Article

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

Abstract

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.
REVIEW
published: 11 June 2021
doi: 10.3389/fnagi.2021.647285
Frontiers in Aging Neuroscience | www.frontiersin.org 1June 2021 | Volume 13 | Article 647285
Edited by:
Daniel Ortuño-Sahagún,
University of Guadalajara, Mexico
Reviewed by:
Haúla Faruk Haider,
CUF Infante Santo Hospital, Portugal
Don J. McFerran,
Colchester Hospital University NHS
Foundation Trust, United Kingdom
*Correspondence:
Eleni Genitsaridi
eleni.genitsaridi@nottingham.ac.uk
Jorge Piano Simoes
jorge.simoes@ukr.de
Maryam Shabbir
maryam.shabbir@nottingham.ac.uk
Elza Daoud
elzadaoud@gmail.com
These authors have contributed
equally to this work and share first and
senior authorship
Received: 29 December 2020
Accepted: 19 March 2021
Published: 11 June 2021
Citation:
Simoes JP, Daoud E, Shabbir M,
Amanat S, Assouly K, Biswas R,
Casolani C, Dode A, Enzler F,
Jacquemin L, Joergensen M, Kok T,
Liyanage N, Lourenco M, Makani P,
Mehdi M, Ramadhani AL, Riha C,
Santacruz JL, Schiller A,
Schoisswohl S, Trpchevska N and
Genitsaridi E (2021) Multidisciplinary
Tinnitus Research: Challenges and
Future Directions From the
Perspective of Early Stage
Researchers.
Front. Aging Neurosci. 13:647285.
doi: 10.3389/fnagi.2021.647285
Multidisciplinary Tinnitus Research:
Challenges and Future Directions
From the Perspective of Early Stage
Researchers
Jorge Piano Simoes 1
*, Elza Daoud 2
*, Maryam Shabbir 3
*, Sana Amanat 4,
Kelly Assouly 5,6,7 , Roshni Biswas 3,8 , Chiara Casolani 9,10,11 , Albi Dode 12, Falco Enzler 2,
Laure Jacquemin 13,14 , Mie Joergensen 9,15, Tori Kok 16, Nuwan Liyanage 17,18 ,
Matheus Lourenco 19,20 , Punitkumar Makani 21,22, Muntazir Mehdi 23 ,
Anissa L. Ramadhani 24,25 , Constanze Riha 26, Jose Lopez Santacruz 21,22 , Axel Schiller 1,
Stefan Schoisswohl 1, Natalia Trpchevska 27 and Eleni Genitsaridi 3,28
*
1Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany, 2Centre National de la
Recherche Scientifique, Aix-Marseille University, Marseille, France, 3Hearing Sciences, Mental Health and Clinical
Neurosciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom, 4Otology & Neurotology Group
CTS 495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research Pfizer/University of
Granada/Junta de Andalucía, PTS, Granada, Spain, 5Department of Otorhinolaryngology and Head & Neck Surgery,
University Medical Center Utrecht, Utrecht, Netherlands, 6Department of Clinical and Experimental Neuroscience, University
Medical Center Utrecht Brain Center, Utrecht University, Utrecht, Netherlands, 7Cochlear Technology Centre, Mechelen,
Belgium, 8Laboratory of Lifestyle Epidemiology, Department of Environmental Health Sciences, Istituto di Ricerche
Farmacologiche Mario Negri IRCCS, Milan, Italy, 9Hearing Systems, Department of Health Technology, Technical University of
Denmark, Lyngby, Denmark, 10 Oticon A/S, Smoerum, Denmark, 11 Interacoustics Research Unit, Lyngby, Denmark, 12 Institute
of Databases and Information Systems, Ulm University, Ulm, Germany, 13 Department of Otorhinolaryngology Head and Neck
Surgery, Antwerp University Hospital, Edegem, Belgium, 14 Department of Translational Neurosciences, Faculty of Medicine
and Health Sciences, Antwerp University, Wilrijk, Belgium, 15 WS Audiology, Lynge, Denmark, 16 Ear Institute, University
College London, London, United Kingdom, 17 University of Zurich, Zurich, Switzerland, 18 Department of Otorhinolaryngology,
Head and Neck Surgery, University Hospital Zurich, Zurich, Switzerland, 19 Experimental Health Psychology, Faculty of
Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands, 20 Health Psychology Research Group, Faculty
of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium, 21 Department of Otorhinolaryngology, Head
and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, 22 Graduate
School of Medical Sciences (Research School of Behavioral and Cognitive Neurosciences), University of Groningen,
Groningen, Netherlands, 23 Institute of Distributed Systems, Ulm University, Ulm, Germany, 24 Radiological Sciences, Mental
Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom, 25 Sir Peter
Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom, 26 Chair of
Neuropsychology, Department of Psychology, University of Zurich, Zurich, Switzerland, 27 Department of Physiology and
Pharmacology, Experimental Audiology Laboratory, Karolinska Institutet, Stockholm, Sweden, 28 Nottingham Biomedical
Research Centre, National Institute for Health Research, Nottingham, United Kingdom
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)
Simoes et al. Challenges and Future Directions in Tinnitus Research
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.
Keywords: tinnitus, review, heterogeneity, standardization, interdisciplinary collaborations, big data, treatment
development
1. INTRODUCTION
Tinnitus, the perception of sound in the absence of an external
acoustic stimulus, is a common condition with prevalence often
estimated between 10 and 15% in the adult population (Baguley
et al., 2013). The burden of tinnitus on society is not only reflected
in its impact on an individual’s Quality of Life (QoL), but also on
that of their significant other (Kennedy et al., 2004; Zeman et al.,
2014; Weidt et al., 2016; Hall et al., 2018a). Tinnitus management
requires a multidisciplinary approach due to the heterogeneity of
tinnitus and the absence of a cure (Cima et al., 2020). The average
cost of tinnitus treatment per patient per year is approximately
USD 660 in the United States (USA) (Goldstein et al., 2015), GBP
717 in the United Kingdom (UK) (Stockdale et al., 2017), and
EUR 1,544 in the Netherlands (Maes et al., 2013).
The tinnitus research field has benefited from
multidisciplinary consortia such as the Tinnitus Research
Initiative (TRI) (Langguth et al., 2006), the TINnitus
research NETwork (TINNET, 2014), the European School
on Interdisciplinary Tinnitus Research (ESIT) (Schlee et al.,
2018), the Tinnitus Genetic and Environmental Risks (TIGER,
2019), the TINnitus - Assessment, Causes and Treatments
(TIN-ACT, 2017), and the Unification of Treatments and
Interventions for Tinnitus Patients (Schlee et al., 2021). Despite
all the efforts by these welcomed initiatives, tinnitus still
remains an under-researched field. Although the annual
number of scientific publications on other conditions
such as depression, anxiety, and deafness has increased
drastically in the last years, this has not been the case for
tinnitus (McFerran et al., 2019).
Many long-established research questions still remain
unanswered, including the underlying pathophysiology, and
whether there can be a cure (McFerran et al., 2019). However,
there are many challenges when investigating these questions,
such as the lack of standardization in tinnitus research, the lack
of objective measures in the assessment of tinnitus, and the
under-characterized heterogeneous nature of tinnitus (Langguth
et al., 2011a; Jackson et al., 2019). In this review, the various
challenges hindering progress in tinnitus research are discussed,
and suggestions for future research priorities are provided with
a focus on interdisciplinary approaches. These suggestions were
based on the experiences and expertise of young researchers
affiliated with two of the biggest training school consortia
for tinnitus, ESIT and TIN-ACT. No formal search for the
identification of relevant references was conducted, but literature
databases were searched in a non-systematic way. This article
is divided into dedicated sections for the main categories of
tinnitus research, each providing an overview of the current
knowledge, a summary of the most significant challenges, and
suggestions for essential next steps.
2. TINNITUS HETEROGENEITY
2.1. Overview
Tinnitus is characterized by heterogeneous manifestations and
underlying mechanisms (Cederroth et al., 2019a). Great effort
has been made to understand this heterogeneity and identify
more homogeneous subgroups of the investigated underlying
conditions, or the dimensions across which to characterize
individual cases. Measuring heterogeneity, however, is a big
challenge (Nunes et al., 2020), and identifying subtypes is an open
question for numerous conditions including mental disorders,
diabetes, and asthma (Ahlqvist et al., 2018; Brückl et al., 2020;
Schoettler and Strek, 2020). In the case of tinnitus, efforts to
understand heterogeneity are still ongoing (Cederroth et al.,
2019a). In the following sections, commonly investigated aspects
of tinnitus heterogeneity are discussed, and important challenges
and future directions are highlighted.
One aspect of tinnitus heterogeneity is with regards to its
pathophysiology. It is well-known that the two main types of
tinnitus, subjective and objective, are generated by different
underlying mechanisms (Zenner, 1998; Lockwood et al., 2002).
Subjective tinnitus refers to a phantom perception, whereas
objective tinnitus refers to perceived sounds generated from an
acoustic source located within the body. Pathologies causing
objective tinnitus are rather heterogeneous and research to
understand and treat this form of tinnitus is ongoing (Liu et al.,
2019; Choi et al., 2020). It is, however, far less common than
subjective tinnitus and its underlying mechanisms are usually
clearer (Tunkel et al., 2014). Therefore, the majority of tinnitus
research focuses on subjective tinnitus, which is also the focus of
this article (henceforth referred to as tinnitus).
Current evidence suggests that the pathophysiology of
(subjective) tinnitus is also multifactorial (Vanneste and
De Ridder, 2016; Schmidt et al., 2017). Such heterogeneity
may be a major contributing factor for the limited progress
in understanding the neural correlate of tinnitus and the
inexistence of effective treatments (Landgrebe et al., 2010;
Cederroth et al., 2019a; Kleinjung and Langguth, 2020).
Although various underlying pathologies (e.g., different
pathologies affecting hearing such as in presbycusis) can be
associated with tinnitus (Baguley et al., 2013), whether or not
a common pathophysiological pathway for tinnitus emergence
exists remains unanswered.
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Simoes et al. Challenges and Future Directions in Tinnitus Research
Due to the lack of an objective measure and the limited
understanding of the mechanisms, research on tinnitus
heterogeneity and tinnitus subtypes most often focuses on
phenotypic heterogeneity of people with tinnitus; that is
measurable traits that vary across individuals with tinnitus.
These traits can include both general individual characteristics
(not specific to people with tinnitus) such as demographics (e.g.,
gender) and co-existing conditions (e.g., hearing problems), and
tinnitus-specific characteristics such as related to the tinnitus
perception or its impact on the affected individual (Langguth
et al., 2007; van den Berge et al., 2017; Genitsaridi et al., 2020;
Van der Wal et al., 2020).
2.2. Multiple Aspects of Phenotypic
Heterogeneity
2.2.1. Tinnitus-Specific Characteristics
Tinnitus severity, or more broadly, the impact of tinnitus, is
arguably the most significant dimension of phenotypic tinnitus
heterogeneity. From a clinical perspective, not all cases require an
intervention as habituation to the perceived sound can allow an
individual to live an unaffected life (Husain, 2016). Heterogeneity
of tinnitus severity can be assessed not only by the degree of
severity, but also by the domains of life that are affected by
tinnitus (Hall et al., 2018a). Many studies have investigated
associations between tinnitus severity and a number of other
phenotypic characteristics such as presence of comorbidities and
personality traits (Hoekstra et al., 2014; Van der Wal et al., 2020),
but it remains unclear why some people are distressed by tinnitus
while others are not.
Temporal characteristics of tinnitus, particularly tinnitus
duration, also contribute to its phenotypic heterogeneity. Most
commonly, research in the field focuses on chronic cases, partly
because of how difficult it is to recruit individuals with acute
tinnitus. Chronic tinnitus can be defined as tinnitus lasting for
at least six months (Tunkel et al., 2014), however, there is no
universal consensus on the definition (Ogawa et al., 2020).
2.2.2. General Individual Characteristics
In addition, tinnitus heterogeneity can be viewed in terms of
coexisting conditions, such as hearing loss and depression,
creating a complex, multifaceted clinical picture (Baguley
et al., 2013). Cianfrone et al. (2015) proposed a classification
system based on the presence or lack of auditory alterations,
somatosensory-auditory interactions, and psychopathological
disorders, thus highlighting the significance of these
comorbidities. The following sections discuss these common
tinnitus comorbidities.
Tinnitus is often associated with deficits in auditory function.
The majority of tinnitus cases are associated with some degree
of hearing loss (67.7% according to Nondahl et al., 2002).
However, the mechanisms behind how tinnitus and hearing loss
are related still remain unclear. Evidence suggests that subtypes
of tinnitus might be associated with distinct profiles of hearing
loss, but this should be established in future studies (Vanneste
and De Ridder, 2016; Langguth et al., 2017). Importantly, the
definition of hearing loss itself is rather ambiguous. The presence
or absence of hearing loss is usually clinically determined through
pure tone audiometry (PTA) at octave frequencies between
125 and 8,000 Hz. Nevertheless, it is possible that the hearing
loss exists at extended high frequencies or between two tested
frequencies (Vielsmeier et al., 2015; Lefeuvre et al., 2019; Xiong
et al., 2019), despite normal hearing in the range 125–8,000 Hz.
Additionally, since audiometry only assesses sensitivity, it does
not capture deficits in supra thresholds processing. In the case
of cochlear synaptopathy, the hypothesis is that, even though
the hearing thresholds appear normal, a loss of cochlear nerve
synapses causes hearing deficits, and possibly tinnitus (Schaette
and McAlpine, 2011). Such cases of auditory deficits not captured
by standard audiological assessment are often referred to as
“hidden hearing loss” (Kohrman et al., 2020).
Another hearing-related condition commonly co-existing
with tinnitus is hyperacusis. Hyperacusis can be defined as
an increased auditory sensitivity, where everyday sounds are
perceived as louder or more intense compared to what a person
with “normal” hearing function would experience (Fackrell et al.,
2017). It is estimated that 40% of patients with tinnitus as
a primary complaint also report hyperacusis (Jastreboff and
Jastreboff, 2000), while 86% of patients with hyperacusis as
a primary complaint also report tinnitus (Anari et al., 1999).
However, these estimates should be interpreted cautiously as
there is no universally accepted definition of hyperacusis (Tyler
et al., 2014c; Aazh and Moore, 2017; Fackrell et al., 2017). As
such, definitions and tools used to diagnose hyperacusis vary
across studies (Fackrell et al., 2017) and currently, there is
no gold standard for hyperacusis diagnosis (Aazh and Moore,
2017). Furthermore, hyperacusis is also considered to be a rather
heterogeneous condition. For instance, it has been suggested
to differentiate between types of hyperacusis such as loudness,
fear, annoyance, and pain (Tyler et al., 2014c). It is therefore
essential for studies to provide a clear definition of hyperacusis,
and to specify what diagnostic methods were used. Regarding
the mechanisms underlying the observed association between
tinnitus and hyperacusis, it is speculated that the two conditions
might share some common pathophysiological pathways, for
example, an increase of auditory central gain (Noreña and Chery-
Croze, 2007) and/or disruption of the tensor tympani middle ear
muscle after an acoustic shock (Noreña et al., 2018).
Associations between somatosensory system related
conditions and tinnitus have been observed for many decades.
Indeed, a number of researchers agree that somatosensory
system involvement should be considered as an important
domain for tinnitus subtyping (Sanchez and Rocha, 2011;
Cianfrone et al., 2015; Levine and Oron, 2015; Michiels et al.,
2018), with evidence suggesting that the fusiform cells of the
dorsal cochlear nucleus play an important role, integrating
auditory and somatosensory inputs (Levine, 1999; Shore et al.,
2007, 2016; Lanting et al., 2010). Due to the diversity of
the criteria used to characterize somatosensory involvement
across studies, Michiels et al. (2018) conducted a global survey
involving researchers, resulting in a consensus on a set of
criteria for diagnosing somatosensory tinnitus. These included
modulation of tinnitus by somatosensory system activation,
and associations of tinnitus onset or aggravation with somatic
comorbidities (such as temporomandibular joint and cervical
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Simoes et al. Challenges and Future Directions in Tinnitus Research
spine disorders). As the purpose of the criteria are to standardize
assessment of the extent to which the somatosensory system can
influence an individual’s tinnitus, no strict rules for the diagnosis
of somatosensory tinnitus were proposed.
Moving to mental comorbidities, such as depression and
anxiety, these have also been shown to commonly accompany
tinnitus. Depression has been estimated between 14% (Stobik
et al., 2005) and 80% (Hiller and Goebel, 2001) among tinnitus
patients, correlating moderately with tinnitus-related distress
(Langguth et al., 2011a). Additionally, several symptoms such
as irritability, social withdrawal, worry, and insomnia overlap
between the two conditions. Previous studies also highlighted the
potential neural and genetic mechanisms that may account for
tinnitus and depression (Langguth et al., 2011b). With regards
to anxiety disorders, its lifetime prevalence among tinnitus
patients has been estimated at 45% (Pattyn et al., 2016). This
includes conditions such as generalized anxiety disorder, social
and specific phobia, post-traumatic stress, and panic disorder.
A dysfunctional link between the limbic and auditory system
has been implicated as a potential neural mechanism for the co-
occurrence of the two conditions, but the causal mechanisms
linking anxiety and tinnitus remain unclear (Pattyn et al., 2016).
2.3. Challenges and Future Directions
This section discussed various dimensions of tinnitus
heterogeneity, however, not in an exhaustive way. For example,
tinnitus heterogeneity can also be explored in terms of differences
in onset-related characteristics, modulating factors and other
temporal and perceptual characteristics of tinnitus (e.g., tinnitus
being maskable and/or prone to residual inhibition or not),
and characteristics of response to specific treatments (Noreña
et al., 1999; Koops et al., 2019; Simoes et al., 2019). Some of
these sources of heterogeneity are touched upon in the following
sections. Overall, any phenotypic trait of an individual with
tinnitus can contribute to tinnitus heterogeneity. The biggest
challenge is to identify the traits that could help differentiate
subgroups of patients with different underlying mechanisms
and treatment needs. Although many studies have addressed
this question, reviews of existing literature would be very
beneficial. Another widely accepted approach in tackling this
task is to create a large database of high-quality tinnitus-specific
data. Ideally, this would include detailed tinnitus-profiling
information, such as brain imaging, genetic profiling, and
treatment response history. Efforts should be made to collect
information from diverse samples, covering the full range of
tinnitus severity, to ensure all aspects of tinnitus heterogeneity
are captured. Statistical analyses could then be conducted on
this large dataset to address many of the unanswered research
questions regarding tinnitus heterogeneity. Such methodologies
have been successfully applied for other medical conditions
such as diabetes and Alzheimer’s disease (Ahlqvist et al., 2018;
Mitelpunkt et al., 2020).
Collating such large data, however, requires a lot of time and
funds. It is therefore becoming clear to the scientific community
that interdisciplinary collaborations are essential. These should
focus on standardization of tinnitus assessment, which would
allow the creation of large tinnitus-specific databases, allowing
the comparison between various datasets (Langguth et al., 2007;
Hall et al., 2018c). The TRI database is a noteworthy example as it
contains information from more than 5000 tinnitus patients from
different centers (Landgrebe et al., 2010). It is important that such
efforts should not only focus on clinically-relevant tinnitus cases
(Landgrebe et al., 2010), but also population-based cohorts like
the Swedish Tinnitus Outreach Project (STOP, 2015), allowing
a comprehensive exploration of tinnitus heterogeneity. Other
recent initiatives include the ESIT, the TIN-ACT, and the UNITI
European Union funded projects, aiming to further integrate
clinical data from different specialized centers in Europe, but also
information from the general population. Such projects would
allow a much needed multicenter comparison of the profile of
tinnitus patients.
3. EPIDEMIOLOGY, RISK FACTORS, AND
PREVENTION
The prevalence of tinnitus shows widespread variability, with
most studies reporting prevalence estimates between 10 and 15%
(Baguley et al., 2013; Gallus et al., 2015; McCormack et al.,
2016). In the UK alone, 0.5 to 1% of the population experiences
clinically-significant tinnitus (Davis and El Refaie, 2000).
Available information on the epidemiology of tinnitus
is centered around Western Europe, USA, and Australia
(McCormack et al., 2016). Prevalence studies often include
sample populations that are restricted to certain geographic areas
or by specific demographics. For example, the Epidemiology
of Hearing Loss Study (EHLS) is a population-based cohort
providing valuable information on hearing in older adults, aged
43 to 84 years, conducted in Beaver Dam, Wisconsin, USA
(Cruickshanks et al., 1998). Given the specific population and
geographical characteristics, it might not be ideal to generalize
results from such studies (Westreich et al., 2019).
Additionally, using a variety of assessment questions and/or
research definitions across studies inconsistently gives rise to
widespread variability in prevalence estimates (McCormack et al.,
2016). For example, tinnitus can also include cases of sudden
onset, lasting only a few seconds. However, these are not
considered pathological (Levine and Oron, 2015). To exclude
such cases, many studies define tinnitus as the presence of
sound in the head or ears lasting for more than 5 min at a
time (McCormack et al., 2016). However, a consensus on a
standardized tinnitus definition is yet to be reached.
Tinnitus has been associated with many risk factors
such as otological and psychological conditions, infectious
diseases affecting the ear, hypertension, diabetes, systemic lupus
erythematosus, rheumatoid arthritis, trauma, medications, noise
exposure, and other lifestyle-related factors and environmental
exposures (Han et al., 2009; Baguley et al., 2013; Biswas and Hall,
2020). Knowledge of tinnitus-related risk factors is necessary
to identify vulnerable populations and implement adequate
preventive measures to reduce the condition’s burden. However,
some risk factors lack a clear relationship with tinnitus. For
example, although hearing loss has been reported to increase the
risk for developing tinnitus in multiple studies (Nondahl et al.,
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Simoes et al. Challenges and Future Directions in Tinnitus Research
2002; Baguley et al., 2013; Moore et al., 2017), the relationship
between the two conditions is complex, as previously discussed.
This inadequate understanding complicates the implementation
of preventive measures.
Certain factors related to an individual’s lifestyle (such as
smoking and exposure to loud music) are known to increase the
risk of developing tinnitus and avoiding them would decrease
the risk (Zhao et al., 2010; Veile et al., 2018; You et al., 2020).
Analytical observational studies (case-control and cohort) on
tinnitus and potential lifestyle-related risk factors can help form
inferences on causal associations. Unfortunately, in tinnitus
research, most information is derived from cross-sectional data
and there is a scarcity of longitudinal studies to assess the
relationship between potential risk factors and tinnitus (Baguley
et al., 2013).
Prolonged exposure to loud noises over time has been
identified as a main risk factor for the development of tinnitus
in individuals of all ages. Therefore, the need for educational
preventive programs focusing on ear protection are paramount
(Williams et al., 2010). The challenge of measuring the efficacy
of this type of intervention lies in the associated costs and the
time needed for the programs to have an impact, thus receiving
low priority. Consequently, there is a lack of empirical studies
evaluating the feasibility and implementation (e.g., classroom vs.
internet-based) of such preventive programs.
Several steps can be undertaken to tackle the challenges
discussed in tinnitus epidemiological research. Firstly, addressing
the lack of a standard definition and developing unambiguously
phrased research questions are crucial for understanding tinnitus
epidemiology. To ensure uniformity in assessment and for ease of
comparison between populations, there is a clear need for cross-
culturally adapted assessment questions using good practice
guidelines (Hall et al., 2018e), instead of verbatim translations.
To address this issue, Biswas et al. (2019) proposed a set of
standardized questions on tinnitus prevalence and severity in
12 European languages following good practice guidelines for
translating hearing-related questionnaires (Hall et al., 2018e).
Secondly, there is an evident geographical bias with tinnitus
prevalence studies predominantly emanating from a limited
number of regions (McCormack et al., 2016). To have a better
global perspective, it is important to encourage epidemiological
research in other regions. Thirdly, conducting analytical
observational studies as well as exploring existing data sets
might reveal new and significant associations between tinnitus
and potential risk factors. Lastly, there remains a clear need
to evaluate the feasibility and efficacy of preventive measures.
Addressing knowledge gaps in future studies and synthesizing
existing knowledge, using systematic literature reviews, could
lead to significant progress in tinnitus epidemiological research.
4. TINNITUS MECHANISMS
4.1. Overview
Theories and experimental evidence on tinnitus pathophysiology
are rather diverse as highlighted by a systematic review (Haider
et al., 2018). The site of tinnitus generation is still debated,
with the potential involvement of both peripheral and central
structures. For example, Noreña (2015) proposed differentiating
three subtypes of tinnitus: cochlear (abnormal activity at
the peripheral auditory system), peripheral-dependent central
(tinnitus neural activity in higher centers but dependent on
peripheral activity), and peripheral-independent central tinnitus
(tinnitus neural activity in higher centers independent of
peripheral activity). According to another model based on
predictive coding, the presence of a tinnitus precursor in the
form of spontaneous activity at subcortical auditory pathways
was speculated (Sedley et al., 2016). It was suggested that this
spontaneous activity is normally ignored by higher cortical
structures, but increase in its precision gives rise to tinnitus. In
the following sections, evidence and models for the involvement
of hearing-related and other neural structures, as well as genetics
in tinnitus, are discussed. Additionally, key challenges and future
directions for these research domains are highlighted.
4.2. Hearing Deprivation and Brain
Plasticity
The brain has the capability to transform its existing circuitry
and functions in response to intrinsic or extrinsic stimuli,
which is referred to as brain plasticity or neural plasticity
(Mateos-Aparicio and Rodríguez-Moreno, 2019). This ability is
subject to homeostatic regulation to maintain an environment
where it can function optimally (Turrigiano and Nelson, 2004;
Turrigiano, 2008). However, deprivation of auditory input can
cause a harmful plasticity effect that could lead to the onset
of tinnitus (Noreña and Farley, 2013). This is supported by
the finding that tinnitus may disappear when hearing recovers
(Schreiber et al., 2010).
Disruptions from lower levels of the auditory pathway could
lead to alterations in synaptic transmission and neurotransmitter
release in more central areas of the auditory system. This creates
an imbalance between neuronal excitation and inhibition and re-
routing of auditory pathways, leading to overall abnormal neural
activity (Møller, 2007; Shore et al., 2016). More specifically,
reduction of the main inhibitory neurotransmitter, GABA
(gamma-aminobutyric acid), has been associated with tinnitus
(Yang et al., 2011; Sedley et al., 2015). Changes in GABA
neurotransmission may dysregulate the necessary inhibition
controlling spontaneous neural activity in the auditory system.
The abnormal neural activity linked to the tinnitus percept
involves not only the auditory system as thought previously, but
also non-auditory neural networks including networks of the
sensory, cognitive, and affective systems (Rossiter et al., 2006;
Adjamian et al., 2009; De Ridder et al., 2011; Schmidt et al., 2013;
Leaver et al., 2016). However, the current evidence is too spread
out, indicating neural activity abnormalities in different parts of
the brain. For an in-depth review, see Lanting et al. (2009) and
Husain and Schmidt (2014).
4.3. Neuroimaging
Neuroimaging attempts to identify putative models that underlie
tinnitus emergence and the persistent nature of the perception.
In recent years, several neuroimaging techniques have succeeded
in finding structural, functional and neurochemical changes
in individuals with tinnitus (Adjamian et al., 2014; Elgoyhen
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Simoes et al. Challenges and Future Directions in Tinnitus Research
et al., 2015; Sedley et al., 2015; Shahsavarani et al., 2019;
Adams et al., 2020).
Various brain imaging studies using voxel-based
morphometry (VBM), diffusion tensor imaging (DTI),
functional magnetic resonance imaging (fMRI), and positron
emission tomography (PET) revealed structural and functional
changes associated with tinnitus across distributed auditory and
non-auditory neural networks. Identified regions of interest
include areas of the auditory system (e.g., the primary and
secondary auditory cortices, medial geniculate body, and inferior
colliculus), the limbic system (e.g., the anterior cingulate cortex,
amygdala, insula, parahippocampus, and nucleus accumbens),
attention-related networks (e.g., the occipito-parietal cortex
and supramarginal cortex), and the default mode network
(e.g., medial prefrontal cortex and precuneus) (Adjamian et al.,
2014; Elgoyhen et al., 2015; Raichle, 2015; Sedley et al., 2015;
Shahsavarani et al., 2019; Adams et al., 2020). In particular,
reduced gray matter (Landgrebe et al., 2009; Schneider et al.,
2009; Aldhafeeri et al., 2012) and changes in activity (Arnold
et al., 1996; Langguth et al., 2006; Boyen et al., 2014) in auditory
system areas have been linked to tinnitus perception. Abnormal
structural (Crippa et al., 2010; Besteher et al., 2019) and
functional (Schmidt et al., 2013; Davies et al., 2017) changes of
the amygdala and parahippocampus have also been associated
with tinnitus. Moreover, imaging studies have revealed structural
and functional abnormalities in the anterior cingulate cortex
and the insula (Carpenter-Thompson et al., 2014; Chen et al.,
2018; Besteher et al., 2019). Additionally, decreased brain matter
volume (Aldhafeeri et al., 2012) in the default mode network
and changes in functional connectivity (Schmidt et al., 2013;
Chen et al., 2018) in the default mode and attention networks
may play a pivotal role in neuropathological features underlying
tinnitus. However, results from structural and functional
neuroimaging are highly heterogeneous, which could be due
to small sample sizes, lack of standardized sample selection
criteria and heterogeneity of sample characteristics (e.g., degree
of hearing loss and presence of psychiatric comorbidities), and
differences in imaging and data analysis methods. More in-depth
reviews on tinnitus structural and functional neuroimaging can
be found in Adjamian et al. (2014), Elgoyhen et al. (2015), and
Adams et al. (2020).
Further, neurophysiological investigations using
electroencephalography (EEG) or magnetoencephalography
(MEG) were able to identify tinnitus-associated pathological
spontaneous brain activity patterns. In particular, enhanced
activity in the gamma and delta frequency range along with
reduced alpha activity over the auditory cortices was observed in
tinnitus patients (Weisz et al., 2005, 2007b; Moazami-Goudarzi
et al., 2010; Adjamian et al., 2012; Balkenhol et al., 2013; Schlee
et al., 2014). These oscillatory aberrations were subsumed under
the framework of the thalamo-cortical dysrhythmia model
(TCD) (Llinás et al., 1999, 2005; De Ridder et al., 2015) and
further extended to the synchronization by loss of Inhibition
model (SLIM) (Weisz et al., 2007a). However, results of other
studies are not in accordance with these observations (Ashton
et al., 2007; Moazami-Goudarzi et al., 2010; Meyer et al., 2014;
Pierzycki et al., 2016), emphasizing instead on the importance
of other frequency bands in neural activity related to tinnitus
(Moazami-Goudarzi et al., 2010; Balkenhol et al., 2013; Meyer
et al., 2014). In view of these ambivalent findings, it still remains
unclear how and which altered ongoing brain activity patterns
are associated with tinnitus.
To observe the brain’s neurochemical characteristics in
tinnitus, magnetic resonance spectroscopy (MRS) can be used.
MRS data is taken using an MRI scanner, producing a graphical
spectrum with peaks corresponding to different chemical
concentrations from voxels of interest (McRobbie et al., 2017). As
discussed earlier, altered GABA levels were observed in tinnitus
patients with hearing loss (Sedley et al., 2015). Confirmatory
evidence of decreased GABA inhibition was also seen in patients
with hearing loss alone (Gao et al., 2015), which might suggest
that reduced GABAergic tone may directly result from the loss
of peripheral input. Following these results, additional research
is required in order to observe the exact role of different
neurotransmitters and how big are the changes related to
tinnitus specifically. Other neurotransmitters such as glycine and
glutamate are also well-associated with signaling mechanisms of
the central auditory pathway (Lee and Godfrey, 2015) and thus
also need to be investigated in future research studies.
To date, both functional and structural findings have been
very inconsistent with little replication, potentially due to the
heterogeneity of tinnitus characteristics, relatively small sample
sizes, and variability in data acquisition and analysis methods.
Conducting and updating systematic reviews of methods and
results of previous studies is essential in order to understand
common patterns and inconsistent findings, guiding future
studies. An important consideration for future work is to
dissociate findings that are tinnitus-specific, rather than due to
hearing loss or hyperacusis. In order to reliably identify the main
neural structures and pathways related to the various aspects
of tinnitus, carefully designed studies with detailed phenotyping
of recruited participants (both cases and controls), and large
sample sizes for sufficient statistical power (Button et al., 2013)
need to be conducted. Standardization in methodological aspects
of the aforementioned techniques would additionally facilitate
comparing findings across studies.
4.4. Tinnitus Genetics
Research related to the genetic components of tinnitus is sparse
(Vona et al., 2017). Nevertheless, it has been speculated that
tinnitus is related to a multifactorial genetic etiology (Lopez-
Escamez et al., 2016). To study the genetic contribution to
diseases, various study designs can be implemented including
heritability twin studies and linkage analysis (Sahebi et al.,
2013). To investigate the genetic susceptibility to tinnitus, a
study was conducted on a Swedish twins cohort of 10,464 pairs
with self-reported tinnitus (Maas et al., 2017). A higher rate of
concordance was reported in monozygotic pairs compared to
dizygotic. Heritability was 56% for bilateral tinnitus compared
to 27% for unilateral tinnitus and further stratification by sex
showed an increased heritability for males (68%). Additionally,
a study on Swedish adoptees with clinically significant tinnitus
showed that the shared environment was not associated with
tinnitus presence (Cederroth et al., 2019b).
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Simoes et al. Challenges and Future Directions in Tinnitus Research
In order to explore the association between common genetic
variants across the whole genome and a phenotype of interest,
genome-wide association studies (GWAS) are considered a
robust approach (McCarthy et al., 2008). These are hypothesis-
free, case-control linkage studies, that have been successful
in revealing genetic mechanisms of common diseases such
as diabetes (Todd et al., 2007), inflammatory bowel diseases
(Parkes et al., 2007), major depression (Wray et al., 2018), and
breast cancer (Easton et al., 2007). A pilot GWAS on tinnitus
was performed in an adult population (55-65 years old) of
a homogeneous ethnic background from Belgium, comprising
of 167 self-reported tinnitus cases and 794 controls (Gilles
et al., 2017). None of the single nucleotide polymorphisms
(SNPs) reached genome-wide significance, possibly due to the
small sample size. However, a subsequent gene-set enrichment
analysis asking whether any biological pathway is significantly
associated with the results of the GWAS revealed seven metabolic
pathways such as involvement of endoplasmic reticulum stress,
NRF2-mediated oxidative stress response, and serotonin receptor
mediated signaling pathways (Gilles et al., 2017). GWAS meta-
analysis is a solution to overcome the restrictions of the
sample size and investigate potential sources of heterogeneity.
Additionally, a candidate-gene approach can be used to look
at the variation associated with a disease within a number of
predefined genes. Such candidate-gene studies have investigated
the role of genes such as BDNF (Sand et al., 2012), GDNF
(Orenay-Boyacioglu et al., 2016), KCNE1, and SLC12A2
(Pawełczyk et al., 2012) in tinnitus development, susceptibility,
and severity.
Several challenges emerge during attempts to map the genetic
architecture of tinnitus. First, due to the lack of a clear Mendelian
pattern of inheritance, tinnitus is considered to be a complex
trait. Such complex traits are difficult to link to a specific genetic
marker due to several reasons such as incomplete penetrance,
genetic heterogeneity, and polygenic inheritance (Lander and
Schork, 1994; Brown et al., 2019). Second, the self-reported
nature of tinnitus diagnosis (due to the lack of a biomarker)
and the lack of standardization for defining tinnitus and tinnitus
subgroups can lead to an inclusion of heterogeneous tinnitus
cases, affecting results of any subsequent analysis. Lastly, tinnitus
can be associated with many other disorders including Meniere’s
disease, hearing loss, depression and sleep disorders, making it
difficult to clearly define the independent genetic component
of tinnitus.
To overcome these challenges, like in the case of neuroimaging
studies, careful selection of tinnitus cases with adequate
phenotyping and sufficient sample sizes in future studies are
essential (Riley et al., 2020). In addition, specific study designs
can help overcome some of these challenges. For example, genetic
association studies with a case-control design and a candidate-
gene approach looking at the variation associated with tinnitus
within a number of predefined genes can be conducted (Lopez-
Escamez et al., 2016). Another methodology that can prove useful
is extreme phenotype design, which is a case-control study design
with the assumption that the furthest cases on both extremes of a
phenotype distribution can play an important role in identifying
rare variants and candidate genes contributing to a particular
trait. Using this strategy, sequencing a moderate sample size is
enough to find enrichment of rare variants in extremes of a
quantitative trait (Bamshad et al., 2011).
5. TINNITUS ASSESSMENT
5.1. Overview
Despite efforts for standardization, as of yet there is no
universally accepted protocol for tinnitus assessment for either
clinical or research settings (Langguth et al., 2006; Henry,
2016). Nevertheless, clinicians and researchers tend to agree
that many pieces of information are essential in order to
sufficiently characterize an individual with tinnitus (Langguth
et al., 2006; Levine and Oron, 2015). Table 1 presents an overview
of elements for tinnitus assessment summarized from selected
sources (Langguth et al., 2007; Tunkel et al., 2014; Levine and
Oron, 2015; Durai and Searchfield, 2016; Fuller et al., 2017; Cima
et al., 2019) and/or used from the authors of this article. Across
tinnitus literature, even more variables have been assessed for
their relevance for tinnitus profiling such as biochemical markers
(Ban et al., 2018). Neuroimaging and genetic profiling have been
discussed in previous sections. The focus of this section is tinnitus
profiling based on case history and audiological assessment.
Which of these elements should be included in any tinnitus
assessment protocol for clinical and/or research settings remains
to be established.
5.2. Case History Assessment
Numerous characteristics of patient case history have
demonstrated importance for tinnitus profiling, including
demographics, co-existing conditions, and tinnitus perceptual
characteristics (van de Heyning et al., 2014). Ideally, such
information should be collected using standardized interviews,
clinical examinations, diagnostic tests and medical record
assessment to ensure data quality. However, for practical reasons,
they are often self-reported and as they can be assessed with
standardized questionnaires (Langguth et al., 2017; Genitsaridi
et al., 2019). For conditions that cannot be sufficiently assessed
with single questions, such as personality traits, psychological
conditions, hyperacusis and noise exposure history, specific
multi-item questionnaires have been developed (Khalfa et al.,
2002; Durai and Searchfield, 2016; Guest et al., 2018).
An essential part of tinnitus assessment is the measurement
of tinnitus severity and more generally, the impact of tinnitus
on the affected individual which can vary largely from one
individual to another (Hall et al., 2018a). Such measurement
is also essential for assessing the effectiveness of a tinnitus
intervention. Numerous multi-item self-report questionnaires
have been developed for this purpose (Haider et al., 2016),
such as the Tinnitus Handicap Inventory (THI) (Newman et al.,
1996) and the Tinnitus Functional Index (TFI) (Meikle et al.,
2012). Visual analog scales and numeric rating scales are also
commonly used instruments to quantify tinnitus loudness and
distress (Adamchic et al., 2012).
Even though previous recommendations have been made
regarding which instruments to use for assessing the impact of
tinnitus and treatment efficacy (Langguth et al., 2007; Jacquemin
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Simoes et al. Challenges and Future Directions in Tinnitus Research
TABLE 1 | Overview of elements for tinnitus assessment.
Elements Examples of specific measures
Non tinnitus-specific
General individual characteristics
Sociodemographic, lifestyle characteristics Standardized tinnitus case history questionnaires such as the TSCHQ and the
ESIT-SQ
Personality traits Personality questionnaires such as the Eysenck personality inventory (Eysenck
and Eysenck, 1964; see Durai and Searchfield, 2016 for a review)
Noise and other exposures Structured interview or self-reported questionnaires for noise exposure (see
Guest et al., 2018 for a review)
Ear and hearing-related conditions
Ear, noise, and throat conditions Ear, noise, and throat assessment
(complete ear, nose and throat clinical examination including otoscopy,
auscultation of head and neck area for audible sounds, palpation of head and
neck area for masses or trigger points, examination of the temporomandibular
joint)
Auditory and vestibular function Audiological assessment
(standard air conduction and bone conduction PTA, speech audiometry,
immittance tympanometry, acoustic reflex assessment, auditory brainstem
responses, high frequency PTA, otoacoustic emission, loudness discomfort
levels, caloric testing, vestibular evoked myogenic potential), self-report
questionnaires for assessing hearing disabilities such as the SSQ
Vertigo, hyperacusis, and other hearing and vestibular comorbidities
Clinical examination, structured interview, or self-report case history questionnaires
such as the ESIT-SQ, self-report questionnaires for assessing hyperacusis
(Hyperacusis Questionnaire from Khalfa et al., 2002; see Margol-Gromada et al.,
2020 for an overview), psychoacoustic ratings of natural sounds (Enzler et al., 2021)
Psychological conditions
(e.g., mood disorders, anxiety disorders, reaction to severe stress)
Psychological and/or psychiatric assessment, medical records review, structured
interview, self-report questionnaires for psychological disorders such as the
Hospital Anxiety and Depression Scale and the Beck Depression Inventory
(Zigmond and Snaith, 1983; Beck et al., 1988; see Durai and Searchfield, 2016
for a review)
Treatment history
(e.g., medication and procedures)
Medical records review, structured interview, or self-report questionnaires such
as the ESIT-SQ
Other medical history and relevant co-existing conditions
(e.g., dental conditions, cervical conditions, headaches, neurological conditions,
cognitive abilities, pain syndromes, overall quality of life)
Physical examination by relevant clinicians (e.g., dentist, physiotherapist,
neurologist), cognitive-attention tasks, medical records review, structured
interview, or self-report questionnaires such as the ESIT-SQ for general
comorbidities or the WHOQOL-BREF (WHO, 1998) and EQ5D (Herdman et al.,
2011; Stolk et al., 2019) for quality of life assessment.
Brain anatomy and function Electroencephalography (EEG), magnetoencephalography (MEG), magnetic
Resonance Imaging (MRI), positron emission tomography (PET)
Genetic profile Isolated DNA from saliva.
Tinnitus specific
Tinnitus history
Onset related characteristics including duration, age at onset, onset related events,
and sudden or gradual onset
Presence pattern including frequency of presence, and being constant or
intermittent
Other perceptual characteristics including quality, being pulsatile, pitch, spatial
perception, variability (e.g., loudness fluctuation)
Modulating factors (e.g., somatic modulation)
Structured interview or self-report questionnaires such as ESIT-SQ
Tinnitus Impact Structured interview (Tunkel et al., 2014; Cima et al., 2019) or self-report
questionnaires such as the Tinnitus Handicap Inventory (Newman et al., 1996),
the Tinnitus Functional Index (Meikle et al., 2012), the Tinnitus Handicap
Questionnaire (Kuk et al., 1990), and the Tinnitus Reaction Questionnaire (Wilson
et al., 1991) (see Tunkel et al., 2014; Durai and Searchfield, 2016; Cima et al.,
2019 for reviews)
Tinnitus psychoacoustic assessment
Pitch matching
Loudness matching
Minimum Masking Level (MML)
Residual inhibition
As in Fournier et al., 2018;Neff et al., 2017;Hoare et al., 2014a;Roberts, 2007
ESIT-SQ, European School for Interdisciplinary Tinnitus Research Screening Questionnaire (Genitsaridi et al., 2019); PTA, Pure Tone Audiometry; SSQ, Speech Spatial and Qualities of
Hearing Scale (Gatehouse and Noble, 2004); TSCHQ, Tinnitus Sample Case History Questionnaire (Langguth et al., 2007).
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Simoes et al. Challenges and Future Directions in Tinnitus Research
et al., 2018), there is no consensus yet in the tinnitus scientific
community and new instruments are still being developed (Tyler
et al., 2014a).
5.3. Audiological Assessment
Tinnitus profiling cannot be complete without an assessment
of the auditory system. Although sometimes self-reported
instruments are used to collect information about subjective
hearing problems, hyperacusis, noise exposure history, and
other hearing-related conditions, an audiological assessment
remains essential. This usually includes hearing and tinnitus
psychoacoustic assessment.
5.3.1. Hearing Assessment
As discussed previously, hearing assessment often involves
only standard PTA. However, a more comprehensive hearing
assessment, including higher frequency resolution and extended
high frequencies, would benefit tinnitus profiling as it would
provide higher sensitivity for auditory system impairments
(Vielsmeier et al., 2015; Lefeuvre et al., 2019; Xiong et al., 2019).
Besides PTA, numerous other audiological tests can be used for
a more in depth characterization of hearing function, including
speech in noise audiometry, immittance tympanometry,
acoustic reflex assessment, auditory brainstem responses (ABR),
otoacoustic emissions (mainly distortion product otoacoustic
emissions [DPOAE]), and loudness discomfort levels. However,
the more tests added to an assessment protocol, the more time
required to collect the desired information per participant.
Therefore, researchers need to consider if more detailed hearing
assessments would be beneficial for their specific studies, thus
being critical when deciding which measures to include in
their assessment protocols. One solution to reduce testing time
while gaining additional information is the use of machine
learning techniques, for example, as applied in audiometry
(Schlittenlacher et al., 2018). In this case, the sound trials tested
would be those with higher uncertainty, lowering the total
number of trials tested and, consequently, the duration of testing.
Furthermore, the procedure can be automatized relieving the
audiologist from the task.
5.3.2. Tinnitus-Specific Psychoacoustics
The subjective nature of tinnitus requires further tinnitus-specific
psychoacoustic assessment. An adequate matching of pitch and
loudness can help better understand the underlying mechanisms
of tinnitus perception and to ensure correct application of sound-
based therapies on an individual level (Schaette et al., 2010;
McNeill et al., 2012; Pantev et al., 2012). For pitch matching
various methods have been investigated. For example, methods
like the “2AFC” (Penner and Bilger, 1992), the “likeness rating”
(Noreña et al., 2002) or the “method of adjustment” (Wier et al.,
1976) have been broadly used in previous studies. These methods
vary in their reliability, duration or subjective satisfaction of
participants, and future research should try to combine their
strengths (Neff et al., 2019a). With regards to loudness, the
most common methods of assessment are loudness matching
and loudness rating. Loudness matching can be done at the
tinnitus frequency or at prespecified frequency such as at 1
kHz, by presenting and adjusting the intensity of an external
sound until it is perceived as equal to tinnitus loudness (Mitchell
et al., 1993; Hoare et al., 2014a; Hall et al., 2017). The matched
loudness can be expressed in either dB HL (hearing level) or in
dB SL (sensation level, i.e., the difference between the identified
loudness level and the hearing threshold at the given frequency).
Learning effects seem to play a main role in the subjectivity
of the assessment (Hoare et al., 2014a). In addition, loudness
matching has been shown to not correlate with loudness ratings,
which better describes tinnitus intrusiveness and severity and
provide more useful information from a clinical perspective
(Henry, 2016).
Regarding tinnitus maskability, it is known that some tinnitus
patients report that external sounds can not mask their tinnitus,
while others report that even weak sounds at any frequency
mask it (Henry and Meikle, 2000). A common method to assess
tinnitus maskability is the minimum masking level (MML),
which is the lowest level of a noise required to mask tinnitus,
and it is a useful tool to measure the intrusiveness of tinnitus
and the acceptance of masking (Vernon et al., 1990; Andersson,
2003). Other methods of masking aim to target the tinnitus
frequency, such as the Tinnitus Tuning Curve (TTC). The TTC
assesses the maskability of tinnitus at different frequencies and
levels. Fournier et al. (2019) investigated differences in perception
of external sounds and tinnitus, and compared TTC and
Psychophysical Tuning Curves (PTC) in people with tinnitus.
Their results indicated the presence of different subgroups within
the whole cohort.
Another psychoacoustic measure routinely assessed in the
clinic is residual inhibition (RI). It can be defined as the
temporary suppression of tinnitus that occurs following exposure
to a noise presented for 30 s or 1 min at a level 10 dB above the
tinnitus masking threshold (the minimum level required to mask
tinnitus or minimum masking level) (Feldmann, 1971, 1983;
Vernon and Meikle, 2003; Roberts, 2007). This phenomenon
is observed in approximately 60–80% of tinnitus patients.
Suppression patterns appear to vary across individuals and are
dependent on stimulation intensity, duration and/or frequency
(Roberts et al., 2006, 2008; Schaette et al., 2010; Neff et al., 2017).
A new method has recently been developed by Fournier et al.
(2018), where the measure of RI duration is replaced by a measure
of minimum sound intensity, which allows RI for a short and
fixed time interval (1 s). The stimulation used for the measures
consisted of pulsed narrowband noises of a 3-s duration followed
by 1-s silence intervals between the pulses. MML was obtained
by increasing the intensity of the narrowband noise until the
tinnitus was masked during the 3-s noise presentation, and the
minimum residual inhibition level (MRIL) by further increasing
the stimulus intensity until the tinnitus was suppressed during
the silence period between the acoustic pulses. Besides being
less time-consuming than the classic method, this method was
proven to provide minimum masking and residual inhibition
levels in 98.5 and 86.7% of the patients, respectively. However, the
reliability and reproducibility of the measurements obtained with
this method remain to be verified. Furthermore, by investigating
the consequences of various modulated or filtered sounds (Reavis
et al., 2012; Henry et al., 2013; Tyler et al., 2014b; Neff et al.,
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Simoes et al. Challenges and Future Directions in Tinnitus Research
2017, 2019b; Schoisswohl et al., 2019), the groundwork for new
potential long term sound therapies can be laid.
5.4. Challenges and Future Directions
One of the main challenges in tinnitus assessment is to define
a minimum set of essential information to collect. For clinical
practice, the aim would be to have enough information pointing
to a specific etiology that would require specific treatment
(Cima et al., 2019). For example, a person with tinnitus,
no comorbidities, audiometrically normal hearing and neck
problems would require a different approach than a person with
tinnitus and moderate hearing loss without other comorbidities
or a person with tinnitus and depression. Similarly, in a research
setting, the aim would be to define homogeneous populations
with common underlying pathophysiology. In both cases, this
minimum set of information can only be finalized once questions
about tinnitus mechanisms and heterogeneity are answered.
Another important challenge in tinnitus assessment is the
standardization of measures that would enable comparisons
between independent research findings. For all the previously
mentioned aspects of tinnitus assessment (including self-
reported information and audiological assessment), a plethora of
measures for data collection exist. This is also true for measures of
treatment outcome, as is further discussed in section 6.6. Similar
to the previously discussed tinnitus domains, systematic reviews
to identify the most relevant and reliable measures for tinnitus
assessment are essential. In addition, it is clear that for tinnitus
research to move forward, a consensus for tinnitus assessment
involving researchers from various fields is required, and such
efforts are ongoing (Hall et al., 2018c; Schlee et al., 2018).
Given the challenges in tinnitus assessment, the need for
identifying an objective measure for tinnitus is evident. Measures
such as genetic, neuroimaging, biochemical and audiological
markers, are prime candidates for objectively measuring the
presence of tinnitus or of a particular tinnitus subtype. A
recent systematic review could not identify any reliable objective
measure for tinnitus but discussed some emerging areas of
research; blood and neuroimaging tests, for instance (Jackson
et al., 2019). Other studies discussed the role of Middle Ear
Muscle Reflex (MEMR), also known as Acoustic Stapedial
Reflex (ASR), as an objective tinnitus marker, however, with
contradicting results (Wojtczak et al., 2017; Guest et al., 2019).
Further research is required toward establishing the value of
existing markers for objectively measuring tinnitus or toward
identifying new markers.
6. TREATMENT DEVELOPMENT
6.1. Overview
Although tinnitus is a commonly reported condition, the
available treatment options are limited and aimed at managing
tinnitus, rather than eliminating the percept (McFerran et al.,
2019). From a clinical standpoint, the attenuation of the
tinnitus percept and/or burden is a successful goal. In this
context, the tinnitus-related burden can also be attenuated by
managing comorbidities (Tunkel et al., 2014). Since tinnitus is
a heterogeneous condition, and the perception of one’s tinnitus is
entirely subjective, the current efficacy of treatments varies. There
are currently two main categories of treatment options; sound-
based and psychology-based treatments (Tunkel et al., 2014;
Fuller et al., 2017). Although there are currently no medications
approved for tinnitus, pharmacology-based interventions are also
under investigation. Research, challenges and future directions
regarding these interventions and other therapeutic approaches,
such as non-invasive neurostimulation, neurofeedback, and
tinnitus mobile phone applications, will be discussed in the
following sections.
6.2. Psychology-Based Interventions
Psychology-based approaches, including counseling and
cognitive behavioral therapy (CBT), can help manage how
tinnitus impacts emotions and behavior (Thompson et al., 2017;
Landry et al., 2020). CBT comprises various components (e.g.,
relaxation, exposure, psychoeducation) which aim at changing
cognitive, behavioral and emotional responses to tinnitus. It
has been used for tinnitus treatment with positive results such
as decreased tinnitus disability (Cima et al., 2012). A recent
Cochrane review on CBT for tinnitus (Fuller et al., 2020)
corroborates the reduction of the negative impact of tinnitus on
quality of life. Moreover, CBT for tinnitus treatment received
the highest level of recommendation by a multidisciplinary
group who reviewed thirteen current treatment options (Cima
et al., 2019). Despite the benefits of CBT, treatment is not always
delivered to those who need it (Cima et al., 2020). In order to
bridge the gap, internet-based CBT (iCBT) is currently being
developed to facilitate the delivery to patients (e.g., Beukes et al.,
2018). While a full iCBT treatment proves difficult, current
research also focuses on dismantling treatment components to
understand which parts work best for whom (e.g., Lourenco
2019). As such, future research aims at tailoring CBT to
reduce the time of treatment and increase positive outcomes
as well as exploring alternative platforms for delivery, such as
online applications.
6.3. Sound-Based Interventions
6.3.1. Sound Generators
Sound-based interventions include use of electronic devices such
as sound generators, hearing aids, and cochlear implants. The
principle of sound generators, which were developed decades
ago, was to distract tinnitus patients with a more pleasant and
acceptable sound, rendering tinnitus inaudible (Vernon, 1976). It
is still not fully understood whether the effect of sound generators
is by masking (Henry et al., 2008), interactions with putative
tinnitus mechanisms (Jastreboff and Hazell, 1993), or affecting
cognitive mechanisms such as attention or stress management.
Tailor-made notched music training (TMNMT) is a sound-
therapy approach based on the long-term application of a signal
where the frequencies around the tinnitus pitch are filtered
out. This is thought to reverse maladaptive reorganization of
auditory cortical areas (Okamoto et al., 2010; Pantev et al.,
2012). Overall, many studies have shown a positive effect of
sound generators with tinnitus subjects experiencing some relief
in tinnitus annoyance (Sereda et al., 2018). However, very few
included a placebo condition, and the vast majority have included
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Simoes et al. Challenges and Future Directions in Tinnitus Research
other components in the treatment, such as amplification or
counseling (Hobson et al., 2012; Sereda et al., 2018). This
has made it very difficult to evaluate the effect of the sound
generators. It is therefore essential that future studies solely focus
on assessing the effectiveness of various sound generators in
well-designed randomized controlled trials (RCTs). Furthermore,
the wide range of outcome measures used in these studies
make comparisons difficult, and it is recommended that future
studies use more meticulous methodology along with proper
blinding and randomization, to secure high-quality evidence
(Sereda et al., 2018).
6.3.2. Hearing Aids
Hearing aids can also be used for tinnitus management, but
the mechanisms of their effect are complex and not fully
understood, as in the case of sound generators. They might
have physiological effects on brain activity by reversing or
preventing the maladaptive plasticity (Noreña, 2011), or by
decreasing the neuronal response gain (Schaette et al., 2010).
Moreover, people with hearing loss and tinnitus might also
benefit from hearing aids due to the masking and distraction
from tinnitus that they can provide (Sereda et al., 2015), and by
improving their communication which could lead to a reduction
in stress and anxiety. Although hearing aids have been used
in tinnitus management since the 1940s (Saltzman and Ersner,
1947), evidence supporting their effectiveness is limited. Previous
work has demonstrated the lack of evidence to support or refute
hearing aids prescription in tinnitus management in patients with
co-existing hearing loss (Hoare et al., 2014b). Shekhawat et al.
(2013) highlighted the lack of high-quality evidence for the effect
of hearing aids since most studies do not use RCTs. Moreover,
limitations and differences in clinical guidelines for diagnosis and
management of tinnitus make the assessment of this particular
treatment more difficult (Sereda et al., 2015). Future research on
hearing aids and tinnitus management must be carried out by
well-designed RCTs under a standard framework for diagnosis
and prescription. Besides general fitting procedures, assessing
individual tinnitus characteristics could help personalize hearing
aid fitting which could lead to increased effectiveness. For
example, previous studies have suggested that there can be a
higher reduction in tinnitus loudness and scores of the Tinnitus
Reaction Questionnaire (TRQ) when the tinnitus pitch is located
within the frequency range of the amplification (Schaette et al.,
2010; McNeill et al., 2012). Approaches like TMNMT should be
investigated in-depth for hearing aids. Furthermore, more focus
has recently been put on individualized compensation strategies
that consider additional parameters when fitting hearing aids to
improve speech intelligibility (Vlaming et al., 2011; Santurette
and Dau, 2012; Sanchez-Lopez et al., 2020). In the future, it
would be interesting to develop unique auditory profiles and
compensation strategies for tinnitus patients and investigate
whether these more specialized fittings will improve the benefits
of hearing aids on tinnitus. Combination aids can be used
for both amplification and sound stimulation, and they might
be an interesting option for some tinnitus patients. However,
the available evidence is not sufficient, and recommendations
on the type of noise, level of noise or laterality of fitting
should be standardized to shed some light on their efficacy
(Tutaj et al., 2018).
6.3.3. Cochlear Implants
Over the years, many research groups have investigated the
efficiency of cochlear implants (CI) that specifically aim to reduce
the perception of tinnitus (Van de Heyning et al., 2008; Ramakers
et al., 2015; Macías et al., 2018; Peter et al., 2019; Assouly et al.,
2020). Although the methods used to objectively measure and
record the tinnitus levels before and after the surgery, the number
of patients in a study cohort and the follow up periods vary
significantly among the research groups, these studies collectively
show a clear improvement for tinnitus patients. However, like
hearing aids, little is known about the involved mechanisms. One
popular claim is the neural plasticity induced by intracochlear
electrical stimulation provided by CIs (Fallon et al., 2008).
However, after long term follow-up, CI recipients report that
once the implant is turned off, the tinnitus comes back (Mertens
et al., 2016). Additionally, in some cases worsening or induction
of tinnitus has been reported (Quaranta et al., 2004; Baguley and
Atlas, 2007; Di Nardo et al., 2007; Pan et al., 2009; Kompis et al.,
2012). Due to this heterogeneity in outcomes, researchers have
tried to develop models to predict positive and negative effects
of cochlear implantation for tinnitus (Ramakers et al., 2018;
Kloostra et al., 2019; Dixon et al., 2020), but further research
needs to be carried out using prospective studies and extensive
databases. Optimized CI programming for tinnitus patients is
another important but under-researched domain (Pierzycki et al.,
2019). Long term follow-up studies, standardization of outcome
measures, and additional research are required to gather more
evidence to convince medical authorities and decision-making
bodies that CIs could be a successful treatment option for patients
who suffer from severe and disabling tinnitus (Newman et al.,
1996; Meikle et al., 2012; Hall et al., 2018b; McFerran et al.,
2019). This approach must involve not only audiologists and
ENT physicians, but also insurance bodies and policymakers to
create a clear pathway to provide CI to patients seeking help
for tinnitus.
6.4. Pharmacology-Based Interventions
A wide variety of therapeutic drugs have been used to relieve
tinnitus (Elgoyhen and Langguth, 2010). For acute tinnitus, a
dose-dependent reduction in tinnitus intensity was observed
with intravenous lidocaine (Trellakis et al., 2006). However,
its use is controversial due to its short-lasting response, its
potentially life threatening arrhythmogenic side effects, and the
low bioavailability of its oral form (Israel et al., 1982; Trellakis
et al., 2007; Gil-Gouveia and Goadsby, 2009). A potential goal
of pharmacologic tinnitus research could be to identify the
mechanism by which lidocaine interferes with tinnitus and
mimic this effect using a drug with better tolerance that can
be orally administered. For chronic tinnitus, the off-label use of
medicines like betahistine (Hall et al., 2018d), anticonvulsants
(Hoekstra et al., 2011), and glutamate receptor antagonists
have shown little or no effect in clinical trials. Prescription
of antidepressants and benzodiazepines is limited to tinnitus-
associated comorbidities such as depression, insomnia and
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anxiety (Langguth et al., 2019). Moreover, three clinical research
programs, in the last few years, were discontinued in phase
II and III. AMPA antagonist selurampanel (BGG492) has not
resulted in a new compound (Cederroth et al., 2018). NMDA
receptor antagonists (AM-101) have been discontinued in phase
III for not meeting endpoints (van de Heyning et al., 2014).
Many other treatments decreasing tinnitus percept or targeting
central auditory processing pathways are at a preclinical phase
(Schilder et al., 2019). The modulator of voltage-gated potassium
channels (Kv3.1) (AUT00063) was not effective in alleviating
tinnitus symptoms (Hall et al., 2019b).
The search for pharmacological treatments involves not
only identification of targets (genes/proteins), but also routes
of administration allowing optimal bioavailability. No clear
endophenotype or neural substrate has been identified for
tinnitus (Elgoyhen and Langguth, 2010). Tinnitus is described as
a side effect of a non-negligible number of compounds (Campbell
and Le Prell, 2018). The side-effect network integration revealed
many potential targets involved in its generation (which confirms
its heterogeneity) (Elgoyhen et al., 2014). Efforts for the
development of otoprotective agents and gene therapies for
gene correction and hair cells regeneration in sensorineural
hearing loss (SNHL) have been increasing with four programs
in preclinical phase and one in clinical development (Phase I/II)
(Schilder et al., 2019). Besides, intratympanic injections can be
used for efficient and reliable drug delivery. They remediate for
the loss of effectiveness of systemic routes of administration
(oral or intravenous) due to bioavailability due to the blood-
labyrinth barrier and have reduced side effects. Formulation
strategies including hydrogels, polymers and nanoparticulate
systems could potentiate the pharmacokinetics and drug delivery
to the otic compartment (Piu and Bishop, 2019). Although there
is a substantial medical need for a “tinnitus pill” (McFerran
et al., 2019), many challenges hinder its development including
tinnitus heterogeneity, insensitive outcome measures and the
lack of objective measurements, impeding the translation from
animal data to clinical application (Cederroth et al., 2018).
6.5. Other Interventions
6.5.1. Non-invasive Neurostimulation
Non-invasive neuromodulation techniques, such as transcranial
magnetic stimulation (TMS), transcranial electrical stimulation
(tES), and neurofeedback (NFB), have also been used for the
treatment of tinnitus. Traditionally, low-frequency repetitive
TMS (rTMS) was introduced to reduce tinnitus-related
hyperactivity of the auditory cortex (Langguth et al., 2003).
Apart from several studies that investigated the effect of low-
frequency rTMS in tinnitus (Schoisswohl et al., 2019), other trials
examined the efficacy of continuous theta-burst stimulation
(cTBS) (Plewnia et al., 2012; Schecklmann et al., 2016), high-
frequency rTMS over the temporal cortex (Khedr et al., 2008,
2010), as well as multi site stimulation protocols such as an
additional excitatory stimulation of the dorsolateral prefrontal
cortex (DLPFC) (Lehner et al., 2013, 2016; Langguth et al.,
2014; Formánek et al., 2018). Additionally, a combination of
rTMS with specific medications (Kleinjung et al., 2009; Okamoto
et al., 2010), relaxation techniques (Kreuzer et al., 2016), and
peripheral muscle stimulation (Vielsmeier et al., 2018) have
been investigated. However, there is still uncertainty regarding
the efficacy of rTMS for the treatment of tinnitus, as indicated
by several reviews with varying conclusions (Meng et al., 2011;
Soleimani et al., 2016; Zenner et al., 2017; Londero et al., 2018),
and two RCTs reporting conflicting results (Landgrebe et al.,
2010; Folmer et al., 2015). Other than apparent differences
in the investigated samples, potential reasons for inconsistent
findings might be associated to gene polymorphisms related to
neuroplasticity (Antal et al., 2010; Polania et al., 2018) or the
intrinsic state prior stimulation (Silvanto and Pascual-Leone,
2008). For example, Weisz et al. (2012) demonstrated state-
dependency effects of low-frequency rTMS applied over the
auditory cortex. Another possible explanation could be the
lack of clarity about appropriate stimulation parameters for the
treatment of tinnitus (Schoisswohl et al., 2019). A promising
approach to overcome this issue is provided by test sessions and
the application of a reduced number of pulses. In test sessions,
various stimulation frequencies or positions can be evaluated
concerning brief tinnitus suppression to identify an efficient and
individualized rTMS protocol (Schoisswohl et al., 2020). A pilot
study already emphasized the utilization of personalized rTMS
for the treatment of tinnitus (Kreuzer et al., 2017). Nevertheless,
further systematic groundwork is needed to identify factors
influencing the efficacy of rTMS in tinnitus.
In addition to TMS, since 2006 (Fregni et al., 2006), various
forms of non-invasive tES have been explored as potential
options for tinnitus management. tES is a neuromodulatory
technique in which the weak current applied to the scalp is
thought to modify neural processing (Bestmann and Walsh,
2017). The current can be constant, as is the case in
transcranial direct current stimulation (tDCS), or alternating, as
in transcranial random noise stimulation (tRNS) and transcranial
alternating current stimulation (tACS). All three methods have
been shown to increase cortical excitability in healthy subjects
(Inukai et al., 2016). In tDCS, a small, constant current (1.0–
2.0 mA) is applied to the scalp through two pad electrodes for
10–30 min. In tinnitus research, DLPFC has been targeted most
often, followed by left temporoparietal area (LTA) (Kok et al.,
2020). One challenge faced in tDCS research is the non-focal
stimulation pattern created by the electrodes, which makes it
challenging to target specific brain regions. Another technique
called high-definition transcranial direct current stimulation
(HD-tDCS) can overcome this as it results in more focal
stimulation (Datta et al., 2009). Shekhawat et al. (2016) carried
out a cross-over optimization study for HD-tDCS in tinnitus
patients, comparing different stimulation intensities, duration,
and locations. It was found that 77.78% of the participants were
responsive to the treatment, with stimulation of 2.0 mA for 20
min to either DLPFC or LTA being the most effective stimulation
paradigm. Jacquemin et al. (2018) compared tDCS of either
LTA or DLPFC to HD-tDCS of DLPFC and found a clinically
significant improvement in 32% of the participants regardless of
stimulation position. Two systematic reviews with meta-analysis
on the efficacy of tDCS for tinnitus have been carried out,
showing a significant reduction in either tinnitus loudness (Song
et al., 2012) or tinnitus-related distress (Wang et al., 2018) when
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Simoes et al. Challenges and Future Directions in Tinnitus Research
compared to sham protocols. These reviews only included six
and eight studies respectively and both concluded more RCTs are
needed to draw firm conclusions. As in the case of TMS, there is a
lack of replicability of results, which can be due to the difference
in stimulation protocols and tinnitus heterogeneity. In tACS and
tRNS, instead of a constant current, an alternating current is
applied through the electrodes. To our knowledge, no systematic
reviews have been published on the effect of these techniques on
people with tinnitus. However, a recent narrative review of tES
for tinnitus concluded that the effects of tACS, tRNS and tDCS
are inconsistent and dependent on the method and montage used
(Langguth, 2020).
Neurofeedback (NFB) is a