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How to cite this article Zeigelboim BS, Teive HAG, Sampaio R, Arruda WO, Jurkiewicz AL, Marques JM, Klagemberg KF, et al. Spinocerebellar ataxia is a disease belonging to a genetically and clinical heterogeneous group of neurodegenerative diseases characterized by progressive cerebellar ataxia1.
Spinocerebellar ataxias (SCAs) have an average incidence of about 1 to 5 cases for 100.000 people2. Its etiology is mostly mutations characterized by the presence of expanded trinucleotide CAG repeat unstable in the codified region of evaluated gene2,5. Electronystagmography (ENG) has allowed to sensitize the study of the labyrinth and its relationships with central nervous system (CNS), and allows differential topographical diagnosis of central and peripheral labyrinthopathies. Oculomotor abnormalities in patients with cerebellar dysfunction support the functional role of the cerebellum in maintenance of gaze eccentric portion, eye pursuit movements, modulation of the amplitude of saccadic movements and the visual suppression of caloric-induced nystagmus8.
The aim of the present study is to describe the alterations observed in ENG in patients affected by spinocerebellar ataxias.
Forty-three patients (17 female and 26 male) were evaluated at the Neurology Service, Clinical Hospital, Federal University of Parana, with established diagnosis of SCA (number of patients from each form: 12 SCA 3, 8 SCA 2, 1 SCA 4, 1 SCA 6, 1 SCA 7, 6 SCA 10), according to molecular genetics techniques with the use of PCR (polymerase chain reaction)9-11.
The patients were submitted to the following procedures: Anamnesis - a questionnaire with emphasis on otoneurological signs and symptoms. We performed ENG with a three-channel equipment (Berger Eletromedicina, model VN316, Sao Paulo, Brazil), rotating chair (Ferrante, model COD 14200, Sao Paulo, Brazil), a visual stimulator (Neurograff Eletromedicina, model EV VEC, Sao Paulo, Brazil), and an air caloric stimulator (Neurograff Eletromedicina, model NGR 05, Sao Paulo, Brazil).
We compared the results with normal control data, obtained from epidemiological studies for the Brazilian population13-15.
In the evaluation of vestibular function, caloric test, saccadic movements, positional, spontaneous, gaze nystagmus, optokinetic and rotatory nystagmus the finding in SCAs are depicted in Table 4. We verified that the ratio of bilateral vestibular hyporeflexia and dysmetric saccades were more prevalent and significant when compared to controls.
Regarding the results of vestibular examination, a higher incidence of central vestibular abnormalities was observed (74.42%) and more common in males, as show Tables 5 and 6.
The symptoms more commonly reported by SCA patients were also observed by other authors1,2-4. Nacamagoe et al.16 reported that the combination of vestibular dysfunction with the presence of cerebellar atrophy can contribute significantly to the emergence of instability during walking, which is part of the initial symptoms of SCA.
Amongst the damaged neuronal structures, it is known of the occurrence of vestibular hypofunction, but little is known regarding when and why it occurs18,19. Zeigelboim et al.7 showed that the loss of ciliated cells in the ampullary cupula and maculae, decreased number of neuronal bodies of the vestibular ganglion (Scarpa's), degeneration of otoliths, reduction of labyrinth blood flow, progressive depression of neural stability, reduction in the capacity of the compensation from vestibulo-ocular and vestibulospinal reflexes all these changes contribute to the reduction of the speed of the pursuit movements and rotational and caloric hyporeactivity of the central and peripheral vestibular system which are typically present in SCAs. MRI examination in SCA 3 patients reveals cerebellar atrophy, with or without brainstem involvement (olivopontocerebellar atrophy)2,9,10,22. Anatomopathological studies23 of the vestibular complex and the association of its fiber bundles in four patients with SCA 3 revealed that the five nuclei of the vestibular complex (interstitial, lateral, medial, inferior and superior vestibular nuclei have neurodegenerative changes caused by the disease, demonstrating that all the associated fiber tracts (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fasciculus, cranial vestibular contest portion of the eighth nerve), suffer widespread neuronal loss causing atrophy and demyelination of the structures. SCA 2 is characterized by cerebellar atrophy with a loss of Purkinje and granular cells, olivary neurons, substantia nigra and cells in the anterior horn of the spinal cord9,25. SCA 4 is a rare kind of ataxia characterized by cerebellar ataxia association to peripheral neuropathy and involvement of the pyramidal tract. SCA 6 studies show a reduction of Purkinje cells and also gliosis of the inferior olivary complex. SCA 7 presents from the neuropathological point of view of a olivopontocerebellar degeneration associated to a reduction of ganglion cells of the retina and pigmentary macular dystrophy31. SCA 10 studies demonstrate the presence of pan-cerebellar atrophy, without abnormalities in other regions32. The study showed that alterations in ENG are related to the severity of SCAs or clinical stage of the disease.
Tinnitus has been defined as the perceptual correlate of altered spontaneous neural activity occurring without an external auditory stimulus.
Tinnitus is a serious clinical symptom that may affect 30-40 million individuals nationally [1,2].
Our understanding of the functional biochemistry of the medial efferent olivocochlear system has advanced at a steady rate [22-24], whereas comparatively little in the way of function is known of the lateral efferent olivocochlear system. Opioid peptides and their unique receptors exhibit a widespread distribution in central and peripheral nervous system structures involved in vision, audition, olfaction, and somatic sensation. The activation of opioid receptors by endogenous opioid substances produces alterations in intercellular ionic conductances, resulting in either neural inhibition or neural excitation l50,66]. In contrast to their more widely studied inhibitory properties, opioid peptides also produce neural excitation [70,73,74).
As indicated, dynorphin-and enkephalin-like immunoreactivities have been found in the terminal varicosities of lateral efferent neurons in some species, indicating the presence of these neuroactive peptides in mammalian cochleas [27].
Intravenous (IV) administration of the opioid κ-receptor drug agonist (-) pentazocine produces an enhancement in auditory sensitivity and intensitydependent amplitude changes in the auditory nerve compound action potential (CAP) in chinchillas [83). The initiation of auditory signaling in the mammalian cochlea is highly dependent on the release of excitatory neurotransmitter from the IHCs.
However, evidence supports the gene expression of NMDA receptor subunits in the adult guinea pig cochlea [106].
Approximately 40% of the radial type I afferent dendrites form two morphologically and functionally distinct groups that contact the modiolar-oriented surface of each IHC. As is well-known, peripheral tissue inflammation produces functional changes in neurons of the spinal cord dorsal horn. Recently, a pathophysiological analogy was constructed between chronic nociception (pain) and chronic tinnitus [124]. Overstimulation of NMDA receptors constitutes a major mechanism in glutamate-induced neurotoxicity; for this reason, NMDA receptor antagonists have been used as neuroprotectants in the prevention of excitotoxic cell injury [120,121]. Higher-than-normal levels of reactive anxiety have been reported in tinnitus sufferers, and some speculate that certain individuals may have a greater psychological predisposition or susceptibility to tinnitus than do others [134,135].
Therefore, how might endogenous dynorphins be used in the auditory periphery to modulate or maintain the aversive qualities of excessive (or even abnormally synchronous) auditory neural activity? Type I afferent dendrites innervating cochlear IHCs are themselves innervated by lateral efferent axons [31,32] and, as indicated, some evidence suggests that the lateral efferent system modulates auditory neural sensitivity [36,37].
Peripheral inflammation also is associated with peripheral (and central) receptive field enlargement [116]. Intracochlear perfusion of glutamate or aspartate at high doses has been reported to reduce the discharge of auditory units during the presentation of sound [150]. Consistent with this hypothesis are the intensitydependent biphasic changes in neural amplitude recently observed after a cochlear RW administration of the κ-receptor ligands U-50488H (see Fig. Similar intensity-dependent changes in neural amplitude have been observed consistently after IV administrations of (-) pentazocine [79,80,83]. As indicated, some 80% of tinnitus sufferers have problems that can be traced to, or associated with, changes occurring in the inner ear [1]. Tinnitus may, in some cases, be the immediate source of a stressful experience, though many individuals report that they begin to notice their tinnitus only during periods of high stress [167]. Results from an early investigation of cochlear neurotransmitter candidates in guinea pig perilymph (though excluding an analysis of perilymphatic dynorphin-like neuropeptides) indicated that exposure to intense and presumably stressful wide-band noise (80-115 dB SPL) significantly elevates levels of [Met5]-enkephalin-like opioid peptides, relative to control values obtained in quiet [168,169]. A physiological shift of the auditory periphery into a temporary state of vigilance is, in our view, synonymous with the production of a " hyperacusic" state, whereby most auditory stimuli are amplified.
Alternatively, depending on NMDA receptor sensitivity (or susceptibility) or on the reactivity of the lateral efferent system to the stressor, dynorphins released into an uncompromised cochlea nevertheless could result in the generation of spectral alterations in the ensemble spontaneous discharge (Fig. At higher levels of the neuraxis, of course, response selection would become advantageously limited or narrowed, as all the enhanced signals from the auditory periphery, including the aberrant activity interpreted as tinnitus, are assigned a significant though equal motivational saliency. A detailed account of the NMDA receptor-dynorphin peptide distribution in the central nervous system is beyond the scope and intent of this article. First is the evidence supporting the existence of lateral efferent projections to the cochlear nuclear complex [31]. Furthermore, both pharmacological [174,175] and in situ hybridization investigations [176,177] have provided evidence for the existence of NMDA and nonNMDA receptors in the mammalian cochlear nuclear complex. Finally, a likely certainty is that the mechanisms involved in the generation and maintenance of tinnitus are represented neither simply nor narrowly in central auditory pathways or in the auditory periphery (or in both). In a pilot study involving cochlear whole-mount preparations, we have observed dense immunohistochemical staining for CGRP in the IHC region of the organ of Corti in this species.
We have presented a biochemical model to explain one possible cause of the phenomenon called tinnitus. Portions of this manuscript were presented at the Second International Tinnitus Think Tank: The Neurochemistry of Tinnitus, Martha Entenmann Tinnitus Research Center and The State University of New York Health Sciences Center at Brooklyn, NY, November 5-6, 1998. Symptoms such as vertigo and unsteady gait occur in various diseases and are among the relatively common chief complaints. Also, we reported a significant correlation between a prolonged period until resolution of BPPV and histories of lifestyle-related illnesses, including hypertension and hyperlipemia [2]. We examined patients with peripheral vestibular disorders for the presence or absence of hypertension, diabetes mellitus (DM), and lipid abnormalities and determined carotid artery intima-media thickness (IMT) by carotid (arterial) ultrasonography. However, only one report has considered IMT thickness in patients with peripheral vestibular disorders [1]. We divided patients with BPPV into groups with and without an abnormally thick IMT and discussed the relation of IMT to the rate of a residual feeling of positional vertigo. Our subjects were 110 patients who had been examined at Kitasato University Hospital between April 2007 and December 2008 and reported vertigo and unsteady gait as chief complaints. At the initial examination, we determined serum total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, blood glucose levels, and HbA1c.
The protocol involved obtaining a single longitudinal lateral view of the distal 10 mm of the right and left CCA and three longitudinal views (anterior-oblique, lateral, and posterior-oblique) of each internal carotid artery.
The present cross-sectional study suggests that the rate of a residual feeling of positional vertigo at the halfway point in the observation period correlates with max IMT in patients with BPPV.
Carotid ultrasonography, a noninvasive examination for arteriosclerotic changes, is useful for determining max IMT and max CCA IMT. Our results indicate that cervical ultrasonography is useful for noninvasive examination of arteriosclerotic changes in patients with peripheral vestibular disorders. These observations indicate that precise evaluation and treatment of arteriosclerotic changes, which are present as background factors in patients with peripheral vestibular disorders, can reduce the risk of cerebral infarction, cerebral hemorrhage, myocardial infarction, and angina pectoris and can improve the prognosis in peripheral vestibular disorders. During the examination of patients who complain of vertigo or who have equilibrium disorders, often identifying the etiology of the disorders is difficult. Spontaneous nystagmus of peripheral origin is wellknown to have little influence on the eye-tracking pattern (ETP) [1]. The results obtained on a normal subject are shown in Figure 1 and are typical of the findings of the 17 normal subjects tested. During 3 years prior to his first visit, a 32-year-old male patient had monthly attacks of rotatory vertigo without cochlear sign. During a period of 2 months, a 52-year-old female patient presented with a rotatory vertigo with alternating, fluctuating glove-and-stocking paresthesia, tremor, hoarseness, dysphagia, and motor weakness of the lower extremities. A 33-year-old female patient had severe rotatory vertigo with laryngeal paralysis, hoarseness, seesaw nystagmus, crossed sensory disturbance, and Homer's sign, but no cochlear sign. The method described in this report-three patterns of ENG recording-is presented as a basis for diagnosis. Obviously, normal subjects and patients with vestibular peripheral disorders exhibit no oculomotor disorders.
This work was presented as a memorial lecture for Jan Parmentier at the Twenty-Seventh Meeting of the Neurootological and Equilibriometric Society in Bad Kissingen, Germany, March 23-26, 2000. Tinnitus is a common symptom for which few existing therapeutic approaches can produce reliable reduction or elimination. Chemical perfusion is a treatment option that involves the delivery of medication directly into the inner ear via the round-window membrane, thus achieving higher cochlear concentration without systemic side effects. This study describes the application of glucocorticoids, specifically dexamethasone, or gentamicin to the round-window membrane in individuals who have various inner ear diseases and in whom disturbing tinnitus is one of the symptoms. Chemical perfusion of the inner ear with gentamicin was offered to patients who had Menière's disease, frequent vertigo with attacks, and fair to poor hearing and in whom vestibular nerve section or endolymphatic sac surgery had failed or who were poor surgical candidates. Of the 20 patients reported in this study, the initial 14 patients (5 male, 9 female; age range, 27-79 years) underwent chemical perfusion of the round window. The intratympanic method of chemical perfusion does not permit accurate instillation of any medication into the inner ear.
The Round Window Microcatheter (IntraEar, Inc., Denver, CO) appears to be a major advance in permitting the precise delivery of medication over a specified period.
Additionally, chemical perfusion may lessen the need for some types of traditional surgery and for alternative therapies provided for tinnitus. Precise delivery of medication into the inner ear is a goal, which is obtainable because the round-window micro catheter technique can deliver the required precise quantity of medication into the inner ear.
This study was presented at the International Tinnitus Forum Meeting, San Antonio, TX, September 22, 1998. Clinical medicine teaches that the key to achieving positive treatment results for any diagnostic category of patient complaints is based on the clinical establishment of an accurate diagnosis.
The definition of tinnitus, originally defined as the perception of a sound unrelated to an external source of sound stimulation (1979), is considered to be dynamic, reflecting advances in what is and is not known of the cochleovestibular system and brain function. A tinnitus-targeted therapy (TTT), a combined treatment of medication and instrumentation focusing on pharmacotherapy, has evolved from an ongoing clinical experience since 1977 (in more than 10,000 patients with SIT 1. Briefly, the identification of principles of tinnitology for diagnosis and treatment of SIT patients has evolved from our ongoing TTT experience since 1977.
At this time, the principles of tinnitology are divided into those for diagnosis (Table 1) and treatment (Table 2). Our clinical experience with the MATPP has been the development of a rationale for establishing an accuracy in tinnitus diagnosis and attempting tinnitus relief 1,9. Critical for both the SIT patient and tinnitus professionals attempting tinnitus relief is to be aware of the realities of the state of the art of tinnitus diagnosis and treatment at this time. The following definitions are considered significant in reporting results of modalities of tinnitus treatment and relief.
The medical significance of a symptom or disease process in a patient is defined as "a clinical manifestation of abnormal function of a living cell, tissue, organ, or organ system(s)" 4. Treatment of a symptom or disease is "the management or care of a patient or the combating of a disease or disorder. Tinnitogenesis is a seizure-type activity resulting in the perception of an aberrant auditory stimulus (tinnitus) 12. The sensory component of tinnitus refers to the subjective perception of the sensation of the aberrant auditory stimulus-tinnitus-as described by tinnitus patients.
Clinical types of SIT have been identified based upon the clinical history and metabolic and electrophysiological correlates of brain activity and cochleovestibular function.
Neurodegeneration, in this report, is a term "reflective of process(es) involved in the progressive damage or death of neurons and reflected clinically in a gradual deterioration and interference in function of the affected neural substrates of the nervous system" 17,18. Neuroprotection refers to "processes involved in the maintenance and repair and restoration of normal neuronal function" 17-19. The final common pathway (FCP) for tinnitus has been hypothesized for all clinical types of tinnitus. The tinnitus dyssynchrony-synchrony theory is a hypothesis that considers tinnitus to be an abnormal, conscious, auditory percept. We present an update on TTT, a combined treatment of medication and instrumentation focusing on pharmacotherapy 1. The clinical course of tinnitus, particularly SIT, is highlighted by its individuality and chronicity. To appreciate clinical advances that have been made for tinnitus diagnosis and treatment since 2006, it is necessary to briefly review the past. Clinically, however, tinnitus is still considered by many professionals and patients to be a unitary symptom. The recent publication of the Tinnitus Research Initiative (TRI) database has recognized the clinical reality that tinnitus is not a unitary symptom 25! The classic site of lesion audiometric hearing threshold testing of 250 Hz-kHz is recommended in tinnitus patients to be extended to include the ultra-high frequencies of 10 to 20 kHz.
For patients with either unilateral or bilateral tinnitus and an asymmetrical sensorineural hearing loss, completion of tests of auditory brainstem response or magnetic resonance imaging (or both) of the brain and internal auditory canals with gadolinium is recommended to identify the presence or absence of acoustic tumor. The incidence of SEH occurrence in our experience continues to be approximately 35% overall. Evaluating tinnitus includes identifying its psychophysical and psychoacoustical characteristics, cochleovestibular testing, and masking curves 28. Supplemental testing with auditory brainstem responses, nuclear medicine brain imaging with SPECT and PET, and quantitative electroencephalography (QEEG) are reserved for SIT patients resistant to conventional modalities attempting relief.
A special clinical type of a predominantly centraltype SIT has been identified in a cohort of SIT patients with cerebrovascular disease, epilepsy, and memory and cognitive disorders, reflecting neurodegenerative disease 17,18. Masking is a term used to refer to the effect of one tone or one sound on another tone or sound or combinations thereof 35.
Auditory masking, the replacement of one source of acoustic stimulation by another, a "covering up" or "blockage" of one sound by another, is a normal function of the auditory system. Tinnitus treatment recommendations continue to focus on identifying the tinnitus etiology and on the conceptualization of the past that tinnitus is a unitary symptom. Although no tinnitus cure is available in our experience for patients at this time, protocols of combined treatment modalities that are available attempt to provide accuracy in diagnosis and identifying the medical significance of the tinnitus and tinnitus treatment, relief, and control 9,40.
The neuro-otological consultation focus is on the clinical history, clinical course of the complaint, neuro-otological physical examination, and review of past medical records. Hypotheses of the role of biophysiological mechanisms in producing tinnitus are selected for translation to the attempt to establish accuracy for the tinnitus diagnosis and attempted treatment.
The selection of a particular modality of treatment is individualized for each patient and differentiated between the components of the tinnitus (see Figs.
Basic pharmacotherapeutic management principles have been followed since 1979 1 (see Table 6). Instrumentation is recommended to tinnitus patients resistant to pharmacotherapeutic modalities for attempting tinnitus relief, approximately 10% to 15% since 2000.
Step 2: Removal of keratotic debris and cerumen from external canal and tympanic membrane as appropriate. In our experience, a majority of the patients report significant tinnitus relief and control after completing steps 1 to 4 and do not require instrumentation. Innovative receptor-targeted therapies (RTT) based on identification of the underlying neurotransmitter systems 37. Titration of gabapentin should begin at the lowest possible dose: The goal is to do no harm. A psychiatric consultation is recommended for evaluation and treatment of associated anxiety and depression or both and to consider the drug Klonopin if no medical contraindication (see Table 4).
Step 6: Tinnitus patients, predominantly central type, resistant to attempts tinnitus relief in steps 1-5 are recommended instrumentation in consultation with audiology. Transcranial magnetic stimulation (TMS) research protocols have reported significant short-term tinnitus relief 48,49. In general, the results of surgery, both clinical and as research protocols for tinnitus relief, have increased since 2006. Significant tinnitus relief with intratympanic steroid therapy has been reported for a predominantly cochleartype tinnitus 51,52. We look to the future for advances in the discipline of tinnitology for tinnitus theory, diagnosis, and auditory neuroscience of sensation and brain function to provide translation for development of new and increased efficacy of existing modalities of therapy for all clinical types of tinnitus. These advances will reinforce the alteration in the paradigm of thinking of tinnitus, as recommended in 1983, from a focus on the ear and the psychoacoustic and psychophysical characteristics of the tinnitus to that of the ear and associated multiple brain functions as reflected clinically in the heterogeneity of tinnitus at this time.
In summary, we look forward to the pharmacological evolution of tinnitopharmaco-proteogenomics, defined as pharmacology for tinnitus based on what is known of the genetic diversity and protein functions demonstrated by tinnitus patients with different clinical types of tinnitus. We hypothesize that future identification of epilepsy genes can provide an insight into the molecular basis of neuronal excitability and brain function, which will have application for a particular central-type tinnitus.
For surgery, we look forward to expansion of intratympanic drug delivery systems, with a focus on hearing conservation, which we predict will result in increasing degrees of reported tinnitus relief. Alternate therapies will report in the future an increased significance for tinnitus relief with cognitive therapy and acupuncture as an accompaniment of anticipated advances in understanding brain function. The MATPP is presented as a dynamic neurootological-audiological protocol reflecting advances in tinnitology and neuroscience; it provides increased diagnostic accuracy, a monitoring system for all clinical types of tinnitus, and translation for increased efficacy of tinnitus relief. A paradigm switch for clinical thinking of tinnitus is recommended to concentrate on brain function responses to an aberrant dyssynchronous auditory sensory input and in particular consciousness and affect, respecting the psychophysical and psychoacoustic characteristics of the tinnitus.
A biochemical marker, the GABA-A receptor, that has been identified provides translation for treatment, called RTT-GABA, of a predominantly central-type tinnitus. They are classified as sensitive, frontal, vestibular and cerebellar, being this last one of interest for the present study1. The most common clinical manifestations are walking and appendicular ataxia (dysmetria, dysdiadochokinesia, intention tremor), dysarthria, nystagmus, ophthalmoplegia, dysphagia, pyramidal signs, lower motor neuron disease, cognitive dysfunction, epilepsy, visual disorders (pigmentary retinopathy), peripheral neuropathy, dementia and movement disorders (including parkinsonism, dystonia, myoclonia and chorea)1,2-4. In Brazil, more specifically in the South region, a great number of families affected by SCA2,5 has been identified.
The evaluation of the vestibular system is done through an otoneurological evaluation consisting of a set of procedures that allows a pathophysiological assessment of the vestibular system and its relation with the CNS with an emphasis in vestibulo-oculomotor, vestibulocerebellar, vestibulospinal and vestibuloproprioceptive- cervical interrelations7. Otorhinolaryngological Evaluation - to exclude any other unrelated physical abnormality that might interfere with the exam.
The criteria used to analyze each test as well as to distinguish central from peripheral vestibulopathy is shown in Table 2. Due to the multiplicity of clinical forms, different manifestations may occur during the evolution of the disease. Injuries of the cerebellar vermis cause ataxia of the superior limbs, head titubation, dysmetria and tremor of the ocular movements and this is the part that manifests electric activity in the extension of ocular muscles and the neck.
21 reported a reduction in the size of the pontine tegmentum and medulla seen at MRI scans, where vestibular nuclei, prepositus perihypoglossal (nucleus intercalates, nucleus prepositus, and the nucleus of Roller - all located in the gray matter of the medulla) and neurons of the paramedian tract related with vestibular system are all located. These lesions can explain the alterations of the brainstem, postural instability with disequilibrium, oculomotor deficits (impaired optokinetic nystagmus, slow saccadic eye movements and absent caloric response) and presence of pathological vestibulo-ocular reflex (VOR)24.
Neurological examination showed slow saccades, saccadic smooth pursuit, scanning speech and ataxia26. Neuropathological studies revealed a reduction of Purkinje and ganglionar cells of the dorsal and the dorsal column of spinal cord27. Ishikawa et al.29 reported that SCA 6 patients present intense vertiginous episodes that precede the beginning of ataxia, the presence of spontaneous and gaze-evoked downbeat nystagmus as the predominant signs30. There are also pyramidal signals, slow ophthalmoplegia, parkinsonism and saccadic movements in particular10,25.
Various authors have suggested that detailed analysis of abnormal eye movements may help to identify some SCAs forms (types 2, 3 and 6).
Tsutsumi et al.33 evaluated 72 patients with cerebral degeneration and observed a high incidence of saccadic pursuit and upward ocular dysmetria.
We emphasize the importance of studying the vestibular system concomitantly to clinical and genetic follow up. Rub U, Brunt ER, Del Turco D, de Vost RAI, Del Tredici K, Gierga K, Schultz C, Ghebremedhin E, Burks K, Auburger G, Braak H. Hyperacusis, defined as a collapse of tolerance to sound, is present in 40-86% of those who suffer from disabling forms of tinnitus.
In approximately 10 million individuals, the symptom is severe enough to compromise the quality of life significantly [1].
Dynorphin-like and enkephalin-like opioid peptides are codistributed within lateral efferent brainstem nuclei, in their descending fiber bundles and, in lateral efferent terminal varicosities, in the cochlea of such species as the guinea pig and rat [25-27]. The axons of descending, lateral efferent brainstem neurons [30] are well-known to terminate on the auditory spiral ganglion type I dendrites that, in turn, innervate the cochlear in-ner hair cells [31,32]. These three identified peptide families are (1) proopiomelanocortin (2) proenkephalin (proenkephalin A), and (3) prodynorphin (proenkephalin B). This fact has underscored their neurotransmitter-neuromodulatory role in the filtering of sensory information and in the enhancement and fine tuning of the regulatory functions exerted by other neurotransmitters or hormones [53-58].
As with most neuropeptides, the receptor-activated ion-channel properties of opioid peptides are mediated by a class of membranebound, pertussis toxin-sensitive "G" -proteins [50,61,66]. As is often the case in the central nervous system [69], the ion channel actions of opioid-receptor linked G-proteins are mediated by the regulation of adenylate cyclase that catalyzes the synthesis of the second messenger, cyclic adenosine 3',5'-monophosphate (cAMP) [47,6 1). For instance, opioid receptors can be linked to a Gs-protein that, when stimulated, activates adenylate cyclase and increases cAMP [61,67]. In that investigation, the nonopioid (+) pentazocine, administered at an equivalent IV dose and concentration, was without effect (Fig. Biphasic intensity-dependent amplitude changes after administration of the κ-receptor drug agonist U-50488H (50 mM) delivered to the cochlear round window (RW) in five animals. Though some uncertainty still exists [99], many investigators have argued that glutamate is the afferent neurotransmitter in the mammalian cochlea [27,100-104]. In addition, alpha-amino-3 hydroxy-5-methyl-isoxazol-propionic acid-induced excitotoxicity and degeneration of cochlear spiral ganglion neurons is accompanied by a neurotropic NMDA receptor action of glutamate in this species [100]. Here, the overall synaptic density of afferents generally is greater as compared to the density of dendrites on the pillar surfaces of the THCs.
These changes consist of alterations in SDR, a lowering of thresholds, and an enlargement of receptive fields, producing an increased sensitivity to both noxious and innocuous stimuli [73,114-116]. More specifically, it was constructed between the wind-up phenomena and the associated hyperalgesia observed in chronic pain, and the auditory symptoms of hyperacusis and chronic tinnitus [125].
Noteworthy is that nonNMDA receptors also can mediate neurotoxicity, especially during prolonged or widespread insults [120,132]. A reasonable assumption is that constitutional differences exist with respect to individual reactivities to environmental and physical stress. The opioid effects of μ-receptor ligands, however, often are accompanied by emotional states of dysphoria, disorientation, or depersonalization [59,98,138], and whether dynorphins are capable of producing any form of antinociception is questionable [74,139]. Does any evidence support that a neuropharmacological link exists between endogenous μ-receptor-sensitive dynorphins (or enkephalins) and neural excitability? The preceding review seems to clarify that only a few studies have investigated the potential effects of specific opioid receptor agonist-antagonist substances on the discharge of the auditory nerve. Endogenous dynorphins have been reported to interact with glutamate-sensitive NMDA receptors in rat cortical neurons [143], though the precise mechanism is not yet understood [144].
In addition, peripheral inflammation leads to a large increase in prodynorphin gene expression (increased mRNA) in dorsal horn neurons, and this central nervous system increase parallels the development of hyperalgesia [74,146]. However, in these investigations, neural suppression never was observed at higher stimulus levels.
Endogenous opioids have been suggested to modulate excitation at NMDA receptors [147] by (1) increasing the affinity of the ligand for the receptor (2) decreasing the degree of dissociation of the ligand from the receptor, or (3) by producing a change in the second messenger response to receptor activation. However, as with all perceptions (and especially those that involve aversion), the experience of tinnitus certainly must involve central auditory pathways and cortical regions and non auditory cortical-subcortical regions.
According to one view, tinnitus results from the stress-induced central enhancement and magnification of abnormal but weak triggering signals passing from the auditory periphery to the auditory cortex, where they are perceived [1]. Intense emotional stress has been reported also to improve auditory thresholds temporarily in guinea pigs [l70], and we have observed improved auditory thresholds after the cochlear administration of opioid κ-receptor ligands [19]. The amplitude enhancement of weak auditory patterns characterizing tinnitus and hyperacusis has been suggested to be part of an evolutionary survival reflex [171]. Individual constitutional differences naturally would dictate the degree to which peripheral (and central) dynorphin systems are activated (and consequently the severity of the subjective hyperacusis). In the long term, the consequence of this prolonged vigilant state is expected to produce a vicious feed-forward cycle. Investigations designed to determine the distribution of κ-receptors and dynorphins in specific brainstem auditory pathways and in cell layers of critical auditory nuclei have yet to be performed. Opioid prodynorphin (and proenkephalin) derivatives have been detected throughout the medullary brainstem, in regions that have included the separate divisions of this nuclear complex [54,172,173].
Additionally, a considerable number of prodynorphin-positive neurons have been detected within the inferior colliculus [173]. For instance, the release of excitatory amino acids (and therefore the observed hyperexcitability at NMDA receptors in neurons of the spinal cord dorsal horn) is facilitated by the release of the calcitonin gene-related peptide (CGRP) [73]. Such evidence raises the possibility that a dynorphin modulation of neural excitability through, perhaps, an enhancement of glutamate effects at NMDA receptors may occur at serial locations along the auditory pathway. Recognizing that this symptom represents a broad spectrum of auditory experiences, we acknowledge the possibility of an equally broad spectrum of auditory generators. Monaghan DT, Bridges RJ, Cotman CWo The excitatory amino acid receptors:their classes, pharmacology, and distinct properties in the function of the central nervous system. Correlation Between Arteriosclerotic Changes and Prognosis in Patients with Peripheral Vestibular Disorders. In our otorhinolaryngology department, patients with chief complaints of vertigo and unsteady gait-considered to be attributable mainly to peripheral vestibular disorders-are routinely examined and treated. IMT can be determined simply and noninvasively by ultrasonography and is regarded as a nonspecific indicator of systemic arteriosclerosis promoted by various factors, including hypertension, DM, lipid abnormalities, and aging.
We examined arteriosclerotic changes with B-mode ultrasonographic images of the carotid artery, and we examined the relation of IMT to the recovery period for patients with BPPV, a representative disease of peripheral vestibular disorders.
They had diagnoses of peripheral vestibular disorders based on comprehensive evaluation of magnetic resonance imaging (MRI) findings, neurological findings, presence of nystagmus, and equilibrium test findings. As regards the rate of a residual feeling of positional vertigo at the halfway point in the observation period in patients with BPPV, the rate was significantly higher in the group of patients with an IMT of .
They also indicate that patients with peripheral vestibular disorders show progression of arteriosclerotic changes. Caloric Eye-Tracking Pattern Test: Visual Suppression and the Possibility of Simplified Differential Diagnosis Between Peripheral and Central Vertigo. To attempt to determine the etiology in these cases, we devised a new method: the caloric eye-tracking pattern test. In contrast, spontaneous nystagmus of central origin has an influence on the ETP, for instance, as the congenital nystagmus is superimposed on the ETP [1-4]. However, he had hand tremor, diplopia, motor weakness, and "glove-and-stocking" paresthesia during these attacks. In normal subjects, pattern A is normal, and caloric nystagmus has little influence on the ETP. Chemical perfusion involves the delivery of medication directly into the inner ear via the round-window membrane. It is primarily a subjective complaint for which objective indicators usually are sparse and lack a proven animal model. Chemical perfusion shows great promise in controlling severe peripheral tinnitus either as the sole symptom or in association with other symptoms present from a variety of causes (Menière's disease, frequent attacks of vertigo, failed vestibular nerve section, sudden sensorineural hearing loss, inner ear vestibular dysfunction, and failed endolymphatic sac shunt surgery).


Various reports have shown that, in selected cases, these medications can control vertigo, improve hearing, and reduce tinnitus [3-11].
Of these 14 patients, 6 suffered Menière's disease, 6 had severe tinnitus, and 3 had experienced sudden deafness. These patients had dry Gelfoam placed into the round-window niche through an extended tympanostomy incision, allowing the practitioner to inspect the round window to ensure the absence of false membranes or mucosal bands [16]. This impediment is significant to the precision necessary to control, monitor, and gain a desired outcome and not a failed or deleterious effect. The catheter tip of the dual-lumen microcatheter is a fenestrated, hollow, compressible bulb that fits snugly into the round-window niche. The delivery of medications into the inner ear (chemical perfusion) shows promise in controlling a host of cochleovestibular symptoms, including tinnitus, without systemic effects.
Background: The completion of a MATPP has been recommended since 1977 for each tinnitus patient in an attempt to establish an accurate diagnosis. The term tinnitus in this article refers to subjective idiopathic tinnitus of the severe disabling type (SIT). Tinnitology is an integrated multidiscipline of basic science, neuroscience, and clinical and nuclear medicine used in an attempt to understand an aberrant auditory phenomenon unrelated to an external source of sound and how it becomes transformed into one of affect.
Principles of diagnosis and treatment for SIT have evolved from the TTT experience, which provide a rationale for attempting tinnitus relief. The clinical application is resulting in a significant increase in the efficacy of modalities of therapy available for attempting tinnitus relief for all clinical types of tinnitus.
Repetitive findings both from the clinical history and the MATPP in this combined neuro-otological-audiological approach for SIT are the basis of what we identified initially to be principles of tinnitology 1,4; (see Tables 1 and 2).
Anything that lessens tension or strain, or offers a pleasing change as to the mind or eye 10. Its identification provides an objective basis for an innovative anti-seizure medication attempting tinnitus relief for a predominantly central SIT. They are (1) the sensory component (sensory stimulus), (2) the affect component (behavioral response to the sensory stimulus), and (3) the psychomotor component (the motor response to express the behavioral response to the sensation) 13. The affect component of tinnitus refers to the emotional response of the patient to the sensory component. Tinnitus is believed to originate as an initial dyssynchrony in pre- or postsynaptic neuronal transmission within the peripheral or central nervous system (cortical or subcortical).
All have visited the tinnitus clinic at the Downstate Medical Center of the State University of New York (DMC-SUNY) and the Martha Entenmann Tinnitus Research Center, Inc. Our clinical experiences for both tinnitus diagnosis and treatment since 1977 were summarized in 1991 and updated in 2006.
The principles of diagnosis and treatment (see Tables 1 and 2), , and modalities of treatment available at the present time (see Tables 3-5), are presented not as menu-driven recommendations for tinnitus treatment, control, and relief but rather as a selection based on a rationale targeting hypothesized underlying biophysical processes. A paradigm change is recommended in clinical thinking both for the symptom itself and for the response to treatment.
At this time, tinnitus is considered clinically to be a symptom, heterogeneous in its etiology, clinical course, and clinical manifestation as different clinical types. Algorithm for tinnitus diagnosis and treatment: the medicalaudiological tinnitus patient protocol. The original concept of clinical types of tinnitus (CTT) 23 is considered to be fundamental for translation to any and all attempts for tinnitus relief. The establishment of this data base will be a significant advance for both diagnosis and translation for an increased efficacy for any and all modalities of therapy attempting tinnitus relief and control.
Tinnitus patients with hearing thresholds within the range of "normal" (250 Hz-8 kHz) have been found to have elevated thresholds in excess of what is expected for their age. These modalities are used in the attempt to improve the accuracy of the tinnitus diagnosis and provide a monitoring system for evaluating the efficacy of therapeutic modalities aimed at tinnitus, which included control of factors influencing the clinical course of the tinnitus and a previous trial of instrumentation 33,34. Identifying and treating this particular central-type SIT has been accompanied with relief.
Itard 23,35 believed that utilizing external sounds to interfere with the tinnitus was the most effective relief procedure. Algorithms of the final common pathway (sensory, affect, psychomotor components) and tinnitus treatment. The brain functions associated with each component of the aberrant auditory sensory stimulus (tinnitus) are integrated in each algorithm with the involved neuroanatomical substrates. The clinical course of SIT, a stressor, becomes clinically manifest with increased severity by a reduction in the inhibitory activity of the GABA-A receptor, which is deficient and cannot inhibit the aberrant auditory signal 7. A menu-driven approach is that of the majority of tinnitus professionals for recommendations of instrumentation, medication, or surgery. The MATPP has provided our team with a basis for the selection of existing modalities of treatment with resultant increased efficacy of tinnitus treatment, relief, and control, which we have called a tinnitustargeted therapy (TTT) 1, 9. We have focused on masking, glutamate neuroexcitotoxicity theory, inhibition, benzodiazepine deficiency, neurodegeneration, neuroprotection, calpain theory of apoptosis, kindling, long-term potentiation, lateral inhibition, epileptogenesis, stress, neurotransmitter action at synaptic levels of activity and alteration in the homeostasis of function between the fluid compartments of ear and brain 5,12,20-22,37, 41 For the associated compliant of hyperacusis, a plan for sound attenuation utilizing white noise is recommended. The goal is pharmacological short-term tinnitus relief therapy, but planning must be made for long-term benefit.
If the clinical type of tinnitus is a predominantly cochlear type, intratympanic drug therapy with steroids, preceded by computed tomography of the temporal bones is recommended 43. If the clinical type of tinnitus is a predominantly the central type, innovative drug therapies are recommended.
There should be some indication of involvement of the CNS before use of an innovative application of AEDs 9,16,33,37. Tinnitus relief with auditory cortical stimulation has been reported 53 as has the surgical application of a cochlear implant in a tinnitus patient 54. Cortical brain approaches with extra- or intracranial TMS (electrical stimulation), alone or in combination with drug therapies, will offer to patients with predominantly central-type tinnitus an increased degree of efficacy for tinnitus relief. A "cure" for tinnitus is the ultimate goal of both tinnitus patients and all professionals involved in tinnitology. Tinnitopharmacolgy and tinnitopharmacoproteogenomics is the future for pharmacotherapeutic treatment of different clinical types of tinnitus. Strashun, MD, Director, Nuclear Medicine, and Matthew J Avitable, MD, Director Scientific Computing Center; and the support of Richard Rosenfeld, MD, Prof. Rothschild G, Nelkon I, MizrahiA: Functional organization and population dynamics in the mouse primary auditory cortex. Machado- Joseph (DMJ) disease (SCA 3) is most common form of autosomal dominant ataxia identified in Brazil, in keeping with most epidemiologic world2,5,6. Patients undertook a special diet, starting 72 hours before the otoneurological exams (avoid intake of coffee, any kind of soda or caffeinated tea, chocolate, smoking, or alcohol intake).
There is evidence showing that injuries in the cerebellar vermis cause vertical dysmetria whereas more lateral or paravermian injuries cause horizontal dysmetria. 20 evaluated two patients with SCA 3 with genetic at the beginning of symptoms, that is, one year in case 1 and three years in case 2. Hellenbroichet al.28 in a post-mortem study of a SCA 4 patient report severe neuronal loss in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller.
The mains abnormalities, such as changes in the amplitude and speed of saccadic movements, the presence of gaze-evoked nystagmus and impairment of de VOR, are common in certain types of SCA25. They also observed moderate incidences of horizontal ocular dysmetria, gaze-evoked and rebound nystagmus, vertical positioning nystagmus and impaired visual suppression appeared to reflect the degree of dysfunction, while optokinetic nystagmus seems to reflect both the presence of disease and its severity.
Avaliacao clinica e genetica de oito familias Brazileiras com ataxia espinocerebelar tipo 10. A survey of spinocerebellar ataxia in South Brazil-66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations.
As alteracoes eletronistagmograficas na ataxia cerebelar autossomica dominante relacionadas ao estagio da doenca. Normal limits of parameters for evaluation with digital vectoelectronystagmography neurograff [in Portuguese]. Vestibulo-ocular arreflexia in families with spinocerebellar ataxia type 3 (Machado- Joseph disease). Magneti resonance imaging demonstrates differential atrophy of pontine base and tegmentum in Machado-Joseph disease. Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance. Spinocerebellar ataxia type 4 (SCA4): Initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration. Tinnitus has been described as the perceptual correlate of altered spontaneous neural activity occurring in the absence of an external auditory stimulus [3-6].
Though the existence of prodynorphin peptides has yet to be shown in the human auditory system, products of proenkephalin synthesis have been detected in the lateral efferent terminal varicosities of the human cochlea [28].
The axodendritic innervation pattern of these dynorphin-containing terminals suggests that the lateral efferent system participates in modulating auditory neural sensitivity [33-35]. Neuroactive opioid peptides modulate sensory input through separate and often distinct opioid receptors.
Antinociception (analgesia) is the most familiar and most intensively investigated property of such opioid substances as morphine; by definition, all opioids are analgesics [49,59]. The G-proteins derive their name from the fact that they bind the guanine nucleotides, guanosine triphosphate, and guanosine diphosphate [67]. Therefore, the binding of opioid ligands to their respective receptors often activates a Gi-protein that inhibits adenylate cyclase and decreases cAMP [61,67). Nevertheless, specific receptor subtypes that bind endogenous enkephalins and dynorphins (a and κ, respectively) have yet to be identified in the cochlea of any mammalian species. Each plotted point represents the mean percentage of amplitude change relative to a grand baseline amplitude mean (±SE) obtained during each of six 30-minute recording periods. Each plotted point represents the mean percentage of amplitude change relative to a grand baseline amplitude mean (±SE) for the two dependent measures, obtained during each of six 30-minute recording periods. 3) produces increased auditory sensitivity and intensity-dependent amplitude changes in the auditory nerve CAP when administered intracochlearly [93,19]. Each plotted point represents the mean percentage of amplitude change relative to a grand baseline amplitude mean (±SE) obtained during each of six 30-minute recording periods recorded at the six stimulus intensities indicated.
Adding to the complexity is the fact of even less certainty regarding the receptor type activated by putative excitatory afferent neurotransmitters in the cochlea [99]. Furthermore, a significant body of pharmacological evidence supports a functional auditory role for glutamate-sensitive NMDA receptors in the adult guinea pig cochlea [101-104, 107-109]. Tn general, the modiolar-oriented units are characterized by relatively lower spontaneous discharge rates (SDRs), higher auditory thresholds, smaller fiber diameters, and lower mitochondrial densities [33,110-112].
According to Moller [125], both pain and tinnitus involve neural sensitization that leads to a reduction in threshold or increased levels of neural excitability (or both).
Characteristically, NMDA receptor-gated activity produces an influx of extracellular Ca++, which in excess activates a variety of potentially destructive processes [120,121]. Equally reasonable is the expectation of individual differences with regard to the degree to which certain endogenous biochemical systems are likely to become activated during stressful events. Also endogenous dynorphins have been demonstrated to potentiate, rather than to suppress, behavioral changes induced by stressful events [63].
The results of those investigations indirectly have supported the existence of opioid receptor subtypes in the cochlea. Unlike previously reported δ-receptor ligand effects [142], dynorphins do not appear to interact with excitatory non-NMDA receptors [143], though potential interactions between these substances and glutamate-sensitive NMDA and non-NMDA receptors have yet to be demonstrated in the mammalian cochlea. Dynorphins have been implicated also in the wind-up-like activation of NMDA receptors, leading ultimately to neurotoxicity [147]. A tempting speculation is to envision the changes that high concentrations of cochlearly administered κ-receptor drug agonists would produce on auditory neural discharge as an auditory stimulus is progressively increased in intensity from threshold. At threshold and at relatively lower stimulus levels, these substances each promoted or enhanced neural excitation. Whether these changes reflect actions at glutamate-sensitive NMDA, non-NMDA, or both receptor types, or at some other nonopioid receptor requires further investigation.
Nevertheless, a peripherally generated tinnitus can result from any number of insults to the inner ear, ranging from advancing age to excessive noise exposure [2,151].
Our position however, is that during stressful episodes, these abnormal signals (triggers) are not weak but are in fact abnormally amplified in the periphery.
Therefore, we are proposing that a stress-induced release of neuroactive dynorphin-like opioid peptides from the lateral efferent terminals located beneath the IHCs contributes to an increase in auditory neural sensitivity and to spectral alterations in the ensemble spontaneous discharge activity of the auditory nerve. However, those auditory (type I) neurons innervating a cochlea having sustained weakened or damaged OHCs (and therefore preordained to generate aberrant spectral discharge patterns) would be additionally susceptible to stress. Therefore, under certain stressful conditions, dynorphins alone may serve as a trigger for tinnitus. Step 1: Excitatory neurotransmitter (glutamate) is released by the inner hair cell (A) during the presentation of a stimulus or (B) spontaneously during periods of quiet and binds to glutamate-sensitive (possibly N-methyl-D aspartate) receptors located postsynaptically on the type I auditory dendrites. This hypothesized feedforward cycle is similar conceptually to the wind-up phenomenon, which could serve to advance the organism to a state of peripheral and central auditory neural excitotoxicity and neurotoxicity. However, an important note is that though the focus of this article has been the auditory periphery, the possibility also exists for concurrent interactions of endogenous dynorphins with NMDA receptors at locations within the central auditory system.
We have found CGRP immunoreactivity in a significant number of cells in the dorsal cochlear nucleus and in neurons of the ventromedial region of the lateral superior olive (LSO) [178]. This possibility and the precise relationship of κ-receptor ligands to NMDA receptor-activated neural discharge in the inner ear will be the focus of future investigations. However, we are compelled to conclude that when a human organism is confronted with any number of stressful events, conditions are optimal for the overall release of neuroactive opioid substances and the generation and perception of tinnitus. Neural mechanisms of tinnitus: the pathological ensemble spontaneous activity of the auditory system.
Changes in the auditory neural response following cochlear administration of U-50488H and (-) pentazocine.
Modulation of synaptic efficacy as a basis for tinnitus:hints suggested from the effects of quinine and aspirin on cochlear neurotransmission. Effects of electrical stimulation of efferent olivocochlear neurons on cat auditory-nerve fibers: I. Effects of electrical stimulation of efferent olivocochlear neurons on cat auditory-nerve fibers:II. Coexistence of putative neuroactive substances in lateral olivocochlear neurons in guinea pig and rat.
Prodynorphin peptides are co-localized within auditory structures of the Chinchilla brainstem. Efferent innervation of the inner hair cell region:origins and terminations of two lateral olivocochlear systems. Efferent synapses in the inner hair cell area of the cat cochlea:an electron-microscopic study of serial sections. Physiology of cochlear efferent and afferent neurons:direct comparisons in the same animal.
Acetylcholine potentiation of glutamate-induced response in guinea pig spiral ganglion cells. Long-term physiological consequences of cutting the olivocochlear bundle (OCB) in neonatal animals. Partial characterization of the mRNA that codes for enkephalins in bovine adrenal medulla and human pheochromocytoma. Molecular cloning establishes proenkephalin as precursor of enkephalin-containing peptides. Cloning and sequence analysis of cON A for porcine β-neoendorphinl dynorphin precursor.
Immunohistochemical localization of the cloned κl receptor in the rat CNS and pituitary. Endogenous opioid peptides acting at μ-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons. Opioid peptide modulation of circulatory and endocrine response to mental stress in humans.
Behavioral changes induced by stressful situations:effects of enkephalins, dynorphin, and their interactions.
Modulatory effects of Gs-coupled excitatory opioid receptor functions on opioid analgesia, tolerance, and dependence. Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture. Dynorphin prolongs the action potential duration of mouse sensory ganglion neurons by decreasing a K+ conductance whereas the specific kappa opioid, U-50, 488H does so by increasing a Ca2+ conductance. Dynorphin prolongs the action potential of mouse sensory ganglion neurons by decreasing a potassium conductance whereas another specific kappa opioid does so by increasing a calcium conductance. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS:an in situ hybridization study. Improvement in auditory function following pentazocine suggests a role for dynorphins in auditory sensitivity. Effects of opioid drugs on auditory evoked potentials suggest a role of lateral efferent olivocochlear dynorphins in auditory function. Binaltorphimine-related bivalent ligands and their K opioid receptor antagonist selectivity. Implication of NMDA type glutamate receptors in neural regeneration and neoformation of synapses after excitotoxic injury in the guinea pig cochlea.
Receptor pharmacological models for inner ear therapies with emphasis on glutamate receptors:a survey.
The role of glutamate at the afferent synapses of mammalian inner hair cells:a microiontophoretic study.
A microiontophoretic study of the role of excitatory amino acids at the afferent synapses of mammalian inner hair cells. N-methyl-D-aspartate-induced oscillations in excitatory afferent neurotransmission in the guinea pig cochlea. Transient expression of NMDA receptors during rearrangement of AMPA-receptor expressing fibers in the developing ear. Electrophysiological evidence for the presence of NMDA receptors in the guinea pig cochlea.
Morphological differences among radial afferent fibers in the cat cochlea:an electron-microscopic study of serial sections.
Morphometry of intracellularly labeled neurons of the auditory nerve:correlations with functional properties. Response properties of cochlear efferent neurons:monaural vs binaural stimulation and the effects of noise. Contribution of central neuroplasticity to pathological pain:review of clinical and experimental evidence. A comparative study of the changes in receptive-field properties of multireceptive and nociceptive rat dorsal hom neurons following noxious mechanical stimulation.
The induction and maintenance of central sensitization is dependent on N-methylD-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. The relation between net calcium, alkali cation and chloride movements in red cells exposed to salicylate. Concomitant salicylate-induced alterations of outer hair cell subsurface cisternae and electromotility. Mu agonist induced euphoria as opposed to dysphoria elicited by κ-agonists in humans and experimental animals. Intrathecal dynorphin 1-13 results in an irreversible loss of the tail-flick reflex in rats. A direct non-opiate interaction of dynorphin 1-13 with the N-methyl-D-aspartate NMDA receptor. The influence of sustained opioid receptor blockade in a model of long-term, localized inflammatory pain in rats.
In situ hybridization cytochemistry and immunocytochemistry reveal an increase in spinal dynorphin biosynthesis in a rat model of peripheral inflammation and hyperalgesia. Selective potentiation of NMDA-induced activity and release of excitatory amino acids by dynorphin:possible roles in paralysis and neurotoxicity.
Norbinaltorphimine protection against N-methyl-D-aspartic acid-induced convulsions and mortality. Acute ultrastructural changes in acollstic trauma:serial-section reconstruction of stereocilia and cuticular plates.
Effect of sound stimulation at several levels on concentrations of primary amines, including neurotransmitter candidates, in perilymph of the guinea pig inner ear.
Immunocytochemicallocalization of glycine in a subset of cartwheel cells of the dorsal cochlear nucleus in rats. Differential expression of N-methyl-D-aspartate receptor in the cochlear nucleus of the mouse.
Localization of calcitonin gene-related peptide (CGRP) within auditory structures of the chinchilla brainstem.
We report a significant correlation between a prolonged period of resolution of benign paroxysmal positional vertigo (BPPV) and histories of lifestyle-related illnesses. Typical examples of peripheral vestibular disorders are benign paroxysmal positional vertigo (BPPV), Meniere's disease, and vestibular neuronitis. Previous studies have shown cross-sectional associations between IMT and cardiovascular risk factors and the prevalence of cardiovascular disease [3-5].
We diagnosed peripheral vestibular disorders by the following: (1) a clinical history of clearly defined rotational vertigo or presence of spontaneous nystagmus, (2) normal results in the eye-tracking test, (3) absence of a structural abnormal lesion on MRI, and (4) absence of any central nervous system symptom. The maximum IMT was defined as the maximum thickness of the blood vessel wall in the area of the common carotid artery (CCA).
This study further suggests that the arteriosclerotic change was related to the rate of a residual feeling of positional vertigo at the halfway point in the observation period in patients with BPPV. Arteriosclerotic changes as background factors in patients with peripheral vestibular disorders. Inner ear function test in cases of posterior canal type benign paroxysmal positional vertigo.
Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: Cardiovascular Health Study Collaborative Research Group. Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Common carotid intima-media thickness and risk of stroke and myocardial infarction: The Rotterdam Study.
Carotid artery intima-media thickness and reactive oxygen species formation by monocytes in hypertensive patients.
In normal subjects and in patients with peripheral disorders, as is well-known, caloric nystagmus has little influence on the eye-tracking pattern. In normal subjects and in patients with peripheral disorders, even if vestibular asymmetry is revealed by the caloric test, only a slight influence is evoked on the ETP [5].
The cases of central disorders were limited to those patients whose ETP before caloric stimulation was normal or borderline.
The results from the normal subjects, as shown in Figure 2, illustrate the well-known fact that nystagmus of peripheral origin has little influence on the ETP. Pattern A is normal , but in patterns Band C it is seen that the caloric nystagmus is superimposed on both the quick and slow phases. On the caloric eye-tracking pattern test, pattern A is normal but, in patterns Band C, it is seen that the caloric nystagmus is superimposed. Therefore, even if vestibular asymmetry is revealed by the caloric test, the superimposed nystagmus is not remarkable. Results of electronystagmography in man: The value of optokinetic, vestibular, and spontaneous nystagmus for neurologic diagnosis and research. This report discusses the use of dexamethasone or gentamicin in 20 individuals who had inner ear diseases in which disturbing cochlear tinnitus was one of the symptoms. Though tinnitus often is associated with other symptoms, the degree of suffering it produces ranges from an occasional awareness to the contemplation of suicide [1]. Dexamethasone has as its probable mechanism an increase in blood flow to the cochlea, a decrease in any inflammatory component, and antioxidant properties [14].
A ventilation tube was placed, the gentamicin was instilled, and patients remained supine with their head turned away 30 degrees for 45 minutes.
The inflow-outflow design permits the physician, with the device in place, (1) to add medication, (2) to remove medication, (3) to flush the device, and (d) to relieve or avoid buildup of air or fluid pressure. However, further investigation and analysis of chemical perfusion's role in the control of tinnitus are needed.
Dexamethasone perfusion of the labyrinth plus intravenous dexamethasone for Menière's disease. Corticosteroid pharmacokinetics in the inner ear: A comparison of different drugs and route of administration.
Predictive monitoring of highfrequency vestibulo-ocular reflex rehabilitation following gentamicin ototoxicity. A tinnitus-targeted therapy (TTT), a combined treatment of medication and instrumentation focusing on pharmacotherapy, has evolved from our ongoing clinical experience since 1977 (now in excess of 10,000 SIT patients) [1-4].
It is believed to originate as an initial dyssynchrony in pre- or postsynaptic neuronal transmission within the peripheral or central nervous system (cortical or subcortical). All patients visited the tinnitus clinic at the Downstate Medical Center at the State University of New York (DMC-SUNY) and the Martha Entenmann Tinnitus Research Center, Inc.
Future advances in tinnitology are expected to add to, subtract from, or modify the principles of tinnitology as set forth in this manuscript. The psychomotor component of the tinnitus refers to a patient's motor response accompanying the emotional and subjective perception of the sensation of the aberrant auditory stimulus (tinnitus). They have been identified as involved in sensory processing underlying cochleovestibular function (peripheral and central) and in the neuroscience of brain function. Since 1979, our team has continued to report the clinical identification of clinical types and subtypes of tinnitus, particularly for a predominantly central-type SIT. These findings provide a basis for understanding the heterogeneity in the quality of the tinnitus as described by tinnitus patients and for the future potential application for attempting tinnitus control.
The ultra-high frequency findings, when positive, have clinical application for both diagnosis and treatment 28,29.
These factors include cerumen in the external auditory canal with or without tympanic membrane involvement, fluctuating aeration in middle ears, SEH, noise exposure, stress, metabolic abnormalities in glucose, cholesterol, triglyceride or thyroid function, and hypertension with or without fluctuation and occurring either alone or in combination. Such drugs include the vasodilator papaverine for cerebrovascular insufficiency, clopidogrel bisulfate (Plavix) in transient ischemic attack and poststroke patients, and anti-seizure drugs for epilepsy. The FCP proposes clinical consideration of auditory masking to be predominantly a brain function with peripheral and central components. The reciprocal interacting neuroanatomical substrates of the three components complete a circuit-the final common pathway sensory-affect transformation. All patients are interviewed by telephone prior to receiving the appointment and are requested to have undergone a complete physical examination within 6 months prior to neuro-otologicalaudiometric consultation and to provide past hearing and balance testing, imaging and pharmacological record results, and a short narrative of the clinical course of the tinnitus for review. The clinical types of tinnitus in this group are predominantly of the middle ear and cochlea, alone or in combination. Ultra-quiet therapy utilizing ultra-high-frequency stimulation has provided tinnitus relief in a particular cohort of SIT patients , however is not available at this time 47. It will come as an accompaniment of advances reported in auditory neuroscience and that of sensation and brain function.
Tinnitus dyssynchrony-synchrony theory: A translational concept for diagnosis and treatment and a model for the clinical diagnosis of different clinical type(s) of tinnitus. Central tinnitus-diagnosis and treatment: Observations of simultaneous auditory brainstem responses with monaural stimulation in the tinnitus patient.
Neuroprotective drug therapy: A medical and pharmacological treatment for tinnitus control. Final common pathway for tinnitus: Theoretical and clinical implications of neuroanatomical substrates.
The Tinnitus Research Initiative TRI database: A new approach for delineation of tinnitus subtypes and generation of predictors of treatment outcome.
Adaptive, behaviorally gated, persistent encoding of task-relevant auditory information in the ferret frontal cortex. GABA-A- benzodiazepinechloride receptor-targeted therapy for tinnitus control: Preliminary report. Fluid dynamics vascular theory brain and inner ear function in traumatic brain injury: A translational hypothesis for diagnosis and treatment. Worldwide experience with sequential phase-shift sound cancellation treatment of predominant tone tinnitus. Transcranial magnetic stimulation for the treatment of tinnitus: A new coil positioning method and first results. Transcranial magnetic stimulation: Summary of the Proceedings of the 26th Annual Meeting of the International Tinnitus Forum.
Incapacitating unilateral tinnitus in single-sided deafness treated by cochlear implantation. Analgesics, tranquilizers, and antihistaminic and antivertigo medications were stopped during this period to minimize possible interferences with the test results. Moreover, anterior vermal lesions are related to upper gaze dysmetria, whereas down gaze dysmetria is usually observed in posterior vermal lesions17. The functional role of the affected nuclei and related fiber bundles may explain the symptoms that occur during the course of the disease (ataxia, dysarthria, somatosensory deficit, diplopia, gaze-evoked nystagmus, auditory impairments, altered brainstem auditory evoked potentials, saccadic smooth pursuits, impaired somatosensory functions in the face and dysphagia28. Biological systems known to regulate the body's overall response to stress use and release endogenous neuroactive opioid peptides. Some 80% of tinnitus sufferers have problems that can be traced to or are associated with changes in the inner ear [1]. Preliminary work has indicated also that dynorph in-related derivatives are codistributed within lateral efferent brain stem nuclei of the chinchilla [29], though it remains to be determined whether the descending axons that project into the cochlea also contain dynorphins in this species. Data from recent pharmacologic studies [36,37] and developmental studies [38,39] also suggest an important role for this system in modulating auditory sensitivity.
Also well-known is that opioid peptides function as neurotransmitters or neuromodulators and that they play an important role in modulating nociceptive sensory input [59-61]. In many other instances, the opioid receptor-linked stimulation of a G-protein may regulate a specific type of ion channel directly, such as a potassium (K+) or a calcium (Ca++) channel, independent of adenylate cyclase-cAMP.


Furthermore, results of a subsequent investigation [79] indicated that large auditory neural amplitude changes at twice the dose were naloxone-reversible and occurred with no corresponding changes in the hair cell-generated cochlear microphonic potential (Fig.
Considerable evidence supports the existence of excitatory non-N-methyl-D-aspartate (NMDA) receptors in the normal adult mammalian cochlea [27,99]. Cochlear NMDA receptors may, however, be restricted to the type I auditory dendrites innervating the modiolar side, as opposed to the pillar side, of the IHCs [109].
Tn approximately 70% of these units (25-30% of the total), the auditory dendrites may be innervated by a range of 1-32 lateral efferent axons (mean, 10).
The enlargement of receptive fields and the ensuing hyperalgesia occur via the facilitation of excitatory amino acid effects at NMDA receptors [73,114]. Recently, inner ear damage from overstimulation was shown to be prevented by the cochlear administration of leupeptin, an inhibitor of intracellular Ca++ -activated cytosolic proteases (calpains) [15,133]. As with pain, what is becoming clear is that tinnitus must consist of both central and peripheral components; certainly, the response of an organism to stress surely involves the entire organism, both its peripheral and central nervous systems. Furthermore, evidence suggests that the aversive motivational properties of endogenous and exogenous opioids are mediated through peripheral κ-opioid receptors [140,141].
Nevertheless, dynorphins have been proposed to playa significant role in pathologies of central and peripheral inflammation [73,115,144,145].
For example, dynorphins produce neurotoxic effects in the spinal cord [139], and the κ-receptor-induced neurotoxicity and neurological dysfunction occur through an enhanced excitotoxic activity at NMDA receptors [73,144,148]. As the stimulus level is increased, glutamate concentrations in the inner ear also would increase but would be potentiated abnormally at each level of increase as a consequence of a κ-receptor facilitation of glutamate at NMDA receptors.
The OHCs appear to be the inner ear structures most susceptible to damage in general and to noise damage in particular [152-155], and often tinnitus is associated with OHC dysfunction [3,156,157]. Though signal enhancement or increased synchronicity (or both) may occur at any location in the auditory system during extreme episodes of anxiety or stress [1], the initial neural changes involved in most forms of tinnitus begin in the auditory periphery [127].
Therefore, as part of an overall response to stress during actual or perceived life-threatening situations (as in extreme anxiety), endogenous neuroactive dynorphin peptides are released into the mammalian cochlea at axodendritic synapses beneath the IHCs and are released throughout the central nervous system. The release of dynorphins and perhaps the subsequent enhanced neural sensitivity to excitatory neurotransmitter activation [73, 148] would result in amplified spectral alterations in the ensemble spontaneous discharge activity associated with tinnitus [4], thereby exacerbating or revealing the preexisting symptom. This event might occur in a manner that perhaps is similar to that described after receipt of sodium salicylate [4,5,21], shown recently to potentiate glutamate effects at NMDA receptors in the mammalian cochlea (20). Step 2: Endogenous dynorphin-related opioid peptides released from lateral efferent terminals tonically, or during physical or emotional stress, interact with N-methyl-D-aspartate receptors located postsynaptically on the type I auditory dendrites, to potentiate the excitatory properties of glutamate.
Presently unknown is whether this group of LSO neurons projects specifically to the chinchilla cochlea as palt of the lateral efferent system. In Abstracts of the Twenty-Second Midwinter Meeting of the Association for Research in Otolaryngology 836:209-210, 1999. In Abstracts of the Twenty-First Midwinter Meeting of the Associationfor Research in Otolaryngology, 447, 1998.
In Abstracts of the Eighteenth Midwinter Meeting of the Associatiollfor Research in Otolaryngology, 679:170, 1995.
In Abstracts of the Twentieth Midwinter Meeting of the Associationfor Research in Otolaryngology, 600:20,1997. In Abstracts of the Twentieth Midwinter Meeting of the Association for Research in Otolaryngology, 213:54, 1997.
In GJ Siegel, BW Agranoff, RW Albers, SK Fisher, MD Uhler (eds), Basic Neurochemistry (6th ed). In JG Hardman, LE Limbird, PB Molinoff, et al.(eds), Goodman and Gilman's The Pharmacological Basis of Therapeutics (9th ed). In R Quirion, K Jhamandas, C Gianoulakis (eds), Progress in Clinical and Biological Research: The International Narcotics Research Conference INRC '89. Proceedings of the Second International Tinnitus Think Tank: The Neurochemistry of Tinnitus. In AG Gilman, TW Rail, AS Nies, P Taylor (eds), Goodman and Gilman's The Pharmacological Basis of Therapeutics (8th ed). In GE Reich, JA Vernon (eds), Proceedings of the Fifth International Tinnitus Seminar, 1995. In Abstracts of the Nineteenth Midwinter Meeting of the Associationfor Research in Otolaryngology, 469:118, 1996. We consider the possibility of correlating between BPPV prognosis and arteriosclerotic changes. When systolic blood pressure was > 140 mmHg or diastolic blood pressure was > 90 mmHg, the patient was determined to have hypertension. Maximum IMT (max IMT) was defined as the single thickest wall of the far right and left walls of the CCA and internal carotid artery.
In contrast, in patients with central vestibular disorders, caloric nystagmus evoked abnormalities in the eye-tracking pattern, either superimposed or as saccades, despite the fact that the eye-tracking pattern before caloric stimulation was normal. In patients with central disorders, however, caloric nystagmus evoked abnormalities on the ETP, either superimposed or as saccades, despite the fact that the ETP before caloric stimulation was normal.
The eye movement (upper traces of patterns B and C) is affected only slightly by the caloric nystagmus; we can say that this is a case of borderline recording. These results are obviously quite different from those illustrated for normal subjects and for patients with vestibular peripheral disorders. On the CETP test, pattern A is normal, but patterns Band C demonstrate superimposed caloric nystagmus (Fig. At that time, neither seesaw nystagmus nor neurological signs were evident, but she complained of slight dizziness. In patterns Band C, however, it is obvious that the caloric nystagmus is superimposed on the eyetracking pattern, although its amplitude is very small. In contrast, in central vestibular disorders, 121 of 128 patients exhibited abnormalities on the ETP. In some cases of central disorders, if the disorder of the oculomotor system is slight, the ETP is normal. Zur Beurteilung ihrer diagnostischen Bedeutung und Begrenzung bei GleichgewichtsstCirung mit und ohne Schwindel, in Riicksicht auf die gegenwiirtige Lage. Preliminary results indicate that chemical perfusion is a promising option for the treatment of cochlear tinnitus.
Approximately 20% of individuals with tinnitus have what is described as a severe or extreme form, which significantly interferes with the quality and productivity of life. Three patients had severe tinnitus as their most disturbing symptom; hearing loss, vertigo, and ear fullness were of greater concern to 17 patients. All three patients had severe vertigo or imbalance and severe tinnitus, two had poor hearing, and one had no hearing. Attachment to an infusion pump allows continuous and exact delivery of medication to the inner ear. Presented at the American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc., annual meeting, San Antonio, TX, September 13-16, 1998.
Principles for SIT treatment have evolved from the TTT experience that provides a rationale for attempting tinnitus relief. It interferes in the excitatory and inhibitory process or processes involved in maintaining homeostasis for brain neurofunction in multiple neural substrates and acts as an aberrant auditory stimulus to express this dysfunction via the auditory system 5. It is expected that these principles will be expanded and modified to reflect future advances in tinnitology. Neuroanatomical substrates that have been identified in brain contribute to an evolving pathophysiology for all clinical types of tinnitus.
According to the definition of tinnitus, the perception of tinnitus is a central function in all CTT . Particularly significant for tinnitus is the finding of a labyrinthine asymmetry that, when correlated with the symptom of ear blockage and a positive Metz test for recruitment, provides the basis for the clinical diagnosis of a secondary endolymphatic hydrops (SEH) 30. Identification, treatment, and maintenance of normal aeration of the middle ears, when identified and treated, have resulted in tinnitus relief and control in approximately 15% of our SIT patients. For memory and cognition, we recommend the neuroprotective drugs donepezil hydrochloride (Aricept), Cognex (tacrine), memantine hydrochloride, gabapentin, and clonazepam (Klonopin). The manifestation of the symptom of tinnitus is considered to be a reduction in the normal auditory masking function in the brain: The neuroanatomical substrates are hypothesized to involve the cochlea, the brainstem, the thalamus, and multiple cerebral cortices (Figure 2). Similarly, tinnitus relief, when reported, is clinically considered by our team to reflect a return of adequate masking.
Second, drug selection should take into account agents that have a short half-life so as to minimize the incidence and duration of side effects. The dose for the sensory component is based on the tinnitus intensity index (TII) and the tinnitus annoyance index (TAI), both on a scale from 0 to 7.
Patients with significant visual, psychiatric, rheumatological, and musculoskeletal vulnerabilities or any abnormality that prevented completion of the evaluation, were excluded from the study. The most common alterations reported in other studies were the presence of positional nystagmus, irregular calibration of ocular movements, spontaneous rebound and multiple gaze nystagmus, optokinetic abnormality, pendular tracking, vestibular hypofunction and absence of the inhibiting effect of ocular, what is in keeping with our findings7,17. These stress-related neuromodulators consist of products derived from three genetically distinct precursor hormones. Hyperacusis has been defined as a collapse of tolerance to sound, often occurring with no significant loss in hearing sensitivity [7,8]. Consistent with what is currently known regarding neuroactive opioid peptides is our view that auditory neural modulation occurs at axodendritic synapses beneath the IHCs and involves (at least in part) the actions of endogenous opioid substances [40]. In addition to modulating the sensation-perception of pain, opioid peptides exert a wide spectrum of physiological-behavioral effects on autonomic function, affect, mood, attention, and physical or psychological stress [62,63]. In postnatal rats, glutamate-sensitive NMDA receptor subtypes have been reported to appear only transiently in the developing cochlea prior to the onset of hearing [105].
The remaining 33% of the modiolar-oriented units (10-15% of the total) are extremely mitochondria-poor, exhibit very low SDRs, and have the highest auditory thresholds of all the type I auditory units. In addition, chronic (prolonged) pain has been attributed to a gradual increase in action potential discharge and excitability in high-threshold spinal cord neurons in response to repeated peripheral stimulation. Moreover, patients with severe tinnitus report discomfort from intense auditory stimuli, and repeated exposure to such stimuli actually lowers their tolerance to all sounds [125-127].
Though clearly no single drug panacea exists, neuroprotective drug therapy has been proposed also for the alleviation of tinnitus [15,122,123]. As has been emphasized, endogenous opioid peptides play a role in the fine-tuning and filtering of sensory information and are released from neural systems in response to stress [53,57].
Iontophoretic application of the δ-opioid receptor ligand [Met5]-enkephalin produces a naloxone-reversible reduction in excitatory amino acidinduced auditory neural excitation in the guinea pig cochlea.
For example, in the spinal cord (dorsal horn), dynorphins induce an NMDA receptor antagonist-reversible enlargement of neural receptive fields. The excitotoxic and neurotoxic actions of dynorphins at the NMDA receptor arise through a κ-receptor mediated facilitation of NMDA receptor sensitivity to glutamate or to aspartate [114,147].
Therefore different-even oppositeeffects on neural amplitude would be predicted at each progressive increase in stimulus level from auditory neural threshold.
Abnormally elevated spontaneous discharge rates within single auditory neurons often are observed when cochlear noise damage is confined to the OHCs [153,154,158]. The result is to advance an affected organism to a heightened state of auditory vigilance [40], which may be adaptive in the short-term when a rapid fight-or-flight response is required.
Step 3A: Neural responses to relatively low levels of an auditory stimulus are enhanced [19].
In the rat, however, the medial limb of the LSO contains a large percentage of efferent neurons [179], suggesting that the CGRP-positive neurons observed in the chinchilla may be part of the lateral efferent system of neurons projecting to the cochlea. Presented at the Martha Entenmann Tinnitus Research Center and the State University of New York SUNY Health Sciences Center at Brooklyn. Using carotid ultrasonography, we examined maximum intima-media thickness (IMT), maximum common carotid artery IMT, and biochemical examinations in 105 patients with peripheral vertigo. We obtained all B-mode ultrasonographic images of the carotid artery with an Aloka SSD-5500 system with a 15-MHz probe.
Maximum CCA IMT (max CCA IMT) was defined as the thickest wall of the far right and left walls of the CCA.
However, these patients do not complain of tinnitus; their audiological examination and caloric test results are normal. These results suggest to us the possible differential diagnosis of both peripheral and central disorders. Pursuit eye movements were recorded with the aid of electronystagmography (ENG), which results in a sinusoidal curve tracing for the horizontal component.
Concerning the eye velocity (lower traces of patterns B and C), the change of speed is slight, as the figure shows. Pattern A is normal, but patterns Band C demonstrate the caloric nystagmus superimposed on both the quick and slow phases. One question that arises is whether the amplitude of the calorically induced nystagmus has an influence on the ETP. However, once the vestibular asymmetry is shown by the caloric test, the caloric nystagmus is superimposed clearly on the ETP.
Despite numerous identifiable or idiopathic causes of tinnitus (Table 1), the variety of therapies used for its eradication or reduction has been uniformly disappointing, offering only temporary or no relief (Table 2) [2]. Patient evaluation and testing were dictated by the diagnosis and, for Menière's disease, by stage (Shea I-V). Of the three, two experienced significant reduction in and one experienced elimination of tinnitus (Table 5). The IntraEar Round Window Microcatheter was used in three patients in this report (Table 6). Understanding the pathophysiology of this transformation in brain is considered to be fundamental to diagnosing and treating tinnitus of all clinical types. The CTT are identified by the correlation of the clinical history, physical examination, electrophysiological correlates of cochleovestibular function, and an evaluation of metabolic and electrophysiological activity in brain. Visual suppression of the vestibuleocular reflex, a sign of cerebellar dysfunction, is significant for the identification of a central component for the tinnitus and involvement of the acousticomotor system 31. These drugs may influence the SIT by improving the underlying neuronal anatomic substrate(s) that may be contributing to SIT 1.
The cerebellum, via the acousticomotor system, has reciprocal projections to and from the somatosensory cortex, IC, thalamus, PAC, and parietal lobe [18]. We recommend selection of RTT-GABA for patients with SIT of more than a year's duration and a diagnosis of a predominantly central-type tinnitus based on completion of the MATPP.
In H Feldmann (ed), Proceedings of the Third International Tinnitus Seminar, Munster, 1987.
Conclusion: The study showed that alterations in ENG are related to the severity of SCAs or clinical stage of the disease. Vestibular Evaluation - vestibular function evaluation consisted in several labyrinthine function and ocular tests. Hyperacusis is present in approximately 40-86% of those who suffer from disruptive forms of tinnitus; it also can compromise the quality of life in those individuals so afflicted [7-9]. Indeed, considerable evidence indicates that endogenous opioid peptides are found within, and are released from, neural systems that regulate the body 's overall biological response to stress [53,64,65]. Therefore, in many neural systems, opioid receptors are coupled to either the Gi-or Go-protein, wherein the actions of opioid ligands inhibit adenylate cyclase and K+ or Ca++ channels are regulated [61). Such powerful IV μ-receptor agonists as fentanyl and morphine are without effect on the same auditory measures [84-87]. Tn fact, this smaller subset of modiolar-oriented units exhibits thresholds that are 20-80 dB poorer than are the thresholds of the more numerous type I units innervating the IHC pillar side [33,110,111,113]. The windup phenomenon associated with pain depends on NMDA receptor activation in high-threshold neurons [118]. Some suggested pharmacological therapies have included antianxiolytics, antioxidants, antihistamines, antidepressants, anticonvulsants, antiepileptogenics, diuretics, Ca++ channel blockers, dexamethasone, lidocaine, and (of course) glutamate-receptor antagonists [11,12,15]. Emotional or physical stress is known also to induce potent analgesic effects [53,117,136], and "stress-induced analgesia" is likely to involve multiple opioid systems [65,137]. The δ-receptor effect, however, occurs at both NMDA and glutamate-sensitive non-NMDA receptors, though enkephalin appears to exert a stronger inhibitory effect on non-NMDA receptor-induced auditory neural activity [142]. The receptive field enlargement results in a greater number of stimulated neurons and produces hyperalgesia [73,115]. Moreover, the existence of an activity-dependent neuronal plasticity in response to tissue injury has been hypothesi zed to account for the increased sensitivity and spontaneous pain associated with enhanced dorsal horn excitability at NMDA receptors by endogenous dynorphin peptides [114,73].
Normally, OHCs serve to damp activity in unstimulated regions of the cochlear partition, thereby decreasing the auditory sensitivity at (irrelevant) frequencies corresponding to those regions [153,159-161]. Alternatively, spectral anomalies in the ensemble spontaneous discharge associated with tinnitus may be amplified or generated, as illustrated in step 3B. However, we reported [1] that patients with peripheral vestibular disorders show progression of arteriosclerotic changes. We can conclude that the visual suppression to vestibular nystagmus is evoked more strongly by pursuing a moving visual stimulus than by gazing at a stationary target. These results are obviously fairly different from those illustrated for normal subjects and for patients with vestibular peripheral disorders. In patterns Band C, however, obviously the caloric nystagmus is superimposed on the ETP, although its amplitude is very small (Fig.
As the amplitude of caloric nystagmus is small in patients with peripheral vestibular disorders, it may not be superimposed on the ETP.
Where indicated, tests included comprehensive audiometry, tinnitus matching, electronystagmography, electrocochleography, vestibular autorotation testing [12], osmotic diuresis, and radiological studies.
Although each patient had different underlying pathology, all three had severe cochlear tinnitus. When viewed in terms of sensory processing, the FCP hypothesis is considered to be expanded and broader in its application for all sensations, normal or aberrant 8,20. Critical for attempting tinnitus treatment, control, and relief for any and all clinical types and subtypes of tinnitus is the clinical establishment of accuracy for the tinnitus diagnosis 14,24. Again, the accuracy of the tinnitus diagnosis is the key to selecting modalities of treatment in attempting tinnitus treatment, relief, and control.
Hyperpolarization and depolarization of GABA-influenced thalamic neuron activity results in thalamocortical oscillations in a synchronous signal at brain cortex [204,254].
Plans should be made for longterm treatment, particularly for the affective behavioral component. The first part of the evaluation was simply clinical and consisted of a systematic search for spontaneous, gaze, and positional nystagmus - Brandt and Daroff's maneuver12. Enkephalin and dynorphin-related peptides exist within the efferent olivocochlear systems (lateral and medial) of several mammalian species, including humans. In a large percentage of those suffering from both phenomena, the debility has been traced to the auditory periphery [10-12]. In addition to the wide range of observed behavioral responses, a wide range of neurophysiological responses also is produced by the binding of endogenous opioid ligands to their receptors. Opioid receptor activation of the Gi-or the Go-protein has been linked to neural inhibition through an activation of voltage-or Ca++ dependent, inward-rectifying K+ channel conductances or inhibition of voltage-dependent inward Ca++ channel conductances [61,66,70-72]. From these investigations, some have argued that the observed auditory neural changes after IV (-) pentazocine reflect drug actions within the cochlea [79,80,83].
The dendrites of each of these very low SDR-very high threshold units are innervated by 7-32 lateral efferent axons (mean, 20), an amount twice the number of lateral efferent axons terminating on each of the pillar-oriented type I auditory dendrites [33]. Cochlear NMDA receptors also are activated primarily by the presentation of repetitive or relatively intense auditory stimuli [27, 108].
Therefore, an important component of an organism's response to a real or perceived life-threatening emergency is a reduction in responsiveness to pain. Such evidence is consistent with the widely observed inhibitory properties of enkephalins, and indicates that endogenous enkephalins acting through δ-receptors modulate excitatory neural activity at glutamate-sensitive NMDA and non-NMDA receptors in the mammalian cochlea. Finally, the κ-receptor antagonist norbinaltorphimine has been found to be a potent antagonist of NMDA receptor activity, and a neuroprotective role has been suggested for this agent in the treatment of NMDA-induced convulsions and neurotoxicity [144, 149]. This property of OHCs contributes greatly to the sharp tuning of the cochlear partition [161-164]. These results are interesting, not only from the physiological viewpoint but from the clinical viewpoint.
Moreover, no disorders of the central nervous system are disclosed either in their medical histories or in their neurological examination results.
During the evoked caloric nystagmus, we administered the eye-tracking test, and the ETP was recorded for 20 seconds beginning 50 seconds after the start of the ice-water injection. Figure 3 shows the results obtained in a case of left-sided Meniere's disease, which is representative of this group. Conversely, in central vestibular disorders, because caloric nystagmus has a large amplitude, it may be superimposed on the ETP. In conclusion, we can say that the visual suppression to the vestibular nystagmus is evoked more strongly by pursuing a moving visual stimulus than by gazing at a stationary target. Failure to respond to reassurance, dietary and lifestyle changes, medical intervention (diuretics, vestibular suppressants, systemic steroids, calcium channel blockers, vasodilators, anticholinergics, and lipid reduction), and vestibular physical therapy, considered in conjunction with the stage of the disease, resulted in the option of chemical perfusion with dexamethasone or gentamicin. Under general anesthesia, the patients had their cathetersfilled with the gentamicin solution (l.25 ml)-placed into the round-window niche via a tympanomeatal flap and were released to home.
For the future, it is hypothesized, a particular clinical type of a predominantly central tinnitus, now considered to be a symptom, will be identified to be a specific disease entity.
Reciprocal innervation from the thalamus to the medial temporal lobe system (MTLS), including the amygdala (AG), hippocampus (HP), paparahippocampal formation (PH), entorhinal cortex (EC), perirhinal cortex (PC), ACG, and hypothalamus (HYP), comprise an endogenous system of the CNS as hypothesized for sensory processing [53,54].
The main clinical manifestation of tinnitus is that of multifactorial characteristics; therefore, single drugs may have multiple sites of action. The second part consisted of interpretation of the ENG test results, with objective register of variations in the corneoretinal potentials, captured by sensitive electrodes. Prodynorphin derivatives, however, may be restricted exclusively to lateral efferent neurons.
For instance, in one investigation, hyperacusis was shown to involve the peripheral auditory system in 59% of cases [6]. This finding is suggested by (-) pentazocine's relatively high tissue solubility [88] and relatively low molecular weight [89,90], factors that should permit an easy passage of (-) pentazocine across the blood-labyrinthine barrier.
This anatomical array suggests that the lateral efferent system exerts relatively more influence on type I auditory neurons characterized by very low rates of spontaneous discharge and very high thresholds. NMDA receptor-linked and non-NMDA receptor-linked neurotoxic effects of glutamate or aspartate have been implicated also in a number of severe pathophysiological neurodegenerative disorders [119-121], in auditory neural excitotoxicity [15], in acute ischemia of radial auditory dendrites [27,109] and, of course, in tinnitus [10,11,15,101,122,123]. As indicated, cochlear NMDA receptors appear to be restricted to the much higher threshold, modiolar-oriented type I auditory dendrites [109].
Though such evidence argues that glutamate activation of cochlear NMDA receptors plays a substantial role in inner ear neuroexcitotoxicity and in the etiology, maintenance, or exacerbation of peripheral neural generators of tinnitus, what has become clear also is that stress-related events are more powerful triggers for tinnitus than are strictly auditory-related events [6,7,15,16]. This reaction creates little diffi-culty in envIsioning that in meeting the behavioral demands prompted by such exposure, an animal's normal reactions to pain could prove deleterious [117].
Also fairly likely is that such effects normally are initiated via the lateral efferent system. Such evidence, taken together with more recent data [19], is consistent with the widely observed excitatory properties of dynorphins, further suggesting the possibility that endogenous dynorphins, acting through κ-receptors, facilitate the excitatory neural actions of glutamate in the inner ear. One popular theory [157,165] is that damaged or dysfunctional OHCs decouple from the tectorial membrane, owing to a loss in their hydrostatic pressure [166] or to stereocilia damage [153]. Effects of electrical stimulation of efferent olivocochlear neurons on cat auditory-nerve fibers: III.
We cannot diagnose their conditions with confidence, for instance, as vertebral basilar artery insufficiencies. The CETPs are normal, just as they are for the normal subjects (as illustrated in Figure 2). The records that were obtained from a patient with Wallenberg's syndrome would seem to answer this question. Moreover, this CETP test seems to afford the possibility of a simplified differential diagnosis between peripheral and central disorders and the ability to judge the results of treatment over time. At a follow-up office visit, the gentamicin within the catheter was removed and was replaced with new solution.
For tinnitus, the endogenous system is hypothesized to result in the establishment of a "paradoxical memory" for the aberrant auditory sensory stimulus (tinnitus) and has a reciprocal interaction with the thalamus [16]. We recommend a combination drug strategy to increase the efficacy of attempts at tinnitus relief. The ENG test is composed of: calibration of ocular movements, search for spontaneous and gaze nystagmus, the oscillatory tracking test, optokinetic nystagmus search, and rotatory and caloric tests. Descending lateral efferent axons terminate solely on primary (type I) auditory dendrites innervating cochlear inner hair cells in most species. Furthermore, both auditory phenomena are associated with or are induced or exacerbated by physical fatigue or psychological stress [2,6,13-16]. Naloxone Hel (Narcan), the antagonist drug of choice for opioid intoxication, also is known to pass easily through blood-endothelial barriers [59].
Finally, sodium salicylate, well-known for its anti nociceptive properties and its capacity to produce transient tinnitus, also increases intercellular Ca++ levels in neurons [125] and in cochlear outer hair cells (OHCs) [129]. Consequently, during threatening conditions, reactions to pain would be suppressed in favor of more adaptive behaviors, enabling an organism to escape or defend itself (fight or flight).
The corresponding loss in their normal damping properties leads to an increased production of thermal noise within specified regions of the cochlear partition. The results in each case were presented as three patterns of ENG recording: pattern A obtained before caloric stimulation, pattern B obtained during caloric testing of the right ear, and pattern C obtained during caloric testing of the left ear. The eye-tracking pattern is recorded for 20 seconds, beginning 50 seconds after the start of the icewater injection. No patients complained of any pain or discomfort from this brief procedure (approximately 40 minutes). The associated brain function processes within the neuroanatomical substrates of the sensory component include memory, stress, masking, fear, reward, and autonomic functions. For the affect component, particular attention is directed with pharmacotherapy to avoid drug tolerance and or habituation. Response to treatment is monitored by telephone communication and follow-up office visits as determined by the clinical course of the SIT 1,37. This action indicates that they play an important role in modulating auditory nerve sensitivity and spontaneous discharge.
An association has been drawn also between clinical depression (dysphoria) and severe forms of tinnitus, with an incidence reported as high as 60-80% [16-18].
Alternatively, the observed auditory neural changes subsequent to IV administration of (-) pentazocine or naloxone may have been, at least in part, an indirect reflection of the actions of both drugs in the brainstem, leading to the subsequent release-suppression of dynorphins, or of some other neurotransmitter-modulator at the lateral efferent-type I auditory synapse.
Perhaps more important, however, was the recent demonstration that sodium salicylate potentiates the excitatory effects of glutamate at NMDA receptors in the mammalian inner ear [20], an action consistent with the observations and conclusions made by previous tinnitus investigators [3,130,131]. This added shift in the neural discharge spectra then is interpreted erroneously by the central auditory system as a genuine signal [3,4]. We call the pattern while the caloric nystagmus is evoked the caloric eye-tracking pattern. The results demonstrated that 121 of 128 cases had obvious superimposed nystagmus or saccades. In patterns Band C, however, obviously the caloric nystagmus is superimposed on the ETP, although its amplitude is very small.
Stress is considered to be a modulator of the clinical course of the tinnitus with the accompanying reduction and alteration in auditory masking [2,230-232]. In a fashion similar to that exhibited by the observed excitatory mechanism of action of dynorphins in the spinal cord, sodium salicylate (aspirin) recently was shown to facilitate the excitatory effects of glutamate in the cochlea.
As discussed later, opioid κ-receptor ligands administered into the cochlea have been observed to alter auditory neural sensitivity to low-intensity sounds [19].
Whether and to what extent such effects occurred from indirect drug actions in the brainstem or from direct actions in the cochlea cannot be evaluated at present. The middle part of the eyetracking pattern is deleted and indicated by the breaks in the curves.
Algorithm 2, Affect (Emotional-Behavioral) Component: The neuroanatomical substrates of the affect (emotional) component are highlighted by the OFC, PFC of the frontal lobe, PAC, MTLS of the temporal lobe, and insula. This article provides support for a neurochemical model in which endogenous dynorphins may induce hyperacusis and can contribute to the induction, maintenance, or exacerbation of tinnitus in the auditory periphery by altering auditory type I neural excitability to glutamate. In a fashion similar to that of the reported effects of dynorphins in the spinal cord, sodium salicylate recently was shown to facilitate the excitatory effects of glutamate in the cochlea [20]. Still unknown is whether κ-receptors exist in the chinchilla brainstem and whether IV (-) pentazocine effects are eliminated in animals, maintaining ablations to the lateral efferent pathways. Reciprocal innervation is hypothesized to occur between the PAC of the sensory component and the OFC, ACG, PFC, MTLS, and insula.
Furthermore, salicylate produces tinnitus concomitant with quantifiable spectral alterations in the "ensemble spontaneous discharge activity" of the auditory nerve [4,5,21]. The insula, by its central location, is hypothesized to exert a modulating effect among the sensory, affect, and psychomotor components. Our position is that endogenous dynorphin peptides are liberated into the inner hair cell (IHC) synaptic region by the lateral efferent olivocochlear system.
The thalamic activity is ongoing with reciprocal projections to the PFC, OFC, and parietal lobe.
These neuroactive substances then interact with nearby excitatory neurotransmitter receptors, producing quantifiable alterations in stimulus-evoked and spontaneous auditory neural activity. During periods of physical or emotional stress, this interaction may be especially pertinent. Algorithm 3, Psychomotor Component: The neuroanatomical substrates of the psychomotor component include the insula, parietal lobe, striatum, and cerebellum. Furthermore, this hypothesized association may not be restricted only to tinnitus generated at the level of the auditory periphery.
The thalamic activity is ongoing with reciprocal innervation of the parietal lobe, OFC, and PFC.
Significant for the sensory-affect transformation is considered to be the interaction between the striatum, parietal lobe, and OFC via the insula.



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