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A final common pathway for tinnitus is hypothesized to exist for all patients with tinnitus. Its function is the transition of the sensory to the affect component of the symptom of tinnitus.
Single Photo Emission Computerized Tomography (SPECT) with the radio isotope TC99-HMPAO has identifie side to side perfusion asymmetries highlighted by that of the amygdala - hippocampal complex. It is hypothesized that a fundamental function of the amygdala - hippocampal structures is the establishment of a paradoxical auditory memory for tinnitus. A Final Common Pathway (FCP) is hypothesized to exist for all patients with tinnitus, particularly of the severe disabling type (SIT). Historically, this search for understanding how the transition from sensory to affect occurs in the brain is not new.
The concept of William James, the Father of American Psychology is suggested to find application to a FCP for tinnitus. Single Photon Emission Computerized Tomography (SPECT) with the radioi sotope Tc-99 HMPAO is a detection method which provides information of cerebral perfusion in brain. Based on clinical experience with tinnitus particularly of the severe disabling type and supported by SPECT imaging of the brain, the medial temporal lobe system is speculated to be a key site of action of processing of an aberrant auditory signal resulting in a paradoxical auditory memory; and an accompanying parallel transition in processing of the sensory to the affect component of the symptom of tinnitus.
In other words, the eterogeneity of the symptom of tinnitus is reflected in FCP for tinnitus.
The FCP is presented as a hypothesis focusing on a process within the MTLS of a paradoxical auditory memory with speculations as to its clinical applications for both diagnosis and treatment. It is hypothesized that for all sensory systems the sensory and affect components are linked by memory.2 The experience of the sensation is a perceptual image of the stimulus.
Psychology and neuroscience evidence have differentiated between long term and short term memory. The modulator of the sensory component is considered to be the efferent system and the process of masking.3 The modulator of the afferent component is considered to be stress. In the patient with tinnitus, particularly of the severe disabling type it is hypothesized that both the hippocampus and amygdala of the MTLS are significant for the transition of the sensory to the affect component. In summary, the FCP model for tinnitus involving the medial temporal lobe system is initiated in the MTLS by the process of establishment of a paradoxical memory.
Our approach is clinical and attempts to identify not all components of the FCP but rather to focus on one aspect, specifically memory which is considered at present to be clinically most significant; and is explainable by what has been reported for understanding brain function specifically memory. The activity in the brain that corresponds to memory can be found in the medial temporal lobe system. Crick's comments on the problem of visual awareness I believe can be applied to that of tinnitus - an auditory perceptual phenomenon.6,31 Specifically, investigations for tinnitus are necessary from a psychological and a neuro-science perspective for the issues of attention and very short term memory. The MTLS can be considered an information processing pathway for the integration of sensory and affect components of all sensory inputs. The perception of a auditory image, considered to be "normal", is hypothesized to be determined by a normal masking function. It has become apparent to us from our clinical experience with SPECT since 1989, that the manner in which the brain processes auditory sensory information is radically different with or without the presence of tinnitus. The consequences of the identification of a FCP for tinnitus and the role of the MTLS are considered significant.
The following SPECT images of the brain demonstrate multiple perfusion asymmetries, highlighted by the MTLS (Fig.
The FCP for tinnitus provides a rationale and model for understanding the integration, interaction, translation, and transformation of the sensory auditory signal to the affect behavioral response. An initial process, in the MTLS, is hypothesized to be the establishment of a paradoxical auditory memory for tinnitus.
SPECT imaging of brain provides an ability to identify regions of interest in the brain which demonstrate perfusion asymmetries frequently found in patients with tinnitus of the severe disabling type. The processes involved in the establishment of the symptom of tinnitus particularly of the severe disabling type and the problems encountered, relate to the overall problem and question over centuries of what is the relationship of mind and brain and what are the processes involved in such identification. 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. Tinnitus is associated with the most important symptoms in neurootology besides vertigo, nausea, and hearing loss. Since about 1985, via vestibular evoked potentials (VestEP) and brain electrical activity mapping (BEAM), the Wurzburg Neurootology Group of Claussen et al.
For this study, we randomly selected a sample of 757 patients suffering from an endogenous tinnitus according to the tetrad of tinnitus differentiation described. We followed with a thorough audiometric investigation to obtain measurements of the hearing threshold, the acoustic discomfort threshold, the calculation of the acoustic dynamics, tinnitus masking, impedanciometry, and stapedial muscle reflexes. In assessing the vestibulospinal pathways, we regularly applied craniocorpography (CCG) in the form of ultrasonographic computed craniocorpography (UCCCG). The test results from our analyses helped us to demonstrate that these 757 patients were suffering from an endogenous tinnitus. At the Neurootological Research Institute at Bad Kissingen, we recorded statistics from our 757 patients suffering from an endogenous tinnitus. After exploring the vertigo mechanisms, we analyzed the different sensations in hearing distortion in our patient sample (Fig. Figure 20 shows our analysis of trigeminal nerve complaints: Although no patient reported trigeminal nerve disorders, the medical investigators found such disorders by direct inspection relative to patients' obtained medical history.
The special set of questions regarding our patients' history dealt with specific neurological disorders (Fig. Very well known is that after head and neck trauma, many patients complain of various types of tinnitus.
Cardiovascular diseases were very important background disorders for our neurootological patients.
We also questioned our patients about diabetes mellitus and categorized these cases with respect to their therapy. For this study, we randomly selected 757 tinnitus patients who reported that they felt better in a noisy environment. The question underlying this study is whether tinnitus is a monosymptomatic disease or is bound into a complex spectrum of complaints within a multisensory disorder. We saw a very varied picture in the subjective descriptions of the quality of tinnitus sensations.
Of background disorders, various cardiovascular diseases showed a high occurrence rate (Fig.
All in all, we must conclude that our evaluations in studying our 757 cases demonstrate that the spectrum of subjective complaints is very complex and individually mingled. Overall, our evaluation of 757 patients with endogenous tinnitus posits that the most important accompanying general diseases are cardiovascular.
From all these patterns of interactive complaints, we also must conclude that endogenous tinnitus points to a "cybernetopathia" deriving from dysfunctions at various points of the statoacoustic and interrelated supportive neurosensory pathways. Hyperacusis is due to an alteration in the central processing of sound in the auditory pathways where there is an abnormally strong reaction from exposure to moderate sound levels. Sometimes because of the belief that it will damage the ear, or makes symptoms (sensitivity, or tinnitus) worse. In treating these conditions, it is important to diagnose which condition is present and which is dominant. The 30,000 fibres in the auditory nerve carry information about the individual frequencies of each complex sound that we hear. The central auditory system is first of all concerned with extracting important messages from unimportant background noise.
In misophonia and phonophobia the connections of the auditory pathways leading from ear to brain interact strongly with the limbic and autonomic nervous systems to which they are connected. The purpose of this ability to amplify small signals and to suppress others is to facilitate the detection of potential threats in the environment and is a natural part of our defence mechanism. Very often the over-sensitivity for sounds is begun by an irrational fear which nevertheless becomes a very strongly held belief. Changes in emotional state, particularly mood fluctuations or anxiety can increase overall arousal and make us more able to detect potential threats in our environment.
The process of developing an increased sensitivity to specific sound always involves the limbic system and autonomic nervous system. Where there is a hearing loss and a need for a hearing aid fitting, this must be done without overloading the ear with amplified sound. Digital and programmable hearing aids frequently make the task of appropriate hearing aid fitting easier and more appropriate.
Damage is related not only to the intensity of sound, but also to the duration of exposure, so careful calculations need to be made to establish who is really at risk.
Research in the 1980s (Hazell & Sheldrake1991) showed that the use of wide band noise applied to the ear by wearable sound generators can in help in the treatment of abnormal hypersensitivity of hearing.
The sound from the instruments needs to be applied very gently and gradually to the ear beginning at a low level, always to both ears, and under the supervision of an audiologist with experience in this process of desensitization and with training in TRT. This article may be circulated to patients, their friends and families, freely, provided it is not altered in any way. Neuroplasticity (NPL), neuromodulation (NM), and neuroprotection (NPT) are ongoing biophysiological processes that are linked together in sensory systems, the goal being the maintenance of a homeostasis of normal sensory function in the central nervous system. Keywords: tinnitus, neuroplasticity, neuromodulation, neuroprotection, electrical stimulation, inhibition, auditory and somatosensory cortex. The biophysiological processes of NPL, NM, NPT are considered in our experience to provide a "bridge for continuity of function" between both a sensation and its transformation into one of behavior and affective and somatomotor response. It is hypothesized that when the balance between excitatory-inhibitory action is broken in sensory systems, predominantly due to neuromodulatory activity with reduced induced inhibition and excitation predominates, sensory circuits become plastic with adaptation at synaptic levels to environmental inputs.
In this manuscript, tinnitus refers to a predominantly central type subjective idiopathic tinnitus of the severe disabling type (SIT).Tinnitus an aberrant auditory sensation, for all clinical types, is clinically considered to reflect a failure of NPL, NM, and NPT to maintain normal auditory function at synaptic levels in sensory cortex and projected downstream to levels in the central auditory system and sensorineural elements in ear.
Clinically, the tinnitus sensation becomes behaviorally manifest with varying degrees of annoyance, reflecting a principle of sensory physiology that each sensation has components, i.e.
Sensory inputs to brain are considered to have resulted in the phylogenetic development of multiple brain functions for survival of the species. A global arousal system (GA) has been proposed that involves the activation of all vertebrate behaviors in response to all brain inputs. A physiological process of significance for NPL and NPT is hypothesized to be inhibition and as reflected in pharmacological and approaches attempting tinnitus relief1,11-15.
Both the somatosensory and auditory systems demonstrate "plasticity" changes with respect to behavior. Clinically the translation of sensory physiology for tinnitus has resulted in the identification of a discipline tinnitology, principles of tinnitology, a theory for all clinical types of tinnitus, an accuracy for the tinnitus diagnosis and a combined tinnitus targeted therapy (TTT) approach for attempting tinnitus relief17-20.
Clinically fundamental for all sensory systems is the relationship between structure and function and the identification in neuroanatomic substrates of the underlying involved processes and mechanisms.
The significance and intimacy of brain function and sensation was recognized as early as the first century AD by the Roman philosopher and politician Lucius Aenneus Seneca (*c.
The dilemma which faces both the tinnitus patient and professionals attempting tinnitus relief is the one posed originally by Descartes R, i.e. The terminologies of NPL, NM, NPT have increasingly been introduced into the tinnitus lexicon as advances in understanding the physiology of normal brain function and pathophysiology underlying brain function for specific diagnostic categories is being investigated. Our ongoing clinical experiences with SIT at SUNY Downstate since 1979 has an increased relevance for tinnitus diagnosis and treatment when integrated with evidence connecting synaptic plasticity to functional plasticity, perceptual learning and memory, and the emergence of a neurobiology for sensation and perception.
The focus specifically on neural plasticity and tinnitus was initially presented from the perspective of a basic science sensorineural approach with animal physiology studies of normal and abnormal predominantly peripheral and central auditory function24-26.
Increasingly, and ongoing since mid 1980s, advances in sensory physiology, neuroscience and auditory science, have included evidence for understanding that a linkage exists between sensory biophysiological processes of neural synchrony, dysynchrony, neural plasticity, neuromodulation, thalamocortical oscillation, thalamocortical dysrhythmia and neuroprotection, all of which underlies and results in central auditory and nonauditory brain function. Tinnitus is marked clinically by its heterogeneity for etiolgy, clinical type and subtype, factors influencing its clinical course, and response to treatment.
The underlying biophysiology, originally reported in 1991, is considered to be epileptiform activity in auditory and nonauditory multiple regions of interest in brain2,32. It has been hypothesized that commonalities and differences in both developmental and adult plasticity exist in sensory cortices. Significant to be considered as demonstration of a commonality in sensory systems are inhibitory plasticity experiences reported in the visual and auditory systems with deprivation. In the auditory system an auditory deprivation effect for the unfitted ears of the subjects with monaural hearing aids has been reported40. The term "deprivation" is used in its everyday sense to refer to the bilateral absence of acoustic stimulation. Increased sensory cortical plasticity and improvement in perception and the behavioral response are hypothesized to result by targeting the cortical interneurons and neuromodulatory centers43.
This hypothesis is supported by reports demonstrating control over cognititive and emotional behavioral performance by optogenetic and pharmacogenetic targeting of different types of inhibitory and excitatory interneurons or neuromodulatory neurons and for different aspects of auditory perception by targeting the cholinergic system44-46. In our clinical experiences since 1979 the commonalities and differences are reflected in the clinical heterogeneity of different clinical types of tinnitus. The cited publication by Carcea & Froemke is recommended reading to tinnitus professionals and patients for understanding the complexity of tinnitus and projection to the future for tinnitus diagnosis and treatment1. The following is a brief edited summary of what the authors of this manuscript consider in their tinnitus experience to be fundamental and essential of what is known at this time for cortical plasticity and for its translation to tinnitus diagnosis and treatment. Basal forebrain- cholinergic, gabaergic and glutaminergic projection neurons and local GABAergic interneurons.Locus Coeruleus-noradrenergic neurons innervate forebrain including sensory cortices. 2) cholinergic inputs trigger disinhibition in the upper cortical layers by activation of nicotinic receptors on layer 1 inhibitory neurons51. Thalamo cortical dysrhythmia - a pathophysiologic model of brain wave activity of brain function is proposed for neurogenic pain, tinnitus, abnormal movements, epilepsy, and neuropsychiatric disorders. A lesion results in deafferentation of excitatory inputs on thalamic relay cells which initiates tinnitus. It is hypothesized for tinnitus that the spontaneous and constant gamma band of hyperactivity causes tinnitus. Neural plasticity, clinically, is a reorganization in brain structure and or function in response to constant, single or repetitive, internal and or external stimulation e.g. Brain plasticity has been defined by "the father of sensory substitution and brain plasticity as the adaptive capacities of the central nervous system - its ability to modify its own structural organization and functioning57". Neuromodulation in neuroscience, is considered to be a complex biology of physiological process(es) which exerts a positive or negative influence on an existing neural signal input or output, but does not eliminate the existing neural signal.
In our tinnitus experience, neural plasticity can result in or be accompanied by neuromodulation and neuroprotection. Neuroprotection: refers to processes that protect neuronal function from injury or that improve such function after injury.
Pharmacological agents that are considered to be neuroprotective have been identified and include calcium channel blockers, free radical scavengers, corticosteroids, antagonists of glutamate at N-methyl-Daspartate (NMDA) and non-NMDA receptors, and various thrombolytic agents. A review of the NPL NM NPT literature finds translation and significance for tinnitus of all clinical types for basic science, clinical medicine, diagnosis and treatment. Varied changes in spectral content in the EEG of patients were reported with tinnitus throughout the frontal and temporal lobes.
Tinnitus related distress was correlated with an abnormal pattern of spontaneous activity in particular in right temporal and left frontal brain areas77. With the electroencephalogram (EEG), an increase of band power and local field potential (LFP) signals is typically interpreted as an increase in neuronal synchronization in terms of coincident firing within a neuronal population78. An inverse relationship has been reported with PET between thalamic activity and EEG alpha power in depressed and healthy patients, i.e. Clinically, this paper is cited for future neuromodulatory pharmacological approaches attempting treatment of the affect component of tinnitus.
Functional brain imaging, metabolic with Cerebral F-18 2-deoxy-fluoroglucose (FDG) Positron Emission Tomography (PET) and electrophysiologic with quantitative electroencephalography (QEEG) was recommended to a cochlear implant patient (CI) age 74, who reported in 2008 an increase in tinnitus intensity and decreased hearing function with the CI ON of 6 months duration. PET data was acquired in 3D mode with a Siemens Exact 47 HR + after administration of weight adjusted doses of F-18 2-deoxy-fluoroglucose. Preselected regions of interest (ROIs) in this report include medial temporal lobe, frontal, primary auditory cortex and thalamus. In addition it is hypothesized that the activated ROIs reflect metabolic correlates of the underlying biophysiological processes in brain of NPL, NM and NP.
Electroencephalographic functional brain imaging provides a quantitative demonstration of the spectral analysis of the raw EEG brain wave activities (QEEG)73 c): Low resolution brain electromagnetic tomography (LORETA) is a family of analyses which provides a 3D demonstration of the distribution of the generating electric neuronal activity. Thalamus: The SUV% asymmetry between rt and lt metabolic activity of the thalamus with the new cochlear implant CI #2 reveals a reduction but persistence of SUV asymmetry.
With activation asymmetries reduced thalamus lt > rt, primary auditory cortex absent asymmetry rt lt, reduced asymmetry medial temporal lobes lt > rt. With deactivation asymmetries reduced thalamus rt > lt, primary auditory cortex absent asymmetry rt lt, medial temporal lobe increased reduction asymmetry lt > rt. The results of the QEEG include reference database comparisons for relative power Z scores at 1-Hz intervals in the frequency domain, in a numerical table from which topographical maps are derived. Initially a high beta with was recorded bilateral essentially equal from all recording electrodes. The neural plasticity process is dramatically demonstrated in the alteration in activity between the thalamus and frontal cortex in the PET CT images with CI #1 on and off. The neuromodulation process, both positive and negative is clinically considered to be reflected in the sequential QEEG relative power Z scores. The neuroprotective process is clinically demonstrated by the efficacy of cochlear implant #2 in the both PETCT images and QEEG recordings. The focus of this manuscript has been on biophysiological processes in brain of NPL, NM, and NPT and their translation for tinnitus. Evidence has been presented linking synaptic plasticity, functional activity and learning1. The neuroscience evidence underlying NPL NM PNPT is contributing to an evolving neurobiology for the diagnosis and treatment of all clinical types of tinnitus by linking synaptic plasticity, not only with functional activity, and learning but also memory, sensory perception and behavior. The original sensorineural approach for understanding tinnitus with a focus predominantly on the ear and also brain reflected what had been known in the past of auditory and brain function. Significant is considered the correlation of the data between nuclear medicine brain imaging (PET CT) and electrophysiology quantitative electroencephalography (QEEG).
Specifically, the metabolic activity in ROIs of thalamus and primary auditory cortex with the ES CI #1 and CI #2, is hypothesized to reflect a reorganization in both with ES On and OFF i.e. Significant metabolic improvement in the thalamus, primary auditory cortex and medial temporal lobe with both conservative therapy and new CI #2 electrical stimulation. It is hypothesized that the SUV result in the primary auditory cortex clinically reflects the neuroprotective effect of the ES CI #2 for the sensory component of the SIT.
The interconnectivity between medial temporal lobe and frontal lobes are clinically considered to reflect process(es) underlying neuromodulation.
The clinical recommendation of functional brain imaging, metabolic with F-18 PET brain, and electrophysiology quantitative electroencephalography (QEEG) provide an objectivity for improvement of the accuracy of the tinnitus diagnosis and provide a rationale for treatment. The significant elimination of asymmetry with CI #2 in primary auditory cortex is not reflected in the degree of change in the F-18 FDG PET SUV hypometabolic activity in the medial temporal lobe.
3) The neuronal interconnectivity between thalamus, primary auditory cortex and medial temporal lobe reflect a medical significance other than limited to tinnitus. Clinically the correlation of tinnitus relief with the reduction in SUV asymmetry between the F-18 FDG PET and QEEG reduction in excess brain activity in delta and beta demonstrate the NM and NPT function of CI #2 ES. The neuroprotective process is clinically demonstrated by the efficacy of cochlear implant #2 in the both F18- FDG PET CT images, SUV, and QEEG recordings. Clinically significant is considered the correlation between the metabolic F18 FDG PET PET SUV in the thalamus, primary auditory cortex, mesial temporal lobes and the relative power Z-scores from the recording sites of the QEEG.
The perception of tinnitus has clinically been considered to be a "phantom sensory phenomenon90", i.e. A phantom symptom is physiologically defined as the lack of or inability to identify a underlying neural substrate.
Clinically the authors of this manuscript have recommended since 1989 that subjective idiopathic tinnitus of all clinical types and subtypes no longer be considered a "phantom" sensory auditory percept.
Evidence has been accumulating since 2004 that an imbalance between excitation and inhibition in multiple neuroanatomic substrates in brain underlies NPL NM NPT1,4,41. Synaptic plasticity has been reported to be reduced in adult brain compared to developmental brain1.
Identification in the clinical history of factors influencing the clinical course of the tinnitus, and treatment as appropriate, can result in tinnitus relief in individual tinnitus patients23,86,90. The responses to modalities of treatment are clinically oreflective of positive NPL, NM and NPT. The elimination of the negative effect of the ES of CI #1 and the positive effect ES of CI #2 is a clinical manifestation of NPL NM NPT underlying the reported subjective tinnitus relief. The ultimate goal is to identify multiple targets of tinnitus activity and develop multimodal tinnitus treatment approaches for all clinical types and subtypes of tinnitus, eg.
Functional brain imaging results presented in this manuscript provided clinical objective demonstration of the positive and negative effects of ES.
The authors gratefully express their appreciation to the Department of Otolaryngology, SUNY Downstate, Richard M. Non contrast CTB demonstrates a region of irregular density in the left temporal lobe, slightly hyperdense to adjacent white matter. CTA confirms the presence of a left temporal lobe arteriovenous malformation (AVM) which appears to receive the vast majority of its supply from the left middle cerebral artery. This case demonstrates characteristic CT and CTA appearances of a cerebral arteriovenous malformation (AVM). Adjacent perfusion asymmetries involving the frontal, temporal and parietal lobes suggest a interneuronal network resulting in the transition of the sensory to the affect components of the symptom of tinnitus. Descartes regarded the mind as something immaterial, separate from brain but interacting with it in some manner. Fear and stress in tinnitus patients particularly of the severe disabling type are a result of a paradoxical auditory memory of an aberrant dysynchronous auditory signal. The establishment of a paradoxical auditory memory for tinnitus is hypothesized to be the initial process localized in the medial temporal lobe. Demonstrations of SPECT imaging of rain in patients are presented to support this hypothesis.
The heterogeneity of response both for sensory and affect has been reported by professionals of all disciplines who are involved in tinnitus diagnosis and attempts for its control. The Papez circuit proposed the anatomical basis of emotion to consist of the cingulate gyrus which connects with the parahippocampal gyrus and peripheral area of the temporal lobe.
The anatomical components are best seen by a saggital section of the medial surface of the brain; and ventral views of the base of brain. Non-declarative memory, also called implicit memory, includes all abilities which are unconscious and expressed through performance.16 Such abilities provide for cumulative changes in perceptual and response systems of new skills and habits, priming, simple classical conditioning, and non-associative learning. Its chieffunction is the transition of a aberrant dysynchronous auditory sensory signal to a affective behavioral response (Fig. This conceptualization is a basic tenet of the FCP for tinnitus of the cochleovestibular system. The sensory and affect components are considered to be in a constant state of reciprocal interaction. For memory, alterations occur in the hippocampal formation with the establishment of a paradoxical memory for an aberrant dysynchronous signal.
I consider the experimental and theoretical work of consciousness as reflected in memory, to be a starting point to explain our SPECT findings to date.
Neurobiological theories of tinnitus awareness need to be developed and tested using a combination of molecular, neurobiological and clinical imaging studies.
It is possible that there is a localization in the MTLS for all sensory inputs similar to that which exists in the motor cortex. Specifically, the anatomic substrate where integration of sensory and affect components occurs for the auditory system, is suggested at this time to be in the MTLS.
Interference in masking within brain, initially at brain stem is hypothesized to set in motion a cascade of events wherein the sensory component is overwhelmed by that of the affect due to the establishment of a paradoxical auditory memory. Hinton et al.35 have described such neuronal networking in investigations simulating brain damage.
For the first time, here is a model which may differentiate tinnitus between its sensory and affect components both from its clinical and basic science perspectives. Jacobson L, Sapolsky R: The role of the hippocampus in feedback regulation of the hippothalamic - pituitary - adrenal cortex axis. LeDoux JE: Information flow from sensation to emotion plasticity in the neural computation of stimulus value.
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. Often, we find multisensory syndromes combined with tinnitus, hearing impairment, vertigo, and nausea.
Low-tone tinnitus is more frequently found in Meniere's disease and some other cochleo-apical disorders. In the high-tone range, most frequently tinnitus is matched and related to such conditions as noise trauma, whiplash, head and skull trauma, cardiovascular failures, stress, and toxic events, including pharmaceutical use, nicotine or drug abuse, and acoustic neuromas. Owing to the size of the workload, we limited ours efforts to constructing a sample from those 757 patients randomly selected from a major group of neurootological patients (we process more than 10,000 files of neurootological patients, many of whom suffer from one or another type of tinnitus).
We then conducted objective and quantitative electrophysiological measurements of the acoustic pathways via otoacoustic emissions, acoustic brainstem-evoked potentials, and acoustic late or cortical evoked potentials. We performed vestibulospinal recording of the CCG with the Romberg standing test and the Unterberger-Fukuda stepping test using USCCG and the human space trail. However, for this study, we present the broad spectrum of subjective complaints as reported by the patients with a broad variety of findings. This is shown for instance, in Figures 6 and 7, wherein the typical tinnitus phenomena are matched on different hearing zones in the audiograms of the right and left sides. Therefore, we prepared a specific, detailed analysis of the background of head and neck trauma (Fig.
Our search presented us with a great amount of data (more than 500 parameters per case), which we transferred into a digital version of the databank to preserve the anonymity of this sample of patients.
The other identification indicators (weight, height, body mass index, and average systolic and diastolic blood pressure) lie within the expected range of this sample taken for Germany.
For vegetative symptoms, such as the occurrence of nausea in perhaps one of four patients, see Figure 9. Acoustic, vestibular, and behavioral and psychosomatic symptoms are intertwined and seemingly interact with one another.
In a subsequent publication, we will deal with the outcome of the objective and quantitative measurements in audiology, equilibriometry, and the like in our group of 757 cases of endogenous tinnitus. However some people have especially sensitive hearing and are unable to tolerate ordinary levels of noise. The cochlea is often completely normal, although patients frequently wrongly believe it is irreversibly damaged.
This is what creates the feeling of unpleasntness, annoyance or fear in the presence of certain sounds.
This a€?programminga€™ results in a) invariable detection of the unpleasant sound – even when so quiet that others cant hear it, b) invariable limbic and autonomic reaction causing distress c) enhancement of auditory processing of this and other sounds leading to hyperacusis. This is commonly the source of distress in those who believe that their lives are ruined by environmental noise from nearby factories,generators or low frequency sounds transmitted through the ground (which other people may be unable to hear). You listen through headphones to sounds from a carefully calibrated instrument (audiometer), and respond (e.g.
Where phonophobia or misophonia exists there is an inevitable association of fear or dislike, associated with the appearance of the sound, whenever it occurs. Nearly all hearing aids have some form of compression,which stops loud sounds entering the hearing aid from being over-amplified.
In fitting hearing aids to sensitive ears, it is often best to leave the ear canal as un-occluded as possible, particularly to begin with.
A complete understanding of the Jastreboff model is necessary for both professional and subsequently the patient. This is particularly true in hyperacusis, where on some occasions, particularly in young children, it is all the treatment required. The effect, which in some cases may be quite dramatic, results in a a€?turning downa€™ of central auditory gain and a reduced perception of loudness for previously distressing sounds. It is hypothesized that when the balance between excitatory - inhibitory action is broken in sensory systems, predominantly due to neuromodulatory activity with reduced induced inhibition and excitation predominates, sensory circuits become plastic with adaptation at synaptic levels to environmental inputs1.
The cognitive brain function of "memory" is the predominant brain function that is hypothesized to bind the two together2. The resulting alterations in synaptic transmission and neuronal network function depend on the extent of calcium signaling and NMDA activation in response to different patterns of stimulation1,3,4. The roles of excitatory amino acids, specifically glutamate, and calcium as mediators of excitotoxicity has been reported with resultant cellular neuronal death. The reported role of NMDA receptors as the predominant molecular mechanism for the control of synaptic plasticity and memory function7.
Clinically, the excitatory hypothesis is considered significant for the development of an auditory memory, hypothesized to be "paradoxical" for tinnitus8.
The biophysiological processes of NPL, NM, NPT are ongoing and considered to have been and are critical in this development.
It has also been hypothesized that the neuroanatomical, neurophysiological and molecular properties of reticular neurons within the nucleus gigantocellularis (NGC) of the mammalian medulla, have a major role in GA.
When a stimulus is cognitively associated with reinforcement, its cortical strength is strengthened and enlarged.
Specifically, a hypothesis that attempts to explain how an aberrant auditory sensory stimulus becomes transformed into one of affect and somatosensory (motor) response(s). Initially the focus was on the sensorineural approach to understand tinnitus, limited predominantly to the ear, reflective of what was known of the cochleovestibular system.
Basic science investigations and clinical efforts for the diagnosis and treatment of all clinical types of tinnitus have been and continue to be grounded in translation of principles of sensory physiology for tinnitus. These advances have been integrated into expansion and supplementation of the predominant peripheral and original sensorineural theoretical approach for tinnitus based predominantly on the ear and brain to a focus on both brain and ear, which has found translation for tinnitus theory, diagnosis and treatment18,27-29. Interference in the precision, specificity involved in synaptic transmission for normal and interneuronal function reflects the complexity of the tinnitus symptom. Common to both is considered to be a "transient" imbalance between inhibition and excitation. In the visual system inhibitory plasticity has been considered to be important in circuit refinement that can contribute both to the compensatory forms of circuit plasticity in the early stages of development and to the pathological loss of function induced by visual deprivation during the critical period. The multiple biophysiological processes of NPL, NM, NPT reflect adaptation in neuroanatomic brain substrates and interconnectivities between neural circuits internal and external environments. Neural plasticity, NM, NP are biophysiological processes, linked together to assure structural maintenance and modification of neuronal ensembles with their synapses and circuitries, in response to internal and external sensory stimulation.
The sensory cortex responds to behavioral stimuli by different neuromodulators which control plasticity in the human brain by coordination of modifications at selected sets of neuronal synapses45.
Synaptic transmission and network function are dependent on which neuromodulatory systems are activated and on the extent to which intracellular Ca2+ signaling and NMDA receptor activation are engaged in stimulus patterns1.
The correlation between excitatory and inhibitory inputs may dictate the stability of synaptic fields in the developing auditory cortex.
The relationship between the strength and timing of excitatory and inhibitory currents control input integration48.
Sensory maps reflect the development of synaptic and spiking receptive fields at a neuronal population level49. Developmental windows called critical periods, are characteristic for most sensory cortices and structures important for emotion, eg Amygdala50. The relationship between synaptic plasticity and excitatory-inhibitory balance is consistent in the adult sensory cortex.
Activation of various modulatory systems can alter excitatory- inhibitory balance and enable experience -dependent modifications.
Neuromodulators, single or multiple including - acetylcholine, dopamine, serotonin or peptide modulators eg oxytocin result in activation different behavioral states, i.e. N-methyl-D- aspartate receptor, a glutamate receptor, is the predominant molecular device to control synaptic plasticity and memory function7. Failure to establish a synchrony of activity in response to the dysynchronous auditory stimulus may become clinically manifest by seizure activity, other neuropsychiatric symptoms, behavioral abnormalities, and tinnitus. It is hypothesized that common etiological agents that cause injury to the CNS have similar effects on the inner ear It is hypothesized that common etiological agents that cause injury to the CNS have similar effects on the inner ear. Neural plasticity is reported to be "considerable" in healthy individuals across life spans. Aging is associated with progressive losses in function across multiple systems, including sensation, cognition, memory, motor control, and affect. Behavioral training has been demonstrated in a reliable training gain for (intra modal) auditory but not for the (across-modal) visual transfer task.
Cognitive training was reported to be to be a potential tool for investigation of basic mechanisms of adaptive behavior, neuronal functioning, and design training69-72. Significantly in this study patients with impaired hearing identified with audiometry were excluded from this study73. Alpha band power was significantly reduced, whereas delta and gamma band power was significantly increased in the temporal regions74.
These data suggest that a physiologic link exists between the EEG and cerebral metabolism during anesthesia that is mathematically quantifiable80.
Clinically, to illustrate this point, are the reports of significant tinnitus relief with instrumentation, i.e. Summary: The positive and negative subjective results reported with multimodalities attempting tinnitus relief are clinically considered to reflect degree of success or failure of underlying biophysiological processes of NPL, NM, NPT. Routine PET processed standard uptake value data (SUV) was in turn analyzed by the NeuroQ program which provided a comparative three dimensional quantitative normative data base with statistical analysis of 240 neurologically appropriate ROIs normalized to whole brain counts after spatial morphing of subject data to the standardized 3D template.
To obtain objective evidence of activation of regions of inters(ROIs)t in brain by electrical stimulation with the implanted cochlear implant ear rt reported by the patient to result in an increased tinnitus severity. Visual interpretation of the PET images and QEEG data demonstrate a significant association between the thalamus and frontal lobes. Cerebral F-18 FDG Positron - CT brain Tomography color images represent greater to lesser relative ROI metabolic activity reconstructed from red (greater SUV) to blue (lesser SUV) multicolor display.
Treatment recommendations included diuretic therapy for presumed secondary endolymphatic hydrops lt; Gabapentin 300 mg bid, and Klonopin 5 mg hs for control. Color images identify clinically critical regions of thalamus (A), posterior frontal cortex (B), primary auditory cortex (C), and medial temporal lobe (D).
All results reported are based on an analysis of the data referenced to Z scores in the database described88,89. The QEEG clinically provides an electrophysiological correlate of brain wave of activity of multiple brain functions in the presence of the tinnitus signal.
Specifically, demonstration of a correlation between metabolic reduction in asymmetries in and between regions of interest in brain and electrophysiologic reduction in relative power Z-scores with cochlear implant #2 compared to cochlear implant #1. The complexities involved in NPL, NM, NPT are hypothesized to be reflected clinically in the heterogeneity of all clinical types and subtypes of tinnitus, and to underlie an ongoing attempt to maintain a normal homeostasis of function in underlying neuroanatomical substrates in brain. Advances in sensory physiology, auditory science, neuroscience of brain function, results of functional brain imaging technology all have dramatically shifted the focus for tinnitus to the brain. The FCP is suggested to be expanded for and to have clinical application for all sensations. Demonstration of evidence of tinnitus suppression in multiple brain ROIs with ES and pharmacological therapy. Positive and negatives effects of electrical stimulation (ES) clinically are demonstrated with functional brain imaging.
These are two different metrics which demonstrate and support the recommendation of clinical translation of these technologies particularly for SIT for improvement of accuracy for the tinnitus diagnosis and a monitor for treatment efficacy.
Reversal in the pattern of for activation and deactivation of the thalamus with activation and deactivation the CI #1 and CI #2. Correlation of the subjective tinnitus complaint with the alteration in SUV values is greatest in the order of the primary auditory cortex > thalamus, > medial temporal lobe.
The difference in SUV uptake values between the therapy and no ES CI #1 and CI #2 is highest in the significant reduction in the primary auditory cortex. The mild FDG-18 PET SUV asymmetry % in the thalamus with CI #2 on and off is clinically hypothesized to reflect a lack of total tinnitus suppression at the level of the thalamus - But-total tinnitus suppression at the level of the primary auditory cortex.
The Inter-connectivity between thalamus and primary auditory cortex, are clinically considered to reflect the process (es) underlying neuromodulation and reflected in the FDG -18 PET SUV% asymmetry indices. It is hypothesized that the brain functions of affect, behavioral response and memory functions, are in response to the presence of the tinnitus signal in brain and are reflected to the limits of this examination by the interconnectivity between medial temporal and frontal lobes. The tinnitus relief reported with the activation and use of CI #2 is an example of the neuroprotective function of electrical stimulation (ES). The hypo metabolic function in the medial temporal lobe is a reflection of the low level of metabolism associated with the low frequency brain wave activity. The striking feature in the FDG -18 PET SUV% asymmetry indices is the absence of asymmetry in the primary auditory cortex with the CI #2 on and off, and the marked reduction in asymmetry in the thalamus, primary auditory cortex, and medial temporal lobe with CI #2 and therapy including elimination CI #1 electrical stimulation.
The F-18 FDG PET and QEEG brain data provide objective evidence that CI #1 was a cochlear implant soft failure in this patient. The QEEG clinically provides an electrophysiological correlate of multiple brain wave activities accompanying multiple brain functions in the presence of the tinnitus signal. The identification of the biophysiology underlying NPL NM NPT for all tinnitus types and subtypes. Identification of similarities and differences, based on etiologies of tinnitus, in the neurobiology underlying the biophysiological processes of NPL, SD, NPT, and its linkage with functional plasticity, affect behavior, learning auditory perception and memory. Specifically, the development of a tinnitopharmacology reflective of the molecular genetic code of the individual tinnitus patient, i.e.
What is 'common' and shared for all clinical types of tinnitus in sensory auditory and non auditory for NPL NM NPT cortices and what is different, "special" for a particular clinical type of tinnitus, with "top down" or "bottom up" processing?
What significance is the etiology of the tinnitus in the activation of neuromodulator(s) at different neuromodulatory centers? Is the neurobiology underlying each of the four components of a particular type of tinnitus the same or different for the processes of NPL, NM, and NPT? How can the present evidence connecting synaptic plasticity to functional plasticity, perceptual learning and memory be translated to an increased accuracy for tinnitus diagnosis and efficacy for treatment for all clinical types and subtypes of tinnitus? Is the neurobiology the same for each of the four components of a particular type of tinnitus? Evidence has been presented connecting synaptic plasticity with functional plasticity, affect behavior, learning, auditory memory and perception and the underlying biophysiological processes of NPL, NSD, NPT. It is hypothesized that an imbalance between excitatory and inhibitory inputs at synaptic neuronal circuits in brain triggers synaptic plasticity, functional plasticity and the biophysiological processes of NPL ND and NPT. Neural plasticity, NM, NPT are biophysiological processes, linked together to maintain structure, maintain a homeostasis of normal function and reflect modification of selected neuronal ensembles with their synapses and circuitries, in response to internal and external sensory stimulation. The degree of efficacy of modalities of treatment attempting tinnitus relief are clinically considered to reflect varying degrees of activity of the biophysiological processes of NPL, NM, and NP. The clinical implications of Cerebral F-18 FDG PET CT SUV are multiple and highlighted by the significant absence of asymmetry at primary auditory cortex and reduction in the asymmetries for the non auditory thalamus and medial temporal lobes with CI #2.
Functional brain imaging is recommended to be considered for the clinical identification of a cochlear implant soft failure (CISF) in a predominantly central type subjective idiopathic tinnitus of the severe disabling type92. It is hypothesized that the input and output from the Olivary System in brain has a significant influence on normal and aberrant auditory function and maintenance of a balance between excitation and inhibition at sensory auditory cortex and the resulting biophysiological processes of NPL, NM and NPT93. In most institutions the next test would be non-invasive and either CT angiography or MR angiography. Contribution from the posterior cerebral artery is although likely via the lateral posterior choroidal arteries. Given its location in the dominant (assuming right handed patient) temporal lobe, likely deep drainage and a small (<3cm) nidus, this would have a S-M grade of 3. Localization of brain action is now possible and is being investigated with both Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT) brain imaging. The transition is acknowledged to be complex, involving an integration of multiple neuronal networks within the brain. The underlying mechanism is that of dysynchronization, that is, a lack of synchrony or interference in timing of the discharge rate and phase locking of the auditory signal having a location peripheral, central or both.
To date 48 patients were selected for SPECT imaging of the brain identified with the MATPP to have severe disabling tinnitus of the central type.
The clinical application of this hypothesis for present and future tinnitus diagnosis and treatment is conside d significant. It includes the subcallosal, cingulate, and parahippocampal gyri, the hippocampal formation, and the dentate gyrus. The temporal lobe connects with the hippocampus (AMMONS horn) via the temporoammonic tract.
The entorhinal cortex is a major source of projections at the hippocampus and in turn receives input from adjacent perirhinal, parahippocampal cortices.
Final Common Pathway for Tinnitus - The Medial Temporal Lobe System (Presentation at the Charles Univ. It is hypothesized based on our tinnitus experience that in the normal auditory system a sequence of auditory images, results first in establishment of an auditory memory for a sensory input, both short and long term; and secondarily a positive affective behavioral response. It is possible that there may be further or additional localization for a particular sensation. Feldmann reported the difference in interaction of signal and masker in patients with and without tinnitus by masking curves.
SPECT findings at this time suggest a common neural pathway and not an abstract algorithmic description. The FCP is a biological model which is an outgrowth of our ongoing attempts to integrate the basic sciences with our clinical experience for the diagnosis and treatment of all types and subtypes of tinnitus. Presented at the Fourth International Seminar Inner Ear Medicine and Surgery, July 1994, Snowmass, Colorado.
Observations of simultaneous auditory brainstem responses with monaural stimulation in the tinnitus patient.
On the Functional State of Central Vestibular Structures in Monaural Symptomatic Tinnitus Patients. 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. From more than 10,000 cases, we evaluated 757 randomly selected neurootological patients suffering from endogenous tinnitus.
However, what could be proved by various authors since 1985 is that endogenous tinnitus is significantly related to dysfunctions in the human temporal lobe (Brodmann area 41). We administered a full spectrum of neurootometric testing to all 757 patients; the investigation protocol for thorough data analysis (more than 500 parameters) included five procedures.
After all the files of the patients were transferred into digital lists and nets of digital data, we could select the various groups of complaints to derive a representative statistic. The most frequent quality of tinnitus distortion reported was a whizzing sound in either ear or in both (54.02%). Figure 21 demonstrates a specific differentiation with respect to facial nerve paralysis cases. We easily designated a group of patients who demonstrate a genuine objective sound in the head as experiencing bruits. In future, this must be taken into consideration in developing a spectrum of therapeutic procedures not only in the field of pharmacotherapy but in psychotherapy and physiotherapy and in applying such physical measures as magnetotherapy. We found diabetes mellitus more frequently in the group with the exogenous or unmaskable tinnitus, whereas hyperlipidemia was reported twice as often in the group with endogenous or maskable tinnitus as in those with the unmaskable type.
On the functional state of central vestibular structures in monaural symptomatic tinnitus patients. About the Strength of the Neck in Linking the Head to the Trunk as Measured by the US-CCG .
Interdisciplinary clinical vertigo studies in whiplash lesions to the ligamenta alaria by means of dynamic MRI-findings in combination with ultrasound cranio-corpo-graphy (USCCG).
Medical classification of tinnitus between bruits exogenous and endogenous tinnitus and other types of tinnitus. Die Differenzierung zwischen endogenem und exogenem Tinnitus [The differentiation between endogenous and exogenous tinnitus].
Often normal environmental sounds like traffic, kitchen sounds, doors closing, or even loud speech, cannot be tolerated, even though under any circumstances they cannot be damaging to anyone. In addition some sounds are inherently unpleasant, like the squeak of chalk on a slate, even though the number of decibels produced by this is very small. An example of this would be the detection of the quiet sound of an approaching predator by an animal living in a hostile environment. These emotional changes can also increase the apparent loudness and irritation of sounds to which we are already hypersensitive.
The attentional focus becomes filled with that sound, so that interference with concentration (on another task) occurs.
Over a period of months, due to changes in the auditory neuronal networks, there is a permanent change in loudness discomfort, which can be demonstrated by audiometric testing of loudness discomfort levels. Tinnitus an aberrant auditory sensation, for all clinical types, is clinically considered to reflect a failure of NPL, NM, and NPT to maintain normal auditory function at synaptic levels in sensory cortex and projected to downstream levels in the central auditory system in brain and sensorineural elements in ear. Modalities of tinnitus therapies, eg instrumentation, pharmacology, surgery, target a particular component of tinnitus, with resultant activation of neuromodulators at multiple neuromodulatory centers in brain and ear.
The neuronal circuits of control and regulation of the GA are considered central to understanding the origin and motivated behaviors e.g. The changes are caused by both the sensation and "learning of the sensory experience, particularly when associated with reward and classical conditioning behaviors16". The hypothesis of the FCP for tinnitus and the identified neuroanatomical substrates, highlighted by hypometabolism in the medial temporal lobe, and structures in the pontomesencephalic region of brain including the nucleus accumbens, 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 aberrant2.
Investigations for tinnitus, both clinical and basic science, attempting to answer this question for tinnitus are resulting in advances in the understanding of the ear and brain function, of the peripheral and central cochleovestibular system, translated for tinnitus diagnosis and treatment.
Neurotologic complaints of hearing loss, tinnitus, vertigo, ear blockage, hypercusis, alone or in combination, are a reflection of and associated with a damaged hearing system, but not tinnitus severity. Neuroanatomic substrates associated with tinnitus have been identified in brain with nuclear medicine single photon emission computerized tomography (SPECT) since 1989, which precludes by definition consideration of subjective idiopathic tinnitus to be a "phantom phenomenon2,6,8,32-34". Inhibitory plasticity as an important player in circuit refinement can contribute both to the compensatory forms of circuit plasticity in the early stages of development and to the pathological loss of function induced by visual deprivation during the critical period39. Outcomes also show acclimatization in the form of significant improvements in performance over time after implantation41. Developmental abnormalities in synaptic plasticity result in abnormal connectivity, functional disintegration and immaturity of auditory cortical areas, the smearing of feature representations in the auditory system, cross-modal recruitment of some auditory areas for non-auditory functions, and the reorganization of cognitive functions due to absence of auditory input42.
The goal is functional maintenance of an ongoing homeostasis of normal function to assure survival. Synaptic transmission and network function is dependent on which neuromodulatory systems are activated and on the extent to which intracellular Ca2+ signaling and NMDA receptor activation are engaged in stimulus patterns. The critical window is considered to exist not only for different modalities of treatment but for different functions of the same sensory system.
Neuromodulatory systems can differ one from the other with significant effects on functional maps and sensory performance52. Multiple ongoing processes and levels of activity are involved at organ, tissue, cellular, synaptic and molecular genetic locations. It involves and reflects adaptive and maladaptive changes in neuronal activity at cortical and subcortical levels of neuronal activity.

The chief etiologies to be considered include ischemia, trauma, or hemorrhage, and neurodegenerative disease. Alterations in local excitatory circuitry increase the spread of spared representations into deprived cortical regions61.
The mechanisms involved are reported to support cognition and are influenced by normal ageing, particularly in the medial temporal lobe and prefrontal cortex, changes in which can clinically demonstrate interference in behavior62-67. Training-induced activation decreases in the auditory transfer task were found in two regions in the right inferior frontal gyrus. Given the heterogeneity reported apparently other conditions must modify the EEG content in these tinnitus patients75,76. A widespread inverse relationship of delta power to metabolism was found between various regions; additionally, delta power was negatively correlated to cerebral glucose metabolism in individual regions. C-R neuromodulation, a potential significant advance for all clinical types of tinnitus treatment objective electrophysiological evidence is demonstrated of improvement in particular neural circuitry(ies) neuroanatomical substrates of brain functions, and resultant reported tinnitus84. In rodents, an increase in dopamine neurons in the nucleus accumbens modulated the neural encoding of depression related behaviors, suggesting that processes affecting depression symptoms may involve alterations in neural encoding action in the limbic system85.
Before and after activation of cochlear implant sequential FDG scan coronal images reveal that following activation of cochlear implant which produced greater tinnitus especially of the right side (R), FDG activity is markedly elevated in ipsilateral right thalamus and primary auditory cortex. The impedance measured at each electrode site with respect to the reference was less than 5,000 Ohms. Multicolor display for each study is designed to maximize visualization of relative functional ROI asymmetry and not absolute activity as expressed in standard uptake value (SUV). With removal of cochlear implant #1 and reimplantation with cochlear implant #2 the brain wave activities for all frequencies returned within the normal range. Tinnitus is a symptom of neurotologic disease in which ear and brain functions are of equal significance.
The metabolic activity between thalamus and frontal cortex clinically is hypothesized to reflect a thalamocortical oscillation and dysrhythmia.
Specifically with the new CI #2, the patient reported significant subjective tinnitus relief ear rt and improvement hearing. Significant is considered the absence of asymmetry with ES CI #2 in the primary auditory cortex. Clinically the PET SUV values are considered to reflect the metabolic effects of neuroplasticity (NPL), neuromodulation (NM), and neuroprotection (NPT) associated with electrical stimulation. Clinically, the thalamo cortical interconnectivity may have a dynamic range of activity greater for overall sensory function than that between the temporal and frontal lobes. The affect, behavioral response to the presence of the tinnitus and memory functions are individual for each tinnitus patient for all clinical types of tinnitus.
The tinnitus relief is a clinical manifestation of the linkage between the biophysiological processes of NPL, NM, NPT. This is correlated with the delta frequency of brain wave activity demonstrated in the QEEG.
Clinically this provides objective evidence in support of the recommendation for attempting tinnitus relief by identification and treatment of factors influencing the clinical course of all clinical types of tinnitus, individual for each tinnitus patient.
The recommendations to specify, alone or in combination, which component(s) of the aberrant tinnitus sensation, is being targeted by a particular modality of tinnitus treatment.
The goal short and long term is functional maintenance of an ongoing homeostasis of normal function for survival.
Clinically, this result is demonstration of the specificity of ES for the sensory component of the tinnitus as well as the affect behavior, i.e. D, Professor and Chairman, and the Martha Entenmann Tinnitus Research Center, Inc., for support of this educational and research effort. Final common pathway for tinnitus: theoretical and clinical implications of neuroanatomical substrates. Unilateral cochlear ablation produces greater loss of inhibition in the contralateral inferior colliculus.
Electrodiagnostics, Electrotherapeutics, and other Approaches to the management of tinnitus. Tinnitus dyssynchrony-synchrony theory: a translational concept for diagnosis and treatment.
Catheter angiography, although usually required eventually, is usually a second step, at which time intervention can also be contemplated. Underlying mechanisms are hypothesized to exist and to be highlighted by a diminution of inhibition mediated by gamma aminobutyric acid (GABA) due to disconnection from excitatory (glutamate) inputs.
It is considered to transcend the classica thinking of tinnitus as an auditory signal restricted to the auditory pathway.
The limbic system is a term used to include the limbic lobe and associated subcortical nuclei (amygdaloid complex, septal nuclei, hypothalamus, epithalamus and other thalamic nuclei). The frontal, temporal, parietal lobes project to the perirhinal, parahippocampal cortices from unimodal and polymodal areas.
A paradoxical memory modulates the transition between the sensory and behavioral component of tinnitus. It is speculated that for tinnitus the amygdala is significant for the alteration in emotional behavior described by the patient. It is speculated that the primary auditory cortex projects to the hippocampus and amygdaloid complex. The masking curves "can be thought of as contour lines of the neural elements involved in processing signal and masker."34 Tinnitus is believed to produce or reflect a instability or interruption in auditory masking function. The future is to identify neural networks and to create idealized computer simulates of groups of neurons. For auditory perception this includes the inner ear and Organ of Corti; transmission within the ascending auditory system to registration of impulses within the auditory cortex. 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. First, we classified the 10,000 patients into those suffering from the basic tetrad of tinnitus forms: bruits, endogenous (maskable) tinnitus, exogenous (nonmaskable) tinnitus, and other syndromes such as the slow brainstem syndrome. Patients with a maskable or endogenous tinnitus prefer covering up their tinnitus by external sounds. We found typical shortenings in the latencies of the vestibular evoked quantitative electroencephalography (QEEG), an enlarged DC shift of the vestibular evoked QEEG, and typical cortical electrical burst expansion in three phases on the brain surface as shown by BEAM. First we recorded a thorough neurootological history with a systematic preprinted history scheme of Neurootologisches Anamneseschema Claussen (Neurootological History Scheme). As the sum of all the tinnitus spots being masked amounts to 141.74%, we were able to derive that nearly one-half of the sample suffered from a bilateral maskable tinnitus. The majority of patients (consistent through all age groups) reported so-called whiplash-related tinnitus problems after a car accident. The frequently reported sensation of a roaring in the right or the left ear occurred in only 0.13% (left ear) in our sample. In Vertigo, Nausea, Tinnitus and Hearing Loss in Central and Peripheral Vestibular Diseases . In JM Aran, R Dauman (eds), Proceedings of the Fourth International Tinnitus Seminar, Bordeaux, 1991 . There are different components which can contribute to sensitive hearing hyperacusis, phonophobia and misophonia recruitment. In misophonia and phonophobia certain complex sounds produce discomfort, on the basis of their meaning or association, while other sounds which are enjoyed (such as music) can be tolerated at much higher intensity levels. During the passage of this coded signal, it undergoes a great deal of processing, similar to a computer, but much more complex.
Another example would be the ability to detect the sound of one’s name across a crowded room, while other names, even if spoken quite loudly would go unnoticed. The responses are set up because of experiences, or beliefs about sound which have been previously learned.
These conditioned responses act like survival reflexes and have to carry a message of unpleasant emotion, in order to ensure that a response occurs. In the relative silence of houses with doubled-glazed windows, often hermetically sealed from the outside world, the absence of sound stimulation leads to an increase in auditory gain (amplification) in the subconscious auditory pathways.
In patients where a severe increase of symptoms occurs, which genuinely persists after a good nights sleep, very careful use of sound therapy needs to be applied, under the guidance of an experienced professional. In some children with hyperacusis it may be the dominant problem and respond quickly to desensitization due to the increased neural plasticity in this age group .
Effective neuromodulation at sensory neuronal synaptic levels results in NPL in sensory cortex, NPT and tinnitus relief. Specifically for tinnitus this has resulted clinically in an alteration in the definition of tinnitus, theories of hearing and balance, introduction of new concepts of central auditory function, relationship between tinnitus and hearing loss, expansion of existing teachings in neurotology to include principles of sensory physiology for complaints of hearing loss, tinnitus and vertigo; and the translation of concepts of heterogeneity, homeostasis of function for tinnitus diagnosis and treatment. This focus has resulted in an emerging neurobiology for tinnitus reflective of which brain function(s) are elicited in the presence of the tinnitus signal. Whereas alterations during the early development of sensory cortices are very long lasting and frequently permanent37 plasticity in the adult sensory cortex is frequently transient38. Patterned stimulation increased the correlation between excitatory and inhibitory inputs nonspecifically, with improvement in the overall balance47.
The result of the reorganization is a positive or negative alteration in structure and or function from the normal, i.e.
A brain-plasticitybased intervention targeting normal age-related cognitive decline may potentially offer benefit to a broad population of older adults68. The right inferior frontal gyrus is frequently found in maintaining modality-specific auditory information. Frontal theta power correlated especially with rostral thalamic central medial nucleus (CMR). Patient ROI count data falling more than 1.65 STD beyond the mean value for a longitudinally validated control group ROI is flagged as abnormal by the NeuroQ analysis. The SUV% asymmetry between rt and lt thalamic metabolic activity is decreased bilateral with activation and deactivation, but reversed asymmetry compared to the old CI #1. This predominance of the ES effect in the primary auditory cortex clinically supports the observation of the high association of "tinnitus" with sensorineural hearing loss but not with severity.
The "plasticity" may be of a higher order reflecting an "older "origin of brain structure and function in the hierarchy of phylogenetic development of the brain. Significantly, the functional brain imaging with FDG -18 PET and the SUV% asymmetry indices correlate with the electrophysiology quantitative electroencephalography (QEEG) relative power scores (Tables 1 and 2). At synaptic levels in brain, for each component of all sensations, there is an attempt to connect synaptic neuronal plasticity with functional plasticity, affect behavior, somatomotor response, learning and memory.
Blockage of GABA mediated inhibition results in Tinnitogenesis, a epileptiform auditory phenomena. The clinical manifestations of the affective behavior of the tinnitus patient can be considered to be components of the FCP for tinnitus. Physiologic evidence suggests functional differences between the various components although most are related to visceral or behavioral activities (Fig.
The mamillary body connects with the anterior nucleus of the thalamus via the mamillothalamic tract. Severe memory impairment associated with hippocampal and amygdala lesions were attributed not to the addition of the amygdala to the hippocampal lesion but instead to the addition of cortical regions that lie adjacent to the amygdala and that are necessarily damaged when the amygdala is removed or impaired. This sequence of events is hypothesized to exist in general for other sensory systems and specifically for the cocheovestibular system. The central efferent system at a cortical and subcortical level at brainstem is speculated to control the masking capability of the auditory system. 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. Next, we examined all the patients otologically, including bilateral microscopical inspection of the outer ear, ear canal, and tympanic membrane. They also reported posttraumatic complaints of whiplash injury (also consistent through all the age groups but especially frequent in the age group 30-40 years). Significantly different from the group identified as having endogenous tinnitus are the behavior and the sensation of those with exogenous tinnitus or nonmaskable tinnitus, who find relief in a completely silent environment. The majority of our patients described their tinnitus as lasting from one to several years (as seen in Fig. We found that 3.70% of patients complained about a reduced acuity in their taste (hypogeusia). Our knowledge based on the Jastreboff model and desensitization techniques developed in the 1980s now allows effective treatment of hyperacusis and misophonia.
If there is a difference in the intensity of different sounds which produce discomfort, then it is very likely that a degree of misophonia exists. In the subconscious part of the auditory system brain, an important signal is detected on the basis of previously learnt experience. An equally important, but less frequently used test measures the upper limit of loudness tolerance (loudness discomfort levels). Alternatively it may present only as a part of a wider problem, which will not respond to TRT. The GA hypothesis is recommended to be considered for translation of the affect behavioral component of all clinical types of tinnitus9.
In this case the neurobiology for tinnitus that is being identified in brain is "top down".
This is another example of two of the three components of the aberrant tinnitus sensation, i.e. These results might reflect increased neural efficiency in auditory working memory processes. Three hundred (300) epochs were recorded; twenty five (25) were selected as being representative and artifact-free, processed and compared with the normative database. The SUV for thalamus, primary auditory cortex, medial temporal lobes with CI #1 and CI #2 provide objective data reflective of a reduction in metabolic activation in all three ROIs which correlates with the reduction in the relative power Z scores.
The asymmetries and brain location of the PET SUVs for the thalamus clinically are considered to support the thalamocortical and thalamocortical dysrhythmia hypothesis translated for tinnitus.
In the future, as the clinical experience of multiple disciplines increases for the symptom of tinnitus, it is predicted that additional components will be identified. The anterior nucleus of the thalamus connects with the cingulate gyrus via the superior thalamic peduncle, thus completing the circuit.
The entorhinal cortex was suggested to be the principle route by which information from the neocortex reaches the hippocampus.
Other aberrant sensations experienced by patients include hyperacusis, dysacusis, vertigo, etc. For tinnitus such abilities may reflect cumulative changes in perceptual and response systems and for the development of new skills and habits personified by increasing attention to tinnitus and inability to "cope" with tinnitus. The reciprocal projections between the entorhinal cortex, hippocampus and amygdala result in an emotional response. The degree of inhibition regulated by GABA function is hypothesized to be reflected in the degree of development of the paradoxical memory for tinnitus. Kassirer stated it well in discussing a visual image in clinical medicine that "often we are creating mental models of physical models. 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.
Car accidents and whiplash occur more frequently in the younger age groups, whereas reports of cerebral concussions are more frequent in the old-age group (> 70 years).
Finally, via our complex neurootometric tests, we demonstrated slowing deregulations in the statoacoustic pathways. We heard no complaints about trigeminal disorders; however, we found both peripheral and central facial nerve paresis, though in a small number (see Fig.
28) played a minor role in our sample, as was evident for the major hormonal diseases (Fig. Misophonia can lead to hyperacusis (changes in central auditory processing), and a consequent persistence of abnormal loudness perception.
You should indicate when the tones become uncomfortable to the ear (before they become painful). This process is enhanced by silence which is considered to be one of the signs of possible predator activity . This does not mean that treating the decreased sound tolerance component with TRT is not worthwhile, and it frequently contributes in a positive way to the overall life quality of the child. There is a need to differentiate between the dysynchronous signal hypothesized to be tinnitus and the synchrony of neuronal activity at the brain cortex, which is expressed as the function of perception and conscious awareness of tinnitus19. The goal is to attempt to restore and or to maintain a homeostasis of normal neural function in the peripheral and or central nervous system56. The increasing identification of neuroanatomic substrates in subjective idiopathic tinnitus (SIT) for all clinical types and subtypes of SIT supports consideration that tinnitus no longer be considered to be a "phantom" sensory auditory percept. Additional feeding pathways to the circuit were described to include the septal and olfactory regions and amygdala. Increasing attention and a probable relationship to sleep phenomena also is considered to be a reflection or projection from the amygdala to sleep areas in cortex. 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 statistical results demonstrate that tinnitus is interconnected to a multifactorial disease background with a broad spectrum of individual complaints. Only 0.13% of our patients described a subjective roaring sound in the left ear, whereas none attributed it to right ear.
In such cases, the visual acuity problems were corrected most frequently by use of eye glasses (74.50%).
Here the auditory pathways may be functioning normally, but there is an abnormally strong reaction of the limbic (emotional system) and autonomic nervous system (body control system) to which the auditory system is intimately connected.
For patients who are frightened of loud sounds this test must be done very carefully and with proper instruction by a TRT trained professional. The raw data EEG results were submitted to the Lexicor Company for analysis, and that firm generated a report called the Datalex report for clinical application (Lexicor Medical Technology, Inc. It is hypothesized that this is reflected clinically in the high incidence of association between sensorineural hearing loss and tinnitus - but - not in the tinnitus severity and auditory brain function of memory. The reciprocal interconnections between primary and secondary associated auditory cortices and vestibular cortices of the cochleovestibular system reflect multiple neuronal networks which have the capability to adapt to changes reflecting alteration in sensory input and output due to different factors influencing neuronal activity of the cochleovestibular system and other systems at a cortical and subcortical levels.
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. Finally, the topodiagnostics of the functional neurootometric analysis shows that this type of endogenous tinnitus constitutes decidedly more central than peripheral statoacoustic pathology.
Astonishingly, even the number of occurrences of basic neurological disorders (paralysis, paresthesias, apoplexies, epilepsia, Parkinson's disease, and brain tumors) was very low (as shown in Fig. Patterns of frequencies of sound are enhanced or suppressed to varying degrees on the basis of their meaning, but nothing od significance is heard until it is matched with a pattern in auditory memory. None of the sounds from the audiometer are capable of damaging the ear, even in a sensitive individual.
External sounds may then increase dramatically in their perceived intensity and intrusiveness.
Functional brain imaging, metabolic (PET brain) and electrophysiology quantitative electroencephalography (QEEG) data in a cochlear implant soft failure patient demonstrates what is clinically considered to reflect NPL, NM, NPT.
It is considered to provide a clinical objective demonstration of neural electrical activity, neural plasticity, neuromodulation with and without tinnitus treatment e.g. Young (1991) considered for depression that the location of cortisol control to be not in the hypothalamus but rather in the hippocampus.26 It is proposed for tinnitus that a cycle can be established wherein reciprocal projections between hippocampus, amygdala, entorhinal cortex and hypothalamus vary in the degree of control of cortisol levels resulting in further strengthening of an already established paradoxical memory with resultant additional negative affect behavioral manifestations of emotion, fear, anxiety, depression, etc. 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 high-frequency tinnitus often develops close to the C5 dip and can be masked below the hearing threshold (see Fig. Clearly, a typical interrelation of tinnitus with a single major disease group is highly unlikely. The strength of this pattern matching dictates the loudness and intrusiveness of the sound perceived.
It is very important to have a good knowledge of the level of loud sound tolerance when diagnosing and treating decreased sound tolerance, or when fitting a sound generator or hearing aid to any patient, whether they have hyperacusis or not. Some people take to wearing ear plugs, perhaps at night, to avoid sounds becoming intrusive, and this simply worsens the sensitivity. The reader is provided with a rationale for tinnitus diagnosis and treatment, with a focus on ES, reflecting the biology underlying NPL, NM, NPT. Neuronal networks are hypothesized to exist which in the past were identified as primary and secondary areas. 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]. This can be quite different from the intensity or energy of the sound in the environment outside. When hyperacusis develops there is a great temptation to plug the ear to exclude unwelcome sounds. In each case carefully explanation of the mechanism of central processing must be given, so that individuals can understand and believe what has happened to them, and that the whole process is reversible with time, and the appropriate therapy. 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. This is actually making things worse, as it encourages further increase in the amplification of sounds on their way to the auditory (hearing) cortex.
Where misophonia (dislike) or phonophobia (fear of sound) exists, no permanent change in discomfort can be achieved without a successful behavioural programme aimed at reversing inappropriate beliefs responsible for the conditioned aversive response.
Such regulation includes mechanisms that have been subdivided into two distinct pathways:GABA-A receptor downregulation and GABA-A receptor upregulation.
When these sounds are heard in the absence of plugs, their perceived loudness is greatly increased. It is conceived that the excitatory action of the amino acid glutamate may result in more than one physiological function. 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 whole process of desensitization can take quite a long time, commonly six months to a year, but is achievable in most cases. 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. In rare cases where phonophobia is present alone without any hyperacusis, WSGs are not indicated. 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. It is speculated that the GABAergic inhibition and resultant glutamate excess produces a disruption in calcium homeostasis. 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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