RESUMEN
The search for an effective medication that will eliminate tinnitus has a long history. Currently, no drugs exist that universally cure tinnitus. Pharmacologic interventions that have been investigated can be divided into those that attempt to eliminate the perception of tinnitus, and those that are designed to treat the negative comorbidities associated with tinnitus, thereby mitigating tinnitus' negative impact on quality of life. A third category of drugs can also be considered that addresses an identified pathologic condition that has tinnitus as an associated symptom (for example, Meniere's disease, otosclerosis, migraine-associated vertigo). This third category is not addressed.
Asunto(s)
Acúfeno/tratamiento farmacológico , Ansiedad/etiología , Depresión/etiología , Humanos , Enfermedad de Meniere/fisiopatología , Neurotransmisores/uso terapéutico , Otosclerosis/fisiopatología , Psicoacústica , Ensayos Clínicos Controlados Aleatorios como Asunto , Acúfeno/psicología , Vértigo/fisiopatologíaAsunto(s)
Estimulación Acústica , Terapia Cognitivo-Conductual , Acúfeno/terapia , Audiometría , Pérdida Auditiva/complicaciones , Pérdida Auditiva/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Factores de Riesgo , Acúfeno/diagnóstico , Acúfeno/etiologíaRESUMEN
OBJECTIVES: The goal of this study was to compare treatment outcomes for chronic bothersome tinnitus after Tinnitus Retraining Therapy (TRT) versus standard of care treatment (SC) and to determine the longevity of the effect over an 18-month period. STUDY DESIGN: A randomized controlled trial comparing TRT to SC for chronic tinnitus. METHODS: Adults with subjective, stable, bothersome chronic tinnitus associated with hearing loss amenable to aural rehabilitation with hearing aids were recruited. The Tinnitus Handicap Inventory (THI) was the primary outcome measure and the Tinnitus Functional Index (TFI) the secondary outcome measure of tinnitus severity and impact. Data were collected at screening, entry (0 months), and 6, 12, and 18 months after the beginning of treatment, using an integrated digitized suite of evaluation modules. TRT consisted of directive counseling and acoustic enrichment using combination hearing aids and sound generators; SC consisted of general aural rehabilitation counseling and hearing aids. RESULTS: Significant improvement in tinnitus impact occurred after both TRT and SC therapy, with a larger treatment effect obtained in the TRT group. Lasting therapeutic benefit was evident at 18 months in both groups. THI initial scores were unstable in 10% of enrolled participants, showing moderate bidirectional fluctuation between screening and baseline (0 month) assessment. CONCLUSION: Adults with moderate to severe tinnitus and hearing loss amenable to amplification, benefit from either TRT or SC treatment when combined with hearing aid use. TRT benefit may exceed that of SC. The global improvement in tinnitus severity that accrued over an 18-month period appeared to be robust and clinically significant. LEVEL OF EVIDENCE: I.
RESUMEN
Animal model research has shown that the central features of tinnitus, the perception of sound without an acoustic correlate, include elevated spontaneous and stimulus-driven activity, enhanced burst-mode firing, decreased variance of inter-spike intervals, and distortion of tonotopic frequency representation. Less well documented are cell-specific correlates of tinnitus. Unipolar brush cell (UBC) alterations in animals with psychophysical evidence of tinnitus has recently been reported. UBCs are glutamatergic interneurons that appear to function as local-circuit signal amplifiers. UBCs are abundant in the dorsal cochlear nucleus (DCN) and very abundant in the flocculus (FL) and paraflocculus (PFL) of the cerebellum. In the present research, two indicators of UBC structure and function were examined: Doublecortin (DCX) and epidermal growth factor receptor substrate 8 (Eps8). DCX is a protein that binds to microtubules where it can modify their assembly and growth. Eps8 is a cell-surface tyrosine kinase receptor mediating the response to epidermal growth factor; it appears to have a role in actin polymerization as well as cytoskeletal protein interactions. Both functions could contribute to synaptic remodeling. In the present research UBC Eps8 and DCX immunoreactivity (IR) were determined in 4 groups of rats distinguished by their exposure to high-level sound and psychophysical performance: Unexposed, exposed to high-level sound with behavioral evidence of tinnitus, and two exposed groups without behavioral evidence of tinnitus. Compared to unexposed controls, exposed animals with tinnitus had Eps8 IR elevated in their PFL; other structures were not affected, nor was DCX IR affected. This was interpreted as UBC upregulation in animals with tinnitus. Exposure that failed to produce tinnitus did not increase either Eps8 or DCX IR. Rather Eps8 IR was decreased in the FL and DCN of one subgroup (Least-Tinnitus), while DCX IR decreased in the FL of the other subgroup (No-Tinnitus). Neuron degeneration was also documented in the cochlear nucleus and PFL of exposed animals, both with and without tinnitus. Degeneration was not found in unexposed animals. Implications for tinnitus neuropathy are discussed in the context of synaptic remodeling and cerebellar sensory modulation.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Cerebelo/metabolismo , Núcleo Coclear/metabolismo , Interneuronas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Acúfeno/metabolismo , Animales , Percepción Auditiva , Conducta Animal , Biomarcadores/metabolismo , Cerebelo/patología , Cerebelo/fisiopatología , Enfermedad Crónica , Núcleo Coclear/patología , Núcleo Coclear/fisiopatología , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Potenciales Evocados Auditivos del Tronco Encefálico , Audición , Interneuronas/patología , Masculino , Degeneración Nerviosa , Ruido , Ratas Long-Evans , Acúfeno/patología , Acúfeno/fisiopatología , Acúfeno/psicologíaRESUMEN
Tinnitus is a consequence of changes in auditory and nonauditory neural networks following damage to the cochlea. Homeostatic compensatory mechanisms occur after hearing loss and these mechanisms alter the balance of excitatory and inhibitory neurotransmitters. In many individuals with hearing loss, chronic tinnitus and related phenomena emerge. Some people with tinnitus are disturbed by this subjective sensation. When auditory network dysfunction is coupled with limbic-gating dysfunction, an otherwise meaningless auditory percept such as tinnitus may acquire negative emotional features. The development of effective treatment options is enhanced by the understanding of the neural networks underpinning tinnitus.
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Neuroimagen/métodos , Acúfeno/diagnóstico por imagen , Acúfeno/patología , Cóclea/diagnóstico por imagen , Cóclea/patología , Diagnóstico por Imagen , Humanos , Neurociencias , Acúfeno/terapiaRESUMEN
The Tinnitus Research Consortium funded three clinical trials investigating treatments for chronic bothersome tinnitus at Southern Illinois University School of Medicine. The trials were designed to measure the subjective changes in tinnitus distress using standardized questionnaires and objective changes in tinnitus loudness using psychophysical matching procedures. The results of the first two trials have been published and are summarized here. The first trial investigated the effect of gabapentin on the loudness and annoyance of tinnitus in adults with chronic bothersome tinnitus with and without a history of acoustic trauma. A small but significant number of subjects reported decreased tinnitus annoyance that corresponded with a decrease in objective measures of tinnitus loudness during active drug treatment with a washout effect during placebo treatment. The second trial compared the effect of tinnitus retraining therapy (TRT) on adults with normal to near-normal hearing and chronic bothersome tinnitus to treatment with general counseling without acoustic enrichment. Significant improvements in tinnitus severity, but not in objective psychometric measures of tinnitus loudness, occurred in both treatment groups, however a greater effect was observed in the TRT group compared with the control group. The third trial is nearing completion and investigates the long-term results of tinnitus retraining therapy on chronic bothersome tinnitus in adults with hearing loss. Significant lessons and observations on conducting tinnitus clinical trials were learned from these three trials. The challenges of recruiting and retaining study participants is discussed. More importantly, the reliability and stability of the Tinnitus Handicap Inventory (THI) over long intervals is presented. The implications of this variability for the design and interpretation of future tinnitus studies is discussed. This article is part of a Special Issue entitled
Asunto(s)
Acúfeno/terapia , Aminas/uso terapéutico , Ensayos Clínicos como Asunto , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Gabapentina , Humanos , Illinois , Percepción Sonora/efectos de los fármacos , Psicometría , Apoyo a la Investigación como Asunto , Encuestas y Cuestionarios , Acúfeno/fisiopatología , Acúfeno/psicología , Universidades , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
Presented is a thematic review of animal tinnitus models from a functional perspective. Chronic tinnitus is a persistent subjective sound sensation, emergent typically after hearing loss. Although the sensation is experientially simple, it appears to have central a nervous system substrate of unexpected complexity that includes areas outside of those classically defined as auditory. Over the past 27 years animal models have significantly contributed to understanding tinnitus' complex neurophysiology. In that time, a diversity of models have been developed, each with its own strengths and limitations. None has clearly become a standard. Animal models trace their origin to the 1988 experiments of Jastreboff and colleagues. All subsequent models derive some of their features from those experiments. Common features include behavior-dependent psychophysical determination, acoustic conditions that contrast objective sound and silence, and inclusion of at least one normal-hearing control group. In the present review, animal models have been categorized as either interrogative or reflexive. Interrogative models use emitted behavior under voluntary control to indicate hearing. An example would be pressing a lever to obtain food in the presence of a particular sound. In this type of model animals are interrogated about their auditory sensations, analogous to asking a patient, "What do you hear?" These models require at least some training and motivation management, and reflect the perception of tinnitus. Reflexive models, in contrast, employ acoustic modulation of an auditory reflex, such as the acoustic startle response. An unexpected loud sound will elicit a reflexive motor response from many species, including humans. Although involuntary, acoustic startle can be modified by a lower-level preceding event, including a silent sound gap. Sound-gap modulation of acoustic startle appears to discriminate tinnitus in animals as well as humans, and requires no training or motivational manipulation, but its sensitivity, reliability, mechanism, and optimal implementation are incompletely understood. While to date animal models have significantly expanded the neuroscience of tinnitus, they have been limited to examining sensory features. In the human condition, emotional and cognitive factors are also important. It is not clear that the emotional features of tinnitus can be further understood using animal models, but models may be applied to examine cognitive factors. A recently developed model is described that reveals an interaction between tinnitus and auditory attention. This research suggests that effective tinnitus therapy could rely on modifying attention to the sensation rather than modifying the sensation itself. This article is part of a Special Issue entitled
Asunto(s)
Modelos Animales de Enfermedad , Acúfeno/fisiopatología , Estimulación Acústica , Animales , Conducta Animal , Audición , Pérdida Auditiva , Humanos , Reflejo , Reflejo de Sobresalto , Reproducibilidad de los Resultados , SonidoRESUMEN
OBJECTIVE: Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient's quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. PURPOSE: The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. ACTION STATEMENTS: The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (≥ 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (≥ 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus.
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Guías de Práctica Clínica como Asunto , Acúfeno/diagnóstico , Acúfeno/terapia , Adolescente , Adulto , Humanos , Adulto JovenRESUMEN
The American Academy of Otolaryngology--Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Tinnitus. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 13 recommendations developed address the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the impact of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers.
Asunto(s)
Acúfeno/diagnóstico , Acúfeno/terapia , Audiometría , Terapias Complementarias , Consejo Dirigido , Audífonos , Humanos , Educación del Paciente como Asunto , Acúfeno/etiologíaRESUMEN
Manganese enhanced magnetic resonance imaging (MEMRI) is a method used primarily in basic science experiments to advance the understanding of information processing in central nervous system pathways. With this mechanistic approach, manganese (Mn(2+)) acts as a calcium surrogate, whereby voltage-gated calcium channels allow for activity driven entry of Mn(2+) into neurons. The detection and quantification of neuronal activity via Mn(2+) accumulation is facilitated by "hemodynamic-independent contrast" using high resolution MRI scans. This review emphasizes initial efforts to-date in the development and application of MEMRI for evaluating tinnitus (the perception of sound in the absence of overt acoustic stimulation). Perspectives from leaders in the field highlight MEMRI related studies by comparing and contrasting this technique when tinnitus is induced by high-level noise exposure and salicylate administration. Together, these studies underscore the considerable potential of MEMRI for advancing the field of auditory neuroscience in general and tinnitus research in particular. Because of the technical and functional gaps that are filled by this method and the prospect that human studies are on the near horizon, MEMRI should be of considerable interest to the auditory research community. This article is part of a Special Issue entitled
Asunto(s)
Percepción Auditiva , Encéfalo/metabolismo , Canales de Calcio/metabolismo , Medios de Contraste , Imagen por Resonancia Magnética/métodos , Manganeso , Acúfeno/diagnóstico , Animales , Encéfalo/fisiopatología , Medios de Contraste/efectos adversos , Medios de Contraste/metabolismo , Modelos Animales de Enfermedad , Humanos , Activación del Canal Iónico , Manganeso/efectos adversos , Manganeso/metabolismo , Potenciales de la Membrana , Ruido , Valor Predictivo de las Pruebas , Salicilatos , Acúfeno/etiología , Acúfeno/metabolismo , Acúfeno/fisiopatología , Acúfeno/psicologíaRESUMEN
Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA) receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.5 mM), was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI). In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.
Asunto(s)
2-Amino-5-fosfonovalerato/administración & dosificación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Acúfeno/tratamiento farmacológico , Estimulación Acústica , Animales , Corteza Auditiva/efectos de los fármacos , Corteza Auditiva/fisiopatología , Umbral Auditivo , Cerebelo/efectos de los fármacos , Enfermedad Crónica , Nervio Coclear/efectos de los fármacos , Nervio Coclear/fisiopatología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Infusiones Parenterales , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Ratas , Ratas Long-Evans , Acúfeno/fisiopatologíaRESUMEN
Unipolar brush cells (UBCs) are excitatory interneurons found in the dorsal cochlear nucleus (DCN) and the granule cell layer of cerebellar cortex, being particularly evident in the paraflocculus (PFL) and flocculus (FL). UBCs receive glutamatergic inputs and make glutamatergic synapses with granule cells and other UBCs. It has been hypothesized that UBCs comprise local networks of tunable feed-forward amplifiers. In the DCN they might also participate in feed-back amplification of signals from higher auditory centers. Recently it has been shown that UBCs, in the vestibulocerebellum and DCN of adult rats, express doublecortin (DCX), previously considered a marker of newborn and migrating neurons. In an animal model, both the DCN, and more recently the PFL, have been implicated in contributing to the sensation of acoustic-exposure-induced tinnitus. These studies support the working hypothesis that tinnitus emerges after loss of peripheral sensitivity because inhibitory processes homeostatically down regulate, and excitatory processes up regulate. Here we report the results of two sequential experiments that examine the potential role of DCN and cerebellar UBCs in tinnitus, and the contribution of glutamatergic transmission in the PFL. In Experiment 1 it was shown that adult rats with psychophysical evidence of tinnitus induced by a single unilateral high-level noise exposure, had elevated DCX in the DCN and ventral PFL. In Experiment 2 it was shown that micro-quantities of glutamatergic antagonists, delivered directly to the PFL, reversibly reduced chronically established tinnitus, while similarly applied glutamatergic agonists induced tinnitus-like behavior in non-tinnitus controls. These results are consistent with the hypothesis that UBC up regulation and enhanced glutamatergic transmission in the cerebellum contribute to the pathophysiology of tinnitus.
Asunto(s)
Corteza Cerebelosa/fisiopatología , Núcleo Coclear/fisiopatología , Glutamatos/metabolismo , Interneuronas/metabolismo , Sinapsis/metabolismo , Acúfeno/metabolismo , Acúfeno/fisiopatología , Animales , Corteza Cerebelosa/citología , Corteza Cerebelosa/efectos de los fármacos , Núcleo Coclear/citología , Núcleo Coclear/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína Doblecortina , Agonistas de Aminoácidos Excitadores/administración & dosificación , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Interneuronas/efectos de los fármacos , Masculino , Ratas , Acúfeno/tratamiento farmacológicoRESUMEN
The role of the cerebellum in auditory processing is largely unknown. Recently it was shown that rats with psychophysical evidence of tinnitus had significantly elevated neural activity in the paraflocculus of the cerebellum (PFL), as indicated by functional imaging. It was further shown that PFL activity was not elevated in normal rats listening to a tinnitus-like sound. This suggests that plastic changes in the PFL may underpin chronic tinnitus, i.e., it may serve as a tinnitus generator. Using a rat model of acoustic trauma-induced tinnitus, the role of the cerebellum was further examined in a series of experiments:The PFL was surgically ablated in animals with established tinnitus; the PFL was surgically ablated in animals before induction of tinnitus; the PFL was reversibly inactivated by chronic lidocaine infusion into the subarcuate fossa of animals with established tinnitus. It was found that PFL ablation eliminated established tinnitus without altering auditory discrimination. Similar to the ablation results, PFL inactivation with lidocaine reversibly eliminated existing tinnitus. In contrast however, PFL ablation before tinnitus induction attenuated, but did not completely eliminate, tinnitus. In a rat model of noise-induced chronic tinnitus, the cerebellar PFL may serve as a sufficient but non-obligatory generator of tinnitus.
Asunto(s)
Cerebelo/fisiopatología , Acúfeno/etiología , Acúfeno/fisiopatología , Animales , Percepción Auditiva/fisiología , Umbral Auditivo/fisiología , Cerebelo/efectos de los fármacos , Cerebelo/lesiones , Modelos Animales de Enfermedad , Pérdida Auditiva Provocada por Ruido/complicaciones , Pérdida Auditiva Provocada por Ruido/fisiopatología , Hiperacusia/etiología , Hiperacusia/fisiopatología , Lidocaína/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Psicoacústica , Ratas , Ratas Long-EvansRESUMEN
Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus.
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Ensayos Clínicos como Asunto/normas , Proyectos de Investigación/normas , Acúfeno/terapia , Medicina Basada en la Evidencia , HumanosRESUMEN
Damage to the auditory system following high-level sound exposure reduces afferent input. Homeostatic mechanisms appear to compensate for the loss. Overcompensation may produce the sensation of sound without an objective physical correlate, i.e., tinnitus. Several potential compensatory neural processes have been identified, such as increased spontaneous activity. The cellular mechanisms enabling such compensatory processes may involve down-regulation of inhibitory neurotransmission mediated by γ-amino butyric acid (GABA), and/or up-regulation of excitatory neurotransmission, mediated by glutamic acid (Glu). Because central processing systems are integrated and well-regulated, compensatory changes in one system may produce reactive changes in others. Some or all may be relevant to tinnitus. To examine the roles of GABA and Glu in tinnitus, high resolution point-resolved proton magnetic resonance spectroscopy ((1)H-MRS) was used to quantify their levels in the dorsal cochlear nucleus (DCN), inferior colliculus (IC), medial geniculate body (MGB), and primary auditory cortex (A1) of rats. Chronic tinnitus was produced by a single high-level unilateral exposure to noise, and was measured using a psychophysical procedure sensitive to tinnitus. Decreased GABA levels were evident only in the MGB, with the greatest decrease, relative to unexposed controls, obtained in the contralateral MGB. Small GABA increases may have been present bilaterally in A1 and in the contralateral DCN. Although Glu levels showed considerable variation, Glu was moderately and bilaterally elevated both in the DCN and in A1. In the MGB Glu was increased ipsilaterally but decreased contralaterally. These bidirectional and region-specific alterations in GABA and Glu may reflect large-scale changes in inhibitory and excitatory equilibrium accompanying chronic tinnitus. The present results also suggest that targeting both neurotransmitter systems may be optimal in developing more effective therapeutics.
RESUMEN
Animal experiments suggest that chronic tinnitus ("ringing in the ears") may result from processes that overcompensate for lost afferent input. Abnormally elevated spontaneous neural activity has been found in the dorsal cochlear nucleus (DCN) of animals with psychophysical evidence of tinnitus. However, it has also been reported that DCN ablation fails to reduce established tinnitus. Since other auditory areas have been implicated in tinnitus, the role of the DCN is unresolved. The apparently conflicting electrophysiological and lesion data can be reconciled if the DCN serves as a necessary trigger zone rather than a chronic generator of tinnitus. The present experiment used lesion procedures identical to those that failed to decrease pre-existing tinnitus. The exception was that lesions were done prior to tinnitus induction. Young adult rats were trained and tested using a psychophysical procedure shown to detect tinnitus. Tinnitus was induced by a single unilateral high-level noise exposure. Consistent with the trigger hypothesis, bilateral dorsal DCN lesions made before high-level noise exposure prevented the development of tinnitus. A protective effect stemming from disruption of the afferent pathway could not explain the outcome because unilateral lesions ipsilateral to the noise exposure did not prevent tinnitus and unilateral lesions contralateral to the noise exposure actually exacerbated the tinnitus. The DCN trigger mechanism may involve plastic circuits that, through loss of inhibition, or upregulation of excitation, increase spontaneous neural output to rostral areas such as the inferior colliculus. The increased drive could produce persistent pathological changes in the rostral areas, such as high-frequency bursting and decreased interspike variance, that comprise the chronic tinnitus signal.
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Núcleo Coclear/patología , Núcleo Coclear/fisiopatología , Desnervación/métodos , Acúfeno/patología , Acúfeno/prevención & control , Estimulación Acústica/métodos , Potenciales de Acción/fisiología , Animales , Umbral Auditivo/fisiología , Ablación por Catéter , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Lateralidad Funcional/fisiología , Masculino , Ruido/efectos adversos , Ratas , Ratas Long-Evans , Acúfeno/fisiopatologíaRESUMEN
OBJECTIVES: Subjective tinnitus is the sensation of hearing a sound in the absence of an external stimulus. Although an estimated 30 million Americans experience chronic tinnitus, only a small percentage are significantly bothered by the sensation. However, this population is currently in need of effective therapy that reduces the impact of tinnitus. Tinnitus retraining therapy has been promoted as an effective intervention for treating chronic bothersome tinnitus from any etiology. The aim of this study was to compare the effect of tinnitus retraining therapy on the loudness and annoyance of tinnitus with a control group. DESIGN: Subjects with subjective, stable, bothersome, chronic tinnitus, and normal to near-normal hearing in the speech frequencies (average pure-tone thresholds for 0.5, 1, 2, and 4 kHz ≤ 30 dB HL) were recruited to participate in a study for the effect of tinnitus retraining therapy (TRT) on the loudness and annoyance of their tinnitus. Participants were assigned to either the TRT arm or a control arm, with assignment balanced between groups by tinnitus severity. After baseline evaluation, participants received acoustic stimulation devices and 3 mos of individual counseling. An integrated computerized test battery of questionnaires and psychophysical procedures were used to evaluate participants at 6, 12, and 18 mos after enrollment. The primary outcome measure was the change in total score on the tinnitus handicap inventory. Secondary outcome measures were change in global tinnitus impact on a tinnitus experience questionnaire, subjective tinnitus loudness rating, and tinnitus loudness objectively measured using a psychophysical matching procedure. RESULTS: Both TRT and general counseling without additional sound therapy are effective in reducing the annoyance and impact of tinnitus. The largest effect on overall tinnitus handicap was observed in the TRT participants, with an effect size of 1.13. However, a clinically significant effect was also observed in the control group, with an effect size of 0.78. CONCLUSIONS: Individuals with moderate to severe tinnitus, without hearing loss in the speech frequency range, benefit from treatment with either TRT or general counseling. The global improvement in tinnitus handicap with TRT accrues over an 18-mo period and seems to be a robust and clinically significant effect.
Asunto(s)
Estimulación Acústica/métodos , Percepción Sonora/fisiología , Acúfeno/terapia , Estimulación Acústica/instrumentación , Consejo , Femenino , Humanos , Masculino , Sonido , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Loss of central inhibition has been hypothesized to underpin tinnitus and impact auditory acuity. Taurine, a partial agonist at inhibitory glycine and γ-amino butyric acid receptors, was added to the daily diet of rats to examine its effects on chronic tinnitus and normal auditory discrimination. Eight rats were unilaterally exposed once to a loud sound to induce tinnitus. The rats were trained and tested in an operant task shown to be sensitive to tinnitus. An equivalent unexposed control group was run in parallel. Months after exposure, 6 of the exposed rats showed significant evidence of chronic tinnitus. Two concentrations of taurine in drinking water were given over several weeks (attaining average daily doses of 67 mg/kg and 294 mg/kg). Water consumption was unaffected. Three main effects were obtained: (1) The high taurine dose significantly attenuated tinnitus, which returned to near pre-treatment levels following washout. (2) Auditory discrimination was significantly improved in unexposed control rats at both doses. (3) As indicated by lever pressing, taurine at both doses had a significant group-equivalent stimulant effect. These results are consistent with the hypothesis that taurine attenuates tinnitus and improves auditory discrimination by increasing inhibitory tone and decreasing noise in the auditory pathway.
Asunto(s)
Percepción Auditiva/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Suplementos Dietéticos , Discriminación en Psicología/efectos de los fármacos , Taurina/administración & dosificación , Acúfeno/prevención & control , Estimulación Acústica , Animales , Umbral Auditivo , Condicionamiento Operante , Modelos Animales de Enfermedad , Agonismo Parcial de Drogas , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Masculino , Inhibición Neural/efectos de los fármacos , Ratas , Ratas Long-Evans , Receptores de GABA-A/efectos de los fármacos , Receptores de Glicina/efectos de los fármacos , Factores de Tiempo , Acúfeno/etiología , Acúfeno/fisiopatología , Acúfeno/psicologíaRESUMEN
OBJECTIVE: Atrial natriuretic peptide (ANP) is a key regulator in the homeostasis of water excretion and has emerged as an important prognostic marker for symptomatic chronic heart failure (CHF). The stability of ANP represents a crucial factor in assessing its use as a cardiac biomarker. Accordingly, we assessed the stability of ANP in blood samples collected from healthy controls and CHF subjects for a 12 month period. METHODS: Blood samples from 10 healthy controls and 12 symptomatic CHF subjects with left ventricular systolic dysfunction were drawn. Determination of plasma ANP was performed by a standardized radioimmunoassay protocol. RESULTS: The ANP levels of healthy subjects were 68.5+/-11.6 pg/mL at baseline and 69.9+/-17.2 pg/mL at 12 months (p=0.71). The ANP concentrations of CHF subjects were 199.25+/-44.8 pg/mL at baseline and 197.83+/-47.4 pg/mL at 12 months (p=0.70) respectively. CONCLUSION: ANP is a stable molecule with no evidence of degradation when stored at -80 degrees C.