Pyroptosis Accelerates Spiral Ganglion Neuronal Degeneration Induced by Aminoglycosides in the Cochlea

Background In aminoglycoside-induced hearing loss, damage to spiral ganglion neurons (SGNs) accelerates gradually after the acute outer hair cell death, accompanied by macrophage infiltration and cytokine release. Pyroptosis plays a critical role in neurodegenerative diseases. Here, we explored the potential role of pyroptosis in SGN degeneration. Methods C57BL/6J mice were randomly divided into a kanamycin plus furosemide group and saline control group. Auditory functions were evaluated by auditory brainstem response tests conducted before treatment and at 1, 5, 15, and 30 days after treatment. HCs and SGNs were assessed for morphological alterations. SGNs were subjected to RNA sequencing and mRNA and protein analyses of NLRP3 inflammasome-related molecules. Macrophage activation was evaluated based on morphological and mRNA alterations. The effect of NLRP3 inhibition on SGN survival after kanamycin treatment was evaluated in organ explant cultures treated with Mcc950, a specific inhibitor of the NLRP3 inflammasome. Results Kanamycin and furosemide administration led to irreversible deterioration of the auditory brainstem response threshold, accompanied by acute loss of outer hair cells and gradually progressive loss of inner hair cells. SGNs showed a progressive decrease in quantity, as well as swelling and membrane rupture, at 15 and 30 days. RNA sequencing of SGNs showed that inflammation and immune-related responses were significantly upregulated, as was the expression of the inflammasome-related gene NLRP3. During 30 days of kanamycin exposure, the canonical pyroptosis pathway was constantly activated in SGNs. Activation and infiltration of microglia-like cells/macrophages, and increased production of cytokines, hallmarks of neuroinflammation, were also observed. Mcc950 significantly ameliorated SGN degeneration by inhibiting NLRP3 expression and promoting release of interleukins 1β and 18. Conclusions Pyroptosis causes cell death during aminoglycoside-induced SGN degeneration. Activation of the NLRP3 inflammasome leads to a cascade of inflammatory events in SGNs. Inhibition of the NLRP3 inflammasome significantly alleviates SGN damage, suggesting that it could serve as a new molecular target for the treatment of aminoglycoside-induced SGN degeneration.

Diffusion Tensor Imaging of Auditory Pathway in Patients With Crigler-Najjar Syndrome Type I: Correlation With Auditory Brainstem Response

Aim: To evaluate the role of diffusion tensor imaging of the auditory pathway in patients with Crigler Najjar syndrome type I and its relation to auditory brainstem response. Methods: Prospective study was done including 12 patients with Crigler Najjar syndrome type I and 10 age- and sex-matched controls that underwent diffusion tensor imaging of brain. Mean diffusivity and fractional anisotropy at 4 regions of the brain and brainstem on each side were measured and correlated with the results of auditory brainstem response for patients. Results: There was significantly higher mean diffusivity of cochlear nucleus, superior olivary nucleus, inferior colliculus, and auditory cortex of patients versus controls on both sides for all regions ( P = .001). The fractional anisotropy of cochlear nucleus, superior olivary nucleus, inferior colliculus, and auditory cortex of patients versus controls was significantly lower, with P values of, respectively, .001, .001, .003, and .001 on the right side and .001, .001, .003, and .001 on left side, respectively. Also, a negative correlation was found between the maximum bilirubin level and fractional anisotropy of the left superior olivary nucleus and inferior colliculus of both sides. A positive correlation was found between the mean diffusivity and auditory brainstem response wave latency of the right inferior colliculus and left cochlear nucleus. The fractional anisotropy and auditory brainstem response wave latency of the right superior olivary nucleus, left cochlear nucleus, and inferior colliculus of both sides were negatively correlated. Conclusion: Diffusion tensor imaging can detect microstructural changes in the auditory pathway in Crigler Najjar syndrome type I that can be correlated with auditory brainstem response.

Pilot Study to Assess Changes in the Blink Reflex Across Age

ObjectiveThe objective was to conduct a preliminary study to access blink reflex parameters across age using the Eyestat.BackgroundThe blink reflex is a primitive brainstem response to an external stimulus is affected by multiple neurologic disorders, including those that affect the dopaminergic circuit that controls the eyelid. Our laboratory has utilized a potential objective measure to identify concussions within a college aged sport population called Eyestat, which measures changes in blink reflex parameters. Prior research cited significant differences in various blink reflex parameters between active play, concussion, and baseline. However, data with older, non-athlete populations has not defined.Design/MethodsOne hundred forty three subjects between the ages of 8–80 participated in this study. Once the subject was seated, the test sequence was initiated, in which the subject placed their face into the mask and 5 random air puffs were applied to the corner of the left or right eyes over a course of 20 seconds. High-speed videography (280 frames/sec.) captured the response of the subject's eyes before and after each stimuli.ResultsDescription statistics of the data indicated differences across age with the following parameters: Latency (ms): 46.02 (ages 8–21); 47.12 (ages 22–30); 48.96 (ages 31–40); 47.44 (ages 41–50); 55.20 (ages 51–60); and 55.39 (ages 61–80). Oscillations (qty): 14.10 (ages 8–21); 14.25 (ages 22–30); 12.19 (ages 31–40); 12.75 (ages 41–50); 9.98 (ages 51–60); and 9.78 (ages 61–80). Excursions (px): 127.57 (ages 8–21); 137.46 (ages 22–30); 135.34 (ages 31–40); 144.88 (ages 41–50); 147.72 (ages 51–60); and 148.85 (ages 61–80).ConclusionsAlthough more research is warranted to determine if these differences occur with a larger subject pool, this data substantiates the need for longitudinal assessments of the blink reflex as a potential biomarker, providing a non-invasive assessment of brain health in various populations.

Effect of Ischemia-Induced Cochlear Inflammation on Auditory Responses in Male Rats

Background and Aim: Ischemic injury is a major cause of hearing loss and oxidative stress is an important part of ischemic injury. The goal of this study was to evaluate the cochlear oxidative stress effect on auditory responses in male rats. Methods: Cochlear oxidative stress was induced by bilateral carotid artery occlusion for 20 minutes. The rats were evaluated by biochemical inflammatory factors tumor necrosis factor-α [TNF-α] and C-reactive protein (CRP) in the day before and 1st, 4th, and 7th days following surgery. The auditory brainstem response (ABR) and electrocochleography (ECochG) were evaluated on the day before surgery and 14th, 21th and 28th days after surgery. Results: TNF-α and CRP levels concentrations increased one day after ischemia and subsequently decreased on the 7th day. The click and tone burst evoked ABR showed increased thresholds on day14th, 21th, and 28th. The highest threshold was recorded on day14th. The ECochG results also were abnormal for 55%, 70%, and 45% of cases on day 14th, 21th, and 28th, respectively. Conclusion: Cochlear oxidative stress affects hearing sensitivity. The ABR shows elevated thresholds and abnormal ECochG was found in many cases.

Evaluation of Cochlear Synaptopathy in Tinnitus Patients with Normal Hearing UsingAuditory Brainstem Response and Electrocochleography Tests

Background and Aim: Tinnitus is defined a phantom sound percept. Few studies have examined the occurrence of synaptopathy in tinnitus patients utilizing a battery of tests that indicate synaptopathy. This study aimed to investigate the role of synaptopathy in tinnitus production and compare the various characteristics of the auditory brainstem response (ABR) test and electrocochleography (ECochG) in normal-hearing people with and without tinnitus. Methods: This cross-sectional study was conducted on 34 normal-hearing individuals, 20 without tinnitus as controls (11 females and 9 males) and 14 with tinnitus (8 females and 6 men). The test components (amplitude, growth and slope of wave I, V/I ratio, action potential (AP) amplitude, and summating potential (SP)/AP) ratio were recorded during the ABR and ECochG tests for each subject. Results: The control group had higher mean values of amplitude, growth and slope of wave I, and AP amplitude compared to the tinnitus group, and this difference was statistically significant (p<0.05). The mean V/I ratio and SP/AP ratio were lower in the control group than in the tinnitus group, and this difference was statistically significant (p<0.05). Conclusion: The significant difference in the parameters of ABR and ECochG tests between normal-hearing people with and without tinnitus indicates that these parameters can be used to evaluate the presence of synaptopathy in tinnitus patients. These findings suggest the need for proper interpretation of the results of ABR and ECochG tests in tinnitus patients with a focus on the parameters indicating synaptopathy.

Neural Measures of Pitch Processing in EEG Responses to Running Speech

Linearized encoding models are increasingly employed to model cortical responses to running speech. Recent extensions to subcortical responses suggest clinical perspectives, potentially complementing auditory brainstem responses (ABRs) or frequency-following responses (FFRs) that are current clinical standards. However, while it is well-known that the auditory brainstem responds both to transient amplitude variations and the stimulus periodicity that gives rise to pitch, these features co-vary in running speech. Here, we discuss challenges in disentangling the features that drive the subcortical response to running speech. Cortical and subcortical electroencephalographic (EEG) responses to running speech from 19 normal-hearing listeners (12 female) were analyzed. Using forward regression models, we confirm that responses to the rectified broadband speech signal yield temporal response functions consistent with wave V of the ABR, as shown in previous work. Peak latency and amplitude of the speech-evoked brainstem response were correlated with standard click-evoked ABRs recorded at the vertex electrode (Cz). Similar responses could be obtained using the fundamental frequency (F0) of the speech signal as model predictor. However, simulations indicated that dissociating responses to temporal fine structure at the F0 from broadband amplitude variations is not possible given the high co-variance of the features and the poor signal-to-noise ratio (SNR) of subcortical EEG responses. In cortex, both simulations and data replicated previous findings indicating that envelope tracking on frontal electrodes can be dissociated from responses to slow variations in F0 (relative pitch). Yet, no association between subcortical F0-tracking and cortical responses to relative pitch could be detected. These results indicate that while subcortical speech responses are comparable to click-evoked ABRs, dissociating pitch-related processing in the auditory brainstem may be challenging with natural speech stimuli.

Detecting Noise-Induced Cochlear Synaptopathy by Auditory Brainstem Response in Tinnitus Patients With Normal Hearing Thresholds: A Meta-Analysis

Noise-induced cochlear synaptopathy (CS) is defined as a permanent loss of synapses in the auditory nerve pathway following noise exposure. Several studies using auditory brainstem response (ABR) have indicated the presence of CS and increased central gain in tinnitus patients with normal hearing thresholds (TNHT), but the results were inconsistent. This meta-analysis aimed to review the evidence of CS and its pathological changes in the central auditory system in TNHT. Published studies using ABR to study TNHT were reviewed. PubMed, EMBASE, and Scopus databases were selected to search for relevant literature. Studies (489) were retrieved, and 11 were included for meta-analysis. The results supported significantly reduced wave I amplitude in TNHT, whereas the alternations in wave V amplitude were inconsistent among the studies. Consistently increased V/I ratio indicated noise-induced central gain enhancement. The results indicated the evidence of noise-induced cochlear synaptopathy in tinnitus patients with normal hearing. However, inconsistent changes in wave V amplitude may be explained by that the failure of central gain that triggers the pathological neural changes in the central auditory system and/or that increased central gain may be necessary to generate tinnitus but not to maintain tinnitus.