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INTRODUCTION: Tinnitus Handicap Inventory (THI) was developed in English to quantify the handicap caused due to tinnitus.
OBJECTIVES: India being a multilingual country needs to develop and standardize THI in Indian languages. MATERIALS AND METHODS: Questions from English version of THI were translated and modified by two professionals who have a degree of MA Kannada. RESULTS: Analysis revealed 14% of the patients fall under the category of Slight, 38% under Mild, 26% under Moderate, 16% under Severe and 6% under Catastrophic group. CONCLUSION: Scores of Cronbach-alpha test shows that Kannada version of THI is a standard and reliable tool for measuring the handicap caused by tinnitus and can successfully classify individuals on a severity basis.
Recent interest has surfaced in symptom - specific handicap outcome measures for many audiological and otological diseases4. A symptom specific assessment of many otological disorders will aid in understanding the severity of the symptom and effects of this on routine life.
The English version of THI which is shown in Appendix 1 was the only tool available for quantifying the handicap caused by tinnitus.
The beta version of THI developed by Newman and Jacobson in 1996 consists of 25 questions under the 3 sub scales of emotional, functional and catastrophic. Individuals who were suffering from tinnitus with or without any otological diseases were selected for the study.
Tinnitus questionnaire was administered on the participants using a structured interview by the clinician to have a record of the demographic details and to cognize the type, nature, and the lateralization of the tinnitus, factors that affect tinnitus, presence of hearing loss, and the concern about the tinnitus. Following the administration of the tinnitus questionnaire, the participants were instructed regarding the self - assessing Kannada version of THI, its importance and the system to grade it.
Among all the participants, 94% of the participants had a minimum qualification of SSLC and a maximum qualification of a degree and could fill up the Kannada version of THI without the help of the clinician.
The results of the THI and the self assessing questionnaire were tabulated and are graphically represented below in Graph 1. After the complete analysis of the obtained data, the percentages of the patients coming under various severities were found out.
The purpose of this study was to develop a handicap inventory in native language (Kannada), to obtain a standard measurement instrument for evaluating tinnitus in patients to apprehend the effects caused due to tinnitus. From the study, we could observe that the perception of tinnitus handicap differs drastically between subjects as demonstrated by high values of standard deviations, which may be due to effective coping starategies5. Related to the emotional aspects, the Kannada THI allows assessing the relation between tinnitus and manifestation of stress, depression, anxiety & frustration.
The result of the current study shows good reliability and internal consistency as indicated by the Cronbach alpha test.
Hence this inventory can serve as an effective tool to successfully classify the individuals into different grades according to the symptoms. Since the main focus of this study was to develop and standardize the THI into Kannada language, and to be administered on all Kannada patients who complain of tinnitus.
The main aim of this study was to develop and standardize the Tinnitus Handicap Inventory in Kannada; hence it can be administered on Kannada patients without difficulty. Paper submitted to the ITJ-SGP (Publishing Management System) on December 17, 2012; and accepted on January 17, 2013.
Los cuestionarios como el Test de incapacidad del tinnitus, se consideran buenos predictores. 17E ¿Siente que el zumbido de oído ha echado a perder las relaciones con sus familiares y amigos?
El grado de discapacidad a través del Tinnitus Handicap Inventory (THI), se ha clasificado en 5 niveles . People with tinnitus often characterize their tinnitus as “ringing in the ears” or a “buzzing sound.” The American Tinnitus Association (ATA) describes it as a subjective noise that only the patient can hear. About 50 million people in the United States experience tinnitus to some degree and, in severe cases, seek medical attention. HR: Why should hearing care professionals who traditionally focus on hearing impairment get involved in tinnitus? Clint Keifer, AuD: As audiologists, we possess an in-depth understanding of the anatomical, physiological, and psychoacoustical aspects of the auditory system.
Wendy Switalski, AuD: In conversations I’ve had as an audiologist and as a consultant to audiologists, it is clear that these conditions coexist for so many of our patients. Clement Sanchez, AuD: Tinnitus can be a problem for those who are hearing impaired and have a hearing loss. Sanchez: Hearing aids can be very effective if they can reduce the symptoms related to the tinnitus. A clinician can play a vital role in helping the patient deal with the sounds of everyday living, instead of avoiding sounds all together. Switalski: Professionals interested in expanding their services have so many resources available.
Practices may begin by simply offering tinnitus assessment, patient questionnaires, or surveys. Keifer: Ideally, practices would be “full-service,” but in practical terms, it is difficult for any one practice to offer every possible solution. Sanchez: Assessing tinnitus can be challenging, so clinicians who decide to add a full-service tinnitus treatment plan have a few details to consider. Aside from my traditional practice, I used to schedule consultation with tinnitus patients 1 day a week and this worked well. HR: I’ve heard that tinnitus patients can consume huge amounts of practice time and many dispensing professionals are not adequately staffed for that.
Sanchez: Yes, tinnitus patients will need time to express their fears, frustrations, and the discomfort they are experiencing because the sounds they hear are unclear and can be difficult to describe. I would describe the tinnitus consultation as “a mix of charisma and empathy,” where clinicians can focus on gathering the information that can benefit the treatment. The MADSEN Astera2 features a dedicated tinnitus assessment module designed to help clinicians address increased claims for tinnitus and hearing loss disability.
The new tinnitus test module we have developed as part of fundamental audiometry in MADSEN Astera2 supports the professional through a series of integrated questionnaires. Keifer: Tinnitus treatment protocols should not be rigid, but rather they should adapt to the individual. The treatment may also involve retraining strategies, amplification, masking, sound therapy device application, support group attendance, and so forth.
Sanchez: In addition, it will entail an in-depth hearing assessment, such as audiometry with UCL, immittance, otoacoustic emissions (OAE), and auditory brainstem response (ABR).
The full tinnitus psychoacoustic test battery is designed to improve patient counseling and test precision. Visualization of the tinnitus on the audiogram is a great experience for a patient who has looked for help for years and may have felt misunderstood at times. The electronic questionnaires—Tinnitus Functional Index (TFI), Tinnitus Handicap Inventory (THI) and Tinnitus and Hearing Survey (THS)—can be saved in NOAH and are designed to eliminate the need for paper records. The next step is explaining that, for example, a 7 dB tinnitus is quite a small issue that can be managed. Once again, dialogue with other professionals is important and should be considered from the very beginning. HR: What types of equipment should you consider for your practice when starting up a tinnitus treatment program? Switalski: Having access to the proper audiometer features is important for performing a tinnitus assessment. Otometrics has developed a dedicated tinnitus management tool for audiologists, which is integrated with our clinical audiometer, the MADSEN Astera2.
INTRODUCTION: The present study investigated the relationship between the perceived tinnitus severity, depressive and anxiety symptoms in individuals with tinnitus. MATERIALS AND METHODS: Fifty individuals (31 males, 19 females) with tinnitus (age range 19 to 60 years) were enrolled in the study.
CONCLUSION: The results support the view that there is a strong relation between tinnitus and anxiety-depressive symptoms.
Tinnitus has been defined as a condition where there is a sensation of sound but there is no corresponding sound in the acoustic environment1.
Psychoacoustic measures, such as loudness or pitch, are reported to show little or no relationship to the distress reported by tinnitus individuals4,14. One of the most common psychopathologies clinically observed in tinnitus individuals is depression.
Though there is enormous literature on various psychopathologies and emotional distress resulting from tinnitus, only a couple of studies17-19 have attempted to reveal the relation between the perceived tinnitus severity and the degree of emotional distress.
Review of literature shows a clear relation between hearing loss and tinnitus20-22 and it can be a symptom of a condition that causes hearing loss, or it can exist without any hearing loss23. Though there is enormous data available regarding the psychological and audiological profiles of individuals with tinnitus in western context, such studies are very limited27 in Indian context. Fifty individuals with tinnitus in the age range of 19 to 60 years were enrolled for the study.
Tinnitus Handicap Inventory (THI).The subjective severity of the handicap experienced due to tinnitus was assessed using the 25 item, beta version of the THI18. The scores obtained from the 50 participants on the audiometric and psychological measures were tabulated.
In this study, the relationship between perceived tinnitus severity, anxiety and depression was investigated among 50 adults with tinnitus.
A high correlation between state and trait anxiety has been supported by the state-trait models. The results of the study also showed that there was no significant relationship between perceived tinnitus severity, age and gender.
We found no correlation between the hearing status of the individual and the degree of annoyance experienced by tinnitus.
The present study aimed to examine the relationship between the perceived tinnitus severity, depressive and anxiety symptoms in individuals with tinnitus.
Paper submitted to the ITJ-SGP (Publishing Management System) on September 19, 2013; and accepted on February 12, 2014.
As regards the symptom of a predominantly central tinnitus of the severe, disabling type, it has been hypothesized that a deficiency in the benzodiazepine receptor exists in the medial temporal lobe system of brain and is directly related to affect impairments including anxiety, stress, depression, and fear. Visual analysis revealed preliminary results of diminished benzodiazepine-binding sites in the medial temporal cortex of all patients with severe tinnitus (N = 6), a finding that is consistent with the hypothesis implicating GABAergic mechanisms in the pathophysiology of the disorder. Tinnitus is a disorder of auditory perception due to an altered state of excitation or inhibition in neuronal networks that results in a dysynchrony in neuronal signaling (1992) [1-4]. The tracer 123I Iomazenil is a benzodiazepine receptor analog single-photon emission computed tomography (SPECT) tracer that has previously demonstrated an accurate measure of intracerebral regional GABA activation [20-23; JP Seibyl, personal communication, June 1999].
123I Iomazenil binding to benzodiazepine receptors has been measured in human brain using kinetic and equilibrium methods.
Six patients with a predominantly central tinnitus of the severe, disabling type were selected for this study. Outcome data included a stress questionnaire, depression questionnaire, and tinnitus handicap inventory completed by each patient prior to this study and were consistent with a diagnosis of tinnitus of the severe, disabling type (Table 2). The six subjects who met the inclusion criteria and who did not meet the exclusion criteria were enrolled into the study after they agreed to participate and signed the informed consent for the designed protocol. The following safety measures were applied for each patient:Vital signs (temperature, pulse, respirations, and blood pressure) were measured and recorded immediately prior to and at 15 minutes and 30 minutes after the 123I Iomazenil injection and again prior to obtaining the scan.
Projection data were acquired on the PICKER PRISM 3000 camera fitted with high-resolution fan-beam collimators (acquisitions obtained for 60 minutes, 128 ? 128 matrix) into a 20% symmetrical window centered on 159 keV [JP Seibyl, personal communication, June 1999]. Individual SPECT scans were registered to the patient's MRI scan using previously published methods [25]. Quality control of the SPECT imaging system included uniformity correction flood and center-of-rotation (COR) determination, performed prior to imaging of subjects. Visual analysis of the 123I Iomazenil SPECT images by two board-certified nuclear medicine physicians suggested consistent areas of diminished tracer uptake in five of six patients (Fig. Regions of interest, drawn on standardized brain regions identified on MRI and transferred to coregistered SPECT images in patients, were used to develop leftright homotypic brain ratios (Fig. Figure 3 indicates another measure of regional brain asymmetry based on the absolute percentage differences for the same regions as were analyzed previously.
A multistep statistical process was used to realign and coregister all the cases and controls to one another and to incorporate them into a standard spatial volume (Talairach space).
In the SPM case-control analysis, a statistically significant decrease in benzodiazepine receptor density in the cerebellar region was noted, particularly on the right (p =.054). Brain SPECT perfusion imaging demonstrated for the first time in 1991 the in vivo significance of the organicity of brain for a predominantly central tinnitus [1,4].
Tinnitus is hypothesized also to be a consequence of an alteration in auditory masking resulting from regional diminution of neural inhibition. Since 1977, more than 6,000 patients with subjective, idiopathic, severe, disabling tinnitus have completed the MATPP in the Tinnitus Clinic of the Health Sciences Center at Brooklyn, State University of New York [3,24].
The adverse influence of stress has been found, in our experience, to be practically universal for all tinnitus patients [34]. The concept of the final common pathway for all clinical types of tinnitus embodies the hypothesis that the benzodiazepine receptor and its relationship to GABA-A are considered significant in the transition of the sensory to the affect component of tinnitus.
The selection of 123I Iomazenil for SPECT measurement in our study of benzodiazepine receptors was based on experience and a review of the literature [20-23; IP Seibyl, personal communication, June 1999]. The brain uptake of this radiotracer represents reversible and selective binding to the benzodiazepine receptor. The results of our study are consistent with the hypothesis implicating GABAergic mechanisms in the pathophysiology of some clinical types of tinnitus. Significant neurochemical implications for treatment are suggested by the proposed final common pathway for tinnitus [30]. The concept of a final common pathway for tinnitus reflects new images of tinnitus-specifically, a neurochemistry of tinnitus [41]. It has been hypothesized that a benzodiazepine deficiency syndrome exists in the MTLS that influences sensory or affect transformation [18,30,44].
Preliminary results of 123I Iomazenil SPECT imaging have shown diminished benzodiazepine-binding sites in the medial temporal cortex in patients with severe, disabling tinnitus [JP Seibyl, personal communication, June 1999]. The high concentration of steroid and benzodiazepine receptors in the MTLS of brain was reported by McEwen et al.
Glucocorticoids are important in signaling and coordinating a variety of physiological responses, ranging from immune inflammatory processes to promoting the production of energy in the form of carbohydrates and fat [45]. The consequences of glucocorticoid excess are twofold:the effect of hippocampus on glucocorticoid secretion and the effect of glucocorticoids on the hippocampus.
Our study, which focuses on the MTLS of brain, suggests that in the tinnitus patient, the medical significance for the patient may be that of "an aging hippocampus" and that tinnitus may be a "soft" sign of aging.
Basic scientific reports describe variations in chronic benzodiazepine effects on both binding sites and function and varying regional specificity.
Chronic benzodiazepine administration has been associated with tolerance and downregulation of GABAA receptor binding and function. A recent basic scientific investigation demonstrated that a potential circuitry underlying the normal auditory map may exist in the absence of stimulation but may be functionally inactivated by GABA-A receptormediated inhibition [54]. Neurosteroids is a term referring to steroids of central origin that are independent of peripheral sources. Upregulation of GABA-A receptors is observed as one of the neurotrophic actions of GABA, primarily in cultured cerebellar granule cells. The issue of drug therapy for tinnitus control is further complicated by what is and is not known of GABA-A receptor activity in vivo. GABA-A receptor agonists or inhibitors of GABA degradation that are chronically administered produce a tolerance to the anticonvulsant effects.
Benzodiazepine agonists in vitro significantly increase GABA-A receptor currents by increasing the sensitivity of the receptor to GABA. GABA-benzodiazepine coupling was evaluated in eight regions of rat brain by the ability of GABA to stimulate 0.5 nM [3H]f1unitrazepam binding [66]. Considerations of the benzodiazepine deficiency syndrome must take into account the issue of benzodiazepine tolerance.
GABA-A receptor subunits have been increased by the addition of NMDA to granule cell preparations in the cerebellum. For tinnitus control treatment, both upregulation and downregulation are needed to activate and control the GABA-A receptors in brain. At least two types of central benzodiazepine receptors with specific regional distribution are found in the mammalian brain. Knowledge of both receptor binding affinities and pharmacokinetic properties of benzodiazepines is considered important in the rational clinical use of such drugs.
Preliminary results with 123I Iomazenil SPECT imaging of brain have revealed diminished benzodiazepinebinding sites in the medial temporal cortex in all six studied patients identified to have predominantly central, subjective, idiopathic, severe, disabling tinnitus.
A benzodiazepine deficiency syndrome may exist in some tinnitus patients distinguished clinically by a severe, disabling tinnitus highlighted by the affect component-that is, patients complaining of alteration of behavior or emotion, stress, fear, anxiety, or depression.
Finally, the finding of diminished benzodiazepinebinding sites in the medial temporal cortex of brain with 123I Iomazenil and SPECT imaging of brain is considered clinical support for the hypothesis of a final common pathway for tinnitus in the MTLS. The authors express their appreciation to the Martha Entenmann Tinnitus Research Center, Inc., and to the Beech Fund Trust B, New York Community Trust, for supporting this study.
Translated inventory was given to 50 native Kannada speakers for the familiarity check & the most familiar sentences were included in the study. According to the data obtained from the National Center for Health Statistics, tinnitus is more commonly seen in males than females and increases in prevalence with advancing age.
There are two important aspects of symptom - specific evaluation that is generally done by a valid and reliable inventory5. A Tinnitus Handicap Inventory (THI) was developed in order to measure the handicap caused by tinnitus.
India being a multilingual country with a multicultural background, there is no such inventory available in any of the Indian languages other than in Tamil.
For the present study, the English version of THI was translated to Kannada using the standard Translation-back-translation method (Bardley, 1994) by two professors who have a degree of MA in Kannada. Participants were interviewed briefly regarding tinnitus and those who complained tinnitus for more than 3 months were included for the further procedures, so that, they can quantify accurately the physical, emotional and catastrophic impacts of tinnitus on their daily acvtivities.
Thereafter based on the subject's grading for all the questions, the total scores were calculated. Rest percentages of participants were from a lower socio-economic status and could fill up the questionnaire only with the help of the clinician due to their inability to read and understand Kannada.
Cronbach alpha test was administered to check for the internal consistency and reliability of the Kannada version of the THI and also an Item-Total Correlation was also carried out.
Thus, according to the Cronbach alpha score, the Kannada version of THI has got a good internal consistency and reliability to administer on the tinnitus patients in the Kannada population.
With the administration of Kannada THI it was found that, all the subjects could quantify the severity of tinnitus from slight degree to catastrophic degree, and thus fulfilled the aim of the study. Tinnitus assessment not only involves to match the tinnitus, ascertain the intensity of the tinnitus and to find out the intensity of wide band noise that can mask the tinnitus, but also involve administration of various inventories like THI to rate and assess the severity of tinnitus in order to help the clinician to counsel the patient as well as to know the level at which the management options should begin8. With respect to the functional aspect, the Kannada THI allows to identify the relationship between tinnitus and activities involving concentration, hearing acuity, attention & reading. This inventory could easily be understood to all the laymen and 94% of patients could fill the inventory without any help from the clinician. Following all the analysis and standardization, the Kannada version of THI came out successfully for the evaluation of tinnitus and found to be reliable. The Kannada version will help the patients with tinnitus to comprehend the severity and intensity of their problem and also considered as a reliable instrument for the verification of the impairment in the quality of life due to tinnitus. Department of Speech Language Pathology - All India Institute of Speech & Hearing - Mysore - India. En ellos podremos valorar de manera objetiva el grado de incapacidad provocado por los acufenos. El grado de incapacidad del acufeno viene determinado por la suma total de todas las respuestas y equivale a un valor comprendido entre 0 (no incapacidad) hasta 100  (incapacidad total).
Sin embargo, la terapia manual puede actuar desde el grado 1, evitando el progreso y aumento del acufeno. In some cases of objective tinnitus, physicians can identify the symptom with the use of a stethoscope placed on the neck or directly in the ear canal.
There is currently no known cure for tinnitus; however, there are advanced devices and treatments today that can help alleviate tinnitus symptoms. Drs Sanchez, Switalski, and Keifer share their thoughts on the benefits of tinnitus assessment, and provide advice to audiologists and hearing care professionals who are interested in adding tinnitus assessment to their practice.
As hearing care professionals, we are skilled in diagnostic, counseling, and rehabilitative approaches to managing auditory disorders.
And for some of them, treating the tinnitus is necessary to address the concerns that led them to seek hearing care in the first place. They may have difficulty sleeping, be unable to concentrate, and experience irritability and high stress levels.
A hearing aid can amplify soft sounds, which can have a “masking” effect and helps to decrease the contrast between the environmental sounds and the tinnitus. This is an important step to address the patient’s fears and provide supportive tools when the tinnitus is too intense.
Today, tinnitus management tools also include sound enrichment devices, sound generation pillows, as well as sound generators like MP3 and relaxing music.
Are there different levels at which practices can participate, or should every hearing care practice seek to have a full-service tinnitus treatment plan?
They can also provide informational counseling and supplement their fittings with hearing instruments that include features and options for tinnitus relief. My recommendation would be to offer as many options as possible within the means of the practice and the practitioner. Collaboration with other professionals like ENTs, psychologists, and general practitioners is helpful.
Prior to the consultation, patients can fill out questionnaires in the waiting room to avoid external influences during the test.
While proper diagnostic testing and quantification measures should be performed for hearing and tinnitus aspects, the treatment options will vary greatly based on the individual and should focus on addressing identifiable needs. Tinnitus can be viewed as a spectrum disorder where trying a combination of approaches may be necessary. Highlighted in magnifying glass on lower left is the electronic questionnaires for the TFI, THI, and Tinnitus and Hearing Survey (THS), which saves in NOAH and eliminates the need for paper records. Clinicians should ensure they are working with a subjective tinnitus and characterization via the existing questionnaires, like the Tinnitus Handicap Inventory (THI), Tinnitus Functional Index (TFI), and Tinnitus Handicap Questionnaire (THQ). Testing efficiency and immediate availability of measurement results allow more time for consultation. Test results will provide the professional with information concerning the effect of an external sound on the tinnitus. A high-resolution audiometer in frequency (1 Hz) and intensity (1 dB) is required to perform a characterization of the tinnitus. Today’s clinicians and audiologists can now more effectively evaluate the tinnitus and its impact on the lives of their patients. The relationship of perceived severity of tinnitus with depression, anxiety, hearing status, age and gender in individuals with tinnitus. An attempt was also made to see if any relationship exists between the perceived tinnitus severity and the age, gender or hearing status of the sufferer.


After the routine pure tone audiometry, each participant completed the Tinnitus Handicap Inventory, the State-Trait Anxiety Inventory and the Inventory of Depressive Symptomatology-Self Report-30. Further, perceived severity of tinnitus is not influenced by age, gender and hearing status of the individual. Subjective tinnitus is found to be present in about 85% of the individuals seeking help from an Otologist2. Hiller & Goebel5 showed that the most common associated otologic condition was subjective hearing loss, followed by vertigo or dizziness and hyperacusis.
Both chronic pain and tinnitus are subjective, invisible symptoms which only the patient can experience. Hence, self-report measures are the standard means of determining severity of tinnitus-related distress. In comparison to 14 control individuals presenting with hearing loss but no tinnitus, Harrop-Griffiths et al.15 found tinnitus individuals to have a greater lifetime prevalence of major depression than the controls (62% vs. Various authors have found that the majority of tinnitus individuals have some degree of hearing loss21,24,25.
Further, a more significant difference is reported between men and women with 12% of men over age 65 reporting tinnitus, compared with 7% of women (National Center for Health Statistics, 1960-1962). In this context, the present study examined the relation between the tinnitus severity, depressive and anxiety symptoms. Pure-tone thresholds were obtained at octave intervals between 250 Hz and 8000 Hz for air conduction and between 250 Hz and 4000 Hz for bone conduction using the modified Hughson-Westlake procedure28. State anxiety has been defined as an unpleasant emotional response while coping with threatening or dangerous situations32, which includes cognitive appraisal of threat as a precursor for its appearance33.
For each item on the inventory, the participants were instructed to respond with "yes" (4 points), "sometimes" (2 points), or "no" (0 point). Distribution of participants according to Tinnitus Handicap Inventory (THI) and Inventory for Depressive Symptomatology (IDS). The large standard deviations associated with all three handicap measures show that reactions to tinnitus varied among individuals. This finding shows that the tinnitus may be noticed even in the presence of background or environmental noise, although daily activities may still be performed and it frequently interferes with sleep and quiet activities35. Spielberger et al.34 characterized trait anxiety as a general disposition to experience transient states of anxiety, suggesting that these two constructs are interrelated. This shows that the presence of depressive symptoms also indicated the presence of anxiety conditions, and this is consistent with the hypothesis of a learned helplessness phenomenon39. Pinto et al.40 also found similar results in a group of 68 individuals with tinnitus in the age range of 24 to 83 years using the THI.
Baskill & Coles43 suggested that the influence of hearing loss on the severity of tinnitus remains uncertain; they found that the auditory thresholds and perceived severity of tinnitus were poorly correlated. The results support the existence of a significant relation between the perceived severity of tinnitus and reported anxiety and depressive symptoms manifesting in the form of a vicious cycle. Department of Speech & Hearing - Manipal College of Allied Health Sciences - Manipal - AC - India. Department of Clinical Psychology - Manipal College of Allied Health Sciences - Manipal - India.
This hypothesis has been investigated with single-photon emission computed tomography using the benzodiazepine radioligand 123I Iomazenil.
An abnormal γ-aminobutyric acid-A benzodiazepine receptor density may be an objective neurochemical measure of the severity of a central-type tinnitus and a rationale for treatment. The pathophysiology of tinnitus is inadequately understood, although alterations in normal GABAergic function have been implicated in patients with the symptom of a predominantly central, subjective, idiopathic tinnitus of the severe, disabling type, in part due to the observation of a lessening of the symptom while the patient is on γ-aminobutyric acid-active (GABA-A) benzodiazepine medications. The studies demonstrated the feasibility of quantifying receptor binding with SPECT [20-23]. Each patient reported that his or her subjective idiopathic tinnitus was severe and disabling and had been problematic for longer than 1 year. Psychiatric consultation and treatment for anxiety or depression were ongoing for each patient included in this study. Informed consent was signed before screening procedures were performed [JP Seibyl, personal communication, June 1999]. Before each injection, subjects were pretreated with stable iodine (10 drops of a saturated solution of potassium iodide) to reduce the uptake of 123I.
Visual analysis of the images was performed by two nuclear medicine physicians blinded to clinical information about patients. A one-time 120-rnillion-count (128 ? 128 matrix) extrinsic uniformity correction flood was acquired using 123I for SPECT reconstruction in a fillable phantom. Coregistered magnetic resonance images (top panel) and 123I Iomazenil single-photon emission tomographic images in chronic central tinnitus patient demon states diminished medial left temporal lobe density of benzodiazepine binding sites. Left-right homotypic brain ratios in six patients with severe, disabling central tinnitus undergoing 123I Iomazenil singlephoton emission tomographic image scanning.
Absolute percentage (ABS %) differences for selected homotypic brain regions based on the magnetic resonance imaging-derived regions of interest used in Figure 2. Control subjects (n = 12) were age-and gender-matched healthy subjects with no history of neurological or psychiatric illness based on physical examination and a history obtained by a research psychiatrist. Neurootological and neurological implications, including cerebrovascular disease, neurodegenerative disorders, dementia, and neuropsychiatric mood disorders, were suggested [26]. From 1989 through 1999, SPECT imaging of brain has been performed on 95 selected patients identified on the MATPP to have a predominantly central-type tinnitus. The stress diathesis model for depression explains the relationship between increasing levels of change in affect, highlighted by anxiety and depression, and increasing levels of cortisol. Theoretically, stress is considered to be a modulator for the final common pathway for tinnitus in the MTLS. The benzodiazepine receptor's role, particularly with respect to GABA-A and modulation of the GABA-A benzodiazepine receptor by cortisol (especially under stress), is considered to be significant in the clinical course of especially those patients affected by severe, disabling tinnitus [18]. SPECT imaging of brain with 123I Iomazenil has shown significant uptake of the radioligand in a distribution consistent with benzodiazepine receptor binding.
The high affinity of Iomazenil for the benzodiazepine receptor is considered to explain in part its high brain uptake and slow washout.
The preliminary findings of our report are considered, on both a basic scientific and a clinical level, to be a forerunner for clinical application of current knowledge about the GABA-glutamate neurotransmitter systems in attempting control of the symptom of predominantly central tinnitus. These results support the rationale of treating regional perfusion asymmetries, which reflects a neurochemical basis for tinnitus control directed at restoring homeostasis between the sensory and affect components of tinnitus, which are regulated by the GABA-A benzodiazepine receptor [41].
The concept of a final common pathway for tinnitus, which has evolved since 1983 from our clinical experiences with tinnitus, stems from observations that all patients with tinnitus, particularly those with the severe, disabling type, exhibit as a common denominator a disorder in affect [18]-that is, a behavioral disorder in response to and as an accompaniment of an aberrant auditory sensory stimulus.
SPECT or positron emission tomography of brain (or both) provide an opportunity to establish a relationship between the clinical manifestations of tinnitus and specific chemical and receptor abnormalities in the anatomic regions of interest. The positive effect of benzodiazepine therapy for tinnitus control is hypothesized to be the reestablishment of a benzodiazepine level sufficient to allow normal processing and development of affect, expressed clinically as a restoration of a normal mood with elimination or control of fear, anxiety, or depression. This is consistent with the original hypothesis of a final common pathway for tinnitus, which implicated GABAergic mechanisms in the pathophysiology of some clinical types of tinnitus. During aging, sustained stress, and in some neuropsychiatric disorders, glucocorticoid secretion is interrupted. Recent work has shown that N-methyl-Daspartate (NMDA) receptor blockade is also affected in preventing stress-induced dendritic atrophy [48]. Are the findings of diminished benzodiazepinebinding sites reflective of or influenced by prior use of anxiolytic or antidepressant medications? The differential effects of the various drugs may be due to the binding characteristics of the drug in question and to site specificity. The effects of chronic benzodiazepine administration on the GABA-A receptor may be both region-specific and receptor subtypespecific. Are the findings of diminished benzodiazepinebinding sites specific for the symptom of tinnitus or reflective of the behavioral (i.e., affective) component of the symptom of tinnitus? Is the finding of diminished benzodiazepine-binding sites clinically specific for the sensory component of tinnitus, with an associated interference in affect?
This finding warrants consideration with respect to the relief of the sensory component of tinnitus that is reported after benzodiazepine therapy. What is the neurochemical significance of the reduction of benzodiazepine-binding sites as demonstrated by the use of Iomazenil?
What is the role of neurosteroids on the benzodiazepine receptor, and specifically, on the binding affinity of Iomazenil reported in tinnitus patients in this study? What is the effect on the clinical course of tinnitus of prolonged occupancy of GABA-A receptors by such ligands as GABA and benzodiazepine agonists (a condition known as use-dependent regulation of GABA-A receptors)?
Both upregulation and downregulation of GABA-A receptors appear to represent use-dependent pathways for guiding synaptic plasticity in the vertebral central nervous system [61].
The underlying mechanism is not known, but a reduction in GABA synthesis might contribute to this behavioral tolerance [65]. The mechanism of GABA-A receptor uncoupling by benzodiazepines in vitro may be a permanent conformational change in existing receptors, production of an endogenous regulatory GABA-A receptor ligand, a change in phosphorylation, or a displacement of GABA-A receptor subunits. GABA increased benzodiazepine binding maximally 40% in cerebellum and medulla and at least 25% in the olfactory bulb [66].
Such tolerance is linked to losses in GABA-A receptor function and must be considered with respect to results currently reported [67]. GABA has a role not only as an inhibitory neurotransmitter but also as a neurotrophic agent-namely, acting as a signal for neuronal growth, differentiation, and synapse formation [68]. This practice has led to speculation that the trophic actions of GABA and NMDA may share a common calcium-based mechanism.
Chemical and metabolic labeling of GABA-A receptor polypeptides and tagging with high-affinity subunit-specific antibodies are planned in the future, to define and resolve remaining questions concerning up-and downregulation and use-dependent regulation of the GABA-A receptors in the tinnitus patient. What are the regional localization effects of various benzodiazepines (e.g., Klonopin versus alprazolam or lorazepam)? This is particularly true during chronic therapy with benzodiazepines that have active metabolites with a higher or lower affinity for benzodiazepine-binding sites than does the parent compound. Diminished benzodiazepine-binding sites in the medial temporal cortex are considered consistent with the hypothesis implicating GABAergic mechanisms in the pathophysiology of tinnitus. Preliminary results ofthis study recommend that a neurochemical or neuropharmacological approach toward tinnitus control include treatment directed at the GABA-A-benzodiazepine-chloride receptor. Tinnitus questionnaire was then administered, followed by the Kannada version of THI on 140 patients and total scores were obtained.
The diagnosis and rational management of tinnitus is one of the legacies of the past millennium, which the medical profession has carried unsolved to this century2. Initially, the self-assessment tool assesses the severity of symptoms and provides objective data about the severity of the symptomand later, the evaluation allows investigators to accurately assess and compare the pre-treatment and post-treatment periods. THI is a method of quantifying the impact that tinnitus has on an individual's daily living conditions. The translated form of the inventory was given to 50 native Kannada speakers who were exposed to Kannada language or had first language as Kannada, who were able to read and write Kannada, for the content validation. Individuals with any significant neurological history, history of psychiatric or psychological counseling with regard to their tinnitus were excluded from the study.
Under the functional subscale, 30% of responses were for YES and 50% of responses were for NO and 20% of responses were for SOMETIMES. 38% of patients fall under the category of mild, 26% of patients fall under the category of Moderate, and 16% fall under the category of severe and 6% fall under the category of catastrophic group which is represented in Graph 2. Also a comparative study was carried out between the English version of THI and the Kannada version of THI. The quality and intensity of tinnitus can affect daily routine of an individual which have an effect on the individual's psychological functioning7. The catastrophic aspect of Kannada THI allows identification of negative sensations produced by the tinnitus in the patient's lives such as intolerance, loss of control of the sensation.
The English version of THI is currently used by most of the audiologists and otorhinolaryngologist to find out the severity of the problem in different patient population and found to be difficult to administer on native speakers of Karnataka. The recruited subjects for this research presented changes in their Quality of Life (QL) as regards to the functional, emotional and catastrophic aspects due to tinnitus.
The functional neuroanatomy of tinnitus: evidence for limbic system links and neural plasticity. Validity of the Italian adaptation of the Tinnitus Handicap Inventory; focus on quality of life and psychological distress in tinnitus-sufferers. Brazilian Portuguese Language version of the "Tinnitus Handicap Inventory": validity and reproducibility. With this clinical foundation, few other health professionals are as well suited to help those with tinnitus. For example, the US Center for Health Statistics estimates that tinnitus was reported by 25% of those who are hearing impaired and have hearing loss. The hearing care professional needs to consider these issues if they want to succeed in managing the hearing loss on top of the tinnitus. However, it’s important to check the effect of the external sound on the tinnitus before introducing the benefits of wearing a hearing aid to the patient. Additionally, training from hearing instrument manufacturers and collaborating with colleagues can be valuable.
Then be sure to include information that the patient may benefit from—like additional options or resources not offered at your practice. It is important to consider that treating patients with tinnitus requires the ability to listen and a high degree of patience.
When testing patients with tinnitus, clinicians should consider scheduling a dedicated time just for consultation because it will take longer than usual and the patient is expecting a solution. For this, I would recommend using an analog visual scale of relief to set the objective from the very beginning.
When the patient becomes more comfortable describing their situation, the clinician should then begin to drive the conversation.
Then the follow-up treatment can be done online, where the answers provided previously can help clinicians evaluate the impact of this strategy. This may include education, information, or recommendations for further medical evaluation or treatment by other professionals. Psychoacoustical tests are also important and can include pitch and loudness matching and minimum masking level (MML). If there is a positive impact, like an attenuation of the perception, a strategy like the TRT (Tinnitus Retraining Therapy) can be considered.
It affects around 15% of the world population and this prevalence increases to 33% in individuals aged over 60 years3.
Sanchez6 studied the association between tinnitus and hearing loss and found that 85 to 90% of the individuals with tinnitus present some level of hearing loss and only 4 to 8% present normal hearing sensitivity.
Also, in both there is a constant, aversive stimulation which can dominate the sufferer's thoughts and lifestyle, causing a significant interference with daily functioning. Vernon & Meikle26 reported that 70% to 80% of their tinnitus individuals have "significant hearing difficulties". Also, an attempt was made to see if there was any relation between hearing status, age and gender with the participants' tinnitus severity, depressive and anxiety symptoms. Participant has to select from the four options for each of the 30 items based on his past 7 days experience.
Trait anxiety refers to stable individual differences in a tendency to respond with an increase in state anxiety while anticipating a threatening situation. 20% of the participants showed no signs of depression whereas 32%, 34% and 14% of them showed mild, moderate and severe depressive symptoms respectively. Further, the observed wide range of scores demonstrates that the sample was heterogeneous with respect to self-perceived tinnitus handicap.
No correlation between age and gender with the annoyance of tinnitus has also been reported by Meric et al.41 Various studies5,42 have also shown controversial results regarding the effect of age and gender on tinnitus annoyance. Savastano44 using THI found that more severe hearing loss did not correlate with the severity of bothersome tinnitus. The study also indicates the absence of relation between hearing status, age and gender with the perceived tinnitus severity. A multiple-baseline evaluation of the treatment of subjective tinnitus with relaxation training and biofeedback.
Guidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999. Psychometric adequacy of the Tinnitus Handicap Inventory (THI) for evaluating treatment outcome. Psychiatric disorders in tinnitus patients without severe hearing impairment: 24 month follow-up of patients at an audiological clinic. Psychopathological profile of tinnitus sufferers: evidence concerning the relationship between tinnitus features and impact on life.
Hearing disorders in the population: first phase findings of the MRC national study of hearing. Abnormal auditory mismatch response in tinnitus sufferers with high-frequency hearing loss is associated with subjective distress level. Clinical correlation with the history, clinical course of the patient, and stress questionnaire are presented. GABA, as measured by the GABA-A receptors, is the major inhibitory neurotransmitter of brain.
Kinetic and equilibrium methods provided adequate measures of regional total equilibrium distribution of 123I Iomazenil. Consent forms were discussed with each patient and included an invitation to participate, description of the project, description of procedures, explanations of risks and inconveniences, benefits, economic considerations, confidentiality, coverage in case of injury, and the voluntary nature of participation. Subjects had five external plastic fiducial markers containing 1 to 4 µCi of 99mTc affixed along the canthomeatal line for post hoc realignment of the SPECT images. Regions of interest were drawn using an identical circular region of interest (1,467 mm3) in standardized locations in the hippocampus, frontal lobes, thalamus, cerebellum, and frontal region. Assuming the leftright asymmetry as the a priori control region, ratios for superior temporal gyri were significantly more asymmetrical relative to frontal lobes (p =.0411, twotailed).
Nonparametric statistical assessment demonstrates significantly greater left-right asymmetry in the superior temporal lobe relative to the frontal control region (p = .0411, two-tailed).
Using a standard statistical software package-SPM-the mean and standard deviations of each pixel coordinate of the case and control groups were calculated and, subsequently, a paired Student's t-test was performed in which each pixel coordinate of the cases was compared to each pixel coordinate of the controls. SPECT of brain with the radioisotope 99Tc-HMPAO identified persistent sideto-side perfusion asymmetries highlighted by the amygdala hippocampal complex of the MTLS [1,4,27,28, 29,30]. Theoretically, blockage of GABA-mediated inhibition results in tinnitogenesis, an epileptiform auditory phenomenon [4,26]. In general, Klonopintreated tinnitus patients emphasized that primarily the affect component of the tinnitus symptom was influenced:That is, they reported improved sleep, an increased ability to "cope" with tinnitus, and occasional reduction in tinnitus intensity. The resultant hypercortisolemia acts on the hypothalamic-pituitary axis, though recent reports suggest that the site of the hypocortisolemia lesion, with a consequent increase in anxiety and depression, is not the hypothalamus but the hippocampus, which is part of the MTLS [15-17,35-37].
It is proposed that for the tinnitus patient, a cycle is established wherein reciprocal projections among hippocampus, amygdala, entorhinal cortex, and hypothalamus vary in the degree of control of cortisol levels that arise during stress and have a resultant influence on the sensory and affect components of tinnitus. In the study, which measured the whole-body distribution of activity after intravenous administration of 123I Iomazenil, evaluation of organ irradiation confirmed that 123I Iomazenil has favorable in vivo imaging characteristics and that this agent may be useful in assessing disease states in which the function of benzodiazepine GABAA receptors is abnormal. Our study allowed the measurement of free parent compound in plasma and examination of the kinetics and clearance of 123I Iomazenil in human and nonhuman primates. Our study provides a preliminary, partial understanding of the complex mechanisms underlying the production of different types and subtypes of predominantly central tinnitus.
Clinical neuroscientific reports have identified the MTLS's central role in memory, emotion, and behavior [14,43]. Specifically, when a benzodiazepine is administered to tinnitus patients, the reported tinnitus relief experienced is thought to reflect neurochemical replacement of the deficient benzodiazepine receptor. It has been reported that the benzodiazepine receptor exerts its effect by attaching to the GABA-A receptor.
One of the most important brain areas responding to circulating adrenal steroids is the hippocampal formation, which contains high concentrations of adrenal steroid receptors [45,47]. A consequence of glucocorticoid excess is damage to certain neurons in the brain, particularly those in the area of the hippocampus; this has been demonstrated by aging the rat [35].
Cortisol or stress may alter CA3 neuronal atrophy by regulating GABAergic synaptic inhibition. This finding supports the hypothesis that GABAergic neurochemical mechanisms playa role in the classic course of tinnitus, particularly of the severe, disabling type. SPECT brain imaging studies of healthy subjects conducted with Iomazenil demonstrate very minimal effects of alprazolam on brain measurements [49].
Finally, a particular benzodiazepine may affect another neurotransmitter system with indirect effects on the GABA functions of the GABA-A complex. All patients with idiopathic, severe, disabling tinnitus not only are adversely influenced by stress but have a significant alteration in affect manifested by changes in emotion, fear, anxiety, and depression [53]. In the original hypothesis of the final common pathway for tinnitus, a homeostasis in the normal patient between the sensory component and affect was considered to be modulated by stress. The study indicated that changes in patterns of inhibition as well as adjustments in patterns of excitation can contribute to adaptive plasticity in the central nervous system, as has been demonstrated in the external nucleus of the inferior colliculus. Possibly, the reduction shown on brain SPECT using 123I Iomazenil does, in fact, reflect an actual reduction in the total number of binding sites. Discussions of steroid activity as a modulator for the benzodiazepine-GABA-A-chloride receptor have centered primarily around cortisol, its production and regulation. McEwen et al.[46,56] provided evidence that steroids can influence neuronal excitability and that some endogenous neurosteroids may playa role in the regulation of central nervous system excitability.
Prolonged treatment (>24 hr) of cortical cultures with GABA induces an uncoupling of ligand binding sites on the GABA-A receptor as well as a reduction in site density. Animals exposed to GABAmimetic drugs exhibit an inconsistent pattern of effects on the GABA-A receptor. These results support the hypothesis that a functional uncoupling of the benzodiazepine recognition site from the GABA receptor in cortex, but not from the ion recognition site, may playa role in tolerance development. The benzodiazepines' hypnotic, anxiolytic, and anticonvulsant effects are revealed with development of tolerance after prolonged exposure to the drugs in both animals and humans. GABA-A-evoked upregulation of the GABA-A receptor observed in cultured cerebellum granule cells is contrasted with downregulations of cerebellar receptors observed in vivo. Such investigations will provide answers to basic scientific questions about synthesis, assembly, and disassembly of GABA receptor subunits but also will enhance our understanding of the mechanisms behind GABA ligand-evoked actions in different clinical types and SUbtypes of predominantly central tinnitus. The data suggest that the effects of chronic benzodiazepine administration on the GABAA receptor may be region-specific and receptor subtypespecific. Type II receptors are concentrated in the hippocampus, specifically the dentate gyrus and portions of the basal ganglia [72]. A reduction in the number of benzodiazepine-binding sites in the medial temporal lobe cortex of tinnitus patients being studied supports the clinical recommendation for a trial of benzodiazepine therapy in attempting to control the affect component of tinnitus. Neurospect Cerebral Blood Flow Studies in Patients with a Central Type Tinnitus:Preliminary Study. Neurotransmitter receptor alterations in Huntington's disease:Autoradiographic and homogenate studies with special reference to benzodiazepine receptor complexes. Increased GABA receptor binding in superficial layers of cingulate cortex in schizophrenics. Reduced [3HJflunitrazepam binding in cingulate cortex and hippocampus of postmortem schizophrenic brains:Is selective loss of glutamatergic neurons associated with major psychoses? Effects of antidepressants and a benzodiazepine on the dendritic structure of CA3 pyramidal neurons after chronic stress. Pharmacokinetics of the SPECT benzodiazepine receptor radioligand (I-123) Iomazenil in human and nonhuman primates.


Human biodistribution and dosimetry of the SPECT benzodiazepine receptor radioligand iodine 123-Iomazenil. SPECT measurements of benzodiazepine receptors in human brain with Iodine 123-Iomazenil:Kinetic and equilibrium paradigms. Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Uptake of corticosterone by the rat brain and its concentration in certain limbic structures. Subtypes of gamma-aminobutyric acid A receptors; classification on the basis of subunit structure and receptor function. Neuroprotective drug therapy: A medical and pharmacological treatment for tinnitus control. Stress and the Brain: A Paradoxical Role for Adrenal Steroids in Vitamins and Hormones, vol 51. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons:Involvement of glucocorticoid secretion and excitatory amino acid receptors.
A phase 3 clinical trial of 1-123 Iomazenil, a new central-type benzodiazepine receptor imaging agent:2.
Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABA-A receptor function. Chronic neurosteroid treatment produces functional heterologous uncoupling at the gammaaminobutyric acid-Albenzodiazepine receptor complex in mammalian cortical neurons. Stressinduced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. GABAA receptor alpha 4 subunit suppression prevents withdrawal properties of an endogenous steroid.
Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis.
Gammaaminobutyric acid, receptor regulation in culture:Altered allosteric interactions following prolonged exposure to benzodiazepines, barbiturates, and methylxanthines.
Chronic GABA exposure downregulates GABA benzodiazepine receptor-ionophore complex in cultured cerebral cortical neurons. Development of tolerance to anti-convulsant effect of GABAmimetic drugs in genetically epilepsy prone gerbils.
Biochemical and electrophysiological mechanisms underlying benzodiazepine tolerance and dependence. GABA receptor subunit polypeptides increase in parallel but exhibit distinct distributions in the developing rat cerebellum. Binding of benzodiazepines and some major metabolites at their sites in normal human frontal cortex in vitro.
Benzodiazepine receptor binding of triazolobenzodiazepine in vivo:Increased receptor number with low-dose alprazolam.
The THI was developed by the British Association of Otolaryngologist, Head and Neck surgeons, which consists of 50 questions6. The speakers were given a five-point rating scale to grade the items from very familiar to non-familiar.
A score of 4 was given for YES and a score of 0 was given for NO and a score of 2 was given for SOMETIMES. The overall Cronbach alpha score of both the THI versions and the individual scores for all the three subscales in both the versions were compared. From the current study, it is clear that the Kannada version of THI is readily available, easy to understand and is a reliable tool for measuring the handicap occurring due to tinnitus. Good tinnitus resources are needed in every community to bring new exposure and business to your office. The Tinnitus Clinic at Oregon Health and Science University found that 90% of their patients who have tinnitus also have some degree of hearing loss.
If the patient can accept a sound generating strategy, many hearing instrument manufacturers deliver interesting solutions today—with or without an amplifier for the hearing loss.
Approximately 20% of tinnitus individuals experience the disorder to a degree that their quality of well-being and productivity are impaired4. Psychological reactions and negative associations can exacerbate the condition and, in effect, amplify the perception of tinnitus resulting in subsequent anxiety, depression, and other somatic complaints8,10. Folmer et al.17 found that tinnitus individuals with current depression scored significantly higher than individuals without depression on all 12 questions relating to tinnitus severity.
But, the relation between the hearing status and the handicap experienced due to tinnitus has not been reported in any of these studies. The findings of the study would help in understanding the degree of tinnitus and its influence on psychological status of an individual and further developing an appropriate counseling tool in tinnitus management.
Participants with a pure-tone threshold of less than or equal to 25 dB29 HL were considered as having normal hearing sensitivity. Form Y of STAI34 was utilized for the present study to assess the presence or absence of state and trait-anxiety in individuals with tinnitus. Depending on the total score the handicap caused by tinnitus could be identified as slight, mild, moderate, severe and catastrophic35.
To study the relationship of the perceived severity of tinnitus with depression, anxiety and age Pearson's product moment correlation was carried out.
However, a direct comparison of the results of these studies cannot be made as the assessment tools used differ from one study to another. Diverging from our findings, Coles45 found that individuals with mild hearing loss were mildly bothered and severe to profound hearing loss individuals severely bothered by tinnitus. Relationship of tinnitus questionnaires to depressive symptoms, quality of well-being, and internal focus. The SPECT results were considered to compare favorably with positron emission tomography measurements of benzodiazepine receptors in terms of absolute values and identifiability of parameters. Next, subjects were injected with 8 to 10 cm of 123I Iomazenil administered as a bolus plus constant infusion over approximately 6 hours using previously published methods. All subjects had an MRI scan for coregistration with the SPECT images and accurate region-of-interest placement. On the basis of visual analysis, other brain regions, including other cortical regions and cerebellum, did not demonstrate clear relative changes in Iomazenil uptake.
Areas with significantly increased or decreased activity in controls as compared to case subjects were displayed on an SPM brain map.
Adjacent perfusion asymmetries involving the frontal, temporal, and parietal lobes suggested an interneuronal network that could result in the transition of the sensory to the affect components of the symptom of tinnitus.
The patients selected for this study demonstrated no evidence of central nervous system disease either by clinical history or physical examination.
The Alprazolam-treated tinnitus patients reported reduction in tinnitus, improvement in affect, and occasional hearing improvement [32].
Variations in control of cortisol levels result in further strengthening of an already established paradoxical memory, with additional negative affect behavioral manifestations of mood, fear, anxiety, depression, and the like.
123I Iomazenil is cleared from human and nonhuman primate arterial plasma in a triexponential manner. It also attempts to develop a neuropharmacology for control of different clinical types and subtypes of tinnitus.
Neurontin, an anticonvulsant, is structurally related to the neurotransmitter GABA but does not interact with GABA receptors if it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation [42]. Such reports likely are related to the SPECT findings of significant perfusion asymmetries in our tinnitus patients. In situ radioactive tracers are hypothesized to serve as biochemical markers in tinnitus studies and to have the potential for providing direction for drug development and treatment application to alter the tinnitus symptom or disease process. Steroid receptors are known to modulate GABA-A activity, whereas stress is known to be intermittently involved in cortisol steroid benzodiazepine activity (36,37,47-49). It appears that cortisol may alter the excitability of hippocampal neurons via regulation of GABA-A receptor expression. In contrast, previous SPECT brain imaging studies conducted with 1231 Iomazenil in a limited number of patients affected with panic disorder and depression suggest decreases in the frontal and parietal lobes [50]. A combination of drugs for tinnitus relief may differentially affect the GABA-A receptor subunit's gene expression. Receptor alterations induced by lorazepam occurred in cortex, hypothalamus, and hippocampus, whereas alterations associated with alprazolam occurred in cortex and hypothalamus only. All patients in our study were adversely influenced by stress and also were being treated by psychiatrists for anxiety or depression. The plasticity of auditory spatial representation in the owl brain has been shown to depend not only on new excitatory connections but on the persistence of old connections mediated by inhibition. However, it also is possible that the change reflects the binding affinity of the benzodiazepine receptor for Iomazenil. Chronic neurosteroid treatment produces functional heterologous uncoupling at the GABA-A-benzodiazepine receptor complex in mammalian cortical neurons [57].
The GABA-A receptor is the major transducer of rapid inhibitory transmission in the vertebrate central nervous system. Such inconsistencies may be due to the high levels of endogenous GABA in the brain and low permeability of the blood-brain barrier to GABA and specific GABA-A agonists.
In vitro studies must be directed to identifying the role of endogenous GABA in benzodiazepine-evoked downregulation of GABA activity. Changes in coupling may represent a common mechanism by which chronic benzodiazepine treatment can alter interactions at the macromolecular complex, resulting in benzodiazepine tolerance [66]. Losses in GABA-A receptor function have been linked to a substantial number of cases of benzodiazepine tolerance.
A functional pentamerous GABA-A receptor is formed by coassembly of subunits selected from the family of 16 genes. Our study demonstrated, on a molecular level, a deficiency in GABAergic activity predominantly in the MTLS and cerebellum of brain in all six patients. Presented at the Twenty-Fifth Congress of the Neurootological and Equilibriometric Society, Bad Kissingen, Germany, March 19, 1998. Presented at Charles University Tinnitus Symposium, Prague, Czech Republic, January 17, 1995. Report on clinical usefulness in diagnosis of degenerative neurological diseases and mental disorders. Later, a modified beta version with 25 questions was developed by Newman et al.5 which is in the form of a self-assessment report that a person suffering from the condition can fill in.
In such circumstance administering these inventories becomes difficult and sometimes impossible too. Later, all the 50 filled inventories were assessed to find out if all the words and the meaning of the questions were understood by the Kannada speakers. Once the subject finished rating the questions, they were grouped under 5 categories based on the severity that is Slight, Mild, Moderate, Severe and Catastrophic.
For example, a clinician may have to wait for the patient to fall asleep using a sound generator pillow. Several studies7,11,12 ave also found that individuals with tinnitus were more socially withdrawn, reactive to stress, alienated, emotionally disturbed and less self-controlled.
Stephens & Hallam16 also found elevations on the anxiety and depression scales of the Crown-Crisp Experiential Index for individuals suffering from tinnitus.
Participants then completed both the distress and the tinnitus severity measures which are described below.
Based on the total score, which ranges from 0 to 84, the severity of depressive symptoms can be profiled as mild, moderate, severe and very severe. Nonparametric Mann-Whitney test was carried out to study the relation between perceived severity of tinnitus with gender and hearing status. The results support the view that there is a connection between tinnitus and psychiatric disorders.
Similar findings have also been reported by Crocetti et al.38 This attracts a heightened concern in the Indian context as there are no adequate tinnitus specialty clinics for detailed assessment and providing treatment with a systematic approach such as tinnitus retraining therapy. Weisz et al.46 suggested that increasing hearing loss was associated with absence from work due to tinnitus. Abnormalities of these central benzodiazepine receptors have previously been identified in neuropsychiatric conditions including epilepsy [5-7], Alzheimer's disease [8], Huntington's chorea [9-11], schizophrenia [12-14], and stress [15-17].
Each patient completed a medical-audiological tinnitus patient protocol (MATPP) in an attempt to establish an accurate tinnitus diagnosis [24]. The purpose of the constant infusion was to obtain an equilibrium-binding condition at the brain benzodiazepine receptor.
Using the count density data derived from these regions, a left-right asymmetry ratio was developed for each region.
Subcortical structures, including basal ganglia and thalamic nuclei, showed low uptake consistent with the known lower density of benzodiazepine-binding sites in these regions. Results of gadolinium-enhanced MRI studies of brain in all patients were reportedly negative. The radioactivity detected in the various regions of brain was almost exclusively 123I Iomazenil. Because the method used is continuous infusion, the effects of regional heterogeneity of blood flow are eliminated.
This hypothesis formed the basis for this study, which attempts to establish the role of GABAergic mechanisms in the pathophysiology of tinnitus and to explain the significant efficacy of benzodiazepine therapy, which has been reported clinically to provide tinnitus relief. In the future, the question of whether corticosteroid effects on neuronal morphology involve changes in the number of pharmacological properties of the GABA-A receptors needs to be examined [M Orchinik, NG Weiland, BS McEwen, unpublished observations, 1995]. A possible mechanism for this discrepancy is the differential effects of the two drugs on benzodiazepine receptor subtypes [51]. Future investigation is planned to identify whether the findings in this study are specific for the underlying tinnitus sensory component and the behavioral affect response to tinnitus or for the affect response accompanying stress or for stress in general.
By combining and overlaying different plasticity mechanisms, one of which is the GABA-A receptor in the auditory pathway, particularly at the external nucleus of the inferior colliculus, the owl was found to be able to adjust its various sensory maps so that they remain in harmony:For example, homeostasis is regulated by the GABA-A receptor mechanism.
Alternatively, the results reported in this study might reflect an overall reduction in sensitivity to glutamate. Significant are metabolites of progesterone and dioxycorticosteroid, which are found in both cerebral cortex and hypothalamus.
GABA-A contains binding sites for a number of anxiolytic and hypnotic drugs including benzodiazepine, barbiturates, and neurosteroids. The downregulation of ligand binding and chloride flux can be prevented by GABAA antagonists. Data indicate that normal GABA-A receptor functions decline during prolonged exposures to GABA in vivo. The in vivo finding that benzodiazepineevoked GABA-A receptor downregulation produced inconsistent results is significant [67]. Also, endogenous GABA present in the granule cells in the embryonic cerebellum may be bathed in significant quantities of GABA, and the addition of GABA to cultures may restore this environment. Substantial neurochemical evidence exists to support the concept of multiple benzodiazepine receptors [70]. Different subunits are responsible for sedativemotor effects, whereas other subtypes are primarily responsible for anxiolytic activity [40].
It was concluded that the decrease of benzodiazepine receptor densities may be a major mechanism for tolerance development in humans. The self report has been developed subsequent to previous studies that have thrown up reliable data that can be used to classify tinnitus into different grades according to the degree to which the tinnitus has affected a subject.
As this inventory quantified the alterations of the daily life of an individual due to tinnitus and due to the non capability of multilingual Speech & Hearing professionals to translate accurately the English version of THI to the regional languages and to avoid communication interpretation, there is a need to develop and standardize the Tinnitus Handicap Inventory in Indian languages. The questions which were rated as 1 or 2 were selected for the inventory and any questions with ratings over 3 were re-framed according to the familiarity of the speakers.
All the participants underwent assessment by an otorhinolaryngologist and complete audiological evaluation prior to the administration of the inventory.
Study by Makar et al.13 found a significant correlation between the tinnitus severity and sleep disturbances, depression and anger. In a study by Folmer et al.17, 160 participants with tinnitus completed the State-Trait Anxiety Inventory (STAI) and an abbreviated version of the Beck Depression Inventory (aBDI). The participants were instructed to respond on a 4 point rating scale to indicate his feeling at the time of evaluation and general feeling on the state and trait evaluation questionnaires respectively.
Hallam et al.47 opined that adjustment to tinnitus does not closely relate to the severity of the condition.
In addition, significant deterioration in normal affective functioning is a key feature of severe tinnitus patients and manifest by increasing difficulties with emotional regulation, anxiety, stress, depression, and fear. All reported a bilateral tinnitus that was more intense in one ear than the other (see Table 1). Under such conditions, analysis of the SPECT signal provided an outcome measure linearly related to the density of benzodiazepine receptors, unaffected by brain blood flow effects on the delivery of tracer to brain binding sites. In addition, the absolute percentage difference for either the right or left homotypic regions was determined. These results led the authors to believe that a final common pathway exists for all patients with tinnitus, particularly tinnitus of the severe, disabling type, which we have studied. Our goal was to provide clinical justification for benzodiazepine therapy in tinnitus patients and to attempt to understand the underlying mechanisms involved in the reported improvement in affect or tinnitus intensity. Increasing evidence supports an increased occurrence and severity of disease processes with stress, the focus being on alterations in the hippocampus [15-17,45-48].
After chronic diazepam use, regional specificity for GABA-dependent chloride uptake has been identified in the cortex but not the cerebellum [52]. Whether exogenous steroid in a tinnitus patient worsens the condition has not yet been determined.
The elevated levels of these two neurosteroids have been reported to be of sufficient strength to modulate GABA receptors [15,58-60].
Both the synthesis and degradation of GABA-A receptors appear to play roles in GABA-Ainduced downregulation.
What is significant is that an uncoupling of GABA-A receptors is induced by prolonged treatment of cortical cultures. Significantly, the cerebellum has been identified as an area of unique sensitivity to GABA-evoked downregulation in vivo [65]. Such variations have been attributed to differences in drug, treatment protocol, and tissue sampling after treatment. It is likely that several GABA-A receptors exist with different benzodiazepine-binding characteristics and that these subtypes have different regional specificities.
The affinities of different benzodiazepines for their receptors are considered significant if one is to understand the drugs' clinical pharmacology and their application for tinnitus therapy. A small but significant decrease of receptor densities (10%) has been reported during chronic alprazolam administration. THI consists of 25 questions under the 3 sub-scales of emotional, functional and catastrophic.
The self-rated tinnitus severity was found to be highly correlated with individuals degree of sleep disturbance, STAI, and aBDI scores. It was also made sure that the participants did not have any previously diagnosed psychological problems prior to the onset of tinnitus through informal questioning. Budd & Pugh48 concluded that tinnitus sufferers adopt different and identifiable coping styles for dealing with their tinnitus irrespective of their peripheral hearing status.
A specific abnormality of benzodiazepine function is hypothesized to exist in the medial temporal lobe system (MTLS) of brain in severe central tinnitus, as it is this area that influences sensory or affect transformation [18,19]. Three reported that the symptom was not confined to their ears but also was located in the head. SPECT images were acquired on the PICKER PRISM 3000XP camera (Marconi Medical, Cleveland, OH). Both left-right homotypic ratios and absolute percentage difference statistical comparisons between brain regions and frontal control were assessed using nonparametric statistics (Mann-Whitney U test). Within the final common pathway, the amygdalahippocampus structures of the MTLS are particularly critical in the development of what we believe is a paradoxical auditory memory [28-30].
Prolonged occupancy of GABA-A receptors by GABA or other ligands produces a series of control mechanisms collectively termed use-dependent regulation. Use-dependent receptor sequestration, degradation, and alterations in gene expression may be physiologically important in the tinnitus patient, separate from total uptake or total number of GABA-A receptors identified in this study. Clinical and animal data suggest that the duration of pharmacodynamic action of benzodiazepines correlates with the affinity of these drugs for their specific binding sites.
The THI beta version is one of the best and most standardized tinnitus measuring tools and has got a good reliability, validity and a good internal consistency to administer on tinnitus patients. The authors concluded that the severity of chronic tinnitus is correlated with the severity of insomnia, anxiety, and depression. Their findings explain for the absence of correlation between the annoyance due o tinnitus and hearing status of the sufferer.
The masking curves were consistent with a predominantly central tinnitus (N = 5) (see Table 1). GABA-A receptors are heterooligometric proteins that belong to a superfamily of ligand-gated ion channels, which include the nicotinic acetylcholine receptor, glycine receptor, and 5-hydroxytryptamine receptor. Although a decrease of receptor densities and the development of tolerance were detected, the time courses of these events differed, and correlations between changes in the receptor during a state of tolerance in individual subjects were poor. A gadolinium-enhanced magnetic resonance imaging (MRI) scan of brain and SPECT imaging of brain with technetium 99m hexamethyl propylenearnine oxine (99Tc-HMPAO) had been performed in the past and revealed perfusion asymmetries. Molecular cloning has revealed diverse subunits for GABA-A receptors, which are grouped into four major classes:alpha, beta, gamma, and lambda. These discrepancies indicate that the decrease of the receptor densities may be only one of several mechanisms involved in tolerance development.
The exact composition and subunit stoichiometry of GABA-A receptors in vivo has not yet been established. Animal studies have shown that low-dose alprazolam increased receptor densities [74] and motor activities [75], changes that were not detected with administration of other benzodiazepines [76]. All subjects had functional asymmetries on SPECT imaging of brain, highlighted by perfusion asymmetries in the MTLS.
GABA-A receptor phosphorylation represents a major form of modification that produces profound changes in receptor function. Such regulation includes mechanisms that have been subdivided into two distinct pathways:GABA-A receptor downregulation and GABA-A receptor upregulation.
Culture of cortical neurons treated with GABA-A or benzodiazepines opens the pathway for GABA-A receptor downregulation.
This includes desensitization, tachyphylaxis, sequestering endocytosis of subunit polypeptides, the uncoupling of allosteric interactions between GABA and benzodiazepine-binding sites with subunit polypeptide degradation, and repression of subunit gene expression. The end point of GABA-A receptor downregulation, a reduction in receptor number, is postulated to be established initially by degradation of the receptor protein and then to be maintained by a diminished level of de novo synthesis. Benzodiazepine treatment of many animal experimental preparations may elicit only desensitization, sequestration, or uncoupling, without a decline in receptor number. Components of the GABA-A receptor downregulation pathway can also be evoked by chronic administration of GABAmimetics, benzodiazepines, barbiturates, and neurosteroids in animals.
Such downregulation correlates with the establishment of tolerance to and physical dependence on pharmacological effects of these drugs, suggesting a cellular model for this behavior.



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