Auditory Neurophysiology publications

Speech perception requires that sounds be transformed into speech-related objects with lexical and semantic meaning. It is unclear at what level in the auditory pathways this transformation emerges. Primary auditory cortex has been implicated in both representation of acoustic sound attributes and sound objects. While non-primary auditory cortex located on the posterolateral superior temporal gyrus (PLST) is clearly involved in acoustic-to-phonetic pre-lexical representations, it is unclear what role this region plays in auditory object formation. Additional data support the importance of prefrontal cortex in the formation of auditory objects, while other data would implicate this region in auditory object selection. To help clarify the respective roles of auditory and auditory-related cortex in the formation and selection of auditory objects, we examined high gamma activity simultaneously recorded directly from Heschl's gyrus (HG), PLST and prefrontal cortex, while subjects performed auditory semantic detection tasks. Subjects were patients undergoing evaluation for treatment of medically intractable epilepsy. We found that activity in posteromedial HG and early activity on PLST was robust to sound stimuli regardless of their context, and minimally modulated by tasks. Later activity on PLST could be strongly modulated by semantic context, but not by behavioral performance. Activity within prefrontal cortex also was related to semantic context, and did co-vary with behavior. We propose that activity in posteromedial HG and early activity on PLST primarily reflect the representation of spectrotemporal sound attributes. Later activity on PLST represents a pre-lexical processing stage and is an intermediate step in the formation of word objects. Activity in prefrontal cortex appears directly involved in word object selection. The roles of other auditory and auditory-related cortical areas in the formation of word objects remain to be explored.

Children with autism often have language impairments and degraded cortical responses to speech. Extensive behavioral interventions can improve language outcomes and cortical responses. Prenatal exposure to the antiepileptic drug valproic acid (VPA) increases the risk for autism and language impairment. Prenatal exposure to VPA also causes weaker and delayed auditory cortex responses in rats. In this study, we document speech sound discrimination ability in VPA exposed rats and document the effect of extensive speech training on auditory cortex responses. VPA exposed rats were significantly impaired at consonant, but not vowel, discrimination. Extensive speech training resulted in both stronger and faster anterior auditory field (AAF) responses compared to untrained VPA exposed rats, and restored responses to control levels. This neural response improvement generalized to non-trained sounds. The rodent VPA model of autism may be used to improve the understanding of speech processing in autism and contribute to improving language outcomes.

Spatial patterns of functional organization, resolved by microelectrode mapping, comprise a core principle of sensory cortices. In auditory cortex, however, recent two-photon Ca2+ imaging challenges this precept, as the traditional tonotopic arrangement appears weakly organized at the level of individual neurons. To resolve this fundamental ambiguity about the organization of auditory cortex, we developed multiscale optical Ca2+ imaging of unanesthetized GCaMP transgenic mice. Single-neuron activity monitored by two-photon imaging was precisely registered to large-scale cortical maps provided by transcranial widefield imaging. Neurons in the primary field responded well to tones; neighboring neurons were appreciably cotuned, and preferred frequencies adhered tightly to a tonotopic axis. By contrast, nearby secondary-field neurons exhibited heterogeneous tuning. The multiscale imaging approach also readily localized vocalization regions and neurons. Altogether, these findings cohere electrode and two-photon perspectives, resolve new features of auditory cortex, and offer a promising approach generalizable to any cortical area.

Certain retroviruses induce progressive spongiform motor neuron disease with features resembling prion diseases and amyotrophic lateral sclerosis. With the neurovirulent murine leukemia virus (MLV) FrCasE, Env protein expression within glia leads to postsynaptic vacuolation, cellular effacement, and neuronal loss in the absence of neuroinflammation. To understand the physiological changes associated with MLV-induced spongiosis, and its neuronal specificity, we employed patch-clamp recordings and voltage-sensitive dye imaging in brain slices of the mouse inferior colliculus (IC), a midbrain nucleus that undergoes extensive spongiosis. IC neurons characterized by postinhibitory rebound firing (PIR) were selectively affected in FrCasE-infected mice. Coincident with Env expression in microglia and in glia characterized by NG2 proteoglycan expression (NG2 cells), rebound neurons (RNs) lost PIR, became hyperexcitable, and were reduced in number. PIR loss and hyperexcitability were reversed by raising internal calcium buffer concentrations in RNs. PIR-initiated rhythmic circuits were disrupted, and spontaneous synchronized bursting and prolonged depolarizations were widespread. Other IC neuron cell types and circuits within the same degenerative environment were unaffected. Antagonists of NMDA and/or AMPA receptors reduced burst firing in the IC but did not affect prolonged depolarizations. Antagonists of L-type calcium channels abolished both bursts and slow depolarizations. IC infection by the nonneurovirulent isogenic virus Friend 57E (Fr57E), whose Env protein is structurally similar to FrCasE, showed no RN hyperactivity or cell loss; however, PIR latency increased. These findings suggest that spongiform neurodegeneration arises from the unique excitability of RNs, their local regulation by glia, and the disruption of this relationship by glial expression of abnormal protein.

Much less is known about the organization of the human auditory cortex compared to non-human primate auditory cortices. In an effort to further investigate the response properties of human auditory cortex, we present preliminary findings from human subjects implanted with depth electrodes in Heschl's gyrus (HG) as part of their neurosurgical treatment of epilepsy. Each subject had electrocorticography (ECoG) responses taken from medial and lateral HG in response to both speech and non-speech stimuli, including during speech production. Responses were somewhat variable across subjects, but posteromedial HG demonstrated frequency following responses to the stimuli in all subjects to some degree. Results and implications are discussed.

The ability to detect unexpected or deviant events in natural scenes is critical for survival. In the auditory system, neurons from the midbrain to cortex adapt quickly to repeated stimuli but this adaptation does not fully generalize to other rare stimuli, a phenomenon called stimulus-specific adaptation (SSA). Most studies of SSA were conducted with pure tones of different frequencies, and it is by now well-established that SSA to tone frequency is strong and robust in auditory cortex. Here we tested SSA in the auditory cortex to the ear of stimulation using broadband noise. We show that cortical neurons adapt specifically to the ear of stimulation, and that the contrast between the responses to stimulation of the same ear when rare and when common depends on the binaural interaction class of the neurons.

In the visual, auditory, and electrosensory modalities, stimuli are defined by first- and second-order attributes. The fast time-pressure signal of a sound, a first-order attribute, is important, for instance, in sound localization and pitch perception, while its slow amplitude-modulated envelope, a second-order attribute, can be used for sound recognition. Ascending the auditory pathway from ear to midbrain, neurons increasingly show a preference for the envelope and are most sensitive to particular envelope modulation frequencies, a tuning considered important for encoding sound identity. The level at which this tuning property emerges along the pathway varies across species, and the mechanism of how this occurs is a matter of debate. In this paper, we target the transition between auditory nerve fibers and the cochlear nucleus angularis (NA). While the owl's auditory nerve fibers simultaneously encode the fast and slow attributes of a sound, one synapse further, NA neurons encode the envelope more efficiently than the auditory nerve. Using in vivo and in vitro electrophysiology and computational analysis, we show that a single-cell mechanism inducing spike threshold adaptation can explain the difference in neural filtering between the two areas. We show that spike threshold adaptation can explain the increased selectivity to modulation frequency, as input level increases in NA. These results demonstrate that a spike generation nonlinearity can modulate the tuning to second-order stimulus features, without invoking network or synaptic mechanisms.

Neurons in sensory brain regions shape our perception of the surrounding environment through two parallel operations: decomposition and integration. For example, auditory neurons decompose sounds by separately encoding their frequency, temporal modulation, intensity, and spatial location. Neurons also integrate across these various features to support a unified perceptual gestalt of an auditory object. At higher levels of a sensory pathway, neurons may select for a restricted region of feature space defined by the intersection of multiple, independent stimulus dimensions. To further characterize how auditory cortical neurons decompose and integrate multiple facets of an isolated sound, we developed an automated procedure that manipulated five fundamental acoustic properties in real time based on single-unit feedback in awake mice. Within several minutes, the online approach converged on regions of the multidimensional stimulus manifold that reliably drove neurons at significantly higher rates than predefined stimuli. Optimized stimuli were cross-validated against pure tone receptive fields and spectrotemporal receptive field estimates in the inferior colliculus and primary auditory cortex. We observed, from midbrain to cortex, increases in both level invariance and frequency selectivity, which may underlie equivalent sparseness of responses in the two areas. We found that onset and steady-state spike rates increased proportionately as the stimulus was tailored to the multidimensional receptive field. By separately evaluating the amount of leverage each sound feature exerted on the overall firing rate, these findings reveal interdependencies between stimulus features as well as hierarchical shifts in selectivity and invariance that may go unnoticed with traditional approaches.

The primary auditory cortex (AI) modulates the sound information processing in the lemniscal subcortical nuclei, including the anteroventral cochlear nucleus (AVCN), in a frequency-specific manner. The dorsal cochlear nucleus (DCN) is a non-lemniscal subcortical nucleus but it is tonotopically organized like the AVCN. However, it remains unclear how the AI modulates the sound information processing in the DCN. This study examined the impact of focal electrical stimulation of AI on the auditory responses of the DCN neurons in mice. We found that the electrical stimulation induced significant changes in the best frequency (BF) of DCN neurons. The changes in the BFs were highly specific to the BF differences between the stimulated AI neurons and the recorded DCN neurons. The DCN BFs shifted higher when the AI BFs were higher than the DCN BFs and the DCN BFs shifted lower when the AI BFs were lower than the DCN BFs. The DCN BFs showed no change when the AI and DCN BFs were similar. Moreover, the BF shifts were linearly correlated to the BF differences. Thus, our data suggest that corticofugal modulation of the DCN is also highly specific to frequency information, similar to the corticofugal modulation of the AVCN. The frequency-specificity of corticofugal modulation does not appear limited to the lemniscal ascending pathway.

The mammalian superior paraolivary nucleus (SPON) is a major source of GABAergic inhibition to neurons in the inferior colliculus (IC), a well-studied midbrain nucleus that is the site of convergence and integration for the majority ascending auditory pathways en route to the cortex. Neurons in the SPON and IC exhibit highly precise responses to temporal sound features, which are important perceptual cues for naturally occurring sounds. To determine how inhibitory input from the SPON contributes to the encoding of temporal information in the IC, a reversible inactivation procedure was conducted to silence SPON neurons, while recording responses to amplitude-modulated tones and silent gaps between tones in the IC. The results show that SPON-derived inhibition shapes responses of onset and sustained units in the IC via different mechanisms. Onset neurons appear to be driven primarily by excitatory inputs and their responses are shaped indirectly by SPON-derived inhibition, whereas sustained neurons are heavily influenced directly by transient offset inhibition from the SPON. The findings also demonstrate that a more complete dissection of temporal processing pathways is critical for understanding how biologically important sounds are encoded by the brain.

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus‐specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME 20.4‐ SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II / III and in the infragranular layers. Labelled fibres with small en‐passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.

From behavioral studies it is known that auditory spatial resolution of azimuthal space declines over age. To date, it is not clear how age affects the respective sensory auditory processing at the pre-attentive level. Here we tested the hypothesis that pre-attentive processing of behaviorally perceptible spatial changes is preserved in older adults. An EEG-study was performed in older adults (65-82 years of age) and a mismatch negativity (MMN) paradigm employed. Sequences of frequent standard stimuli of defined azimuthal positions were presented together with rarely occurring deviants shifted by 10° or 20° to the left or to the right of the standard. Standard positions were at +5° (central condition) from the midsagittal plane and at 65° in both lateral hemifields (±65°; lateral condition). The results suggest an effect of laterality on the pre-attentive change processing of spatial deviations in older adults: While for the central conditions deviants close to MAA threshold (i.e., 10°) yielded discernable MMNs, for lateral positions the respective MMN responses were only elicited by spatial deviations of 20° toward the midline (i.e., ±45°). Furthermore, MMN amplitudes were found to be insensitive to the magnitude of deviation (10°, 20°), which is contrary to recent studies with young adults (Bennemann et al., 2013) and hints to a deteriorated pre-attentive encoding of sound sources in older adults. The discrepancy between behavioral MAA data and present results are discussed with respect to the possibility that under the condition of active stimulus processing older adults might benefit from recruiting additional attentional top-down processes to detect small magnitudes of spatial deviations even within the lateral acoustic field.

The auditory steady state response (ASSR) is an oscillatory brain response, which is phase locked to the rhythm of an auditory stimulus. ASSRs have been recorded in response to a wide frequency range of modulation and/or repetition, but the physiological features of the ASSRs are somewhat different depending on the modulation frequency. Recently, the 20-Hz ASSR has been emphasized in clinical examinations, especially in the area of psychiatry. However, little is known about the physiological properties of the 20-Hz ASSR, compared to those of the 40-Hz and 80-Hz ASSRs. The effects of contralateral noise on the ASSR are known to depend on the modulation frequency to evoke ASSR. However, the effects of contralateral noise on the 20-Hz ASSR are not known. Here we assessed the effects of contralateral white noise at a level of 70 dB SPL on the 20-Hz and 40-Hz ASSRs using a helmet-shaped magnetoencephalography system in 9 healthy volunteers (8 males and 1 female, mean age 31.2 years). The ASSRs were elicited by monaural 1000-Hz 5-s tone bursts amplitude-modulated at 20 and 39 Hz and presented at 80 dB SPL. Contralateral noise caused significant suppression of both the 20-Hz and 40-Hz ASSRs, although suppression was significantly smaller for the 20-Hz ASSRs than the 40-Hz ASSRs. Moreover, the greatest suppression of both 20-Hz and 40-Hz ASSRs occurred in the right hemisphere when stimuli were presented to the right ear with contralateral noise. The present study newly showed that 20-Hz ASSRs are suppressed by contralateral noise, which may be important both for characterization of the 20-Hz ASSR and for interpretation in clinical situations. Physicians must be aware that the 20-Hz ASSR is significantly suppressed by sound (e.g. masking noise or binaural stimulation) applied to the contralateral ear.

Electrophysiological studies on duration-tuned neurons (DTNs) from the mammalian auditory midbrain have typically evoked spiking responses from these cells using monaural or free-field acoustic stimulation focused on the contralateral ear, with fewer studies devoted to examining the electrophysiological properties of duration tuning using binaural stimulation. Because the inferior colliculus (IC) receives convergent inputs from lower brainstem auditory nuclei that process sounds from each ear, many midbrain neurons have responses shaped by binaural interactions and are selective to binaural cues important for sound localization. In this study, we used dichotic stimulation to vary interaural level difference (ILD) and interaural time difference (ITD) acoustic cues and explore the binaural interactions and response properties of DTNs and non-DTNs from the IC of the big brown bat (Eptesicus fuscus). Our results reveal that both DTNs and non-DTNs can have responses selective to binaural stimulation, with a majority of IC neurons showing some type of ILD selectivity, fewer cells showing ITD selectivity, and a number of neurons showing both ILD and ITD selectivity. This study provides the first demonstration that the temporally selective responses of DTNs from the vertebrate auditory midbrain can be selective to binaural cues used for sound localization in addition to having spiking responses that are selective for stimulus frequency, amplitude, and duration.

Auditory cortex (AC) contains several primary-like, or "core," fields, which receive thalamic input and project to non-primary "belt" fields. In humans, the organization and layout of core and belt auditory fields are still poorly understood, and most auditory neuroimaging studies rely on macroanatomical criteria, rather than functional localization of distinct fields. A myeloarchitectonic method has been suggested recently for distinguishing between core and belt fields in humans (Dick F, Tierney AT, Lutti A, Josephs O, Sereno MI, Weiskopf N. 2012. In vivo functional and myeloarchitectonic mapping of human primary auditory areas. J Neurosci. 32:16095-16105). We propose a marker for core AC based directly on functional magnetic resonance imaging (fMRI) data and pattern classification. We show that a portion of AC in Heschl's gyrus classifies sound frequency more accurately than other regions in AC. Using fMRI data from macaques, we validate that the region where frequency classification performance is significantly above chance overlaps core auditory fields, predominantly A1. Within this region, we measure tonotopic gradients and estimate the locations of the human homologues of the core auditory subfields A1 and R. Our results provide a functional rather than anatomical localizer for core AC. We posit that inter-individual variability in the layout of core AC might explain disagreements between results from previous neuroimaging and cytological studies.

The frequency extent over which fine structure is coded in the auditory nerve has been physiologically characterized in laboratory animals but is unknown in humans. Knowledge of the upper frequency limit in humans would inform the debate regarding the role of fine structure in human hearing. Of the presently available techniques, only the recording of mass neural potentials offers the promise to provide a physiological estimate of neural phase locking in humans. A challenge is to disambiguate neural phase locking from the receptor potentials. We studied mass potentials recorded on the cochlea and auditory nerve of cat and used several experimental manipulations to isolate the neural contribution to these potentials. We find a surprisingly large neural contribution in the signal recorded on the cochlear round window, and this contribution is in many aspects similar to the potential measured on the auditory nerve. The results suggest that recording of mass potentials through the middle ear is a promising approach to examine neural phase locking in humans.

A listener's capacity to discriminate between sounds is related to the amount of acoustic variability that exists between these sounds. However, a full understanding of how this natural variability impacts neural activity and behavior is lacking. Here, we tested monkeys' ability to discriminate between different utterances of vocalizations from the same acoustic class (i.e., coos and grunts), while neural activity was simultaneously recorded in the anterolateral belt region (AL) of the auditory cortex, a brain region that is a part of a pathway that mediates auditory perception. Monkeys could discriminate between coos better than they could discriminate between grunts. We also found AL activity was more informative about different coos than different grunts. This difference could be attributed, in part, to our finding that coos had more acoustic variability than grunts. Thus, intrinsic acoustic variability constrained the discriminability of AL spike trains and the ability of rhesus monkeys to discriminate between vocalizations.

Hearing thresholds and wave amplitudes measured using auditory brainstem responses (ABRs) to brief sounds are the predominantly used clinical measures to objectively assess auditory function. However, frequency-following responses (FFRs) to tonal carriers and to the modulation envelope (envelope-following responses or EFRs) to longer and spectro-temporally modulated stimuli are rapidly gaining prominence as a measure of complex sound processing in the brainstem and midbrain. In spite of numerous studies reporting changes in hearing thresholds, ABR wave amplitudes, and the FFRs and EFRs under neurodegenerative conditions, including aging, the relationships between these metrics are not clearly understood. In this study, the relationships between ABR thresholds, ABR wave amplitudes, and EFRs are explored in a rodent model of aging. ABRs to broadband click stimuli and EFRs to sinusoidally amplitude-modulated noise carriers were measured in young (3-6 months) and aged (22-25 months) Fischer-344 rats. ABR thresholds and amplitudes of the different waves as well as phase-locking amplitudes of EFRs were calculated. Age-related differences were observed in all these measures, primarily as increases in ABR thresholds and decreases in ABR wave amplitudes and EFR phase-locking capacity. There were no observed correlations between the ABR thresholds and the ABR wave amplitudes. Significant correlations between the EFR amplitudes and ABR wave amplitudes were observed across a range of modulation frequencies in the young. However, no such significant correlations were found in the aged. The aged click ABR amplitudes were found to be lower than would be predicted using a linear regression model of the young, suggesting altered gain mechanisms in the relationship between ABRs and FFRs with age. These results suggest that ABR thresholds, ABR wave amplitudes, and EFRs measure complementary aspects of overlapping neurophysiological processes and the relationships between these measurements changes asymmetrically with age. Hence, measuring all three metrics provides a more complete assessment of auditory function, especially under pathological conditions like aging.

Cochlear trauma causes increased spontaneous activity (hyperactivity) to develop in central auditory structures, and this has been suggested as a neural substrate for tinnitus. Using a guinea pig model we have previously demonstrated that for some time after cochlear trauma, central hyperactivity is dependent on peripheral afferent drive and only later becomes generated intrinsically within central structures. Furosemide, a loop diuretic, reduces spontaneous firing of auditory afferents. We investigated in our guinea pig model the efficacy of furosemide in reducing 1) spontaneous firing of auditory afferents, using the spectrum of neural noise (SNN) from round window recording, 2) hyperactivity in inferior colliculus, using extracellular single neuron recordings and 3) tinnitus at early time-points after cochlear trauma. Tinnitus was assessed using gap prepulse inhibition of acoustic startle (GPIAS). Intraperitoneal furosemide, but not saline, caused a marked decrease in both SNN and central hyperactivity. Intracochlear perfusion with furosemide similarly reversed central hyperactivity. In animals in which GPIAS measurements suggested the presence of tinnitus (reduced GPIAS), this could be reversed with an intraperitoneal injection with furosemide but not saline. The results are consistent with furosemide reducing central hyperactivity and behavioural signs of tinnitus by acting peripherally to decrease spontaneous firing of auditory afferents. The data support the notion that hyperactivity may be involved in the generation of tinnitus and further suggest that there may be a therapeutic window after cochlear trauma using drug treatments that target peripheral spontaneous activity.

Neurons throughout the mammalian central auditory pathway respond selectively to stimulus frequency and amplitude, and some are also selective for stimulus duration. First found in the auditory midbrain or inferior colliculus (IC), these duration-tuned neurons (DTNs) provide a potential neural mechanism for encoding temporal features of sound. In this study, we investigated how having an additional neural response filter, one selective to the duration of an auditory stimulus, influences frequency tuning and neural organization by recording single-unit responses and measuring the dorsal-ventral position and spectral-temporal tuning properties of auditory DTNs from the IC of the awake big brown bat ( Eptesicus fuscus). Like other IC neurons, DTNs were tonotopically organized and had either V-shaped, U-shaped, or O-shaped frequency tuning curves (excitatory frequency response areas). We hypothesized there would be an interaction between frequency and duration tuning in DTNs, as electrical engineering theory for resonant filters dictates a trade-off in spectral-temporal resolution: sharp tuning in the frequency domain results in poorer resolution in the time domain and vice versa. While the IC is a more complex signal analyzer than an electrical filter, a similar operational trade-off could exist in the responses of DTNs. Our data revealed two patterns of spectro-temporal sensitivity and spatial organization within the IC: DTNs with sharp frequency tuning and broad duration tuning were located in the dorsal IC, whereas cells with wide spectral tuning and narrow temporal tuning were found in the ventral IC.