Search

Neuroinflammation is the central nervous system's response to: injury, infection, and abnormal neural activity. Inflammatory processes are known to mediate many diseases, and recently evidence indicates that neuroinflammation underlies hearing disorders such as presbyacusis, middle-ear disease, ototoxicity, noise-induced hearing loss, and tinnitus. This chapter provides a review of the role of neuroinflammation in the etiology and treatment of tinnitus. Specifically, our research team has demonstrated that both tumor necrosis factor alpha (TNF-α) and calpain signaling pathways are involved in noise-induced tinnitus and that blocking them yielded therapeutic effects on tinnitus. Other efforts such as controlling acute inflammatory response via specialized pro-resolving mediators may help provide insight into preventing and treating tinnitus-related inflammatory processes.

This volume has highlighted the many recent advances in tinnitus theory, models, diagnostics, therapies, and therapeutics. But tinnitus knowledge is far from complete. In this chapter, contributors to the Behavioral Neuroscience of Tinnitus consider emerging topics and areas of research needed in light of recent findings. New research avenues and methods to explore are discussed. Issues pertaining to current assessment, treatment, and research methods are outlined, along with recommendations on new avenues to explore with research.

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-syn by proteases such as calpain may have a role. Therefore, inhibition of calpain may be of value. The main objective of this study was to evaluate the effects of systemically administered novel low molecular weight calpain inhibitors on α-syn pathology in a transgenic mouse model. For this purpose, non-tg and α-syn tg mice received the calpain inhibitors - Gabadur, Neurodur or a vehicle, twice a day for 30 days. Immunocytochemical analysis showed a 60% reduction in α-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus α-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in α-spectrin breakdown products (SBDPs) SBDPs with Gabadur and 63% reduction using Neurodur. There was a 65% reduction in the active calpain form with Gabadur and a 45% reduction with Neurodur. Moreover, treatment with calpain inhibitors improved activity performance of the α-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies.

One aspect of secondary injury in traumatic brain injury is the marked increase in intracellular calcium and resultant over-activation of the calcium-dependent neutral cysteine protease calpain. Gabadur is a novel protease inhibitor with calpain-inhibition properties formulated from the classic protease inhibitor leupeptin linked to a pregabalin carrier. This construction allows the entire compound to cross the blood-brain barrier after peripheral administration to better target the site of injury. In this study, a single intraperitoneal dose of Gabadur was administered immediately following controlled cortical impact injury in rats. Neocortical slices were examined at 48 h post-injury via Fluoro-Jade B staining, revealing an improvement in cortical neurodegeneration in Gabadur treated rats. Levels of detrimental active calpain-2 measured via western blot were also decreased in rats receiving Gabadur. This data supports the benefit of targeted protease inhibition in the treatment of traumatic brain injury.

The clinical significance of QEEG LORETA data analysis performed sequentially within 6 months is presented in a case report of a predominantly central type severe disabling subjective idiopathic tinnitus (SIT) before and following treatment. The QEEG LORETA data is reported as Z-scores of z = ± 2.54, p < 0.013. The focus is on demonstration of patterns of brain wave oscillations reflecting multiple brain functions in multiple ROIs in the presence of the tinnitus signal (SIT). The patterns of brain activity both high, middle and low frequencies are hypothesized to reflect connectivities within and between multiple neuronal networks in brain. The Loreta source localization non auditory ROI Images at the maximal abnormality in the very narrow band frequency spectra (24.21 Hz), showed the mathematically most probable underlying sources of the scalp recorded data to be greatest in the mid-cingulate, bilateral precuneus, cingulate and the bilateral caudate nucleus. Clinical correlation of the data with the history and course of the SIT is considered an objective demonstration of the affect, behavioral, and emotional component of the SIT. The correlation of the caudate activity, SIT as the traumatic event with the clinical course of PTSD, and the clinical diagnosis of PTSD is discussed. The clinical translation for patient care is highlighted in a SIT patient with multiple comorbidities by translation of QEEG/LORETA electrophysiologic data, as an adjunct to: provide an objectivity of patterns of brain wave activity in multiple regions of interest (ROIs) reflecting multiple brain functions, in response to and in the presence of the tinnitus signal, recorded from the scalp and analyzed with the metrics of absolute power, relative power, asymmetry, and coherence, for the subjective tinnitus complaint (SIT); 2) provide an increase in the accuracy of the tinnitus diagnosis; 3) assess/monitor treatment efficacy; 4) provide a rationale for selection of a combined tinnitus targeted therapy of behavioral, pharmacologic, sound therapy modalities of treatment attempting tinnitus relief; 5) provide insight into the medical significance of the SIT; 6) attempt discriminant function analysis for identification of a particular diagnostic clinical category of CNS neuropsychiatric disease; and 7) attempt to translate what is known of the neuroscience of sensation, brain function, QEEG/LORETA source localization, for the etiology and prognosis of the individual SIT patient.

The theme of the AAO-HNS Tinnitus Miniseminar, 09/23/2014, was “Tinnitus Lessons Learned from Combat and Service.” The speakers discussed their clinical experiences as well as lessons learned from combat and service for translation to tinnitus theory, basic science and clinical research, and tinnitus patient diagnosis and treatment. The program chairman and moderator was: - Michael E. Hoffer, M.D., F.A.C.S., Professor of Otolaryngology, Department Otolaryngology HNS, University of Miami

The tympanic membrane displacement test (TMDT) is an attempt to record intracranial pressure (ICP) reflective of an intracranial pulse pressure amplitude wave (IPPA) transmitted to the inner ear and tympanic membrane with a probe placed into the external ear canal. Twelve tinnitus patients, divided into two groups, who were resistant to attempts to achieve tinnitus control or relief were selected for the TMDT. The group 1 TMDT recordings were obtained on one session test date, and group 2 (n = 6) recordings were obtained sequentially on different session test dates. Patient selection with the medical audiologic tinnitus patient protocol (MATPP) identified all to have a nonpulsatile, predominantly central-type severe disabling subjective idiopathic tinnitus (SIT) resistant to attempts for tinnitus relief with instrumentation or medication. Associated complaints in all selected SIT patients included persistent ear blockage in the SIT ear, normal middle-ear function, controlled secondary endolymphatic hydrops in the SIT ear, sensorineural hearing loss of high frequency, hyperacusis, occasional vertigo, and central nervous system complaints of headache, head pressure, and cognitive interference in memory and/or speech expression. Clinical concern is for the presence of an increased ICP reflecting an idiopathic intracranial hypertension (IIH) which, if not identified and treated, may be a factor influencing the clinical course of this particular cohort of SIT patients, highlighted by persistent ear blockage and associated complaints as described.We set out to accomplish a number of goals: (1) To identify abnormal intracranial pulse pressure (IPPA ICP) with the extracranial TMD in a preselected particular cohort of SIT patients clinically suspected (by use of the MATPP) to have an abnormal ICP (i.e., IIH); (2) to identify the abnormal IPPA ICP as a positive indicator for IIH and as a factor - not an etiology - influencing the clinical course of SIT in a preselected cohort of SIT patients; (3) to identify with the TMDT in SIT patients spontaneous nonevoked recordings of intra-aural pressure and test-retest reliability of the TMDT; (4) to identify with the TMDT levels of normal and abnormal IPPA ICP in real time in the clinical course of SIT (i.e., an objective diagnostic and treatment monitor function of the TMD targeting ICP and IIH before and after treatment); (5) to attempt to establish a correlation of treatment efficacy, targeting preand post-ICP as a manifestation of IIH, with SIT subjective tinnitus relief; (6) to identify the limitations and complications of the TMDT; and (7) to share with the reader the evolution of a new science of brain pulsatility and a technology having a clinical application for otology and neurotology complaints of hearing loss, tinnitus, ear blockage, and vertigo. The results reported in the literature complement and alter conventional medical teaching focusing on brain pulsation, absolute intracranial pressure, and brain disease.The Southampton Tympanic Membrane Displacement Analyzer was used to record spontaneous intra-aural pressure waves in 12 SIT patients. Patients selected for the TMDT were divided into two groups: Group 1 (n = 6) recordings were obtained on one session test date, and group 2 (n = 6) recordings were obtained sequentially on different session test dates. Multiple recordings were attempted in all patients to identify test-retest reliability in both groups. An attempt for treatment and control of an elevated ICP with or without reduced cerebral compliance (CC) was recommended in 4 patients.With single and multiple recordings using the TMDT, the IPPA (i.e., ICP) was demonstrated to be abnormal and to fluctuate in the clinical course of 10 of the 12 predominantly central-type tinnitus patients (SIT): abnormal IIPA with reduced CC in 8 of 12 patients and normal IPPA with reduced compliance in 2 of 12. Tinnitus treatment results targeting ICP as a manifestation of IIH with Diamox were positive in the short term in 2 patients and incomplete in 3. The SIT relief is reflective of fluctuation in the ICP and the overall issue of multifactorial brain pulsatility.(1) The TMDT demonstrated repeated and consistent spontaneous nonevoked recordings of displacement of the tympanic membrane, reflective of intra-aural pressure, abnormal IPPA ICP in a preselected particular cohort of SIT patients clinically suspected to have an abnormal ICP (i.e., IIH). (2) Test-retest reliability of the TMDT was positive. (3) The results of the TMDT application for identification of an elevated ICP and reduced CC were positive in 10 of 12 particular preselected patients with nonpulsatile, predominantly central-type SIT resistant to attempts for tinnitus relief with instrumentation or medication. These positive findings support clinical and basic science investigations previously reported in the literature. (4) The clinical significance of these preliminary results of an elevated ICP in a particular cohort of SIT patients supports the clinical impression of the presence of an IIH and its influence on the clinical course and overall treatment of SIT. (5) A final conclusion as to the clinical significance of an elevated ICP and reduced CC for IIH and the diagnosis and treatment of tinnitus remains to be established.

Background Exposure to continuous and impulse noise can induce a hearing loss. Leupeptin is an inhibitor of the calpains, a family of calcium-activated proteases which promote cell death. The objective of this study is to assess whether Leupeptin could reduce the hearing loss resulting from rifle impulse noise. Methods A polyethelene tube was implanted into middle ear cavities of eight fat sand rats (16 ears). Following determination of auditory nerve brainstem evoked response (ABR) threshold in each ear, the animals were exposed to the noise of 10 M16 rifle shots. Immediately after the exposure, saline was then applied to one (control) ear and non-toxic concentrations of leupeptin determined in the first phase of the study were applied to the other ear, for four consecutive days. Results Eight days after the exposure, the threshold shift (ABR) in the control ears was significantly greater (44 dB) than in the leupeptin ears (27 dB). Conclusion Leupeptin applied to the middle ear cavity can reduce the hearing loss resulting from exposure to impulse noise.

Program Description: Tinnitus is one of the most common health problems in the United States and recent figures show that tinnitus is increasing in frequency. As otolaryngologists we are the primary specialty responsible for the diagnosis and management of tinnitus. Despite a great deal of work in this area definitive treatment options for tinnitus are lacking in many cases. Recognizing the importance of this issue the AAO-HNSF and the Martha Entenmann Tinnitus Foundation have endowed a series of miniseminars to address tinnitus. This year’s panel will once again be comprised of national and international experts who will discuss advances in tinnitus treatment using implantable devices. The panel will discuss the use of cochlear implants, implantable hearing aids, and other, more novel, implantable devices. In particular the presenters will focus on the physiologic basis for tinnitus response to electrical or mechanical stimulation, cases series and outcomes, and patient selection for various treatments. ...

To provide to the tinnitus professional a rationale for establishing accuracy in tinnitus diagnosis and the selection of modalities of therapy (i.e., medication, instrumentation, and surgery) for attempting tinnitus relief for patients with tinnitus diagnosed by completion of a medical-audiological tinnitus protocol (MATPP) and clinical course and found to be subjective idiopathic tinnitus of the severe disabling type (SIT).The completion of a MATPP has been recommended since 1977 for each tinnitus patient in an attempt to establish an accurate diagnosis. 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]. Principles for SIT treatment have evolved from the TTT experience that provides a rationale for attempting tinnitus relief. In this report, the term tinnitus refers to SIT.The strategies of TTT are based on the clinical translation for SIT diagnosis and treatment of (1) fundamentals of neuro-otological diagnosis; (2) fundamentals of sensory physiology; (3) extrapolation for treatment of known underlying neurochemistries from nuclear medicine imaging results e.g. single-photon emission computed tomography and positron emission tomography; (4) hypothesis of mechanism of tinnitus production , Tinnitus Dysynchrony Synchrony Theory (TDST) [5] , and hypothesis of the transformation-transition of the sensation of an aberrant auditory sensation-tinnitus (i.e., sensory component)-to one of affect (i.e., the emotional-behavioral component), Final Common Pathway of Tinnitus (FCP)[8]; and (5) innovative application of drug therapies designed for indications other than tinnitus [2,3].The ongoing clinical application of a rationale based on principles of diagnosis and treatment for SIT, which has evolved from our TTT clinical experience in SIT patients, continues to result in long-term tinnitus relief: in excess of 1 year in approximately 75% to 85% with medication and in 10% to 15% with instrumentation. SIT patients resistant to therapy persist at 10% to 15%.

It is hypothesized that in all traumatic brain injury (TBI) patients with a clinical history of closed or penetrating head injury, the initial head trauma is associated with a vibratory sensation and noise exposure, with resultant alteration in vascular supply to the structures and contents of the fluid compartments of brain and ear (i.e., the fluid dynamics vascular theory of brain-inner-ear function [FDVTBE]). The primary etiology-head trauma-results in an initial fluctuation, interference, or interaction in the normal fluid dynamics between brain and labyrinth of the inner ear, with a resultant clinical diversity of complaints varying in time of onset and severity. Normal function of the brain and ear is a reflection of a normal state of homeostasis between the fluid compartments in the brain of cerebrospinal fluid and perilymph-endolymph in the labyrinth of the ear. The normal homeostasis in the structures and contents between the two fluid compartment systems--intracerebral and intralabyrinthine--is controlled by mechanisms involved in the maintenance of normal pressures, water and electrolyte content, and neurotransmitter activities. The initial pathophysiology (a reflection of an alteration in the vascular supply to the brain-ear) is hypothesized to be an initial acute inflammatory response, persistence of which results in ischemia and an irreversible alteration in the involved neural substrates of brain-ear. Clinically, a chronic multisymptom complex becomes manifest. The multisymptom complex, individual for each TBI patient regardless of the diagnostic TBI category (i.e., mild, moderate, or severe), initially reflects processes of inflammation and ischemia which, in brain, result in brain volume loss identified as neurodegeneration and hydrocephalus ex vacuo or an alteration in cerebrospinal fluid production (i.e., pseudotumor cerebri) and, in ear, secondary endolymphatic hydrops with associated cochleovestibular complaints of hearing loss, tinnitus, vertigo, ear blockage, and hyperacusis. The FDVTBE integrates and translates a neurovascular hypothesis for Alzheimer's disease to TBI. This study presents an FDVTBE hypothesis of TBI to explain the clinical association of head trauma (TBI) and central nervous system neurodegeneration with multisensory complaints, highlighted by and focusing on cochleovestibular complaints. A clinical case report, previously published for demonstration of the cerebrovascular medical significance of a particular type of tinnitus, and evidence-based basic science and clinical medicine are cited to provide objective evidence in support and demonstration of the FDVTBE.

Management protocols and treatment methods for the symptom of tinnitus, particularly of the severe disabling type, are numerous and varied.’ Although no definitive single protocol and/or cure exists at this time, clinical guidelines are now available that, when followed, can offer both the professional and the patient a significant degree of tinnitus control. Guidelines for successful tinnitus management are both medical and audiologic. In the past, both the evaluation and treatment of the symptom of tinnitus have been primarily audiologic, stressing the psychophysical and psychoacoustical aspects of the complaint. Medical evaluation has been primarily to exclude regional and/or systemic disease that may accompany the symptom of tinnitus. Single and/or combined methods of treatment exist and have been reported.‘,’ This article presents a management protocol, the Medical Audiologic Tinnitus Patient Protocol (MATPP), for the symptom of subjective tinnitus, particularly of the severe disabling type (SIT). It consists of the clinical experience since 1977 of more than 2,500 patients observed at the Tinnitus Clinic of the Health Science Center at Brooklyn-State University of New York [HSCB-SUNY]. The MATPP offers a unified strategy for both diagnosis and attempted treatment/control (TT/

A final common pathway (FCP) for tinnitus has been hypothesized since 1989 for all clinical types of tinnitus, particularly subjective idiopathic tinnitus (SIT) of the severe disabling type. This was intended to explain the transformation-transition of the sensation of an aberrant auditory sensation-tinnitus (i.e., the sensory component)-to one of affect (i.e., the emotional-behavioral component) or, conversely, that an emotional-behavioral stimulus (affect) can result in the clinical manifestation of a sensation (a sensory stimulus). Understanding the pathophysiology of this transformation is fundamental for the diagnosis of tinnitus and the treatment of the patient, and it presents a dilemma to basic science, neuroscience, and clinical medicine. Clinically, tinnitus is not a unitary symptom; it constitutes many clinical types; can have its origin in the auditory or nonauditory systems and in the peripheral or central nervous system; and may be clinically manifest or subclinical. Accumulating evidence is presented to support the original hypothesis of an FCP. The resolution of this dilemma involves sensory processing (i.e., the integration, identification, and understanding of the ongoing, underlying, simultaneous, multiple associated brain function processes not only from one sensory modality but from multiple sensory modalities accompanying and associated with an FCP). In the FCP, the predominant brain function process is that of the sensory-affect transformation of a sensation and its conscious awareness by the affected patient. The neuroanatomical substrates identified in 1989 in tinnitus patients (reported originally in 1991 and published in 1995) are presented as a common framework for the hypothesis of an FCP. They further the understanding of the clinical heterogeneity of the tinnitus symptom, clinically manifest as multiple brain functions associated with the clinical course of tinnitus patients, particularly those with SIT. The FCP provides a model for tinnitus theory, diagnosis, and treatment. The FCP is not a tinnitus theory. Specifically, it is a hypothesis that attempts to explain how an aberrant auditory sensory stimulus becomes transformed into one of affect and somatomotor response. The neuroanatomical substrates of the FCP provide a basis for the identification of the involved neurocircuitries and neurochemistries. The physiology and biochemistry underlying the neuroanatomical substrates of the FCP provide a basis for translation for tinnitus diagnosis and treatment. The neuroanatomical substrates of the FCP are presented as algorithms of (1) components of a sensation (i.e., sensory, affect, and psychomotor), a translation from basic sensory physiology for tinnitus; (2) clinically manifest biophysiological brain functions and underlying processes associated with the tinnitus; (3) a model for investigation of metabolic-electrophysiological correlates for tinnitus; (4) the basis for an integrated theory of tinnitus and brain function (i.e., tinnitus dyssynchrony-synchrony theory; (5) a model for the identification of underlying neurocircuitries and neurochemistries involved in brain for the sensory-affect transformation of an aberrant auditory stimulus (tinnitus); (6) a model for the selection-introduction of innovative therapies attempting tinnitus relief; and (7) its clinical translation for objective monitoring systems for the determination of the efficacy of modalities of therapy attempting tinnitus relief. The hypothesis of the FCP for tinnitus and the identified neuroanatomical substrates, when viewed in terms of the physiology of sensory processing, is considered to be expanded and broader in its application for all sensations, normal or aberrant.

This article integrates the highlights of the authors' clinical experiences derived from existing protocols for tinnitus diagnosis and treatment with the evolving discipline of palliation medicine. Specifically, it demonstrates how the inclusion of principles of palliation medicine contributes to the efficacy of treatment.

The translation of a neurovascular hypothesis for Alzheimer's disease to subjective idiopathic tinnitus (SIT) is presented as a challenge to the predominantly sensorineural view of SIT and its clinical application for tinnitus treatment. The concept of neurovascular dysfunction and neurodegeneration (ND) in SIT patients has been proposed and reported as an etiology in a particular subset of tinnitus patients with a diagnosis of medical-audiological tinnitus, through a medical-audiological tinnitus patient protocol, to be a predominantly central-type, severe, disabling SIT (n = 54 of 96). A medical-audiological ND tinnitus profile was the basis for selection of 18 SIT patients (n = 18 of 54) for nuclear medicine brain imaging (i.e., single-photon emission computed tomography or positron emission tomography, or both). Objective findings were reported in 16 of this cohort of 18 SIT patients selected for nuclear medicine imaging (88.9%). Classification of central nervous system (CNS) ND and tinnitus differentiated between (1) ND, nonspecific and of unknown etiology; (2) ND manifested by perfusion asymmetries in brain associated with ischemia (n = 11 of 18); and (3) ND CNS disease consistent with nuclear medicine criteria for senile dementia Alzheimer's-type disease (n = 5 of 18). The diagnosis was associated with cerebrovascular disease (n = 16 of 18). The identification of pathological processes of inflammation and ischemia, linked to ND, in a particular cohort of SIT patients may provide a basis for establishing the medical significance and treatment of SIT and influence the clinical course of the tinnitus.

The insula cortex (Brodmann's 13-16) has distinct auditory and multisensory areas that have been identified through imaging to be active or hypoactive in cases of severe tinnitus. As such, the insula is a candidate for inclusion in the final common pathway (FCP) for tinnitus. The insula has connection with the prefrontal and auditory cortices, amygdala, thalamus, parabrachial nucleus, orbitofrontal cortex, striate, cuneus, and cerebellum. The insula, as part of the medial temporal lobe system-which also includes the amygdala and the hippocampus-modulates its metabolic activity after high-frequency stimulation. The FCP is characterized by numerous areas in the lemniscal and extralemniscal pathways, including the auditory regions in the thalamus, the cortex, and the cerebellum. It is suggested that elements of the FCP, formulated into a general model of tinnitus, should be considered as beads on a string in designing treatment strategies. This view is the direct result of our past and recent new experiences using ultra-high-frequency sound therapy in cases of severe disabling tinnitus, presented at this time. Behaviorally, tinnitus symptoms decrease by self-report and changes in minimal masking levels with high-frequency sound therapy. The use of multisensory vibration stimulation (somatosensory and high-frequency jointly) should also be explored to maintain or reprogram the auditory cor tical map and induce activity in the FCP circuit, including the parabrachial nucleus and the in sula, which may be the physiological substrate of tinnitus behavioral tests.

We assessed ultrasonic transmission in a dry skull; in a dry skull with water, simulating the living condition; in a cadaver head; and in six human subjects, one of whom exhibited no measurable hearing. By using these preparations, we concluded that fluid conduction is essential in the propagation of sound across the head, whereas the bone pathway is far less effective in that regard. Thus, there is little ear isolation beyond 10 dB even up to 80 kHz, extending the masking dilemma in cases of unilateral hearing loss.

In an evolving clinical experience since 1979, the medical significance of the symptom of tinnitus has been identified as a "soft" sign of neurodegeneration (ND) in the central nervous system (CNS) in a particular subset of tinnitus patients diagnosed with a predominantly central-type, severe, disabling, subjective idiopathic tinnitus. To highlight this experience, a retrospective review and analysis of consecutive tinnitus patients (N = 96) was conducted. Ninety-six tinnitus patients (ages 22-90 years) were seen in neurotological consultation from November 1, 2005, to June 30, 2007, all of whom had subjective idiopathic tinnitus of the severe disabling type (SIT). Of these 96 patients, 54 had SIT of the predominantly central type and of these, 18 (ages 39-75 years) were recommended for nuclear medicine imaging (single-photon emission computed tomography [SPECT] and fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]). Patient selection for nuclear medicine imaging fulfilled the criteria of a medical-audiological ND tinnitus profile: completion of a patient protocol that diagnosed a predominantly central-type, severe, disabling, subjective, idiopathic tinnitus lasting in excess of 1 year, and failure of existing modalities of treatment attempting tinnitus relief. In 16 of the 18 patients, objective evidence of ND was reported in multiple neural substrates of brain obtained with SPECT or FDG-PET/CT of brain. Classification of CNS ND and tinnitus differentiated between (1) ND of nonspecific or unknown etiology; (2) ND manifested by perfusion asymmetries in brain associated with ischemia (n = 11/18); and (3) neurodegenerative CNS disease consistent with nuclear medicine criteria for senile dementia of the Alzheimer's type (n = 5/18). The diagnosis has been associated with cerebrovascular disease (n = 16/18). The identification of neurodegenerative CNS disease in a selected cohort of patients with subjective idiopathic tinnitus as a soft sign of such CNS disease has implications for diagnosis and treatment.

The final common pathway in severe tinnitus is modified to include the parabrachial nucleus, which has been identified by c-fos immunocytochemistry as an active, non-auditory site. The parabrachial nucleus acts in conjunction with the amygdala and insula (part of the medial temporal lobe system) to produce a somatic emotional sense that can result in a "bad" feeling. The activation of the final common pathway is rapid, suggesting that early treatment is prudent to prevent neuroplastic changes that would likely lessen affect.

Our goal was to establish the efficacy, in a 12-week period, of Clear Tinnitus for tinnitus relief in patients with tinnitus of the severe, disabling type.We hypothesized that tinnitus relief with Clear Tinnitus reflects improvement in the sensory component of the tinnitus complaint by controlling the factor of aeration of the middle ears and improving eustachian tube function.In a prospective clinical trial of a homeopathic preparation--Clear Tinnitus--we attempted to identify in 15 tinnitus patients (14 male, 1 female; mean age, 47.6 years) its clinical efficacy for establishing tinnitus relief for a 3-month period. We employed a descriptive data analysis method across dimensions of risk to evaluate a base of multidimensional evidence and establish support for our hypothesis. A medical-audiological tinnitus patient protocol completed by each patient identified the clinical type of tinnitus as predominantly cochlear, with a central and middle-ear component bilaterally. We identified fluctuation in middle-ear pressure (MEP) via patients' clinical history, supported by physical examination and established with tympanometry, as a factor influencing the clinical course of the tinnitus in each patient.Eleven of 15 patients completed the study. Seven responders reported tinnitus relief; four did not respond. Descriptive data analysis failed to detect any trends in a change in response with audiometric tests across the hearing spectrum; thus, we could derive no coefficients of hearing change. Evaluation revealed high-frequency tinnitus in 11 patients. The Feldmann masking curve comparison at the start and end of the study showed no significant change in the 11 patients. There was no significant alteration in the minimum masking levels or loudness discomfort levels before and after the study. Tympanometry and MEP measurement indicated a significant difference in MEP with an improvement on average of -58.18 in the right ear and -40.90 in the left ear for the 11 patients. Quantitative electroencephalography analysis revealed a marked difference in the number of significant abnormal recordings between the different frequency bands, with the delta band significantly higher than the theta, alpha, and beta bands for both the overall cohort of patients (n = 11) and those reporting tinnitus relief (n = 7). The tinnitus outcome questionnaires--the tinnitus intensity index, the tinnitus annoyance index, and the tinnitus reaction questionnaire--revealed a significant difference for the patients (7 of 11) obtaining tinnitus relief. Results of the tinnitus stress test, the tinnitus handicap index, and the measurement of depression scale before and after the study were not statistically significant.Patients who completed the study demonstrated with tympanometry a statistical and clinical significance in MEP improvement or maintenance of MEP (or both). Patients with tinnitus of the severe disabling type selected for this study and responding to Clear Tinnitus reported tinnitus relief accompanied by improvement in or maintenance of MEP of the middle ears. The statistical and clinical significance of Clear Tinnitus for establishing tinnitus relief remains to be established with a larger cohort of tinnitus patients.

We report a descriptive analysis-interpretation of quantitative electroencephalography (QEEG) data for the metric of power in patients with tinnitus of the severe disabling type (N = 61). The results are based on a statistical analysis of the data compared to a normative database as calculated in Z scores, controlling for the factors of age, gender, IQ, and the like.We analyzed the QEEG data for the metric of power to measure (1) the number of significant recordings, normal and abnormal; (2) the significant recordings by electrode recording sites; (3) distribution of the electroencephalographic (EEG) frequency bands; and (4) occurrence of the EEG frequency bands correlated with the electrode recording sites. In the analysis of the occurrence of the EEG frequency bands by electrode recording area, we corrected for the number of recording sites.We recorded normal power recordings in 20 of 61 patients (32.8%) and abnormal power recordings in 41 of 61 patients (67.2%); power distribution by frequency band in 41 of 61 patients,revealing the number of significant recordings of delta (119), alpha (69), beta (91), and theta (17); and the power distribution by location for all frequencies, which were revealed as recording site activity in the frontal greater than in the temporal sites, which in turn was greater than in the parietal site, and equal activity in parietal, occipital, and central sites. The analysis of the occurrence of the EEG frequency bands by electrode recording area as corrected for the number of recording sites reinforced our initial results.Z-score analyses of QEEG recordings--based on a large normative database--for the metric of power for patients having tinnitus of the severe disabling type (N = 61) revealed statistically significant abnormalities in frontal greater than temporal electrode recording sites. We reported no difference between male and female tinnitus patients in the number of abnormal power QEEG recordings. However, we observed significant differences in the average Z scores between males and females in the alpha and theta bands. The results suggest multiple central electrophysiological correlates for different clinical types of tinnitus identifiable with QEEG, for the metric of power, by frequencies of brain activity of delta greater than beta greater than alpha greater than theta bands of activity, reflecting physiologically the individuality of brain function and clinically the heterogeneity of the symptom of tinnitus for tinnitus patients. Clinical interpretation of the QEEG data in terms of brain function in a tinnitus patient, with a focus on theories of a neuroanatomical homeostatic system that regulates baseline levels of local synchrony in multiple neuronal assemblies and on theories of consciousness, introduces a paradigm switch in our clinical understanding of the symptom of tinnitus and an application for tinnitus diagnosis and treatment.

We present a tinnitus-targeted therapy (TTT), a combined treatment of medication and instrumentation focusing on pharmacotherapy. It embodies ongoing clinical experience (since 1977) in an excess of 8,500 patients with subjective idiopathic tinnitus of the severe disabling type (SIT). All have visited the Tinnitus Clinic of the Downstate Medical Center at the State University of New York (DMC/SUNY) and the Martha Entenmann Tinnitus Research Center, Inc. Since 1989, as a result of our evolving experience with single-photon emission computed tomography (SPECT) of brain, we have defined tinnitus as a sensory disorder of auditory perception exhibiting an aberrant auditory signal produced by interference in the excitatory-inhibitory process or processes involved in neurotransmission. This definition is considered to be dynamic: It embodies the integration of clinical observations and advances reported from neuroscience and nuclear medicine. These investigations have sought to identify an underlying mechanism of tinnitus production and have assisted in the establishment of the medical significance of tinnitus. In general, the goal of tinnitus therapy in 2005-2006 is to attempt to provide tinnitus relief for all clinical types of subjective idiopathic tinnitus (SIT). Although no cure for SIT exists currently, available protocols for diagnosis and treatment increase the efficacy of therapeutic modalities for attempting tinnitus relief. The strategies of TTT are based on the clinical translation of fundamentals of sensory physiology, extrapolation of underlying neurochemistry from nuclear medicine imaging results with SPECT in SIT patients, hypotheses of mechanisms of tinnitus production, and the innovative application of drug therapies designed for indications other than tinnitus. Such strategies have contributed to the development of a new discipline, tinnitology, an integrated multidiscipline of basic science, neuroscience, and clinical medicine attempting to understand an aberrant auditory phenomenon, unrelated to an external source of sound, and how it becomes transformed into one of affect. The goal of increasing accuracy of the SIT diagnosis is the impetus for increased efficacy of therapeutic modalities recommended for tinnitus relief.

The tinnitus dyssynchrony-synchrony theory (TDST) is a hypothesis that considers tinnitus to be an abnormal, conscious, auditory percept. 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). 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. The conscious auditory percept for tinnitus is hypothesized to reflect clinically a summation of synchronous activities of neuronal activity recordable from multiple neural substrates at the brain cortex. The transformation from the dyssynchrony of the aberrant auditory stimulus to one of synchrony and individual brain function of affect, somatosensory response, and consciousness is clinically considered to be a final common pathway for tinnitus. The clinical application of the TDST has increased the accuracy of tinnitus diagnosis and improved the efficacy of treatment modalities attempting tinnitus relief.

Secondary endolymphatic hydrops (SEH) has clinically been found to have a significant incidence of occurrence in patients with subjective idiopathic tinnitus (SIT) of a severe disabling type. The diagnosis is made clinically and has been established by integration in a medical audiological tinnitus patient protocol of the clinical history with results of electrodiagnostic cochleovestibular testing that fulfill the diagnostic criteria of inner-ear disease consistent with Ménière's disease. SEH is hypothesized to be a factor, not an etiology, influencing the clinical course of SIT. Alterations over time (i.e., delay in the homeostatic mechanisms in normnal function of the fluid compartments of the inner-ear perilymph, endolymph, or brain cerebrospinal fluid) result in endolymphatic hydrops and interference in normal function of the inner ear, with resultant inner-ear complaints that can be highlighted by tinnitus rather than by vertigo. The endolymphatic hydrops may be either localized or diffuse within the cochlear or vestibular labyrinth. The etiologies and mechanisms of cochleovestibular-type tinnitus are multiple and are influenced by the SEH. Classically, the tetrad of symptoms--episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and ear blockage--associated with the histopathological correlate endolymphatic hydrops has been diagnosed as Ménière's disease. Specifically, key etiological agents that have been identified as playing a role in the clinical course of tinnitus (e.g., noise exposure, stress) may serve as "triggers" or stressors (or both), resulting in interference in normal biochemical and physiological function of sensorineural structures in the inner ear or in neural structures in the brain. In both conditions, the alterations over time (i.e., delay) in the clinical manifestation of the tetrad of symptoms of inner-ear dysfunction, when highlighted by SIT rather than vertigo, otherwise fulfill the criteria for diagnosing SEH. The chief complaint of SIT, when presenting as one of the tetrad of inner-ear symptoms and otherwise diagnosed as Ménière's disease, has also been associated clinically with perfusion asymmetries in brain, identified by nuclear medicine brain imaging (single-photon emission computed tomography [SPECT] of brain), and reflects an interference in homeostasis in the blood-brain labyrinth or blood-brain barriers, with a resulting SEH. The medical significance of the SIT in some patients may be a gradual, progressive sensorineural hearing loss. The inclusion of SPECT of brain in SIT patients demonstrates a global approach for improving the accuracy of diagnosing the SIT symptom, for focusing on the contribution of central nervous system dysfunction to the development of SEH, and for understanding and influencing the clinical course of SIT.

Congenital atresia of the external ears and severe tinnitus has been reported by two patients to be contralateral to the atretic ear. The use of the nuclear medicine imaging technique of single-photon emission computed tomography (SPECT) of brain has demonstrated hypoperfusion in brain areas supplied by the middle cerebral artery on the side of the atretic ear. Ultrahigh-frequency audiometry (UHFA) has revealed a bilateral loss of hearing greater than expected for the age of affected patients. Quantitative electroencephalography (QEEG) has shown a significant central nervous system electrical dysfunction correlated with the SPECT of brain findings. One case is reported in detail at this time. Completion of the medical audiological tinnitus patient protocol, including SPECT of brain, UHFA, and QEEG, accurately established the clinical tinnitus diagnosis of predominantly a central-type tinnitus, a clinical hypothesis that the medical significance of the tinnitus is a "soft" sign of cerebrovascular disease, and provided a rationale for treatment directed to a presumed ischemia of brain based on a receptor-targeted therapy targeted to the GABA-A receptor, resulting in significant tinnitus relief. Questions that have arisen include (1) the incidence of occurrence of hypoperfusion of the middle cerebral artery in congenital atresia patients; (2) implications and long-term consequences of this finding in this patient population for development of cerebrovascular disease; (3) brain plasticity for tinnitus relief (i.e., neuronal reprogramming, particularly in response to treatment recommendations for complaints of the cochleovestibular system in general and specifically for tinnitus); (4) the clinical significance of the UHFA thresholds of bilateral hearing loss greater than expected for the age of the patient; and (5) whether congenital atresia of the external ear may be part of a syndrome that includes hypoperfusion in brain areas supplied by the middle cerebral artery on the side of the atretic ear, ultra-high-frequency bilateral loss of hearing greater than expected for the age of the patient, and significant central nervous system electrical dysfunction. As far as we can determine, these findings, highlighted by the brain SPECT, have not previously been reported in patients with congenital atresia of the external ear.

We proposed a method for patient selection and application of criteria for predicting success with bone-conduction external acoustic stimulation using high-audio-frequency sound in the ranges of 10-20 kHz and 20-26 kHz for individuals with subjective idiopathic tinnitus (SIT) of the severe disabling type. Ultra-high-frequency (UHF) stimulation for tinnitus relief has been found to be most effective when residual neuronal function exists in the acoustic ranges of 10-14 kHz, with thresholds no greater than 40-50 dB sound pressure level (SPL). Ultrasonic (US) acoustic stimulation is recommended for patients with audiometric thresholds greater than 50-60 dB SPL for frequencies of 10-14 kHz. Fifty-two consecutive patients seen for the primary complaint of SIT of the severe disabling type received a trial of either UHF or US bone-conduction acoustic stimulation. Tinnitus relief was reported in 22 of the 52 patients. The application of criteria for patient selection predicted tinnitus relief in 20 of the 22.

This study reports on the long-term benefit of ultra-high-frequency masking with the UltraQuiet device. A commercial product, UltraQuiet provides a new form of high-frequency bone conduction therapy. To assess its effectiveness in tinnitus treatment, we selected 15 patients with problematic tinnitus and randomly assigned them to three variations of the medical-audiological tinnitus patient protocol modified for the UltraQuiet study. We assessed tinnitus relief by questionnaires directed at weighing patient response to overall effectiveness, tinnitus loudness, tinnitus severity, and tinnitus annoyance. Additionally, we performed audiological measures (including pure-tone and speech audiometry, minimal masking levels, pitch and loudness matching, and residual inhibition). All patients showed some long-term gains, and most exhibited relief in at least one measurement parameter, providing support for the use of high-frequency vibration in the treatment of tinnitus.

Ultra-high-frequency (UHF) external acoustic stimulation with the UltraQuiet device (UQ) has been reported to provide significant relief of severe disabling-type tinnitus. The nuclear medicine imaging technique of positron emission tomography (PET) was selected as a monitoring system to compare objectively metabolic alterations in brain function before and after UHF/UQ and to correlate the PET data with the subjective behavioral response of patients reporting tinnitus relief. PET of brain was completed on 6 patients randomly selected from a cohort of 15 patients included in a protocol to establish long-term tinnitus relief with UHF/UQ. Twelve specific regions of interest (ROI) were selected for PET of brain examination on the basis of results obtained with single-photon emission computed tomography (SPECT) of brain examinations recommended for patients with severe disabling-type tinnitus and demonstrating significant perfusion asymmetries in the right and left brain ROI of the primary auditory cortex; frontal, temporal, parietal, and medial temporal lobes; and cerebellum. PET of brain results included ratios of post- and pre-UHF/UQ stimulation that demonstrated no random response in the selected PET of brain ROI and ratios of post- and pre-UHF/UQ stimulation that demonstrated three categories of response in the selected PET brain ROI for all six patients: hypermetabolism in three patients; hypometabolism in two; and a mixed response in one. Correlation was established for each patient among PET and electrophysiological responses of alteration in minimal masking levels, the residual UHF neuronal response as reflected in the UHF audiogram, and the subjective reported behavioral responses of patients (obtained from outcome questionnaires for tinnitus relief, which focused on tinnitus intensity, annoyance, severity index, and a subjective scale of value of the UHF/UQ device for tinnitus relief. The subjective behavioral response for tinnitus relief with UHF/UQ was found to reflect a dual effect: acoustic stimulation of the residual neuronal function in the UHF range (10-14 kHz) and audiometric thresholds of 40-50 dB sound pressure level (SPL), and the metabolic activity at brain cortex for neuronal reprogramming. The PET of brain categories of response suggested that the UHF/UQ "masking" is predominantly reflective of neuronal reprogramming at the brain cortex. Nuclear medicine PET of brain imaging has provided an objective monitoring system for attempting to establish the efficacy of UHF/UQ for tinnitus relief. No complication of the tinnitus was reported secondary to the PET of brain examination. This limited PET of brain study supports the clinical recommendation of the efficacy of UHF/UQ external acoustic stimulation for a selected population of patients with tinnitus of the severe disabling type.

Tinnitus affects nearly 50 million people in the United States, with a minority demonstrating marked functional impairment. Alterations of gamma aminobutyric acid (GABA) neuronal function and benzodiazepine receptor (BZR) function in particular have been implicated in the pathophysiology of severe, chronic tinnitus. The purpose of our study was to evaluate the distribution of BZR in the brain using 123I-iomazenil single-photon emission computed tomography (SPECT) imaging in patients with severe, intractable central tinnitus. Six patients with severe intractable tinnitus received a bolus and constant infusion of 123I-iomazenil intravenously over 7 hours with SPECT and magnetic resonance imaging of the brain. After magnetic resonance imaging coregistration, standardized regions of interest were placed over the cerebellar, frontal (control), superior temporal, hippocampal, and thalamic regions bilaterally on (SPECT) images. Venous blood samples were drawn at specified intervals to determine equilibrium distribution volumes (V3') for each of the regions. Variation in V3' values in homotypic regions were calculated using a Wilcoxon signed rank test. Twelve normal control subjects were compared to the study subjects using statistical parametric mapping. Comparison of homotypic brain regions showed statistically significant asymmetry in the V3' data in the superior temporal cortex (p = .03 for both). No statistically significant difference was noted in any of the other regions studied. Comparison of the group of study subjects to healthy controls revealed an insignificant trend toward reduction in BZR density in the frontal lobes bilaterally (p = .000) and a reduction in the cerebellum (p = .045). Current understanding suggests GABA receptors and the temporal lobe system as the final common pathway. This pilot study suggests possible alterations on 123I-iomazenil SPECT imaging and the need for larger studies.

Transtympanic medical therapy is becoming an increasingly popular modality for the treatment of "inner-ear disorders." While investigators continue to examine the best dosing paradigms for gentamicin in the treatment of Ménière's disease and for steroids in the treatment of hearing loss, they have also begun to focus on the use of other agents. In particular, transtympanic therapy has been advocated as a plausible route for the treatment of tinnitus. Transtympanic therapy for tinnitus is not new, and a number of groups have reported success in the past. Despite this success, a number of laboratories have been focusing on newer agents that might yield higher success rates in the treatment of tinnitus and other inner-ear disorders. Many of these agents could have systemic side effects when delivered in high enough doses; therefore, they are ideal candidates for transtympanic administration. The goal of this study is to begin to define the effects of one of these agents--leupeptin, a calpain antagonist--on the normal inner ear of an animal model. In this investigation, we demonstrate the effects of sustained-release delivery of leupeptin (2.5 micrograms/ml) on the hearing of chinchillas. The medicine produced no hearing loss at the early time points but did produce some hearing loss at later time points. We discuss these results and begin to outline the next steps in the investigation of this agent.

This preliminary report is an account of 21 consecutive patients who had tinnitus of the severe disabling type and were examined with quantitative electroencephalography (QEEG). A multimetric analysis of the raw data was highlighted by an abnormal incidence of significant central nervous system electrical dysfunction identified in each patient (21 of 21). Relative power was increased or decreased in the temporal region in 10 of 21 patients. Relative power was reported to be increased or decreased in temporal frontal regions in 20 of 21 patients. Coherence irregularity was identified in all 21 patients. QEEG preliminary data support the hypothesis of a final common pathway for tinnitus and the significant role of the temporal and temporofrontal regions of interest in patients with tinnitus of the severe disabling type. QEEG with multimetric analysis is considered a significant addition to the medical audiological tinnitus patient protocol as one of a battery of electrophysiological tests for the clinical identification of a predominantly central type of tinnitus.

Our goal was to attempt to establish neuropharmacological tinnitus control (i.e., relief) with medication directed to restoration of a deficiency in the gamma-aminobutyric acid-benzodiazepine-chloride receptor in tinnitus patients with a diagnosis of a predominantly central type tinnitus. Thirty tinnitus patients completed a medical audiological tinnitus patient protocol and brain magnetic resonance imaging and single-photon emission computed tomography of brain. Treatment with GABAergic and benzodiazepine medication continued for 4-6 weeks. A maintenance dose was continued when tinnitus control was positive. Intake and outcome questionnaires were completed. Of 30 patients, 21 completed the trial (70%). Tinnitus control lasting from 4-6 weeks to 3 years was reported by 19 of the 21 (90%). The trial was not completed by 9 of the 30 (30%). No patient experienced an increase in tinnitus intensity or annoyance. Sequential brain single-photon emission computed tomography in 10 patients revealed objective evidence of increased brain perfusion. Patients with a predominantly central type tinnitus experience significant tinnitus control with medication directed to the gamma-aminobutyric acid-benzodiazepine-chloride receptor.