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1.  The Neural Substrate for Binaural Masking Level Differences in the Auditory Cortex 
The Journal of Neuroscience  2015;35(1):209-220.
The binaural masking level difference (BMLD) is a phenomenon whereby a signal that is identical at each ear (S0), masked by a noise that is identical at each ear (N0), can be made 12–15 dB more detectable by inverting the waveform of either the tone or noise at one ear (Sπ, Nπ). Single-cell responses to BMLD stimuli were measured in the primary auditory cortex of urethane-anesthetized guinea pigs. Firing rate was measured as a function of signal level of a 500 Hz pure tone masked by low-passed white noise. Responses were similar to those reported in the inferior colliculus. At low signal levels, the response was dominated by the masker. At higher signal levels, firing rate either increased or decreased. Detection thresholds for each neuron were determined using signal detection theory. Few neurons yielded measurable detection thresholds for all stimulus conditions, with a wide range in thresholds. However, across the entire population, the lowest thresholds were consistent with human psychophysical BMLDs. As in the inferior colliculus, the shape of the firing-rate versus signal-level functions depended on the neurons' selectivity for interaural time difference. Our results suggest that, in cortex, BMLD signals are detected from increases or decreases in the firing rate, consistent with predictions of cross-correlation models of binaural processing and that the psychophysical detection threshold is based on the lowest neural thresholds across the population.
doi:10.1523/JNEUROSCI.1131-14.2015
PMCID: PMC4287143  PMID: 25568115
auditory cortex; binaural unmasking; BMLD; hearing
2.  Classification of frequency response areas in the inferior colliculus reveals continua not discrete classes 
The Journal of Physiology  2013;591(Pt 16):4003-4025.
A differential response to sound frequency is a fundamental property of auditory neurons. Frequency analysis in the cochlea gives rise to V-shaped tuning functions in auditory nerve fibres, but by the level of the inferior colliculus (IC), the midbrain nucleus of the auditory pathway, neuronal receptive fields display diverse shapes that reflect the interplay of excitation and inhibition. The origin and nature of these frequency receptive field types is still open to question. One proposed hypothesis is that the frequency response class of any given neuron in the IC is predominantly inherited from one of three major afferent pathways projecting to the IC, giving rise to three distinct receptive field classes. Here, we applied subjective classification, principal component analysis, cluster analysis, and other objective statistical measures, to a large population (2826) of frequency response areas from single neurons recorded in the IC of the anaesthetised guinea pig. Subjectively, we recognised seven frequency response classes (V-shaped, non-monotonic Vs, narrow, closed, tilt down, tilt up and double-peaked), that were represented at all frequencies. We could identify similar classes using our objective classification tools. Importantly, however, many neurons exhibited properties intermediate between these classes, and none of the objective methods used here showed evidence of discrete response classes. Thus receptive field shapes in the IC form continua rather than discrete classes, a finding consistent with the integration of afferent inputs in the generation of frequency response areas. The frequency disposition of inhibition in the response areas of some neurons suggests that across-frequency inputs originating at or below the level of the IC are involved in their generation.
doi:10.1113/jphysiol.2013.255943
PMCID: PMC3764642  PMID: 23753527
3.  The Effect of Correlated Neuronal Firing and Neuronal Heterogeneity on Population Coding Accuracy in Guinea Pig Inferior Colliculus 
PLoS ONE  2013;8(12):e81660.
It has been suggested that the considerable noise in single-cell responses to a stimulus can be overcome by pooling information from a large population. Theoretical studies indicated that correlations in trial-to-trial fluctuations in the responses of different neurons may limit the improvement due to pooling. Subsequent theoretical studies have suggested that inherent neuronal diversity, i.e., the heterogeneity of tuning curves and other response properties of neurons preferentially tuned to the same stimulus, can provide a means to overcome this limit. Here we study the effect of spike-count correlations and the inherent neuronal heterogeneity on the ability to extract information from large neural populations. We use electrophysiological data from the guinea pig Inferior-Colliculus to capture inherent neuronal heterogeneity and single cell statistics, and introduce response correlations artificially. To this end, we generate pseudo-population responses, based on single-cell recording of neurons responding to auditory stimuli with varying binaural correlations. Typically, when pseudo-populations are generated from single cell data, the responses within the population are statistically independent. As a result, the information content of the population will increase indefinitely with its size. In contrast, here we apply a simple algorithm that enables us to generate pseudo-population responses with variable spike-count correlations. This enables us to study the effect of neuronal correlations on the accuracy of conventional rate codes. We show that in a homogenous population, in the presence of even low-level correlations, information content is bounded. In contrast, utilizing a simple linear readout, that takes into account the natural heterogeneity, even of neurons preferentially tuned to the same stimulus, within the neural population, one can overcome the correlated noise and obtain a readout whose accuracy grows linearly with the size of the population.
doi:10.1371/journal.pone.0081660
PMCID: PMC3864845  PMID: 24358120
4.  A novel behavioural approach to detecting tinnitus in the guinea pig 
Journal of Neuroscience Methods  2013;213(2):188-195.
Highlights
► Prepulse inhibition can be reliably and robustly measured using the Preyer reflex. ► The Preyer reflex is a more reliable response than the whole-body startle in guinea pigs. ► Salicylate impairs gap detection at specific background noise frequencies, indicating the presence of tinnitus. ► Measuring gap detection using the Preyer reflex is a suitable method for identifying tinnitus.
Tinnitus, the perception of sound in the absence of an external stimulus, is a particularly challenging condition to demonstrate in animals. In any animal model, objective confirmation of tinnitus is essential before we can study the neural changes that produce it. A gap detection method, based on prepulse inhibition of the whole-body startle reflex, is often used as a behavioural test for tinnitus in rodents. However, in the guinea pig the whole-body startle reflex is subject to rapid habituation and hence is not an ideal behavioural measure. By contrast, in this species the Preyer or pinna reflex is a very reliable indicator of the startle response and is much less subject to habituation. We have developed a novel adaptation of the gap detection paradigm, which uses the Preyer reflex to measure the startle response, rather than whole-body movement. Using this method, we have demonstrated changes in gap detection, in guinea pigs where tinnitus had been induced by the administration of a high dose of salicylate. Our data indicate that the Preyer reflex gap detection method is a reliable test for tinnitus in guinea pigs.
doi:10.1016/j.jneumeth.2012.12.023
PMCID: PMC3580292  PMID: 23291084
Tinnitus; Guinea pig; Preyer reflex; Pinna reflex; Gap detection; Prepulse inhibition; Sodium salicylate; Whole-body startle
5.  Morphological and Physiological Characteristics of Laminar Cells in the Central Nucleus of the Inferior Colliculus 
The central nucleus of the inferior colliculus (IC) is organized into a series of fibro-dendritic laminae, orthogonal to the tonotopic progression. Many neurons have their dendrites confined to one lamina while others have dendrites that cross over a number of laminae. Here, we have used juxtacellular labeling in urethane anesthetized guinea pigs to visualize the cells with biocytin and have analyzed their response properties, in order to try and link their structure and function. Out of a sample of 38 filled cells, 15 had dendrites confined within the fibro-dendritic laminae and in 13 we were also able to reconstruct their local axonal tree. Based on dendritic morphology they were subdivided into flat or less flat; small, medium, or large; elongated or disk-shaped cells. Two of the elongated cells had many dendritic spines while the other cells had few or none. Twelve of the cells had their local axonal tree restricted to the same lamina as their dendrites while one cell had its dendrites in a separate lamina from the axon. The axonal plexus was more extensive (width 0.7–1.4 mm) within the lamina than the dendrites (width generally 0.07–0.53 mm). The intrinsic axons were largely confined to a single lamina within the central nucleus, but at least half the cells also had output axons with two heading for the commissure and five heading into the brachium. We were able to identify similarities in the physiological response profiles of small groups of our filled cells but none appeared to represent a homogeneous morphological cell type. The only common feature of our sample was one of exclusion in that the onset response, a response commonly recorded from IC cells, was never seen in laminar cells, but was in cells with a stellate morphology. Thus cells with laminar dendrites have a wide variety of physiological responses and morphological subtypes, but over 90% have an extensive local axonal tree within their local lamina.
doi:10.3389/fncir.2012.00055
PMCID: PMC3422721  PMID: 22933991
inferior colliculus; microcircuits; fibro-dendritic laminae; flat cells; juxtacellular labeling; neuronal reconstruction; intrinsic axon
6.  Cortical Inactivation by Cooling in Small Animals 
Reversible inactivation of the cortex by surface cooling is a powerful method for studying the function of a particular area. Implanted cooling cryoloops have been used to study the role of individual cortical areas in auditory processing of awake-behaving cats. Cryoloops have also been used in rodents for reversible inactivation of the cortex, but recently there has been a concern that the cryoloop may also cool non-cortical structures either directly or via the perfusion of blood, cooled as it passed close to the cooling loop. In this study we have confirmed that the loop can inactivate most of the auditory cortex without causing a significant reduction in temperature of the auditory thalamus or other subcortical structures. We placed a cryoloop on the surface of the guinea pig cortex, cooled it to 2°C and measured thermal gradients across the neocortical surface. We found that the temperature dropped to 20–24°C among cells within a radius of about 2.5 mm away from the loop. This temperature drop was sufficient to reduce activity of most cortical cells and led to the inactivation of almost the entire auditory region. When the temperature of thalamus, midbrain, and middle ear were measured directly during cortical cooling, there was a small drop in temperature (about 4°C) but this was not sufficient to directly reduce neural activity. In an effort to visualize the extent of neural inactivation we measured the uptake of thallium ions following an intravenous injection. This confirmed that there was a large reduction of activity across much of the ipsilateral cortex and only a small reduction in subcortical structures.
doi:10.3389/fnsys.2011.00053
PMCID: PMC3122068  PMID: 21734869
auditory cortex; cooling inactivation; cryoloop; thallium autometallography
7.  Variation in the Phase of Response to Low-Frequency Pure Tones in the Guinea Pig Auditory Nerve as Functions of Stimulus Level and Frequency 
The directionality of hair cell stimulation combined with the vibration of the basilar membrane causes the auditory nerve fiber action potentials, in response to low-frequency stimuli, to occur at a particular phase of the stimulus waveform. Because direct mechanical measurements at the cochlear apex are difficult, such phase locking has often been used to indirectly infer the basilar membrane motion. Here, we confirm and extend earlier data from mammals using sine wave stimulation over a wide range of sound levels (up to 90 dB sound pressure level). We recorded phase-locked responses to pure tones over a wide range of frequencies and sound levels of a large population of auditory nerve fibers in the anesthetized guinea pig. The results indicate that, for a constant frequency of stimulation, the phase lag decreases with increases in the characteristic frequency (CF) of the nerve fiber. The phase lag decreases up to a CF above the stimulation frequency, beyond which it decreases at a much slower rate. Such phase changes are consistent with known basal cochlear mechanics. Measurements from individual fibers showed smaller but systematic variations in phase with sound level, confirming previous reports. We found a “null” stimulation frequency at which little variation in phase occurred with sound level. This null frequency was often not at the CF. At stimulation frequencies below the null, there was a progressive lag with sound level and a progressive lead for stimulation frequencies above the null. This was maximally 0.2 cycles.
doi:10.1007/s10162-008-0151-x
PMCID: PMC2674197  PMID: 19093151
auditory nerve; phase response; basilar membrane; guinea pig
8.  Responses to Diotic, Dichotic, and Alternating Phase Harmonic Stimuli in the Inferior Colliculus of Guinea Pigs 
Humans perceive a harmonic series as a single auditory object with a pitch equivalent to the fundamental frequency (F0) of the series. When harmonics are presented to alternate ears, the repetition rate of the waveform at each ear doubles. If the harmonics are resolved, then the pitch perceived is still equivalent to F0, suggesting the stimulus is binaurally integrated before pitch is processed. However, unresolved harmonics give rise to the doubling of pitch which would be expected from monaural processing (Bernstein and Oxenham, J. Acoust. Soc. Am., 113:3323–3334, 2003). We used similar stimuli to record responses of multi-unit clusters in the central nucleus of the inferior colliculus (IC) of anesthetized guinea pigs (urethane supplemented by fentanyl/fluanisone) to determine the nature of the representation of harmonic stimuli and to what extent there was binaural integration. We examined both the temporal and rate-tuning of IC clusters and found no evidence for binaural integration. Stimuli comprised all harmonics below 10 kHz with fundamental frequencies (F0) from 50 to 400 Hz in half-octave steps. In diotic conditions, all the harmonics were presented to both ears. In dichotic conditions, odd harmonics were presented to one ear and even harmonics to the other. Neural characteristic frequencies (CF, n = 85) were from 0.2 to 14.7 kHz; 29 had CFs below 1 kHz. The majority of clusters responded predominantly to the contralateral ear, with the dominance of the contralateral ear increasing with CF. With diotic stimuli, over half of the clusters (58%) had peaked firing rate vs. F0 functions. The most common peak F0 was 141 Hz. Almost all (98%) clusters phase locked diotically to an F0 of 50 Hz, and approximately 40% of clusters still phase locked significantly (Rayleigh coefficient >13.8) at the highest F0 tested (400 Hz). These results are consistent with the previous reports of responses to amplitude-modulated stimuli. Clusters phase locked significantly at a frequency equal to F0 for contralateral and diotic stimuli but at 2F0 for dichotic stimuli. We interpret these data as responses following the envelope periodicity in monaural channels rather than as a binaurally integrated representation.
doi:10.1007/s10162-008-0149-4
PMCID: PMC2644390  PMID: 19089495
pitch; unresolved harmonics; binaural; integration; alternating phase
9.  Contributions of Intrinsic Neural and Stimulus Variance to Binaural Sensitivity 
The discrimination of a change in a stimulus is determined both by the magnitude of that change and by the variability in the neural response to the stimulus. When the stimulus is itself noisy, then the relative contributions of the neural (intrinsic) and stimulus induced variability becomes a critical question. We measured the contribution of intrinsic neural noise and interstimulus variability to the discrimination of interaural time differences (ITDs) and interaural correlation (IAC). We measured discharge rate versus characteristic frequency (CF) tone ITD functions, and CF-centered narrowband noise ITD and IAC functions in interleaved blocks in the same units in the inferior colliculus of urethane-anesthetized guinea pigs. Ten “frozen” tokens of noise were synthesized and the responses to each token were separately analyzed to allow the relative contributions of intrinsic and stimulus variability to be assessed. ITD and IAC discrimination thresholds were determined for a simulated two-interval forced-choice experiment, based on the firing rate distributions, using receiver operating characteristic analysis. On average, between stimulus variability contributed 19% (range, 1.5–30%) of the variance in noise ITD discrimination and 27% (range, 3–50%) in IAC discrimination. Noise ITD thresholds were slightly higher than tone ITD thresholds. Taking the mean of the thresholds for individual noise tokens gave a similar result to pooling across all noise tokens. This implies that although the stimulus induced variability is measurable, it is insignificant in relation to the intrinsic noise in ITD and IAC discrimination.
doi:10.1007/s10162-006-0054-7
PMCID: PMC2504630  PMID: 17053864
binaural; discrimination; guinea pig; inferior colliculus; interaural correlation; jnd; interaural time difference (ITD); intrinsic variability; stimulus variability
10.  Sensitivity to Interaural Correlation of Single Neurons in the Inferior Colliculusof Guinea Pigs 
Sensitivity to changes in the interaural correlation of 50-ms bursts of narrowband or broadband noise was measured in single neurons in the inferior colliculus of urethane-anaesthetized guinea pigs. Rate vs. interaural correlation functions (rICFs) were measured using two methods. These methods compensated in different ways for the inherent variance in interaural correlation between tokens with the same expected correlation. The shape of all rICFs could be best described by power functions allowing them to be summarized by two parameters. Most rICFs were best fit by a power below 2, indicating that they were only slightly nonlinear. However, there were a few fitted functions that had a power of 3–6, indicating marked curvature. Modeling results indicate that the nonlinearity of the majority of rICFs was explicable in terms of the monaural transduction stages; however, some of the rICFs with power greater than 2 require either multiple inputs to the coincidence detector or additional nonlinearities to be included in the model. Discrimination thresholds were estimated at reference correlations of −1, 0, and +1 using receiver operating characteristic (ROC) analysis of the spike-count distribution at each correlation. Thresholds spanned the full possible range, from a minimum of 0.1 to the maximum possible of 2. Thresholds were generally highest with a reference correlation of −1, intermediate with a reference of 0, and lowest with a reference correlation of +1. Thresholds were lowest for the most steeply sloped rICFs, but thresholds were not strongly correlated to the spike rate variance. The lowest thresholds occurred using narrowband noise that was compensated for internal delays, but they were still about three times larger than human psychophysical thresholds measured using similar stimuli. The data suggest that, unlike pure tone interaural time difference, discrimination of a population measure is required to account for behavioral interaural correlation discrimination performance.
doi:10.1007/s10162-005-0005-8
PMCID: PMC2504597  PMID: 16080025
interaural correlation; jnd; discrimination threshold; inferior colliculus; guinea pig; binaural
11.  Onset Neurones in the Anteroventral Cochlear Nucleus Project to the Dorsal Cochlear Nucleus 
Considerable circumstantial evidence suggests that cells in the ventral cochlear nucleus, that respond predominantly to the onset of pure tone bursts, have a stellate morphology and project, among other places, to the dorsal cochlear nucleus. The characteristics of such cells make them leading candidates for providing the so-called “wideband inhibitory input” which is an essential part of the processing machinery of the dorsal cochlear nucleus. Here we use juxtacellular labeling with biocytin to demonstrate directly that large stellate cells, with onset responses, terminate profusely in the dorsal cochlear nucleus. They also provide widespread local innervation of the anteroventral cochlear nucleus and a small innervation of the posteroventral cochlear nucleus. In addition, some onset cells project to the contralateral dorsal cochlear nucleus.
doi:10.1007/s10162-003-4036-8
PMCID: PMC2538402  PMID: 15357418
stellate cells; anteroventral cochlear nucleus; dorsal cochlear nucleus; wideband inhibitor; onset responses
12.  Classification of frequency response areas in the inferior colliculus reveals continua not discrete classes 
The Journal of Physiology  2013;591(16):4003-4025.
A differential response to sound frequency is a fundamental property of auditory neurons. Frequency analysis in the cochlea gives rise to V-shaped tuning functions in auditory nerve fibres, but by the level of the inferior colliculus (IC), the midbrain nucleus of the auditory pathway, neuronal receptive fields display diverse shapes that reflect the interplay of excitation and inhibition. The origin and nature of these frequency receptive field types is still open to question. One proposed hypothesis is that the frequency response class of any given neuron in the IC is predominantly inherited from one of three major afferent pathways projecting to the IC, giving rise to three distinct receptive field classes. Here, we applied subjective classification, principal component analysis, cluster analysis, and other objective statistical measures, to a large population (2826) of frequency response areas from single neurons recorded in the IC of the anaesthetised guinea pig. Subjectively, we recognised seven frequency response classes (V-shaped, non-monotonic Vs, narrow, closed, tilt down, tilt up and double-peaked), that were represented at all frequencies. We could identify similar classes using our objective classification tools. Importantly, however, many neurons exhibited properties intermediate between these classes, and none of the objective methods used here showed evidence of discrete response classes. Thus receptive field shapes in the IC form continua rather than discrete classes, a finding consistent with the integration of afferent inputs in the generation of frequency response areas. The frequency disposition of inhibition in the response areas of some neurons suggests that across-frequency inputs originating at or below the level of the IC are involved in their generation.
doi:10.1113/jphysiol.2013.255943
PMCID: PMC3764642  PMID: 23753527
13.  Neural changes accompanying tinnitus following unilateral acoustic trauma in the guinea pig 
The European Journal of Neuroscience  2014;40(2):2427-2441.
Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise-exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates (SFRs) and burst firing in the inferior colliculus (IC), evoked auditory brainstem responses (ABRs), and the number of neurons in the cochlear nucleus containing nitric oxide synthase (NOS). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFRs and incidences of burst firing were elevated in the IC of all noise-exposed animals, but there were no differences between tinnitus and no-tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral–contralateral asymmetry in NOS staining in the ventral cochlear nucleus (VCN) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS-containing neurons on the noise-exposed side, whereas no-tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABRs supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus.
doi:10.1111/ejn.12580
PMCID: PMC4215599  PMID: 24702651
auditory; behaviour; electrophysiology; inferior colliculus; nitric oxide synthase

Results 1-13 (13)