Recovering Hidden Responder Groups in Individuals Receiving Neurofeedback for Tinnitus.

The widespread understanding that chronic tinnitus is a heterogeneous phenomenon with various neural oscillatory profiles has spurred investigations into individualized approaches in its treatment. Neurofeedback, as a non-invasive tool for altering neural activity, has become increasingly popular in the personalized treatment of a wide range of neuropsychological disorders. Despite the success of neurofeedback on the group level, the variability in the treatment efficacy on the individual level is high, and evidence from recent studies shows that only a small number of people can effectively modulate the desired aspects of neural activity. To reveal who may be more suitable, and hence benefit most from neurofeedback treatment, we classified individuals into unobserved subgroups with similar oscillatory trajectories during the treatment and investigated how subgroup membership was predicted by a series of characteristics. Growth mixture modeling was used to identify distinct latent subgroups with similar oscillatory trajectories among 50 individuals suffering from chronic subjective tinnitus (38 male, 12 female, mean age = 47.1 ± 12.84) across 15 neurofeedback training sessions. Further, the impact of characteristics and how they predicted the affiliation in the identified subgroups was evaluated by including measures of demographics, tinnitus-specific (Tinnitus Handicap Inventory) and depression variables, as well as subjective quality of life subscales (World Health Organization-Quality of Life Questionnaire), and health-related quality of life subscales (Short Form-36) in a logistic regression analysis. A latent class model could be fitted to the longitudinal data with a high probability of correctly classifying distinct oscillatory patterns into 3 different groups: non-responder (80%), responder (16%), and decliner (4%). Further, our results show that the health-related wellbeing subscale of the Short Form-36 questionnaire was differentially associated with the groups. However, due to the small sample size in the Responder group, we are not able to provide sufficient evidence for a distinct responder profile. Nevertheless, the identification of oscillatory change-rate differences across distinct groups of individuals provides the groundwork from which to tease apart the complex and heterogeneous oscillatory processes underlying tinnitus and the attempts to modify these through neurofeedback. While more research is needed, our results and the analytical approach presented may bring clarity to contradictory past findings in the field of tinnitus research, and eventually influence clinical practice.

Corrigendum: Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers.

[This corrects the article DOI: 10.3389/fnagi.2021.647285.].

Application of Latent Growth Curve modeling to predict individual trajectories during neurofeedback treatment for tinnitus.

Tinnitus is a heterogeneous phenomenon indexed by various EEG oscillatory profiles. Applying neurofeedback (NFB) with the aim of changing these oscillatory patterns not only provides help for those who suffer from the phantom percept, but a promising foundation from which to probe influential factors. The reliable attribution of influential factors that potentially predict oscillatory changes during the course of NFB training may lead to the identification of subgroups of individuals that are more or less responsive to NFB training. The present study investigated oscillatory trajectories of delta (3-4Hz) and individual alpha (8.5-12Hz) during 15 NFB training sessions, based on a Latent Growth Curve framework. First, we found the desired enhancement of alpha, while delta was stable throughout the NFB training. Individual differences in tinnitus-specific variables and general-, as well as health-related quality of life predictors were largely unrelated to oscillatory change prior to and across the training. Only the predictors age and sex at baseline were clearly related to slow-wave delta, particularly so for older female individuals who showed higher delta power values from the start. Second, we confirmed a hierarchical cross-frequency association between the two frequency bands; however, in opposing directions to those anticipated in tinnitus. The establishment of individually tailored NFB protocols would boost this therapy's effectiveness in the treatment of tinnitus. In our analysis, we propose a conceptual groundwork toward this goal of developing more targeted treatment.

Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson's Disease: A Randomized, Placebo-Controlled, Phase 1 Study.

BACKGROUND: Immunotherapies targeting α-synuclein aim to limit its extracellular spread in the brain and prevent progression of pathology in Parkinson's disease (PD). PD03A is a specific active immunotherapy (SAIT) involving immunization with a short peptide formulation. OBJECTIVE: This phase 1 study characterized the safety and tolerability of PD03A in patients with early PD. A key secondary objective was to evaluate immunological activity following immunization. METHODS: This was a phase 1 study of two different doses of PD03A versus placebo in PD patients. Patients were randomized (1:1:1) to receive four priming plus one booster vaccination of PD03A 15µg, PD03A 75µg or placebo and were followed for 52 weeks. RESULTS: Overall, 36 patients were randomized, of which 35 received five immunizations and completed the study. All patients experienced at least one adverse event. Transient local injection site reactions affected all but two patients; otherwise most AEs were considered unrelated to study treatment. A substantial IgG antibody response against PD03 was observed with a maximum titer achieved at Week-12. Differences in titers between both active groups versus placebo were statistically significant from the second immunization at Week-8 until Week-52. CONCLUSION: The safety profile and positive antibody response of PD03A supports the further development of active immunotherapeutic approaches for the treatment of PD.

Multidisciplinary Tinnitus Research: Challenges and Future Directions From the Perspective of Early Stage Researchers.

Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: (1) Further establishment of multicenter and multidisciplinary collaborations; (2) Systematic reviews and syntheses of existing knowledge; (3) Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; (4) The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity.

Doctoral Studies as part of an Innovative Training Network (ITN): Early Stage Researcher (ESR) experiences.

Background: The Marie-Sklodowska-Curie Actions' (MSCA) Innovative Training Network (ITN) is a doctoral training programme jointly implemented by academic institutions and industries from countries across Europe and beyond. To our knowledge no study has examined the experience of students participating in MSCA-ITNs. This study aims to evaluate and report MSCA-ITN Early Stage Researcher (ESR) experiences. Methods: The Innovative Training Network - Evaluation Questionnaire (ITN-EQ) was developed to assess supervision, training, collaborations and experiences of ESRs and forwarded to two tinnitus-related ITNs and seven ITNs of other disciplines. Results: Key advantages identified included better career prospects, multidisciplinary research opportunities/collaborations, international exposure, personal/professional development, plus generous salaries and research budgets. However, lack of a common EU framework resulted in the experience being largely dependent on the host institution, country and supervisor. Moreover, managing the dual requirements of ITNs and host institutions while completing a three-year PhD seemed challenging for most ESRs. ESR involvement in workshop and training school planning was desirable. More than 80% of ESRs rated the overall ITN experience favourably and 98.3% would recommend the same to prospective PhD students. Conclusions: This report could provide valuable insights in planning and management of future ITNs and could assist prospective students in their decision of joining an ITN for their PhD.

Smartphone and Mobile Health Apps for Tinnitus: Systematic Identification, Analysis, and Assessment.

BACKGROUND: Modern smartphones contain sophisticated high-end hardware features, offering high computational capabilities at extremely manageable costs and have undoubtedly become an integral part in users' daily life. Additionally, smartphones offer a well-established ecosystem that is easily discoverable and accessible via the marketplaces of differing mobile platforms, thus encouraging the development of many smartphone apps. Such apps are not exclusively used for entertainment purposes but are also commonplace in health care and medical use. A variety of those health and medical apps exist within the context of tinnitus, a phantom sound perception in the absence of any physical external source. OBJECTIVE: In this paper, we shed light on existing smartphone apps addressing tinnitus by providing an up-to-date overview. METHODS: Based on PRISMA guidelines, we systematically searched and identified existing smartphone apps on the most prominent app markets, namely Google Play Store and Apple App Store. In addition, we applied the Mobile App Rating Scale (MARS) to evaluate and assess the apps in terms of their general quality and in-depth user experience. RESULTS: Our systematic search and screening of smartphone apps yielded a total of 34 apps (34 Android apps, 26 iOS apps). The mean MARS scores (out of 5) ranged between 2.65-4.60. The Tinnitus Peace smartphone app had the lowest score (mean 2.65, SD 0.20), and Sanvello-Stress and Anxiety Help had the highest MARS score (mean 4.60, SD 0.10). The interrater agreement was substantial (Fleiss κ=0.74), the internal consistency was excellent (Cronbach α=.95), and the interrater reliability was found to be both high and excellent-Guttman λ6=0.94 and intraclass correlation, ICC(2,k) 0.94 (95% CI 0.91-0.97), respectively. CONCLUSIONS: This work demonstrated that there exists a plethora of smartphone apps for tinnitus. All of the apps received MARS scores higher than 2, suggesting that they all have some technical functional value. However, nearly all identified apps were lacking in terms of scientific evidence, suggesting the need for stringent clinical validation of smartphone apps in future. To the best of our knowledge, this work is the first to systematically identify and evaluate smartphone apps within the context of tinnitus.

Accounting for Heterogeneity: Mixed-Effects Models in Resting-State EEG Data in a Sample of Tinnitus Sufferers.

In neuroscience, neural oscillations and other features of brain activity recorded by electroencephalography (EEG) are typically statistically assessed on the basis of the study's population mean to identify possible blueprints for healthy subjects, or subjects with diagnosable neurological or psychiatric disorders. Despite some inter-individual similarities, there is reason to believe that a discernible portion of the individual brain activity is subject-specific. In order to encompass the potential individual source of variance in EEG data and psychometric parameters, we introduce an innovative application of linear mixed-effects models (LMM) as an alternative procedure for the analysis of resting-state EEG data. Using LMM, individual differences can be modelled through the assumptions of idiosyncrasy of all responses and dependency among data points (e.g., from the same subject within and across units of time) via random effects parameters. This report provides an example of how LMM can be used for the statistical analysis of resting-state EEG data in a heterogeneous group of subjects; namely, people who suffer from tinnitus (ringing in the ear/s). Results from 49 participants (38 male, mean age of 46.69 ± 12.65 years) revealed that EEG signals were not only associated with specific recording sites, but exhibited regional specific oscillations in conjunction to symptom severity. Tinnitus distress targeted the frequency bands beta3 (23.5-35 Hz) and gamma (35.5-45 Hz) in right frontal regions, whereas delta (0.5-4 Hz) exhibited significant changes in temporal-parietal sources. Further, 57.8% of the total variance in EEG power was subject-specific and acknowledged by the LMM framework and its prediction. Thus, a deeper understanding of both the underlying statistical and physiological patterns of EEG data was gained.

Smartphone Apps in the Context of Tinnitus: Systematic Review.

Smartphones containing sophisticated high-end hardware and offering high computational capabilities at extremely manageable costs have become mainstream and an integral part of users' lives. Widespread adoption of smartphone devices has encouraged the development of many smartphone applications, resulting in a well-established ecosystem, which is easily discoverable and accessible via respective marketplaces of differing mobile platforms. These smartphone applications are no longer exclusively limited to entertainment purposes but are increasingly established in the scientific and medical field. In the context of tinnitus, the ringing in the ear, these smartphone apps range from relief, management, self-help, all the way to interfacing external sensors to better understand the phenomenon. In this paper, we aim to bring forth the smartphone applications in and around tinnitus. Based on the PRISMA guidelines, we systematically analyze and investigate the current state of smartphone apps, that are directly applied in the context of tinnitus. In particular, we explore Google Scholar, CiteSeerX, Microsoft Academics, Semantic Scholar for the identification of scientific contributions. Additionally, we search and explore Google's Play and Apple's App Stores to identify relevant smartphone apps and their respective properties. This review work gives (1) an up-to-date overview of existing apps, and (2) lists and discusses scientific literature pertaining to the smartphone apps used within the context of tinnitus.

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.