2018 ATRR: Understanding tinnitus heterogeneity: Echoes from the social buzz Download: ATRR_2018_Understanding_tinnitus_heterogeneity_echoes_from_the_social_buzz_FINAL.pdf Abstract In 2014, the TINnitus NETwork (TINNET) funded by the EU Cooperation in Science and Technology (COST) office emerged with the aim of better understanding the complexity of tinnitus. TINNET was created with the ambition of improving tinnitus patient care, understanding tinnitus heterogeneity by means of neuroimaging and genetics, defining outcome measures, and modelling this thanks to big data collection and analysis . With TINNET entering its final year of EU funding, the results were published in a special research topic on tinnitus, which turned out to become the most viewed research topic in the journal Frontiers  in 2017. We provide here some insights into the understanding of tinnitus and its complexity and discuss the public outreach achieved by this initiative. Introduction Patients often ask us: “Why is it taking so long to find a cure for tinnitus?” The answer is simple: because it is a complex condition! Imagine that you have a large pile of puzzle pieces in front of you. You know that the pieces belong to different jigsaw puzzle pictures, but you are unaware of how many pictures there are. In addition, to increase the challenge, the pictures on the jigsaw puzzles have very similar colours and motifs. This is what tinnitus researchers are confronted with in order to solve the tinnitus riddle. Tinnitus is a very complex disorder. A large number of factors are associated with tinnitus and it often involves the ear, the auditory pathway and additional brain networks   . A large number of people experience it occasionally, others perceive it all the time. It can be defined as acute or chronic and be experienced as a sound of varying perceptual complexities (e.g. buzzing, a tone, beeping, crickets). Similarly, some people can live with it, whilst for others it is an unbearable torture. A number of studies have emerged suggesting there could be a combination of environmental, genetic and lifestyle factors that determine the development and the chronic manifestation of tinnitus. Nowadays, most researchers agree that there is not a single type of tinnitus; rather there are many different types of tinnitus. And depending on the tinnitus type, some treatments may help to reduce tinnitus for a patient, while other treatments don’t. TINNET Action started in April 2014 with the goal to increase the scientific understanding of this tinnitus heterogeneity and to improve our research methods. A standardisation of tinnitus assessment tools was needed in order to allow comparison between the different laboratories in Europe. Such a standardisation was needed to form the basis for developing new and improving existing tinnitus treatments. TINNET Action was funded by the COST organisation and with this funding, tinnitus researchers from 30 participating European countries were able to meet together, organise scientific and clinical meetings, teach young researchers and promote knowledge exchange between the partners within the network. To promote TINNET’s work, we decided to unite a combination of research articles in a single journal series originating from fields that address tinnitus in different ways (e.g. audiology, neurology, psychology, genetics, experimental biology, molecular biology, neuroscience) with the aim of better understanding the complexity of tinnitus. Frontiers offered such an opportunity for a specialist Research Topic, with 14 associated journals and 24 topic editors representing various tinnitus fields. The Research Topic on ‘Towards an Understanding of Tinnitus Heterogeneity’ has now achieved 70 open-access articles (with some more articles currently under revision). The close collaboration of TINNET with patient organisations (such as Tinnitus Hub and the British Tinnitus Association) has helped achieve an unprecedented number of over 2 million views. The overall output reflects the increasing involvement of the scientific community in tinnitus research, and the clear interest of clinicians and patients in better understanding this condition. Major research questions addressed in the Frontiers Research Topic The majority of the articles published addressed aspects of tinnitus treatment (n=25; 35%, Figure 1). The majority of these were related to sound therapy treatments and cochlear implants (20% and 16% respectively). Studies investigating co-occurring conditions were also high in number (14%). Neuronal mechanisms, assessment methods and animal models accounted for nearly 10% each. Three articles addressed the effects of combined therapies, such as Cognitive Behavior Therapy (CBT) coupled with repetitive Transcranial Magnetic Stimulation (rTMS). The remainder concerned a wide range of novel treatment approaches such as Acoustic Coordinated Reset Neuromodulation®, electric stimulation, neurofeedback, physical therapy, rTMS, and vagus nerve stimulation. Two novel topics of interest are genetics (n=5, 7%) and mobile smartphone applications and social media (n=3, 4%). Both of these topics are promising areas of research and attracted a lot of views. Figure 1: Tinnitus research fields published in the Research Topic in Frontiers on tinnitus heterogeneity to February 2018. Proportions of pie chart represent number of articles by fields/topic. Corrigendums are not included. Percentages do not add up to 100% because of rounding. Genetics With there being no licensed drugs for hearing loss and/or tinnitus, human genetics research is a promising way to identify signalling pathways and relevant candidate drugs. This new knowledge will help drug development move from pre-clinical towards Phase I, II and III human trials  . The Research Topic presents the first genome-wide association study (GWAS) that was performed on a small sample of 167 tinnitus subjects and 749 controls (. Although it found no association, a gene set enrichment analysis revealed some pathways (e.g. oxidative stress, endoplasmatic reticulum (ER) stress, and serotonin reception) to be predominantly recruited in people with tinnitus. The opportunities for successful mapping of those novel genes that are involved in tinnitus is likely to happen with research that recruits larger samples of participants and has more refined subtyping . For example, Cederroth has commented that left- and right-sided tinnitus subtypes may present different heritability . Subtyping is a topic that is addressed in more detail in the article in this review series by Genitsaridi and Kypraios. Mobile smartphone applications and social media The publication by Probst and colleagues  opened the door to a new world of doing tinnitus research. In this study, the authors compared patient data of three studies with different data collection methods: using the online Tinnitus Talk patient discussion forum via the smartphone app ‘TrackYourTinnitus’ and clinical data collected at the outpatient clinic at the University Hospital Regensburg, Germany. The authors evaluated differences and similarities between these three methods. One of the most important differences concerned the duration of tinnitus experienced by the participants. In contrast with the more traditional clinical route to data collection, patients who participated in the online forum or used the smartphone application tended to have either tinnitus of short duration (less than six months) or tinnitus of very long duration (over 20 years). This finding indicates that these new technologies are better suited to reach certain types of tinnitus patients who are difficult to recruit in clinic. Furthermore, this study evidences the benefits of scientific cooperation between clinical researchers and patient organisations (a topic which is addressed by Horobin and Frost in more detail in another article in this review series). The article by Probst et al  received the greatest number of views for any Frontiers Research Topic article published in 2017. At the time of writing (September 2018), it had received 76,798 total views. Articles provoking the greatest debate The interactive nature of the Frontiers Research Topic platform allows members to comment on articles in a scientific debate. Two articles published in 2016 provoked scientific debate in 2017. Both of these articles reported on the translation and adaptation of a standardised tinnitus questionnaire into another language, respectively on the Tinnitus Functional Index (TFI) in Swedish  and the Tinnitus Handicap Inventory in Polish . The debate highlighted the challenge of how to conduct the translation itself with the need to consider maintaining the meaning of the questions as well as being sensitive to any necessary cultural adaptations, and it also highlighted issues relating to how the performance of the translated questionnaire is then evaluated statistically. These are all issues which have recently been addressed in good practice guidelines for how to make good translations  – guidelines that were co-produced by TINNET and are endorsed by the International Journal of Audiology. Another interesting point of debate arising from these two translations is that after they were published in the Frontiers Research Topic, duplicate translations were subsequently published independently by other teams: the TFI in Swedish , and the THI in Polish . Clearly close communication within the tinnitus community, and with the original source-language questionnaire developer are important for avoiding wasted time and resources. Clinicians and researchers in Sweden and Poland now have the conundrum of which version to choose. Articles with the greatest Altmetrics scores Other than the views, and the scientific debate, the social media buzz is increasingly used as a means for evaluating the impact of scientific articles. Altmetrics quantifies the dissemination of an article using data about the number of times it is mentioned on certain websites (e.g. Wikipedia, F1000), blogs and posts on social media networks (e.g. Facebook, Twitter, Google+ and LinkedIn). Altmetrics scores are calculated based on the weight that each specific type of mention carries. For instance, news stories in the traditional media are eight times more important than Twitter tweets or Google+ mentions. Facebook posts are four times less important than Twitter tweets. The total score is then used to estimate where to situate the article within all the research outputs scored by Altmetric. We evaluated the impact of the articles published in the Frontiers Research Topic across a wider audience via Altmetrics. Figure 2 shows the top ten articles. The article from Langguth et al  scored 67 and is in the top 5% of the most mentioned research articles captured by Altmetrics. This article presents an analysis on co-morbid headache in tinnitus: patients with tinnitus and headache suffer more from their tinnitus than patients with tinnitus alone. Also among the top ten, we give special mention to the article presenting the tinnitus training curriculum for the European School of Interdisciplinary Tinnitus Research (ESIT), a newly funded Marie Skłodowska-Curie Innovative Training Network . In forthcoming years, we expect this project to produce 15 excellent young scientists with unique multi-disciplinary expertise in tinnitus Figure 2: Top ten articles from the Frontiers Research Topic based on altmetric scores at the time of writing (March 2018) Future perspectives The Frontiers Research Topic on tinnitus has achieved an unprecedented outreach, with more than 2 million views — something no other Research Topic has reached. This has been a wonderful opportunity to appraise the four years of TINNET’s activity and gather contemporary knowledge on how to solve the tinnitus riddle. References  TINNET. Welcome to TINNET: An action for better understanding the heterogeneity of tinnitus to improve and develop new treatments [online]. Available from http://tinnet.tinnitusresearch.net/  Frontiers. Towards an understanding of tinnitus heterogeneity [Research Topic] [online]. Available from: https://www.frontiersin.org/research-topics/4725/towards-an-understanding-of-tinnitus-heterogeneity  Baguley D, McFerran D, and Hall D. Tinnitus. The Lancet 2013: 382: 1600-1607. doi: 10.1016/S0140-6736(13)60142-7  Langguth B, Kreuzer PM, Kleinjung T and De Ridder D. Tinnitus: causes and clinical management. Lancet Neurology. 2013: 12: 920-930. doi: 10.1016/S1474-4422(13)70160-1  Cook D, Brown D, Alexander R, March R, et al. Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nature Reviews Drug Discovery. 2014 13, 419-431. doi: 10.1038/nrd4309  Morgan P, Brown DG, Lennard S, Anderton MJ, et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nature Reviews Drug Discovery. 2018. doi: 10.1038/nrd.2017.244.  Gilles A, Van Camp G, Van de Heyning P and Fransen E. A pilot genome-wide association study identifies potential metabolic pathways involved in Tinnitus. Frontiers in Neuroscience. 2017 11, 71. doi: 10.3389/fnins.2017.00071  Lopez-Escamez JA, Bibas T, Cima RF, Van de Heyning P, et al. Genetics of tinnitus: an emerging area for molecular diagnosis and drug development. Frontiers in Neuroscience. 2016 10, 377. doi: 10.3389/fnins.2016.00377.  Cederroth CR, Kahler AK, Sullivan PF and Lopez-Escamez JA. Genetics of tinnitus: time to biobank phantom sounds. Frontiers in Genetics 2017 8, 110. doi: 10.3389/fgene.2017.00110  Probst T, Pryss RC, Langguth B, Spiliopoulou M, Landgrebe M, et al. Outpatient tinnitus clinic, self-help web platform, or mobile application to recruit tinnitus study samples? Frontiers in Aging Neuroscience. 2017 9, 113. doi: 10.3389/fnagi.2017.00113  Muller K, Edvall NK, Idrizbegovic E, Huhn R, Cima R, et al. Validation of online versions of tinnitus questionnaires translated into Swedish. Frontiers in Aging Neuroscience. 2016 8, 272. doi: 10.3389/fnagi.2016.00272  Wrzosek M, Szymiec E, Klemens W, Kotylo P, Schlee W, et al. Polish translation and validation of the Tinnitus Handicap Inventory and the Tinnitus Functional Index. Frontiers in Psychology. 2016 7, 1871. doi: 10.3389/fpsyg.2016.01871  Hall DA, Zaragoza Domingo S, Hamdache LZ, Manchaiah V, Thammaiah S, Evans C and Wong LLN. A good practice guide for translating and adapting hearing-related questionnaires for different languages and cultures. International Journal of Audiology. 2018 Mar 57(3):161-175. doi:10.1080/14992027.2017.1393565  Hoff M and Kahari K. A Swedish cross-cultural adaptation and validation of the Tinnitus Functional Index. International Journal of Audiology. 2017 56, 277-285. doi: 10.1080/14992027.2016.1265154  Skarzynski PH, Raj-Koziak D, Rajchel JJ, Pilka A, Wlodarczyk AW and Skarzynski H. Adaptation of the Tinnitus Handicap Inventory into Polish and its testing on a clinical population of tinnitus sufferers. International Journal of Audiology 2017 56, 711-715. doi: 10.1080/14992027.2017.1319080  Langguth B, Hund V, Landgrebe M and Schecklmann M. Tinnitus patients with comorbid headaches: the influence of headache type and laterality on tinnitus characteristics. Frontiers in Neurology. 2017 8, 440. doi: 10.3389/fneur.2017.00440  Schlee W, Hall DA, Canlon B, Cima RFF, de Kleine E, et al. Innovations in doctoral training and research on tinnitus: The European School on Interdisciplinary Tinnitus Research (ESIT) Perspective. Frontiers in Aging Neuroscience. 2017 9, 447. doi: 10.3389/fnagi.2017.00447 About the authors Dr Winfried Schlee Department of Psychiatry & Psycho-therapy University Hospital, Regensburg Dr. Schlee studied psychology, statistics and philosophy at the University of Konstanz and the University of Alabama at Birmingham. He investigates factors influencing the conscious perception of tinnitus, among them the influence of age, stress and emotional arousal. Since 2014 he has chaired the European TINNET Action and, since 2017, the European School on Interdisciplinary Tinnitus Research (ESIT). Dr Christopher Cederroth Senior Lecturer Karolinska Institutet Christopher R. Cederroth received his PhD in 2009 from the University of Geneva, Switzerland. His PhD work was awarded the Denber-Pinard Prize from the University of Geneva and led to the creation of a start-up company in the medical food sector, Amazentis S.A. In 2009, he moved to New York as a Swiss National Foundation Advanced Fellow at the Rockefeller University researching tinnitus in mice. In 2012, thanks to the Wenner Gren Stiftelse and the Nicholson Postdoctoral Fellowship initiated by Torsten Wiesel to enhance collaborations between the Rockefeller University and Karolinska Institutet, he joined the laboratory of Prof. Barbara Canlon at the Karolinska Institutet to work on the circadian influence on hearing sensitivity.