domingo, 1 de diciembre de 2013
En ocasión del 66 Congreso Aniversario de la federacion de Sociedades de Otorrinolaringologia de Argentina, que tuvo lugar en Mar Del Plata, entre el 27 y el 29 de noviembre de 2013, brindaron conferencias sobre Acúfenos la Dra. Claudia Barros Cohelo, de la Universidad de San Pablo, Brasil e investigadora de la Universidad de Iowa y del TRI (Tinnitus Research Initiative), quien se refirió a aspectos modernos de la fisiopatologia y tratamiento de los acúfenos, y el Dr. Dario Roitman, de la Universidad de Buenos Aires, quien se refirió a los acúfenos objetivos secundarios a mioclonías de los músculos del oido medio.
domingo, 17 de noviembre de 2013
Counteracting tinnitus by acoustic
coordinated reset neuromodulation
Peter A. Tass
, Ilya Adamchic
, Hans-Joachim Freund
, Tatjana von Stackelberg
and Christian Hauptmann
Research Center J ̈
ulich, Institute for Neuroscience and Medicine – Neuromodulation INM-7, J ̈
Department of Stereotaxic and Functional Neurosurgery, University Hospital, Cologne, Germany
Ear, Nose and Throat (ENT) Center, Meerbusch, Germany
Purpose: Subjective tinnitus is associated with pathologic enhanced neuronal synchronization. We used a model based desynchronization technique, acoustic coordinated reset (CR) neuromodulation, to specifically counteract tinnitus-related
neuronal synchrony thereby inducing an unlearning of pathological synaptic connectivity and neuronal synchrony.
Methods: In a prospective, randomized, single blind, placebo-controlled trial in 63 patients with chronic tonal tinnitus and up
to 50 dB hearing loss we studied safety and efficacy of different doses of acoustic CR neuromodulation. We measured visual
analogue scale and tinnitus questionnaire (TQ) scores and spontaneous EEG.
Results: CR treatment was safe, well-tolerated and caused a significant decrease of tinnitus loudness and symptoms.
Placebotreatment did not lead to any significant changes.
Effects gained in 12 weeks of treatment persisted through a preplanned 4-weektherapy pause and showed sustained long-term effects after 10 months of therapy: Response, i.e. a reduction of at least 6 TQpoints, was obtained in 75% of patients with a mean TQ reduction of 50% among responders. CR therapy significantly loweredtinnitus frequency and reversed the tinnitus related EEG alterations.
Placebotreatment did not lead to any significant changes.
Effects gained in 12 weeks of treatment persisted through a preplanned 4-weektherapy pause and showed sustained long-term effects after 10 months of therapy: Response, i.e. a reduction of at least 6 TQpoints, was obtained in 75% of patients with a mean TQ reduction of 50% among responders. CR therapy significantly loweredtinnitus frequency and reversed the tinnitus related EEG alterations.
Conclusion: The CR-induced reduction of tinnitus and underlying neuronal characteristics indicates a new non-invasive therapy
which might also be applicable to other conditions with neuronal hypersynchrony.
sábado, 16 de noviembre de 2013
Science & Technology Updated: Nov. 6, 2013, 11:28 a.m. ET
Neuroscience may offer hope to millions robbed of silence by tinnitus
Chronic tinnitus affects millions of Americans, and is the most widely reported disability among veterans.
New research reveals the roots of the disease lie deep within the brain, and experimental therapies are providing hope for a cure.
BY JENNY MARDER
National Science Foundation provided funding for this projectOn Easter Sunday in 2008, the phantom noises in Robert De Mong’s head dropped in volume -- for about 15 minutes. For the first time in months, he experienced relief, enough at least to remember what silence was like. And then they returned, fierce as ever.
It was six months earlier that the 66-year-old electrical engineer first awoke to a dissonant clamor in his head. There was a howling sound, a fingernails-on-a-chalkboard sound, “brain zaps” that hurt like a headache and a high frequency "tinkle" noise, like musicians hitting triangles in an orchestra.
De Mong was diagnosed in 2007 with tinnitus, a condition that causes a phantom ringing, buzzing or roaring in the ears, perceived as external noise.
When the sounds first appeared, they did so as if from a void, he said. No loud noise trauma had preceded the tinnitus, as it does for some sufferers -- it was suddenly just there. And the noises haunted him, robbed him of sleep and fueled a deep depression. He lost interest in his favorite hobby: tinkering with his ‘78 Trans Am and his two Corvettes. He stopped going into work.
That month, De Mong visited an ear doctor, who told him he had high frequency hearing loss in both ears. Another doctor at the Stanford Ear, Nose and Throat clinic confirmed it, and suggested hearing aids as a possibility. They helped the hearing, but did nothing for the ringing.
Meanwhile, he scoured the internet for cures. He spent $700 on “miracle drugs” and vitamins marketed for tinnitus. He tried 10 sessions of acupuncture. But his depression and insomnia were getting worse. He had become suicidal.
“I just wanted to go into a cave and either get well or die,” he said.
So in November, at the urging of a therapist and fearful of his own behavior, he checked himself into the nearest emergency room.
“If I had a light switch, and I could have clicked that light switch and been dead, I would have done it,” he said. “I would have done it. But suicide is a complicated thing. I didn’t have a gun, I didn’t have the medicine to do it, I didn’t like heights. So how do you take yourself off the planet?”
When relief finally came for De Mong, it was not in the form of a tinnitus specialist or an ear doctor, but a psychiatrist. He was referred to the doctor after several hours of hospital observation. While he insisted his problem was the ringing, she diagnosed him as depressed and prescribed sleeping pills and an antidepressant, Effexor. Finally, he said, he began to sleep. And slowly, the depression -- and along with it, the severity of his tinnitus -- began to improve. It’s a message he wants others suffering from the condition to know.
“If you’ve got ringing in the ears, the first thing you should do is see a psychiatrist,” he said. “She saved my life.”
Watch PBS NewsHour science correspondent Miles O'Brien report on the latest tinnitus research and his own experience battling the condition.
Inside the Tinnitus Brain
De Mong is not alone. Of the 50 million Americans who experience tinnitus at some point in their lives and the 16 million who are bothered enough to seek help, 2 million have it to a degree so severe that it’s debilitating, according to the American Tinnitus Association. It is the leading disability among veterans, outranking even post traumatic stress disorder, according to disability claims from the Veterans Administration’s 2012 fiscal year report. There is no cure for tinnitus, and no medication known to effectively treat it.
While tinnitus originates with hearing loss, the problem is actually rooted deep in the brain and caused, researchers believe, by a complex interplay of brain signals gone wrong.
It begins with damage to tiny vibrating receptors called hair cells in the snail-shaped cochlea of the inner ear. That injury results in two things: hearing loss -- gaps in certain frequency ranges of hearing -- but also a remapping in the auditory cortex of the brain, where signals received from the inner ear are processed.
"That's where the first thing goes wrong," said Josef Rauschecker, a professor of neuroscience at the Georgetown University Medical Center, who has been researching tinnitus for nearly a decade.
The brain tries to fill in the gaps, and it does so by creating phantom sounds. On MRI scans, scientists see evidence of this as hyperactivity: an excess firing of neurons in the brain’s auditory cortex.
It's not unlike the phantom pain one gets after losing a limb. It's common for amputees to feel itching or aching in an arm or leg after it's gone.
This is because even after the amputation, neurons in the brain continue to fire, signaling the presence of that limb. A similar thing is happening in the auditory system. Even though the receptors are damaged, the brain continues to fire, but excessively so.
These facts are undisputed. But Rauschecker’s team takes it a step farther. He believes that something else is happening in the ventral medial prefrontal cortex, a region in the brain’s executive center.
That part of the brain tries to stifle the phantom sounds, and it does so using a “noise-cancellation system,” a sort of volume control that cranks down their intensity.
It doesn't just suppress tinnitus sounds, he says. It also keeps you from hearing noises inside of your body at full throttle -- your heartbeat, for example, and your breathing.
"This is something that's become very interesting in the last several years," Rauschecker said. "People realize that perception is not just a bottom-up process, where something comes into your sensory organs -- your eyes or your ears -- and then goes up to the brain and that’s it. There is also something coming down from the higher centers that can then control those sensory signals. And that’s very handy in everyday situations. You don't want to hear everything."
Rauschecker is a soft-spoken man with rosy cheeks and an Austrian accent who smiles with his whole face. Driving his research is his own struggle with tinnitus. It started about a decade ago in his left ear as a high-frequency hiss, coming and going at first, like an unwelcome houseguest.
But as time passed, it began to stick around longer and longer. He describes it as uncomfortable, sometimes very loud, but, he’s quick to point out, not debilitating. Still, his experience has allowed him to make certain observations. When he is stressed or sleep deprived, the tinnitus gets worse, for example. Relaxation helps. So do weekends.
Among three independent cohorts of tinnitus patients, Rauschecker and his team have found volume loss -- a loss of neurons, he believes, and possibly glial cells -- in the ventral medial prefrontal cortex, home to this suppression system.
What’s more, the degree of volume loss correlates with the loudness of the tinnitus. What they’re seeing when they look at the scans, he believes, is the suppression system broken. What they’re seeing is chronic tinnitus.
"It's really a robust finding," he said. "We're very confident about this."
But here’s the puzzle: Why do some people with hearing loss live happily, even blissfully unaware of it, while others hear dental drills and hissing power lines? Why do only 30 percent of hearing loss cases progress to chronic tinnitus?
“This is where the field has to shift now,” Rauschecker said, “Toward asking exactly that question.”
Among his future goals is to better understand what causes this system to become compromised.
Rauschecker believes that many understand tinnitus backwards, assuming a causal relationship between the tinnitus and the behavioral problems so common among patients with the condition, as if tinnitus was the cause, and the depression, anxiety and insomnia, the effect.
When in fact, he says, they’re all part of the same underlying disorder. And in some cases, the depression is what’s making the tinnitus worse, not the other way around.
“We’re saying, Well, there’s an underlying disorder maybe having to do with serotonin
depletion or whatever that causes the insomnia and the tinnitus,” he said. “So they are both effects of the same affliction, in a way. You can’t really say one is the consequence of the other. They’re mutually dependent.”
Targeting the neurotransmitters involved could open up new avenues for treatment, he said. For example, he’s hoping to conduct a rigorous study on SSRI antidepressants, drugs that block the reuptake of serotonin in the brain, as a possible treatment for turning down the volume on the tinnitus.
In San Francisco, a separate research team is has found another part of the brain actively involved in tinnitus: the basal ganglia.
Using state-of-the-art MRI scanners to peer deep inside the brains of tinnitus patients, Cheung and his team have managed to pinpoint an important source of the phantom noise.
The basal ganglia takes care of many involuntary processes in the human body, from establishing balance, to repeating often-rehearsed motions, to maintaining a sense of passing time.
Cheung believes this part of the brain contains a sort of gating system.
When the gate is closed, the tinnitus is held back -- and on mute.
When it’s opened, the noise floods through. Cheung and his team believe if they can go in and manipulate that part of the brain, they just might be able to muffle the noise -- and provide some real relief.
The basal ganglia rests just below the cerebellum and above the brain stem in the human brain. The structure may help regulate the ringing in the ears known as tinnitus. Video still from PBS NewsHour
And they have good reason to believe that. In a pilot study on Parkinson’s patients with tinnitus, Cheung’s team found that by using a probe to send pulses of electricity into the brain, they could turn the volume up or down on the patients’ tinnitus, at least temporarily.
“It is an exciting finding, and it’s led to other studies with imaging and a trial, a phase one trial, of deep brain stimulation for tinnitus,” Cheung said, adding that he’s confident that the field is advancing.
“There’s not yet a cure,” he said. “We will find a cure.”
Seeking Help in Unlikely Places
For now, with that cure still looming in the distance, patients seeking treatment are often met with frustration and dead ends.
“The ENT's say, ‘well it's not in the ear, so we can't help you,’” Rauschecker said. “And the neurologists usually aren't very interested in this either, because they don't understand it, and tinnitus is a small domain.”
There’s no lack of homeopathic drugs, vitamins and herbs online, boasting a quick fix for tinnitus. James Henry, who works for the National Center for Rehabilitative Auditory Research at the VA Medical Center in Portland,said to beware of these online “remedies.”
“My advice would be to be skeptical of anything on the internet,” Henry said. “Don’t be taken in on unproven methods. Don’t spend money on things that aren’t proven to work.”
But sufferers are not without options. Henry has been researching treatment methods for tinnitus for 20 years.
These include methods to use sound in various ways as therapy, counseling and behavioral training. While their success varies according to the patient, the methods can be helpful for many patients.
A combination of counseling, sound therapy and coping techniques that help a sufferer learn to manage reactions to the tinnitus can be very effective, he said.
His team has developed a five-step program that includes audiology testing and evaluations, the use of external sounds to manage tinnitus, and cognitive behavioral therapy, which teaches coping techniques. The stepped-care program provides services only to the level required by each patient.
“These can include deep breathing and relaxation exercises -- anything to calm the patient down,” he said. “If patients are stressed, they learn to sit down, get comfortable, use deep breathing, close their eyes and imagine something pleasant.
A psychologist also teaches them distraction techniques.”
Cognitive behavioral therapy, in particular, has proven helpful for many severe tinnitus sufferers, he said.
Jennifer Gans is a clinical psychologist and researcher who specializes in this kind of therapy for tinnitus.
She calls it mindfulness. Sixteen years ago,
Gans was hit by a truck and sent into a five-day coma. That accident, and the painful recovery that followed, made her especially attuned to managing pain.
She has since developed a mindfulness program for tinnitus, modeled after techniques used for chronic pain. Key to the program is accepting the tinnitus, she said. Focusing on it, rather than pushing it away and turning inward to harness existing powers of healing.
“There’s a Buddhist saying: pain in life is inevitable, but suffering is optional,” she said. “I’m working with the people on their suffering about their tinnitus, helping them to change their relationship to the tinnitus or whatever pain in life comes their way.”
She calls it “moving into” the tinnitus, and compares it to driving on ice.
“If you turn away from the skid as we’re not supposed to, the car spins out of control,” she explains. “But if you move into the skid, there’s this moment of skidding with it where all of a sudden, you reestablish balance, eventually. And so that is essentially what I see as what’s helpful for tinnitus -- it’s not pulling away from it.”
De Mong, who took one of Gans’s eight-week tinnitus workshops, recalls one of the final exercises, a method that Gans called “breathing into the tinnitus.”
The idea of doing such a thing terrified him, he recalls.
“I argued with her. I didn’t want to do it,” he said. “I thought, ‘it’s going to be too painful.’ But I did it.
And I found that it softens the tinnitus. It softens it a lot. It doesn’t make it go away. But it softens my reaction to it. It’s what I still do today.”
Even with the help of mindfulness and medication, De Mong faces a constant struggle, with both the tinnitus and the depression always looming in his brain, ready to manifest as more darkness, louder sounds.
Doing interviews for this story made his tinnitus worse and his depression more prominent.
About five years ago, he wrote a personal account of his experience with tinnitus, documenting all of his doctors appointments, his medication and the treatments that both did and didn’t help.
“Quiet times used to be one of my favorite things,” he wrote. “Now, silence is just torture… It hurts. When I'm in a quiet room I just want to run out of the room as fast as I can.”
The act of writing about his tinnitus made it so loud “that it would feel like a dentist was drilling into my brain with his high speed drill,” he wrote. “This was the most painful document that I have ever written,” it ends. “To have to think about how tinnitus has changed my life is just brutal.”
But when it gets worse, he sees his psychiatrist or revisits the coping methods he learned from Gans and her mindfulness program.
“In the program, we did yoga, we did mindful living, we did breathing exercises and we did relaxation techniques,” he said. “What I do today from that program is breathing exercises and mindful living.
To be mindful that I’m talking to you, mindful that I’m in a comfortable room, mindful that I’m not hungry. That I’m alive.”
In May, Gans ran an introduction to her eight-week workshop with a roomful of veterans. She asked everyone to share their experience with their tinnitus.
Tyler Brown, an army veteran, listed the loud noises he was exposed to during his three deployments in Iraq: fighter jets, machine guns, explosives.
His tinnitus makes him more sensitive to certain sounds. For example, he avoids being around dogs or small children.
“It’s a weird thing,” Brown said. “Sometimes the tinnitus will just be there passing in the background, and it’s just annoying, it hurts in my ears. The other time I get it, it reminds me of setting a demo charge on a door then blowing it up.”
At the workshop, Gans directed the veterans to close their eyes and focus on their breathing. She had them hold a raisin in their mouths and think about the flavor, the texture and the taste. That’s mindfulness, she said. “Being present and being aware that you’re present.”
She ended the workshop with a story about wild monkeys in ancient India. She described a coconut with a hole carved out and a banana inside. The coconut was nailed to the base of a tree, and used as a trap, she explained.
“Now, this hole in the coconut was a special hole,” she said. “Just large enough for the monkey’s paws to go in, but too small for a monkey’s fist to pull out.”
Again and again, she said, monkeys run to the trap, stick their hand in the coconut, make a fist around the banana, and get stuck -- trapped.
“All the monkey needed to do in order to be free was just to let go, but the monkey doesn’t always think to do that,” she said. “Now I'm not calling us monkeys, but maybe think about how you might be holding onto something, when all you need to do is just let go to have your freedom.”
“Maybe we’re like this around our tinnitus,” she continued. “Maybe we can practice just letting go and see what happens. Holding things a little bit more gently.”
Mechanisms of tinnitus
+ Author Affiliations
The generation of tinnitus is a topic of much scientific enquiry. This chapter reviews possible mechanisms of tinnitus, whilst noting that the heterogeneity observed within the human population with distressing tinnitus means that there may be many different mechanisms by which tinnitus can occur. Indeed, multiple mechanisms may be at work within one individual. The role of the cochlea in tinnitus is considered, and in particular the concept of discordant damage between inner and outer hair cells is described. Biochemical models of tinnitus pertaining to the cochlea and the central auditory pathway are considered. Potential mechanisms for tinnitus within the auditory brain are reviewed, including important work on synchronised spontaneous activity in the cochlear nerve. Whilst the number of possible mechanisms of tinnitus within the auditory system is considerable, the identification of the physiological substrates underlying tinnitus is a crucial element in the design of novel and effective therapies.
Hypotheses regarding mechanisms of tinnitus generation abound. Given the heterogeneity observed in the tinnitus population1, it may be considered that no single theory, model or hypothesis will explain the presence of tinnitus in all those affected. Thus, the mechanisms described in this chapter are not mutually exclusive, and multiple mechanisms may be present in an individual with tinnitus. The focus of this review is upon physiological mechanisms of tinnitus generation rather than the psychological impact that tinnitus may have, or therapies and treatments.
The word tinnitus derives from the Latin tinnire meaning ‘to ring’, and in English is defined as ‘a ringing in the ears’2. In an attempt at a scientific definition, McFadden3 considered that: ‘tinnitus is the conscious expression of a sound that originates in an involuntary manner in the head of its owner, or may appear to him to do so’. This definition has been widely adopted.
Tinnitus is a common experience in adults and children. Adult data from the MRC Institute of Hearing Research4 indicate that, in the UK, 10% of adults have experienced prolonged spontaneous tinnitus, and that in 5% of adults tinnitus is reported to be moderately or severely annoying. In 1% of the adult population, tinnitus has a severe effect on quality of life. The incidence data from the MRC study indicate that 7% of the UK adult population have consulted their doctor about tinnitus, and 2.5% have attended a hospital with regard to tinnitus. Up to one-third of children experience occasional tinnitus, and in approximately 10% tinnitus has been bothersome5.
A complex relationship between epidemiological factors and tinnitus has been identified4. The prevalence of tinnitus increases with age and with hearing impairment. Women are more likely to report tinnitus than men, and occupational noise and lower socio-economic class are also associated with increased tinnitus. These factors are not independent of each other, and further work is needed in this area.
A large number of descriptors of tinnitus have been reported, the most common being hissing, sizzling and buzzing, these reflecting the clinical finding that tinnitus is usually high pitched. An individual may localise tinnitus to one ear or other, to both, within the head or occasionally external to the head. In a clinical context, many individuals may hear more than one tinnitus sound.
Tinnitus is an element of the symptom profile of several significant otological pathologies (such as otosclerosis, vestibular schwannoma and Menière's disease) that necessitate medical or surgical treatment. Whilst such conditions are rare within both the general and tinnitus-complaint populations, there is a consensus that an informed clinical opinion should be sought by an individual with troublesome tinnitus (especially when unilateral) in order to exclude such pathologies. This review does not consider pathology-specific mechanisms other than the cochlear dysfunction implicated in sensorineural hearing loss.
Any model which considered the cochlea in isolation from the rest of the auditory pathway in relation to tinnitus would not now be considered adequate, but there are situations where cochlear dysfunction has been implicated in tinnitus generation.
Spontaneous oto-acoustic emissions
The concept that a normal healthy cochlea may produce low intensity tonal or narrow-band sound in the absence of any acoustic stimulation (spontaneous oto-acoustic emissions, SOAEs) was introduced by Gold in 19486 as an element of a model of active processes within the cochlea. The identification of such activity7 (see Kemp this volume) was greeted with enthusiasm by the scientific community concerned with tinnitus as ‘our hope was that they corresponded to their owner's tinnitus and thus, at long last, we could measure tinnitus objectively’8.
This hope was not well founded, as it became clear that whilst 38–60% of normal-hearing adults have measurable SOAEs, the majority of such individuals are not aware of this activity9. Penner and Burns10 noted that when SOAEs do occur in the ear of a tinnitus patient, they rarely correspond to the judged frequency of the tinnitus. These authors considered that if a SOAE could be suppressed by a suitable low-level external tone without affecting the tinnitus perception, and, conversely, if tinnitus could be masked in an individual without affecting the SOAE, then the inference of physiological independence could be made. This suppression/masking paradigm has been used to determine the incidence of tinnitus complaint caused by SOAEs. Penner11 found that 4.1% of a series of tinnitus patients (n = 96) had tinnitus originating as an SOAE. Baskill and Coles12 found an incidence of 2%, and Coles (cited in Penner13) of 4.5%.
One additional piece of evidence that SOAEs are not largely responsible for tinnitus generation is as follows. SOAEs are largely abolished by aspirin (salicylate)14, but tinnitus perception is not generally improved by salicylate, there being only one report of such an experience15, this in a case where SOAE and tinnitus were demonstrably linked. Penner13 notes that the treatment of SOAE-generated tinnitus with salicylate is done at the risk of ototoxic hearing loss and the possible generation of new tinnitus perceptions.
Discordant damage of IHC and OHC
Jastreboff16 noted that intense noise and ototoxic agents initially damage the basal turn of the cochlea, and outer hair cells (OHCs), and only later affect inner hair cells (IHCs) if continued or repeated, IHCs being more resistant to such damage17. The inference was made that, within a partially affected organ of Corti, there will be an area with both OHCs and IHCs affected, an area with OHCs are affected but IHCs are intact, and an area with both intact. In the second of these three categories, the coupling between the tectorial membrane and the basilar membrane would be affected, to the extent that the tectorial membrane might directly impinge upon the cilia of the IHCs, thus causing them to depolarise. Clinical support for such modification of auditory afferent activity leading to tinnitus perception has been cited, in that some patients with tinnitus and high-frequency hearing loss match their tinnitus frequency to the point at which the loss begins18,,19. The role that increased neural activity in the auditory periphery may have in tinnitus generation is considered in detail below. Jastreboff20 went on to consider not only the afferent activity generated by the IHCs, but also the possibility that afferent activity of the IHCs might be interpreted in the light of attempted (but failed) reduction of cochlear gain via OHCs, giving rise to increased perceived intensity. It was further suggested that this model might apply to both permanent and temporary discordant damage, the example of temporary damage being temporary tinnitus associated with temporary threshold shift following noise exposure. Chery-Croze et al21 noted that, in an area where IHC damage was present, any efferent inhibition of the OHCs in that area will be reduced due to the reduced afferent input. That efferent innervation may be shared with neighbouring OHCs partnering undamaged IHCs, due to the diffuse nature of efferent innervation (one fibre for 20–30 OHCs), and so the undamaged area neighbouring the damaged IHCs may also have reduced efferent inhibition, giving rise to a highly active area of the basilar membrane, resulting in tonal tinnitus.
LePage22 suggested an alternative mechanism by which an area of the basilar membrane with damaged OHCs but intact IHCs might contribute to tinnitus generation. The role of the normal OHCs in fixing the operating point of IHCs was considered, that is an ability of OHCs to control the sensitivity of IHCs by setting the operating point on the IHCs' transfer characteristic to a value which the brain normally interprets as no sound. This point would not actually correspond to zero sound input, but a sound level regarded as background. A loss of motility in OHCs might reduce the ability to set the operating point of the IHCs appropriately, thus causing a ‘virtual’ sound input, so that this normally inaudible activity might be perceived as tinnitus. If this were to occur over a short length of the basilar membrane, the perception would be interpreted according to the tonotopic frequency normally transduced at that point, and hence would be tonal. LePage notes that if there were functional OHCs adjacent to the dysfunctional OHCs, then no loss of audiometric sensitivity might be evident. Zenner and Ernst23 suggested that tinnitus generated by such a mechanism should be classified as ‘DC motor tinnitus’.
A further role for OHC in tinnitus has been suggested by Patuzzi24, who noted that OHC dysfunction may cause excessive release of neurotransmitter from IHCs following an increase in the endocochlear potential. This phenomenon might then lead to a ‘rate tinnitus’, so called because of the excessive rate of glutamate release from IHCs. Patuzzi predicted that the tinnitus percept would have a ‘hiss’ quality.
A biochemical model of peripheral tinnitus has recently been proposed25 based partly on the clinical observation that adult humans with distressing tinnitus have experiences of agitation, stress and anxiety, and partly on cochlear neurochemistry. Endogenous dynorphins (associated with stress) are postulated to potentiate the excitatory function of glutamate within the cochlea, mimicking the action of sodium salicylate in increasing spontaneous neural activity.
The biochemistry of the central auditory system has also been considered in the tinnitus literature. A role for serotonin (5-HT) in persistent tinnitus was postulated by Simpson and Davies26, based on the consideration that disrupted or modified 5-HT function might cause a reduction in auditory filtering abilities and in tinnitus habituation (see later). The identification of a role of 5-HT in persistent distressing tinnitus is important as it may facilitate the development of effective pharmacological intervention. The need for investigation of the effect of selective serotonin re-uptake inhibitors upon tinnitus is urgent27.
Non-cochlear mechanisms of tinnitus generation
Considerable attention has been paid to the possible involvement of cochlear mechanisms in tinnitus generation, but in recent years the interest of the scientific community has shifted towards retro-cochlear and central mechanisms16,,28–31. In many cases, the models and hypotheses proposed do not preclude a role for the cochlea, but have as their primary concern neural mechanisms of tinnitus generation and persistence.
Jastreboff neurophysiological model
In a review of tinnitus from a neurophysiological perspective, Jastreboff16 considered a role for ‘signal recognition and classification circuits’ in persistent tinnitus, that function as neural networks becoming tuned to the tinnitus signal, even when that signal is transitory, fluctuating or intermittent. It was suggested that cochlear processes might be involved in the generation of weak tinnitus-related activity, but since the majority of individuals with normal hearing perceive tinnitus-like sound in quiet surroundings32, it was not necessary for a lesion of the auditory system to be present for tinnitus to be heard. The Jastreboff ‘neurophysiological model’, which involves the auditory perceptual, emotional and reactive systems involved in tinnitus, was published in 199633 and in slightly more detailed form (Fig. 1) in 199934. In many individuals after a short period of awareness of tinnitus-related activity, a process of habituation occurs, such that the activity is no longer consciously perceived. However, in cases where there is some ‘negative emotional re-inforcement’, described as fear, anxiety or tension, limbic system and autonomic activation cause the activity to be enhanced and perception persists. The distinction between the perception of, and the behavioural and emotional reaction to, tinnitus was explicit, as was the potential for a feed-back loop between these processes. A treatment protocol arising from this perspective, and based upon facilitating habituation to both the tinnitus signal and to the reaction to that perception, has been entitled Tinnitus Retraining Therapy33. The Jastreboff model has been widely accepted as a synthesis that has utility for patients, clinicians and researchers alike. Whilst direct empirical evidence to support this model has not been forthcoming, the concepts involved are congruent with a modern understanding of the auditory system. A potential criticism is that the model does not represent the full complexity and dynamism of the human auditory system, but if the primary aim was a model of tinnitus that was easily understood by patients then this may have been intentional.
Increased neural activity
Evans et al35 noted that then contemporary theories of tinnitus generation made the assumption, either implicit or explicit, that it was associated with spontaneous overactivity of the cochlear nerve. This was at odds with the literature which indicated that experimentally induced chronic cochlear pathology resulted in a decrease in such spontaneous activity. Such a decrease had been reported by Kiang et al36 on the basis of a study involving kanamycin-deafened cats. Evans et al35, however, reported that doses of salicylate in the cat equivalent to blood-concentration doses known to induce tinnitus in humans (in excess of 300–400 mg/l) had the effect of increasing spontaneous activity. Tyler37 noted the different methodology of these studies, and that the recording from single units in the cochlear nerve might miss hyperactivity occurring elsewhere. Eggermont30 also considered the discrepancy between these findings, and concluded that increased spontaneous activity in the human cochlear nerve was unlikely to be involved in tinnitus generation (assuming that animal data can be applied to humans) since tinnitus-inducing events in humans are as likely to reduce spontaneous activity as increase it.
Increased neural activity at levels above the cochlear nerve may be implicated in tinnitus generation. Increases in spontaneous activity in the dorsal cochlear nucleus (DCN) in the golden hamster after intense sound exposure have been reported38–40. Salvi et al41 subjected chinchillas to intense sound exposure (2 kHz tone, 105 dB SPL, 30 min) and reported increases of spontaneous activity in the inferior colliculus and the dorsal cochlear nucleus; in addition, they noted tonotopic re-organisation in these structures. Increased activity in the inferior colliculus has also been reported after salicylate administration in the rat42 and the guinea pig43. Chen et al44 studied the effect of intense sound exposure (125 dB SPL, 10 kHz tone, 4 h) on spontaneous activity in the DCN of the rat. They found an increase in bursting spontaneous activity and a decrease in regular (simple spiking) spontaneous activity. The authors suggested that such activity might represent increased auditory efferent activity.
Increased cortical activity in the gerbil following salicylate administration has been demonstrated using 2-deoxyglucose methods45 and c-fos immunochemistry46, one study43 using impulse noise as well as salicylate to induce cochlear dysfunction. Wallhausser-Franke and Langner47 also noted evidence of increased activity in the amygdalae of these animals, and considered this a response to induced tinnitus, though they noted that the changes may have been produced by the stress of the animals. Langner and Wallhauser-Franke48 proposed a model for tinnitus generation based on these findings. The lack of increased activity in the ventral cochlear nucleus (VCN)49 after salicylate administration was claimed as evidence that the reported effects of salicylate are not due to increased afferent activity in the cochlear nerve. The altered activity reported in the DCN was suggested to result either from increased efferent activity from the cortex or inferior colliculus (IC), or from a lack of inhibition from other cochlear nucleus units. The amplification of spontaneous activity within this feedback loop, influenced also by processes of attention (involving the reticular formation) and the limbic system (specifically the amygdala) was thought to be the cause of tinnitus perception.
A mechanism of disinhibition in the IC and DCN has been proposed30,,50. In the DCN type II/III, interneurones act in an inhibitory manner upon spontaneously active type IV neurones30. If these inhibitory interneurones have reduced afferent input due to peripheral auditory dysfunction, there may be a loss of inhibition of the spontaneous activity of the type IV neurones, thus resulting in abnormally high spontaneous activity which might be audible. Eggermont30 furthered this proposal, suggesting, after Moller51, additional disinhibition in the IC.
Synchronisation of spontaneous neural activity
Eggermont30 has reviewed the evidence for a theory that tinnitus may result from the imposition of a temporal pattern upon stochastic cochlear nerve activity. Hudspeth and Corey52 reported that, in the saccular hair cells of the bull frog, an increase in the concentration of extracellular calcium could lead to increased firing. Eggermont29 proposed that if such a calcium-induced increase were present in dysfunctional human cochleae, then it might lead to enhanced neurotransmitter release from IHC, and thence to increased activity in auditory nerve fibres, some of the spikes occurring in bursts. This pattern of activity (burst-firing) may mimic that seen in response to sound stimulation. Burst-firing can occur in the cat auditory nerve after exposure to kanamycin36, and in the rat inferior colliculus after salicylate administration42. Increased burst-firing in the rat DCN following intense sound exposure has also been reported44. Kaltenbach31 argued that a link between such bursting activity and tinnitus perception is problematic, in the light of the finding of Ochi and Eggermont53,,54 that, in the cat, no increase in cortical bursting activity is demonstrated after administration of salicylate or quinine. It is possible, however, that bursting activity in the auditory periphery could be re-coded as a rate change in more central nuclei.
Eggermont50 proposed that the synchronised activity of a small number of fibres in the auditory periphery may give rise to a sensation of sound, and thus of tinnitus. Moller55 drew an analogy with hemifacial spasm and trigeminal neuralgia patients, noting that the surgical decompression of vessels impinging upon the Vth cranial nerve relieved trigeminal neuralgia, and upon the VIIth cranial nerve relieved hemifacial spasm. Moller noted that these cranial nerves were sensitive to such compression at the root entry zone, where they were covered by myelin. He hypothesised that compression of the nerve caused cross-talk between nerve fibres, the breakdown of the myelin insulation of the nerve fibres establishing ephaptic coupling between them. This concept was applied to the cochlear-vestibular nerve, which is covered by central myelin for the majority of its length, and hence is vulnerable to compression from blood vessels or tumours impinging upon the nerve, such as vestibular schwannoma. Such compression and consequent ephaptic coupling might lead to tinnitus perception, if synchronisation of the stochastic firing in the human cochlear nerve is perceived as sound. Eggermont29 modelled the effect of ephaptic interaction between fibres of the auditory nerve, and proposed that the effect of the interaction was to increase the number of interspike intervals around 10 ms. He concluded that the ephaptic interaction model had a ‘potential real-life parallel in the demyelinating effects of tumours of the eighth nerve’ (e.g. vestibular schwannoma).
Several terms have been used for such measures of synchronised activity – ensemble spontaneous neural activity (ESNA)56, average spectrum of electrophysiological cochlear activity (ASECA)57, ensemble spontaneous activity (ESA)58, and spectrum of background neural noise (SNN)59. Evidence for synchronised spontaneous neural activity associated with tinnitus is emergent. Martin et al60 recorded spontaneous auditory nerve activity from 10 cats pre- and post-salicylate administration using an incoherent spectral averaging technique, which allows the identification of continuous signals that have consistent frequency characteristics. It was noted that the results needed to be interpreted with caution because of the physiological stress salicylate places upon the animal. Marked changes in the spectral analysis of auditory nerve activity pre- and post-salicylate administration were reported, with a new peak of activity centred at or near 200 Hz being identified in all post-administration recordings. A higher-frequency, broader peak was also identified. Two animals in whom saline was administered did not demonstrate the new peaks of activity. Cazals et al61 reported the effects of long-term salicylate administration in the guinea pig. Changes (specifically an immediate decrease followed by a progressive increase) in spontaneous activity recorded from the round window predated changes in hearing sensitivity, which the authors felt was an indication of high-frequency salicylate-induced tinnitus as this would be expected in humans under such conditions. Martin56 described spectral average recordings from the cochlear nerve of 14 human adult patients undergoing cerebellopontine angle surgery. In 12 patients with tinnitus, a prominent peak in the spectral average near 200 Hz was reported (see Fig. 2). Further animal studies report that ESNA is influenced by contralateral acoustic stimulation62.
The origin of peaks within the spectrum of spontaneous neural activity recorded from guinea pigs undergoing salicylate administration was explored by McMahon and Patuzzi63. They questioned the assumption of Cazals and Huang57 that the peaks are indicative of synchronous activity. Two spectral peaks were identified. A peak at 170 Hz was thought to be consistent with the 200 Hz peak previously reported by Martin56 in humans (see Fig. 2). A spectral peak at 900 Hz was thought to arise from resonance of the primary afferent nerve membrane, with a potential contribution from neurones with similar membrane properties in the ventral cochlear nucleus. Evidence favouring the existence of these two peaks has also been reported by Searchfield et al64. McMahon and Patuzzi suggested that the peaks of spontaneous activity recorded at 200 Hz and 900 Hz may in future be used to determine the location of physiological generators of tinnitus.
Medial efferent system involvement
Eggermont50 suggested that the efferent system might influence the perceived intensity of tinnitus, and associated annoyance, based on the observation that stressful situations may exacerbate tinnitus, and that techniques such as biofeedback may reduce tinnitus. In addition, the connection of the auditory efferent system with the reticular formation within the brain stem had been linked with the persistence of tinnitus as an alerting stimulus by Hazell and Jastreboff19. Jastreboff and Hazell61 additionally suggested a role for the efferent system in modulating a cochlear mechanism of tinnitus generation.
Veuillet et al66 investigated the possibility that dysfunction of the medial efferent system was involved in tinnitus perception by measuring the suppressive effect of contralateral noise upon transient evoked oto-acoustic emissions (TEOAE) in subjects with tinnitus localised to one ear only. The hypothesis that efferent dysfunction in the tinnitus ear would result in a smaller suppressive effect of noise upon TEOAE amplitude than in the non-tinnitus ear was only marginally supported. Large intersubject variability in the suppressive effect was noted.
Lind67 also measured the suppressive effect of contralateral broad-band noise on TEOAE in 20 patients with unilateral tinnitus and symmetrical hearing, finding no significant difference between the suppression effect in tinnitus and non-tinnitus ears.
An alternative mechanism of efferent system involvement in tinnitus perception has been suggested by Robertson et al68, following experimental evidence that, in the guinea pig, olivocochlear inputs to the cochlear nucleus can be excitatory, thus directly affecting ascending activity in the auditory pathway, separately from influence upon the cochlea. Efferent dysfunction might, therefore, be implicated in tinnitus perception generated at a brain stem level. However, a review69 of tinnitus experience following vestibular nerve section in humans, which involves ablation of the medial efferent pathway in the inferior vestibular nerve, indicated that total medial efferent dysfunction was not associated with troublesome or exacerbated tinnitus.
The modulation of tinnitus by somatosensory input was considered by Levine70. Patients were first interviewed about their experiences of somatic modulation of their tinnitus, such as changes in pitch or intensity associated with face stroking or head movements. They were then asked to perform manoeuvres of a few seconds' duration to test for somatic effects, including teeth clenching, pressure on the occiput, forehead, vertex and temples, head turning and shoulder abductions. In the interview, 16 of 70 patients reported that they could somatically modulate their tinnitus (23%). On testing, however, 48 patients (68%) reported modulation of their tinnitus with at least one of the manoeuvres. The pattern of modulation reported was highly variable involving changes in intensity (both increase and decrease) and pitch. In all cases, these changes were transient. The results led Levine to conclude that ‘somatic modulation appears to be a fundamental attribute of tinnitus’, and to propose interactions between auditory perception and somatosensory input at the dorsal cochlear nucleus. Higher centres where such interaction also occurs (such as the SOC and IC) were not considered as somatically modifiable tinnitus is largely localised to one or other ear, and it was thought that binaural interactions in the SOC and higher centres would not have given rise to tinnitus heard to just one side. Levine71,,72 also noted that cranial nerves V, VII, IX and X converge in the medullary somatosensory nuclei (MSN; Fig. 3) and that anatomical links between the MSN and the DCN had previously been described73. The ability of some mammals to incorporate information about pinna position in sound localisation is indicative of such a pathway74. Levine hypothesised that decreases in inhibitory MSN input to the DCN (specifically inhibition) might result in disinhibition of DCN activity leading to increased activity and the perception of tinnitus. Levine71 noted potential criticisms of this model. The DCN may not be the site of somatic and auditory interaction involved in tinnitus. The argument that the lateralisation of the tinnitus perception being evidence for the role of DCN somatic modulation of tinnitus is strong, but a role of the extralemniscal pathway in interactions between somatic and auditory pathways, as proposed by Moller et al75, is also worthy of consideration and would allow unilateral tinnitus perception. Another potential criticism is that, whilst the anatomical links between the MSN and DCN have been identified in the cat, the situation is humans is less clear, and in particular no pathway from the cunate/spiral tract of cranial nerve V to the DCN has been identified.
Analogies with pain
Analogy with chronic pain
Analogies between pain and tinnitus have been made many times in the literature (see House & Brackmann76 and Evans77 for early examples). It has been noted that: (i) pain, like tinnitus, can arise from a great variety of lesions; (ii) there is no one specific mechanism for pain perception; (iii) pain is a subjective phenomenon that is difficult to quantify; and (iv) treatment of pain symptoms is difficult and often ineffective79,,80. More specifically, Moller1,,80,81 considered the analogy between tinnitus and chronic pain in terms of peripheral generation and of central persistence once the acute injury has resolved. Whilst chronic pain is often a consequence of peripheral injury, that injury may not in itself account for the sustained nature of chronic pain. Moller81 considered that the involvement of the CNS in such sustained perception was indicated by the relevant literature (see Basbaum & Jessell82 for a comprehensive review). Such involvement implies plasticity within the CNS. Similarly, while tinnitus is often associated with peripheral auditory dysfunction, that dysfunction may not account for the sustained and distressing tinnitus perception. Emotional and environmental influences upon pain perception have been noted82. The consequent large variation between individual experience of pain, makes the development of effective therapy very difficult.
Cortical re-organisation, tinnitus, and analogies with phantom pain
The possible analogy between tinnitus and phantom limb pain was first drawn by Goodhill in 195083. The concept that cortical re-organisation similar to that involved in phantom limb pain84 might occur in auditory cortical areas following change in the auditory periphery was first reviewed in detail by Meikle85 and more recently by Salvi et al86. The precise tonotopicity that has been demonstrated in the central auditory pathways means that de-afferentation of a specific portion of the cochlea will, in the short-term, lead to reduced activity in the cortical area with corresponding characteristic frequency (CF). If similar measurements are made some months later, that area is again responsive to sound, but many neurones now have CFs adjacent to that of the lesioned region86. This phenomenon has been demonstrated in animals87,,88 (one study in particular reported that even a modest noise induced hearing loss resulted in significant cortical re-organisation89) and in humans90,,91. One consequence of this re-organisation is that a disproportionately large number of neurones will be sensitive to frequencies at the upper and lower borders of the hearing loss. Salvi et al86 proposed that spontaneous activity in these areas might be perceived as tinnitus. Meikle85 suggested that the mechanism of such re-organisation might be the disinhibition of previously weak synaptic connections, and that the area of re-organisation might be limited to 1–2 mm, leading her to suggest that cortical re-organisation effects larger than this might represent re-organisation at a lower level in the auditory pathway where the tonotopic maps are smaller (the inferior colliculus for example). Re-organisation of the tonotopic map in the IC of the chinchilla following a high-frequency cochlear lesion has been demonstrated92.
Evidence for re-organisation of the auditory cortex being a mechanism of tinnitus generation in humans was reported by Mulnickel et al93 and Dietrich et al91. Whilst these studies involve small numbers of subjects, there are early indications that the identification of tinnitus mechanisms involving re-organisation and plasticity within the central auditory system may facilitate the development of novel pharmacological therapies for tinnitus60,,94.
This review indicates that there are many potential mechanisms for tinnitus, and so the population of people with troublesome tinnitus will be heterogeneous in aetiology and experience, as is observed in clinical practice. It is envisaged that the objective of tinnitus mechanism research in coming years will be to determine the validity and relevance of the hypotheses regarding tinnitus generation to the clinical population, and to use that evidence to design effective clinical treatments.
Key points for clinical practice
There are multiple potential mechanisms of tinnitus, and this accounts for the heterogeneity evident in the clinical population.
The development of new and effective treatments will be greatly facilitated by identification of mechanisms in humans.
The analogy between tinnitus and phantom limb pain, and the possibility of a role for 5-HT dysfunction in tinnitus, indicate the possibility of effective clinical intervention in tinnitus where these mechanisms are evident.
Discussions with Ian Winter and his detailed critical review of the manuscript were extremely helpful in writing this chapter. Brian Moore was a kind and diligent editor. Thanks also are due to David Moffat, Ross Coles and Jonathan Hazell for nurturing my interest in tinnitus.
Correspondence to: Mr David M Baguley, Audiology Department (Box 94), Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
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