A Journey of Tinnitus
Aasef G Shaikh | J Neurol Neurosurg Psychiatry. 2012;83(8):765-767.
Copyright © 2012 BMJ Publishing Group. All rights reserved.
Abstract and Introduction
Tinnitus is one of the most common neurological symptoms. Approximately, one-third adults experience it once in their life time, 10% of them experience prolonged tinnitus and 5% suffer from severely disturbing tinnitus. The term ‘tinnitus’ is derived from the Latin word ‘tinnire’, which means ‘ringing’. Tinnitus is defined as perception of sound in the absence of corresponding external auditory stimuli.
Tinnitus is not a ‘modern’ condition. The famous composer Ludwig van Beethoven (1770–1827) suffered from tinnitus and Charles Darwin (1809–1882) kept daily records of his tinnitus. The description of tinnitus in the ancient literature was remarkably influenced by the cultural factors. The ancient Egyptians believed that tinnitus occurred from a ‘bewitched’ ear and the ancient Asian mysticism considered tinnitus as ‘sensitivity to the divine’. The Romans presumed that tinnitus had common pathophysiology as seizures.
Clinical observations and psychoacoustic studies drove tinnitus research for several decades in the 20th century, but without definite answers for its pathophysiology. Studies in the late 1970s and early 1980s suggested the role of increased activity in the auditory nerve as a cause of tinnitus.[3,4] However, the peripheral theory for tinnitus had significant caveats. Eighth nerve transaction did not resolve tinnitus in human subjects, but it rather remained unchanged or even got worse. Development of animal models of tinnitus was a breakthrough in the late 1980s. Since then, tinnitus research has captured a remarkable pace. The rodent models were developed with exposure to chemicals that are known to cause tinnitus in humans, cochlear ablation, or intense sound exposure. These animal models had increased spontaneous neuronal activity at various levels along the central auditory pathway.[6–8] Thus in retrospect, perhaps the Romans were right, tinnitus could have a common pathophysiology with other disorders of hyperexcitable nervous system, such as seizures.
One may ask few fundamental questions: Which areas of the brain are hyperexcitable? What triggers the hyperexcitable state? What is the electrophysiological nature of central hyperexcitability? How does this pathophysiology reconcile with the contemporary treatment of tinnitus? Animal models of tinnitus provided important insight into these questions. These models had pinned down key areas of central hyperexcitability. Elegant neural recording techniques had identified the nature of abnormal electrical discharge of spontaneously hyperactive neurons. Cutting edge biological research had identified the likely culprit molecules that trigger maladaptive changes and possibly resultant neuronal hyperexcitability. Finally, all together these basic neuroscience findings had translated to bedside and taught clinicians the rationale for the pharmacological treatment of tinnitus.
Neuronal Hyperexcitability-Anatomical Localisation
General consensus is that insults triggering tinnitus in humans also cause hyperexcitable state in rodent central auditory system. Acutely after the insult, the spontaneous activity increases in the auditory nerve, inferior colliculus and auditory cortex.[10–12] The dorsal cochlear nucleus, inferior colliculus and primary auditory cortex neurons are hyperexcitable during chronic phases of tinnitus.[8,13–15] Most experimental evidences support the central origin of hyperexcitability. Surplus of externally driven excitation (ie, increased excitatory projections), paucity of externally driven inhibition (ie, decreased inhibitory projections), or molecular changes inside the neuron affecting the intrinsic membrane property and neuronal firing threshold can trigger the hyperexcitable state.
The disruption of the balance between excitation and inhibition is the most popular theory describing the central origin of the hyperexcitability in tinnitus. Degeneration of the inhibitory projections or readjustment of synaptic arboratizations at tinnitus-generating neurons could disrupt the fine balance. This theory has received strong line of support. Intense sound exposure results in the loss of inhibitory synapses, inhibitory post-synaptic glycine, and inhibitory γ-aminobutyric acid (GABA) receptors in the cochlear nucleus, superior olivary complex and inferior colliculus.[16–19] The upregulation of excitation, in the form of increased glutamate release, vesicular glutamate transport and redistribution of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors was also observed in animal models of tinnitus. Impaired balance between excitation and inhibition can also result from plastic changes in the response to neuromodulators. Alterations in the expression of ion-channels and intrinsic membrane properties of the brainstem auditory neurons was proposed after deafferentation induced by cochlear damage.[22,23] Each of these mechanisms or their combination can cause the hyperexcitable state and increase the spontaneous discharge of central auditory neurons.
Electrophysiological Nature of Increased Spontaneous Activity-Bursting versus Increased Synchronicity
At least two types of spontaneous activity described tinnitus in animal models—bursting activity and increased synchronicity. Both of these types are capable of triggering substantial post-synaptic responses in the central auditory system to drive tinnitus. Indeed bursting activity of the auditory nerve, dorsal cochlear nucleus and inferior colliculus was noted in animal models.[6,25] Increased synchrony at auditory nerve, inferior colliculus and primary auditory cortex was also seen in animal models of tinnitus.[13,26]
Increased Spontaneous Activity and Pharmacotherapy of Tinnitus-Bench to Bedside Transition
Basic neuroscience literature has established the convincing evidence of increased spontaneous activity in the animal models of tinnitus. Does this stand true for humans? Positron emission tomography and functional MRI had revealed increased neural activity in the medial geniculate nucleus, inferior colliculus and auditory cortex in patients with tinnitus.[27–29] This concept of increased spontaneous neuronal activity in tinnitus also predicts the favourable response to drugs that can reduce neuronal activity. Indeed a number of studies provided proof of this principle. Drugs that enhance neuronal inhibition (eg, benzodiazepine, vigabatrin, tiagabine), or reduce neural excitability (eg, gabapentin, memantine, lidocaine), or affect neuromodulators (eg, nortriptyline, amitriptyline and trimipramine) had benefited tinnitus patients. Flowchart in figure 1 illustrates an outline of contemporary pathophysiology of tinnitus and rationale for the effects of various pharmacological agents.
(Panoramic summary of the aetiology, pathophysiolgy of tinnitus and possible mechanisms of action of known pharmacotherapy for tinnitus.)
Han and colleagues report a cross-over trial of clonazepam and ginko biloba for the treatment of tinnitus (see page 821) . In this methodically and analytically strong report, the authors used comprehensive psychophysical techniques to objectively assess the severity of tinnitus and used such quantitative outcome measures to prove the efficacy of clonazepam for the treatment of tinnitus. This study along with others provide convincing evidence that increased spontaneous activity in the central auditory system could be correlated with tinnitus in humans and the aberrantly increased activity can be ‘silenced’ with a number of suppressor medications.
Studied over the centuries, tinnitus is not a ‘bewitched’ disease; rather it has transformed basic research and treatment with advances in suppressor medications. Perhaps in the future, newer generation antiepileptics could offer superior selectivity for specific inhibitory neurotransmitters or optimal ability to reduce neural excitability, but with minimal side effects. The comprehensive methodology reported by Han and colleagues may be an optimal and accessible approach to objectively assess the efficacy of contemporary antiepileptics for the treatment of tinnitus. After enormous progress in understanding the pathophysiology of tinnitus and exceptional advancement in developing novel and selective neuromodulatory compounds, we aspire to be able to efficiently treat tinnitus.