Auditory Neurophysiology publications

Study objectives: Sleep is defined as a reversible state of reduction in sensory responsiveness and immobility. A long-standing hypothesis suggests that a high arousal threshold during non-rapid eye movement (NREM) sleep is mediated by sleep spindle oscillations, impairing thalamocortical transmission of incoming sensory stimuli. Here we set out to test this idea directly by examining sensory-evoked neuronal spiking activity during natural sleep. Methods: We compared neuronal (n = 269) and multiunit activity (MUA), as well as local field potentials (LFP) in rat core auditory cortex (A1) during NREM sleep, comparing responses to sounds depending on the presence or absence of sleep spindles. Results: We found that sleep spindles robustly modulated the timing of neuronal discharges in A1. However, responses to sounds were nearly identical for all measured signals including isolated neurons, MUA, and LFPs (all differences < 10%). Furthermore, in 10% of trials, auditory stimulation led to an early termination of the sleep spindle oscillation around 150-250 msec following stimulus onset. Finally, active ON states and inactive OFF periods during slow waves in NREM sleep affected the auditory response in opposite ways, depending on stimulus intensity. Conclusions: Responses in core auditory cortex are well preserved regardless of sleep spindles recorded in that area, suggesting that thalamocortical sensory relay remains functional during sleep spindles, and that sensory disconnection in sleep is mediated by other mechanisms.

Unlabelled: Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS. Significance: Fragile X Syndrome (FXS) is the leading known genetic cause of autism spectrum disorders. Individuals with FXS show symptoms of auditory hypersensitivity. These symptoms may arise due to sustained neural responses to repeated sounds, but the underlying mechanisms remain unclear. For the first time, this study shows deficits in habituation of neural responses to repeated sounds in the Fmr1 KO mice as seen in humans with FXS. We also report an abnormally high level of matrix metalloprotease-9 (MMP-9) in the auditory cortex of Fmr1 KO mice and that deletion of Mmp-9 from Fmr1 KO mice reverses habituation deficits. These data provide a translation relevant electrophysiological biomarker for sensory deficits in FXS and implicate MMP-9 as a target for drug discovery.

Hidden hearing refers to the functional deficits in hearing without deterioration in hearing sensitivity. This concept is proposed based upon recent finding of massive noise-induced damage on ribbon synapse between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea without significant permanent threshold shifts (PTS). Presumably, such damage may cause coding deficits in auditory nerve fibers (ANFs). However, such deficits had not been detailed except that a selective loss of ANFs with low spontaneous rate (SR) was reported. In the present study, we investigated the dynamic changes of ribbon synapses and the coding function of ANF single units in one month after a brief noise exposure that caused a massive damage of ribbon synapses but no PTS. The synapse count and functional response measures indicates a large portion of the disrupted synapses were re-connected. This is consistent with the fact that the change of SR distribution due to the initial loss of low SR units is recovered quickly. However, ANF coding deficits were developed later with the re-establishment of the synapses. The deficits were found in both intensity and temporal processing, revealing the nature of synaptopathy in hidden hearing loss.

Significance Musicians show enhanced musical pitch and meter processing, effects that generalize to speech. Yet potential differences between musicians and nonmusicians limit conclusions. We examined the effects of a randomized laboratory-controlled music intervention on music and speech processing in 9-mo-old infants. The Intervention exposed infants to music in triple meter (the waltz) in a social environment. Controls engaged in similar social play without music. After 12 sessions, infants’ temporal information processing was assessed in music and speech using brain measures [magnetoencephalography (MEG)]. Compared with controls, intervention infants exhibited enhanced neural responses to temporal violations in both music and speech, in both auditory and prefrontal cortices. The intervention improves infants’ detection and prediction of auditory patterns, skills important to music and speech.

Accurate localization of sound sources is essential for survival behavior in many species. The inferior colliculi (ICs) are the first point in the auditory pathway where cues used to locate sounds, ie, interaural time differences (ITDs), interaural level differences (ILDs), and pinna spectral cues, are all represented in the same location. These cues are first extracted separately on each side of the midline in brainstem nuclei that project to the ICs. Because of this segregation, each IC predominantly represents stimuli in the contralateral hemifield. We tested the hypothesis that commissural connections between the ICs mediate gain control that enhances sound localization acuity. We recorded IC neurons sensitive to either ITDs or ILDs in anesthetized guinea pig, before, during, and following recovery from deactivation of the contralateral IC by cryoloop cooling or microdialysis of procaine. During deactivation, responses were rescaled by divisive gain change and additive shifts, which reduced the dynamic range of ITD and ILD response functions and the ability of neurons to signal changes in sound location. These data suggest that each IC exerts multiplicative gain control and subtractive shifts over the other IC that enhances the neural representation of sound location. Furthermore, this gain control operates in a similar manner on both ITD- and ILD-sensitive neurons, suggesting a shared mechanism operates across localization cues. Our findings reveal a novel dependence of sound localization on commissural processing. SIGNIFICANCE STATEMENT Sound localization, a fundamental process in hearing, is dependent on bilateral computations in the brainstem. How this information is transmitted from the brainstem to the auditory cortex, through several stages of processing, without loss of signal fidelity, is not clear. We show that the ability of neurons in the auditory midbrain to encode azimuthal sound location is dependent on gain control mediated by the commissure of the inferior colliculi. This finding demonstrates that commissural processing between homologous auditory nuclei, on either side of the midline, enhances the precision of sound localization.

Natural sounds exhibit statistical variation in their spectrotemporal structure. This variation is central to identification of unique environmental sounds and to vocal communication. Using limited resources, the auditory system must create a faithful representation of sounds across the full range of variation in temporal statistics. Imaging studies in humans demonstrated that the auditory cortex is sensitive to temporal correlations. However, the mechanisms by which the auditory cortex represents the spectrotemporal structure of sounds and how neuronal activity adjusts to vastly different statistics remain poorly understood. In this study, we recorded responses of neurons in the primary auditory cortex of awake rats to sounds with systematically varied temporal correlation, to determine whether and how this feature alters sound encoding. Neuronal responses adapted to changing stimulus temporal correlation. This adaptation was mediated by a change in the firing rate gain of neuronal responses rather than their spectrotemporal properties. This gain adaptation allowed neurons to maintain similar firing rates across stimuli with different statistics, preserving their ability to efficiently encode temporal modulation. This dynamic gain control mechanism may underlie comprehension of vocalizations and other natural sounds under different contexts, subject to distortions in temporal correlation structure via stretching or compression.

In natural acoustic environments, perception of acoustic stimuli depends on the recent contextual history. Forward masking describes a phenomenon whereby the detection threshold of a probe stimulus is markedly increased when it is preceded by a masking stimulus. The aim of this study was to characterize the offset response of single units in the superior paraolivary nucleus (SPON) to a forward masking paradigm. We observed two distinct response types to forward-masked stimuli, namely inhibited and facilitated responses. In the presence of a default masking stimulus, inhibited responses to probe stimuli were characterized by elevated thresholds and/or diminished spike counts, whereas facilitated responses were characterized by reduced thresholds and increased spike counts. In units with inhibited responses to the probe stimuli, probe thresholds increased and spike counts decreased as masker intensity was raised or the masker-to-probe delay was shortened. Conversely, in units with facilitated responses to the probe stimuli, probe thresholds decreased and spike counts increased as masker intensity was raised or the masker-to-probe delay was shortened. Neither inhibited nor facilitated responses to the forward masking paradigm were significantly dependent on masker frequency. These findings suggest that SPON responses are not themselves consistently subject to the same forward masking properties observed in other nuclei along the ascending auditory pathway. The potential neural mechanisms of the forward masking responses observed in the SPON are discussed.

The auditory cortex is well-known to be critical for music perception, including the perception of consonance and dissonance. Studies on the neural correlates of consonance and dissonance perception have largely employed non-invasive electrophysiological and functional imaging techniques in humans as well as neurophysiological recordings in animals, but the fine-grained spatiotemporal dynamics within the human auditory cortex remain unknown. We recorded electrocorticographic (ECoG) signals directly from the lateral surface of either the left or right temporal lobe of eight patients undergoing neurosurgical treatment as they passively listened to highly consonant and highly dissonant musical chords. We assessed ECoG activity in the high gamma (γhigh, 70-150 Hz) frequency range within the superior temporal gyrus (STG) and observed two types of cortical sites of interest in both hemispheres: one type showed no significant difference in γhigh activity between consonant and dissonant chords, and another type showed increased γhigh responses to dissonant chords between 75 and 200 ms post-stimulus onset. Furthermore, a subset of these sites exhibited additional sensitivity towards different types of dissonant chords, and a positive correlation between changes in γhigh power and the degree of stimulus roughness was observed in both hemispheres. We also observed a distinct spatial organization of cortical sites in the right STG, with dissonant-sensitive sites located anterior to non-sensitive sites. In sum, these findings demonstrate differential processing of consonance and dissonance in bilateral STG with the right hemisphere exhibiting robust and spatially organized sensitivity toward dissonance.

Acetylcholine (ACh) release in the cortex is critical for learning, memory, attention, and plasticity. Here, we explore the cholinergic and noncholinergic projections from the basal forebrain (BF) to the auditory cortex using classical retrograde and monosynaptic viral tracers deposited in electrophysiologically identified regions of the auditory cortex. Cholinergic input to both primary (A1) and nonprimary auditory cortical (belt) areas originates in a restricted area in the caudal BF within the globus pallidus (GP) and in the dorsal part of the substantia innominata (SId). On the other hand, we found significant differences in the proportions of cholinergic and noncholinergic projection neurons to primary and nonprimary auditory areas. Inputs to A1 projecting cholinergic neurons were restricted to the GP, caudate-putamen, and the medial part of the medial geniculate body, including the posterior intralaminar thalamic group. In addition to these areas, afferents to belt-projecting cholinergic neurons originated from broader areas, including the ventral secondary auditory cortex, insular cortex, secondary somatosensory cortex, and the central amygdaloid nucleus. These findings support a specific BF projection pattern to auditory cortical areas. Additionally, these findings point to potential functional differences in how ACh release may be regulated in the A1 and auditory belt areas.

The GABAergic agonist muscimol is used to inactivate brain regions in order to reveal afferent inputs in isolation. However, muscimol's use in primary auditory cortex (A1) has been questioned on the grounds that it may unintentionally suppress thalamocortical inputs. We tested whether muscimol can preferentially suppress cortical, but not thalamocortical, circuits in urethane-anesthetized mice. We recorded tone-evoked current source density profiles to determine frequency receptive fields (RFs) for three current sinks: the “layer 4” sink (fastest onset, middle-layer sink) and current sinks 100 μm above (“layer 2/3”) and 300 μm below (“layer 5/6”) the main input. We first determined effects of muscimol dose (0.01–1 mM) on the characteristic frequency (CF) tone-evoked layer 4 sink. An “ideal” dose (100 μM) had no effect on CF-evoked sink onset latency or initial response but reduced peak amplitude by >80%, implying inhibition of intracortical, but not thalamocortical, activity. We extended the analysis to current sinks in layers 2/3 and 5/6 and for all three sinks determined RF breadth (quarter-octave steps, 20 dB above CF threshold). Muscimol reduced RF breadth 42% in layer 2/3 (from 2.4 ± 0.14 to 1.4 ± 0.11 octaves), 14% in layer 4 (2.2 ± 0.12 to 1.9 ± 0.10 octaves), and not at all in layer 5/6 (1.8 ± 0.10 to 1.7 ± 0.12 octaves). The results provide an estimate of the laminar and spectral extent of thalamocortical projections and support the hypothesis that intracortical pathways contribute to spectral integration in A1.

Mammals perceive a wide range of temporal cues in natural sounds, and the auditory cortex is essential for their detection and discrimination. The rat primary (A1), ventral (VAF), and caudal suprarhinal (cSRAF) auditory cortical fields have separate thalamocortical pathways that may support unique temporal cue sensitivities. To explore this, we record responses of single neurons in the three fields to variations in envelope shape and modulation frequency of periodic noise sequences. Spike rate, relative synchrony, and first-spike latency metrics have previously been used to quantify neural sensitivities to temporal sound cues; however, such metrics do not measure absolute spike timing of sustained responses to sound shape. To address this, in this study we quantify two forms of spike-timing precision, jitter, and reliability. In all three fields, we find that jitter decreases logarithmically with increase in the basis spline (B-spline) cutoff frequency used to shape the sound envelope. In contrast, reliability decreases logarithmically with increase in sound envelope modulation frequency. In A1, jitter and reliability vary independently, whereas in ventral cortical fields, jitter and reliability covary. Jitter time scales increase (A1 < VAF < cSRAF) and modulation frequency upper cutoffs decrease (A1 > VAF > cSRAF) with ventral progression from A1. These results suggest a transition from independent encoding of shape and periodicity sound cues on short time scales in A1 to a joint encoding of these same cues on longer time scales in ventral nonprimary cortices.

Exposure to loud sounds damages the auditory periphery and induces maladaptive changes in central parts of the auditory system. Diminished peripheral afferentation and altered inhibition influence the processing of sounds in the auditory cortex. It is unclear, however, which types of inhibitory interneurons are affected by acoustic trauma. Here we used single-unit electrophysiological recording and two-photon calcium imaging in anesthetized mice to evaluate the effects of acute acoustic trauma (125 dB SPL, white noise, 5 min) on the response properties of neurons in the core auditory cortex. Electrophysiological measurements suggested the selective impact of acoustic trauma on inhibitory interneurons in the auditory cortex. To further investigate which interneuronal types were affected, we used two-photon calcium imaging to record the activity of neurons in cortical layers 2/3 and 4, specifically focusing on parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. Spontaneous and pure-tone-evoked firing rates of SST+ interneurons increased in layer 4 immediately after acoustic trauma and remained almost unchanged in layer 2/3. Furthermore, PV+ interneurons with high best frequencies increased their evoked-to-spontaneous firing rate ratios only in layer 2/3 and did not change in layer 4. Finally, acoustic trauma unmasked low-frequency excitatory inputs only in layer 2/3. Our results demonstrate layer-specific changes in the activity of auditory cortical inhibitory interneurons within minutes after acoustic trauma.

An appropriate conditioning noise exposure may reduce a subsequent noise-induced threshold shift. Although this "toughening" effect helps to protect the auditory system from a subsequent traumatic noise exposure, the mechanisms that regulate this protective process are not fully understood yet. Accordingly, the goal of the present study was to characterize physiological processes associated with "toughening" and to determine their relationship to metabolic changes in the cochlea and cochlear nucleus (CN). Auditory brainstem responses (ABR) were evaluated in Wistar rats before and after exposures to a sound conditioning protocol consisting of a broad-band white noise of 118 dB SPL for 1 h every 72 h, four times. After the last ABR evaluation, animals were perfused and their cochleae and brains removed and processed for the activity markers calretinin (CR) and neuronal nitric oxide synthase (nNOS). Toughening was demonstrated by a progressively faster recovery of the threshold shift, as well as wave amplitudes and latencies over time. Immunostaining revealed an increase in CR and nNOS levels in the spiral ganglion, spiral ligament, and CN in noise-conditioned rats. Overall, these results suggest that the protective mechanisms of the auditory toughening effect initiate in the cochlea and extend to the central auditory system. Such phenomenon might be in part related to an interplay between CR and nitric oxide signaling pathways, and involve an increased cytosolic calcium buffering capacity induced by the noise conditioning protocol.

The scalp-recorded frequency-following response (FFR) is a measure of the auditory nervous system's representation of periodic sound, and may serve as a marker of training-related enhancements, behavioural deficits, and clinical conditions. However, FFRs of healthy normal subjects show considerable variability that remains unexplained. We investigated whether the FFR representation of the frequency content of a complex tone is related to the perception of the pitch of the fundamental frequency. The strength of the fundamental frequency in the FFR of 39 people with normal hearing was assessed when they listened to complex tones that either included or lacked energy at the fundamental frequency. We found that the strength of the fundamental representation of the missing fundamental tone complex correlated significantly with people's general tendency to perceive the pitch of the tone as either matching the frequency of the spectral components that were present, or that of the missing fundamental. Although at a group level the fundamental representation in the FFR did not appear to be affected by the presence or absence of energy at the same frequency in the stimulus, the two conditions were statistically distinguishable for some subjects individually, indicating that the neural representation is not linearly dependent on the stimulus content. In a second experiment using a within-subjects paradigm, we showed that subjects can learn to reversibly select between either fundamental or spectral perception, and that this is accompanied both by changes to the fundamental representation in the FFR and to cortical-based gamma activity. These results suggest that both fundamental and spectral representations coexist, and are available for later auditory processing stages, the requirements of which may also influence their relative strength and thus modulate FFR variability. The data also highlight voluntary mode perception as a new paradigm with which to study top-down vs bottom-up mechanisms that support the emerging view of the FFR as the outcome of integrated processing in the entire auditory system.

Objective. Micro-electrocorticography ( μ ECoG) offers a minimally invasive neural interface with high spatial resolution over large areas of cortex. However, electrode arrays with many contacts that are individually wired to external recording systems are cumbersome and make recordings in freely behaving rodents challenging. We report a novel high-density 60-electrode system for μ ECoG recording in freely moving rats. Approach. Multiplexed headstages overcome the problem of wiring complexity by combining signals from many electrodes to a smaller number of connections. We have developed a low-cost, multiplexed recording system with 60 contacts at 406 μ m spacing. We characterized the quality of the electrode signals using multiple metrics that tracked spatial variation, evoked-response detectability, and decoding value. Performance of the system was validated both in anesthetized animals and freely moving awake animals. Main results . We recorded μ ECoG signals over the primary auditory cortex, measuring responses to acoustic stimuli across all channels. Single-trial responses had high signal-to-noise ratios (SNR) (up to 25 dB under anesthesia), and were used to rapidly measure network topography within ∼10 s by constructing all single-channel receptive fields in parallel. We characterized evoked potential amplitudes and spatial correlations across the array in the anesthetized and awake animals. Recording quality in awake animals was stable for at least 30 days. Finally, we used these responses to accurately decode auditory stimuli on single trials. Significance . This study introduces (1) a μ ECoG recording system based on practical hardware design and (2) a rigorous analytical method for characterizing the signal characteristics of μ ECoG electrode arrays. This methodology can be applied to evaluate the fidelity and lifetime of any μ ECoG electrode array. Our μ ECoG-based recording system is accessible and will be useful for studies of perception and decision-making in rodents, particularly over the entire time course of behavioral training and learning.

Significance Understanding how excitatory and inhibitory inputs are integrated to achieve sensory selectivity is an important, but elusive, goal in neuroscience. Whole-cell recordings in vivo have revealed excitation and inhibition, but the computational mechanisms are generally unclear. In the inferior colliculus, neurons exist that respond selectively to short-duration sounds; the mechanistic basis of this selectivity has long been debated. We combined whole-cell recordings, in vivo, with conductance extraction algorithms and focal pharmacological manipulations to show that duration selectivity results from an anticoincidence of suprathreshold excitation and inhibition. These results challenge the widely held view that postinhibitory rebound depolarization must coincide with subthreshold excitation to generate duration selectivity.

Extracting temporal regularities in external stimuli in order to predict upcoming events is an essential aspect of perception. Fluctuations in induced power of beta band (15-25 Hz) oscillations in auditory cortex are involved in predictive timing during rhythmic entrainment, but whether such fluctuations are affected by prediction in the spectral (frequency/pitch) domain remains unclear. We tested whether unpredicted (i.e., unexpected) pitches in a rhythmic tone sequence modulate beta band activity by recording EEG while participants passively listened to isochronous auditory oddball sequences with occasional unpredicted deviant pitches at two different presentation rates. The results showed that the power in low-beta (15-20 Hz) was larger around 200-300 ms following deviant tones compared to standard tones, and this effect was larger when the deviant tones were less predicted. Our results suggest that the induced beta power activities in auditory cortex are consistent with a role in sensory prediction of both "when" (timing) upcoming sounds will occur as well as the prediction precision error of "what" (spectral content in this case). We suggest, further, that both timing and content predictions may co-modulate beta oscillations via attention. These findings extend earlier work on neural oscillations by investigating the functional significance of beta oscillations for sensory prediction. The findings help elucidate the functional significance of beta oscillations in perception.

Stimulus-specific adaptation (SSA) in single neurons of the auditory cortex was suggested to be a potential neural correlate of the mismatch negativity (MMN), a widely studied component of the auditory event-related potentials (ERP) that is elicited by changes in the auditory environment. However, several aspects on this SSA/MMN relation remain unresolved. SSA occurs in the primary auditory cortex (A1), but detailed studies on SSA beyond A1 are lacking. To study the topographic organization of SSA, we mapped the whole rat auditory cortex with multiunit activity recordings, using an oddball paradigm. We demonstrate that SSA occurs outside A1 and differs between primary and nonprimary cortical fields. In particular, SSA is much stronger and develops faster in the nonprimary than in the primary fields, paralleling the organization of subcortical SSA. Importantly, strong SSA is present in the nonprimary auditory cortex within the latency range of the MMN in the rat and correlates with an MMN-like difference wave in the simultaneously recorded local field potentials (LFP). We present new and strong evidence linking SSA at the cellular level to the MMN, a central tool in cognitive and clinical neuroscience.

In humans, listening to speech evokes neural responses in the motor cortex. This has been controversially interpreted as evidence that speech sounds are processed as articulatory gestures. However, it is unclear what information is actually encoded by such neural activity. We used high-density direct human cortical recordings while participants spoke and listened to speech sounds. Motor cortex neural patterns during listening were substantially different than during articulation of the same sounds. During listening, we observed neural activity in the superior and inferior regions of ventral motor cortex. During speaking, responses were distributed throughout somatotopic representations of speech articulators in motor cortex. The structure of responses in motor cortex during listening was organized along acoustic features similar to auditory cortex, rather than along articulatory features as during speaking. Motor cortex does not contain articulatory representations of perceived actions in speech, but rather, represents auditory vocal information.

Noise-induced hearing loss (NIHL) is an important occupational disorder. However, the molecular mechanisms underlying NIHL have not been fully clarified; therefore, the condition lacks effective therapeutic methods. Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the synthesis of prostaglandins, and has been implicated in many pathophysiological events, such as oxidative stress and inflammation. In this study, we investigated the possible role of Cox-2 in the mechanisms of NIHL and the therapeutic effect of the Cox-2 inhibitor NS398 on NIHL using a mouse model. We demonstrated that Cox-2 is constitutively expressed in the mouse cochlea, and its expression could be dramatically up-regulated by high levels of noise exposure. Furthermore, we demonstrated that pre-treatment with the Cox-2 inhibitor NS398 could inhibit Cox-2 expression during noise overstimulation; and could attenuate noise-induced hearing loss and hair cell damage. Our results suggest that Cox-2 is involved in the pathogenesis of NIHL; and pharmacological inhibition of Cox-2 has considerable therapeutic potential in NIHL.