, available translations, and treatment contexts requires ongoing psychometric replication and validation efforts.ObjectiveTo investigate the convergent validity and responsiveness of the German versions of the Tinnitus Questionnaire [TQ], Tinnitus Handicap Inventory [THI], and Tinnitus Functional Index [TFI] in a large German-speaking sample of patients with chronic tinnitus who completed a psychologically anchored 7-day Intensive Multimodal Treatment Programme.MethodsTwo-hundred-and-ten patients with chronic tinnitus completed all three questionnaires at baseline and post-treatment. Intraclass correlation coefficients determined the convergent validity of each questionnaire’s total and subscale scores. Treatment responsiveness was investigated by [a] comparing treatment-related change in responders vs. non-responders as classified by each questionnaire’s minimal clinically important difference-threshold, and [b] comparing agreement between the questionnaires’ responder classifications.ResultsThe total scores of all three questionnaires showed high agreement before and after therapy (TQ | THI: 0.80 [Pre], 0.83 [Post], TQ | TFI: 0.72 [Pre], 0.78 [Post], THI | TFI: 0.76 [Pre] 0.80 [Post]). All total scores changed significantly with treatment yielding small effect sizes. The TQ and TFI yielded comparable (19.65 and 18.64%) and the THI higher responder rates (38.15%). The TQ | THI and TQ | TFI showed fair, and the THI | TFI moderate agreement of responder classifications. Independent of classification, responders showed significantly higher change rates than non-responders across most scores. Each questionnaire’s total change score distinguished between responders and non-responders as classified by the remaining two questionnaires.ConclusionThe total scores of all three questionnaires show high convergent validity and thus, comparability across clinical and research contexts. By contrast, subscale scores show high inconsistency. Whilst the TFI appears well suited for research purposes, the THI may be better suited to measure psychological aspects of tinnitus-related distress and their changes with accordingly focused treatment approaches.

High comorbidity rates, especially mental–physical comorbidity, constitute an increasing health care burden, with women and men being differentially affected. To gain an overview of comorbidity rates stratified by sex across a range of different conditions, this study examines comorbidity patterns within and between cardiovascular, pulmonary, skin, endocrine, digestive, urogenital, musculoskeletal, neurological diseases, and psychiatric conditions. Self-report data from the LifeGene cohort of 31,825 participants from the general Swedish population (62.5% female, 18–84 years) were analyzed. Pairwise comorbidity rates of 54 self-reported conditions in women and men and adjusted odds ratios (ORs) for their comparison were calculated. Overall, the rate of pairwise disease combinations with significant comorbidity was higher in women than men (14.36% vs. 9.40%). Among psychiatric conditions, this rate was considerably high, with 41.76% in women and 39.01% in men. The highest percentages of elevated mental–physical comorbidity in women were found for musculoskeletal diseases (21.43%), digestive diseases (20.71%), and skin diseases (13.39%); in men, for musculoskeletal diseases (14.29%), neurological diseases (11.22%), and digestive diseases (10%). Implications include the need for integrating mental and physical health care services and a shift from a disease-centered to an individualized, patient-centered focus in clinical care.

BackgroundPsychological factors link the co-occurrence of tinnitus-related distress and pain perceptions in patients with chronic tinnitus.ObjectiveThis study examines, if treatment-related changes in these factors ameliorate both tinnitus-related distress and pain perceptions in a sample of patients with chronic tinnitus.MethodsN = 1238 patients with chronic tinnitus provided pre- and post-treatment ratings of tinnitus-related distress and affective or sensory pain perceptions alongside measures of depressive symptoms and perceived stress. Treatment comprised an intensive tinnitus-specific multimodal treatment program. Using serial indirect-effects analyses, we examined association patterns between baseline values and change rates of those variables that were found to respond to treatment.ResultsSmall effect sizes emerged for changes in tinnitus-related distress, affective (but not sensory) pain perceptions, depressive symptoms, emotional tension and worry. At pre- or post-treatment respectively, baseline values and change rates intercorrelated. Across timepoints, (1) baseline tinnitus-related distress and affective pain perceptions were positively associated with improvements in tinnitus-related distress, affective pain perceptions and depressive symptoms. (2) Baseline depressive symptoms or emotional tension mediated positive associations between baseline tinnitus-related distress and improvement in affective pain perceptions. (3) Change in depressive symptoms mediated the effect of baseline tinnitus-related distress on change in affective pain perceptions-partly through associated change in emotional tension or worry. Mood-independent aspects of emotional tension were negatively associated with improvement in affective pain perceptions.ConclusionsDepressive symptoms, emotional tension and worry emerge as key predictors of treatment response and transdiagnostic treatment targets for alleviating tinnitus-related distress and functionally associated affective pain perceptions.

ObjectiveThis study aims to identify gender-specific risk factors associated with the presence of bothersome tinnitus (compared with non-bothersome tinnitus), including sociodemographic and lifestyle factors, tinnitus-associated phenomena (hearing loss, traumatic experiences, sleep disturbances), and physical as well as mental comorbidities.MethodsWe conducted a cross-sectional study using survey data from the Swedish LifeGene cohort containing information on self-reported tinnitus (N = 7615). We (1) analyzed risk factor and comorbidity frequencies, (2) computed multivariate logistic regression models to identify predictors of bothersome tinnitus within both genders, and (3) moderated logistic regression models to compare effects between genders.Results(1) The majority of factors that differed in frequencies between bothersome and non-bothersome tinnitus were equal for both genders. Women with bothersome tinnitus specifically reported higher rates of cardiovascular disease, thyroid disease, epilepsy, fibromyalgia, and burnout, and men with bothersome tinnitus reported higher rates of alcohol consumption, Ménière’s disease, anxiety syndrome, and panic (compared with non-bothersome tinnitus, respectively). (2) Across both genders, multivariate logistic regression analyses revealed significant associations between bothersome tinnitus and age, reduced hearing ability, hearing-related difficulties in social situations, and reduced sleep quality. In women, bothersome tinnitus was specifically associated with cardiovascular disease and epilepsy; in men, with lower education levels and anxiety syndrome. (3) Moderated logistic regression analyses revealed that the effects of low education and anxiety syndrome were present in men, but not in women, whereas the effects of age, reduced hearing ability and related difficulties, cardiovascular disease, epilepsy, and burnout were not gender specific.ConclusionIrrespective of gender, bothersome tinnitus is associated with higher age, reduced hearing ability, hearing-related difficulties, cardiovascular disease, epilepsy, and burnout. Gender-specific effects comprise low levels of education and the presence of anxiety syndrome for men. These findings need to be interpreted with caution, yet they suggest the presence of gender-specific biopsychosocial influences in the emergence or maintenance of bothersome tinnitus. Future studies ought to investigate the underlying mechanisms of the observed relationships.

Whilst some studies have identified gender-specific differences, there is no consensus about gender-specific determinants for prevalence rates or concomitant symptoms of chronic tinnitus such as depression or anxiety. However, gender-associated differences in psychological response profiles and coping strategies may differentially affect tinnitus chronification and treatment success rates. Thus, understanding gender-associated differences may facilitate a more detailed identification of symptom profiles, heighten treatment response rates, and help to create access for vulnerable populations that are potentially less visible in clinical settings. Our research questions are: RQ1: how do male and female tinnitus patients differ regarding tinnitus-related distress, depression severity, and treatment response, RQ2: to what extent are answers to questionnaires administered at baseline associated with gender, and RQ3: which baseline questionnaire items are associated with tinnitus distress, depression, and treatment response, while relating to one gender only? In this work, we present a data analysis workflow to investigate gender-specific differences in N = 1,628 patients with chronic tinnitus (828 female, 800 male) who completed a 7-day multimodal treatment encompassing cognitive behavioral therapy (CBT), physiotherapy, auditory attention training, and information counseling components. For this purpose, we extracted 181 variables from 7 self-report questionnaires on socio-demographics, tinnitus-related distress, tinnitus frequency, loudness, localization, and quality as well as physical and mental health status. Our workflow comprises (i) training machine learning models, (ii) a comprehensive evaluation including hyperparameter optimization, and (iii) post-learning steps to identify predictive variables. We found that female patients reported higher levels of tinnitus-related distress, depression and response to treatment (RQ1). Female patients indicated higher levels of tension, stress, and psychological coping strategies rates. By contrast, male patients reported higher levels of bodily pain associated with chronic tinnitus whilst judging their overall health as better (RQ2). Variables measuring depression, sleep problems, tinnitus frequency, and loudness were associated with tinnitus-related distress in both genders and indicators of mental health and subjective stress were found to be associated with depression in both genders (RQ3). Our results suggest that gender-associated differences in symptomatology and treatment response profiles suggest clinical and conceptual needs for differential diagnostics, case conceptualization and treatment pathways.

Objectives: (1) To determine which psychosocial aspects predict tinnitus-related distress in a large self-reported dataset of patients with chronic tinnitus, and (2) to identify underlying constructs by means of factor analysis. Methods: A cohort of 1958 patients of the Charité Tinnitus Center, Berlin completed a large questionnaire battery that comprised sociodemographic data, tinnitus-related distress, general psychological stress experience, emotional symptoms, and somatic complaints. To identify a construct of “tinnitus-related distress”, significant predictive items were grouped using factor analysis. Results: For the prediction of tinnitus-related distress (linear regression model with R2 = 0.7), depressive fatigue symptoms (concentration, sleep, rumination, joy decreased), the experience of emotional strain, somatization tendencies (pain experience, doctor contacts), and age appeared to play a role. The factor analysis revealed five factors: “stress”, “pain experience”, “fatigue”, “autonomy”, and low “educational level”. Conclusions: Tinnitus-related distress is predicted by psychological and sociodemographic indices. Relevant factors seem to be depressive exhaustion with somatic expressions such as sleep and concentration problems, somatization, general psychological stress, and reduced activity, in addition to higher age.

Objective It is widely acknowledged that efforts to change professional practice are more successful if barriers are identified and implementation activities are systematically tailored to the specific determinants of practice. The aim of this study was to administer a health service evaluation survey to scope current practice and knowledge of standards in tinnitus care across Europe. The purpose of this survey was to specifically inform the development process of a European clinical guideline that would be implementable in all European countries.Design A health service evaluation survey was carried out.Setting The survey was carried out online across Europe.Participants Clinical experts, researchers and policy-makers involved in national tinnitus healthcare and decision-making.Outcome measures A survey was developed by the study steering group, piloted on clinicians from the TINNET network and underwent two iterations before being finalised. The survey was then administered to clinicians and policy-makers from 24 European countries.Results Data collected from 625 respondents revealed significant differences in national healthcare structures, use of tinnitus definitions, opinions on characteristics of patients with tinnitus, assessment procedures and particularly in available treatment options. Differences between northern and eastern European countries were most notable.Conclusions Most European countries do not have national clinical guidelines for the management of tinnitus. Reflective of this, clinical practices in tinnitus healthcare vary dramatically across countries. This equates to inequities of care for people with tinnitus across Europe and an opportunity to introduce standards in the form of a European clinical guideline. This survey has highlighted important barriers and facilitators to the implementation of such a guideline.

BACKGROUND:Chronic tinnitus is a complex condition that can be associated with considerable distress. Whilst cognitive-behavioral treatment (CBT) approaches have been shown to be effective, not all patients benefit from psychological or psychologically anchored multimodal therapies. Determinants of tinnitus-related distress thus provide valuable information about tinnitus characterization and therapy planning. OBJECTIVE:The study aimed to develop machine learning models that use variables (or "features") obtained before treatment to characterize patients' tinnitus-related distress status after treatment. Whilst initially all available variables were considered for model training, the final model was required to achieve highest predictive performance using only a small number of features. METHODS:1,416 tinnitus patients (decompensated tinnitus: 32%) who completed a 7-day multimodal treatment encompassing tinnitus-specific components, CBT, physiotherapy and informational counseling were included in the analysis. At baseline, patients were assessed using 205 features from 10 questionnaires comprising sociodemographic and clinical information. A data-driven workflow was developed consisting of (a) an initial exploratory correlation analysis, (b) supervised machine learning to predict tinnitus-related distress after treatment (T1) using baseline data only (T0), and (c) post-hoc analysis of the best model to facilitate model inspection and understanding. Classification methods were embedded in a feature elimination wrapper that iteratively learned on features found to be important for the model in the preceding iteration, in order to keep the performance stable while successively reducing the model complexity. 10-fold cross-validation with area under the curve (AUC) as performance measure was implemented for model generalization error estimation. RESULTS:The best machine learning classifier (gradient boosted trees) can predict tinnitus-related distress in T1 with AUC = 0.890 using 26 features. Subjectively perceived tinnitus-related impairment, depressivity, sleep problems, physical health-related impairments in quality of life, time spent to complete questionnaires and educational level exhibited a high attribution towards model prediction. CONCLUSIONS:Machine learning can reliably identify baseline features recorded prior to treatment commencement that characterize tinnitus-related distress after treatment. The identification of key features can contribute to an improved understanding of multifactorial contributors to tinnitus-related distress and thereon based multimodal treatment strategies.

ObjectiveTo investigate the co-occurrence of tinnitus-related distress and pain experiences alongside psychological factors that may underlie their association.MethodPatients with chronic tinnitus (N = 1238) completed a questionnaire battery examining tinnitus-related distress and affective and sensory pain perceptions. A series of simple, parallel- and serial multiple mediator models examined indirect effects of psychological comorbidities as well as -process variables including depressivity, perceived stress and coping attitudes. Moderator and moderated mediation analyses examined differential relational patterns in patients with decompensated vs. compensated tinnitus.ResultsThere were significant associations between tinnitus-related distress and pain perceptions. These were partially mediated by most specified variables. Psychological comorbidities appeared to influence tinnitus-pain associations through their impact on depressivity, perceived stress, and coping attitudes. Some specific differences in affective vs. sensory pain perception pathways emerged. Patients with decompensated tinnitus yielded significantly higher symptom burden across all measured indices. Tinnitus decompensation was associated with heightened associations between [1] tinnitus-related distress and pain perceptions, depressivity and negative coping attitudes; and [2] most psychological comorbidities and sensory, but not affective pain perception. Moderated mediation analyses revealed stronger indirect effects of depressivity and anxiety in mediating affective-, and anxiety in mediating sensory pain perception in patients with decompensated tinnitus.ConclusionPsychological constructs mediate the co-occurrence of tinnitus- and pain-related symptoms across different levels of tinnitus-related distress. Psychological treatment approaches should conceptualize and address individualised interactions of common cognitive-emotional processes in addressing psychosomatic symptom clusters across syndromatic patients with varying distress levels.

BackgroundDespite vulnerability-stress models underlying a variety of distress-related emotional syndromes, few studies have investigated interactions between personality factors and subjectively experienced stressors in accounting for tinnitus-related distress.AimThe present study compared personality characteristics between patients with chronic tinnitus and the general population. Within the patient sample, it was further examined whether personality dimensions predicted tinnitus-related distress and, if so, whether differential aspects or levels of perceived stress mediated these effects.MethodApplying a cross-sectional design, 100 patients with chronic tinnitus completed the Freiburger Persönlichkeitsinventar (FPI-R) measuring personality, the Perceived Stress Questionnaire (PSQ-20) measuring perceived stress and the German version of the Tinnitus Questionnaire (TQ) measuring tinnitus-related distress. FPI-R scores were compared with normed values obtained from a representative German reference population. Mediation analyses were computed specifying FPI-R scores as independent, PSQ20 scores as mediating and the TQ-total score as dependent variables.ResultsPatients with chronic tinnitus significantly differed from the general population across a variety of personality indices. Tinnitus-related distress was mediated by differential interactions between personality factors and perceived stress dimensions.ConclusionIn conceptualizing tinnitus-related distress, idiosyncratic assessments of vulnerability-stress interactions are crucial for devising effective psychological treatment strategies. Patients’ somatic complaints and worries appear to be partly informed by opposing tendencies reflecting emotional excitability vs. aggressive inhibition – suggesting emotion-focused treatment strategies as a promising new direction for alleviating distress.

Good practice in clinical trials advocates common standards for assessing and reporting condition-specific complaints (“outcome domains”). For tinnitus, there is no common standard. The Core Outcome Measures in Tinnitus International Delphi (COMiT’ID) study created recommendations that are relevant to the most common intervention approaches for chronic subjective tinnitus in adults using consensus methods. Here, the objectives were to examine why it is important to tailor outcome domain selection to the tinnitus intervention that is being evaluated in the clinical trial and to demonstrate that the COMiT’ID recommendations are robust. The COMiT’ID study used an online three-round Delphi method with three separate surveys for sound-, psychology-, and pharmacology-based interventions. Survey data were analyzed to assess quality and confidence in the consensus achieved across surveys and stakeholder groups and between survey rounds. Results found participants were highly discriminatory in their decision-making. Of the 34 outcome domains reaching the prespecified consensus definition in the final round, 17 (50%) were unique to one intervention, while only 12 (35%) were common to all three. Robustness was demonstrated by an acceptable level of agreement across and within stakeholder groups, across survey rounds, across medical specialties (for the health-care practitioners), and across health-care users with varying tinnitus duration. There were few dissenting voices, and results showed no attrition bias. In conclusion, there is compelling evidence that one set of outcomes does not fit all therapeutic aims. Our analyses evidence robust decisions by the electronic Delphi process, leading to recommendations for three unique intervention-specific outcome domain sets. This provides an important starting point for standardization.

Many aspects of stress-induced physiological and psychological effects have been characterized in people and animals. However, stress effects on the auditory system are less explored and their mechanisms are not well-understood, in spite of its relevance for a variety of diseases, including tinnitus. To expedite further research of stress-induced changes in the auditory system, here we compare the reactions to stress among Wistar and Lewis rats. The animals were stressed for 24 h, and subsequently we tested the functionality of the outer hair cells (OHCs) using distortion product otoacoustic emissions (DPOAEs) and auditory neurons using evoked auditory brainstem responses (ABR). Lastly, using Western blot, we analyzed the levels of plasticity-related proteins in the inferior colliculus, confirming that the inferior colliculus is involved in the adaptive changes that occur in the auditory system upon stress exposure. Surprisingly, the two strains reacted to stress quite differently: Lewis rats displayed a lowering of their auditory threshold, whereas it was increased in Wistar rats. These functional differences were seen in OHCs of the apical region (low frequencies) and in the auditory neurons (across several frequencies) from day 1 until 2 weeks after the experimental stress ended. Wistar and Lewis rats may thus provide models for auditory threshold increase and decrease, respectively, which can both be observed in different patients in response to stress.

Subjective tinnitus is a chronic heterogeneous condition that is typically managed using intervention approaches based on sound devices, psychologically informed therapies, or pharmaceutical products. For clinical trials, there are currently no common standards for assessing or reporting intervention efficacy. This article reports on the first of two steps to establish a common standard, which identifies what specific tinnitus-related complaints (“outcome domains”) are critical and important to assess in all clinical trials to determine whether an intervention has worked. Using purposive sampling, 719 international health-care users with tinnitus, health-care professionals, clinical researchers, commercial representatives, and funders were recruited. Eligibility was primarily determined by experience of one of the three interventions of interest. Following recommended procedures for gaining consensus, three intervention-specific, three-round, Delphi surveys were delivered online. Each Delphi survey was followed by an in-person consensus meeting. Viewpoints and votes involved all stakeholder groups, with approximately a 1:1 ratio of health-care users to professionals. “Tinnitus intrusiveness” was voted in for all three interventions. For sound-based interventions, the minimum set included “ability to ignore,” “concentration,” “quality of sleep,” and “sense of control.” For psychology-based interventions, the minimum set included “acceptance of tinnitus,” “mood,” “negative thoughts and beliefs,” and “sense of control.” For pharmacology-based interventions, “tinnitus loudness” was the only additional core outcome domain. The second step will next identify how those outcome domains should best be measured. The uptake of these intervention-specific standards in clinical trials will improve research quality, enhance clinical decision-making, and facilitate meta-analysis in systematic reviews.

Noise that is capable of inducing the hearing loss (NIHL) has a strong impact on the inner ear structures and causes early and most obvious pathophysiological changes in the auditory periphery. Several studies indicated that intrinsic apoptotic cell death mechanisms are the key factors inducing cellular degeneration immediately after noise exposure and are maintained for days or even weeks. In addition, studies demonstrated several changes in the central auditory system following noise exposure, consistent with early apoptosis-related pathologies. To clarify the underlying mechanisms, the present study focused on the noise-induced gene and protein expression of the pro-apoptotic protease activating factor-1 (APAF1) and the anti-apoptotic B-cell lymphoma 2 related protein a1a (BCL2A1A) in the cochlear nucleus (CN), inferior colliculus (IC) and auditory cortex (AC) of the murine central auditory pathway. The expression of Bcl2a1a mRNA was upregulated immediately after trauma in all tissues investigated, whereas the protein levels were significantly reduced at least in the auditory brainstem. Conversely, acute noise has decreased the expression of Apaf1 gene along the auditory pathway. The changes in APAF1 protein level were not statistically significant. It is tempting to speculate that the acoustic overstimulation leads to mitochondrial dysfunction and induction of apoptosis by regulation of proapoptotic and antiapoptotic proteins. The inverse expression pattern on the mRNA level of both genes might reflect a protective response to decrease cellular damage. Our results indicate the immediate presence of intrinsic apoptosis following noise trauma. This, in turn, may significantly contribute to the development of central structural deficits. Auditory pathway-specific inhibition of intrinsic apoptosis could be a therapeutic approach for the treatment of acute (noise-induced) hearing loss to prevent irreversible neuronal injury in auditory brain structures and to avoid profound deficits in complex auditory processing.

Cochlear implantation (CI) is increasingly being used in the auditory rehabilitation of deaf patients. Here, we investigated whether the auditory rehabilitation can be influenced by the psychological burden caused by mental conditions. Our sample included 47 patients who underwent implantation. All patients were monitored before and 6 months after CI. Auditory performance was assessed using the Oldenburg Inventory (OI) and Freiburg monosyllable (FB MS) speech discrimination test. The health-related quality of life was measured with Nijmegen Cochlear implantation Questionnaire (NCIQ) whereas tinnitus-related distress was measured with the German version of Tinnitus Questionnaire (TQ). We additionally assessed the general perceived quality of life, the perceived stress, coping abilities, anxiety levels and the depressive symptoms. Finally, a structured interview to detect mental conditions (CIDI) was performed before and after surgery. We found that CI led to an overall improvement in auditory performance as well as the anxiety and depression, quality of life, tinnitus distress and coping strategies. CIDI revealed that 81% of patients in our sample had affective, anxiety, and/or somatoform disorders before or after CI. The affective disorders included dysthymia and depression, while anxiety disorders included agoraphobias and unspecified phobias. We also diagnosed cases of somatoform pain disorders and unrecognizable figure somatoform disorders. We found a positive correlation between the auditory performance and the decrease of anxiety and depression, tinnitus-related distress and perceived stress. There was no association between the presence of a mental condition itself and the outcome of auditory rehabilitation. We conclude that the CI candidates exhibit high rates of psychological disorders, and there is a particularly strong association between somatoform disorders and tinnitus. The presence of mental disorders remained unaffected by CI but the degree of psychological burden decreased significantly post-CI. The implants benefitted patients in a number of psychosocial areas, improving the symptoms of depression and anxiety, tinnitus, and their quality of life and coping strategies. The prevalence of mental disorders in patients who are candidates for CI suggests the need for a comprehensive psychological and psychosomatic management of their treatment.

Subjective tinnitus is the perception of sound in the absence of external or bodily-generated sounds. Chronic tinnitus is a highly prevalent condition affecting over 70 million people in Europe. A wide variety of comorbidities, including hearing loss, psychiatric disorders, neurodegenerative disorders and temporomandibular joint dysfunction, have been suggested to contribute to the onset or progression of tinnitus, however the precise molecular mechanisms of tinnitus are not well understood and the contribution of genetic and epigenetic factors remains unknown. Human genetic studies could enable the identification of novel molecular therapeutic targets, possibly leading to the development of novel pharmaceutical therapeutics. In this article, we briefly discuss the available evidence for a role of genetics in tinnitus and consider potential hurdles in designing genetic studies for tinnitus. Since multiple diseases have tinnitus as a symptom and the supporting genetic evidence is sparse, we propose various strategies to investigate the genetic underpinnings of tinnitus, first by showing evidence of heritability using concordance studies in twins, and second by improving patient selection according to phenotype and/or etiology in order to control potential biases and optimize genetic data output. The increased knowledge resulting from this endeavor could ultimately improve the drug development process and lead to the preventive or curative treatment of tinnitus.

In Europe alone, over 70 million people experience tinnitus; for seven million people, it creates a debilitating condition. Despite its enormous socioeconomic relevance, progress in successfully treating the condition is somewhat limited. The European Union has approved funding to create a pan-European tinnitus research collaboration network (2014–2018). The goal of one working group is to establish an international standard for outcome measurements in clinical trials of tinnitus. Importantly, this would enhance tinnitus research by informing sample-size calculations, enabling meta-analyses, and facilitating the identification of tinnitus subtypes, ultimately leading to improved treatments. The first meeting followed a workshop on “Agreed Standards for Measurement: An International Perspective” with invited talks on clinimetrics and existing international initiatives to define core sets for outcome measurements in hearing loss (International classification of functioning, disability, and health core sets for hearing loss) and eczema (Harmonizing outcome measures for eczema). Both initiatives have taken an approach that clearly distinguishes the specification of what to measure from that of how to measure it. Meeting delegates agreed on taking a step-wise roadmap for which the first output would be a consensus on what outcome domains are essential for all trials. The working group seeks to embrace inclusivity and brings together clinicians, tinnitus researchers, experts on clinical research methodology, statisticians, and representatives of the health industry. People who experience tinnitus are another important participant group. This meeting report is a call to those stakeholders across the globe to actively participate in the initiative.