David McAlpine

Precise inhibition is essential for microsecond interaural time difference coding

Microsecond differences in the arrival time of a sound at the two ears (interaural time differences, ITDs) are the main cue for localizing low-frequency sounds in space. Traditionally, ITDs are thought to be encoded by an array of coincidence-detector neurons, receiving excitatory inputs from the two ears via axons of variable length (‘delay lines’), to create a topographic map of azimuthal auditory space. Compelling evidence for the existence of such a map in the mammalian lTD detector, the medial superior olive (MSO), however, is lacking. Equally puzzling is the role of a—temporally very precise—glycine-mediated inhibitory input to MSO neurons. Using in vivo recordings from the MSO of the Mongolian gerbil, we found the responses of ITD-sensitive neurons to be inconsistent with the idea of a topographic map of auditory space. Moreover, local application of glycine and its antagonist strychnine by iontophoresis (through glass pipette electrodes, by means of an electric current) revealed that precisely timed glycine-controlled inhibition is a critical part of the mechanism by which the physiologically relevant range of ITDs is encoded in the MSO. A computer model, simulating the response of a coincidence-detector neuron with bilateral excitatory inputs and a temporally precise contralateral inhibitory input, supports this conclusion.

A neural code for low-frequency sound localization in mammals.

We report a systematic relationship between sound-frequency tuning and sensitivity to interaural time delays for neurons in the midbrain nucleus of the inferior colliculus; neurons with relatively low best frequencies (BFs) showed response peaks at long delays, whereas neurons with relatively high BFs showed response peaks at short delays. The consequence of this relationship is that the steepest region of the function relating discharge rate to interaural time delay (ITD) fell close to midline for all neurons irrespective of BF. These data provide support for a processing of the output of coincidence detectors subserving low-frequency sound localization in which the location of a sound source is determined by the activity in two broad, hemispheric spatial channels, rather than numerous channels tuned to discrete spatial positions.

Neural population coding of sound level adapts to stimulus statistics.

Mammals can hear sounds extending over a vast range of sound levels with remarkable accuracy. How auditory neurons code sound level over such a range is unclear; firing rates of individual neurons increase with sound level over only a very limited portion of the full range of hearing. We show that neurons in the auditory midbrain of the guinea pig adjust their responses to the mean, variance and more complex statistics of sound level distributions. We demonstrate that these adjustments improve the accuracy of the neural population code close to the region of most commonly occurring sound levels. This extends the range of sound levels that can be accurately encoded, fine-tuning hearing to the local acoustic environment.

Tinnitus with a Normal Audiogram: Physiological Evidence for Hidden Hearing Loss and Computational Model

Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of “hidden hearing loss” that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.

Optimal neural population coding of an auditory spatial cue

A sound, depending on the position of its source, can take more time to reach one ear than the other. This interaural (between the ears) time difference (ITD) provides a major cue for determining the source location. Many auditory neurons are sensitive to ITDs, but the means by which such neurons represent ITD is a contentious issue. Recent studies question whether the classical general model (the Jeffress model) applies across species. Here we show that ITD coding strategies of different species can be explained by a unifying principle: that the ITDs an animal naturally encounters should be coded with maximal accuracy. Using statistical techniques and a stochastic neural model, we demonstrate that the optimal coding strategy for ITD depends critically on head size and sound frequency. For small head sizes and/or low-frequency sounds, the optimal coding strategy tends towards two distinct sub-populations tuned to ITDs outside the range created by the head. This is consistent with recent observations in small mammals. For large head sizes and/or high frequencies, the optimal strategy is a homogeneous distribution of ITD tunings within the range created by the head. This is consistent with observations in the barn owl. For humans, the optimal strategy to code ITDs from an acoustically measured distribution depends on frequency; above 400 Hz a homogeneous distribution is optimal, and below 400 Hz distinct sub-populations are optimal.

Rapid Neural Adaptation to Sound Level Statistics

Auditory neurons must represent accurately a wide range of sound levels using firing rates that vary over a far narrower range of levels. Recently, we demonstrated that this “dynamic range problem” is lessened by neural adaptation, whereby neurons adjust their input–output functions for sound level according to the prevailing distribution of levels. These adjustments in input–output functions increase the accuracy with which levels around those occurring most commonly are coded by the neural population. Here, we examine how quickly this adaptation occurs. We recorded from single neurons in the auditory midbrain during a stimulus that switched repeatedly between two distributions of sound levels differing in mean level. The high-resolution analysis afforded by this stimulus showed that a prominent component of the adaptation occurs rapidly, with an average time constant across neurons of 160 ms after an increase in mean level, much faster than our previous experiments were able to assess. This time course appears to be independent of both the timescale over which sound levels varied and that over which sound level distributions varied, but is related to neural characteristic frequency. We find that adaptation to an increase in mean level occurs more rapidly than to a decrease. Finally, we observe an additional, slow adaptation in some neurons, which occurs over a timescale of tens of seconds. Our findings provide constraints in the search for mechanisms underlying adaptation to sound level. They also have functional implications for the role of adaptation in the representation of natural sounds.

The ototoxic mechanism of cisplatin

The ototoxic mechanism of cisplatin was investigated. Potentiation of cisplatin ototoxicity by furosemide and amino-oxyacetic acid (AOAA) was observed. Substantial hearing loss in cisplatin-deafened animals was accompanied by normal values of the endocochlear potential and a reduction in the sensitivity of the 2f1-f2 distortion products. The loss in dB of the sensitivity of the distortion products correlated extremely well with the loss of the neural sensitivity in dB. There was also a relationship between the fractional reduction of the low frequency (1000 Hz) microphonic potential and hearing loss in dB. Iontophoresis of cisplatin into scala media resulting in the immediate loss of neural thresholds at the site of iontophoresis. It is concluded that cisplatin caused the hearing loss by blocking OHC transduction channels.

Creating a sense of auditory space

Determining the location of a sound source requires the use of binaural hearing – information about a sound at the two ears converges onto neurones in the auditory brainstem to create a binaural representation. The main binaural cue used by many mammals to locate a sound source is the interaural time difference, or ITD. For over 50 years a single model has dominated thinking on how ITDs are processed. The Jeffress model consists of an array of coincidence detectors – binaural neurones that respond maximally to simultaneous input from each ear – innervated by a series of delay lines – axons of varying length from the two ears. The purpose of this arrangement is to create a topographic map of ITD, and hence spatial position in the horizontal plane, from the relative timing of a sound at the two ears. This model appears to be realized in the brain of the barn owl, an auditory specialist, and has been assumed to hold for mammals also. Recent investigations, however, indicate that both the means by which neural tuning for preferred ITD, and the coding strategy used by mammals to determine the location of a sound source, may be very different to barn owls and to the model proposed by Jeffress.

Interaural delay sensitivity and the classification of low best-frequency binaural responses in the inferior colliculus of the guinea pig

Monaural and binaural response properties of single units in the inferior colliculus (IC) of the guinea pig were investigated. Neurones were classified according to the effect of monaural stimulation of either ear alone and the effect of binaural stimulation. The majority (309/334) of IC units were excited (E) by stimulation of the contralateral ear, of which 41% (127/309) were also excited by monaural ipsilateral stimulation (EE), and the remainder (182/309) were unresponsive to monaural ipsilateral stimulation (EO). For units with best frequencies (BF) up to 3 kHz, similar proportions of EE and EO units were observed. Above 3 kHz, however, significantly more EO than EE units were observed. Units were also classified as either facilitated (F), suppressed (S), or unaffected (O) by binaural stimulation. More EO than EE units were suppressed or unaffected by binaural stimulation, and more EE than EO units were facilitated. There were more EO/S units above 1.5 kHz than below. Binaural beats were used to examine the interaural delay sensitivity of low-BF (BF < 1.5 kHz) units. The distributions of preferred interaural phases and, by extension, interaural delays, resembled those seen in other species, and those obtained using static interaural delays in the IC of the guinea pig. Units with best phase (BP) angles closer to zero generally showed binaural facilitation, whilst those with larger BPs generally showed binaural suppression. The classification of units based upon binaural stimulation with BF tones was consistent with their interaural-delay sensitivity. Characteristic delays (CD) were examined for 96 low-BF units. A clear relationship between BF and CD was observed. CDs of units with very low BFs (< 200 Hz) were long and positive, becoming progressively shorter as BF increased until, for units with BFs between 400 and 800 Hz, the majority of CDs were negative. Above 800 Hz, both positive and negative CDs were observed. A relationship between CD and characteristic phase (CP) was also observed, with CPs increasing in value as CDs became more negative. These results demonstrate that binaural processing in the guinea pig at low frequencies is similar to that reported in all other species studied. However, the dependence of CD on BF would suggest that the delay line system that sets up the interaural-delay sensitivity in the lower brainstem varies across frequency as well as within each frequency band.

Representation of interaural time delay in the human auditory midbrain

Interaural time difference (ITD) is a critical cue to sound-source localization. Traditional models assume that sounds leading at one ear, and perceived on that side, are processed in the opposite midbrain. Using functional magnetic resonance imaging we demonstrate that as the ITDs of sounds increase, midbrain activity can switch sides, even though perceived location remains on the same side. The data require a new model for human ITD processing.