Neuroinflammation and Tinnitus.

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.

Emerging Topics in the Behavioral Neuroscience of Tinnitus.

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.

Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson's disease/dementia with Lewy bodies.

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.

Controlled cortical impact-induced neurodegeneration decreases after administration of the novel calpain-inhibitor Gabadur.

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.

Electrophysiology quantitative electroencephalography/low resolution brain electromagnetic tomography functional brain imaging (QEEG LORETA): Case report: Subjective idiopathic tinnitus - predominantly central type severe disabling tinnitus.

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 tympanic membrane displacement test and tinnitus: preliminary report on clinical observations, applications, and implications.

UNLABELLED: 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. OBJECTIVES: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: (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.

Leupeptin reduces impulse noise induced hearing loss.

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.

Principles of tinnitology: tinnitus diagnosis and treatment a tinnitus-targeted therapy.

OBJECTIVE: 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). BACKGROUND: 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. METHOD: 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]. RESULTS AND CONCLUSION: 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%.

Final common pathway for tinnitus: theoretical and clinical implications of neuroanatomical substrates.

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.

Subjective idiopathic tinnitus and palliative care: a plan for diagnosis and treatment.

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.