Approximately 2% of the population is extremely bothered by tinnitus [1
], showing an increased risk in suicide attempts [2
] and seeking medical support. Patients with severe tinnitus often present themselves with anxiety, depression and stress [4
], thus largely affecting life quality. There are no effective treatments [9
], and health care costs are substantial [12
The reduced tolerance to general everyday sounds is also known as hyperacusis, in which the sounds are uncomfortably loud or painful, ultimately impairing social, occupational and recreational activities [14
]. Experienced by nearly 9% of the population, hyperacusis is more prevalent in people with Williams Syndrome or autism spectrum disorders [15
]. Hyperacusis can also be seen in disorders of perception involving the visual and somatosensory functions with higher light sensitivity, headaches and lower pain thresholds in persons with chronic pain [16
]. Interestingly, about 90% of people with hyperacusis report concurrent tinnitus, suggesting a strong relationship [17
]. While a number of studies investigate the relationship between hyperacusis and tinnitus [18
], estimates of the association between tinnitus and hyperacusis in humans is lacking and remains a major research question [19
Recent studies suggest that tinnitus could emerge as a failure to adapt to missing sensory information from the ear [20
]. This loss of sensory input leads to an enhancement of the auditory stimuli in the auditory central system, also known as central neural gain. This condition is characterized by altered tuning bandwidths, increased spontaneous and synchronous neural activity, which may contribute not only to tinnitus, but also to hyperacusis [21
]. It has, however, been very difficult to distinguish the neural correlates of tinnitus from those of hyperacusis, in both animal and human studies. In a model of salicylate, in which rats displayed behavioral evidence of both tinnitus and hyperacusis, the auditory network was found to be coupled to the cerebellum, the amygdala and the reticular formation, as evidenced with resting-state functional magnetic resonance imaging (fMRI) [22
]. Similar findings were found in humans with tinnitus, but in those studies, hyperacusis was either low or being excluded at recruitment [23
]. Hyperacusis has been correlated with greater sound-evoked activity in the inferior colliculus (IC), the medial geniculate body (MGB), and the auditory cortex (AC). In a model of active loudness, it has been proposed that hyperacusis results from increased non-linear gain, whereas tinnitus results from central noise independent of gain [25
Here, we investigate the association between tinnitus and hyperacusis using data from the Swedish Tinnitus Outreach Project and further analyze the phenotypic traits related to tinnitus with accompanying hyperacusis.
Our findings reveal a strong association between tinnitus and hyperacusis. This association peaked when both tinnitus and hyperacusis were perceived as severe, reaching an OR of 77.4 (95% CI, 35.0–171.3) in a fully adjusted model. This tight relationship was also confirmed by the high prevalence of hyperacusis in participants with severe tinnitus (80%). Severely impaired hearing ability, which here relates to the difficulty to understand speech in a noisy environment (a proxy of retrocochlear damage), is strongly associated with severe tinnitus, as evidenced with an OR of 137.6 (95% CI, 62.8–301.2). In the absence of adjustment of this factor in the regression model, the association between severe hyperacusis and severe tinnitus reaches 251.7 (95% CI, 120.4–526.6), demonstrating the important confounding effect of hearing ability in both severe tinnitus and hyperacusis. Indeed, in line with previous research [44
], hearing disability was strongly related in our dataset, not only with severe tinnitus, but also with severe hyperacusis (OR, 102.3; 95% CI, 56.9–184.2). This relationship with hearing ability is such that once included in the model, multivariable ORs (adjusted for sex, age, level of education and hearing ability) were found below unity with increasing age. In contrast, crude ORs (without any adjustment) reflect the higher percentage of tinnitus among older compared to younger subjects, with ORs above the unity for subjects aged ≥55 compared to those aged <35. How the audiometric profile impacts on the severity of both tinnitus or hyperacusis would require further investigation; nonetheless, our study outlines a link between hyperacusis and tinnitus that will be influential: as hyperacusis is still less well recognized than tinnitus, despite the fact that these go almost hand in hand as severity increases, our work emphasizes the important need for research programs on both tinnitus and hyperacusis. The direction of this relationship (whether hyperacusis leads to tinnitus, or tinnitus leads to hyperacusis) remains however to be investigated.
Participants with severe tinnitus and severe hyperacusis are characterized by a greater proportion of blast exposure, bilateral tinnitus and familial history of tinnitus, which could help defining a clinical profile for patients with both conditions. Since genetics contribute in the familial transmission of bilateral and severe tinnitus in twins and adoptees [45
], it is possible that hyperacusis is also influenced by genetic factors. Recent studies in mice suggest that hyperacusis may be related to a form of pain and/or damage sensing mechanism [47
]. The similarity in brain signatures between chronic pain and tinnitus (and/or hyperacusis) emphasizes the need of investigating the genetic overlap between tinnitus and pain. Furthermore, as recent incentives to biobank tinnitus may lead to interesting mechanistical insights into the pathophysiology of tinnitus [49
], it will be critical to include information on hyperacusis and its severity. Notably, while the phenotyping study refers to hyperacusis as pain like symptoms, the association study employs another definition of hyperacusis as reduced sound tolerance. These two definitions may consist in two distinct or overlapping categories of hyperacusis. The framework proposed by Tyler et al. (2014) of tinnitus characterized by pain, annoyance, loudness or pain reports the various attributes of hyperacusis that are described by patients [51
]. These categories have not been empirically validated as yet, and the extent to which there is a consensus that support this proposal is unknown. Thus, subtyping of hyperacusis remains speculative.
In a study from Schecklmann et al., based on data from the Tinnitus Research Initiative (TRI) database, tinnitus patients with hyperacusis were found younger, displayed higher mental and general distress related to tinnitus, and reported pain disorders and vertigo more frequently than those without hyperacusis [31
]. Participants with tinnitus and hyperacusis could more often remark that external noise influenced their tinnitus, which could also more frequently be modulated by head and neck movements [31
]. Furthermore, these participants reported their subjective hearing function as being worse than those without hyperacusis. While these factors were also found different in the presence or absence of hyperacusis in the any tinnitus group, none were impacted by hyperacusis in the severe group. This may be due to the fact that the sample size of our severe tinnitus group was smaller than the group used in the TRI (n
= 1713), or that the THI ≥ 58 group from the STOP study was much more severe than that of the TRI (THI range; TRI: 41.9–53.6 vs. STOP: 72–73.6). However, in spite of the small sample size of our THI ≥ 58 group, we have previously reported differences in somatosensory modulations in these participants with or without temporomandibular joint (TMJ) complaints or headache [42
], which we could not reveal here being influenced by hyperacusis. It thus appears from this study on hyperacusis and our previous reports on TMJ and headache, that with greater tinnitus severity, fewer differences are found with or without the co-morbidities.
Our study suggests that estimates of an association between tinnitus and another condition may be strongly underestimated when working with a broad definition of tinnitus such as the “any” tinnitus presented here, encompassing occasional and constant forms, various levels of severity and duration. Instead, the severe tinnitus group, in which prevalence is close to that of the clinically relevant tinnitus, may represent the appropriate (and more homogenous) target group to focus research efforts on whether in cross-sectional, longitudinal or case/control studies. A limitation originating from this is the low prevalence of severe tinnitus, thus requiring large datasets to compute risks. In addition, given the growing importance of studying the impacts of sex on disease, stratified analyses will reduce the power of such studies, more so when considering subtypes. For instance, only one man without tinnitus reported severe hyperacusis leading to large confidence intervals. Thus, depending on the research question, datasets 10 to 100 times bigger than STOP may offer the possibility of addressing the epidemiology of severe tinnitus.
The inclusion of non-tinnitus controls is also an important contribution from our dataset. Without this group, one would believe that there is an increased risk for hyperacusis in women with tinnitus, whereas the inclusion of non-tinnitus controls shows this increased prevalence of hyperacusis in women already persists in absence of tinnitus, ultimately leading to equal ORs for tinnitus in men and women when having hyperacusis. Since temporomandibular joint disorders and headaches follow a similar pattern, it is possible that these co-morbidities do not contribute to sex differences in the burden associated with tinnitus.
Assuming the severe tinnitus group is the most relevant group to focus tinnitus research on, we may use it to identify co-morbidities shared or distinct between individuals with hyperacusis, headache or TMJ problems. Unlike the previous studies using data from the TRI, where tinnitus with hyperacusis was found comorbid with vertigo, neck pain and TMJ [31
], similar to tinnitus with headaches [53
], our data indicates that this is not the case (Figure 1
). Our results instead suggest that the general assumption that hyperacusis and headaches share similar somatosensory components is wrong. However, the somatosensory components may be common to tinnitus with TMJ complaints or headaches, both of which share neck pain and an impact on psychological quality of life. Hyperacusis, however, stands out with greater sensitivity and worsening of tinnitus by loud noises, something which is not seen in tinnitus with headaches or TMJ complains. Thus, we propose that while tinnitus with TMJ or headaches may share common mechanisms, hyperacusis is distinct, and shows no links to such somatosensory components (neck pain, vertigo and TMJ complains). The additive or synergistic contributions to tinnitus severity by hyperacusis and TMJ/headache remain to be investigated.
4.1. Implications for Diagnosis and Treatment
The combined occurrence of tinnitus and hyperacusis, particularly evident when both are severe, has some important implications for diagnosis and treatment [54
]. The assessment of both tinnitus and hyperacusis is essential in this population. However, some potential measurements for assessment may be off-limits due to their loud nature (e.g., (f)MRI, auditory brainstem responses, mismatch negativity or gap pre-pulse inhibition of startle response) [55
]. The potential use of hearing aids to reduce the starkness of tinnitus may be restricted by the presence of hyperacusis. Both tinnitus and hyperacusis may be accompanied by anxiety and distress, and these emotional aspects may be compounded by the presence of both symptoms. The determination from the patient of which symptom arose first, and which is their prime complaint could be used in the formulation of a treatment plan. From our data, the benefits of somatosensory [58
] or combined auditory-somatosensory [59
] treatments would appear to be limited in patients with severe tinnitus and hyperacusis in combination, which further highlights the importance of monitoring the two.
First, sample size significantly reduces as both the severity of tinnitus and hyperacusis increase. This could cause bias in the estimates, as for instance only one individual out of 563 men was found with severe hyperacusis in the non-tinnitus group. Thus, larger studies will be required to confirm the strong association between severe tinnitus and severe hyperacusis. Second, both tinnitus and hyperacusis were assessed at one single sample point and therefore the direction of the association remains to be determined. Finally, this study was based on the recruiting of participants from LifeGene, which may pre-empt its generalization to the general population.