Neuromodulation for tinnitus treatment: an overview of invasive and non-invasive techniques

Neuromodulation for tinnitus treatment: an overview of invasive and non-invasive techniques 神经调节方法治疗耳鸣 --侵入性和非侵入性技术概述 corresp first-author ‡Corresponding Author ‡Corresponding Author †E-mail:nicole.peter-siegrist@usz.chtobias.kleinjung@usz.ch †E-mail:nicole.peter-siegrist@usz.chtobias.kleinjung@usz.ch nicole.peter-siegrist@usz.ch †E-mail:nicole.peter-siegrist@usz.chtobias.kleinjung@usz.ch †E-mail:nicole.peter-siegrist@usz.chtobias.kleinjung@usz.ch nicole.peter-siegrist@usz.ch Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zürich, Zürich 8091, Switzerland Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zürich, Zürich 8091, Switzerland Tinnitus is defined as a perception of sound without any external sound source. Chronic tinnitus is a frequent condition that can affect the quality of life. So far, no causal cure for tinnitus has been documented, and most pharmacologic and psychosomatic treatment modalities aim to diminish tinnitus’ impact on the quality of life. Neuromodulation, a novel therapeutic modality, which aims at alternating nerve activity through a targeted delivery of a stimulus, has emerged as a potential option in tinnitus treatment. This review provides a brief overview of the current neuromodulation techniques as tinnitus treatment options. The main intention is to provide updated knowledge especially for medical professionals counselling tinnitus patients in this emerging field of medicine. Non-invasive methods such as repetitive transcranial magnetic stimulation, transcranial electrical stimulation, neurofeedback, and transcutaneous vagus nerve stimulation were included, as well as invasive methods such as implanted vagus nerve stimulation and invasive brain stimulation. Some of these neuromodulation techniques revealed promising results; nevertheless, further research is needed, especially regarding the pathophysiological principle as to how these neuromodulation techniques work and what neuronal change they induce. Various studies suggest that individually different brain states and networks are involved in the generation and perception of tinnitus. Therefore, in the future, individually tailored neuromodulation strategies could be a promising approach in tinnitus treatment for achieving a more substantial and longer lasting improvement of complaints. 概要 2 耳鸣被定义为非外部声音产生的听觉感知,慢性耳鸣是一种影响生活质量的常见病症.目前为止,尚无任何针对耳鸣诱因的治疗方法,大部分的药理和心理治疗方法都旨在减少耳鸣对生活质量的影响.神经调节是一种新型的治疗方式,该方法通过定向刺激来改变神经活动,已经成为耳鸣治疗的一个潜在选择.本文就当前神经调节技术治疗耳鸣做了简要概述,主要目的是为相关人士提供更新的知识介绍,特别是在这个新兴医学领域的专业工作者.本文介绍了包括经颅磁重复刺激、经颅电刺激、神经反馈和经皮迷走神经刺激等非侵入性方法,以及植入的迷走神经刺激和侵入性脑刺激等侵入性方法.虽然一些研究已经展示了神经调节技术的良好应用前景,但是相关的研究还需要加强,尤其是关于神经调节的病理生理学原理,即这些神经调节技术如何发挥作用以及神经调节所引起的神经元变化.多项研究表明,不同个体的大脑活动状态和神经连接网络都参与了对耳鸣的产生和感知.因此,未来个性化定制的神经调节策略可能是一个有前景的耳鸣治疗方法,从而更显著、更持久地改善这个常见病症状. Tinnitus Neuromodulation Invasive technique Non-invasive technique 耳鸣 神经调节 侵入性方法 非侵入性方法 Introduction 1 Tinnitus is defined as a perception of sound (usually a tone or buzzing, but also other sounds) without any external sound source. About 10% to 15% of the population of Europe and the USA are currently experiencing tinnitus, and are seeking medical evaluation and therapy (Axelsson and Ringdahl, 1989 1989 ; Hoffman and Reed, 2004 2004 ; de Ridder et al., 2014a 2014a ). Chronic tinnitus can lead to a lower health-related quality of life (Nondahl et al., 2007 2007 ; Prestes and Daniela, 2009 2009 ) and depressive symptoms (Folmer et al., 1999 1999 ; Dobie, 2003 2003 ; Weidt et al., 2016 2016 ). In about 90% of people with chronic tinnitus, some forms of hearing loss have been documented (Davis and Rafaie, 2000 2000 ; Adjamian et al., 2014 2014 ). The pathophysiology of tinnitus is not yet thoroughly understood. In the distant past, most forms of tinnitus were assumed to be generated in the inner ear or in the cochlear nerve. The fact that tinnitus usually persists after auditory nerve section (Jackson, 1985 1985 ) implicates the essential involvement of the central nervous system in the pathophysiology of tinnitus generation and perception. Nevertheless, tinnitus is still thought to be triggered by a peripheral lesion of hair cells in the cochlea, which results in a loss of input to the central auditory areas. This theory is supported by different studies (van de Heyning et al., 2008 2008 ; Punte et al., 2011 2011 ; Ramos et al., 2012 2012 ) examining cochlear implantation as an effective treatment option for single-sided deaf patients with tinnitus. Besides cochlear implants, other techniques, which aim at restoring hearing function, like conventional hearing aids, also play an important role in the therapy of tinnitus patients. In the initial theories about the involvement of the central nervous system in tinnitus generation, the reorganization of the auditory cortex was considered to be the origin of all further developments. However, various functional imaging studies and animal models have demonstrated that non-auditory areas as well as the auditory cortex are involved and play an important role in chronic tinnitus patients (Schlee et al., 2008 2008 , 2009 2009 ; Vanneste et al., 2010b 2010b ). The involvement of central nervous structures in the pathophysiology of tinnitus has had great implications for further therapeutic attempts to reduce tinnitus-related complaints. This development is reflected by the fact that, on the basis of meta-analytic reviews, most guidelines recommend cognitive behavioral therapy as the standard treatment for chronic disabling tinnitus. Different underlying theories assume that a peripheral lesion of the cochlear hair cells induces a suboptimal or maladaptive plasticity of the central nervous system, inducing reorganization and hyperactivity in central auditory and non-auditory structures (Mühlnickel et al., 1998 1998 ; Kaltenbach and Afman, 2000 2000 ; Salvi et al., 2000 2000 ; Eggermont and Roberts, 2004 2004 ; Vanneste and de Ridder, 2012 2012 ; Hoare et al., 2016 2016 ). One such theory focuses on the alteration in the tonotopic organization of the central auditory specificity as induced by hearing loss due to hair cell damage. Neurons with a loss of afferent sound input in the affected frequencies could still respond to input from nearby intact frequency regions. This could lead to a shift in the neuron’s characteristic frequency, thus resulting in an over-representation of frequencies near the edge of the hearing loss (Eggermont and Roberts, 2004 2004 ; Adjamian et al., 2014 2014 ). Another theory focuses on thalamocortical dysrhythmia (TCD) as a pathophysiologic model for tinnitus generation (Llinás et al., 1999 1999 ; Vanneste and de Ridder, 2012 2012 ). The neuronal plasticity due to the hearing loss affects the thalamocortical signal transmission, resulting in a TCD. Physiologically, an auditory stimulus increases the thalamocortical rhythms from alpha (8‒13 Hz) to gamma ( > 30 Hz) waves (Joliot et al., 1994 1994 ; Vanneste and de Ridder, 2012 2012 ). In deafferentation, an increased spontaneous firing rate of neurons leads to a slowing down of resting state from alpha to theta (4‒7 Hz) oscillations with an increase in surrounding gamma activity (de Ridder et al., 2015b 2015b ). The consequence of specific thalamic nuclei hyperpolarization in TCD is a constant, coupled theta–gamma band activity (Vanneste and de Ridder, 2012 2012 ). In correlation with electroencephalography (EEG) and magnetoencephalography (MEG) studies, tinnitus is associated with a persistent high-frequency gamma band activity in temporal brain areas (Llinás et al., 1999 1999 , 2005 2005 ; Weisz et al., 2005 2005 , 2007 2007 ; Vanneste and de Ridder, 2012 2012 ). Furthermore, theta burst-firing increases the synchronization of neuronal oscillatory activity, which is thought to play a part in the changed neural activity gaining access into consciousness (de Ridder et al., 2015b 2015b ; Hoare et al., 2016 2016 ). Alternatively, a noise-cancelling mechanism involving different non-auditory brain areas has been proposed to diminish or prevent tinnitus perception (de Ridder et al., 2014a 2014a , 2015b 2015b ). The involvement of the non-auditory network in chronic tinnitus patients was first described by Jastreboff ( 1990 1990 ). Since then, various functional neuroimaging studies have demonstrated altered brain structures in tinnitus patients, which led to the modelling of different networks involved in tinnitus generation (Schlee et al., 2008 2008 , 2009 2009 ; Vanneste et al., 2010b 2010b ). de Ridder et al. ( 2011a 2011a ) and Langguth et al. ( 2013 2013 ) identified several such networks that participate alongside the auditory cortex in tinnitus patients and generated a model of involved networks. These networks include a perception network (subgenual and dorsal anterior cingulate cortices, posterior cingulate cortex, precuneus, parietal cortex, and prefrontal cortex), salience network (anterior cingulate cortex, anterior insula), distress network (anterior cingulate cortex (subgenual and dorsal anterior cortical cortices), anterior insula and amygdala), and memory areas (parahippocampal area, amygdala, and hippocampus). As previously mentioned, a different concept focuses on a dysfunctional noise-cancelling mechanism, which seems to be driven by the limbic frontostriatal network (de Ridder et al., 2014a 2014a ; Leaver et al., 2011 2011 , 2012 2012 , 2016a 2016a ; Mühlau et al., 2006 2006 ; Rauschecker et al., 2010 2010 , 2015 2015 ; Seydell-Greenwald et al., 2012 2012 , 2014 2014 ). Various imaging studies have demonstrated structural and functional changes in the ventromedial prefrontal cortex, nucleus accumbens and medial dorsal nucleus in the thalamus (Pandya et al., 1994 1994 ; Tanibuchi and Goldman-Rakic, 2003 2003 ; Mühlau et al., 2006 2006 ; Leaver et al., 2011 2011 , 2012 2012 , 2016a 2016a , 2016b 2016b ; Meyer et al., 2016 2016 ). It is theorized that the limbic structures suppress auditory activity via projections from the ventromedial prefrontal cortex to the thalamic reticular nucleus (Mühlau et al., 2006 2006 ; Rauschecker et al., 2010 2010 ; Leaver et al., 2011 2011 , 2016a 2016a ). All the above-mentioned theories are based on functional imaging studies, which can only indicate the underling mechanism in tinnitus generation. Recently, Sedley et al. ( 2015 2015 ) demonstrated the appropriateness of these theories through the intracranial mapping of the cortical tinnitus in a patient. Another way to gain more information about the essential contributions of specific brain areas could be to investigate the behavioral effects resulting from the transient disturbance of neural activity in these regions due to the different neuromodulation methods (Langguth et al., 2012 2012 ). These interventions can be divided into invasive (e.g. epidural/subdural or deep brain electrical stimulation) and non-invasive methods (Langguth et al., 2012 2012 ). Particularly, the non-invasive methods can be furthermore divided into direct (e.g. transcranial magnetic or electrical stimulation) and indirect neurostimulation (e.g. neurofeedback, acoustic coordinated reset (CR) neuromodulation, and tailored notched music therapy). So far, none of the neuromodulation procedures have been established as a routine therapy method in tinnitus patients. This review covers most of the neuromodulation methods, but the ones induced by different ways of acoustic stimulation were excluded (e.g. cochlea implantation as an invasive neuromodulation, acoustic CR neuromodulation and tailored notched music therapy as an indirect neurostimulation). The aim of this review is to give a short and updated overview of the different neuromodulation approaches in tinnitus research out of the plenty of new literature, especially for medical professionals counselling tinnitus patients. Due to the fact that there is no causal therapy for tinnitus, it is not unusual that often well-informed patients ask medical professionals about a specific neuromodulation therapy which they heard or read about. In the last years more and more data on neuromodulation strategies are available and new techniques were introduced into the field. This article reviews the newest literature of neuromodulation techniques in tinnitus treatment so that medical professionals can counsel their patients according to the latest information and their respective implications in the possible future treatment options of tinnitus. Furthermore, the present value of each technique in clinical routine will be discussed in the particular section. Repetitive transcranial magnetic stimulation 1 Transcranial magnetic stimulation (TMS) is a non-invasive type of neuromodulation. Intermittent magnetic fields are produced by a coil that is in contact with the subject’s scalp and that delivers electromagnetic pulses (Theodoroff and Folmer, 2013 2013 ). These magnetic fields pass largely undistorted through the cranium and affect the neuronal activity of the brain beneath (Kleinjung et al., 2005 2005 ). Different magnetic fields are generated according to the coil design. Figure-eight coils are often used due to their focused pattern of activation, but other coil types are also used (Soleimani et al., 2016 2016 ). In repetitive TMS (rTMS), several TMS pulses are applied to the subject’s head during one session. The utilized frequency of rTMS modulates the cortical activity differently. In the motor cortex, high-frequency rTMS (i.e. 5‒20 Hz) transiently increases the cortical excitability, while low-frequency rTMS (i.e. 1 Hz) usually leads to a reduction of neural activity (Chen et al., 1997 1997 ; Siebner et al., 2003 2003 ; Zaghi et al., 2010b 2010b ). This reduction has led to the proposal of low-frequency rTMS as an innovative treatment strategy for tinnitus, which is a condition associated with increased cortical activity in temporal brain areas (Hoffman and Cavus, 2002 2002 ; Theodoroff and Folmer, 2013 2013 ). A selection of literature (Kleinjung et al., 2005 2005 ; Rossi et al., 2007 2007 ; Khedr et al., 2008 2008 , 2009 2009 ; Anders et al., 2010 2010 ; Marcondes et al., 2010 2010 ; Mennemeier et al., 2011 2011 ; Chung et al., 2012 2012 ; Lee et al., 2013 2013 ) has shown that repeated sessions of low-frequency rTMS applied to temporal or temporoparietal cortical areas had a possible therapeutic efficacy in terms of tinnitus suppression, but the effect at clinical level was usually partial and temporary (Lefaucheur et al., 2014 2014 ). Sham stimulation failed to demonstrate any beneficial effect. Further studies have suggested that the therapeutic efficacy of rTMS could be enhanced by stimulating frontal or prefrontal cortical areas in addition to the temporoparietal cortex (Kleinjung et al., 2008 2008 ; Kreuzer et al., 2011 2011 ; de Ridder et al., 2013 2013 ; Lehner et al., 2013a 2013a , 2013b 2013b ; Langguth et al., 2014 2014 ; Lefaucheur et al., 2014 2014 ). Most recently, studies have combined high-frequency rTMS of the left dorsolateral prefrontal cortex with low-frequency rTMS of the right, left or both temporoparietal cortical areas and have demonstrated a larger tinnitus improvement than unilateral low-frequency rTMS of the temporoparietal cortex alone (Lehner et al., 2013a 2013a , 2013b 2013b , 2015 2015 ; Lefaucheur et al., 2014 2014 ). Furthermore, a new stimulation design has applied burst rTMS to the auditory cortex for tinnitus suppression (de Ridder et al., 2007a 2007a , 2007b 2007b ). In contrast to tonic TMS, which mainly inhibits pure tone tinnitus, burst stimulation transiently suppressed both pure tone and narrow-band tinnitus (de Ridder et al., 2007a 2007a , 2007b 2007b ). Despite some promising results, the therapeutic effect of rTMS on chronic tinnitus is usually partial and temporary. Furthermore, the long-term effects of TMS are still not known yet. For these reasons, rTMS is not recommended as a therapeutic option in clinical routine. Nevertheless, rTMS qualifies as a diagnostic method in research investigating which brain areas are involved in tinnitus generation. On that basis, rTMS has been used for localization purposes in other neuromodulation methods targeting different brain areas for tinnitus suppression. For this purpose, mainly high-frequency rTMS was used, e.g., for determining the correct position of an implanted epidural electrode. Transcranial electrical stimulation 1 Transcranial direct current stimulation 2 In transcranial direct current stimulation (tDCS), another non-invasive method of brain stimulation, a relatively weak, constant current (between 0.5 and 2 mA) is applied via scalp electrodes and passes through the cerebral cortex (Vanneste et al., 2011a 2011a ; Vanneste and de Ridder, 2012 2012 ). Two saline-soaked surface sponges act as surface electrodes, one serving as the anode and the other as the cathode. Anodal tDCS induces a depolarization of neurons leading to an excitatory effect on the underlying cerebral cortex while, under the cathode, a hyperpolarization causes an inhibitory effect. Depending on the polarity of the stimulation, tDCS can increase or decrease cortical excitability in the brain regions to which it is applied (Miranda et al., 2006 2006 ). The application of tDCS led to a temporary reduction in tinnitus loudness or distress ranging from seconds to hours, depending on the location of cortical stimulation (Song et al., 2012 2012 ; Shekhawat et al., 2016 2016 ). Anodal tDCS over the left temporoparietal area with the cathode over the contralateral frontal scalp resulted in a transient suppression of tinnitus in up to 40% of participants (Fregni et al., 2006 2006 ; Garin et al., 2011 2011 ; Shekhawat et al., 2013 2013 ). Furthermore, bifrontal tDCS placement of the electrodes on the dorsolateral prefrontal cortex (with either the anodal electrode on the right and the cathodal electrode on the left side, or the opposite orientation), temporarily suppressed tinnitus perception and tinnitus distress in up to 43% of participants (Vanneste et al., 2010a 2010a , 2011b 2011b , 2013a 2013a ; Vanneste and de Ridder, 2011 2011 ; de Ridder and Vanneste, 2012 2012 ; Faber et al., 2012 2012 ; Frank et al., 2012 2012 ). Lastly, bilateral tDCS over the auditory cortex has been shown to suppress tinnitus loudness (Joos et al., 2014 2014 ). Due to the broad region of brain stimulation in tDCS between and underneath the electrodes, the interpretation of anatomically involved brain areas is difficult. One potential improvement to this problem is the use of high-definition tDCS (HD-tDCS) (Shekhawat et al., 2016 2016 ). For controlled targeting of the stimulation, the conventional large sponge electrodes are replaced with smaller gel electrodes in HD-tDCS. In the setting of a 4×1 HD-tDCS, four electrodes are placed in a ring around a polarity determining the center electrode (Datta et al., 2009 2009 ; Edwards et al., 2013 2013 ). This arrangement of tDCS enables a controlled targeting of the stimulation underneath the electrodes (Shekhawat et al., 2016 2016 ). Shekhawat et al. ( 2016 2016 ) demonstrated that 77.8% of the participants responded to HD-tDCS and referred to suppression of tinnitus loudness and annoyance with equal results. This was with a stimulation location of the left temporoparietal area and right dorsolateral prefrontal cortex. In conclusion, HD-tDCS provides an opportunity to stimulate multiple target sites simultaneously and could therefore be a promising non-invasive neuromodulation method in tinnitus treatment (Shekhawat et al., 2016 2016 ), but further research is required. Transcranial alternating current stimulation 2 Another technique of non-invasive transcranial electrical stimulation is based on the application of alternating currents through an electrode, and is known as transcranial alternating current stimulation (tACS). The frequency of applied alternating currents allows for the manipulation of intrinsic cortical oscillations and it is therefore possible that tACS can interact with rhythmic neuronal activity (Zaghi et al., 2010a 2010a ). It follows that tACS should be able to modulate functions that are closely related to brain oscillations at specific frequencies, such as the decreased alpha and the increased gamma activity in the auditory cortex of tinnitus patients (Lorenz et al., 2009 2009 ; de Ridder et al., 2011b 2011b ; Vanneste et al., 2013b 2013b ). The application of tACS intensifies the individual alpha frequency of the stimulated area (Zaehle et al., 2010a 2010a ) and this is how tACS is presumed to modulate the tinnitus percept (Vanneste et al., 2013b 2013b ). Despite the plausibility of this theoretical model, no effect on the tinnitus percept has been obtained by alpha modulated tACS over the auditory and dorsolateral prefrontal cortex (Zaehle et al., 2010b 2010b ; Zaghi et al., 2010a 2010a ; Vanneste and de Ridder, 2013 2013 ). Although the study of alpha-modulated tACS is at an early stage, further investigation does not seem merited (Claes et al., 2014 2014 ; Hoare et al., 2016 2016 ). Transcranial random noise stimulation 2 A further method of non-invasive transcranial electrical stimulation that has been tested to a greater extent is transcranial random noise stimulation (tRNS). In tRNS, the generated current consists of random oscillations in a normal distribution for amplitude with a frequency spectrum between 0.1 and 640 Hz, which appears similar to “white noise” in structure (Paulus, 2011 2011 ; Vanneste et al., 2013b 2013b ; To et al., 2017 2017 ). Potentially, the application of tRNS might disrupt tinnitus related synchrony in the auditory cortex and could thus induce an improvement of the tinnitus percept (van Doren et al., 2014 2014 ). Vanneste et al. ( 2013b 2013b ) demonstrated a larger transient suppressive effect on tinnitus loudness and tinnitus-related distress with tRNS as compared to tDCS and tACS when applying the electrodes over the auditory cortex bilaterally. In another study (Joos et al., 2015 2015 ), multiple sessions of tRNS showed an increased effect on tinnitus loudness but no further effect on tinnitus distress. Furthermore, a multisite transcranial electrical stimulation protocol with bilateral auditory cortex tRNS after bifrontal tDCS showed more pronounced suppressive effects on tinnitus loudness and distress than the bifrontal tDCS protocol alone (To et al., 2017 2017 ). The whole-frequency spectrum of tRNS is often subdivided into a low-(0.1‒100 Hz) and a high-frequency (100‒640 Hz) tRNS, which can result in diverse effects (Terney et al., 2008 2008 ; Fertonani et al., 2011 2011 ; Saiote et al., 2013 2013 ; Joos et al., 2015 2015 ). Regarding the frequency spectrum, Joos et al. ( 2015 2015 ) demonstrated that both low-and high-frequency tRNS reduced tinnitus loudness while only low-frequency tRNS had an effect on tinnitus-related distress. Whole-frequency tRNS applied bilaterally over the temporoparietal cortex had no significant effects on tinnitus loudness or tinnitus-related distress. Generally, tRNS could be a potential treatment option for tinnitus, but further studies are needed to evaluate the therapeutic effect of tRNS in a clinical routine. Neurofeedback 1 Neurofeedback is based on the principal of operant conditioning, and is another example of a non-invasive neuromodulation technique. In it, relevant aspects of brain signals acquired through EEG or other functional imaging techniques are extracted and processed into visual or acoustic signals, which are then fed back to the participant in real time. The participant has to fulfill a task using the visual or acoustic feedback signals, and gets rewarded for desired changes or punished for undesired changes in brain activity. This kind of operant conditioning of EEG rhythms has already yielded successful results in attention-deficit hyperactive disorder and epilepsy (Lubar and Bahler, 1976 1976 ; Lubar and Shouse, 1976 1976 ; Lansbergen et al., 2011 2011 ). As tinnitus patients also demonstrate abnormal spontaneous brain activity with higher theta (4‒7 Hz), gamma ( > 30 Hz), beta (14‒30 Hz), and lower alpha (8‒13 Hz) band activity, neurofeedback has been studied as a treatment option (Gosepath et al., 2001 2001 ; Schenk et al., 2005 2005 ; Dohrmann et al., 2007a 2007a , 2007b 2007b ; Crocetti et al., 2011 2011 ; Hartmann et al., 2014 2014 ). Both a single change of an increase of alpha frequency, and a combined change with an increase of alpha and a decrease of beta or delta frequency in the region of the auditory cortex correlated with reduced tinnitus distress scores (Gosepath et al., 2001 2001 ; Schenk et al., 2005 2005 ; Dohrmann et al., 2007a 2007a , 2007b 2007b ; Crocetti et al., 2011 2011 ; Hartmann et al., 2014 2014 ). However, besides some methodological shortcomings, difficulties in defining outcome measurements and small group sizes with lacking control condition, the non-invasive technique of neurofeedback seems to have some future potential in the treatment of tinnitus. To date, no source localization algorithms of the EEG recordings (e.g. low-resolution electric tomography analysis (LORETA)) have been used to optimize the spatial resolution in the neurofeedback setting. Neurofeedback training protocols, which specifically focus on different brain areas of tinnitus networks by using an EEG source localization algorithm, could be investigated as an even more specific non-invasive treatment modality for tinnitus in the future. Vagus nerve stimulation (VNS) 1 General concept of VNS 2 Discrimination training as a form of auditory stimulation has been postulated to reverse the pathological neuroplastic changes in the auditory system associated with hearing loss and subsequent tinnitus (Hoare et al., 2014 2014 , 2016 2016 ). However, the clinical benefit of this concept of auditory stimulation has been limited and the demonstrated improvements transitory (Hoare et al., 2010 2010 , 2016 2016 ). As previously mentioned, not only the central auditory structures are involved in the suboptimal or maladaptive neuroplasticity in tinnitus generation and perception; non-auditory brain areas also participate in the plastic changes. Another important part in the modulation of cortical plasticity is played by the cholinergic and noradrenergic forebrain system. Animal studies have illustrated a pronounced and long-lasting change in cortical reorganization as induced by electrical stimulation of the cholinergic nucleus basalis (Kilgard and Merzenich, 1998a 1998a ). This finding led to the idea of pairing auditory stimulation with electrical stimulation of the nucleus basalis as a possible tinnitus treatment (Kilgard and Merzenich, 1998b 1998b ). However, an invasive procedure has to be performed to stimulate the nucleus basalis and therefore this kind of stimulation is not practicable in an extensive application for tinnitus treatment (Hoare et al., 2016 2016 ). Engineer et al. ( 2013 2013 ) demonstrated a similar stimulation of the nucleus basalis by using a much less invasive electrical VNS in noise-exposed rats with hearing loss and behavioral evidence of tinnitus. The pairing of VNS with auditory stimulation—consisting of acoustic tones at frequencies outside the tinnitus range—reversed the abnormal neural activity and behavioral correlates of tinnitus in noise-exposed rats (Engineer et al., 2013 2013 ). Neither VNS nor acoustic stimulation alone showed a similar effect (Engineer et al., 2013 2013 ). It has been postulated that while acoustic tones stimulate the auditory cortex as a target for the neuroplastic change, the VNS promotes the desired cortical reorganization by inducing neuroplastic activity (Engineer et al., 2013 2013 ). Implanted VNS 2 Based on the above-mentioned concept of VNS, several studies have been conducted in the last few years to explore the safety and efficacy of this procedure in humans (de Ridder et al., 2014b 2014b , 2015a 2015a ). As the implantation of a stimulation electrode on the vagal nerve is an invasive procedure, there are several operative risks as well as adverse effects due to VNS. These include general anaesthesiological risks, possible infection of the surgical site by the device, hoarseness due to vocal cord hypomobility, and temporary increases of tinnitus (Hoare et al., 2016 2016 ). In a pilot study, ten participants with chronic moderate to catastrophic tinnitus severity received an implantation of the vagal nerve stimulator (de Ridder et al., 2014b 2014b ). The acoustic stimulation with tones, excluding the tinnitus-matched frequency, was paired with VNS (de Ridder et al., 2014b 2014b ). A clinically meaningful improvement of the tinnitus as well as physiological effects measured by EEG was reported by four of ten participants (de Ridder et al., 2014b 2014b ). Furthermore, it was demonstrated that five of the participants with no improvement were taking different medications including muscarinic antagonists, norepinephrine agonists, and γ-amino butyric acid agonists. These medications could probably interfere with acetylcholine and norepinephrine release induced by VNS. The company MicroTransponder Inc. has recently presented its results of a double blind, randomized, multicenter study with 30 patients titled “Paired VNS™ treatment uses Vagus Nerve Stimulation (VNS) paired with tones” on their website ( http://www.microtransponder.com/en-gb/tinnitus/ http://www.microtransponder.com/en-gb/tinnitus/ physicians/clinical-experiences, data not yet published). The overall clinical responder rate measured with a minimum change of 20% in tinnitus handicap inventory (THI) scores (Newman et al., 1996 1996 ) was 56% in the paired VNS™-treated patient group. Only mild adverse events were reported. Some degree of vocal cord paralysis was described in two patients with ongoing clinical improvement of the hoarseness or voice weakness. The promising results of paired VNS with acoustic could lead to a treatment option for tinnitus patients. However, at the moment the paired VNS™ as a tinnitus treatment is not yet US Food and Drug Administration (FDA)-approved. Transcutaneous VNS 2 Transcutaneous stimulation of the vagus nerve (tVNS) via a nerval branch innervating the skin in the external auditory canal, as a non-invasive approach, has been investigated in parallel (Kreuzer et al., 2012 2012 , 2014 2014 ; Lehtimӓki et al., 2013 2013 ). A pilot study from Kreuzer et al. ( 2014 2014 ) demonstrated the feasibility and safety of tVNS in patients without a history of cardiac disease. However, there was no clinically relevant improvement of tinnitus complaints. Lehtimӓki et al. ( 2013 2013 ) demonstrated acute neuromodulative effects of tVNS paired with tinnitus frequency-filtered music on the evoked auditory cortical responses. Furthermore, some patients showed a significant clinical decrease in tinnitus handicap. Hyvärinen et al. ( 2015 2015 ) showed compatible neuronal changes on MEG and that the tVNS-induced change was correlated with THI scores. At present, there is one ongoing randomized, single-blind, controlled clinical study of tVNS for tinnitus (Li et al., 2015 2015 ). The results of this study are expected to be very informative and could lead to further clinical investigation about tVNS as a therapeutic option for tinnitus. Invasive brain stimulation 1 Based on the theory of neuronal plasticity and reorganization of the central nervous system in tinnitus generation, invasive brain stimulation focuses on altering the neuronal tinnitus network through the electrical stimulation of cortical (epidural or subdural) or deep brain areas using implanted electrodes. Epidural and subdural cortical stimulation 2 de Ridder et al. ( 2004 2004 ) published the first case report of tinnitus suppression by using invasive electrical stimulation of the primary auditory cortex in a single tinnitus patient. The patient suffered from severe left-sided tinnitus subsequent to a sensorineural deafness after acoustic neuroma surgery on the left side. After the tinnitus responded positively to TMS applied to the right auditory cortex, an extradural electrode was implanted for electrical stimulation. Initially, the electrical stimulation caused the patient’s tinnitus to disappear completely. However, three weeks postoperatively, the high-pitched tinnitus returned. This was possibly due to cortical plasticity in response to the constant stimulation. In a following case series from the same group (de Ridder et al., 2006 2006 ), 12 participants with moderate-to-severe tinnitus received an implantation of two-pole electrodes, one electrode positioned intradural on the primary, and the other extradural on the secondary auditory cortex. The electrodes were then connected to an internal impulse generator which was first placed externally for one week and then implanted subcutaneously over the abdomen after beneficial effects of stimulation were noted. Overall, only two patients failed to report any improvement in their tinnitus complaints. Especially those participants with unilateral or pure tone tinnitus had better tinnitus suppression than those with bilateral or white noise tinnitus. Nevertheless, the tinnitus reappeared in all patients after a certain time of stimulation. Based on the model of TCD with hyperactivity in the vicinity of deafferented auditory cortex, Seidman et al. ( 2008 2008 ) attempted to stimulate these neighboring regions of the reorganized auditory cortex. After a tonotopic mapping of the areas with increased activity in Heschl’s gyrus, electrode arrays were placed on these targeted sites in two participants. One participant with bilateral, high-pitched tinnitus experienced a sustained reduction of tinnitus, whereas the other participant with unilateral, high-pitched, narrow band tinnitus did not show a decrease in tinnitus. In another case report (de Ridder and Vanneste, 2014 2014 ), the auditory cortex stimulation induced by implanted electrodes was combined with subcutaneous C2 electrical stimulation. It was hypothesized that these two neuronal pathways interact at the level of the cochlear nuclei. The participant reported a diminished noise-like tinnitus and an absent pure tone tinnitus for a period of at least five years. The anterior cingulate cortex, a proposed responsible brain area in the tinnitus distress network, has been investigated as another location for cortical stimulation (de Ridder et al., 2016 2016 ). In two participants, electrodes were implanted bilaterally over the dorsal anterior cingulate cortex. One participant responded to this kind of stimulation with a dramatic reduction of tinnitus loudness and distress, with a sustained effect for more than two years after implantation. In contrast, the other participant did not report any improvement of the tinnitus although various stimulation parameters were evaluated. It was demonstrated that the participant experiencing an improvement in tinnitus had an increased functional connectivity from the dorsal anterior cingulate cortex to a tinnitus network consisting of the parahippocampal area, subgenual anterior cingulate cortex and insula, whereas the nonresponder had decreased functional connectivity between these areas (de Ridder et al., 2016 2016 ). This example supports the assumption that there are different existing types of tinnitus according to the involved brain areas and their functional connectivity. The analysis of functional connectivity may determine at what localization a cortical implant could lead to an improvement of tinnitus. However, research about cortical stimulation in tinnitus patients is still at an early stage and further investigation is needed. Nevertheless, as an invasive neurosurgical procedure with various risks attached, cortical stimulation as a potential therapeutic option will presumably always be limited to a very select group of tinnitus patients. Deep brain stimulation 2 Deep brain stimulation (DBS) of specific brain regions has become an effective treatment option in patients with therapy-resistant neurological disorders such as tremor (Koller et al., 1999 1999 ; Rehncrona et al., 2003 2003 ), dystonia (Vidailhet et al., 2009 2009 ), Parkinson’s disease (Krack et al., 2003 2003 ; Bittar et al., 2005a 2005a ), and chronic pain (Marchand et al., 2003 2003 ; Bittar et al., 2005b 2005b ; Owen et al., 2006 2006 ). Thus far, an electrode for DBS has not been implanted solely for the purpose of tinnitus treatment. However, in patients with comorbid tinnitus who received DBS to alleviate movement disorders, the concomitant effect on tinnitus perception has been evaluated. In the first study investigating this topic, an electrode was implanted in the ventralis intermedius nucleus of the thalamus of seven patients with movement disorders and comorbid tinnitus (Shi et al., 2009 2009 ). Three of these seven patients reported reduced tinnitus loudness when DBS was turned on (Shi et al., 2009 2009 ). In another study (Cheung and Larson, 2010 2010 ), six patients suffering from Parkinson’s disease and concomitant tinnitus underwent an electrode implantation in the subthalamic or ventralis intermedius nucleus of the thalamus with the electrode lead traversing through, or being adjacent to, a locus of caudate neurons (area LC) in the body of the nucleus, which is a subsidiary of the striatal network. In five patients where the DBS lead tip traversed area LC, tinnitus loudness in both ears was suppressed (Cheung and Larson, 2010 2010 ). In the one subject where the DBS lead was outside area LC, tinnitus remained unchanged (Cheung and Larson, 2010 2010 ). The authors presume that the area LC, a striatal sensorimotor integration center that is not part of the classical auditory pathway, may modulate the integration of phantom sensations generated from the central auditory system to brain areas of perceptual awareness (Cheung and Larson, 2010 2010 ). A recently published study (Smit et al., 2016 2016 ) investigated the effect of DBS on tinnitus in a retrospective multicenter survey. The study indicated that DBS may indeed reduce the handicap caused by tinnitus. It was noted that stimulation of the subthalamic nucleus resulted in the most beneficial effect. It must be stated that in the above-mentioned studies an electrode for DBS was implanted due to another coexisting disease. It follows that the interactive effects of these comorbidities with tinnitus are unknown. To conclude, more research of DBS in tinnitus is needed, particularly with regard to which possible brain regions show the most benefit from stimulation but also to the effects of different stimulation characteristics, such as frequency and intensity on the neuronal level. Concluding remarks 1 In the last two decades, different neuromodulation techniques have been developed, which enable the focal modulation of neuronal activity. The increasing knowledge regarding tinnitus-related activity changes in the brain resulted in the logical consequence that the neuronal correlates of tinnitus were directly targeted in terms of neuromodulation techniques. The innovative idea was that this influencing of the electrical activity of the involved brain networks would serve as an important diagnostic and therapeutic tool in further research. In recent years, multiple invasive and non-invasive techniques have been evaluated for the normalization of tinnitus-related brain activity as a more causally oriented treatment approach. Experimental approaches using different neuromodulation techniques have demonstrated some promising results in reducing tinnitus-related complaints, but have mostly failed in terms of a complete extinction of the tinnitus percept. However, most of the studies mentioned have similar limitations that lower their significance. First, the treatment efficacy is elusive due to the fact that for the outcome measure of tinnitus, only subjective (and no objective) measurements exist. Moreover, different available outcome measures of tinnitus reduce the comparability between the available studies. Further limitations in most of the studies are a small sample size, a lack of adequate placebo condition or no placebo arm, the heterogeneity of the patients, possible previous treatment for tinnitus, ongoing therapy with antidepressant drugs, and no long-term follow-up. It is also important to mention the possible side effects of the different neuromodulation therapies such as seizures in rTMS or surgical risks in invasive neuromodulation techniques. In conclusion, different neuromodulation methods provide a confident outlook to possible therapeutic options in the treatment of tinnitus. In particular, non-invasive neuromodulation techniques are promising as a treatment option for a large proportion of patients suffering from tinnitus, whereas invasive neuromodulation methods due to the neurosurgical risks will presumably be restricted to a select patient group: those with persistent severe tinnitus despite different previous treatment attempts. 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This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1700117 2017-03-05 2017-07-17 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2019 2019 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 02 20