Restoration of Deafferentation Reduces Tinnitus, Anxiety, and Depression: A Retrospective Study on Cochlear Implant Patients.

Patients with profound bilateral deafness (BD) are prone to suffering from tinnitus, which further leads to psychological comorbidities and makes it more difficult for patients to communicate with people. This study was aimed at investigating the effect of cochlear implants (CIs) on tinnitus distress and psychological comorbidities in patients with profound BD. This multicenter retrospective study reviewed 51 patients with severe postlingual BD who underwent cochlear implantation; 49 patients underwent unilateral cochlear implantation, and 2 patients underwent bilateral cochlear implantation. The patients were asked to complete all the questionnaires, including the tinnitus handicap inventory (THI), the visual analog scale (VAS) score, the Hospital Anxiety and Depression Scale Questionnaire (HADS), the Categories of Auditory Performance (CAP), and the Speech Intelligibility Rating (SIR), at least 4 months after implantation when the CI was on or off, in approximately May-June 2019. In our study, 94% (48/51) of BD patients suffered from tinnitus before CI, and 77% (37/48) of them suffered from bilateral tinnitus. In addition, 50.9% (26/51) of the CI patients were suffering from anxiety, 52.9% (27/51) of them were suffering from depression (score ≥ 8), and 66.7% (34/51) (27/51) of them were suffering from anxiety or depression. Cochlear implantation could reduce tinnitus more obviously when the CI was on than when the CI was off. Cochlear implantation also reduced anxiety/depression severity. There were significantly positive correlations between tinnitus severity and anxiety/depression severity before and after surgery. Moreover, hearing improvement is positively correlated with reduction level of tinnitus, the better hearing, and the lesser severity of tinnitus. Thus, along with effective restoration of deafferentation, cochlear implantation shows positive therapeutic effects on tinnitus and psychological comorbidities, providing a reference for future clinical and research work.

Audiogenic Seizures in the Fmr1 Knock-Out Mouse Are Induced by Fmr1 Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading monogenetic cause of autism. One symptom of FXS and autism is sensory hypersensitivity (also called sensory over-responsivity). Perhaps related to this, the audiogenic seizure (AGS) is arguably the most robust behavioral phenotype in the FXS mouse model-the Fmr1 knock-out (KO) mouse. Therefore, the AGS may be considered a mouse model of sensory hypersensitivity. Hyperactive circuits are hypothesized to underlie dysfunction in a number of brain regions in patients with FXS and Fmr1 KO mice, and the AGS may be a result of this. But the specific cell types and brain regions underlying AGSs in the Fmr1 KO are unknown. We used conditional deletion or expression of Fmr1 in different cell populations to determine whether Fmr1 deletion in those cells was sufficient or necessary, respectively, for the AGS phenotype in males. Our data indicate that Fmr1 deletion in glutamatergic neurons that express vesicular glutamate transporter 2 (VGlut2) and are located in subcortical brain regions is sufficient and necessary to cause AGSs. Furthermore, the deletion of Fmr1 in glutamatergic neurons of the inferior colliculus is necessary for AGSs. When we demonstrate necessity, we show that Fmr1 expression in either the larger population of VGlut2-expressing glutamatergic neurons or the smaller population of inferior collicular glutamatergic neurons-in an otherwise Fmr1 KO mouse-eliminates AGSs. Therefore, targeting these neuronal populations in FXS and autism may be part of a therapeutic strategy to alleviate sensory hypersensitivity.SIGNIFICANCE STATEMENT Sensory hypersensitivity in fragile X syndrome (FXS) and autism patients significantly interferes with quality of life. Audiogenic seizures (AGSs) are arguably the most robust behavioral phenotype in the FXS mouse model-the Fmr1 knockout-and may be considered a model of sensory hypersensitivity in FXS. We provide the clearest and most precise genetic evidence to date for the cell types and brain regions involved in causing AGSs in the Fmr1 knockout and, more broadly, for any mouse mutant. The expression of Fmr1 in these same cell types in an otherwise Fmr1 knockout eliminates AGSs indicating possible cellular targets for alleviating sensory hypersensitivity in FXS and other forms of autism.

Specific loss of neural sensitivity to interaural time difference of unmodulated noise stimuli following noise-induced hearing loss.

Sensorineural hearing loss (SNHL) causes an overall deficit in binaural hearing, including the abilities to localize sound sources, discriminate interaural time and level differences (ITDs and ILDs, respectively), and utilize binaural cues to aid signal detection and comprehension in noisy environments. Few studies have examined the effect of SNHL on binaural coding in the central auditory system, and those that have focused on age-related hearing loss. We induced hearing loss in male and female Dutch-belted rabbits via noise overexposure and compared unanesthetized single-unit responses of their inferior colliculi [hearing loss (HL) neurons] with those of unexposed rabbits. Sound-level thresholds of HL neurons to diotic noise were elevated by 75 dB, on average. Sensitivity of firing rates of HL neurons to the azimuth of a broadband noise stimulus was reduced, on average, but was confounded by differences in sound level with respect to detection threshold between groups. We independently manipulated ITD and ILD in virtual acoustic space and found directional sensitivity in binaurally sensitive HL neurons was entirely due to ILD sensitivity and no different than that for unexposed rabbits. However, ITD sensitivity was completely absent in binaurally sensitive HL neurons for noise stimuli both in virtual acoustic space and with ITDs extending to ±3 ms. HL neurons also had weaker spike-timing precision and slightly increased spontaneous rates. Overall, ILD sensitivity was uncompromised, whereas ITD sensitivity was completely lost, implying a specific inability to use information in the timing or correlation of acoustic noise waveforms between the two ears following severe SNHL.NEW & NOTEWORTHY Sensorineural hearing loss compromises perceptual abilities that arise from hearing with two ears, yet its effects on binaural aspects of neural responses are largely unknown. We found that, following severe hearing loss because of acoustic trauma, auditory midbrain neurons specifically lost the ability to encode time differences between the arrival of a broadband noise stimulus to the two ears, whereas the encoding of sound level differences between the two ears remained uncompromised.

Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome.

Sensory processing abnormalities are frequently associated with autism spectrum disorders, but the underlying mechanisms are unclear. Here we studied auditory processing in a mouse model of Fragile X Syndrome (FXS), a leading known genetic cause of autism and intellectual disability. Both humans with FXS and the Fragile X mental retardation gene (Fmr1) knockout (KO) mouse model show auditory hypersensitivity, with the latter showing a strong propensity for audiogenic seizures (AGS) early in development. Because midbrain abnormalities cause AGS, we investigated whether the inferior colliculus (IC) of the Fmr1 KO mice shows abnormal auditory processing compared with wild-type (WT) controls at specific developmental time points. Using antibodies against neural activity marker c-Fos, we found increased density of c-Fos+ neurons in the IC, but not auditory cortex, of Fmr1 KO mice at P21 and P34 following sound presentation. In vivo single-unit recordings showed that IC neurons of Fmr1 KO mice are hyperresponsive to tone bursts and amplitude-modulated tones during development and show broader frequency tuning curves. There were no differences in rate-level responses or phase locking to amplitude-modulated tones in IC neurons between genotypes. Taken together, these data provide evidence for the development of auditory hyperresponsiveness in the IC of Fmr1 KO mice. Although most human and mouse work in autism and sensory processing has centered on the forebrain, our new findings, along with recent work on the lower brainstem, suggest that abnormal subcortical responses may underlie auditory hypersensitivity in autism spectrum disorders.NEW & NOTEWORTHY Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

Nicotinic acetylcholine receptor subunit α7-knockout mice exhibit degraded auditory temporal processing.

The CHRNA7 gene that encodes the α7-subunit of the nicotinic acetylcholine receptor (α7-nAChR) has been associated with some autism spectrum disorders and other neurodevelopmental conditions characterized, in part, by auditory and language impairment. These conditions may include auditory processing disorders that represent impaired timing of neural activity, often accompanied by problems understanding speech. Here, we measure timing properties of sound-evoked activity via the auditory brainstem response (ABR) of α7-nAChR knockout mice of both sexes and wild-type colony controls. We find a significant timing delay in evoked ABR signals that represents midbrain activity in knockouts. We also examine spike-timing properties of neurons in the inferior colliculus, a midbrain nucleus that exhibits high levels of α7-nAChR during development. We find delays of evoked responses along with degraded spiking precision in knockout animals. We find similar timing deficits in responses of neurons in the superior paraolivary nucleus and ventral nucleus of the lateral lemniscus, which are brainstem nuclei thought to shape temporal precision in the midbrain. In addition, we find that other measures of temporal acuity including forward masking and gap detection are impaired for knockout animals. We conclude that altered temporal processing at the level of the brainstem in α7-nAChR-deficient mice may contribute to degraded spike timing in the midbrain, which may underlie the observed timing delay in the ABR signals. Our findings are consistent with a role for the α7-nAChR in types of neurodevelopmental and auditory processing disorders and we identify potential neural targets for intervention.NEW & NOTEWORTHY Disrupted signaling via the α7-nicotinic acetylcholine receptor (α7-nAChR) is associated with neurodevelopmental disorders that include impaired auditory processing. The underlying causes of dysfunction are not known but a common feature is abnormal timing of neural activity. We examined temporal processing of α7-nAChR knockout mice and wild-type controls. We found degraded spike timing of neurons in knockout animals, which manifests at the level of the auditory brainstem and midbrain.

Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment.

Hearing loss leads to a host of cellular and synaptic changes in auditory brain areas that are thought to give rise to auditory perception deficits such as temporal processing impairments, hyperacusis, and tinnitus. However, little is known about possible changes in synaptic circuit connectivity that may underlie these hearing deficits. Here, we show that mild hearing loss as a result of brief noise exposure leads to a pronounced reorganization of local excitatory and inhibitory circuits in the mouse inferior colliculus. The exact nature of these reorganizations correlated with the presence or absence of the animals' impairments in detecting brief sound gaps, a commonly used behavioral sign for tinnitus in animal models. Mice with gap detection deficits (GDDs) showed a shift in the balance of synaptic excitation and inhibition that was present in both glutamatergic and GABAergic neurons, whereas mice without GDDs showed stable excitation-inhibition balances. Acoustic enrichment (AE) with moderate intensity, pulsed white noise immediately after noise trauma prevented both circuit reorganization and GDDs, raising the possibility of using AE immediately after cochlear damage to prevent or alleviate the emergence of central auditory processing deficits.SIGNIFICANCE STATEMENT Noise overexposure is a major cause of central auditory processing disorders, including tinnitus, yet the changes in synaptic connectivity underlying these disorders remain poorly understood. Here, we find that brief noise overexposure leads to distinct reorganizations of excitatory and inhibitory synaptic inputs onto glutamatergic and GABAergic neurons and that the nature of these reorganizations correlates with animals' impairments in detecting brief sound gaps, which is often considered a sign of tinnitus. Acoustic enrichment immediately after noise trauma prevents circuit reorganizations and gap detection deficits, highlighting the potential for using sound therapy soon after cochlear damage to prevent the development of central processing deficits.

Apoptosis and proliferation in the inferior colliculus during postnatal development and epileptogenesis in audiogenic Krushinsky-Molodkina rats.

It is known that audiogenic seizure (AGS) expression is based on the activation of the midbrain structures such as the inferior colliculus (IC). It was demonstrated that excessive sound exposure during the postnatal developments of the IC in rats led to AGS susceptibility in adulthood, which correlated with underdevelopment of the IC. In adult rodents, noise overstimulation induced apoptosis in the IC. The purpose of this study was to investigate postnatal development of the IC in rats genetically prone to AGS and to check if audiogenic kindling would activate apoptosis and/or proliferation in the IC. In our study, we used inbred audiogenic Krushinsky-Molodkina (KM) rats, which are characterized by age-dependent seizure expression. Analysis of postnatal development showed the increased number of proliferating cells in the IC central nucleus of KM rats on the 14th postnatal day (P14) in comparison with those of Wistar rats. Moreover, we also observed increased apoptosis level and decreased general cell population in the IC central nucleus. These data pointed towards a delayed development of the IC in KM rats. Analysis of the IC central nucleus of KM rat after audiogenic kindling for a week, with one AGS per day, demonstrated dramatically increased cell death, which was accompanied with a reduction of general cell population. Audiogenic kindling also decreased proliferation in the IC central nucleus. However, a week after the last AGS, the number of proliferating cells was increased, which supposes a certain compensatory mechanism to prevent cell loss.

Passive stimulation and behavioral training differentially transform temporal processing in the inferior colliculus and primary auditory cortex.

In profoundly deaf cats, behavioral training with intracochlear electric stimulation (ICES) can improve temporal processing in the primary auditory cortex (AI). To investigate whether similar effects are manifest in the auditory midbrain, ICES was initiated in neonatally deafened cats either during development after short durations of deafness (8 wk of age) or in adulthood after long durations of deafness (≥3.5 yr). All of these animals received behaviorally meaningless, "passive" ICES. Some animals also received behavioral training with ICES. Two long-deaf cats received no ICES prior to acute electrophysiological recording. After several months of passive ICES and behavioral training, animals were anesthetized, and neuronal responses to pulse trains of increasing rates were recorded in the central (ICC) and external (ICX) nuclei of the inferior colliculus. Neuronal temporal response patterns (repetition rate coding, minimum latencies, response precision) were compared with results from recordings made in the AI of the same animals (Beitel RE, Vollmer M, Raggio MW, Schreiner CE. J Neurophysiol 106: 944-959, 2011; Vollmer M, Beitel RE. J Neurophysiol 106: 2423-2436, 2011). Passive ICES in long-deaf cats remediated severely degraded temporal processing in the ICC and had no effects in the ICX. In contrast to observations in the AI, behaviorally relevant ICES had no effects on temporal processing in the ICC or ICX, with the single exception of shorter latencies in the ICC in short-deaf cats. The results suggest that independent of deafness duration passive stimulation and behavioral training differentially transform temporal processing in auditory midbrain and cortex, and primary auditory cortex emerges as a pivotal site for behaviorally driven neuronal temporal plasticity in the deaf cat. NEW & NOTEWORTHY: Behaviorally relevant vs. passive electric stimulation of the auditory nerve differentially affects neuronal temporal processing in the central nucleus of the inferior colliculus (ICC) and the primary auditory cortex (AI) in profoundly short-deaf and long-deaf cats. Temporal plasticity in the ICC depends on a critical amount of electric stimulation, independent of its behavioral relevance. In contrast, the AI emerges as a pivotal site for behaviorally driven neuronal temporal plasticity in the deaf auditory system.

An abnormal GABAergic system in the inferior colliculus provides a basis for audiogenic seizures in genetically epilepsy-prone rats.

In this review of neuroanatomical studies of the genetically epilepsy-prone rat (GEPR), three main topics will be covered. First, the number of GABAergic neurons and total neurons in the inferior colliculus of GEPRs will be compared to those of the nonepileptic Sprague-Dawley rat. Next, the number of small neurons in the inferior colliculus will be described in both developmental and genetic analyses of GEPRs and their backcrosses. Last, results from two types of studies on the propagation pathways for audiogenic seizures in GEPRs will be shown. Together, these studies demonstrate a unique GABAergic, small neuron defect in the inferior colliculus of GEPRs that may play a vital role in the initiation and spread of seizure activity during audiogenic seizures. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Audiogenic seizure activity following HSV-1 GAD65 sense or antisense injection into inferior colliculus of Long-Evans rat.

Herpes virus technology involving manipulation of GAD65 was used to study effects on audiogenic seizures (AGS). Audiogenic seizure behaviors were examined following injections of replication-defective herpes simplex virus (HSV-1) vectors incorporating sense or antisense toward GAD65 along with 10% lac-Z into the central nucleus of inferior colliculus (CNIC) of Long-Evans rats. In seizure-sensitive animals developmentally primed by intense sound exposure, injection of GAD65 in the sense orientation increased wild running latencies and reduced incidence of clonus compared with lac-Z only, unoperated, and vehicle seizure groups. In contrast, infection of CNIC with GAD65 antisense virus resulted in 100% incidence of wild running and clonus behaviors in AGS animals. Unprimed animals not operated continued to show uniform absence of seizure activity. Administration of GAD65 antisense virus into CNIC produced novel wild running and clonus behaviors in some unprimed animals. Staining for ß-galactosidase in all vector animals revealed no differences in pattern or numbers of immunoreactive cells at injection sites. Qualitatively, typical small and medium multipolar/stellate and medium fusiform neurons appeared in the CNIC of vector animals. These results demonstrate that HSV-1 vector constructs implanted into the CNIC can predictably influence incidence and severity of AGS and suggest that viral vectors can be useful in studying GABA mechanisms with potential for therapeutic application in epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Suppression of putative tinnitus-related activity by extra-cochlear electrical stimulation.

Studies on animals have shown that noise-induced hearing loss is followed by an increase of spontaneous firing at several stages of the central auditory system. This central hyperactivity has been suggested to underpin the perception of tinnitus. It was shown that decreasing cochlear activity can abolish the noise-induced central hyperactivity. This latter result further suggests that an approach consisting of reducing cochlear activity may provide a therapeutic avenue for tinnitus. In this context, extra-cochlear electric stimulation (ECES) may be a good candidate to modulate cochlear activity and suppress tinnitus. Indeed, it has been shown that a positive current applied at the round window reduces cochlear nerve activity and can suppress tinnitus reliably in tinnitus subjects. The present study investigates whether ECES with a positive current can abolish the noise-induced central hyperactivity, i.e., the putative tinnitus-related activity. Spontaneous and stimulus-evoked neural activity before, during and after ECES was assessed from single-unit recordings in the inferior colliculus of anesthetized guinea pigs. We found that ECES with positive current significantly decreases the spontaneous firing rate of neurons with high characteristic frequencies, whereas negative current produces the opposite effect. The effects of the ECES are absent or even reversed for neurons with low characteristic frequencies. Importantly, ECES with positive current had only a marginal effect on thresholds and tone-induced activity of collicular neurons, suggesting that the main action of positive current is to modulate the spontaneous firing. Overall, cochlear electrical stimulation may be a viable approach for suppressing some forms of (peripheral-dependent) tinnitus.

Postinhibitory rebound neurons and networks are disrupted in retrovirus-induced spongiform neurodegeneration.

Certain retroviruses induce progressive spongiform motor neuron disease with features resembling prion diseases and amyotrophic lateral sclerosis. With the neurovirulent murine leukemia virus (MLV) FrCasE, Env protein expression within glia leads to postsynaptic vacuolation, cellular effacement, and neuronal loss in the absence of neuroinflammation. To understand the physiological changes associated with MLV-induced spongiosis, and its neuronal specificity, we employed patch-clamp recordings and voltage-sensitive dye imaging in brain slices of the mouse inferior colliculus (IC), a midbrain nucleus that undergoes extensive spongiosis. IC neurons characterized by postinhibitory rebound firing (PIR) were selectively affected in FrCasE-infected mice. Coincident with Env expression in microglia and in glia characterized by NG2 proteoglycan expression (NG2 cells), rebound neurons (RNs) lost PIR, became hyperexcitable, and were reduced in number. PIR loss and hyperexcitability were reversed by raising internal calcium buffer concentrations in RNs. PIR-initiated rhythmic circuits were disrupted, and spontaneous synchronized bursting and prolonged depolarizations were widespread. Other IC neuron cell types and circuits within the same degenerative environment were unaffected. Antagonists of NMDA and/or AMPA receptors reduced burst firing in the IC but did not affect prolonged depolarizations. Antagonists of L-type calcium channels abolished both bursts and slow depolarizations. IC infection by the nonneurovirulent isogenic virus Friend 57E (Fr57E), whose Env protein is structurally similar to FrCasE, showed no RN hyperactivity or cell loss; however, PIR latency increased. These findings suggest that spongiform neurodegeneration arises from the unique excitability of RNs, their local regulation by glia, and the disruption of this relationship by glial expression of abnormal protein.

Neural changes accompanying tinnitus following unilateral acoustic trauma in the guinea pig.

Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise-exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates (SFRs) and burst firing in the inferior colliculus (IC), evoked auditory brainstem responses (ABRs), and the number of neurons in the cochlear nucleus containing nitric oxide synthase (NOS). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFRs and incidences of burst firing were elevated in the IC of all noise-exposed animals, but there were no differences between tinnitus and no-tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral-contralateral asymmetry in NOS staining in the ventral cochlear nucleus (VCN) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS-containing neurons on the noise-exposed side, whereas no-tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABRs supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus.

Disinhibition of the midbrain colliculi unmasks coordinated autonomic, respiratory, and somatomotor responses to auditory and visual stimuli.

The midbrain superior and inferior colliculi have critical roles in generating coordinated orienting or defensive behavioral responses to environmental stimuli, and it has been proposed that neurons within the colliculi can also generate appropriate cardiovascular and respiratory responses to support such behavioral responses. We have previously shown that activation of neurons within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus can evoke a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity and phrenic nerve activity. In this study, we tested the hypothesis that, under conditions in which collicular neurons are disinhibited, coordinated cardiovascular, somatomotor, and respiratory responses can be evoked by natural environmental stimuli. In response to natural auditory, visual, or somatosensory stimuli, powerful synchronized increases in sympathetic, respiratory, and somatomotor activity were generated following blockade of GABAA receptors in a specific region in the midbrain colliculi of anesthetized rats, but not under control conditions. Such responses still occurred after removal of most of the forebrain, including the amygdala and hypothalamus, indicating that the essential pathways mediating these coordinated responses were located within the brain stem. The temporal relationships between the different outputs suggest that they are driven by a common population of "command neurons" within the colliculi.

Hearing loss-related altered neuronal activity in the inferior colliculus.

Hearing loss is well known to cause plastic changes in the central auditory system and pathological changes such as tinnitus and hyperacusis. Impairment of inner ear functions is the main cause of hearing loss. In aged individuals, not only inner ear dysfunction but also senescence of the central nervous system is the cause of malfunction of the auditory system. In most cases of hearing loss, the activity of the auditory nerve is reduced, but that of the successive auditory centers is increased in a compensatory way. It has been reported that activity changes occur in the inferior colliculus (IC), a critical nexus of the auditory pathway. The IC integrates the inputs from the brainstem and drives the higher auditory centers. Since abnormal activity in the IC is likely to affect auditory perception, it is crucial to elucidate the neuronal mechanism to induce the activity changes of IC neurons with hearing loss. This review outlines recent findings on hearing-loss-induced plastic changes in the IC and brainstem auditory neuronal circuits and discusses what neuronal mechanisms underlie hearing-loss-induced changes in the activity of IC neurons. Considering the different causes of hearing loss, we discuss age-related hearing loss separately from other forms of hearing loss (non-age-related hearing loss). In general, the main plastic change of IC neurons caused by both age-related and non-age-related hearing loss is increased central gain. However, plastic changes in the IC caused by age-related hearing loss seem to be more complex than those caused by non-age-related hearing loss.

The relation between perception and brain activity in gaze-evoked tinnitus.

Tinnitus is a phantom sound percept that can be severely disabling. Its pathophysiology is poorly understood, partly due to the inability to objectively measure neural correlates of tinnitus. Gaze-evoked tinnitus (GET) is a rare form of tinnitus that may arise after vestibular schwannoma removal. Subjects typically describe tinnitus in the deaf ear on the side of the surgery that can be modulated by peripheral eye gaze. This phenomenon offers a unique opportunity to study the relation between tinnitus and brain activity. We used functional magnetic resonance imaging in humans to show that in normal-hearing control subjects, peripheral gaze results in inhibition of the auditory cortex, but no detectable response in the medial geniculate body (MGB) and inferior colliculus (IC). In patients with GET, peripheral gaze (1) reduced the cortical inhibition, (2) inhibited the MGB, and (3) activated the IC. Furthermore, increased tinnitus loudness is represented by increased activity in the cochlear nucleus (CN) and IC and reduced inhibition in the auditory cortex (AC). The increase of CN and IC activity with peripheral gaze is consistent with models of plastic reorganization in the brainstem following vestibular schwannoma removal. The activity decrease in the MGB and the reduced inhibition of the AC support a model that attributes tinnitus to a dysrhythmia of the thalamocortical loop, leading to hypometabolic theta activity in the MGB. Our data offer the first support of this loop hypothesis of tinnitus, independent of the initial experiments that led to its formulation.

Tonotopic reorganization and spontaneous firing in inferior colliculus during both short and long recovery periods after noise overexposure.

BACKGROUND: Noise induced injury of the cochlea causes shifts in activation thresholds and changes of frequency response in the inferior colliculus (IC). Noise overexposure also induces pathological changes in the cochlea, and is highly correlated to hearing loss. However, the underlying mechanism has not been fully elucidated. In this study, we hypothesized that overexposure to noise induces substantial electrophysiological changes in the IC of guinea pigs. RESULTS: During the noise exposure experiment, the animals were undergoing a bilateral exposure to noise. Additionally, various techniques were employed including confocal microscopy for the detection of cochlea hair cells and single neuron recording for spontaneous firing activity measurement. There were alterations among three types of frequency response area (FRA) from sound pressure levels, including V-, M-, and N-types. Our results indicate that overexposure to noise generates different patterns in the FRAs. Following a short recovery (one day after the noise treatment), the percentage of V-type FRAs considerably decreased, whereas the percentage of M-types increased. This was often caused by a notch in the frequency response that occurred at 4 kHz (noise frequency). Following a long recovery from noise exposure (11-21 days), the percentage of V-types resumed to a normal level, but the portion of M-types remained high. Interestingly, the spontaneous firing in the IC was enhanced in both short and long recovery groups. CONCLUSION: Our data suggest that noise overexposure changes the pattern of the FRAs and stimulates spontaneous firing in the IC in a unique way, which may likely relate to the mechanism of tinnitus.

Impairment of habituation of the auditory brain stem response in migrainous vertigo.

OBJECTIVES: We evaluated the auditory brain stem response (ABR) in migrainous vertigo (MV). METHODS: Four subjects who met clinical criteria for definite MV and 4 subjects with non-vertiginous migraine (NVM) underwent ABR testing while asymptomatic and within 16 hours of a symptomatic episode. Four control subjects were also tested. A set of 4 consecutive 750-click series was administered at 50-, 60-, and 70-dB intensities. We compared the groups in terms of habituation of the amplitude of wave IV-V (habituation of IV-V) from the first through fourth series for each set. RESULTS: The habituation of IV-V amplitude to 50-dB stimuli was significantly less (p = 0.047) in the symptomatic MV group (5.08% +/- 22.32%) than in the symptomatic NVM group (-21.44% +/- 13.50%) or the control group (-26.06% +/- 9.76%). The habituation of IV-V amplitude to 70-dB stimuli in the MV group was significantly less (p = 0.031) during symptomatic testing (-3.43% +/- 8.89%) than during asymptomatic testing (-21.23% +/- 6.41%). CONCLUSIONS: The habituation of IV-V amplitude is reduced during MV attacks. This finding suggests impaired brain stem inhibition at the level of the inferior colliculus, which shares serotonergic connections with the dorsal raphe nucleus, an area hyperactive in migraine.

Impaired auditory temporal selectivity in the inferior colliculus of aged Mongolian gerbils.

Aged humans show severe difficulties in temporal auditory processing tasks (e.g., speech recognition in noise, low-frequency sound localization, gap detection). A degradation of auditory function with age is also evident in experimental animals. To investigate age-related changes in temporal processing, we compared extracellular responses to temporally variable pulse trains and human speech in the inferior colliculus of young adult (3 month) and aged (3 years) Mongolian gerbils. We observed a significant decrease of selectivity to the pulse trains in neuronal responses from aged animals. This decrease in selectivity led, on the population level, to an increase in signal correlations and therefore a decrease in heterogeneity of temporal receptive fields and a decreased efficiency in encoding of speech signals. A decrease in selectivity to temporal modulations is consistent with a downregulation of the inhibitory transmitter system in aged animals. These alterations in temporal processing could underlie declines in the aging auditory system, which are unrelated to peripheral hearing loss. These declines cannot be compensated by traditional hearing aids (that rely on amplification of sound) but may rather require pharmacological treatment.

Efferent pathways modulate hyperactivity in inferior colliculus.

Animal models have demonstrated that mild hearing loss caused by acoustic trauma results in spontaneous hyperactivity in the central auditory pathways. This hyperactivity has been hypothesized to be involved in the generation of tinnitus, a phantom auditory sensation. We have recently shown that such hyperactivity, recorded in the inferior colliculus, is still dependent on cochlear neural output for some time after recovery (up to 6 weeks). We have now studied the capacity of an intrinsic efferent system, i.e., the olivocochlear system, to alter hyperactivity. This system is known to modulate cochlear neural output. Anesthetized guinea pigs were exposed to a loud sound and after 2 or 3 weeks of recovery, single-neuron recordings in inferior colliculus were made to confirm hyperactivity. Olivocochlear axons were electrically stimulated and effects on cochlear neural output and on highly spontaneous neurons in inferior colliculus were assessed. Olivocochlear stimulation suppressed spontaneous hyperactivity in the inferior colliculus. This result is in agreement with our earlier finding that hyperactivity can be modulated by altering cochlear neural output. Interestingly, the central suppression was generally much larger and longer lasting than reported previously for primary afferents. Blockade of the intracochlear effects of olivocochlear system activation eliminated some but not all of the effects observed on spontaneous activity, suggesting also a central component to the effects of stimulation. More research is needed to investigate whether these central effects of olivocochlear efferent stimulation are due to central intrinsic circuitry or to coactivation of central efferent collaterals to the cochlear nucleus.