Gap Detection Deficits Research Articles

Amyloid Pathology in the Central Auditory Pathway of 5XFAD Mice Appears First in Auditory Cortex.

Effective treatment of Alzheimer's disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. We quantified intracellular and extracellular antibody labelling of Aβ42 in 6 regions of the central auditory system from p14 to p150. Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aβ42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. These results suggest that Aβ42 accumulation, but not plaques, may impair gap detection.

Gap detection responses modelled using the Hill equation in adults with well-controlled HIV

Objective This study’s objective was determining whether gap detection deficits are present in a longstanding cohort of people living with HIV (PLWH) compared to those living without HIV (PLWOH) using a new gap detection modelling technique (i.e. fitting gap responses using the Hill equation and analysing the individual gap detection resulting curves with non-linear statistics). This approach provides a measure of both gap threshold and the steepness of the gap length/correct detection relationship. Design The relationship between the correct identification rate at each gap length was modelled using the Hill equation. Results were analysed using a nonlinear mixed-effect regression model. Study sample 45 PLWH (age range 41–78) and 39 PLWOH (age range 38–79) were enrolled and completed gap detection testing. Results The likelihood ratio statistic comparing the full regression model with the HIV effects to the null model, assuming one population curve for both groups, was highly significant (p < 0.001), suggesting a less precise relationship between gap length and correct detection in PLWH. Conclusions PLWH showed degraded gap detection ability compared to PLWOH, likely due to central nervous system effects of HIV infection or treatment. The Hill equation provided a new approach for modelling gap detection ability.

Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity.

Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.

Gap Detection Deficits in Chinchillas with Selective Carboplatin-Induced Inner Hair Cell Loss.

Temporal resolution is essential for processing complex auditory information such as speech. In hearing impaired persons, temporal resolution, often assessed by detection of brief gaps in continuous sound stimuli, is typically poorer than in individuals with normal hearing. At low stimulus presentation levels, hearing impaired individuals perform poorly but the deficits are greatly reduced when the sensation level of the stimuli are adjusted to match their normal hearing peers. In the present study, we evaluated the effect of selective inner hair cell loss on gap detection in chinchillas treated with carboplatin, an anticancer drug that selectively damages inner hair cells and afferents in this species. Treatment with carboplatin-induced inner hair cell loss of ~ 70% but had little effect on audiometric thresholds in quiet and produced no evidence of outer hair cell loss. In contrast, selective inner hair cell loss had a significant effect on gap detection ability across a wide range of presentation levels. These results suggest that gap detection tasks are more sensitive to inner hair cell pathology than audiometric thresholds.

5XFAD mice show early-onset gap encoding deficits in the auditory cortex

Early detection will be crucial for effective treatment or prevention of Alzheimer's disease. The identification and validation of early, noninvasive biomarkers is therefore key to avoiding the most devastating aspects of Alzheimer's disease. Measures of central auditory processing such as gap detection have recently emerged as potential biomarkers in both human patients and the 5XFAD mouse model of Alzheimer's disease. Full validation of gap detection deficits as a biomarker will require detailed understanding of the underlying neuropathology, including which brain structures are involved and how the operation of neural circuits is affected. Here we show that 5XFAD mice exhibit gap detection deficits as early as 2 months of age, well before development of Alzheimer's disease–associated pathology. We then examined responses of neurons in the auditory cortex to gaps in white noise. Both gap responses and baseline firing rates were robustly and progressively degraded in 5XFAD mice compared to littermate controls. These impairments were first evident at 2–4 months of age in males, and 4–6 months in females. This demonstrates early-onset impairments to the central auditory system, which could be due to damage in the auditory cortex, upstream subcortical structures, or both.

Behavioral evaluation of auditory function abnormalities in adult rats with normal hearing thresholds that were exposed to noise during early development

Noise-exposed rat pups provide a model of early deprivation of sensory input to the central auditory system, allowing the study of developmental neuroplasticity. Our previous results have demonstrated that a brief exposure of rats to broadband noise (125 dB SPL 8 min, 14th postnatal day) at the onset of hearing resulted in an altered intensity perception and frequency discrimination in adulthood despite normal hearing thresholds. In this study, we assessed the gap-detection ability and possible presence of tinnitus- and hyperacusis-like behavior in adult rats after the same neonatal acoustic trauma, using measurements of the acoustic startle response (ASR) in quiet and noisy environments and its prepulse inhibition by gaps in noise (gap-PPI). A significant deficit in the ability to detect gap was observed in the exposed rats when 55 dB SPL broadband noise was used as background. An increase of noise intensity to 65–75 dB SPL led to strengthening of the gap-PPI in exposed animals, which approached the gap-PPI values of control animals at these levels. Behavioral signs of tinnitus (gap detection deficits in 10 kHz narrow band noise) were found in 25% of exposed rats. An increased sensitivity to continuous noise was manifested in all exposed rats by suppression of the ASR at significantly lower background noise levels than in the controls. This effect was particularly pronounced in rats with tinnitus-like behavior. Our results indicate that neonatal acoustic trauma, producing only a transient threshold shift, may produce permanent abnormalities in suprathreshold auditory functions and the development of tinnitus and hyperacusis-like behavior.

5XFAD Mice Show Early Onset Gap Detection Deficits.

Alzheimer's patients show auditory temporal processing deficits very early in disease progression, before the onset of major cognitive impairments. In addition to potentially contributing to speech perception and communication deficits in patients, this also represents a potential early biomarker for Alzheimer's. For this reason, tests of temporal processing such as gap detection have been proposed as an early diagnosis tool. For a biomarker such as gap detection deficits to have maximum clinical value, it is important to understand what underlying neuropathology it reflects. For example, temporal processing deficits could arise from alterations at cortical, midbrain, or brainstem levels. Mouse models of Alzheimer's disease can provide the ability to reveal in detail the molecular and circuit pathology underlying disease symptoms. Here we tested whether 5XFAD mice, a leading Alzheimer's mouse model, exhibit impaired temporal processing. We found that 5XFAD mice showed robust gap detection deficits. Gap detection deficits were first detectable at about 2 months of age and became progressively worse, especially for males and for longer gap durations. We conclude that 5XFAD mice are well-suited to serve as a model for understanding the circuit mechanisms that contribute to Alzheimer's-related gap detection deficits.

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.

Saturation of long-term potentiation in the dorsal cochlear nucleus and its pharmacological reversal in an experimental model of tinnitus

Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4–5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.

GLAST Deficiency in Mice Exacerbates Gap Detection Deficits in a Model of Salicylate-Induced Tinnitus.

Gap detection or gap pre-pulse inhibition of the acoustic startle (GPIAS) has been successfully used in rat and guinea pig models of tinnitus, yet this system has been proven to have low efficacy in CBA mice, with low basal GPIAS and subtle tinnitus-like effects. Here, we tested five mouse strains (CBA, BalbC, CD-1, C57BL/6 and 129sv) for pre-pulse inhibition (PPI) and gap detection with varying interstimulus intervals (ISI) and found that mice from a CBA genetic background had the poorest capacities of suppressing the startle response in the presence of a pre-pulse or a gap. CD-1 mice displayed variable responses throughout all ISI. Interestingly, C57BL/6, 129sv and BalbC showed efficient suppression with either pre-pulses or gaps with shorter ISI. The glutamate aspartate transporter (GLAST) is expressed in support cells from the cochlea and buffers the excess of glutamate. We hypothesized that loss of GLAST function could sensitize the ear to tinnitus-inducing agents, such as salicylate. Using shorter ISI to obtain a greater dynamic range to assess tinnitus-like effects, we found that disruption of gap detection by salicylate was exacerbated across various intensities of a 32-kHz narrow band noise gap carrier in GLAST knockout (KO) mice when compared to their wild-type (WT) littermates. Auditory brainstem responses (ABR) and distortion-product otoacoustic emission (DPOAE) were performed to evaluate the effects on hearing functions. Salicylate caused greater auditory threshold shifts (near 15 dB) in GLAST KO mice than in WT mice across all tested frequencies, despite similarly reduced DPOAE. Despite these changes, inhibition using broad-band gap carriers and 32 kHz pre-pulses were not affected. Our study suggests that GLAST deficiency could become a useful experimental model to decipher the mechanisms underlying drug-induced tinnitus. Future studies addressing the neurological correlates of tinnitus in this model could provide additional insights into the mechanisms of tinnitus.

Mind the Gap: Two Dissociable Mechanisms of Temporal Processing in the Auditory System.

The experimental and modeling results reported here suggest a new hypothesis regarding the mechanisms of temporal processing in the auditory system. Using a mouse model of auditory temporal processing deficits, we demonstrate the existence of specific abnormalities in auditory thalamic activity following sound offsets, but not sound onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive mechanisms underlying auditory processing of temporally varying sounds. Furthermore, the findings suggest that auditory temporal processing deficits, such as impairments in gap-in-noise detection, could arise from reduced brain sensitivity to sound offsets alone.

Salicylate-induced hearing loss and gap detection deficits in rats.

To test the “tinnitus gap-filling” hypothesis in an animal psychoacoustic paradigm, rats were tested using a go/no-go operant gap detection task in which silent intervals of various durations were embedded within a continuous noise. Gap detection thresholds were measured before and after treatment with a dose of sodium salicylate (200 mg/kg) that reliably induces tinnitus in rats. Noise-burst detection thresholds were also measured to document the amount of hearing loss and aid in interpreting the gap detection results. As in the previous human psychophysical experiments, salicylate had little or no effect on gap thresholds measured in broadband noise presented at high-stimulus levels (30–60 dB SPL); gap detection thresholds were always 10 ms or less. Salicylate also did not affect gap thresholds presented in narrowband noise at 60 dB SPL. Therefore, rats treated with a dose of salicylate that reliably induces tinnitus have no difficulty detecting silent gaps as long as the noise in which they are embedded is clearly audible.

Age effects on tinnitus and hearing loss in CBA/CaJ mice following sound exposure.

Tinnitus is a maladaptive neuropathic condition that develops in humans and laboratory animals following auditory insult. In our previous study we demonstrated that sound exposure leads to development of behavioral evidence of tinnitus in a sample of exposed mice. However, this tinnitus mouse model did not account for long-term maladaptive plasticity or aging, factors that are commonly linked to the human tinnitus population. Therefore the same group of mice was monitored for tinnitus for 360 days post exposure. Tinnitus was assessed behaviorally by measuring gap-induced pre-pulse suppression of the acoustic startle (GPIAS). Cochlear histology was performed on both control (unexposed) and experimental mice to determine whether sound exposure caused any evident cochlear damage. We found that 360 days after exposure the vast majority of exposed mice exhibited similar gap detection deficits as detected at 84 days post exposure. These mice did not demonstrate significant loss of inner/outer hair cells or spiral ganglion neurons compared to the control sample. Lastly, we demonstrated that GPIAS deficits observed in exposed animals were unlikely exclusively caused by cochlear damage, but could be a result of central auditory maladaptive plasticity. We conclude that CBA/CaJ mice can be considered a good animal model to study the possible contribution of age effects on tinnitus development following auditory insult.

Is noise-induced cochlear neuropathy key to the generation of hyperacusis or tinnitus?

Perceptual abnormalities such as hyperacusis and tinnitus often occur after acoustic overexposure. Although such exposure can also result in permanent threshold elevation, some individuals with noise-induced hyperacusis or tinnitus show clinically normal thresholds. Recent work in animals has shown that a "neuropathic" noise exposure can cause immediate, permanent degeneration of the cochlear nerve despite complete threshold recovery and lack of hair cell damage (Kujawa SG, Liberman MC. J Neurosci 29: 14077-14085, 2009; Lin HW, Furman AC, Kujawa SG, Liberman MC. J Assoc Res Otolaryngol 12: 605-616, 2011). Here we ask whether this noise-induced primary neuronal degeneration results in abnormal auditory behavior, based on the acoustic startle response (ASR) and prepulse inhibition (PPI) of startle. Responses were measured in mice exposed either to a "neuropathic" noise or to a lower-intensity, "nonneuropathic" noise and in unexposed control mice. Mice with cochlear neuropathy displayed hyperresponsivity to sound, evidenced by enhanced ASR and PPI, while exposed mice without neuronal loss showed control-like responses. Gap PPI tests, often used to assess tinnitus, revealed limited gap detection deficits in mice with cochlear neuropathy only for certain gap-startle latencies, inconsistent with the presence of tinnitus "filling in the gap." Despite significantly reduced wave 1 of the auditory brainstem response, representing cochlear nerve activity, later peaks were unchanged or enhanced, suggesting compensatory neural hyperactivity in the auditory brainstem. Considering the rapid postexposure onset of both cochlear neuropathy and exaggerated startle-based behavior, the results suggest a role for cochlear primary neuronal degeneration, per se, in the central neural excitability that could underlie the generation of hyperacusis.

Gap detection deficits in humans with tinnitus as assessed with the acoustic startle paradigm: Does tinnitus fill in the gap?

The measurement of tinnitus in humans relies on subjective measures such as self-report, visual analog scales and questionnaires. Gap detection impairments have been tested in animals in an attempt to objectify the presence of tinnitus. The main purpose of this study was to investigate the gap startle paradigm in human participants with high-frequency tinnitus. Fifteen adults with bilateral high-frequency tinnitus but normal hearing at standard frequencies and seventeen matched controls without tinnitus were tested. The psychoacoustic characteristics of the tinnitus spectrum (pitch and loudness) were assessed using novel participant-directed custom-made methods. The startle task consisted of startle-alone, prepulse inhibition and gap-in-noise condition at low- and high-background noise frequencies. All measurements were retested after several months. Data indicate normal prepulse inhibition but higher reactivity to the startle sounds in the tinnitus group in comparison with controls. Most importantly, the tinnitus group displayed a consistent deficit in gap processing at both low- and high-background noise frequencies. All effects were identified consistently and were reproducible at retest. We propose that the higher reactivity to startle might reflect hyperacusis and that the gap deficit might be an index of abnormal cortical auditory processing in tinnitus.

Isoflurane blocks temporary tinnitus

Temporary tinnitus is a common consequence of noise exposure, and may share important mechanisms with chronic tinnitus. Noise-induced hearing loss is the most prevalent cause of chronic tinnitus. The reversibility of temporary tinnitus offers some practical experimental advantages. We therefore adapted a behavioral method based on gap detection to measure temporary tinnitus following brief acoustic trauma. Although anesthesia is often used during acoustic trauma exposure, many anesthetics can protect against noise-induced hearing loss. Whether anesthesia during acoustic trauma affects temporary tinnitus therefore remains an open question that directly affects experimental design in tinnitus studies. Here we tested whether anesthetizing rats with isoflurane during trauma had any effect on tinnitus. We found that gap-detection deficits, a behavioral measure of tinnitus, were 5 times stronger and lasted 10 times longer when isoflurane was not used. This suggests that isoflurane largely prevents temporary noise-induced tinnitus.

Gap Detection Methods for Assessing Salicylate-Induced Tinnitus and Hyperacusis in Rats

A variety of options for behavioral assessment of tinnitus in laboratory animals are available to researchers today. These options are briefly reviewed, followed by data suggesting that gap detection procedures might be used to efficiently measure acute, salicylate-induced tinnitus and possibly hyperacusis in rats. Fischer Brown Norway rats (n = 10) were given intraperitoneal injections of 350 mg/kg sodium salicylate on 2 consecutive days, and the effects on gap detection were observed across 9 different frequency bands. Pretest, posttest, and washout data were collected. An additional 4 rats were each given 4 different doses of sodium salicylate (0, 150, 250, and 300 mg/kg), and gap detection and prepulse inhibition were measured. Significant gap detection deficits were observed from pre- to posttest that were consistent with tinnitus. Consistent gap detection deficits were found using broadband noise backgrounds, while significant improvements in responding to frequency-specific test bands were found. Similar effects were repeated in the dose response portion of the study. Gap detection procedures efficiently measured salicylate-induced changes in behavior that were consistent with the presence of tinnitus. In addition, the reliable, stronger responses at many frequencies after salicylate injections suggest the possibility of measuring a hyperacusis-like phenomenon using these methods.

Gap detection deficits in rats with tinnitus: A potential novel screening tool.

The study describes a novel method for tinnitus screening in rats by use of gap detection reflex procedures. The authors hypothesized that if a background acoustic signal was qualitatively similar to the rat's tinnitus, poorer detection of a silent gap in the background would be expected. Rats with prior evidence of tinnitus at 10 kHz (n = 14) exhibited significantly worse gap detection than controls (n = 13) when the gap was embedded in a background similar to their tinnitus. No differences between tinnitus and control rats were found with 16 kHz or broadband noise backgrounds, which helped to rule out explanations related to hearing loss or general performance deficits. The results suggest that gap detection reflex procedures might be effective for rapid tinnitus screening in rats.

Perceptual auditory gap detection deficits in male BXSB mice with cerebrocortical ectopias.

Underlying impairments in rapid auditory processing may contribute to disrupted phonological processing, which in turn characterizes developmental language impairment (LI). Identification of a neurobiological feature of LI that is associated with auditory deficits would further support this model. Accordingly, we found that adult male rats with induced cortical malformations were impaired in rapid auditory processing. Since 40-60% of BXSB mice exhibit spontaneous focal cerebrocortical ectopias (as seen in dyslexics brains), we assessed auditory gap detection in adult male BXSB mice. Ectopic mice were significantly worse than non-ectopics in detecting a 5 ms silent gap, but were not significantly impaired at longer gap durations (10-100 ms). Our results confirm that focal cortical malformations are associated with impairments in rapid auditory processing.