Objective diagnostics of tinnitus

Background Tinnitus is the phantom perception of sound reported by around 14% of the population. For over 120 million people worldwide tinnitus is perceived as a major problem. Still, tinnitus is a heterogenous condition with no stratified sub-types or biomarkers for objective assessment. This severely limits the potential for development and evaluation of novel therapies for tinnitus. This thesis aims to I) investigate the relationship between conditions commonly reported by tinnitus patients and II) evaluate the potential of electrophysiology or magnetoencephalography (MEG) to function as an objective biomarker for tinnitus. Methods Studies I-III retrospectively analyzed questionnaire data, in total n = 5 593, collected in the Swedish Tinnitus Outreach Project (STOP) between November 2015 and January 2018. Multivariate logistic regression models were implemented to investigate the association between tinnitus and related conditions - temporomandibular joint (TMJ) pains, hyperacusis and headaches. Study IV used longitudinal data from The Swedish Longitudinal Occupational Survey of Health (SLOSH), in total 20 439 participants, with 53 273 observations. The transition from occasional to constant tinnitus was investigated using Generalized Estimating Equation (GEE) models. The second part of Study IV used ABR data from STOP (n = 405) to evaluate measurements of wave I, III & V amplitude and latency in distinguishing constant from occasional tinnitus, or non-tinnitus controls. Study V recruited n = 22 normal hearing, non-tinnitus participants for optimization of a GPIAS (Gap Pre-pulse Inhibition of Acoustic Startle) protocol for MEG. In this exploratory study sound pulses of 20 ms were presented in 60 or 70 dBA carrier noise with a 50 ms silent gap preceding the pulse by 240, 120, 60 or 0 ms. All MEG were recorded by the Elekta Neuromag TRIUX 306-channel system at NatMEG, Karolinska Institutet. Results TMJ complaints increased to over 30% among those with severe tinnitus, compared to 19% in all participants with tinnitus. For headache, adjusted odds ratios (95% confidence interval) showed an association of OR: 3.8 (2.4-5.9) and a strong association with hyperacusis of OR: 12.1 (7.1-20.6) was found for those with severe tinnitus. Longitudinal analysis indicated that tinnitus progresses towards constant tinnitus and that once established is very unlikely to remit. Changes in the ABR response, particularly wave V latency, distinguished constant from occasional tinnitus and non-tinnitus controls, likely reflecting plastic changes related to this chronification. A GPIAS stimulation protocol with an inter-stimulus interval of 240 ms between silent gap and 90 dBA pulse produced N1-inhibition of ERF responses with much lower variability when compared to traditional EOG responses. Conclusion We identified TMJ complaints and hyperacusis as important factors to consider in future studies of tinnitus. ABR wave V latency can distinguish constant tinnitus from occasional or non-tinnitus at a group level, but is likely not sensitive enough for individual diagnostics. Instead, GPIAS together with MEG is a promising approach to developing a biomarker for tinnitus

Alterations in auditory brain stem response distinguish occasional and constant tinnitus

BACKGROUND. The heterogeneity of tinnitus is thought to underlie the lack of objective diagnostic measures. METHODS. Longitudinal data from 20,349 participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) cohort from 2008 to 2018 were used to understand the dynamics of transition between occasional and constant tinnitus. The second part of the study included electrophysiological data from 405 participants of the Swedish Tinnitus Outreach Project (STOP) cohort. RESULTS. We determined that with increasing frequency of the occasional perception of self-reported tinnitus, the odds of reporting constant tinnitus after 2 years increases from 5.62 (95% CI, 4.83–6.55) for previous tinnitus (sometimes) to 29.74 (4.82–6.55) for previous tinnitus (often). When previous tinnitus was reported to be constant, the odds of reporting it as constant after 2 years rose to 603.02 (524.74–692.98), suggesting that once transitioned to constant tinnitus, the likelihood of tinnitus to persist was much greater. Auditory brain stem responses (ABRs) from subjects reporting nontinnitus (controls), occasional tinnitus, and constant tinnitus show that wave V latency increased in constant tinnitus when compared with occasional tinnitus or nontinnitus. The ABR from occasional tinnitus was indistinguishable from that of the nontinnitus controls. CONCLUSIONS. Our results support the hypothesis that the transition from occasional to constant tinnitus is accompanied by neuronal changes in the midbrain leading to a persisting tinnitus, which is then less likely to remit.publishedVersio

Relationship between headaches and tinnitus in a Swedish study

The heterogeneity of tinnitus is likely accounting for the lack of effective treatment approaches. Headaches have been related to tinnitus, yet little is known on how headaches impact tinnitus. We use cross-sectional data from the Swedish Tinnitus Outreach Project to i) evaluate the association between headaches and tinnitus (n = 1,984 cases and 1,661 controls) and ii) investigate the phenotypic characteristics of tinnitus subjects with tinnitus (n = 660) or without (n = 1,879) headaches. In a multivariable logistic regression model, headache was significantly associated with any tinnitus (odds ratio, OR = 2.61) and more so with tinnitus as a big problem (as measured by the tinnitus functional index, TFI ≥ 48; OR = 5.63) or severe tinnitus (using the tinnitus handicap inventory, THI ≥ 58; OR = 4.99). When focusing on subjects with tinnitus, the prevalence of headaches was 26% and reached 40% in subjects with severe tinnitus. A large number of socioeconomic, phenotypic and psychological characteristics differed between headache and non-headache subjects with any tinnitus. With increasing tinnitus severity, fewer differences were found, the major ones being vertigo, neck pain and other pain syndromes, as well as stress and anxiety. Our study suggests that headaches could contribute to tinnitus distress and potentially its severity.publishedVersio

Association between Hyperacusis and Tinnitus

The following are available online at http://www.mdpi.com/2077-0383/9/8/2412/ s1We gratefully acknowledge the support and generosity of Nancy Pedersen, head of LifeGene.Many individuals with tinnitus report experiencing hyperacusis (enhanced sensitivity to sounds). However, estimates of the association between hyperacusis and tinnitus is lacking. Here, we investigate this relationship in a Swedish study. A total of 3645 participants (1984 with tinnitus and 1661 without tinnitus) were enrolled via LifeGene, a study from the general Swedish population, aged 18–90 years, and provided information on socio-demographic characteristics, as well as presence of hyperacusis and its severity. Tinnitus presence and severity were self-reported or assessed using the Tinnitus Handicap Inventory (THI). Phenotypes of tinnitus with (n = 1388) or without (n = 1044) hyperacusis were also compared. Of 1661 participants without tinnitus, 1098 (66.1%) were women and 563 were men (33.9%), and the mean (SD) age was 45.1 (12.9). Of 1984 participants with tinnitus, 1034 (52.1%) were women and 950 (47.9%) were men, and the mean (SD) age was 47.7 (14.0) years. Hyperacusis was associated with any tinnitus [Odds ratio (OR) 3.51, 95% confidence interval (CI) 2.99–4.13], self-reported severe tinnitus (OR 7.43, 95% CI 5.06–10.9), and THI ≥ 58 (OR 12.1, 95% CI 7.06–20.6). The association with THI ≥ 58 was greater with increasing severity of hyperacusis, the ORs being 8.15 (95% CI 4.68–14.2) for moderate and 77.4 (95% CI 35.0–171.3) for severe hyperacusis. No difference between sexes was observed in the association between hyperacusis and tinnitus. The occurrence of hyperacusis in severe tinnitus is as high as 80%, showing a very tight relationship. Discriminating the pathophysiological mechanisms between the two conditions in cases of severe tinnitus will be challenging, and optimized study designs are necessary to better understand the mechanisms behind the strong relationship between hyperacusis and tinnitus.GENDER-NET Co-Plus Fund GNP-182Decibel Therapeutics, Inc.Svenska Lakaresallskapet SLS-779681Tysta SkolanHorselforskningsfonden 503European Union (EU) 72204655 848261NIHR Nottingham Biomedical Research CentreSwedish Medical Research Council (SMRC) K2014-99X-22478-01-3Karolinska InstitutetNational Institute for Health Research (NIHR

The spatial percept of tinnitus is associated with hearing asymmetry: subgroup comparisons

The spatial percept of tinnitus is hypothesized as an important variable for tinnitus subtyping. Hearing asymmetry often associates with tinnitus laterality, but not always. One of the methodological limitations for cross-study comparisons is how the variables for hearing asymmetry and tinnitus spatial perception are defined. In this study, data from two independent datasets were combined (n= 833 adults, age ranging from 20 to 91 years, 404 males, 429 females) to investigate characteristics of subgroups with different tinnitus spatial perception focusing on hearing asymmetry. Three principle findings emerged. First, a hearing asymmetry variable emphasizing the maximum interaural difference most strongly discriminated unilateral from bilateral tinnitus. Merging lateralized bilateral tinnitus (perceived in both ears but worse in one side) with unilateral tinnitus weakened this relationship. Second, there was an association between unilateral tinnitus and ipsilateral asymmetric hearing. Third, unilateral and bilateral tinnitus were phenotypically distinct, with unilateral tinnitus being characterized by older age, asymmetric hearing, more often wearing one hearing aid, older age at tinnitus onset, shorter tinnitus duration, and higher percentage of time being annoyed by tinnitus. We recommend that careful consideration is given to the definitions of hearing asymmetry and tinnitus spatial perception in order to improve the comparability of findings across studies

Validation of Online Versions of Tinnitus Questionnaires Translated into Swedish

BackgroundDue to the lack of objective measures for assessing tinnitus, its clinical evaluation largely relies on the use of questionnaires and psychoacoustic tests. A global assessment of tinnitus burden would largely benefit from holistic approaches that not only incorporate measures of tinnitus but also take into account associated fears, emotional aspects (stress, anxiety, and depression), and quality of life. In Sweden, only a few instruments are available for assessing tinnitus, and the existing tools lack validation. Therefore, we translated a set of questionnaires into Swedish and evaluated their reliability and validity in a group of tinnitus subjects. MethodsWe translated the English versions of the Tinnitus Functional Index (TFI), the Fear of Tinnitus Questionnaire (FTQ), the Tinnitus Catastrophizing Scale (TCS), the Perceived Stress Questionnaire (PSQ-30), and the Tinnitus Sample Case History Questionnaire (TSCHQ) into Swedish. These translations were delivered via the internet with the already existing Swedish versions of the Tinnitus Handicap Inventory (THI), the Hospital Anxiety and Depression Scale (HADS), the Hyperacusis Questionnaire (HQ), and the World Health Organization Quality of Life questionnaire (WHOQoL-BREF). Psychometric properties were evaluated by means of internal consistency (Cronbach’s alpha α) and test-retest reliability across a 9-week interval (Intraclass Correlation Coefficient ICC, Cohen’s kappa) in order to establish construct as well as clinical validity using a sample of 260 subjects from a population-based cohort.ResultsInternal consistency was acceptable for all questionnaires (α >0.7) with the exception of the ‘social relationships’ subscale of the WHOQoL-BREF. Test-retest reliability was generally acceptable (ICC >.70, Cohens Kappa >.60) for the tinnitus-related questionnaires, except for the TFI ‘sense of control’ subscale and 15 items of the TSCHQ. Spearmen rank correlations showed that almost all questionnaires on tinnitus are significantly related, indicating that these questionnaires measure different aspects of the same construct. The data supported good clinical validity of the tinnitus-related questionnaires. ConclusionOur results suggest that most Swedish adaptations of the questionnaires are suitable for clinical and research settings and should facilitate the assessment of treatment outcomes using a more holistic approach by including measures of tinnitus fears, emotional burden, and quality of life

Standardised profiling for tinnitus research: The European School for Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ)

Background: The heterogeneity of tinnitus is substantial. Its numerous pathophysiological mechanisms and clinical manifestations have hampered fundamental and treatment research significantly. A decade ago, the Tinnitus Research Initiative introduced the Tinnitus Sample Case History Questionnaire, a case history instrument for standardised collection of information about the characteristics of the tinnitus patient. Since then, a number of studies have been published which characterise individuals and groups using data collected with this questionnaire. However, its use has been restricted to a clinical setting and to the evaluation of people with tinnitus only. In addition, it is limited in the ability to capture relevant comorbidities and evaluate their temporal relationship with tinnitus. Method: Here we present a new case history instrument which is comprehensive in scope and can be answered by people with and without tinnitus alike. This ‘European School for Interdisciplinary Tinnitus Research Screening Questionnaire’ (ESIT-SQ) was developed with specific attention to questions about potential risk factors for tinnitus (including demographics, lifestyle, general medical and otological histories), and tinnitus characteristics (including perceptual characteristics, modulating factors, and associations with co-existing conditions). It was first developed in English, then translated into Dutch, German, Italian, Polish, Spanish, and Swedish, thus having broad applicability and supporting international collaboration. Conclusions: With respect to better understanding tinnitus profiles, we anticipate the ESIT-SQ to be a starting point for comprehensive multi-variate analyses of tinnitus. Data collected with the ESIT-SQ can allow establishment of patterns that distinguish tinnitus from non-tinnitus, and definition of common sets of tinnitus characteristics which might be indicated by the presence of otological or comorbid systemic diseases for which tinnitus is a known symptom

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Registered on 12 March 2015 revised on 15 March 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users

The genetic vulnerability to cisplatin ototoxicity: a systematic review

Abstract Ototoxicity is one of the major side-effects of platinum-based chemotherapy, in particular cisplatin (cis-diammine dichloroplatinum II). To our knowledge, no systematic review has previously provided a quantitative summary estimate of the impact of genetics upon the risk of developing hearing loss. We searched Embase, Medline, ASSIA, Pubmed, Scopus, and Web of Science, for studies documenting the genetic risk of ototoxicity in patients with cancer treated with cisplatin. Titles/abstracts and full texts were reviewed for inclusion. Meta-analytic estimates of risk (Odds Ratio) from the pooled data were calculated for studies that have been repeated twice or more. The search identified 3891 papers, of which 30 were included. The majority were retrospective (44%), ranging from n = 39 to n = 317, some including only patients younger than 25 years of age (33%), and some on both genders (80%). The most common cancers involved were osteosarcoma (53%), neuroblastoma (37%), prostate (17%) and reproductive (10%). Most studies performed genotyping, though only 5 studies performed genome-wide association studies. Nineteen single-nucleotide polymorphisms (SNPs) from 15 genes were repeated more than twice. Meta-analysis of group data indicated that rs1872328 on ACYP2, which plays a role in calcium homeostasis, increases the risk of ototoxicity by 4.61 (95% CI: 3.04–7.02; N = 696, p < 0.0001) as well as LRP2 rs4668123 shows a cumulated Odds Ratio of 3.53 (95% CI: 1.48–8.45; N = 118, p = 0.0059), which could not be evidenced in individual studies. Despite the evidence of heterogeneity across studies, these meta-analytic results from 30 studies are consistent with a view of a genetic predisposition to platinum-based chemotherapy mediated ototoxicity. These new findings are informative and encourage the genetic screening of cancer patients in order to identify patients with greater vulnerability of developing hearing loss, a condition having a potentially large impact on quality of life. More studies are needed, with larger sample size, in order to identify additional markers of ototoxic risk associated with platinum-based chemotherapy and investigate polygenic risks, where multiple markers may exacerbate the side-effects

Visualization of Global Disease Burden for the Optimization of Patient Management and Treatment

BackgroundThe assessment and treatment of complex disorders is challenged by the multiple domains and instruments used to evaluate clinical outcome. With the large number of assessment tools typically used in complex disorders comes the challenge of obtaining an integrative view of disease status to further evaluate treatment outcome both at the individual level and at the group level. Radar plots appear as an attractive visual tool to display multivariate data on a two-dimensional graphical illustration. Here, we describe the use of radar plots for the visualization of disease characteristics applied in the context of tinnitus, a complex and heterogeneous condition, the treatment of which has shown mixed success.MethodsData from two different cohorts, the Swedish Tinnitus Outreach Project (STOP) and the Tinnitus Research Initiative (TRI) database, were used. STOP is a population-based cohort where cross-sectional data from 1,223 non-tinnitus and 933 tinnitus subjects were analyzed. By contrast, the TRI contained data from 571 patients who underwent various treatments and whose Clinical Global Impression (CGI) score was accessible to infer treatment outcome. In the latter, 34,560 permutations were tested to evaluate whether a particular ordering of the instruments could reflect better the treatment outcome measured with the CGI.ResultsRadar plots confirmed that tinnitus subtypes such as occasional and chronic tinnitus from the STOP cohort could be strikingly different, and helped appreciate a gender bias in tinnitus severity. Radar plots with greater surface areas were consistent with greater burden, and enabled a rapid appreciation of the global distress associated with tinnitus in patients categorized according to tinnitus severity. Permutations in the arrangement of instruments allowed to identify a configuration with minimal variance and maximized surface difference between CGI groups from the TRI database, thus affording a means of optimally evaluating the outcomes in individual patients.ConclusionWe anticipate such a tool to become a starting point for more sophisticated measures in clinical outcomes, applicable not only in the context of tinnitus but also in other complex diseases where the integration of multiple variables is needed for a comprehensive evaluation of treatment response