Electrophysiology publications

Prefrontal cortex (PFC) are broadly linked to various aspects of behavior. During sensory discrimination, PFC neurons can encode a range of task related information, including the identity of sensory stimuli and related behavioral outcome. However, it remains largely unclear how different neuron subtypes and local field potential (LFP) oscillation features in the mouse PFC are modulated during sensory discrimination. To understand how excitatory and inhibitory PFC neurons are selectively engaged during sensory discrimination and how their activity relates to LFP oscillations, we used tetrode recordings to probe well-isolated individual neurons, and LFP oscillations, in mice performing a three-choice auditory discrimination task. We found that a majority of PFC neurons, 78% of the 711 recorded individual neurons, exhibited sensory discrimination related responses that are context and task dependent. Using spike waveforms, we classified these responsive neurons into putative excitatory neurons with broad waveforms or putative inhibitory neurons with narrow waveforms, and found that both neuron subtypes were transiently modulated, with individual neurons’ responses peaking throughout the entire duration of the trial. While the number of responsive excitatory neurons remain largely constant throughout the trial, an increasing fraction of inhibitory neurons were gradually recruited as the trial progressed. Further examination of the coherence between individual neurons and LFPs revealed that inhibitory neurons exhibit higher spike-field coherence with LFP oscillations than excitatory neurons during all aspects of the trial and across multiple frequency bands. Together, our results demonstrate that PFC excitatory neurons are continuously engaged during sensory discrimination, whereas PFC inhibitory neurons are increasingly recruited as the trial progresses and preferentially coordinated with LFP oscillations. These results demonstrate increasing involvement of inhibitory neurons in shaping the overall PFC dynamics toward the completion of the sensory discrimination task.

Metallic nano-optoelectrode arrays can simultaneously serve as nanoelectrodes to increase the electrochemical surface-to-volume ratio for high-performance electrical recording and optical nanoantennas to achieve nanoscale light concentrations for ultrasensitive optical sensing. However, it remains a challenge to integrate nano-optoelectrodes with a miniaturized multifunctional probing system for combined electrical recording and optical biosensing in vivo. Here, we report that flexible nano-optoelectrode-integrated multifunctional fiber probes can have hybrid optical-electrical sensing multimodalities, including optical refractive index sensing, surface-enhanced Raman spectroscopy, and electrophysiological recording. By physical vapor deposition of thin metal films through free-standing masks of nanohole arrays, we exploit a scalable nanofabrication process to create nano-optoelectrode arrays on the tips of flexible multifunctional fiber probes. We envision that the development of flexible nano-optoelectrode-integrated multifunctional fiber probes can open significant opportunities by allowing for multimodal monitoring of brain activities with combined capabilities for simultaneous electrical neural recording and optical biochemical sensing at the single-cell level.

Noise exposure of a short period at a moderate level can produce permanent cochlear synaptopathy without seeing lasting changes in audiometric threshold. However, due to the species differences in inner hair cell (IHC) calcium current that we have recently discovered, the susceptibility to noise exposure may vary, thereby impact outcomes of noise exposure. In this study, we investigate the consequences of noise exposure in the two commonly used animal models in hearing research, CBA/CaJ (CBA) and C57BL/6J (B6) mice, focusing on the functional changes of cochlear IHCs. In the CBA mice, moderate noise exposure resulted in a typical fully recovered audiometric threshold but a reduced wave I amplitude of auditory brainstem responses. In contrast, both auditory brainstem response threshold and wave I amplitude fully recovered in B6 mice at 2 weeks after noise exposure. Confocal microscopy observations found that ribbon synapses of IHCs recovered in B6 mice but not in CBA mice. To further characterize the molecular mechanism underlying these different phenotypes in synaptopathy, we compared the ratio of Bax/Bcl-2 with the expression of cytochrome-C and found increased activity in CBA mice after noise exposure. Under whole-cell patch clamped IHCs, we acquired two-photon calcium imaging around the active zone to evaluate the Ca 2+ clearance rate and found that CBA mice have a slower calcium clearance rate. Our results indicated that excessive accumulation of calcium due to acoustic overexposure and slow clearance around the presynaptic ribbon might lead to disruption of calcium homeostasis, followed by mitochondrial dysfunction of IHCs that cause susceptibility of noise-induced cochlear synaptopathy in CBA mice.

Homeostatic plasticity is hypothesized to bidirectionally regulate neuronal activity around a stable set point to compensate for learning-related plasticity, but to date only upward firing rate homeostasis (FRH) has been demonstrated in vivo. We combined chronic electrophysiology in freely behaving animals with an eye-reopening paradigm to enhance firing in primary visual cortex (V1) and found that neurons bidirectionally regulate firing rates around an individual set point. Downward FRH did not require N-methyl-D-aspartate receptor (NMDAR) signaling and was associated with homeostatic scaling down of synaptic strengths. Like upward FRH, downward FRH was gated by arousal state but in the opposite direction: it occurred during sleep, not during wake. In contrast, firing rate depression associated with Hebbian plasticity happened independently of sleep and wake. Thus, sleep and wake states temporally segregate upward and downward FRH, which might prevent interference or provide unopposed homeostatic compensation when it is needed most.

The combined development of new technologies for neuronal recordings and the development of novel sensors for recording both cellular activity and neurotransmitter binding has ushered in a new era for the field of neuroscience. Among these new technologies is fiber photometry, a technique wherein an implanted fiber optic is used to record signals from genetically encoded fluorescent sensors in bulk tissue. Fiber photometry has been widely adapted due to its cost-effectiveness, ability to examine the activity of neurons with specific anatomical or genetic identities, and the ability to use these highly modular systems to record from one or more sensors or brain sites in both superficial and deep-brain structures. Despite these many benefits, one major hurdle for laboratories adopting this technique is the steep learning curve associated with the analysis of fiber photometry data. This has been further complicated by a lack of standardization in analysis pipelines. In the present communication, we present pMAT, a 'photometry modular analysis tool' that allows users to accomplish common analysis routines through the use of a graphical user interface. This tool can be deployed in MATLAB and edited by more advanced users, but is also available as an independently deployable, open-source application.

Objective. Decoding neural activity has been limited by the lack of tools available to record from large numbers of neurons across multiple cortical regions simultaneously with high temporal fidelity. To this end, we developed the Argo system to record cortical neural activity at high data rates. Approach. Here we demonstrate a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system, supporting simultaneous recording from 65 536 channels, sampled at 32 kHz and 12-bit resolution. This system was designed for cortical recordings, compatible with both penetrating and surface microelectrodes. Main results. We validated this system through initial bench testing to determine specific gain and noise characteristics of bonded microwires, followed by in-vivo experiments in both rat and sheep cortex. We recorded spiking activity from 791 neurons in rats and surface local field potential activity from over 30 000 channels in sheep. Significance. These are the largest channel count microwire-based recordings in both rat and sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant.

Objectives: Prolonged cardiac arrest is known to cause global ischemic brain injury and functional impairment. Upon resuscitation, electroencephalographic recordings of brain activity begin to resume and can potentially be used to monitor neurologic recovery. We have previously shown that intrathecal orexin shows promise as a restorative drug and arousal agent in rodents. Our goal is to determine the electrophysiology effects of orexin in a rodent model of asphyxial cardiac arrest, focusing on the electroencephalographic activity in the gamma and super-gamma bands (indicative of return of higher brain function). Design: Experimental animal study. Setting: University-based animal research laboratory. Subjects: Adult male Wistar rats. Interventions: In an established model of asphyxial cardiac arrest ( n = 24), we treated half of Wistar rats with orexin administered intranasally by atomizer 30 minutes post return of spontaneous circulation in one of two dose levels (10 and 50 µM); the rest were treated with saline as control. Continuous electroencephalographic recording was obtained and quantitatively analyzed for the gamma fraction. Gamma and high-frequency super-gamma band measures were compared against clinical recovery according to Neuro-Deficit Score. Measurements and Main Results: Compared with the control cohort, the high-dose orexin cohort showed significantly better Neuro-Deficit Score 4 hours after return of spontaneous circulation (55.17 vs 47.58; p < 0.02) and significantly higher mean gamma fraction (0.251 vs 0.177; p < 0.02) in cerebral regions surveyed by rostral electrodes for the first 170 minutes after administration of orexin. Conclusions: Our findings support early and continuous monitoring of electroencephalography-based gamma activity as a marker of better functional recovery after intranasal administration of orexin as measured by Neuro-Deficit Score in an established animal model of asphyxial cardiac arrest.

Vision is the primary sense humans use to evaluate and respond to threats. Understanding the biological underpinnings of the human threat response has been hindered by lack of realistic in-lab threat paradigms. We established an immersive virtual reality (VR) platform to simultaneously measure behavior, physiological state, and neural activity from the human brain using chronically implanted electrodes. Subjects with high anxiety showed increased visual scanning in response to threats as compared to healthy controls. In both healthy and anxious subjects, the amount of scanning behavior correlated with the magnitude of physiological arousal, suggesting that visual scanning behavior is directly linked to internal state. Intracranial electroencephalography (iEEG) recordings from three subjects suggested that high-frequency gamma activity in the insula positively correlates with physiological arousal induced by visual threats and that low-frequency theta activity in the orbitofrontal cortex (OFC) negatively correlates with physiological arousal induced by visual threats. These findings reveal a key role of eye movements and suggest that distinct insula and OFC activation dynamics may be important for detecting and adjusting human stress in response to visually perceived threats.

Key points Sound information is transmitted by different subtypes of spiral ganglion neurons (SGN) from the ear to the brain. Selective damage of SGN peripheral synapses (cochlear synaptopathy) is widely recognized as one of the primary mechanisms of hearing loss, whereas the mechanisms at the SGN central synapses remain unclear. We report that different subtypes of SGN central synapses converge at different ratios onto individual target cochlear nucleus neurons with distinct physiological properties, and show biased morphological and physiological changes during age‐related hearing loss (ARHL). The results reveal a new dimension in cochlear nucleus neural circuitry that systematically reassembles and processes auditory information from different SGN subtypes, which is altered during ageing and probably contributes to the development of ARHL. In addition to known cochlear synaptopathy, the present study shows that SGN central synapses are also pathologically changed during ageing, which collectively helps us better understand the structure and function of SGNs during ARHL. Abstract Sound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerability under pathological conditions. Selective cochlear synaptopathy, the preferential damage of certain subtypes of SGN peripheral synapses, has been recognized as one of the main mechanisms of hearing loss. The organization and function of the auditory nerve (AN) central synapses from different subtypes of SGNs remain unclear, including how different AN synapses reassemble onto individual neurons in the cochlear nucleus, as well as how they differentially change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the convergence pattern and subtype‐specific synaptopathy of AN synapses at the endbulb of Held, as well as the response properties of their postsynaptic bushy neurons in CBA/CaJ mice of either sex under normal hearing and age‐related hearing loss (ARHL). We found that calretinin‐expressing (type I a ) and non‐calretinin‐expressing (type I b /I c ) endbulbs converged along a continuum of different ratios onto individual bushy neurons with varying physiological properties. Endbulbs degenerated during ageing in parallel with ARHL. Furthermore, the degeneration was more severe in non‐calretinin‐expressing synapses, which correlated with a gradual decrease in bushy neuron subpopulation predominantly innervated by these inputs. These synaptic and cellular changes were profound in middle‐aged mice when their hearing thresholds were still relatively normal and prior to severe ARHL. Our findings suggest that biased AN central synaptopathy and the correlated shift in cochlear nucleus neuronal composition play significant roles in weakened auditory input and altered central auditory processing during ARHL.

The connection between stimulus perception and time perception remains unknown. The present study combines human and rat psychophysics with sensory cortical neuronal firing to construct a computational model for the percept of elapsed time embedded within sense of touch. When subjects judged the duration of a vibration applied to the fingertip (human) or whiskers (rat), increasing stimulus intensity led to increasing perceived duration. Symmetrically, increasing vibration duration led to increasing perceived intensity. We modeled real spike trains recorded from vibrissal somatosensory cortex as input to dual leaky integrators–an intensity integrator with short time constant and a duration integrator with long time constant–generating neurometric functions that replicated the actual psychophysical functions of rats. Returning to human psychophysics, we then confirmed specific predictions of the dual leaky integrator model. This study offers a framework, based on sensory coding and subsequent accumulation of sensory drive, to account for how a feeling of the passage of time accompanies the tactile sensory experience.

Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2 . Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

The latency of the auditory steady-state response (ASSR) may provide valuable information regarding the integrity of the auditory system, as it could potentially reveal the presence of multiple intracerebral sources. To estimate multiple latencies from high-order ASSRs, we propose a novel two-stage procedure that consists of a nonparametric estimation method, called apparent latency from phase coherence (ALPC), followed by a heuristic sequential forward selection algorithm (SFS). Compared with existing methods, ALPC-SFS requires few prior assumptions, and is straightforward to implement for higher-order nonlinear responses to multi-cosine sound complexes with their initial phases set to zero. It systematically evaluates the nonlinear components of the ASSRs by estimating multiple latencies, automatically identifies involved ASSR components, and reports a latency consistency index. To verify the proposed method, we performed simulations for several scenarios: two nonlinear subsystems with different or overlapping outputs. We compared the results from our method with predictions from existing, parametric methods. We also recorded the EEG from ten normal-hearing adults by bilaterally presenting superimposed tones with four frequencies that evoke a unique set of ASSRs. From these ASSRs, two major latencies were found to be stable across subjects on repeated measurement days. The two latencies are dominated by low-frequency (LF) (near 40 Hz, at around 41–52 ms) and high-frequency (HF) (> 80 Hz, at around 21–27 ms) ASSR components. The frontal-central brain region showed longer latencies on LF components, but shorter latencies on HF components, when compared with temporal-lobe regions. In conclusion, the proposed nonparametric ALPC-SFS method, applied to zero-phase, multi-cosine sound complexes is more suitable for evaluating embedded nonlinear systems underlying ASSRs than existing methods. It may therefore be a promising objective measure for hearing performance and auditory cortex (dys)function.

Elevated synchronized oscillatory activity in the beta band has been hypothesized to be a pathophysiological marker of Parkinson's disease (PD). Recent studies have suggested that parkinsonism is closely associated with increased amplitude and duration of beta burst activity in the subthalamic nucleus (STN). How beta burst dynamics are altered from the normal to parkinsonian state across the basal ganglia–thalamocortical (BGTC) motor network, however, remains unclear. In this study, we simultaneously recorded local field potential activity from the STN, internal segment of the globus pallidus (GPi), and primary motor cortex (M1) in three female rhesus macaques, and characterized how beta burst activity changed as the animals transitioned from normal to progressively more severe parkinsonian states. Parkinsonism was associated with an increased incidence of beta bursts with longer duration and higher amplitude in the low beta band (8–20 Hz) in both the STN and GPi, but not in M1. We observed greater concurrence of beta burst activity, however, across all recording sites (M1, STN, and GPi) in PD. The simultaneous presence of low beta burst activity across multiple nodes of the BGTC network that increased with severity of PD motor signs provides compelling evidence in support of the hypothesis that low beta synchronized oscillations play a significant role in the underlying pathophysiology of PD. Given its immersion throughout the motor circuit, we hypothesize that this elevated beta-band activity interferes with spatial–temporal processing of information flow in the BGTC network that contributes to the impairment of motor function in PD. SIGNIFICANCE STATEMENT This study fills a knowledge gap regarding the change in temporal dynamics and coupling of beta burst activity across the basal ganglia–thalamocortical (BGTC) network during the evolution from normal to progressively more severe parkinsonian states. We observed that changes in beta oscillatory activity occur throughout BGTC and that increasing severity of parkinsonism was associated with a higher incidence of longer duration, higher amplitude low beta bursts in the basal ganglia, and increased concurrence of beta bursts across the subthalamic nucleus, globus pallidus, and motor cortex. These data provide new insights into the potential role of changes in the temporal dynamics of low beta activity within the BGTC network in the pathogenesis of Parkinson's disease.

Background Electrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity. Methods We implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations. Results Participants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001). Conclusion Electrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

Previous research with speech and non-speech stimuli suggested that in audiovisual perception, visual information starting prior to the onset of corresponding sound can provide visual cues, and form a prediction about the upcoming auditory sound. This prediction leads to audiovisual (AV) interaction. Auditory and visual perception interact and induce suppression and speeding up of the early auditory event-related potentials (ERPs) such as N1 and P2. To investigate AV interaction, previous research examined N1 and P2 amplitudes and latencies in response to audio only (AO), video only (VO), audiovisual, and control (CO) stimuli, and compared AV with auditory perception based on four AV interaction models (AV vs. AO+VO, AV-VO vs. AO, AV-VO vs. AO-CO, AV vs. AO). The current study addresses how different models of AV interaction express N1 and P2 suppression in music perception. Furthermore, the current study took one step further and examined whether previous musical experience, which can potentially lead to higher N1 and P2 amplitudes in auditory perception, influenced AV interaction in different models. Musicians and non-musicians were presented the recordings (AO, AV, VO) of a keyboard /C4/ key being played, as well as CO stimuli. Results showed that AV interaction models differ in their expression of N1 and P2 amplitude and latency suppression. The calculation of model (AV-VO vs. AO) and (AV-VO vs. AO-CO) has consequences for the resulting N1 and P2 difference waves. Furthermore, while musicians, compared to non-musicians, showed higher N1 amplitude in auditory perception, suppression of amplitudes and latencies for N1 and P2 was similar for the two groups across the AV models. Collectively, these results suggest that when visual cues from finger and hand movements predict the upcoming sound in AV music perception, suppression of early ERPs is similar for musicians and non-musicians. Notably, the calculation differences across models do not lead to the same pattern of results for N1 and P2, demonstrating that the four models are not interchangeable and are not directly comparable.

Pain is caused by tissue injury, inflammatory disease, pathogen invasion, or neuropathy. The perception of pain is attributed to the neuronal activity in the brain. However, the dynamics of neuronal activity underlying pain perception are not fully known. Herein, we examined theta-oscillation dynamics of local field potentials in the primary somatosensory cortex of a mouse model of formalin-induced pain, which usually shows a bimodal behavioral response interposed between pain-free periods. We found that formalin injection exerted a reversible shift in the theta-peak frequency toward a slower frequency. This shift was observed during nociceptive phases but not during the pain-free period and was inversely correlated with instantaneous pain intensity. Furthermore, instantaneous oscillatory analysis indicated that the probability of slow theta oscillations increased during nociceptive phases with an association of augmented slow theta power. Finally, cross-frequency coupling between theta and gamma oscillations indicated that the coupling peak frequency of theta oscillations was also shifted toward slower oscillations without affecting coupling strength or gamma power. Together, these results suggest that the dynamic changes in theta oscillations in the mouse primary somatosensory cortex represent the ongoing status of pain sensation.

Detecting the direction of frequency modulation (FM) is essential for vocal communication in both animals and humans. Direction-selective firing of neurons in the primary auditory cortex (A1) has been classically attributed to temporal offsets between feedforward excitatory and inhibitory inputs. However, it remains unclear how cortical recurrent circuitry contributes to this computation. Here, we used two-photon calcium imaging and whole-cell recordings in awake mice to demonstrate that direction selectivity is not caused by temporal offsets between synaptic currents, but by an asymmetry in total synaptic charge between preferred and non-preferred directions. Inactivation of cortical somatostatin-expressing interneurons (SOM cells) reduced direction selectivity, revealing its cortical contribution. Our theoretical models showed that charge asymmetry arises due to broad spatial topography of SOM cell-mediated inhibition which regulates signal amplification in strongly recurrent circuitry. Together, our findings reveal a major contribution of recurrent network dynamics in shaping cortical tuning to behaviorally relevant complex sounds.

Spatial hearing in cochlear implant (CI) patients remains a major challenge, with many early deaf users reported to have no measurable sensitivity to interaural time differences (ITDs). Deprivation of binaural experience during an early critical period is often hypothesized to be the cause of this shortcoming. However, we show that neonatally deafened (ND) rats provided with precisely synchronized CI stimulation in adulthood can be trained to lateralize ITDs with essentially normal behavioral thresholds near 50 μs. Furthermore, comparable ND rats show high physiological sensitivity to ITDs immediately after binaural implantation in adulthood. Our result that ND-CI rats achieved very good behavioral ITD thresholds, while prelingually deaf human CI patients often fail to develop a useful sensitivity to ITD raises urgent questions concerning the possibility that shortcomings in technology or treatment, rather than missing input during early development, may be behind the usually poor binaural outcomes for current CI patients.

Introduction A defect in the cochlear afferent synapse between the inner hair cells and spiral ganglion neurons, after noise exposure, without changes in the hearing threshold has been reported. Animal studies on auditory evoked potentials demonstrated changes in the auditory brainstem response (ABR) measurements of peak I amplitude and the loss of synapses, which affect the temporal resolution of complex sounds. Human studies of auditory evoked potential have reported ambiguous results regarding the relationship between peak I amplitude and noise exposure. Paired click stimuli have been used to investigate the temporal processing abilities of humans and animals. In this study, we investigated the utility of measuring auditory evoked potentials in response to paired click stimuli to assess the temporal processing function of ribbon synapses in noise-induced cochlear synaptopathy. Materials and Methods Twenty-two Sprague Dawley rats were used in this study, and synaptopathy was induced by narrow-band noise exposure (16 kHz with 1 kHz bandwidth, 105 dB sound pressure level for 2 h). ABRs to tone and paired click stimuli were measured before and 1, 3, 7, and 14 days after noise exposure. For histological analyses, hair cells and ribbon synapses were immunostained and the synapses quantified. The relationships among ABR peak I amplitude, number of synapses, and ABR to paired click stimuli were examined. Results Our results showed that ABR thresholds increase 1 day after noise exposure but fully recover to baseline levels after 14 days. Further, we demonstrated test frequency-dependent decreases in peak I amplitude and the number of synapses after noise exposure. These decreases were statistically significant at frequencies of 16 and 32 kHz. However, the ABR recovery threshold to paired click stimuli increased, which represent deterioration in the ability of temporal auditory processing. Our results indicate that the ABR recovery threshold is highly correlated with ABR peak I amplitude after noise exposure. We also established a direct correlation between the ABR recovery threshold and histological findings. Conclusion The result from this study suggests that in animal studies, the ABR to paired click stimuli along with peak I amplitude has potential as an assessment tool for hidden hearing loss.

Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the “central gain theory” posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N -acetylcysteine (NAC) and disodium 2,4-disulfophenyl- N -tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.