Developmental hearing loss impedes auditory task learning and performance in gerbils.

The consequences of developmental hearing loss have been reported to include both sensory and cognitive deficits. To investigate these issues in a non-human model, auditory learning and asymptotic psychometric performance were compared between normal hearing (NH) adult gerbils and those reared with conductive hearing loss (CHL). At postnatal day 10, before ear canal opening, gerbil pups underwent bilateral malleus removal to induce a permanent CHL. Both CHL and control animals were trained to approach a water spout upon presentation of a target (Go stimuli), and withhold for foils (Nogo stimuli). To assess the rate of task acquisition and asymptotic performance, animals were tested on an amplitude modulation (AM) rate discrimination task. Behavioral performance was calculated using a signal detection theory framework. Animals reared with developmental CHL displayed a slower rate of task acquisition for AM discrimination task. Slower acquisition was explained by an impaired ability to generalize to newly introduced stimuli, as compared to controls. Measurement of discrimination thresholds across consecutive testing blocks revealed that CHL animals required a greater number of testing sessions to reach asymptotic threshold values, as compared to controls. However, with sufficient training, CHL animals approached control performance. These results indicate that a sensory impediment can delay auditory learning, and increase the risk of poor performance on a temporal task.

A Decline in Response Variability Improves Neural Signal Detection during Auditory Task Performance.

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity. SIGNIFICANCE STATEMENT: The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds.

Diverse cortical codes for scene segmentation in primate auditory cortex.

The temporal coherence of amplitude fluctuations is a critical cue for segmentation of complex auditory scenes. The auditory system must accurately demarcate the onsets and offsets of acoustic signals. We explored how and how well the timing of onsets and offsets of gated tones are encoded by auditory cortical neurons in awake rhesus macaques. Temporal features of this representation were isolated by presenting otherwise identical pure tones of differing durations. Cortical response patterns were diverse, including selective encoding of onset and offset transients, tonic firing, and sustained suppression. Spike train classification methods revealed that many neurons robustly encoded tone duration despite substantial diversity in the encoding process. Excellent discrimination performance was achieved by neurons whose responses were primarily phasic at tone offset and by those that responded robustly while the tone persisted. Although diverse cortical response patterns converged on effective duration discrimination, this diversity significantly constrained the utility of decoding models referenced to a spiking pattern averaged across all responses or averaged within the same response category. Using maximum likelihood-based decoding models, we demonstrated that the spike train recorded in a single trial could support direct estimation of stimulus onset and offset. Comparisons between different decoding models established the substantial contribution of bursts of activity at sound onset and offset to demarcating the temporal boundaries of gated tones. Our results indicate that relatively few neurons suffice to provide temporally precise estimates of such auditory "edges," particularly for models that assume and exploit the heterogeneity of neural responses in awake cortex.

The neural code for auditory space depends on sound frequency and head size in an optimal manner.

A major cue to the location of a sound source is the interaural time difference (ITD)-the difference in sound arrival time at the two ears. The neural representation of this auditory cue is unresolved. The classic model of ITD coding, dominant for a half-century, posits that the distribution of best ITDs (the ITD evoking a neuron's maximal response) is unimodal and largely within the range of ITDs permitted by head-size. This is often interpreted as a place code for source location. An alternative model, based on neurophysiology in small mammals, posits a bimodal distribution of best ITDs with exquisite sensitivity to ITDs generated by means of relative firing rates between the distributions. Recently, an optimal-coding model was proposed, unifying the disparate features of these two models under the framework of efficient coding by neural populations. The optimal-coding model predicts that distributions of best ITDs depend on head size and sound frequency: for high frequencies and large heads it resembles the classic model, for low frequencies and small head sizes it resembles the bimodal model. The optimal-coding model makes key, yet unobserved, predictions: for many species, including humans, both forms of neural representation are employed, depending on sound frequency. Furthermore, novel representations are predicted for intermediate frequencies. Here, we examine these predictions in neurophysiological data from five mammalian species: macaque, guinea pig, cat, gerbil and kangaroo rat. We present the first evidence supporting these untested predictions, and demonstrate that different representations appear to be employed at different sound frequencies in the same species.

Encoding frequency contrast in primate auditory cortex.

Changes in amplitude and frequency jointly determine much of the communicative significance of complex acoustic signals, including human speech. We have previously described responses of neurons in the core auditory cortex of awake rhesus macaques to sinusoidal amplitude modulation (SAM) signals. Here we report a complementary study of sinusoidal frequency modulation (SFM) in the same neurons. Responses to SFM were analogous to SAM responses in that changes in multiple parameters defining SFM stimuli (e.g., modulation frequency, modulation depth, carrier frequency) were robustly encoded in the temporal dynamics of the spike trains. For example, changes in the carrier frequency produced highly reproducible changes in shapes of the modulation period histogram, consistent with the notion that the instantaneous probability of discharge mirrors the moment-by-moment spectrum at low modulation rates. The upper limit for phase locking was similar across SAM and SFM within neurons, suggesting shared biophysical constraints on temporal processing. Using spike train classification methods, we found that neural thresholds for modulation depth discrimination are typically far lower than would be predicted from frequency tuning to static tones. This "dynamic hyperacuity" suggests a substantial central enhancement of the neural representation of frequency changes relative to the auditory periphery. Spike timing information was superior to average rate information when discriminating among SFM signals, and even when discriminating among static tones varying in frequency. This finding held even when differences in total spike count across stimuli were normalized, indicating both the primacy and generality of temporal response dynamics in cortical auditory processing.

Effects of spectral and temporal disruption on cortical encoding of gerbil vocalizations.

Animal communication sounds contain spectrotemporal fluctuations that provide powerful cues for detection and discrimination. Human perception of speech is influenced both by spectral and temporal acoustic features but is most critically dependent on envelope information. To investigate the neural coding principles underlying the perception of communication sounds, we explored the effect of disrupting the spectral or temporal content of five different gerbil call types on neural responses in the awake gerbil's primary auditory cortex (AI). The vocalizations were impoverished spectrally by reduction to 4 or 16 channels of band-passed noise. For this acoustic manipulation, an average firing rate of the neuron did not carry sufficient information to distinguish between call types. In contrast, the discharge patterns of individual AI neurons reliably categorized vocalizations composed of only four spectral bands with the appropriate natural token. The pooled responses of small populations of AI cells classified spectrally disrupted and natural calls with an accuracy that paralleled human performance on an analogous speech task. To assess whether discharge pattern was robust to temporal perturbations of an individual call, vocalizations were disrupted by time-reversing segments of variable duration. For this acoustic manipulation, cortical neurons were relatively insensitive to short reversal lengths. Consistent with human perception of speech, these results indicate that the stable representation of communication sounds in AI is more dependent on sensitivity to slow temporal envelopes than on spectral detail.

Frequency-dependent interaural delays in the medial superior olive: implications for interaural cochlear delays.

Neurons in the medial superior olive (MSO) are tuned to the interaural time difference (ITD) of sound arriving at the two ears. MSO neurons evoke a strongest response at their best delay (BD), at which the internal delay between bilateral inputs to MSO matches the external ITD. We performed extracellular recordings in the superior olivary complex of the anesthetized gerbil and found a majority of single units localized to the MSO to exhibit BDs that shifted with tone frequency. The relation of best interaural phase difference to tone frequency revealed nonlinearities in some MSO units and others with linear relations with characteristic phase between 0.4 and 0.6 cycles. The latter is usually associated with the interaction of ipsilateral excitation and contralateral inhibition, as in the lateral superior olive, yet all MSO units exhibited evidence of bilateral excitation. Interaural cochlear delays and phase-locked contralateral inhibition are two mechanisms of internal delay that have been suggested to create frequency-dependent delays. Best interaural phase-frequency relations were compared with a cross-correlation model of MSO that incorporated interaural cochlear delays and an additional frequency-independent delay component. The model with interaural cochlear delay fit phase-frequency relations exhibiting frequency-dependent delays with precision. Another model of MSO incorporating inhibition based on realistic biophysical parameters could not reproduce observed frequency-dependent delays.

Transformation of temporal processing across auditory cortex of awake macaques.

The anatomy and connectivity of the primate auditory cortex has been modeled as a core region receiving direct thalamic input surrounded by a belt of secondary fields. The core contains multiple tonotopic fields (including the primary auditory cortex, AI, and the rostral field, R), but available data only partially address the degree to which those fields are functionally distinct. This report, based on single-unit recordings across four hemispheres in awake macaques, argues that the functional organization of auditory cortex is best understood in terms of temporal processing. Frequency tuning, response threshold, and strength of activation are similar between AI and R, validating their inclusion as a unified core, but the temporal properties of the fields clearly differ. Onset latencies to pure tones are longer in R (median, 33 ms) than in AI (20 ms); moreover, synchronization of spike discharges to dynamic modulations of stimulus amplitude and frequency, similar to those present in macaque and human vocalizations, suggest distinctly different windows of temporal integration in AI (20-30 ms) and R (100 ms). Incorporating data from the adjacent auditory belt reveals that the divergence of temporal properties within the core is in some cases greater than the temporal differences between core and belt.

Exploiting development to evaluate auditory encoding of amplitude modulation.

During development, detection for many percepts matures gradually. This provides a natural system in which to investigate the neural mechanisms underlying performance differences: those aspects of neural activity that mature in conjunction with behavioral performance are more likely to subserve detection. In principle, the limitations on performance could be attributable to either immature sensory encoding mechanisms or an immature decoding of an already-mature sensory representation. To evaluate these alternatives in awake gerbil auditory cortex, we measured neural detection of sinusoidally amplitude-modulated (sAM) stimuli, for which behavioral detection thresholds display a prolonged maturation. A comparison of single-unit responses in juveniles and adults revealed that encoding of static tones was adult like in juveniles, but responses to sAM depth were immature. Since perceptual performance may reflect the activity of an animal's most sensitive neurons, we analyzed the d prime curves of single neurons and found an equivalent percentage with highly sensitive thresholds in juvenile and adult animals. In contrast, perceptual performance may reflect the pooling of information from neurons with a range of sensitivities. We evaluated a pooling model that assumes convergence of a population of inputs at a downstream target neuron and found poorer sAM detection thresholds for juveniles. Thus, if sAM detection is based on the most sensitive neurons, then immature behavioral performance is best explained by an immature decoding mechanism. However, if sAM detection is based on a population response, then immature detection thresholds are more likely caused by an inadequate sensory representation.

Temporal codes for amplitude contrast in auditory cortex.

The encoding of sound level is fundamental to auditory signal processing, and the temporal information present in amplitude modulation is crucial to the complex signals used for communication sounds, including human speech. The modulation transfer function, which measures the minimum detectable modulation depth across modulation frequency, has been shown to predict speech intelligibility performance in a range of adverse listening conditions and hearing impairments, and even for users of cochlear implants. We presented sinusoidal amplitude modulation (SAM) tones of varying modulation depths to awake macaque monkeys while measuring the responses of neurons in the auditory core. Using spike train classification methods, we found that thresholds for modulation depth detection and discrimination in the most sensitive units are comparable to psychophysical thresholds when precise temporal discharge patterns rather than average firing rates are considered. Moreover, spike timing information was also superior to average rate information when discriminating static pure tones varying in level but with similar envelopes. The limited utility of average firing rate information in many units also limited the utility of standard measures of sound level tuning, such as the rate level function (RLF), in predicting cortical responses to dynamic signals like SAM. Response modulation typically exceeded that predicted by the slope of the RLF by large factors. The decoupling of the cortical encoding of SAM and static tones indicates that enhancing the representation of acoustic contrast is a cardinal feature of the ascending auditory pathway.

Representation of dynamic interaural phase difference in auditory cortex of awake rhesus macaques.

Neurons in auditory cortex of awake primates are selective for the spatial location of a sound source, yet the neural representation of the binaural cues that underlie this tuning remains undefined. We examined this representation in 283 single neurons across the low-frequency auditory core in alert macaques, trained to discriminate binaural cues for sound azimuth. In response to binaural beat stimuli, which mimic acoustic motion by modulating the relative phase of a tone at the two ears, these neurons robustly modulate their discharge rate in response to this directional cue. In accordance with prior studies, the preferred interaural phase difference (IPD) of these neurons typically corresponds to azimuthal locations contralateral to the recorded hemisphere. Whereas binaural beats evoke only transient discharges in anesthetized cortex, neurons in awake cortex respond throughout the IPD cycle. In this regard, responses are consistent with observations at earlier stations of the auditory pathway. Discharge rate is a band-pass function of the frequency of IPD modulation in most neurons (73%), but both discharge rate and temporal synchrony are independent of the direction of phase modulation. When subjected to a receiver operator characteristic analysis, the responses of individual neurons are insufficient to account for the perceptual acuity of these macaques in an IPD discrimination task, suggesting the need for neural pooling at the cortical level.

Dynamic amplitude coding in the auditory cortex of awake rhesus macaques.

In many animals, the information most important for processing communication sounds, including speech, consists of temporal envelope cues below approximately 20 Hz. Physiological studies, however, have typically emphasized the upper limits of modulation encoding. Responses to sinusoidal AM (SAM) are generally summarized by modulation transfer functions (MTFs), which emphasize tuning to modulation frequency rather than the representation of the instantaneous stimulus amplitude. Unfortunately, MTFs fail to capture important but nonlinear aspects of amplitude coding in the central auditory system. We focus on an alternative data representation, the modulation period histogram (MPH), which depicts the spike train folded on the modulation period of the SAM stimulus. At low modulation frequencies, the fluctuations of stimulus amplitude in decibels are robustly encoded by the cycle-by-cycle response dynamics evident in the MPH. We show that all of the parameters that define a SAM stimulus--carrier frequency, carrier level, modulation frequency, and modulation depth--are reflected in the shape of cortical MPHs. In many neurons that are nonmonotonically tuned for sound amplitude, the representation of modulation frequency is typically sacrificed to preserve the mapping between the instantaneous discharge rate and the instantaneous stimulus amplitude, resulting in two response modes per modulation cycle. This behavior, as well as the relatively poor tuning of cortical MTFs, suggests that auditory cortical neurons are not well suited for operating as a "modulation filterbank." Instead, our results suggest that <20 Hz, the processing of modulated signals is better described as envelope shape discrimination rather than modulation frequency extraction.

Effect of behavioral context on representation of a spatial cue in core auditory cortex of awake macaques.

Primary auditory cortex plays a crucial role in spatially directed behavior, but little is known about the effect of behavioral state on the neural representation of spatial cues. Macaques were trained to discriminate binaural cues to sound localization, eventually allowing measurement of thresholds comparable to human hearing. During behavior and passive listening, single units in low-frequency auditory cortex showed robust and consistent tuning to interaural phase difference (IPD). In most neurons, behavior exerted an effect on peak discharge rate (58% increased, 13% decreased), but this was not accompanied by a detectable shift in the best IPD of any cell. Neurometric analysis revealed a difference in discriminability between the behaving and passive condition in half of the sample (52%), but steepening of the neurometric function (29%) was only slightly more common than flattening (23%). This suggests that performance of a discrimination task does not necessarily confer an advantage in understanding the representation of the spatial cue in primary auditory cortex but nevertheless revealed some physiological effects. These results suggest that responses observed during passive listening provide a valid representation of neuronal response properties in core auditory cortex.

Transformation of temporal properties between auditory midbrain and cortex in the awake Mongolian gerbil.

The neural representation of meaningful stimulus features is thought to rely on precise discharge characteristics of the auditory cortex. Precisely timed onset spikes putatively carry the majority of stimulus-related information in auditory cortical neurons but make a small contribution to stimulus representation in the auditory midbrain. Because these conclusions derive primarily from anesthetized preparations, we reexamined temporal coding properties of single neurons in the awake gerbil inferior colliculus (IC) and compared them with primary auditory cortex (AI). Surprisingly, AI neurons displayed a reduction of temporal precision compared with those in the IC. Furthermore, this hierarchical transition from high to low temporal fidelity was observed for both static and dynamic stimuli. Because most of the data that support temporal precision were obtained under anesthesia, we also reexamined response properties of IC and AI neurons under these conditions. Our results show that anesthesia has profound effects on the trial-to-trial variability and reliability of discharge and significantly improves the temporal precision of AI neurons to both tones and amplitude-modulated stimuli. In contrast, IC temporal properties are only mildly affected by anesthesia. These results underscore the pitfalls of using anesthetized preparations to study temporal coding. Our findings in awake animals reveal that AI neurons combine faster adaptation kinetics and a longer temporal window than evident in IC to represent ongoing acoustic stimuli.

Cortical mechanisms in hearing.

Current understanding of neural processing in the auditory cortex has been shaped by a variety of experimental approaches in animals and humans. It remains a daunting challenge to reconcile data as diverse as synaptic properties recorded in a rodent brain slice and functional images of auditory cortex in a behaving human. Nevertheless, the gaps are narrowing through a renewed focus on humans and other primates, a continuing interest in evidence for functional pathways, a broader application of modern imaging techniques, a growing awareness of cortical sensitivity to dynamic features of sounds, and an improved understanding of auditory cortical circuitry.

Adaptation and inhibition underlie responses to time-varying interaural phase cues in a model of inferior colliculus neurons.

A mathematical model was developed for exploring the sensitivity of low-frequency inferior colliculus (IC) neurons to interaural phase disparity (IPD). The formulation involves a firing-rate-type model that does not include spikes per se. The model IC neuron receives IPD-tuned excitatory and inhibitory inputs (viewed as the output of a collection of cells in the medial superior olive). The model cell possesses cellular properties of firing rate adaptation and postinhibitory rebound (PIR). The descriptions of these mechanisms are biophysically reasonable, but only semi-quantitative. We seek to explain within a minimal model the experimentally observed mismatch between responses to IPD stimuli delivered dynamically and those delivered statically (McAlpine et al. 2000; Spitzer and Semple 1993). The model reproduces many features of the responses to static IPD presentations, binaural beat, and partial range sweep stimuli. These features include differences in responses to a stimulus presented in static or dynamic context: sharper tuning and phase shifts in response to binaural beats, and hysteresis and "rise-from-nowhere" in response to partial range sweeps. Our results suggest that dynamic response features are due to the structure of inputs and the presence of firing rate adaptation and PIR mechanism in IC cells, but do not depend on a specific biophysical mechanism. We demonstrate how the model's various components contribute to shaping the observed phenomena. For example, adaptation, PIR, and transmission delay shape phase advances and delays in responses to binaural beats, adaptation and PIR shape hysteresis in different ranges of IPD, and tuned inhibition underlies asymmetry in dynamic tuning properties. We also suggest experiments to test our modeling predictions: in vitro simulation of the binaural beat (phase advance at low beat frequencies, its dependence on firing rate), in vivo partial range sweep experiments (dependence of the hysteresis curve on parameters), and inhibition blocking experiments (to study inhibitory tuning properties by observation of phase shifts).

Redefining the tonotopic core of rat auditory cortex: physiological evidence for a posterior field.

Previous physiological studies have identified a tonotopically organized primary auditory cortical field (AI) in the rat. Some of this prior research suggests that the rat, like other mammals, may have additional fields surrounding AI. We, therefore, recorded in the Sprague-Dawley rat extracellular responses of single neurons throughout AI, and continued posteriorly to verify the existence of a posterior field (P) and to compare the neuronal properties in the two regions. Acoustic stimuli, including tones, bandpass noise, broadband noise, and temporally modulated stimuli, were delivered dichotically via sealed systems. Consistent with previous findings, AI was characterized by an anterior-to-posterior tonotopic progression from high to low frequencies (ranging from >40 kHz to <1 kHz). A frequency reversal at the posterior border of AI marked entry into a second core tonotopic region, P, with progressively higher frequencies encountered further posteriorly, up to a point (approximately 8 kHz) where cells were no longer tone responsive. Nevertheless, bandpass noise was an effective stimulus in P, enabling characterization of cells up to 15 kHz. Compared with AI, the frequency tuning of response areas was relatively broader in P, the response latency was often longer and more variable, and the response magnitude was more commonly a nonmonotonic function of stimulus level. In both fields, most neurons were binaurally influenced. The presence of multiple auditory cortical fields in the rat is consistent with auditory cortical organization in other mammals. Moreover, the response properties of P relative to AI in the rat also resemble those found in other mammals. Finally, the physiological data suggest that core auditory cortex (temporal area TE1) is composed not only of AI as previously thought, but also of at least two other subdivisions, P and an anterior field (A). Furthermore, our physiological characterization of TE1 reveals that it is larger than suggested by previous anatomical characterizations.

Context-dependent adaptive coding of interaural phase disparity in the auditory cortex of awake macaques.

In the ascending auditory pathway, the context in which a particular stimulus occurs can influence the character of the responses that encode it. Here we demonstrate that the cortical representation of a binaural cue to sound source location is profoundly context-dependent: spike rates elicited by a 0 degrees interaural phase disparity (IPD) were very different when preceded by 90 degrees versus -90 degrees IPD. The changes in firing rate associated with equivalent stimuli occurring in different contexts are comparable to changes in discharge rate that establish cortical tuning to the cue itself. Single-unit responses to trapezoidally modulated IPD stimuli were recorded in the auditory cortices of awake rhesus monkeys. Each trapezoidal stimulus consisted of linear modulations of IPD between two steady-state IPDs differing by 90 degrees. The stimulus set was constructed so that identical IPDs and sweeps through identical IPD ranges recurred as elements of disparate sequences. We routinely observed orderly context-induced shifts in IPD tuning. These shifts reflected an underlying enhancement of the contrast in the discharge rate representation of different IPDs. This process is subserved by sensitivity to stimulus events in the recent past, involving multiple adaptive mechanisms operating on timescales ranging from tens of milliseconds to seconds. These findings suggest that the cortical processing of dynamic acoustic signals is dominated by an adaptive coding strategy that prioritizes the representation of stimulus changes over actual stimulus values. We show how cortical selectivity for motion direction in real space could emerge as a consequence of this general coding principle.