Model Of Tinnitus Research Articles

Tinnitus and brain MRI findings in Japanese elderly

Conclusion. There is evidence of an inverse association between cerebral infarction and tinnitus in this study. The effects of cerebral infarction on tinnitus could be explained by a neurophysiological model of tinnitus. Objectives. We examined the relationship between tinnitus and brain MRI findings including cerebral infarction, brain atrophy, ventricular dilatation, and white matter lesions. Subjects and methods. This was a cross-sectional population-based study of 2193 subjects aged 41–82 years living in Aichi prefecture, Japan. Detailed questionnaires, pure tone audiometry, and brain MRI were performed. Results. After adjusting for potential confounders in a multiple logistic analysis, cerebral infarction was inversely associated with tinnitus (odds ratio (OR)=0.649, 95% confidence interval (CI)=0.477–0.884). Cerebral infarctions of the basal ganglia (OR=0.542), thalamus (OR=0.441), and pons (OR=0.319) were especially associated with tinnitus. Brain atrophy, ventricular dilatation, and white matter lesions had no significant effects on the prevalence of tinnitus.

Age-Related Hearing Loss in C57BL/6J Mice has both Frequency-Specific and Non-Frequency-Specific Components that Produce a Hyperacusis-Like Exaggeration of the Acoustic Startle Reflex

Auditory brainstem-evoked response (ABR) thresholds were obtained in a longitudinal study of C57BL/6J mice between 10 and 53 weeks old, with repeated testing every 2 weeks. On alternate weeks, acoustic startle reflex (ASR) amplitudes were measured, elicited by tone pips with stimulus frequencies of 3, 6, 12, and 24 kHz, and intensities from subthreshold up to 110 dB sound pressure level. The increase in ABR thresholds for 3 and 6 kHz test stimuli followed a linear time course with increasing age from 10 to 53 weeks, with a slope of about 0.7 dB/week, and for 48 kHz a second linear time course, but beginning at 10 weeks with a slope of about 2.3 dB/week. ABR thresholds for 12, 24, and 32 kHz increased after one linear segment with a 0.7 dB slope, then after a variable delay related to the test frequency, shifted to a second segment having slopes of 3-5 dB/week. Hearing loss initially reduced the ASR for all eliciting stimuli, but at about 6 months of age, the response elicited by intense 3 and 6 kHz stimuli began to increase to reach values about three times above normal, and previously subthreshold stimuli came to elicit vigorous responses seen at first only for the intense stimuli. This hyperacusis-like effect appeared in all mice but was especially pronounced in mice with more serious hearing loss. These ABR data, together with a review of histopathological data in the C57BL/6 literature, suggest that the non-frequency-specific slow time course of hearing loss results from pathology in the lateral wall of the cochlea, whereas the stimulus-specific hearing loss with a rapid time course results from hair cell loss. Delayed exaggeration of the ASR with hearing loss reveals a deficit in centrifugal inhibitory control over the afferent reflex pathways after central neural reorganization, suggesting that this mouse may provide a useful model of age-related tinnitus and associated hyperacusis.

Primary afferent dendrite degeneration as a cause of tinnitus

Chronic tinnitus affects millions of people, but the mechanisms responsible for the development of this abnormal sensory state remain poorly understood. This study examined the type and extent of cochlear damage that occurs after acoustic trauma sufficient to induce chronic tinnitus in rats. Tinnitus was evaluated by using a conditioned suppression method of behavioral testing. Cochlear damage was assessed 6 months after acoustic trauma. There was minimal loss of inner and outer hair cells in the exposed cochleas of subjects demonstrating evidence of tinnitus. However, a significant loss of large-diameter fibers in the osseous spiral lamina of exposed cochleas of trauma subjects was observed. The significance of this finding in the context of a model of tinnitus is discussed.

The role of central nervous system plasticity in tinnitus

Tinnitus is a vexing disorder of hearing characterized by sound sensations originating in the head without any external stimulation. The specific etiology of these sensations is uncertain but frequently associated with hearing loss. The “neurophysiogical” model of tinnitus has enhanced appreciation of central nervous system (CNS) contributions. The model assumes that plastic changes in the primary and non-primary auditory pathways contribute to tinnitus with the former perhaps sustaining them, and the latter contributing to perceived severity and emotionality. These plastic changes are triggered by peripheral injury, which results in new patterns of brain activity due to anatomic alterations in the connectivity of CNS neurons. These alterations may change the balance between excitatory and inhibitory brain processes, perhaps producing cascades of new neural activity flowing between brainstem and cortex in a self-sustaining manner that produces persistent perceptions of tinnitus. The bases of this model are explored with an attempt to distinguish phenomenological from mechanistic explanations. Learning outcomes: (1) Readers will learn that the variables associated with the behavioral experience of tinnitus are as complex as the biological variables. (2) Readers will understand what the concept of neuroplastic brain change means, and how it is associated with tinnitus. (3) Readers will learn that there may be no one brain location associated with tinnitus, and it may result from interactions between multiple brain areas. (4) Readers will learn how disinhibition, spontaneous activity, neural synchronization, and tonotopic reorganization may contribute to tinnitus.

Cannabinoid receptor down-regulation in the ventral cochlear nucleus in a salicylate model of tinnitus

Cannabinoid CB1 receptors have not been systematically investigated in the brainstem cochlear nucleus, nor have they been investigated in relation to tinnitus. Using immunohistochemistry and cell counting, we showed that a large number of neurons in the rat cochlear nucleus possess cannabinoid CB1 receptors. Following salicylate injections that induced the behavioural manifestations of tinnitus, the number of principal neurons in the ventral cochlear nucleus expressing CB1 receptors significantly decreased, while the number of CB1-positive principal neurons in the dorsal cochlear nucleus did not change significantly. These results suggest that CB1 receptors in the cochlear nucleus may be important for auditory function and that a down-regulation of CB1 receptors in the ventral cochlear nucleus may be related to the development of tinnitus.

Physiology and phenomenology of tinnitus: Implications for treatment

We examine a contrast in understanding tinnitus and how this impacts on treatment approaches. First, a physiological account of tinnitus is described based on disinhibition and cortical remapping following injury at the receptor level, the analog for tinnitus being the ‘phantom limb pain’ phenomenon. Secondly, an experimental model of tinnitus is reviewed that relies on inference from conditioning animal behaviour. Arising from this, a role for conditioning in people distressed by tinnitus has been proposed, based on the unfounded premise that, for humans, tinnitus is a neutral stimulus, the distress being due to association with other stressful events. We critique this because we believe it influences approaches to tinnitus treatment. Finally, the phenomenology of tinnitus in the human case is analysed, with its nature illuminated via a series of distinctions with hearing impairment. Tinnitus can be intrinsically stressful for some people. Understanding this emphasizes the need to involve concepts and treatment in the area of clinical psychology. A flexible coalition between clinical audiologists and clinical psychologists is proposed as fruitful for tinnitus and related rehabilitation.

Safety Pharmacology Society: 6th Annual Meeting

The Safety Pharmacology (SP) Society annual meeting discussed organ and physiological system safety issues encountered during the course of clinical candidate selection and evaluation for human testing. Plenary sessions were dedicated to embryonic stem cell opportunities, successes, threats and new opportunities of SP, and the remembrance of our forever gone colleague, Dr Munehiro Hashimoto. The day-long QT interval liability session, attended by the majority of the 472 meeting participants, covered all the current facets of this topic with undeniable expertise, but limited novel data. CNS subjects of interest were drug dependence and abuse potential, a behavioural model of tinnitus, the use of electroencephalography in SP and the translation of nonclinical pro-convulsive signals into clinical trial management. Gastrointestinal and renal SP were also discussed in terms of novel experimental approaches. New horizon sessions addressed biowarfare and biodefence, enabling technologies for key decision-making in initial clinical testing and the future of SP. Thus, a wide spectrum of material for both education and reflection was offered to veteran and younger investigators desiring to further their knowledge in current SP themes.

Tinnitus Sensitization

Acquired centralized tinnitus (ACT) is the most frequent form of chronic tinnitus. The proposed ACT sensitization (ACTS) assumes a peripheral initiation of tinnitus whereby sensitizing signals from the auditory system establish new neuronal connections in the brain. Consequently, permanent neurophysiological malfunction within the information-processing modules results. Successful treatment has to target these malfunctioning information processing. We present in this study the neurophysiological and psychophysiological aspects of a recently suggested neurophysiological model, which may explain the symptoms caused by central cognitive tinnitus sensitization. Although conditioned reflexes, as a causal agent of chronic tinnitus, respond to extinction procedures, sensitization may initiate a vicious circle of overexcitation of the auditory system, resisting extinction and habituation. We used the literature database as indicated under "References" covering English and German works. For the ACTS model we extracted neurophysiological hypotheses of the auditory stimulus processing and the neuronal connections of the central auditory system with other brain regions to explain the malfunctions of auditory information processing. The model does not assume information-processing changes specific for tinnitus but treats the processing of tinnitus signals comparable with the processing of other external stimuli. The model uses the extensive knowledge available on sensitization of perception and memory processes and highlights the similarities of tinnitus with central neuropathic pain. Quality, validity, and comparability of the extracted data were evaluated by peer reviewing. Statistical techniques were not used. According to the tinnitus sensitization model, a tinnitus signal originates (as a type I-IV tinnitus) in the cochlea. In the brain, concerned with perception and cognition, the 1) conditioned associations, as postulated by the tinnitus model of Jastreboff, and the 2) unconditioned sensitized stimulus responses, as postulated in the present ACTS model, are actively connected with and attributed to the tinnitus signal. Attention to the tinnitus constitutes a typical undesired sensitized response. Some of the tinnitus-associated attributes may be called essential, unconditioned sensitization attributes. By a process called facilitation, the tinnitus' essential attributes are suggested to activate the tinnitus response. The result is an undesired increase in responsivity, such as an increase in attentional focus to the eliciting tinnitus stimulus. The mechanisms underlying sensitization are known as a specific nonassociative learning process producing a structural fixation of long-term facilitation at the synaptic level. This sensitization model may be important for the development of a sensitization-specific treatment if extinction procedures alone do not lead to satisfactory outcome. Inasmuch as this model considers sensitization as a nonassociative learning process based on cortical plasticity, it is reasonable to assume that this learning process can be altered by counteracting learning procedures. These counteracting learning procedures may consist of tinnitus-specific cognitive and behavioral procedures.

Neuronal nitric oxide synthase expression in the cochlear nucleus in a salicylate model of tinnitus

Although a number of studies suggest that the development of tinnitus is associated with hyperactive neuronal discharges in the brainstem cochlear nucleus (CN), there is relatively little evidence to indicate the neurochemical basis of this phenomenon. While some studies suggest that it may be partly due to a decrease in GABAergic inhibition, it is also possible that increased excitability is a contributing factor. In the current study, we investigated whether the salicylate animal model of tinnitus is associated with changes in the number of CN neurons expressing neuronal nitric oxide synthase (nNOS), one of the NOS isoforms that results in the production of the neurotransmitter, nitric oxide. We used a behavioral conditioning paradigm to confirm that animals receiving salicylate injections experienced tinnitus, and used immunohistochemistry with stereology to quantify the number of nNOS-expressing neurons in the dorsal and ventral CN (DCN and VCN, respectively) in salicylate- and vehicle control-treated animals. We also employed Western blotting to quantify the amount of nNOS protein expression in the total CN (i.e., the DCN and VCN together). We found a significant increase (of approximately 70%) in the number of nNOS-expressing principal neurons in the VCN of salicylate-treated animals compared to controls, with no significant differences in the DCN; nor did we find any significant difference in the overall level of nNOS protein in the total CN using Western blotting. These results suggest that changes in the number of neurons in the VCN expressing nNOS may be implicated in the mechanisms of tinnitus.

Tinnitus

Chronic idiopathic subjective tinnitus is a common condition affecting around one in ten of the population at any given time. For the majority of people it is an annoyance rather than a major health issue but for approximately 0.5 per cent of the population tinnitus interferes with their ability to pursue a normal life. Modern theories of the pathogenesis of the condition concentrate on the central auditory system although the peripheral auditory system can be a trigger or ignition site for tinnitus. Although a cure remains elusive there are several good treatment strategies based on psychological and neurophysiological models of tinnitus that promote habituation to the symptom.

What progress have we made with tinnitus?

Conclusion: The field of tinnitus research is vibrant and active. Prospects for progress are high, but would be optimized by the growth of inter-disciplinary collaborations. Objective: Tinnitus remains a source of urgent scientific investigation, and truly effective treatments continue to be elusive. The Tonndorf Lecture of the International Tinnitus Seminars represents an opportunity to reflect upon progress to date regarding tinnitus, and the actions needed to further that progress in future. Method: Progress regarding tinnitus mechanisms is reviewed, with particular regard to the conceptual distinction between ignition sites for tinnitus, and the physiological mechanisms that then promote the tinnitus through the central auditory pathway. The current status of both the Jastreboff neurophysiological model and the psychological model of tinnitus is reviewed. Some concerns regarding each model are raised, and the need for models that integrate the insights of both perspectives is identified as urgent. Results: There are clear indications of progress in tinnitus, specifically regarding mechanisms, models and treatments. For knowledge to progress further, however, there is a pressing need for an inter-disciplinary approach to tinnitus, more involvement in teaching at a postgraduate level, and the development of experimental models of tinnitus that are both congruent with, and represent the complexity of, human experience of tinnitus.

Strategies of the Tinnitus Research Consortium

Conclusions: Research supported by private philanthropy complements governmental support of research, and its organization can undertake analysis of the whole field, identify the initial steps required to advance the field, draw attention to the intellectual challenge of a field such as tinnitus, recruit scientists to a neglected area, direct support to the most promising research approaches and opportunities, and dedicate support to those endeavors. Objectives: The efforts of the Tinnitus Research Consortium (TRC) are to accelerate progress in basic and clinical research on tinnitus. Methods: The TRC analyzes the field of tinnitus research, brainstorms for new research approaches to tinnitus and provides guidance to the scientific community through requests for applications (RFAs) on promising research approaches and opportunities. The analysis of the research field has focused on the validity of animal models of tinnitus, the need for a standardized outcome measure in clinical trials, and the control of confounding variables in basic and clinical studies of the mechanisms of and site(s) associated with tinnitus. Results: The TRC judged that the existing animal models were worthy of further study and refinement and that additional animal models should be developed. In response to an RFA, a project for the development and validation of the new Tinnitus Functional Index was initiated. A confounding aspect of experimental induction of tinnitus is the occurrence of hearing loss. The experimental manipulation causing the hearing loss may or may not cause tinnitus. Segregation of the correlates of tinnitus from the consequences of hearing loss requires the inclusion of a second control group: animals that have been subjected to the manipulation for the induction of tinnitus and have a hearing loss but fail to exhibit signs of tinnitus. Comparison of normal animals, animals with hearing loss without tinnitus and animals with hearing loss and tinnitus greatly enhances the value of the research. Clinical research on the mechanisms and sites of tinnitus is also confounded by this problem, and the solution is to include controls matched for hearing loss without tinnitus.

Spontaneous activity in the inferior colliculus of CBA/J mice after manipulations that induce tinnitus

Several physiological studies have linked experimentally induced tinnitus to increases in the spontaneous activity of auditory neurons. These results have led to the proposal of hyperactivity models of tinnitus in which elevated neural activity in the absence of auditory stimulation is perceived as phantom sound. Such models are appealing in their simplicity but remain controversial because a generalized elevation of spontaneous rates may not be observed after treatments that induce tinnitus in humans and experimental animals. Our study addressed these issues by characterizing the effects of common methods of tinnitus induction on spontaneous activity in the central nucleus of the inferior colliculus (ICC). The ICC is an interesting structure in tinnitus research because its diverse inputs include putative generator sites in the dorsal cochlear nucleus, as well as brainstem sources that appear to remain normal after tinnitus induction. Groups of CBA/J mice were subjected to one of three induction methods: bilateral or unilateral sound exposure, and acute salicylate intoxication. Relative to normal baselines, bilaterally exposed mice showed increases in the spontaneous rates of neurons with tuning near the exposure frequency. When the sample was separated into physiologically defined response classes, exposure effects were strongest among neurons with broad excitatory bandwidths. By contrast, salicylate decreased the spontaneous rates of low-frequency neurons with transient sound-evoked activity. Our results suggest that the disordered processes of hearing that give rise to tinnitus do not involve a pervasive elevation of spontaneous activity or a single mode of induction.

An integrative model of developing tinnitus - neurobiological tinnitus model

An integrative model of (subjective) tinnitus is presented, based on the most recent neurophysiological data in current discussion. We assume the involvement of altered brain functions in the development and maintenance of perceptions of tinnitus and outline various possibilities which could contribute to decompensation and chronic progression. Results to date suggest cortical plasticity as a likely mechanism to be involved in the chronic progression of tinnitus. In this sense, tonotopical maps in the auditory cortex are altered due either to a lack of afferent connections or to defective auditory perceptions resulting from pathological synaptic impulse transmission processes. The functional connectivity of various limbic, prefrontal, and temporal brain structures can be understood as the basis for particularly intense experiences of impairment and many secondary symptoms of decompensated tinnitus. Relationships between the processing of auditory signals and neural networks associated with somatosensory, attentional, cognitive and emotional processes are relevant for the genesis of the pathology. The discussions surrounding present models of the generation of tinnitus and its reinforcement to the point of decompensation make it clear that a uni-dimensional approach in clinical interventions is insufficient. Patients with decompensated tinnitus suffer from a complex somatic and psychological disorder. The interactive processes involving emotions, behaviour and symptoms, as well as the high comorbidity with affective and psychosomatic illnesses and the important influence of psychosocial factors (distress), make the use of stage-appropriate interdisciplinary treatments necessary.

Recurrent tinnitus and associated ear symptoms in adultsAcúfeno recurrente y síntomas asociados del oído en adultos

This study aimed to reveal in general population the prevalence, associations, and statistical model of recurrent tinnitus by means of a mailed questionnaire. The study sample consisted of 1720 randomly selected adults who were classified into three subgroups: recurrent (once a month or more often), occasional (less often than once a month), and no tinnitus. According to age and gender standardized prevalence, recurrent tinnitus was reported in 15% of the sample. It was statistically highly significantly associated with earache, fullness of ears, shoulder pain, the 25-years age group, and visits to a physician. The strongest predictor of recurrent tinnitus was fullness of ears followed by earache, shoulder ache, and temporomandibular disorder pain. We conclude that recurrent tinnitus seems to be quite common in adults and associated with earache and fullness of ears. In patients with tinnitus without clinical findings, the examination of the stomatognathic system and cervical spine is recommended.

An integrative model of developing tinnitus - neurobiological tinnitus model

An integrative model of (subjective) tinnitus is presented, based on the most recent neurophysiological data in current discussion. We assume the involvement of altered brain functions in the development and maintenance of perceptions of tinnitus and outline various possibilities which could contribute to decompensation and chronic progression. Results to date suggest cortical plasticity as a likely mechanism to be involved in the chronic progression of tinnitus. In this sense, tonotopical maps in the auditory cortex are altered due either to a lack of afferent connections or to defective auditory perceptions resulting from pathological synaptic impulse transmission processes. The functional connectivity of various limbic, prefrontal, and temporal brain structures can be understood as the basis for particularly intense experiences of impairment and many secondary symptoms of decompensated tinnitus. Relationships between the processing of auditory signals and neural networks associated with somatosensory, attentional, cognitive and emotional processes are relevant for the genesis of the pathology. The discussions surrounding present models of the generation of tinnitus and its reinforcement to the point of decompensation make it clear that a uni-dimensional approach in clinical interventions is insufficient. Patients with decompensated tinnitus suffer from a complex somatic and psychological disorder. The interactive processes involving emotions, behaviour and symptoms, as well as the high comorbidity with affective and psychosomatic illnesses and the important influence of psychosocial factors (distress), make the use of stage-appropriate interdisciplinary treatments necessary.

New pharmacological strategies to restore hearing and treat tinnitus

Recent advances in molecular pharmacology of the cochlea have lead to a much better understanding of the physiology, and especially the pathophysiology, of the sensorineural structures of the organ of Corti. Knowledge of the intimate molecular mechanisms of cellular dysfunction is of considerable use in the development of new therapeutic strategies. Herein, we summarize the mechanisms of sensory hair cell death after various injuries. Based on these molecular mechanisms, we propose novel therapeutic strategies to restore hearing. In addition to permanent hearing loss, exposure to noise or ototoxic drugs also induces tinnitus. We thus review recent findings obtained from a behavioral model of tinnitus in rats. In addition to providing evidence for the site and mechanism of generation of tinnitus induced by salicylate, these results support the idea that targeting cochlear N-methyl-D-aspartate receptors may represent a promising therapeutic strategy for treating tinnitus.

Ensemble spontaneous activity in the guinea-pig cochlear nerve

Spectral analysis of electrical noise recorded from the round window (RW) of the cochlea is referred to as the ensemble spontaneous activity (ESA) of the cochlear nerve. The ESA is considered to represent the summed spontaneous activity of single fibers of the auditory nerve and changes in the spectral characteristics of the ESA have been observed in humans with tinnitus. Experiments were undertaken to determine the relationship of the ESA to auditory neurotransmission. The ESA consisted of energy centered at approximately 900 Hz, similar to the spectral peak of single auditory neuron discharges. The amplitude of the ESA was correlated with good auditory sensitivity in the 12–30 kHz region of the cochlea. Constant pure tones of 12–22 kHz suppressed the ESA reducing its amplitude in a frequency and intensity dependent manner implying that the ESA recorded at the RW is generated or dominated by neurons in the basal region of the cochlea. The ESA was significantly suppressed by round window perfusion of the P2X receptor agonist adenosine 5 ′-O-(3-thiotriphosphate) (ATPγS) (10 mM) the glutamate receptor antagonist 6-7-dinitroquinoxaline-2,3-dione (DNQX) (1 mM), and the sodium channel antagonist tetrodotoxin (TTX) (20 μM). Following intravenous furosemide injection (40 mg/kg) reduction and recovery of the ESA correlated with similar changes in the endocochlear potential (EP). Following DNQX and ATPγS an additional spectral peak at 200 Hz was often observed. This peak has been postulated to be a correlate of tinnitus in humans but had not previously been observed in a guinea-pig model of tinnitus. These data confirm the spectral characteristics of the ESA in guinea-pigs and show it is dependent on the sensitivity of the auditory nerve and intact auditory neurotransmission. In addition these experiments support the view that the ESA represents summed spontaneous neural activity in the cochlea and provide a platform for studies of the influence of ototoxic compounds on the spontaneous neural outflow of the cochlea as a model of tinnitus.

Models of tinnitus suffering and treatment compared and contrasted

This paper discusses the two main approaches to tinnitus management: the ‘psychological’ approach that seeks to understand and treat tinnitus within a cognitive behavioural model, and the ‘neurophysiological’ approach that suggests that tinnitus distress can be understood within a classical conditioning paradigm. Both models, and their corresponding approaches to therapy, have strong followings, and this has given rise to debate about their relative merits. However, there is some confusion among practitioners over points of similarity and differences between the two approaches. The psychological model proposes that autonomic nervous system (ANS) arousal is involved, but highlights the importance of cognitive processes in the tinnitus experience. The neurophysiological model also contends that ANS and brain processes play a fundamental role in the perception of tinnitus; it suggests that tinnitus becomes problematic because it becomes associated with something negative. This model stresses the importance o...

Otosclerosis and chronic tinnitus.

Chronic subjective tinnitus is a common feature of clinical otosclerosis. Analysis of the records of 1,014 consecutive cases of clinical otosclerosis, all confirmed by stapes surgery in South Australia between 1960 and 1972, gives a preoperative prevalence of this symptom of 65%. The association of tinnitus with various predictors is considered, and a statistical analysis is presented. Tinnitus has an association with gender (p < .0001), mean preoperative bone conduction (BC) level (p = .0012), mean air conduction (AC) level (p = .0192), and mean air-bone gap (p = .0075). The associations between tinnitus and the age of the patient, the duration of deafness, the presence of Schwartze's sign, and the severity of footplate pathological involvement were all nonsignificant. The association of tinnitus with the AC and BC thresholds is unexpectedly paradoxical. An economic predictive model for tinnitus in otosclerosis has been constructed from the 2 strongly significant variables, gender and mean BC hearing level, by logistic regression. In this large series of cases, the log odds in favor of finding tinnitus are about 0.810 for male subjects and 1.394 for female subjects when the BC level is zero. The log odds fall by 0.014 for each decibel of mean BC rise.