REVIEW PAPER ISSN 1738-9399 AUDIOLOGY • 청능재활 2009;5:13-19 Copyright ⓒ 2009 Korean Academy of Audiology online © ML Comm
Neural Mechanisms and Models of Tinnitus Generation
Woojae Han and Fatima T. Husain Department of Speech and Hearing Science, College of Applied Health Science University of Illinois at Urbana-Champaign, Champaign, IL USA
ABSTRACT
Tinnitus is an auditory phantom sensation - it is the false perception of sound in the absence of an external source. Tinnitus can be managed, but there is no cure. Tinnitus affects approximately 10-20% of the population and is often accompanied by hearing loss. The hearing loss causes reorganization of the central auditory processing pathways and associated areas in the brain, possibly leading to tinnitus. However, the underlying neural mechanisms are poorly understood. This paper reviews possible regions exhibiting activity related to tinnitus, from the cochlea to the primary auditory cortex, and the mechanisms that may underlie tinnitus generation. However, tinnitus is complex phenomenon and no single mechanism or brain region can account for all tinnitus sub-types or symp- toms. In addition, somatosensory system and limbic system, with their strong connections to the central auditory processing pathways may be involved in tinnitus generation and persistence. Although, there have been advances in understanding neural mechanisms of tinnitus, particularly due to brain imaging studies in humans, there is still a paucity of data linking objective measure of tinnitus, obtained using brain imaging techniques, to subjective behavioral measures.
KEY WORDS：Tinnitus·Tinnitus model·Neural mechanism of tinnitus·Tinnitus generator·Auditory system·Somato- sensory system·Limbic system.
INTRODUCTION cure because of its elusive causes and complex neurophy- siological mechanisms. Furthermore, there are inherent Imagine that someone is in a quiet room after coming differences in patient’s ability to cope with the stress of back from a loud rock concert. A few individuals in that tinnitus.48) By location, tinnitus is categorized as middle quiet room may hear sounds or noises ringing in their ear, peripheral neural (cochlear, auditory nerve) and cen- ears or head for a while. This phenomenon is called tin- tral neural (cochlear nucleus, inferior colliculus, thalamus, nitus.48) Tinnitus is, in general, a conscious expression of auditory cortex) systems. Noise-induced hearing loss, Me- the sound that originates in an involuntary manner in the niere’s disease, ototoxicity, presbyacusis, and ‘unknown head and lasts five minutes or more,8)33) yet that varies in etiology’ are some of the major etiologies of tinnitus.7) severity. According to Dauman and Tyler,7) there are two In order to diagnose and treat the symptoms associated types of tinnitus: normal tinnitus that lasts less than five with tinnitus, audiology and tinnitus clinics have used se- minutes and occurs less than once a week, and pathologi- veral assessment techniques and therapeutic approaches. cal tinnitus that lasts more than five minutes and occurs A questionnaire is one of most popular assessments for more than once a week. The latter is often accompanied by tinnitus. Eight questionnaires have been widely used： some degrees of hearing loss. Tinnitus is also classified Tinnitus Questionnaire (TQ),16) Tinnitus Handicap Ques- by severity (i.e., tolerable or intolerable) and by duration tionnaire (THQ),27) Tinnitus Severity Scale (TSS),45) Sub- (i.e., temporary or permanent). jective Tinnitus Severity Scale (STSS),15) Tinnitus Reac- Tinnitus is one of the most difficult hearing disorders tion Questionnaire (TRQ),50) Tinnitus Severity Grading (TSG),6) Tinnitus Handicap Inventory (THI),41) and In- take Interview for Tinnitus Retraining Therapy.21) How- ever, no single questionnaire covers every dimension and Received: November 6, 2009 Accepted: November 26, 2009 it is difficult to compare treatment effects due to many Corresponding Author: Woojae Han, Department of Speech and Hearing differences in format, scaling, and even in the words that Science, 901 South Sixth St. University of Illinois at Urbana-Champaign, are used on these questionnaires. Moreover, typical au- Champaign, IL 61820 USA Tel: +1-217-417-1378·Fax: +1-217-244-2235 diological evaluations, including pure-tone audiometry E-mail: [email protected] (especially with extended high-frequency test up to 12
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14 AUDIOLOGY • 청능재활 2009;5:13-19 kHz), immittance measures, acoustic reflex, and speech audiometry have been conducted for the assessment. Henry RESULTS and Meikle advocate four psychoacoustic measures of tin- nitus：loudness, pitch, masking (ipsi- and contra-lateral) Mechanisms of tinnitus generation along au- and residual inhibition.17) Of the four, loudness and pitch ditory pathway and neurophysiological the- matching have been the most popular in describing the ories tinnitus percept and are a part of most behavioral out- come measures. Lastly, objective measurements such as Is cochlear damage a possible tinnitus generator? otoacoustic emission (OAE), evoked related potentials Many theories have attempted to link cochlear damage (ERPs) and brain imaging techniques (e.g., functional to tinnitus. In 1981, Tonndorf proposed that dysfunctional magnetic resonance imaging or fMRI) have been used stereocilia in OHC could result in tinnitus.46) The func- both in the clinic and in the research laboratory. tional loss of stereocilia would lead to a partial or com- Based upon assessment results, Auditory Frequency plete decoupling of the hair cells from the tectorial mem- Training,12) Biofeedback Training,28) and Tinnitus Retrain- brane, which divides the two chambers of scala media ing Therapy (TRT)23) are currently used to treat tinnitus. and scala ransacti. Such decoupling could create internal Despite much research on tinnitus treatments, the benefits noise at the hair cell synapse up to 55 dB, and create either and shortcomings of these treatments are still unclear. a tone or a hissing sound. Further, excessive and intense Therefore, in this paper, we will review the candidate noise or ototoxic drugs can damage OHCs first in the basal neural mechanisms of tinnitus and brain regions along the part (i.e., high-frequency regions) of the cochlea and con- classic and non-classic auditory pathway that may mediate tinue to lose IHCs located in the same part to OHC if the tinnitus. We review both animal and human experimental noise is sustained or repeated.20) This idea is supported data and in brief, the most influential theories of tinnitus. by clinical observations：some patients with tinnitus and This review will give audiologists and otologists, who high-frequency hearing loss matched their tinnitus fre- diagnose and treat tinnitus, a better understanding of its quency to the point at which the loss began,1) but it is dif- mechanisms and causes. ficult to make a generalization with other patients who have either low- or middle-frequency hearing loss or who MATERIALS AND METHODS have broad-band perception instead of a tonal perception. Bauer and colleagues used an animal experiment to ex- Review of the literatures related to mechanisms amine the relation between cochlear loss by acoustic trau- and models of tinnitus ma and behavioral evidence of tinnitus. They found that Several studies have sought to identify the cause of tin- rats who had been exposed to high intense noise for a pe- nitus in impaired ears, especially in the peripheral struc- riod of time experienced a loss in both OHC and IHC and tures, because most patients with tinnitus have a dysfunc- that the loss was highly correlated with the behavioral test tion in the periphery. However, scientific effort has recently for tinnitus.4) The rat with cochlear hearing loss and tin- shifted toward abnormal functions in neural activity which nitus seemed to hear sounds in the absence of an external originates in the retro-cochlea and/or central auditory me- source. The authors argue that undamaged area bordering chanisms.1)37) For instance, the dorsal cochlear nucleus the damaged IHC might have reduced efferent inhibition, (DCN) has inhibiting role in a normal hearing system, giving rise to a highly active area of the basilar membrane but when hearing is lost, this inhibition becomes less ef- and thus resulting in the tonal tinnitus. Although the ani- fective, allowing the spontaneous neural activity to be in- mal studies could explain this phenomenon, they need to creased and develop internal noise or sound through the be confirmed by human studies. auditory system.1) Other research has pointed to an alternative mechanism There are, however, still several theories which impli- by which an area of the basilar membrane with damaged cate the periphery as the site of tinnitus generation.2)22)43) OHC but intact IHC might contribute to tinnitus genera- Here, we review evidence, both which supports and that tion.37) Although this theory, tinnitus generated from un- which challenges the role of a specific region in mediat- balanced loss in OHC and IHC, seems persuasive in that ing tinnitus：outer hair cells (OHC) and inner hair cells a loss of motility in OHC might reduce the ability to set (IHC) of cochlea, the auditory nerve (or the 8th cranial the operating point of the IHC resulting in the tinnitus, nerve), dorsal part of cochlear nucleus (dorsal cochlear there is a difficulty in separating OHC from IHC loss. Ano- nucleus；DCN), inferior colliculus (IC), medial genicu- ther aspect of cochlear damage is that in most sensorineural late body (MGB) of thalamus, and auditory cortex (AC). hearing-impaired listeners, both IHC and OHC are equ-
W Han, et al：Mechanisms and Models of TinnitusG 15 ally damaged. human studies because tinnitus-inducing events in humans One way to test the theory of the imbalance of OHC are as likely to increase spontaneous activity as reduce and IHC is to investigate cochlear function clinically in it.48) There is also limited support for the assumption that patients with hearing loss and tinnitus. This is accom- tinnitus results from increased spontaneous activity in plished by measuring distortion-product otoacoustic emis- auditory nerve fibers because high doses of salicylate and sion (DPOAE) and psychophysical turning curve, thus not small doses seem to result in tinnitus.11) Thus, recent testing for dysfunction of OHC and normal function of animal studies have focused on the higher level (i.e., the IHC, respectively. Expecting results, which are absent retro-cochlear region) of the auditory system. DPOAE responses and sharply turned normal curves, may give details in separated functioning of the cochlea and Is the dorsal cochlear nucleus a possible site of tin- some tinnitus-related patterns. Nevertheless, since the se- nitus generation? parated function in OHC and IHC can explain only pa- Increased neural activity may occur at one or more le- tients having hearing loss of less than 40-45 dB HL due vels of the auditory system, resulting from peripheral da- to a restricted normal response range in DPOAE, the mage or altered function elsewhere in the system. In other theory has weakness. A good correlation between the words, the increased neural activity beyond the auditory tinnitus patients with either high frequency or notch-like nerve may be implicated in tinnitus generation. Many stu- hearing loss and their cochlear functions from DPOAE dies have reported elevated spontaneous activity in the was observed, but only in cases where hearing loss was cochlear nucleus, primarily in the DCN. For instance, less than 40 dB HL.42) Tinnitus patient who has normal Kaltenbach and Afman have shown increased burst-firing hearing showed reduced DPOAE responses when com- in the DCN of rats after exposure to intense sounds, as ar- pared to non-tinnitus with normal hearing. However, as guing for a link between such bursting activity and tin- age increased, the DPOAE functions were ambiguous due nitus perception. They suggested not only the increasing to a combination with presbyacusis.42) in bursting spontaneous activity but also a decrease in Many theories and animal models simulated in cochlea, regular spontaneous activity.25) Such imbalance between OHC and/or IHC, have shown a logical correlation bet- bursting and regular spontaneous activity may represent ween cochlear hearing loss and tinnitus, but there is a risk increased auditory efferent modulation from the IC or AC in stating that the cochlea is a tinnitus generator. Support and connecting to the DCN, or a lack of inhibition from for the central nature of tinnitus comes from studies that other cochlear nucleus units. In either case, it may result in report persistence of tinnitus in patients with acoustic neu- the false perception of sound, or tinnitus. Others have found romas after transection of the auditory nerve18)32) and from similar burst-firings in the auditory nerve of cats after some brain imaging studies of tinnitus in humans showing wide- exposure to kanamycin and in the rats’ inferior colliculus spread involvement of cortical structures in tinnitus.30)31)35) after being injected with salicylate, and showed results In animal studies, where tinnitus is caused by either ph- that were similar to those of Kaltenbach and Afman. This armacologically or noise-induced trauma, abnormal acti- model of tinnitus, based on altered firing patterns in the vity in the inferior colliculus and other brainstem nuclei DCN, is principally based on data from animal experiments. has been reported.5)44)49) Additionally, the abnormal invol- Baguley pointed out some weakness on animal model. vement of non-classical auditory pathways, which receive He has argued that any possible amplification of sponta- input from the emotion-processing, somatosensory and neous activity within this feedback loop (DCN to either visual pathways, may modulate tinnitus. IC or AC), which could be influenced by processes of attention, emotion, and anxiety in the limbic structures, Does the auditory nerve play a role in generating a might be a potential cause of tinnitus perception.1) Still tinnitus signal? different results between animal and human tinnitus at the Some researchers have suggested that an altered spon- auditory nerve stage were shown due to a lack of data on taneous activity within the auditory nerve might have a limbic system involvement in animal studies of tinnitus. role in generating a tinnitus.26)47) Based on the experiment Thus, it is possible that two or more interconnected sys- with cats deafened by kanamycin, which is used to treat a tems may mediate tinnitus generation. We will discuss this wide variety of infections, deviation from the normal ran- point later in the paper. dom activity within the auditory nerve toward more syn- chronous spontaneous activity may be interpreted by hig- Is the inferior colliculus a possible site for tinnitus her auditory stages as cochlear stimulation. However, the generation? animal experiments are not consistent with results of Most of the evidence regarding altered spontaneous
16 AUDIOLOGY • 청능재활 2009;5:13-19 firing rate as a possible mechanism of tinnitus has been per and lower boundaries) to the lesioned areas, resulting recorded form the IC. Reduced output from the damaged in ‘tonotopic reorganization’. Mulnickel et al. proved that cochlear region causes diminished inhibition in the central the reorganization of AC could be a mechanism of tin- auditory structures as well as excessive excitability of the nitus generation in human using a 37-channel whole-head central auditory system, leading to some degree of tinni- neuromagnetometer system. Patients with tinnitus recon- tus.11) Melcher and her colleagues used fMRI for quanti- structed the tonotopic map, resulting from a shift of the fying tinnitus-related abnormality in IC of humans. Com- tinnitus frequency representation into the both sides of pared to a control group having normal hearing and with- frequency boundary within the tonotopic map. They also out tinnitus, patients with lateralized tinnitus showed ab- reported a strong relation between severity of the tinnitus normally high neural activity in the contralateral IC.34) and the amount of cortical reorganization.40) In addition, Like other human studies using brain imaging, this study several neuroimaging studies of humans have indentified had the drawback of having small number of subjects and tinnitus in AC and linked activity on the limbic system； did not include a tinnitus population that had hearing loss. a strong positive correlation between activity on anterior Collective evidence from human brain imaging studies do cingulated cortex in both sides of the hemisphere and the not show simply a relation to one central structure (e.g., level of anxiety related to AC tinnitus.13)35)36) IC) to tinnitus, but a network of cortical and subcortical Animal studies have demonstrated altered neural acti- regions are implicated. Additionally, an interaction with vity and hyperactivity of the primary and secondary AC the limbic system may exist possibly correlated with the after auditory damage similar to that causing tinnitus in tinnitus patient’s anxiety or fear about the tinnitus.11) human.10)24) However, although these studies of cortical neurophysiology have directly measured tinnitus in their How does activity in thalamus affect tinnitus? animal subjects, we still need to know how the animal ex- The medial geniculate body (MGB) in the thalamus periences tinnitus and how such experiences are related to may play an important role in tinnitus due to descending that perceived by humans because tinnitus is a subjective cortico-thalamic pathways, but little interest has been fo- percept. Therefore, additional measures such as test-retest cused on this level of processing.38) The MRI results from reliability of behavioral experiments or including various Muhlau’s study found that tinnitus patients had signifi- forms of tinnitus (i.e., intermittent and chronic tinnitus) cant decreases in gray-matter size in the subcallosal fron- are needed to make animal models more robust.3) tal cortex and increased gray-matter size in the auditory thalamus, primarily the right MGB region, compared to How can some people have normal hearing and non-tinnitus controls.39) Because of the involvement of tinnitus? subcallosal frontal cortex in the emotion processing net- Although cochlear processes such as damage or dys- work, these findings suggest that effect of tinnitus is not function might be involved in tinnitus-related activity, limited to one area and may show a correlation with emo- some people with normal hearing have tinnitus. This is tions. Such implication brings us that the generation of not explained within the context of previously described tinnitus is reciprocal relation of auditory sensory and emo- models and theories. tional regions. Somatic tinnitus, which arises directly from a disorder of the head and upper neck after events such as a car How does activity in primary auditory cortex affect accident, can be one explanation for tinnitus which is not tinnitus? accompanied by hearing loss. For instance, damaged cra- Several plausible hypotheses about the role of the pri- nial nerves (e.g., V, VII, IX, and X) of head and spinal mary auditory cortex (AC) in tinnitus have been offered. nerve of neck might affect medullary somatosensory nu- They include an increased spontaneous activity and chan- cleus in the brain, resulting in disinhibition of DCN (see ge in the temporal pattern of neural activity such as burst- Fig. 1；the somatosensory system projecting to IC and ing, resulting in alterations of tonotopic representation that DCN). Levine’s group29) has studied non-auditory factors lead to enhanced synchrony. The altered tonotopicity in to tinnitus by somatic tests consisting of jaw contraction, the central auditory region indicates that deafferentation head and neck constriction, or pressure on muscle inser- of specific parts of the cochlea, in the short-term, may lead tions. They found that forceful contractions of the head to a reduced activity in the cortical area corresponding to and neck might modulate the tinnitus without any distur- characteristic frequencies of the damaged region. Some bance to the ear in a majority of tinnitus patients. time later, however, excessive neurons may be produced in the frequency regions adjacent (more sensitivity in up- From models of tinnitus
W Han, et al：Mechanisms and Models of TinnitusG 17
non, make predictions that result in new experiments, in- stantiating and verifying new therapies. Moreover, the modeling allows behavioral, electrical, and neuroimaging data to be simultaneously compared. Extending theore- tical models of early 1990’s,20)37) lateral-inhibition network (or LIN) models were introduced. The main concept of LIN modeling is that a neuronal element affects its ad- jacent elements within the same level by means of inhi- bitory connections. However, if a certain disturbed LIN in central auditory system exists, it will lead to reduced in- hibition and hyper-excitation of the system, leading to a trigger of tinnitus.19) Although we do not describe model- ing of tinnitus in detail, the approach allows us to des- cribed neural mechanisms in greater detail and lead to focused experiments and better verification of tinnitus treatment methods.
Fig. 1. Schematic outline of auditory system and its interconnec- tions with the somatosensory and limbic systems. Somatosensory DISCUSSIONS AND CONCLUSIONS system, with its connection to IC and DCN, may modulate tin- nitus. Limbic system projects from thalamus and AC and back to thalamus and IC；this feedback loop is associated with According to epidemiological studies, tinnitus is pre- emotional processing and may play a role in tinnitus. valent at a rate of 5-15% in the general population. Pre- valence of tinnitus increases with age, peaking at almost A schematic of the regions affected by tinnitus and 40% after the age of 65 years.9) The American Tinnitus which, in turn, may modulate tinnitus is shown in
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