Tinnitus-like “hallucinations” elicited by sensory deprivation in an entropy maximization recurrent neural network

Sensory deprivation has long been known to cause hallucinations or “phantom” sensations, the most common of which is tinnitus induced by hearing loss, affecting 10–20% of the population. An observable hearing loss, causing auditory sensory deprivation over a band of frequencies, is present in over 90% of people with tinnitus. Existing plasticity-based computational models for tinnitus are usually driven by homeostatic mechanisms, modeled to fit phenomenological findings. Here, we use an objective-driven learning algorithm to model an early auditory processing neuronal network, e.g., in the dorsal cochlear nucleus. The learning algorithm maximizes the network’s output entropy by learning the feed-forward and recurrent interactions in the model. We show that the connectivity patterns and responses learned by the model display several hallmarks of early auditory neuronal networks. We further demonstrate that attenuation of peripheral inputs drives the recurrent network towards its critical point and transition into a tinnitus-like state. In this state, the network activity resembles responses to genuine inputs even in the absence of external stimulation, namely, it “hallucinates” auditory responses. These findings demonstrate how objective-driven plasticity mechanisms that normally act to optimize the network’s input representation can also elicit pathologies such as tinnitus as a result of sensory deprivation.     

Discrimination task reveals differences in neural bases of tinnitus and hearing impairment

We investigated auditory perception and cognitive processing in individuals with chronic tinnitus or hearing loss using functional magnetic resonance imaging (fMRI). Our participants belonged to one of three groups: bilateral hearing loss and tinnitus (TIN), bilateral hearing loss without tinnitus (HL), and normal hearing without tinnitus (NH). We employed pure tones and frequency-modulated sweeps as stimuli in two tasks: passive listening and active discrimination. All subjects had normal hearing through 2 kHz and all stimuli were low-pass filtered at 2 kHz so that all participants could hear them equally well. Performance was similar among all three groups for the discrimination task. In all participants, a distributed set of brain regions including the primary and non-primary auditory cortices showed greater response for both tasks compared to rest. Comparing the groups directly, we found decreased activation in the parietal and frontal lobes in the participants with tinnitus compared to the HL group and decreased response in the frontal lobes relative to the NH group. Additionally, the HL subjects exhibited increased response in the anterior cingulate relative to the NH group. Our results suggest that a differential engagement of a putative auditory attention and short-term memory network, comprising regions in the frontal, parietal and temporal cortices and the anterior cingulate, may represent a key difference in the neural bases of chronic tinnitus accompanied by hearing loss relative to hearing loss alone.     

Cortical Reorganisation during a 30-Week Tinnitus Treatment Program

Subjective tinnitus is characterised by the conscious perception of a phantom sound. Previous studies have shown that individuals with chronic tinnitus have disrupted sound-evoked cortical tonotopic maps, time-shifted evoked auditory responses, and altered oscillatory cortical activity. The main objectives of this study were to: (i) compare sound-evoked brain responses and cortical tonotopic maps in individuals with bilateral tinnitus and those without tinnitus; and (ii) investigate whether changes in these sound-evoked responses occur with amelioration of the tinnitus percept during a 30-week tinnitus treatment program. Magnetoencephalography (MEG) recordings of 12 bilateral tinnitus participants and 10 control normal-hearing subjects reporting no tinnitus were recorded at baseline, using 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz tones presented monaurally at 70 dBSPL through insert tube phones. For the tinnitus participants, MEG recordings were obtained at 5-, 10-, 20- and 30- week time points during tinnitus treatment. Results for the 500 Hz and 1000 Hz sources (where hearing thresholds were within normal limits for all participants) showed that the tinnitus participants had a significantly larger and more anteriorly located source strengths when compared to the non-tinnitus participants. During the 30-week tinnitus treatment, the participants’ 500 Hz and 1000 Hz source strengths remained higher than the non-tinnitus participants; however, the source locations shifted towards the direction recorded from the non-tinnitus control group. Further, in the left hemisphere, there was a time-shifted association between the trajectory of change of the individual’s objective (source strength and anterior-posterior source location) and subjective measures (using tinnitus reaction questionnaire, TRQ). The differences in source strength between the two groups suggest that individuals with tinnitus have enhanced central gain which is not significantly influenced by the tinnitus treatment, and may result from the hearing loss per se. On the other hand, the shifts in the tonotopic map towards the non-tinnitus participants’ source location suggests that the tinnitus treatment might reduce the disruptions in the map, presumably produced by the tinnitus percept directly or indirectly. Further, the similarity in the trajectory of change across the objective and subjective parameters after time-shifting the perceptual changes by 5 weeks suggests that during or following treatment, perceptual changes in the tinnitus percept may precede neurophysiological changes. Subgroup analyses conducted by magnitude of hearing loss suggest that there were no differences in the 500 Hz and 1000 Hz source strength amplitudes for the mild-moderate compared with the mild-severe hearing loss subgroup, although the mean source strength was consistently higher for the mild-severe subgroup. Further, the mild-severe subgroup had 500 Hz and 1000 Hz source locations located more anteriorly (i.e., more disrupted compared to the control group) compared to the mild-moderate group, although this was trending towards significance only for the 500Hz left hemisphere source. While the small numbers of participants within the subgroup analyses reduce the statistical power, this study suggests that those with greater magnitudes of hearing loss show greater cortical disruptions with tinnitus and that tinnitus treatment appears to reduce the tonotopic map disruptions but not the source strength (or central gain).     

Ultrasonic singing by the blue-throated hummingbird: a comparison between production and perception

Blue-throated hummingbirds produce elaborate songs extending into the ultrasonic frequency range, up to 30 kHz. Ultrasonic song elements include harmonics and extensions of audible notes, non-harmonic components of audible syllables, and sounds produced at frequencies above 20 kHz without corresponding hearing range sound. To determine whether ultrasonic song elements function in intraspecific communication, we tested the hearing range of male and female blue-throated hummingbirds. We measured auditory thresholds for tone pips ranging from 1 kHz to 50 kHz using auditory brainstem responses. Neither male nor female blue-throated hummingbirds appear to be able to hear above 7 kHz. No auditory brainstem responses could be detected between 8 and 50 kHz at 90 dB. This high-frequency cutoff is well within the range reported for other species of birds. These results suggest that high-frequency song elements are not used in intraspecific communication. We propose that the restricted hummingbird hearing range may exemplify a phylogenetic constraint.     

The ontogenetic development of auditory sensitivity, vocalization and acoustic communication in the labyrinth fish Trichopsis vittata

The anabantoid fish Trichopsis vittata starts vocalizing as 8-week-old juveniles. In order to determine whether juveniles are able to detect conspecific sounds, hearing sensitivities were measured in six size groups utilizing the auditory brainstem response-recording technique. Results were compared to sound pressure levels and spectra of sounds recorded during fighting. Auditory evoked potentials were present in all size groups and complete audiograms were obtained starting with 0.18 to 0.30 g juveniles. Auditory sensitivity during development primarily increased between 0.8 kHz and 3.0 kHz. The most sensitive frequency within this range shifted from 2.5 kHz to 1.5 kHz, whereas thresholds decreased by 14 dB. Sound production, on the other hand, started at 0.1 g and sound power spectra at dominant frequencies increased by 43 dB, while dominant frequencies shifted from 3 kHz to 1.5 kHz. Comparisons between audiograms and sound power spectra in similar-sized juveniles revealed no clear match between most sensitive frequencies and dominant frequencies of sounds. This also revealed that juveniles cannot detect conspecific sounds below the 0.31 to 0.65 g size class. These results indicate that auditory sensitivity develops prior to the ability to vocalize and that vocalization occurs prior to the ability to communicate acoustically.     

Effects of Boat Engine Noise on the Auditory Sensitivity of the Fathead Minnow, Pimephales promelas

Fishes are constantly exposed to various sources of noise in their underwater acoustic environment. Many of these sounds are from anthropogenic sources, especially engines of boats. Noise generated from a small boat with a 55 horsepower outboard motor was played back to fathead minnows, Pimephales promelas, for 2 h at 142 dB (re: 1 Pa), and auditory thresholds were measured using the auditory brainstem response (ABR) technique. The results demonstrate that boat engine noise significantly elevate a fish's auditory threshold at 1 kHz (7.8 dB), 1.5 kHz (13.5 dB), and 2.0 kHz (10.5 dB), the most sensitive hearing range of this species. Such a short duration of noise exposure leads to significant changes in hearing capability, and implies that man-made noise generated from boat engines can have far reaching environmental impacts on fishes.     

Default Mode,Dorsal Attention and Auditory Resting State Networks Exhibit Differential Functional Connectivity in Tinnitus and Hearing Loss

We investigated auditory, dorsal attention, and default mode networks in adults with tinnitus and hearing loss in a resting state functional connectivity study. Data were obtained using continuous functional magnetic resonance imaging (fMRI) while the participants were at “rest” and were not performing any task. Participants belonged to one of three groups: middle-aged adults with tinnitus and mild-to-moderate high frequency hearing loss (TIN), age-matched controls with normal hearing and no tinnitus (NH), and a second control group with mild-to-moderate high frequency hearing loss without tinnitus (HL). After standard preprocessing, (a) a group independent component analysis (ICA) using 30 components and (b) a seeding-based connectivity analysis were conducted. In the group ICA, the default mode network was the only network to display visual differences between subject groups. In the seeding analysis, we found increased connectivity between the left parahippocampus and the auditory resting state network in the TIN group when compared to NH controls. Similarly, there was also an increased correlation between the right parahippocampus and the dorsal attention network when compared to HL controls. Other group differences in this attention network included decreased correlations between the seed regions and the right supramarginal gyrus in TIN patients when compared to HL controls. In the default mode network, there was a strong decrease in correlation between the seed regions and the precuneus when compared to both control groups. The findings of this study identify specific alterations in the connectivity of the default mode, dorsal attention, and auditory resting state networks due to tinnitus. The results suggest that therapies for tinnitus that mitigate the increased connectivity of limbic regions with auditory and attention resting state networks and the decreased coherence of the default mode network could be effective at reducing tinnitus-related distress.     

Acoustical and neural aspects of hearing in the Australian gleaning bats,Macroderma gigas andNyctophilus gouldi

1. The maximum acoustic gain of the external ear in Macroderma gigas was found to be 25-30 dB between 5-8 kHz and in Nyctophilus gouldi it reached 15-23 dB between 7-22 kHz. Pinna gain reached a peak of 16 dB near 4.5-6 kHz in M. gigas and 12-17 dB between 7-12 kHz in N. gouldi, with average gain of 6-10 dB up to 100 kHz. Pinna gain curves resemble that of a finite conical horn, including resonance. 2. The directional properties of the external ear in both species result from sound diffraction at the pinna face, as it approximates a circular aperture. The frequency dependent movement of the acoustic axis in azimuth and elevation is attributed to the asymmetrical structure of the pinnae. 3. Evoked potentials and neuronal responses were studied in the inferior colliculus. In M. gigas, the neural audiogram has sensitivity peaks at 10-20 kHz and 35-43 kHz, with extremely low thresholds (-18 dB SPL) in the low frequency region. In N. gouldi, the neural audiogram has sensitivity peaks at 8-14 kHz (lowest threshold 5 dB SPL) and 22-45 kHz. Removal of the contralateral pinna causes a frequency dependent loss in neural threshold sensitivity of up to 10-15 dB in both species. 4. The high frequency peak in the audiogram coincides with the sonar energy band in both species, whereas the low frequency region is used for social communication. Highly sensitive low frequency hearing is discussed in relation to hunting in bats by passive listening.     

Acoustic communication and the evolution of hearing in fishes

Fishes have evolved a diversity of sound-generating organs and acoustic signals of various temporal and spectral content. Additionally, representatives of many teleost families such as otophysines, anabantoids, mormyrids and holocentrids possess accessory structures that enhance hearing abilities by acoustically coupling air-filled cavities to the inner ear. Contrary to the accessory hearing structures such as Weberian ossicles in otophysines and suprabranchial chambers in anabantoids, sonic organs do not occur in all members of these taxa. Comparison of audiograms among nine representatives of seven otophysan families from four orders revealed major differences in auditory sensitivity, especially at higher frequencies (> 1 kHz) where thresholds differed by up to 50 dB. These differences showed no apparent correspondence to the ability to produce sounds (vocal versus non-vocal species) or to the spectral content of species-specific sounds. In anabantoids, the lowest auditory thresholds were found in the blue gourami Trichogaster trichopterus, a species not thought to be vocal. Dominant frequencies of sounds corresponded with optimal hearing bandwidth in two out of three vocalizing species. Based on these results, it is concluded that the selective pressures involved in the evolution of accessory hearing structures and in the design of vocal signals were other than those serving to optimize acoustic communication.     

Transient reduction of tinnitus intensity is marked by concomitant reductions of delta band power

Background

Tinnitus is an auditory phantom phenomenon characterized by the sensation of sounds without objectively identifiable sound sources. To date, its causes are not well understood. Previous research found altered patterns of spontaneous brain activity in chronic tinnitus sufferers compared to healthy controls, yet it is unknown whether these abnormal oscillatory patterns are causally related to the tinnitus sensation. Partial support for this notion comes from a neurofeedback approach developed by our group, in which significant reductions in tinnitus loudness could be achieved in patients who successfully normalized their patterns of spontaneous brain activity. The current work attempts to complement these studies by scrutinizing how modulations of tinnitus intensity alter ongoing oscillatory activity.

Results

In the present study the relation between tinnitus sensation and spontaneous brain activity was investigated using residual inhibition (RI) to reduce tinnitus intensity and source-space projected magnetencephalographic (MEG) data to index brain activity. RI is the sustained reduction (criteria: 50% for at least 30 s) in tinnitus loudness after cessation of a tonal tinnitus masker. A pilot study (n = 38) identified 10 patients who showed RI. A significant reduction of power in the delta (1.3–4.0 Hz) frequency band was observed in temporal regions during RI (p ≤ 0.001).

Conclusion

The current results suggest that changes of tinnitus intensity induced by RI are mediated by alterations in the pathological patterns of spontaneous brain activity, specifically a reduction of delta activity. Delta activity is a characteristic oscillatory activity generated by deafferented/deprived neuronal networks. This implies that RI effects might reflect the transient reestablishment of balance between excitatory and inhibitory neuronal assemblies, via reafferentation, that have been perturbed (in most tinnitus individuals) by hearing damage. As enhancements have been reported in the delta frequency band for tinnitus at rest, this result conforms to our assumption that a normalization of oscillatory properties of cortical networks is a prerequisite for attenuating the tinnitus sensation. For RI to have therapeutic significance however, this normalization would have to be stabilized.     

Selective Impairment in Frequency Discrimination in a Mouse Model of Tinnitus

Tinnitus is an auditory disorder, which affects millions of Americans, including active duty service members and veterans. It is manifested by a phantom sound that is commonly restricted to a specific frequency range. Because tinnitus is associated with hearing deficits, understanding how tinnitus affects hearing perception is important for guiding therapies to improve the quality of life in this vast group of patients. In a rodent model of tinnitus, prolonged exposure to a tone leads to a selective decrease in gap detection in specific frequency bands. However, whether and how hearing acuity is affected for sounds within and outside those frequency bands is not well understood. We induced tinnitus in mice by prolonged exposure to a loud mid-range tone, and behaviorally assayed whether mice exhibited a change in frequency discrimination acuity for tones embedded within the mid-frequency range and high-frequency range at 1, 4, and 8 weeks post-exposure. A subset of tone-exposed mice exhibited tinnitus-like symptoms, as demonstrated by selective deficits in gap detection, which were restricted to the high frequency range. These mice exhibited impaired frequency discrimination both for tones in the mid-frequency range and high-frequency range. The remaining tone exposed mice, which did not demonstrate behavioral evidence of tinnitus, showed temporary deficits in frequency discrimination for tones in the mid-frequency range, while control mice remained unimpaired. Our findings reveal that the high frequency-specific deficits in gap detection, indicative of tinnitus, are associated with impairments in frequency discrimination at the frequency of the presumed tinnitus.     

Correlation between auditory sensitivity and vocalization in anabantoid fishes

Several anabantoid species produce broad-band sounds with high-pitched dominant frequencies (0.8–2.5 kHz), which contrast with generally low-frequency hearing abilities in (perciform) fishes. Utilizing a recently developed auditory brainstem response recording-technique, auditory sensitivities of the gouramis Trichopsis vittata, T. pumila, Colisa lalia, Macropodus opercularis and Trichogaster trichopterus were investigated and compared with the sound characteristics of the respective species. All five species exhibited enhanced sound-detecting abilities and perceived tone bursts up to 5 kHz, which qualifies this group as hearing specialists. All fishes possessed a high-frequency sensitivity maximum between 800 Hz and 1500 Hz. Lowest hearing thresholds were found in T. trichopterus (76 dB re 1 μPa at 800 Hz). Dominant frequencies of sounds correspond with the best hearing bandwidth in T. vittata (1–2 kHz) and C. lalia (0.8–1 kHz). In the smallest species, T. pumila, dominant frequencies of acoustic signals (1.5–2.5 kHz) do not match lowest thresholds, which were below 1.5 kHz. However, of all species studied, T. pumila had best hearing sensitivity at frequencies above 2 kHz. The association between high-pitched sounds and hearing may be caused by the suprabranchial air-breathing chamber, which, lying close to the hearing and sonic organs, enhances both sound perception and emission at its resonant frequency. Accepted: 26 November 1997     

Hearing in the sea otter (Enhydra lutris): auditory profiles for an amphibious marine carnivore

In this study we examine the auditory capabilities of the sea otter (Enhydra lutris), an amphibious marine mammal that remains virtually unstudied with respect to its sensory biology. We trained an adult male sea otter to perform a psychophysical task in an acoustic chamber and at an underwater apparatus. Aerial and underwater audiograms were constructed from detection thresholds for narrowband signals measured in quiet conditions at frequencies from 0.125–40 kHz. Aerial hearing thresholds were also measured in the presence of octave-band masking noise centered at eight signal frequencies (0.25–22.6 kHz) so that critical ratios could be determined. The aerial audiogram of the sea otter resembled that of sea lions and showed a reduction in low-frequency sensitivity relative to terrestrial mustelids. Best sensitivity was ?1 dB re 20 µPa at 8 kHz. Under water, hearing sensitivity was significantly reduced when compared to sea lions and other pinniped species, demonstrating that sea otter hearing is primarily adapted to receive airborne sounds. Critical ratios were more than 10 dB higher than those measured for pinnipeds, suggesting that sea otters are less efficient than other marine carnivores at extracting acoustic signals from background noise, especially at frequencies below 2 kHz.     

Characterization of beam patterns of bottlenose dolphin in the transversal plane

The characteristics of the absolute auditory sensitivity of the bottlenose dolphin (Tursiops truncatus p.) in the transverse plane have been measured using short broad-band stimuli simulating dolphin clicks (with energy maximum at frequencies 8, 16, 30, 50 and 100 kHz). Experiments were performed using the method of conditioned reflexes with food reinforcement. It was shown that, in the frequency range of 8-30 kHz, the absolute sensitivity of dolphin hearing in any ventral and lateral directions of the transverse plane is only by 2-8 dB worse than in the nasal direction. Moreover, it is approximately by 25-30 dB better than at frequencies of 50-100 kHz. At frequencies of 8-30 kHz, a pronounced dorsoventral asymmetry has been observed. In this frequency range, it reaches approximately 15-18 dB whereas at frequencies of 50-100 kHz, this asymmetry decreases to 2-3 dB. In the dorsal direction, the auditory sensitivity is by 18 dB worse than in the nasal one at frequencies of around 8 kHz, and the difference rises smoothly to 33 dB at frequencies of about 100 kHz. At frequencies of 50-100 kHz, the acoustical thresholds of the cross-section plane in comparison with thresholds for the with nasal direction get worse almost uniformly in all directions by 25-33 dB. As a result, in the transversal plane, the beam patterns have a nearly circular form, unlike the patterns at frequencies of 8-30 kHz. The results are discussed in terms of the model of sound perception through the left and right mental foramens. The biological expediency of the asymmetry is emphasized.     

Temporal summation under masking conditions and speech recognition

Temporal summation was estimated by measuring the detection thresholds for pulses with durations of 1–50 ms in the presence of noise maskers. The purpose of the study was to examine the effects of the spectral profiles and intensities of noise maskers on temporal summation, to investigate the appearance of signs of peripheral processing of pulses with various frequency-time structures in auditory responses, and to test the opportunity to use temporal summation for speech recognition. The central frequencies of pulses and maskers were similar. The maskers had ripple structures of the amplitude spectra of two types. In some maskers, the central frequencies coincided with the spectrum humps, whereas in other maskers, they coincided with spectrum dip (so-called on- and off-maskers). When the auditory system differentiated the masker humps, then the difference between the thresholds of recognition of the stimuli presented together with each of two types of maskers was not equal to zero. The assessment of temporal summation and the difference of the thresholds of pulse recognition under conditions of the presentation of the on- and off-maskers allowed us to make a conclusion on auditory sensitivity and the resolution of the spectral structure of maskers or frequency selectivity during presentation of pulses of various durations in local frequency areas. In order to estimate the effect of the dynamic properties of hearing on sensitivity and frequency selectivity, we changed the intensity of maskers. We measured temporal summation under the conditions of the presentation of on- and off-maskers of various intensities in two frequency ranges (2 and 4 kHz) in four subjects with normal hearing and one person with age-related hearing impairments who complained of a decrease in speech recognition under noise conditions. Pulses shorter than 10 ms were considered as simple models of consonant sounds, whereas tone pulses longer than 10 ms were considered as simple models of vowel sounds. In subjects with normal hearing in the range of moderate masker intensities, we observed an enhancement of temporal summation when the short pulses or consonant sounds were presented and an improvement of the resolution of the broken structure of masker spectra when the short and tone pulses, i.e., consonant and vowel sounds, were presented. We supposed that the enhancement of the summation was related to the refractoriness of the fibers of the auditory nerve. In the range of 4 kHz, the subject with age-related hearing impairments did not recognize the ripple structure of the maskers in the presence of the short pulses or consonant sounds. We supposed that these impairments were caused by abnormal synchronization of the responses of the auditory nerve fibers induced by the pulses, and this resulted in a decrease in speech recognition.     

Tinnitus Intensity Dependent Gamma Oscillations of the Contralateral Auditory Cortex

Background

Non-pulsatile tinnitus is considered a subjective auditory phantom phenomenon present in 10 to 15% of the population. Tinnitus as a phantom phenomenon is related to hyperactivity and reorganization of the auditory cortex. Magnetoencephalography studies demonstrate a correlation between gamma band activity in the contralateral auditory cortex and the presence of tinnitus. The present study aims to investigate the relation between objective gamma-band activity in the contralateral auditory cortex and subjective tinnitus loudness scores.

Methods and Findings

In unilateral tinnitus patients (N = 15; 10 right, 5 left) source analysis of resting state electroencephalographic gamma band oscillations shows a strong positive correlation with Visual Analogue Scale loudness scores in the contralateral auditory cortex (max r = 0.73, p<0.05).

Conclusion

Auditory phantom percepts thus show similar sound level dependent activation of the contralateral auditory cortex as observed in normal audition. In view of recent consciousness models and tinnitus network models these results suggest tinnitus loudness is coded by gamma band activity in the contralateral auditory cortex but might not, by itself, be responsible for tinnitus perception.     

Activation of Auditory Cortex by Anticipating and Hearing Emotional Sounds: An MEG Study

To study how auditory cortical processing is affected by anticipating and hearing of long emotional sounds, we recorded auditory evoked magnetic fields with a whole-scalp MEG device from 15 healthy adults who were listening to emotional or neutral sounds. Pleasant, unpleasant, or neutral sounds, each lasting for 6 s, were played in a random order, preceded by 100-ms cue tones (0.5, 1, or 2 kHz) 2 s before the onset of the sound. The cue tones, indicating the valence of the upcoming emotional sounds, evoked typical transient N100m responses in the auditory cortex. During the rest of the anticipation period (until the beginning of the emotional sound), auditory cortices of both hemispheres generated slow shifts of the same polarity as N100m. During anticipation, the relative strengths of the auditory-cortex signals depended on the upcoming sound: towards the end of the anticipation period the activity became stronger when the subject was anticipating emotional rather than neutral sounds. During the actual emotional and neutral sounds, sustained fields were predominant in the left hemisphere for all sounds. The measured DC MEG signals during both anticipation and hearing of emotional sounds implied that following the cue that indicates the valence of the upcoming sound, the auditory-cortex activity is modulated by the upcoming sound category during the anticipation period.     

Predisposition for and Prevention of Subjective Tinnitus Development

Dysfunction of the inner ear as caused by presbyacusis, injuries or noise traumata may result in subjective tinnitus, but not everyone suffering from one of these diseases develops a tinnitus percept and vice versa. The reasons for these individual differences are still unclear and may explain why different treatments of the disease are beneficial for some patients but not for others. Here we for the first time compare behavioral and neurophysiological data from hearing impaired Mongolian gerbils with (T) and without (NT) a tinnitus percept that may elucidate why some specimen do develop subjective tinnitus after noise trauma while others do not. Although noise trauma induced a similar permanent hearing loss in all animals, tinnitus did develop only in about three quarters of these animals. NT animals showed higher overall cortical and auditory brainstem activity before noise trauma compared to T animals; that is, animals with low overall neuronal activity in the auditory system seem to be prone to develop tinnitus after noise trauma. Furthermore, T animals showed increased activity of cortical neurons representing the tinnitus frequencies after acoustic trauma, whereas NT animals exhibited an activity decrease at moderate sound intensities by that time. Spontaneous activity was generally increased in T but decreased in NT animals. Plastic changes of tonotopic organization were transient, only seen in T animals and vanished by the time the tinnitus percept became chronic. We propose a model for tinnitus prevention that points to a global inhibitory mechanism in auditory cortex that may prevent tinnitus genesis in animals with high overall activity in the auditory system, whereas this mechanism seems not potent enough for tinnitus prevention in animals with low overall activity.     

Gentamicin-Induced Chronotoxicity: Use of Body Temperature as a Orcadian Marker Rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induxed ototoxicity. Two groups of 3 male Sprague-Dawley rats (250–400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16kHz, 24kHz and 32kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80–90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

Gentamicin-induced chronotoxicity: use of body temperature as a circadian marker rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induced ototoxicity. Two groups of 3 male Sprague-Dawley rats (250-400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16 kHz, 24 kHz and 32 kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80-90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.