Elsevier

Neuroscience

Volume 407, 21 May 2019, Pages 120-134
Neuroscience

Review
Rationale and Efficacy of Sound Therapies for Tinnitus and Hyperacusis

https://doi.org/10.1016/j.neuroscience.2018.09.012Get rights and content

Highlights

  • This is a comprehensive review of sound therapies for tinnitus and hyperacusis.

  • Putative mechanisms of T & H, and rationales for sound therapies are discussed.

  • Outcomes of sound therapy studies in animal models and human subjects are reviewed.

Abstract

Sound therapies are a common component of treatments for tinnitus and hyperacusis. The original idea was to partially or completely mask tinnitus with broadband noise delivered by sound generators or hearing aids, for a few hours each day. Over several months, many patients reported that their tinnitus became quieter or easier to bear, and that loud sounds became less aversive. However, it wasn’t always clear that these benefits could be attributed to sound therapy rather than to other aspects of treatment, such as counseling or hearing aid use, and not all patients reported benefits. During the past few decades, many other sound stimuli have been tried, including narrower bands of noise and tone bursts, music, and nature sounds. These sounds have been filtered in relation to the tinnitus pitch, adjusted for hearing loss, amplitude-modulated, and recently paired with electrical nerve stimulation. Many of our ideas about the neural underpinnings of tinnitus and hyperacusis come from animal models. However, studies of sound treatments in animals with putative tinnitus or hyperacusis have been rare. Clinical sound therapy trials are emerging, but outcomes typically remain modest, and few patients achieve complete remission of tinnitus or hyperacusis, unless the underlying hearing loss is treated with hearing aids or implants, in which case success rates are higher. More studies are needed, on both animal models and human subjects, to further explore the rationales for the various sound therapy options reviewed here, and to optimally tailor sounds and treatment approaches to individual patients, so that maximum benefits can be obtained.

Introduction

Subjective tinnitus is a phantom ringing, buzzing, roaring, or hissing that is perceived in one or both ears, in the head, or even externally (Eggermont, 2012). Hyperacusis is an aversive or painful reaction to sound levels that are acceptably loud to most people (Tyler et al., 2014, Pienkowski et al., 2014). The general prevalence of chronic tinnitus is estimated at 10–15% (Davis and El Rafaie, 2000, Shargorodsky et al., 2010, Nondahl et al., 2011), that of hyperacusis at 5–10% (Andersson et al., 2002), and both are more common in older age. About 20% of those with tinnitus or hyperacusis suffer a significantly reduced quality of life.

Tinnitus and hyperacusis are highly comorbid: 30–80% of people with a primary complaint of tinnitus also have hyperacusis (Nelson and Chen, 2004, Dauman and Bouscau-Faure, 2005, Bläsing et al., 2010, Hebert et al., 2013, Schecklmann et al., 2014), and about 85% with hyperacusis also have tinnitus (Anari et al., 1999, Sheldrake et al., 2015). A longitudinal study reported that the prevalence of hyperacusis in a sample of adults with chronic tinnitus increased from 38% to 85% over 5 years (Andersson et al., 2001), potentially explaining the large spread in the numbers cited above. An interesting recent observation was that teenagers who experienced transient tinnitus while in a sound-proof booth had loudness discomfort levels (LDLs) that were about 10 dB lower than for teens who did not experience tinnitus in a booth (Sanchez et al., 2016); both groups had normal audiograms to 16 kHz, and normal otoacoustic emissions. This suggests that the precursors of tinnitus and hyperacusis are also comorbid.

Tinnitus and hyperacusis are most often consequences of sensorineural or conductive hearing loss (Graham, 1981, Axelsson and Ringdahl, 1989, Nicolas-Puel et al., 2002, Nelson and Chen, 2004, Nosrati-Zarenoe et al., 2007, Shargorodsky et al., 2010, Theodoroff et al., 2015). People who have been exposed to high levels of occupational or recreational noise are more likely to have tinnitus or hyperacusis (Chung et al., 1984, Rosenhall and Karlsson, 1991, Griest and Bishop, 1998, Nondahl et al., 2011, Moore et al., 2017, Guest et al., 2017). Tinnitus and hyperacusis tend to be worse in those with more hearing loss, but this correlation is weak, in part because factors such as emotions, stress, attention, and memory can modulate symptom severity (Rauschecker et al., 2010, De Ridder et al., 2011, De Ridder et al., 2014a, Mazurek et al., 2012, Roberts et al., 2013, Chen et al., 2015, Sedley et al., 2016). Cognitive behavioral therapies for tinnitus and hyperacusis are presumably effective for this reason (Cima et al., 2014, Jüris et al., 2014, Thompson et al., 2017).

An estimated 40% of hyperacusis patients have “clinically normal” audiograms (Sheldrake et al., 2015), compared to 10–15% of tinnitus patients (Barnea et al., 1990, Sanchez et al., 2005, Hannula et al., 2011). These numbers are higher in children: 67% with hyperacusis (Myne and Kennedy, 2018) and 44% with tinnitus (Bartnik et al., 2012) had clinically normal hearing (see also Aazh et al., 2018). However, clinically normal audiograms (≤20 dB HL, measured up to 8 kHz) do not necessarily preclude cochlear damage and poor suprathreshold hearing (Pienkowski, 2017). Indeed, there is evidence that some audiometrically normal tinnitus patients have sensorineural hearing loss (Weisz et al., 2006, Schaette and McAlpine, 2011, Paul et al., 2017). However, tinnitus can also reflect aberrant somatosensory activity (Shore, 2011), and result from head injury (MacGregor et al., 2013, Chorney et al., 2017), while hyperacusis is common in conditions such as superior semicircular canal dehiscence (Watson et al., 2000, Minor, 2005), autism (Rosenhall et al., 1999, Wilson et al., 2017), and Williams syndrome (Klein et al., 1990, Gothelf et al., 2006), often without the involvement of hearing loss. On the other hand, many people with hearing loss do not have tinnitus or hyperacusis, topics to which we will return.

Successful treatment of the underlying hearing loss can lead to a partial or even full remission of tinnitus and hyperacusis. This holds for treatment with hearing aids (Surr et al., 1985, Folmer and Carroll, 2006, Trotter and Donaldson, 2008, Forti et al., 2010, Searchfield et al., 2010, Parazzini et al., 2011, Peltier et al., 2012, McNeill et al., 2012, Munro and Merrett, 2013, Jalilvand et al., 2015; but see Moffat et al., 2009), cochlear implants (Van de Heyning et al., 2008, Pan et al., 2009a, Punte et al., 2011, Kompis et al., 2012, Ramos Macías et al., 2015), and surgical fixes of conductive loss (Gersdorff et al., 2000, Sobrinho et al., 2004, Lima Ada et al., 2007), but several caveats are worth mentioning. First, many of the above studies were not placebo-controlled, and relied on questionnaires or other subjective outcome measures, which are generally more susceptible to placebo effects than objective tests. Second, hearing aids may help with tinnitus only if the tinnitus pitch lies within their amplification range (Schaette et al., 2010, McNeill et al., 2012); this typically extends to 4–6 kHz, but should be verified with real-ear measurements. Finally, cochlear implants can give rise to or exacerbate tinnitus in a small minority of patients, and this may be linked to a loss of residual hearing after implantation (Arts et al., 2015, Ramakers et al., 2018).

Many sufferers of bothersome tinnitus and hyperacusis do not have sufficient hearing loss to warrant hearing aid use, or have a high-pitched tinnitus that lies outside of the aidable frequency range. Sound therapies comprise a popular treatment component for unaided and aided patients alike (Formby and Keaser, 2007, Henry et al., 2015, Henry et al., 2017, Tyler et al., 2015, Tutaj et al., 2018). One of the earliest accounts of the use of wearable noise generators in tinnitus management was provided by Vernon (1977). There was always a hope that sound therapy could bring tinnitus (and hyperacusis) patients long-lasting relief, beyond just masking the tinnitus while the generator was turned on, or “residually inhibiting” it for a brief time thereafter.

Ten years ago, McKenna and Irwin (2008) published a provocatively titled review of sound therapies for tinnitus, concluding, “The evidence is mixed but, on balance, it appears that sound therapy does not significantly contribute to the overall therapy package. If and when it does add to tinnitus therapy it seems likely that it does so through the mediation of psychological factors rather than that the sensory stimulation directly leads to neuronal reorganization.” (p. 23). This conclusion was broadly accurate at the time, as many studies did not isolate the effects of sound therapy from other potentially beneficial aspects of treatment, such as counseling (Tyler et al., 2001, Aazh et al., 2016, Gold and Formby, 2017) or hearing aid use (referenced above), and did not report details such as sound bandwidths and levels, tinnitus pitch and loudness, etc. Nevertheless, several of the earlier papers did report promising sound therapy outcomes for tinnitus (Henry et al., 2006, Davis et al., 2007) and hyperacusis (Noreña and Chery-Croze, 2007, Formby et al., 2007), and suggestive results were obtained from experiments on cats (Noreña and Eggermont, 2005, Noreña and Eggermont, 2006).

The past few decades have seen an explosion of sound-based treatments for tinnitus, if not also for hyperacusis. Some of the options now include:

  • broadband (BB) noise, or BB tone ensembles, filtered to match the audiometric loss (i.e., heard with a similar loudness across frequency; Noreña and Chery-Croze, 2007, Schaette et al., 2010), or not matched to the loss (Formby et al., 2007, Formby et al., 2015, Formby et al., 2017, Bauer and Brozoski, 2011, Tyler et al., 2012, Kim et al., 2014, Henry et al., 2016)

  • filtered BB noise combined with music (Davis et al., 2007, Davis et al., 2008, Hanley and Davis, 2008, Távora-Vieira et al., 2011, Wazen et al., 2011)

  • narrowband (NB) noise, or NB tone ensembles, matched to the tinnitus pitch (Tass et al., 2012, Adamchic et al., 2014, Eggermont and Tass, 2015, Hauptmann et al., 2015, Williams et al., 2015, Hall et al., 2016a, Haller and Hall, 2017, Theodoroff et al., 2017), or not matched (Sweetow and Sabes, 2010, Sweetow, 2013, Herzfeld et al., 2014)

  • music notch-filtered around the tinnitus pitch (Okamoto et al., 2010, Teismann et al., 2011, Pantev et al., 2012, Stein et al., 2016, Li et al., 2016)

  • tones at frequencies excluding the tinnitus pitch, and paired with electrical stimulation of the vagus nerve (Engineer et al., 2011, Engineer et al., 2013, De Ridder et al., 2014b, De Ridder et al., 2015, Tyler et al., 2017, Vanneste et al., 2017)

  • tones matched to the tinnitus pitch, and paired with electrical stimulation of the trigeminal nerve (Marks et al., 2018).

In addition to passive exposure, sound-based perceptual/cognitive training has also been tried (Herraiz et al., 2009, Hoare et al., 2010, Spiegel et al., 2015, Wise et al., 2016). In what follows, I’ll outline the neuroscientific basis of sound treatments for tinnitus and hyperacusis, and review the outcomes of recent animal studies and clinical trials.

Pioneering animal work showed that damage to the cochlea which permanently reduced the spike output of auditory nerve fibers (ANFs; Liberman and Kiang, 1978, Heinz and Young, 2004) could surprisingly increase spontaneous firing rates (SFRs) in the auditory brainstem and cortex (dorsal cochlear nucleus [DCN]: Kaltenbach and McCaslin, 1996, Kaltenbach and Afman, 2000, Kaltenbach et al., 2000; central nucleus of the inferior colliculus [ICC]: Bauer et al., 2008, Mulders and Robertson, 2009; primary auditory cortex [A1]: Komiya and Eggermont, 2000, Seki and Eggermont, 2003, Noreña and Eggermont, 2003). This spontaneous hyperactivity is observed in central neurons that correspond tonotopically to the damaged parts of the cochlea, which fits with the finding that most people hear tinnitus with a pitch that lies within the frequency range of their hearing loss (Noreña et al., 2002, König et al., 2006, Roberts et al., 2008, Pan et al., 2009b, Sereda et al., 2011, Schecklmann et al., 2012). Other important studies behaviorally tested noise-traumatized animals for tinnitus, and found a link between the strength of the evidence for tinnitus and elevated SFRs in the DCN (Kaltenbach et al., 2004, Middleton et al., 2011, Li et al., 2013, Wu et al., 2016), ICC (Sturm et al., 2017), and A1 (Basura et al., 2015). However, this link was not seen in all experiments (ICC: Coomber et al., 2014, Ropp et al., 2014, Longenecker and Galazyuk, 2016; A1: Engineer et al., 2011), so the hypothesis that increased central SFRs underlie tinnitus remains somewhat contentious.

Recent animal studies have found that noise trauma causing only temporary hearing threshold shifts can also lead to chronically increased central SFRs (DCN: Wu et al., 2016; ICC: Hesse et al., 2016; A1: Basura et al., 2015). These somewhat lower noise doses can leave outer hair cells (OHCs) intact, but destroy some of the synapses between inner hair cells (IHCs) and ANFs (Kujawa and Liberman, 2009), especially synapses with high-threshold ANFs (Furman et al., 2013). Interestingly, a 2-h exposure to octave-band noise at 100 dB SPL increased SFRs in the mouse ICC by an even greater margin than a more damaging exposure at 105 dB SPL, which likely caused both synaptopathy and OHC loss (Hesse et al., 2016). Modeling work showed that this could be explained by an increased loss of IHC synapses with low-threshold ANFs after the higher noise dose, potentially accounting for some of the heterogeneity in the relation between hearing loss and tinnitus. A paper by Turner and Larsen (2016) corroborated these findings by demonstrating that rats exposed to noise at 110 dB SPL were more likely to display evidence of tinnitus than rats exposed at 116 or 122 dB SPL. However, see Paul et al. (2017), who argued that low-threshold ANF loss contributes to human tinnitus, rather than prevents it. Also notable is recent work by Gao et al. (2016), showing that a 2-min exposure to tones at 109 dB SPL (and even 85 dB SPL) could transiently increase SFRs in the hamster DCN (following a brief initial decrease), thereby providing a plausible mechanism for noise-induced temporary tinnitus (Atherley et al., 1968).

Additional important animal studies described sound-evoked hyperactivity in the auditory brain after cochlear trauma (VCN: Cai et al., 2009; ICC: Salvi et al., 1990; A1: Syka et al., 1994, Noreña et al., 2010), which was linked with behavioral evidence of hyperacusis (Ison et al., 2007, Sun et al., 2011, Sun et al., 2012, Hickox and Liberman, 2014, Xiong et al., 2017, Alkharabsheh et al., 2017). In contrast to spontaneous hyperactivity, sound-evoked hyperactivity appears to be greatest at frequencies below the edge of a mid- or high-frequency cochlear loss. This could be a consequence of the loss of lateral inhibition from the central hearing loss region to lower frequency-regions (Auerbach et al., 2014). On longer time scales, these lesion-edge frequencies can become “over-represented” in the central auditory system, activating more neurons especially in the thalamic medial geniculate body (MGB) and in A1 (Eggermont, 2017). This could account for the finding that hyperacusis is commonly experienced over a broad frequency range, including the lower frequencies at which hearing sensitivity is normal (Anari et al., 1999, Noreña and Chery-Croze, 2007, Sheldrake et al., 2015, Formby et al., 2007).

Central hyperactivity following peripheral loss is generally attributed to the combination of reduced inhibitory synaptic transmission and increased excitatory transmission (DCN: Whiting et al., 2009, Wang et al., 2011, Middleton et al., 2011, Li et al., 2013; ICC: Milbrandt et al., 2000, Vale and Sanes, 2002, Argence et al., 2006, Sturm et al., 2017; A1: Kotak et al., 2005, Sanes and Kotak, 2011, Resnik and Polley, 2017, Asokan et al., 2018). Additionally, sensory deprivation can lead to an upregulation of Na+ channels at post-synaptic axon hillocks (Kuba et al., 2010), intrinsically increasing the excitability of central neurons. The purpose of these synaptic and intrinsic excitability changes is thought to be the maintenance of long-term stable activity levels in the brain (hence the popular term “homeostatic plasticity”), in order to make optimal use of chronically under-stimulated (or over-stimulated) central neurons (Turrigiano, 2011, Nahmani and Turrigiano, 2014). However, central neurons are also capable of rapidly adjusting the operating points of their input/output functions to the prevailing distributions of stimulus intensities (Brenner et al., 2000, Dragoi et al., 2000, Dean et al., 2005, Dean et al., 2008, Robinson and McAlpine, 2009). Perhaps the slower, homeostatic-type changes are a more efficient way of stabilizing the dynamic ranges of central neurons in the longer-term.

Although relatively few human imaging studies have correlated central spontaneous hyperactivity with tinnitus (e.g., see review by Elgoyhen et al., 2015), and sound-evoked hyperactivity with hyperacusis (Gu et al., 2010), the homeostatic plasticity model (Schaette and Kempter, 2006, Noreña, 2011) is supported by the fact that tinnitus (Del Bo et al., 2008, Schaette et al., 2012) and hyperacusis (Formby et al., 2003, Munro and Blount, 2009, Munro et al., 2014) can be reversibly induced in people during a period of auditory deprivation, in the absence of any damage to the cochlea. However, it should be noted that these observations are also consistent with an alternative model of the emergence of central hyperactivity, based on the principle of stochastic resonance (Krauss et al., 2016). Briefly, the idea is that hearing loss (or auditory deprivation more generally) leads to an adaptive increase in the SFR (which is interpreted as “neural noise”), in order to increase the probability of detecting low-level (subthreshold) sounds. Both the homeostatic plasticity and stochastic resonance models also predict that peripheral damage which leaves ANF spontaneous rates relatively unaffected is more likely to trigger tinnitus. This is the case for conductive problems, for OHC loss (but not IHC loss), and for high-threshold/low-spontaneous rate ANF loss (but not low-threshold/high-spontaneous rate ANF loss). While there is some experimental evidence for these predictions (Kaltenbach et al., 2002, Schaette and McAlpine, 2011, Ruttiger et al., 2013), the case is not yet compelling. Also potentially consistent with both of these models are findings that tinnitus is more common in sudden vs. gradual hearing loss (Nosrati-Zarenoe et al., 2007), and that it is rare or non-existent in congenital hearing loss, unless the loss worsens with age (Eggermont and Kral, 2016, Lee et al., 2017).

Also observed in the central auditory system within a short time of cochlear trauma is an increase in the synchrony of spontaneous firing between neurons in the deprived frequency region (DCN: Wu et al., 2016; A1: Noreña and Eggermont, 2003, Seki and Eggermont, 2003). This has been proposed to contribute to tinnitus, and likely reflects an unmasking of local connections in the deprived region (Eggermont and Roberts, 2004, Eggermont and Tass, 2015). Compared to controls, people with tinnitus appear to have more synchronous neural firing in the delta (<4 Hz) and beta/gamma bands (>16 Hz) of electro- and magnetoencephalographic (EEG & MEG) recordings, and less synchronous firing in the alpha band (8–15 Hz) (Llinas et al., 1999, Weisz et al., 2005, Weisz et al., 2007, Vanneste et al., 2018). However, in a recent study, individual EEG amplitudes did not correlate with tinnitus severity as assessed by questionnaires and visual analog scales (Pierzycki et al., 2016). The link between increased neural synchrony and hyperacusis is also speculative, but there is evidence that synchronous firing plays a role in the perceptual salience and loudness of sounds (Eggermont, 1990, Eggermont, 2007).

Just as auditory deprivation can induce tinnitus (Del Bo et al., 2008, Schaette et al., 2012) and hyperacusis (Formby et al., 2003, Munro and Blount, 2009, Munro et al., 2014) in normal-hearing people, persistent low- to moderate-level sound stimulation can induce reversible hypoacusis. Formby et al. (2003) had young adult subjects wear noise generators for 2 weeks; these continuously played binaural noise with an effective bandwidth of 1–8 kHz, peaking at 50 dB SPL near 6 kHz. After the 2 weeks, subjects needed about 6 dB higher SPLs to match their baseline loudness ratings. This temporary hypoacusis was observed at both 0.5 and 2 kHz, despite the limited sound stimulation at 0.5 kHz. Another example of a global change in loudness, but after a frequency-specific deprivation induced by ear plugging, was provided by Munro et al. (2014).

Mostly consistent with the above results, a series of studies on normal-hearing adult cats and rats found that within several weeks of exposure to various types and bandwidths of moderately loud noise (∼70 dB SPL), A1 responses to sound frequencies within the noise band were strongly but reversibly suppressed (Noreña et al., 2006, Pienkowski and Eggermont, 2009, Pienkowski and Eggermont, 2010a, Pienkowski and Eggermont, 2010b, Pienkowski et al., 2011, Pienkowski et al., 2013, Lau et al., 2015). However, along with this “neural hypoacusis” at frequencies within the noise band, both spontaneous and sound-evoked hyperactivity were observed in A1 regions corresponding to frequencies above and below the exposure band, along with increased neural synchrony (Pienkowski and Eggermont, 2011, Pienkowski and Eggermont, 2012, Munguia et al., 2013). This local A1 hyperactivity was puzzling given the findings of Formby et al., 2003, Munro et al., 2014, but we nevertheless hypothesized that moderate noise-exposed animals might develop tinnitus and frequency-specific hyperacusis. However, this hypothesis was not supported by a recent mouse study that used tone- and gap-prepulse inhibition of the acoustic startle reflex (GPIAS) to test for hyperacusis and tinnitus, respectively (Pienkowski, 2018). While any perceptual consequences of the local A1 hyperactivity observed by Eggermont and colleagues remain a mystery, these negative findings bode well for the safety of sound treatments for tinnitus and hyperacusis, although sound levels should be kept low enough to avoid the risk of cochlear synaptopathy (Pienkowski, 2018; see also Sheppard et al., 2017). Nevertheless, a recent conference poster suggested that non-traumatic noise could indeed trigger tinnitus in mice (Screven et al., 2018), and it is possible for sound treatments to exacerbate existing tinnitus (e.g., Jastreboff, 1999, Vanneste et al., 2013).

Relatively few studies have investigated the effects of exposing animals to moderately loud noise after inducing peripheral hearing loss. Noreña and Eggermont (2005) exposed adult cats bilaterally to 5-kHz third-octave noise at 120 dB SPL for 1 h, and followed it immediately with a 1–2-month exposure to 80 dB SPL, high-pass filtered noise (>8 kHz), matched to the expected high-frequency hearing loss. They found that the 80 dB SPL noise led to a reduction of the high-frequency loss, but at the cost of additional mid-frequency loss. However, the 80 dB noise prevented the over-representation of mid-frequencies that was seen in A1 of trauma-only controls, and also prevented the emergence of elevated SFRs and neural synchrony in A1 (Noreña and Eggermont, 2005, Noreña and Eggermont, 2006). Similar exposure with a low-pass noise (<8 kHz) did not prevent any of the changes seen in trauma-only controls.

Sound treatments have recently been revisited by two animal studies which included behavioral testing for tinnitus. Sturm et al. (2017) unilaterally exposed young (P20–23) C57BL/6J mice to a 16-kHz NB noise at 116 dB SPL for 45 min. GPIAS testing was performed before and 7 days after trauma. 19 of 37 mice (51%) showed evidence of tinnitus, and all gap detection deficits were observed at frequencies between 16 and 32 kHz, i.e., in the frequency range of the hearing loss. ABR threshold shifts at 16–32 kHz were 10–20 dB in the exposed ear, and were not different between mice with and without evidence of tinnitus. Importantly, noise trauma resulted in decreased inhibitory transmission and increased excitatory transmission in the ICC, but only in the group of animals which developed gap deficits. Another group of 25 mice was exposed immediately after trauma, for 7 days, to 75 dB SPL pulsed BB noise (138 ms pulses with random inter-pulse intervals of 0–450 ms). This exposure prevented the decrease in inhibition and increase in excitation seen in the ICC of the trauma-only group, and only 3 of the 25 treated mice (12%) showed evidence of tinnitus.

Jones and May (2018) unilaterally exposed adult Sprague–Dawley rats to a 16-kHz tone at 116 dB SPL for 2 h. An operant conditioning technique suggested that 5 of 9 rats developed tinnitus with a pitch of around 16 kHz, 2 rats did not develop tinnitus, and 2 yielded indeterminate results. Another batch of 9 rats was subjected to the same acoustic trauma, and then housed for 2 months in a vivarium with peak noise levels of 30–35 dB SPL from 3 to 10 kHz, remaining above 20 dB SPL up to 20 kHz. Although most of the noise power was below the 16 kHz trauma frequency and tinnitus pitch (in contrast to Noreña and Eggermont, 2005, Noreña and Eggermont, 2006), none of the noise-housed rats (0/9) tested positive for tinnitus: 6 were classified as tinnitus-negative, and 3 were indeterminate. Interestingly and reminiscent of Noreña and Eggermont (2005), the noise-housed rats of Jones and May (2018) showed a greater average hearing loss in the trauma ear than did quiet-housed rats, despite the relatively low noise levels in the vivarium.

Although each of the above studies used very different sound treatments, all appeared to prevent the emergence of the neural and/or behavioral correlates of tinnitus. Further studies are needed to determine whether sound treatments that are delayed with respect to the noise trauma can produce similar benefits. As it stands, these animal findings indicate that sound therapy has particular potential in treating individuals who suffered recent acoustic injury, as is common in military and other situations. Further studies are also needed to investigate the observation that sound treatment may exacerbate trauma-induced hearing loss, even if only over a narrow frequency range (Noreña and Eggermont, 2005, Jones and May, 2018). Other work had found that sound stimulation after a noise trauma reduced hearing loss at all frequencies (Niu et al., 2004, Tanaka et al., 2009), whereas auditory deprivation appeared to exacerbate it (Fukushima et al., 1990). Moreover, exposure to moderate noise has been shown to slow the degeneration of cochlear hair cells and nerve fibers in mice with hereditary progressive hearing loss (Willott and Turner, 1999, Willott and Bross, 2004). Finally, it’s perhaps worth mentioning that in the Niu et al. (2004) study, low-frequency tonal stimulation (1 kHz, 81 dB SPL) reduced the damage caused by a 2.7 kHz tone trauma (103 dB SPL for 30 min), whereas high-frequency tonal stimulation (6.3 kHz, 78 dB SPL) after a 5.5 kHz tone trauma (109 dB SPL for 30 min) had no effect. This contrasts with the findings of Noreña and Eggermont, 2005, Noreña and Eggermont, 2006, where higher-frequency stimulation was protective at high-frequencies (but damaging at mid-frequencies), and lower-frequency stimulation had no effect.

Two additional animal studies have paired sound treatment after noise trauma with electrical stimulation of the vagus or trigeminal nerves. Engineer et al. (2011) exposed rats to 16-kHz octave-band noise for 1 h at 115 dB SPL, and observed that “twice as many A1 recording sites were tuned to frequencies between 2 and 4 kHz in comparison with naive controls (35 ± 7% versus 14 ± 2%, P < 0.05), and very few neurons responded to frequencies above 23 kHz (1.7 ± 1% versus 11.5 ± 3%, P < 0.01)” (p. 101–102). 18 of 28 rats exhibited GPIAS results consistent with tinnitus in the 8–10 kHz range. This is unusual after an exposure centered at 16 kHz, although a tinnitus pitch below the trauma frequency had also been noted in a previous report (Bauer et al., 2008). In contrast with the studies discussed above, which used sound stimulation to prevent the emergence of tinnitus, Engineer et al. (2011) waited for 4 weeks before treating the tinnitus rats with paired tone burst and vagus nerve stimulation (VNS) for 18 days. In control rats, it was shown that VNS produced an expansion of the A1 representational area for the paired tone frequency, likely via vagus activation of the nucleus basalis (Kilgard and Merzenich, 1998). Engineer et al. (2011) paired VNS with tone burst frequencies of 1.3, 2.2, 3.7, 17.8 and 29.9 kHz (one randomly chosen tone per vagus shock), which was meant to stay clear of the 8–10 kHz tinnitus pitch. The idea was to expand the A1 representational area of frequencies below and above the tinnitus pitch, and reduce the representational area of the tinnitus pitch itself. However, it seems that including the 2.2 and 3.7 kHz tones should have added to the above-mentioned over-representation of the 2–4 kHz octave. In any case, treatment was reported to normalize A1 tonotopic maps, and reverse the positive tinnitus results. Interestingly, A1 SFRs remained elevated (or even increased further) after apparent tinnitus remission.

Marks et al. (2018) paired tone bursts with electrical stimulation of the trigeminal nerve, which sends somatosensory information to DCN fusiform cells. Details of the noise trauma were not provided, but it produced GPIAS-based evidence of tinnitus in 16 of 22 guinea pigs (73%), measured after 8 weeks, despite causing only temporary increases in ABR thresholds that recovered after a few days. The tinnitus was most often associated with gap deficits at 8 kHz, and animals with tinnitus exhibited increased SFRs and neural synchrony in the DCN compared to both unexposed controls, and exposed but tinnitus-negative animals. After the 8 weeks, tinnitus animals were treated for 25 days with the paired tonal and trigeminal nerve stimulation. The tone frequency was always 8 kHz, matching the tinnitus pitch, and tone onset preceded electrical shock by 5 ms, an interval shown to produce long-term depression of DCN fusiform cells. This bimodal stimulation decreased SFRs and synchrony between fusiform cells, and reduced GPIAS evidence of tinnitus at 8 kHz. As in the study of Engineer et al. (2011), tonal or electrical stimulation alone had no effect.

While the Engineer et al., 2011, Marks et al., 2018 papers suggest that these approaches could be useful in treating established human tinnitus, a major question mark for many animal studies is whether the behavioral tests for tinnitus are in fact reliable (Eggermont, 2013, Hayes et al., 2014, Galazyuk and Hebert, 2015). It has been shown that people with tinnitus do not have bigger gap detection deficits than hearing loss-matched controls without tinnitus, calling the rationale for the GPIAS method into question (Campolo et al., 2013, Fournier and Hébert, 2013, Boyen et al., 2015). Note that in these human studies, the NB noise in which the gaps are embedded was matched to the tinnitus pitch more closely than is possible in animal work, yet the results were negative. Moreover, a high dose of salicylate known to reliably induce tinnitus in rats failed to produce evidence of gap detection deficits in an operant conditioned task (Radziwon et al., 2015). Given this controversy, cross-validation of GPIAS and operant tests in animal models of tinnitus should be a high research priority. A recent paper showed that noise-traumatized guinea pigs exhibited electrocorticographic evidence of gap detection deficits (Berger et al., 2018), but it was not reported whether or not these correlated with GPIAS-based deficits.

There have been several recent reviews of the outcomes of sound treatments for tinnitus (Hobson et al., 2012, Hoare et al., 2013, Hoare et al., 2014a, Searchfield et al., 2017). A general consensus is that there have been too few placebo-controlled trials that isolated the sound therapy component from other aspects of treatment. Another problem is that outcome measures have varied widely between studies (Hall et al., 2016b), and were often limited to questionnaires, which again are generally more susceptible to placebo effects than objective measures. Additionally, despite the comorbidity of tinnitus and hyperacusis, only a handful of studies (mostly case reports), have assessed sound therapy outcomes for hyperacusis. The aim of this section is to provide a rationale for each of the sound treatments listed in the Introduction, and to review their efficacy, emphasizing recent results. Note that unlike most of the animal work described in the preceding section, human trials have generally been conducted on patients with already established (typically >6 months) chronic tinnitus or hyperacusis. Also, for treatments that rely on tinnitus pitch matches, it should be mentioned that these can vary widely (by as much as an octave or more) between test sessions, so care is required in their measurement and monitoring (Hutter et al., 2014, Hoare et al., 2014b).

The most widely used sound therapy for tinnitus and hyperacusis has been BB noise. This was originally presented at levels loud enough to completely mask tinnitus, rendering it inaudible while the noise was turned on (Vernon, 1977). However, according to the “neurophysiologic model” behind Tinnitus Retraining Therapy (TRT; Jastreboff and Hazell, 1993, Jastreboff and Jastreboff, 2000, Jastreboff, 2015), it is better to use BBN levels that are just below the tinnitus sensation level (sometimes referred to as the “mixing point”), which purportedly allows patients to habituate to the tinnitus. Tyler and Bentler (1987) had also suggested using mixing point BB noise to partially mask tinnitus, and this was incorporated into the Tinnitus Activities Treatment (TAT; Tyler et al., 2006).

Bauer and Brozoski (2011) compared the benefits of counseling alone to counseling with mixing point BB noise, and found a larger improvement in the noise therapy group. This was assessed with the Tinnitus Handicap Inventory (THI; Newman et al., 1996, Newman et al., 1998), and with several visual analog scales (VAS) of tinnitus loudness and annoyance. However, neither counseling nor sound therapy reduced tinnitus loudness when measured psychoacoustically. In another approach, Kim et al. (2014) reported that THI and VAS tinnitus loudness scores showed greater improvement in patients treated with mixing point BB noise compared to another group treated with NB noise matched to the tinnitus pitch. There were no controls but both groups received the same counseling. Henry et al. (2016) conducted a large trial comparing BB noise in total vs. partial tinnitus masking, and found that both groups experienced a similar modest reduction in the THI that was significantly greater than the reduction due to counseling alone. The same conclusions (no differences between patients using mixing point vs. total masking noise) had been drawn in a previous smaller study by Tyler et al. (2012). Formby et al., 2007, Formby et al., 2015, Formby et al., 2017) reported good success with using low-level BB noise to treat hyperacusis, and to expand the loudness dynamic range in patients with hearing loss, a useful precursor to first-time hearing aid use.

Durai and Searchfield (2017) compared the benefits of BB noise to those of natural sounds (surf, cicadas, and rain). Tinnitus subjects selected their preferred natural sound, and on average rated all 3 sounds as more pleasant to listen to than BB noise. Despite this, Tinnitus Functional Index scores (TFI; Meikle et al., 2012, Henry et al., 2016) showed more improvement after BB noise than after any of the natural sounds. (Each subject listened to either BB noise or their chosen natural sound for 8 weeks, then crossed over to the other treatment for another 8 weeks, after a 3 week washout period.) However, even the stronger BB noise effect on the TFI was modest, while psychoacoustic measures of tinnitus loudness and masking levels were unchanged after all treatments.

An important lesson from the Durai and Searchfield (2017) work is that pleasant sounds may be no more likely to reduce long-term tinnitus distress than less pleasant ones, though of course unpleasant sounds may decrease treatment compliance. The ease of listening to “fractal tones” was promoted as facilitating relaxation and reducing long-term tinnitus annoyance (Sweetow, 2013). While a study showed notable improvements in THI and TFI scores after 2 months of treatment (Herzfeld et al., 2014), the potential benefits of the sound therapy were not dissociated from those of counseling, hearing aid use, and a relaxation program.

BB noise, or BB tone ensembles, have also been tailored to match the audiometric loss, i.e., presented at a constant sensation level across frequency (Noreña and Chery-Croze, 2007, Schaette et al., 2010). This approach seems especially promising for hyperacusis, which again is commonly experienced at all frequencies, irrespective of the range and amount of hearing loss (Anari et al., 1999, Noreña and Chery-Croze, 2007, Sheldrake et al., 2015, Formby et al., 2007). In a small study of hyperacusis patients with good low-frequency hearing, average high-frequency losses of 30 dB, and LDLs that were 30–40 dB below normal at all frequencies, Noreña and Chery-Croze (2007) showed that 15 weeks of treatment with audiometrically-matched tone ensembles resulted in 10–15 dB improvements (increases) in LDLs across frequency. While the study was not placebo-controlled, only limited benefits (<5 dB) were seen after 2 weeks of treatment, and measurements made 1 month after the end of the full 15-week treatment period showed that LDLs had significantly decreased again. This suggests that sound therapy was responsible for the reported LDL increases, and that sound therapy needs to be ongoing if its full benefits are to be retained. Unfortunately, no larger follow-up trials have been conducted.

The Neuromonics® tinnitus program combines audiometrically-tailored, low-level BB noise with music (Hanley and Davis, 2008). A number of efficacy studies have been conducted (Davis et al., 2007, Davis et al., 2008, Távora-Vieira et al., 2011, Wazen et al., 2011), all employing the Tinnitus Reaction Questionnaire (TRQ; Wilson et al., 1991) as the primary outcome measure (Távora-Vieira et al. (2011) also used the THI). Although all studies showed considerable improvements in TRQ scores (the Neuromonics® website reports an overall program success rate of 83%), none of them were placebo-controlled, and none separated the sound therapy component from other aspects of treatment.

Another treatment option for tinnitus is NB noise or NB tone ensembles that are matched to the tinnitus pitch. Stimulation at frequencies close to the tinnitus pitch is intended to scale back the increased neural gains that are presumed to underlie central spontaneous hyperactivity and tinnitus. Additionally, an approach termed Acoustic Coordinated Reset (CR®) Neuromodulation aims to reduce the neural synchrony that potentially contributes to tinnitus, by presenting pitch-matched, NB tone ensembles in a temporally random sequence (Eggermont and Tass, 2015). In the first placebo-controlled trial of acoustic CR® neuromodulation, Tass et al. (2012) reported a significant reduction of tinnitus loudness (using VAS) and tinnitus distress (using a German questionnaire; Goebel and Hiller, 1993). In an important follow-up study, Adamchic et al. (2014) showed that CR® neuromodulation reversed the previously mentioned increases in EEG delta and beta/gamma power, and the decrease in alpha power, seen in tinnitus subjects relative to controls. Other uncontrolled studies have also shown positive outcomes with this approach (Hauptmann et al., 2015, Williams et al., 2015), but a recent, placebo-controlled trial apparently did not (Hall et al., 2016a, Haller and Hall, 2017).

Several other commercial devices also employ NB sound stimulation matched to the tinnitus pitch. In a study of the Otoharmonics Levo®, which recommends that the sounds be played through earbuds while patients sleep, Theodoroff et al. (2017) compared the Levo’s custom pitch-matched sounds to identically delivered BB noise, and reported that both treatments resulted in similar improvements in TFI scores and psychoacoustic tinnitus loudness measures, but that the pitch-matched stimulus yielded a greater reduction of VAS-assessed tinnitus loudness.

Another approach is to notch-filter music around the tinnitus pitch, referred to as tailor-made notched music training (TMNMT; Pantev et al., 2012). The hypothesis is that lateral inhibition from the edges of the notch (particularly the low-frequency edge), potentiated by attention to the pleasant music stimulus, will suppress auditory cortical activity at frequencies corresponding to the tinnitus pitch (Pantev et al., 1999, Pantev et al., 2012, Okamoto et al., 2007a, Okamoto et al., 2007b). However, this seems at odds with the observation that a notched BB noise stimulus leads to the transient sensation of a phantom “Zwicker tone”, with a pitch in the notched frequency band (Noreña et al., 2000). Furthermore, after notched BB noise presentation, sensitivity to tones within the notch is transiently increased rather than suppressed (Wiegrebe et al., 1996). Nevertheless, the first small trial of TMNMT reported a significant decrease in subjective tinnitus loudness compared to a group where the noise was notched at frequencies other than the tinnitus pitch, and to a non-treatment control group (Okamoto et al., 2010). In one recent follow-up trial, Li et al. (2016) reported greater THI score improvement in tinnitus patients receiving notched vs. non-notched music therapy. In another, Stein et al. (2016) found no improvement in Tinnitus Handicap Questionnaire scores (THQ; Kuk et al., 1990) after notched music treatment, but did report a decrease in VAS-estimated tinnitus loudness compared to controls.

Human tinnitus trials have also been conducted to test the translatability of the animal studies in which sound treatment was paired with electrical stimulation of the vagus (Engineer et al., 2011, Engineer et al., 2013) or trigeminal nerves (Marks et al., 2018). Because vagus nerve stimulation (VNS) is performed via a surgically implanted device, patients opting for the procedure often have severe tinnitus that has resisted prior treatment attempts. A pair of early reports established the safety and potential efficacy of this approach in a small number of such patients (De Ridder et al., 2014b, De Ridder et al., 2015). In a recent double-blinded, controlled trial, Tyler et al. (2017) reported that 50% of patients (8/16) in the paired VNS group exhibited a clinically meaningful improvement on the THI after 6 weeks of treatment, increasing slightly to 56% after 12 weeks. In the control group, which was implanted but initially sham-stimulated, 28% of patients (4/14) reported improvement after 6 weeks, which increased to 43% at 12 weeks, after crossing over to the paired VNS treatment. In a follow-up paper on some of the same patients, Vanneste et al. (2017) showed that paired VNS stimulation reduced tinnitus loudness ratings by ≥15 points (on a 100 point VAS) in 9 of 18 patients, and that the loudness decreases were correlated with reductions in EEG gamma activity. Note that in all of these studies, VNS was paired with tones that were at least a half-octave away from the tinnitus pitch.

The Marks et al. (2018) study included a double-blinded cross-over human trial, with treatment consisting of tones matched to the tinnitus pitch and paired with somatosensory stimulation via skin electrodes placed on the cervical spine or cheek (with the same 5 ms offset between acoustic and electric stimuli shown to be effective in animals). Sham treatment consisted of acoustic stimulation only. In both subject groups, only the active bimodal treatment produced a significant average decrease in psychoacoustically assessed tinnitus loudness, and 2 of 20 participants reported a complete remission of their tinnitus. Ten subjects had a clinically meaningful reduction on the TFI, compared to 4 subjects during sham acoustic treatment.

Section snippets

Concluding remarks

The number of studies of sound treatments for tinnitus is rapidly growing, whereas the pace for hyperacusis has slowed, despite some promising early results (Hiller and Haerkötter, 2005, Noreña and Chery-Croze, 2007, Formby et al., 2007). Many different sounds and approaches are being tried for tinnitus, including pairing sounds with electrical stimulation of the vagus and trigeminal nerves, to capitalize on plasticity observed in animal studies. Almost all studies have reported some benefits

Acknowledgments

I thank Drs Jos J. Eggermont, Philippe Fournier, Condon Lau, Jeffery T. Lichtenhan, Brian C. J. Moore, and Richard S. Tyler for reading and commenting on earlier versions of this work. And Drs Richard J. Salvi and Larry E. Roberts for organizing this special issue on tinnitus and hyperacusis.

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