Resistance to thyroid hormone due to mutations in THRA , which encodes the thyroid hormone recept... more Resistance to thyroid hormone due to mutations in THRA , which encodes the thyroid hormone receptor α (TRα1), shows variable clinical presentation. Mutations affecting TRβ1 and TRβ2 cause deafness in mice and have been associated with deafness in humans. To test whether TRα1 also affects hearing function, we used mice heterozygous for a frameshift mutation in Thra that is similar to human THRA mutations ( Thra S1/ + mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates, Thra S1/+ mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TRα1 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with THRA mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss.
Annals of Otology, Rhinology, and Laryngology, 2013
We describe the various molecular and cellular pathways that lead to early and delayed loss of re... more We describe the various molecular and cellular pathways that lead to early and delayed loss of residual hearing after cochlear implantation. We performed a systematic review using the Medline database with the key words cochlear implant, residual hearing, inflammation, apoptosis, and necrosis. The mechanisms underlying the loss of residual hearing after cochlear implantation are multiple. Early hearing loss may be provoked by the surgical access to the inner ear spaces and by trauma caused by insertion of the electrode array. After the initial trauma, an acute inflammatory response promotes elevated levels of cytokines and reactive oxygen species, which in turn promote sensory cell loss by apoptosis, necrosis, and necrosis-like programmed cell death. Treatments that counteract such an inflammatory reaction, production of reactive oxygen species, and apoptosis are effective at preventing hair cell degeneration. However, delayed hearing loss appears to be a consequence of chronic inflammation with development of fibrotic tissue. The mechanisms that lead to fibrosis are poorly understood, and standard antiinflammatory drugs are insufficient for preventing its development. Cochlear implantation is followed by an inflammatory response involving several pathways that lead to either short-term or long-term sensory hair cell degeneration. Future studies should focus on revealing the precise molecular mechanisms induced by cochlear implantation to allow the discovery of new targets for the effective prevention and treatment of loss of residual hearing.
<p><b>(A, B)</b> Confocal microscopy of immunolabeled CtBP2 (green) and GluA2 (... more <p><b>(A, B)</b> Confocal microscopy of immunolabeled CtBP2 (green) and GluA2 (red) from the 16-kHz encoding region in artificial perilymph control (<b>A</b>) and ouabain-poisoned cochleae (<b>B</b>). <i>Top panel</i>: enlarged view of inner-hair-cell innervation (6 IHCs; n indicates the nucleus of IHCs). <i>Middle panel</i>: <i>z</i>-projection of the white square shown above (4 μm × 4 μm), showing CtBP2 and GluA2 immunolabeling alone or together (merged). <i>Bottom panel</i>: Three-dimensional (3D) views of the white square shown above (4 μm × 4 μm × 4 μm). Note the presence of an orphan ribbons in ouabain-poisoned condition (<b>B</b>, 12 ± 2% in the basal end (>5.6 kHz) against 1 ± 0.6% in the apical end (<5.6 kHz). (<b>C</b>) Number of synapses per IHC along the gerbil tonotopic axis [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref024" target="_blank">24</a>] in control and ouabain-poisoned cochleae (black, control, 5 cochleae, 324 IHCs, 5790 synapses; red, ouabain, 5 cochleae; 344 IHCs, 5494 synapses). Each dot represents the average over 6 consecutive IHCs [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref014" target="_blank">14</a>]. Black and red curves are fits using the sum of two Gaussian models (control, black, <i>f(x)</i> = 22.6×exp(-((<i>x</i>-30)/35.2)<sup>2</sup>) + 14.2×exp(-((<i>x</i>-78.6)/24.1)<sup>2</sup>), <i>r</i><sup>2</sup> = 0.92; ouabain, red, <i>f(x)</i> = 22.9×exp(-((<i>x</i>-30)/33.4)<sup>2</sup>) + 9.7×exp(-((<i>x</i>-75.2)/23.6)<sup>2</sup>), <i>r</i><sup>2</sup> = 0.88, with <i>x</i> the position from the apex in percent). <i>Inset</i>: Estimates of the number of synapses per cochlea calculated from IHC and synapse counts. (black, control: 19,659 synapses/cochlea; red, ouabain: 17,568 synapses/cochlea). (<b>D</b>) Number of synapses per IHC pooled per octave band, in control (black) and ouabain-poisoned (red) cochleae. Numerical values indicate the number of IHCs for which the number of synapses was assessed. Data were expressed as the mean ± SEM, <i>P</i><0.05, <i>P</i><0.01, two-way ANOVA test followed by <i>post hoc</i> Tukey’s test.</p
<p><b>A.</b> Protocol used to record unit contribution at the round window (fro... more <p><b>A.</b> Protocol used to record unit contribution at the round window (from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref029" target="_blank">29</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref030" target="_blank">30</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref033" target="_blank">33</a>]). Spontaneous action potentials (black trace) recorded with an electrode in the auditory nerve were used as trigger pulses to average the corresponding action potentials recorded with a gross electrode at the round window (blue trace). After more than 10,000 averages, a biphasic waveform of 0.3 μV amplitude, 1 ms second duration, was obtained. Red fit: <i>f(t) = A×((cos(2πf</i><sub><i>1</i></sub><i>t)+1)×sin(2πf</i><sub><i>2</i></sub><i>t)</i> with <i>A</i> = 0.31 ± 0.04 μV, <i>f</i><sub>1</sub> = 997 ± 20 Hz, <i>f</i><sub>2</sub> = 920 ± 33 Hz, <i>R</i><sup>2</sup> = 0.95 ± 0.007, 59 fibers, >10,000 averaging per fiber. <b>B</b>. Parameters of the unit contribution (<i>n</i> = 59 ANFs). <b>C</b>. Amplitude of the spectrum density function (ASD) of the unit contribution (adequate zero padding was applied to improve the frequency resolution of the spectral estimate). The peak in the ASD is around 1 kHz. <i>Inset</i>: Unit contribution model used to estimate the PSD. <b>D</b>. Location of the spectral component as a function of the probe frequency for experimental (black curve, 10 gerbils) and simulated data (red curve) at 60 dB SPL. Note the spectrum shift for a probe frequency below 10 kHz. <i>Inset</i>: 3-dB cut-off frequency of modulation transfer functions as a function of the fiber CF (<i>f(CF) = 2000×(1-exp(-CF/9000))</i> with <i>CF</i> in Hz). <b>E</b>. Low-pass modulation transfer functions obtained from <b>C</b> and <b>D</b> (8<sup>th</sup> order Butterworth filters, 0 dB in band pass and cut-off frequency at 3-dB) for fibers with CF ranging from 1 to 32 kHz in 1 octave steps. Note that cut-off frequency is positively correlated with the CF of the fibers.</p
Sound-level coding in the auditory nerve is achieved through the progressive recruitment of audit... more Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to...
NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion ne... more NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without aff...
Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the fi... more Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the firing of auditory nerve fibers (ANFs). For obvious ethical reasons, single unit recordings from the cochlear nerve have never been performed in human, thus functional hallmarks of ANFs are unknown. By filtering and rectifying the electrical signal recorded at the round window of gerbil cochleae, we reconstructed a peri-stimulus time response (PSTR), with a waveform similar to the peri-stimulus time histograms (PSTHs) recorded from single ANFs. Pair-by-pair analysis of simultaneous PSTR and PSTH recordings in gerbil provided a model to predict the rapid adaptation and spontaneous discharge rates (SR) in a population of ANFs according to their location in the cochlea. We then probed the model in the mouse, in which the SR-based distribution of ANFs differs from the gerbil. We show that the PSTR-based predictions of the rapid adaptation time constant and mean SR across frequency again matche...
The apex or apical region of the cochlear spiral within the inner ear encodes for low‐frequency s... more The apex or apical region of the cochlear spiral within the inner ear encodes for low‐frequency sounds. The disposition of sensory hair cells on the organ of Corti is largely variable in the apical region of mammals, and it does not necessarily follow the typical three‐row pattern of outer hair cells (OHCs). As most underwater noise sources contain low‐frequency components, we expect to find most lesions in the apical region of the cochlea of toothed whales, in cases of permanent noise‐induced hearing loss. To further understand how man‐made noise might affect cetacean hearing, there is a need to describe normal morphological features of the apex and document interspecific anatomic variations in cetaceans. However, distinguishing between apical normal variability and hair cell death is challenging. We describe anatomical features of the organ of Corti of the apex in 23 ears from five species of toothed whales (harbor porpoise Phocoena phocoena, spinner dolphin Stenella longirostris,...
Resumen Los acufenos subjetivos son percepciones auditivas que no responden a una estimulacion so... more Resumen Los acufenos subjetivos son percepciones auditivas que no responden a una estimulacion sonora registrable. Suelen ser sintomaticos de una lesion activa o de una secuela del sistema auditivo periferico. Sin embargo, lo mas probable es que en los mecanismos fisiopatologicos multiples e imbricados que explican tanto su aparicion como su connotacion desagradable, incluso insoportable, intervengan disfunciones centrales, que serian el reflejo de una plasticidad cerebral anormal inducida generalmente por un deficit auditivo. Un analisis clinico riguroso que ponga de manifiesto los factores organicos y psicologicos implicados, asi como unas pruebas complementarias solicitadas de forma justificada, permiten orientar y guiar con eficacia a los pacientes. En el estado actual de los conocimientos, no se dispone de un tratamiento curativo, en particular farmacologico, que sea aplicable sistematicamente a todos los pacientes. Sin embargo, distintos tratamientos paliativos que tienen la finalidad de mejorar la tolerabilidad del sintoma resultan eficaces, como las terapias cognitivo-conductuales y diferentes metodos de rehabilitacion sonora, asi como las intervenciones dirigidas a rehabilitar la audicion mediante audioprotesis o implantes cocleares. La perspectiva de una restauracion ad integrum de la funcion coclear, mediante las herramientas emergentes de la farmacologia intracoclear y de la terapia genica, asi como las tecnicas innovadoras de modulacion de la actividad cerebral constituyen una esperanza para todos los pacientes con acufenos.
Resistance to thyroid hormone due to mutations in THRA , which encodes the thyroid hormone recept... more Resistance to thyroid hormone due to mutations in THRA , which encodes the thyroid hormone receptor α (TRα1), shows variable clinical presentation. Mutations affecting TRβ1 and TRβ2 cause deafness in mice and have been associated with deafness in humans. To test whether TRα1 also affects hearing function, we used mice heterozygous for a frameshift mutation in Thra that is similar to human THRA mutations ( Thra S1/ + mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates, Thra S1/+ mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TRα1 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with THRA mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss.
Annals of Otology, Rhinology, and Laryngology, 2013
We describe the various molecular and cellular pathways that lead to early and delayed loss of re... more We describe the various molecular and cellular pathways that lead to early and delayed loss of residual hearing after cochlear implantation. We performed a systematic review using the Medline database with the key words cochlear implant, residual hearing, inflammation, apoptosis, and necrosis. The mechanisms underlying the loss of residual hearing after cochlear implantation are multiple. Early hearing loss may be provoked by the surgical access to the inner ear spaces and by trauma caused by insertion of the electrode array. After the initial trauma, an acute inflammatory response promotes elevated levels of cytokines and reactive oxygen species, which in turn promote sensory cell loss by apoptosis, necrosis, and necrosis-like programmed cell death. Treatments that counteract such an inflammatory reaction, production of reactive oxygen species, and apoptosis are effective at preventing hair cell degeneration. However, delayed hearing loss appears to be a consequence of chronic inflammation with development of fibrotic tissue. The mechanisms that lead to fibrosis are poorly understood, and standard antiinflammatory drugs are insufficient for preventing its development. Cochlear implantation is followed by an inflammatory response involving several pathways that lead to either short-term or long-term sensory hair cell degeneration. Future studies should focus on revealing the precise molecular mechanisms induced by cochlear implantation to allow the discovery of new targets for the effective prevention and treatment of loss of residual hearing.
<p><b>(A, B)</b> Confocal microscopy of immunolabeled CtBP2 (green) and GluA2 (... more <p><b>(A, B)</b> Confocal microscopy of immunolabeled CtBP2 (green) and GluA2 (red) from the 16-kHz encoding region in artificial perilymph control (<b>A</b>) and ouabain-poisoned cochleae (<b>B</b>). <i>Top panel</i>: enlarged view of inner-hair-cell innervation (6 IHCs; n indicates the nucleus of IHCs). <i>Middle panel</i>: <i>z</i>-projection of the white square shown above (4 μm × 4 μm), showing CtBP2 and GluA2 immunolabeling alone or together (merged). <i>Bottom panel</i>: Three-dimensional (3D) views of the white square shown above (4 μm × 4 μm × 4 μm). Note the presence of an orphan ribbons in ouabain-poisoned condition (<b>B</b>, 12 ± 2% in the basal end (>5.6 kHz) against 1 ± 0.6% in the apical end (<5.6 kHz). (<b>C</b>) Number of synapses per IHC along the gerbil tonotopic axis [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref024" target="_blank">24</a>] in control and ouabain-poisoned cochleae (black, control, 5 cochleae, 324 IHCs, 5790 synapses; red, ouabain, 5 cochleae; 344 IHCs, 5494 synapses). Each dot represents the average over 6 consecutive IHCs [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref014" target="_blank">14</a>]. Black and red curves are fits using the sum of two Gaussian models (control, black, <i>f(x)</i> = 22.6×exp(-((<i>x</i>-30)/35.2)<sup>2</sup>) + 14.2×exp(-((<i>x</i>-78.6)/24.1)<sup>2</sup>), <i>r</i><sup>2</sup> = 0.92; ouabain, red, <i>f(x)</i> = 22.9×exp(-((<i>x</i>-30)/33.4)<sup>2</sup>) + 9.7×exp(-((<i>x</i>-75.2)/23.6)<sup>2</sup>), <i>r</i><sup>2</sup> = 0.88, with <i>x</i> the position from the apex in percent). <i>Inset</i>: Estimates of the number of synapses per cochlea calculated from IHC and synapse counts. (black, control: 19,659 synapses/cochlea; red, ouabain: 17,568 synapses/cochlea). (<b>D</b>) Number of synapses per IHC pooled per octave band, in control (black) and ouabain-poisoned (red) cochleae. Numerical values indicate the number of IHCs for which the number of synapses was assessed. Data were expressed as the mean ± SEM, <i>P</i><0.05, <i>P</i><0.01, two-way ANOVA test followed by <i>post hoc</i> Tukey’s test.</p
<p><b>A.</b> Protocol used to record unit contribution at the round window (fro... more <p><b>A.</b> Protocol used to record unit contribution at the round window (from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref029" target="_blank">29</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref030" target="_blank">30</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169890#pone.0169890.ref033" target="_blank">33</a>]). Spontaneous action potentials (black trace) recorded with an electrode in the auditory nerve were used as trigger pulses to average the corresponding action potentials recorded with a gross electrode at the round window (blue trace). After more than 10,000 averages, a biphasic waveform of 0.3 μV amplitude, 1 ms second duration, was obtained. Red fit: <i>f(t) = A×((cos(2πf</i><sub><i>1</i></sub><i>t)+1)×sin(2πf</i><sub><i>2</i></sub><i>t)</i> with <i>A</i> = 0.31 ± 0.04 μV, <i>f</i><sub>1</sub> = 997 ± 20 Hz, <i>f</i><sub>2</sub> = 920 ± 33 Hz, <i>R</i><sup>2</sup> = 0.95 ± 0.007, 59 fibers, >10,000 averaging per fiber. <b>B</b>. Parameters of the unit contribution (<i>n</i> = 59 ANFs). <b>C</b>. Amplitude of the spectrum density function (ASD) of the unit contribution (adequate zero padding was applied to improve the frequency resolution of the spectral estimate). The peak in the ASD is around 1 kHz. <i>Inset</i>: Unit contribution model used to estimate the PSD. <b>D</b>. Location of the spectral component as a function of the probe frequency for experimental (black curve, 10 gerbils) and simulated data (red curve) at 60 dB SPL. Note the spectrum shift for a probe frequency below 10 kHz. <i>Inset</i>: 3-dB cut-off frequency of modulation transfer functions as a function of the fiber CF (<i>f(CF) = 2000×(1-exp(-CF/9000))</i> with <i>CF</i> in Hz). <b>E</b>. Low-pass modulation transfer functions obtained from <b>C</b> and <b>D</b> (8<sup>th</sup> order Butterworth filters, 0 dB in band pass and cut-off frequency at 3-dB) for fibers with CF ranging from 1 to 32 kHz in 1 octave steps. Note that cut-off frequency is positively correlated with the CF of the fibers.</p
Sound-level coding in the auditory nerve is achieved through the progressive recruitment of audit... more Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to...
NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion ne... more NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without aff...
Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the fi... more Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the firing of auditory nerve fibers (ANFs). For obvious ethical reasons, single unit recordings from the cochlear nerve have never been performed in human, thus functional hallmarks of ANFs are unknown. By filtering and rectifying the electrical signal recorded at the round window of gerbil cochleae, we reconstructed a peri-stimulus time response (PSTR), with a waveform similar to the peri-stimulus time histograms (PSTHs) recorded from single ANFs. Pair-by-pair analysis of simultaneous PSTR and PSTH recordings in gerbil provided a model to predict the rapid adaptation and spontaneous discharge rates (SR) in a population of ANFs according to their location in the cochlea. We then probed the model in the mouse, in which the SR-based distribution of ANFs differs from the gerbil. We show that the PSTR-based predictions of the rapid adaptation time constant and mean SR across frequency again matche...
The apex or apical region of the cochlear spiral within the inner ear encodes for low‐frequency s... more The apex or apical region of the cochlear spiral within the inner ear encodes for low‐frequency sounds. The disposition of sensory hair cells on the organ of Corti is largely variable in the apical region of mammals, and it does not necessarily follow the typical three‐row pattern of outer hair cells (OHCs). As most underwater noise sources contain low‐frequency components, we expect to find most lesions in the apical region of the cochlea of toothed whales, in cases of permanent noise‐induced hearing loss. To further understand how man‐made noise might affect cetacean hearing, there is a need to describe normal morphological features of the apex and document interspecific anatomic variations in cetaceans. However, distinguishing between apical normal variability and hair cell death is challenging. We describe anatomical features of the organ of Corti of the apex in 23 ears from five species of toothed whales (harbor porpoise Phocoena phocoena, spinner dolphin Stenella longirostris,...
Resumen Los acufenos subjetivos son percepciones auditivas que no responden a una estimulacion so... more Resumen Los acufenos subjetivos son percepciones auditivas que no responden a una estimulacion sonora registrable. Suelen ser sintomaticos de una lesion activa o de una secuela del sistema auditivo periferico. Sin embargo, lo mas probable es que en los mecanismos fisiopatologicos multiples e imbricados que explican tanto su aparicion como su connotacion desagradable, incluso insoportable, intervengan disfunciones centrales, que serian el reflejo de una plasticidad cerebral anormal inducida generalmente por un deficit auditivo. Un analisis clinico riguroso que ponga de manifiesto los factores organicos y psicologicos implicados, asi como unas pruebas complementarias solicitadas de forma justificada, permiten orientar y guiar con eficacia a los pacientes. En el estado actual de los conocimientos, no se dispone de un tratamiento curativo, en particular farmacologico, que sea aplicable sistematicamente a todos los pacientes. Sin embargo, distintos tratamientos paliativos que tienen la finalidad de mejorar la tolerabilidad del sintoma resultan eficaces, como las terapias cognitivo-conductuales y diferentes metodos de rehabilitacion sonora, asi como las intervenciones dirigidas a rehabilitar la audicion mediante audioprotesis o implantes cocleares. La perspectiva de una restauracion ad integrum de la funcion coclear, mediante las herramientas emergentes de la farmacologia intracoclear y de la terapia genica, asi como las tecnicas innovadoras de modulacion de la actividad cerebral constituyen una esperanza para todos los pacientes con acufenos.
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