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. 2018 Oct 3;38(40):8563-8573.
doi: 10.1523/JNEUROSCI.1211-18.2018. Epub 2018 Aug 20.

Across Species "Natural Ablation" Reveals the Brainstem Source of a Noninvasive Biomarker of Binaural Hearing

Victor Benichoux  1   2 , Alexander Ferber  2   3 , Samuel Hunt  4 , Ethan Hughes  4 , Daniel Tollin  2   3
Affiliations

Across Species "Natural Ablation" Reveals the Brainstem Source of a Noninvasive Biomarker of Binaural Hearing

Victor Benichoux et al. J Neurosci. .

Abstract

The binaural interaction component (BIC) of the auditory brainstem response is a noninvasive electroencephalographic signature of neural processing of binaural sounds. Despite its potential as a clinical biomarker, the neural structures and mechanism that generate the BIC are not known. We explore here the hypothesis that the BIC emerges from excitatory-inhibitory interactions in auditory brainstem neurons. We measured the BIC in response to click stimuli while varying interaural time differences (ITDs) in subjects of either sex from five animal species. Species had head sizes spanning a 3.5-fold range and correspondingly large variations in the sizes of the auditory brainstem nuclei known to process binaural sounds [the medial superior olive (MSO) and the lateral superior olive (LSO)]. The BIC was reliably elicited in all species, including those that have small or inexistent MSOs. In addition, the range of ITDs where BIC was elicited was independent of animal species, suggesting that the BIC is not a reflection of the processing of ITDs per se. Finally, we provide a model of the amplitude and latency of the BIC peak, which is based on excitatory-inhibitory synaptic interactions, without assuming any specific arrangement of delay lines. Our results show that the BIC is preserved across species ranging from mice to humans. We argue that this is the result of generic excitatory-inhibitory synaptic interactions at the level of the LSO, and thus best seen as reflecting the integration of binaural inputs as opposed to their spatial properties.SIGNIFICANCE STATEMENT Noninvasive electrophysiological measures of sensory system activity are critical for the objective clinical diagnosis of human sensory processing deficits. The binaural component of sound-evoked auditory brainstem responses is one such measure of binaural auditory coding fidelity in the early stages of the auditory system. Yet, the precise neurons that lead to this evoked potential are not fully understood. This paper provides a comparative study of this potential in different mammals and shows that it is preserved across species, from mice to men, despite large variations in morphology and neuroanatomy. Our results confirm its relevance to the assessment of binaural hearing integrity in humans and demonstrates how it can be used to bridge the gap between rodent models and humans.

Keywords: auditory; binaural; brainstem; central processing disorder.

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Figures

Figure 1.
Figure 1.
The BIC of the auditory brainstem response. A, Schematics of the brainstem binaural pathways. CN, Cochlear nucleus; LL, lateral lemniscus; D, dorsal; V, ventral. B, Monaural ABR obtained by presenting a single click to one ear (black trace) in the guinea pig. Background colors indicate from which nucleus ABR waves are thought to emanate from. C, ABRs obtained by monaural stimulation of either the left ear (top trace, red) or the right ear (bottom trace, blue). D, Binaural ABR obtained by simultaneous stimulation of both ears (green trace). E, Sum of the two monaural ABRs. F, The BIC (black trace) is computed by taking the difference between the binaural ABRs (green trace) and the summed response (gray line). G, Color-coded counterparts of the ABRs in C–F as a function of time (abscissa) and ITD (ordinate). Black lines indicate the presentation time of the stimuli at each ear. Note that color-code amplitude differs between panels.
Figure 2.
Figure 2.
BIC analysis by cross-correlation. A, Example BIC recording for a guinea pig subject. The amplitude of the BIC trace is color-coded against ITD and time. Left of the black line is the range of times used for noise-level computations. B, Example of the cross-correlation of two BIC recordings at ITD = 0 and 0.5 ms. C, The maximum of the normalized cross-correlations of all pairs of BIC recordings. This matrix is symmetric by construction, and values close to the diagonal are large, indicating that neighboring BIC recordings are similar. D, Temporally aligned BIC waveforms. E, Subject signature BIC trace with peaks labeled. F, Amplitude of the BIC versus ITD, measured by the cross-correlation gain with respect to the recording at 0 ITD (black trace). DP1 (green) and DN1 (blue) peak amplitudes as a function of ITD. Gray area is the noise level (see text). G, BIC latency versus ITD as measured by the cross-correlation latency (black trace). DP1 (green) and DN1 (blue) peak latencies as a function of ITD.
Figure 3.
Figure 3.
BIC waveforms across species. A, Cross-correlation gain matrix of all signature BICs for individual specimen across species, and within species averages (inset; see Materials and Methods). B, Species signature BIC waveform for each species. Note that the time axis here is not relative to stimulus onset (see text). C, BIC waveform lags for each specimen of each species plotted against the range of ITDs for that species. BIC waveforms for individual subjects are represented on Extended Data Figure 3-1.
Figure 4.
Figure 4.
BIC waveform amplitudes as a function of ITD across species. A, BIC amplitudes (measured by cross-correlation) averaged over animals of the same species. Horizontal bars span the width of the ITD ecological range for each species. B, ITD range for which the cross-correlation is >0.9 in each animal. C, Values of the BIC amplitude as a function of ITD for all individual subjects, grouped per species. D, Same as A except the average DP1 amplitude is reported. E, Same as A except the average DN1 amplitude is reported. Further analyses of the BIC versus ITD relationship can be found on Extended Data Figure 4-1.
Figure 5.
Figure 5.
An excitatory–inhibitory model of the BIC amplitude and latencies. A, Conventions for ITD orientation and LSO naming. For positive ITDs (top), the left LSO receives excitation at −ITD/2 and inhibition at ITD/2, and conversely for the right LSO (bottom row). B, The distribution of relative excitatory/inhibitory spike times is normal of width σ and mean ITD. The inhibition time window is of length w. C, When excitation occurs after inhibition within the time window, there is inhibition (top row). If excitation occurs after the time window has elapsed (middle row) or before inhibition (bottom row), there is no inhibition. D, Predictions of the model for varying width σ and time window duration w. E, Amplitude and latency fits for the same guinea pig subject as for Figures 1 and 2. F, G, Parameters of the fit as a function of species for σ (F) and w (G). Amplitude and latency model fits to the individual data can be found on Extended Data Figure 5-1.
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