Isofrequency Laminae Research Articles

Imaging Voltage Globally and in Isofrequency Lamina in Slices of Mouse Ventral Cochlear Nucleus.

The cochlear nuclei (CNs) receive sensory information from the ear and perform fundamental computations before relaying this information to higher processing centers. These computations are performed by distinct types of neurons interconnected in circuits dedicated to the specialized roles of the auditory system. In the present study, we explored the use of voltage imaging to investigate CN circuitry. We tested two approaches based on fundamentally different voltage sensing technologies. Using a voltage-sensitive dye we recorded glutamate receptor-independent signals arising predominantly from axons. The mean conduction velocity of these fibers of 0.27 m/s was rapid but in range with other unmyelinated axons. We then used a genetically-encoded hybrid voltage sensor (hVOS) to image voltage from a specific population of neurons. Probe expression was controlled using Cre recombinase linked to c-fos activation. This activity-induced gene enabled targeting of neurons that are activated when a mouse hears a pure 15-kHz tone. In CN slices from these animals auditory nerve fiber stimulation elicited a glutamate receptor-dependent depolarization in hVOS probe-labeled neurons. These cells resided within a band corresponding to an isofrequency lamina, and responded with a high degree of synchrony. In contrast to the axonal origin of voltage-sensitive dye signals, hVOS signals represent predominantly postsynaptic responses. The introduction of voltage imaging to the CN creates the opportunity to investigate auditory processing circuitry in populations of neurons targeted on the basis of their genetic identity and their roles in sensory processing.

Developmental spontaneous activity promotes formation of sensory domains, frequency tuning and proper gain in central auditory circuits.

Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective suppression of cochlear supporting cell spontaneous activity disrupts patterned burst firing of central auditory neurons without affecting cell survival or acoustic thresholds. However, neurons in the inferior colliculus of these mice exhibit enhanced acoustic sensitivity and broader frequency tuning, resulting in wider isofrequency laminae. Despite this enhanced neural responsiveness, total tone-responsive regions in the auditory cortex are substantially smaller. Thus, disruption of pre-hearing cochlear activity causes profound changes in neural encoding of sound, with important implications for restoration of hearing in individuals who experience reduced activity during this critical developmental period.

Slicing the Embryonic Chicken Auditory Brainstem to Evaluate Tonotopic Gradients and Microcircuits

The chicken embryo is a widely accepted animal model to study the auditory brainstem, composed of highly specialized microcircuitry and neuronal topology differentially oriented along a tonotopic (i.e., frequency) axis. The tonotopic axis permits the segregated encoding of high-frequency sounds in the rostral-medial plane and low-frequency encoding in caudo-lateral regions. Traditionally, coronal brainstem slices of embryonic tissue permit the study of relative individual iso-frequency lamina. Although sufficient to investigate anatomical and physiological questions pertaining to individual iso-frequency regions, the study of tonotopic variation and its development across larger auditory brainstem areas is somewhat limited. This protocol reports brainstem slicing techniques from chicken embryos that encompass larger gradients of frequency regions in the lower auditory brainstem. The utilization of different slicing methods for chicken auditory brainstem tissue permits electrophysiological and anatomical experiments within one brainstem slice, where larger gradients of tonotopic properties and developmental trajectories are better preserved than coronal sections. Multiple slicing techniques allow for improved investigation of the diverse anatomical, biophysical, and tonotopic properties of auditory brainstem microcircuits.

Slicing the Embryonic Chicken Auditory Brainstem to Evaluate Tonotopic Gradients and Microcircuits.

The chicken embryo is a widely accepted animal model to study the auditory brainstem, composed of highly specialized microcircuitry and neuronal topology differentially oriented along a tonotopic (i.e., frequency) axis. The tonotopic axis permits the segregated encoding of high-frequency sounds in the rostral-medial plane and low-frequency encoding in caudo-lateral regions. Traditionally, coronal brainstem slices of embryonic tissue permit the study of relative individual iso-frequency lamina. Although sufficient to investigate anatomical and physiological questions pertaining to individual iso-frequency regions, the study of tonotopic variation and its development across larger auditory brainstem areas is somewhat limited. This protocol reports brainstem slicing techniques from chicken embryos that encompass larger gradients of frequency regions in the lower auditory brainstem. The utilization of different slicing methods for chicken auditory brainstem tissue permits electrophysiological and anatomical experiments within one brainstem slice, where larger gradients of tonotopic properties and developmental trajectories are better preserved than coronal sections. Multiple slicing techniques allow for improved investigation of the diverse anatomical, biophysical, and tonotopic properties of auditory brainstem microcircuits.

Local targets of T-stellate cells in the ventral cochlear nucleus.

T‐stellate cells in the ventral cochlear nucleus (VCN) are known to have local axon collaterals that terminate in the vicinity of their dendrites and cell bodies within the same isofrequency lamina in parallel with the auditory nerve fibers that innervate them. Excitatory synaptic connections between stellate cells within an isofrequency lamina are hypothesized to be involved in the nitric oxide‐mediated upregulation of T‐stellate responses to their auditory input. This could serve as a mechanism of variable gain control in the enhancement of responses to vowel spectral peaks. Previous studies have provided indirect evidence for these possible synaptic interconnections between T‐stellate cells, but unequivocal identification has yet to be established. Here, we used retrograde neuronal tracing with adeno‐associated viral vector or biotinylated dextran amine injected into the inferior colliculus (IC) to detect the postsynaptic target of T‐stellate cells within the VCN. We show that backfilled T‐stellate cell axons make monosynapatic connections on the labeled cell bodies and dendrites of other labeled T‐stellate cells within an isofrequency lamina. Electron microscopy revealed that T‐stellate terminals can also make synapses on structures not retrogradely labeled from the IC. Glycine antibodies combined with the viral labeling indicated that these nonbackfilled structures that the labeled T‐stellate terminals were synapsing on are most likely the cell bodies and dendrites of two size categories of glycinergic VCN cells, whose sizes and relative numbers indicated they are the D‐ and L‐stellate cells. These cells are known to provide inhibitory inputs back onto T‐stellate cells. Our data indicate that, in addition to their auditory nerve input, T‐stellate cells provide a second modulatable excitatory input to both inhibitory and excitatory cells in a VCN isofrequency lamina and may play a significant role in acoustic information processing.

Neuropeptide Y Expression Defines a Novel Class of GABAergic Projection Neuron in the Inferior Colliculus.

Located in the midbrain, the inferior colliculus (IC) integrates information from numerous auditory nuclei and is an important hub for sound processing. Despite its importance, little is known about the molecular identity and functional roles of defined neuron types in the IC. Using a multifaceted approach in mice of both sexes, we found that neuropeptide Y (NPY) expression identifies a major class of inhibitory neurons, accounting for approximately one-third of GABAergic neurons in the IC. Retrograde tracing showed that NPY neurons are principal neurons that can project to the medial geniculate nucleus. In brain slice recordings, many NPY neurons fired spontaneously, suggesting that NPY neurons may drive tonic inhibition onto postsynaptic targets. Morphologic reconstructions showed that NPY neurons are stellate cells, and the dendrites of NPY neurons in the tonotopically organized central nucleus of the IC cross isofrequency laminae. Immunostaining confirmed that NPY neurons express NPY, and we therefore hypothesized that NPY signaling regulates activity in the IC. In crosses between Npy1rcre and Ai14 Cre-reporter mice, we found that NPY Y1 receptor (Y1R)-expressing neurons are glutamatergic and were broadly distributed throughout the rostrocaudal extent of the IC. In whole-cell recordings, application of a high-affinity Y1R agonist led to hyperpolarization in most Y1R-expressing IC neurons. Thus, NPY neurons represent a novel class of inhibitory principal neurons that are well poised to use GABAergic and NPY signaling to regulate the excitability of circuits in the IC and auditory thalamus.SIGNIFICANCE STATEMENT The identification of neuron types is a fundamental question in neuroscience. In the inferior colliculus (IC), the hub of the central auditory pathway, molecular markers for distinct classes of inhibitory neurons have remained unknown. We found that neuropeptide Y (NPY) expression identifies a class of GABAergic principal neurons that constitute one-third of the inhibitory neurons in the IC. NPY neurons fire spontaneously, have a stellate morphology, and project to the auditory thalamus. Additionally, we found that NPY signaling hyperpolarized the membrane potential of a subset of excitatory IC neurons that express the NPY Y1 receptor. Thus, NPY neurons are a novel class of inhibitory neurons that use GABA and NPY signaling to regulate activity in the IC and auditory thalamus.

Nitric Oxide-Mediated Plasticity of Interconnections Between T-Stellate cells of the Ventral Cochlear Nucleus Generate Positive Feedback and Constitute a Central Gain Control in the Auditory System.

T-stellate cells in the ventral cochlear nucleus (VCN) form an ascending pathway that conveys spectral information from the cochlea to brainstem nuclei, the inferior colliculi, and the thalamus. The tonotopic array of T-stellate cells enhances the encoding of spectral peaks relative to their auditory nerve fiber inputs. The alignment of local collaterals and T-stellate cell dendrites within the isofrequency lamina suggests that the cells make connections within the isofrequency lamina in which they reside. Recordings from pairs of T-stellate cells in mice of both sexes revealed that firing in the presynaptic cell evoked responses in the postsynaptic cell when presynaptic firing was paired with depolarization of the postsynaptic cell. After such experimental coactivation, presynaptic firing evoked EPSCs of uniform amplitude whose frequency depended on the duration of depolarization and diminished over minutes. Nitric oxide (NO) donors evoked EPSCs in T-stellate cells but not in the other types of principal cells. Blockers of neuronal nitric oxide synthase (nNOS) and of NMDA receptors blocked potentiation, indicating that NO mediates potentiation. nNOS and its receptor, guanylate cyclase (NO-GC), are expressed in somata of T-stellate cells. Excitatory interconnections were bidirectional and polysynaptic, indicating that T-stellate cells connect in networks. Positive feedback provided by temporarily potentiated interconnections between T-stellate cells could enhance the gain of auditory nerve excitation in proportion to the excitation, generating a form of short-term central gain control that could account for the ability of T-stellate cells to enhance the encoding of spectral peaks.SIGNIFICANCE STATEMENT T-stellate cells are interconnected through synapses that have a previously undescribed form of temporary, nitric oxide-mediated plasticity. Coactivation of neighboring cells enhances the activation of an excitatory network that feeds back on itself by enhancing the probability of EPSCs. Although there remain gaps in our understanding of how the interconnections revealed in slices contribute to hearing, our findings have interesting implications. Positive feedback through a network of interconnections could account for how T-stellate cells are able to encode spectral peaks over a wider range of intensities than many of their auditory nerve inputs (Blackburn and Sachs, 1990; May et al., 1998). The magnitude of the gain may itself be plastic because neuronal nitric oxide synthase increases when animals have tinnitus (Coomber et al., 2015).

Descending and tonotopic projection patterns from the auditory cortex to the inferior colliculus

The inferior colliculus (IC) receives many corticofugal projections, which can mediate plastic changes such as shifts in frequency tuning or excitability of IC neurons. While the densest projections are found in the IC’s external cortices, fibers originating from the primary auditory cortex (AI) have been observed throughout the IC’s central nucleus (ICC), and these projections have shown to be organized tonotopically. Some studies have also found projections from other core and non-core cortical regions, though the organization and function of these projections are less known. In guinea pig, there exists a non-core ventrorostral belt (VRB) region that has primary-like properties and has often been mistaken for AI, with the clearest differentiating characteristic being VRB’s longer response latencies. To better understand the auditory corticofugal descending system beyond AI, we investigated if there are projections from VRB to the ICC and if they exhibit a different projection pattern than those from AI. In this study, we performed experiments in ketamine-anesthetized guinea pigs, in which we positioned 32-site electrode arrays within AI, VRB, and ICC. We identified the monosynaptic connections between AI-to-ICC and VRB-to-ICC using an antidromic stimulation method, and we analyzed their locations across the midbrain using three-dimensional histological techniques. Compared to the corticocollicular projections to the ICC from AI, there were fewer projections to the ICC from VRB, and these projections had a weaker tonotopic organization. The majority of VRB projections were observed in the caudal–medial versus the rostral–lateral region along an isofrequency lamina of the ICC, which is in contrast to the AI projections that were scattered throughout an ICC lamina. These findings suggest that the VRB directly modulates sound information within the ascending lemniscal pathway with a different or complementary role compared to the modulatory effects of AI, which may have implications for treating hearing disorders.

Effects of location and timing of co-activated neurons in the auditory midbrain on cortical activity: implications for a new central auditory prosthesis

Objective. An increasing number of deaf individuals are being implanted with central auditory prostheses, but their performance has generally been poorer than for cochlear implant users. The goal of this study is to investigate stimulation strategies for improving hearing performance with a new auditory midbrain implant (AMI). Previous studies have shown that repeated electrical stimulation of a single site in each isofrequency lamina of the central nucleus of the inferior colliculus (ICC) causes strong suppressive effects in elicited responses within the primary auditory cortex (A1). Here we investigate if improved cortical activity can be achieved by co-activating neurons with different timing and locations across an ICC lamina and if this cortical activity varies across A1. Approach. We electrically stimulated two sites at different locations across an isofrequency ICC lamina using varying delays in ketamine-anesthetized guinea pigs. We recorded and analyzed spike activity and local field potentials across different layers and locations of A1. Results. Co-activating two sites within an isofrequency lamina with short inter-pulse intervals (<5 ms) could elicit cortical activity that is enhanced beyond a linear summation of activity elicited by the individual sites. A significantly greater extent of normalized cortical activity was observed for stimulation of the rostral–lateral region of an ICC lamina compared to the caudal–medial region. We did not identify any location trends across A1, but the most cortical enhancement was observed in supragranular layers, suggesting further integration of the stimuli through the cortical layers. Significance. The topographic organization identified by this study provides further evidence for the presence of functional zones across an ICC lamina with locations consistent with those identified by previous studies. Clinically, these results suggest that co-activating different neural populations in the rostral–lateral ICC rather than the caudal–medial ICC using the AMI may improve or elicit different types of hearing capabilities.

Predicting neural responses to natural sound in the auditory brainstem

The inferior colliculus is the main processing station in the auditory midbrain and integrates projections from nearly all ascending brainstem nuclei. Apart from being a converging station, the central nucleus of the inferior colliculus (ICC) is essential for extracting time-varying spectrotemporal information [1] and therefore might be important for processing complex sounds such as speech and vocalizations. The ICC has been the target for a human auditory prosthesis [2], which might benefit from model predictions of the neural response in the ICC to incoming sound. Natural sounds such as speech and vocalizations, which display a wide spectrum of acoustic properties, such as harmonics, correlations, amplitude and frequency modulations and are very well suited to study the auditory system. This study is based on several sets of multi-unit activity recorded simultaneously from 32 sites in the contralateral ICC of guinea pigs while acoustically presenting a diverse set of conspecific vocalizations to the right ear. Recordings were taken either along the tonotopic gradient using double-shank electrodes or within iso-frequency lamina using double-tetrode electrodes. We investigated predictive power of several models of temporal responses in the ICC to vocalizations and artificial sound. The tested models include 1) a modified version of the physiologically detailed Meddis Model [4], which was altered in order to match spiking threshold in the guinea pig ICC and to include adaptation effects and output the trial-averaged spiking responses, the peri-stimulus time histograms (PSTH). 2) a generalized linear model and 3) a filtering model with a bandpass filter of 1/3 octaves around the best frequency, with subsequent normalization and rectification for each unit, followed by spatial filtering for nearby units. Predictive power was evaluated by means of the correlation value of the envelope of the PSTHs from the predicted and the experimentally obtained responses. We find that our relatively simple, filtering approach yields surprisingly good overlap of predicted and measured responses for some multi-units, but has poor predictive power for other units. The models (1-2) yield overall better overlap for the whole set of vocalizations but do not perform optimally in predicting the temporal course of the response. Our findings indicate distributions of optimal predictive power in the inferior colliculus over a large best frequency range across and within isofrequency laminae.

Response features across the auditory midbrain reveal an organization consistent with a dual lemniscal pathway.

The central auditory system has traditionally been divided into lemniscal and nonlemniscal pathways leading from the midbrain through the thalamus to the cortex. This view has served as an organizing principle for studying, modeling, and understanding the encoding of sound within the brain. However, there is evidence that the lemniscal pathway could be further divided into at least two subpathways, each potentially coding for sound in different ways. We investigated whether such an interpretation is supported by the spatial distribution of response features in the central nucleus of the inferior colliculus (ICC), the part of the auditory midbrain assigned to the lemniscal pathway. We recorded responses to pure tone stimuli in the ICC of ketamine-xylazine-anesthetized guinea pigs and used three-dimensional brain reconstruction techniques to map the location of the recording sites. Compared with neurons in caudal-and-medial regions within an isofrequency lamina of the ICC, neurons in rostral-and-lateral regions responded with shorter first-spike latencies with less spiking jitter, shorter durations of spiking responses, a higher proportion of spikes occurring near the onset of the stimulus, lower thresholds, and larger local field potentials with shorter latencies. Further analysis revealed two distinct clusters of response features located in either the caudal-and-medial or the rostral-and-lateral parts of the isofrequency laminae of the ICC. Thus we report substantial differences in coding properties in two regions of the ICC that are consistent with the hypothesis that the lemniscal pathway is made up of at least two distinct subpathways from the midbrain up to the cortex.

Multi-unit response correlations along the tonotopic gradient and within isofrequency laminae of the inferior colliculus

Within the central auditory system, the central nucleus of the inferior colliculus (ICC) is a station where all stimulus information converges. Furthermore, it is a target for auditory prostheses due to its tonotopic order and surgical accessibility [1]. To better understand the functional organization of this important nucleus, response similarity along the frequency gradient and within iso-frequency laminae were investigated. Furthermore, the neural discrimination was compared between pooled simultaneous and non-simultaneous responses. Vocalizations, being natural stimuli and showing a variety of spectral and temporal modulations, are particularly interesting and can elicit responses which are not triggered by pure tones, clicks, white noise or other artificial simplified sounds [2]. Conspecific vocalizations (at intensity levels of 30-70 db) were presented monaurally to guinea pigs while recording multi-unit activity from the contralateral ICC. Data were simultaneously recorded from 32 positions either along the tonotopic gradient using double shank electrodes or within two iso-frequency lamina using double tetrode electrodes. We investigated response similarity along these two dimensions of the ICC for multi-unit thresholded spike trains, local field potentials and voltage traces. We evaluated the correlation dependencies of multi-unit pairs on their spatial distance, difference in best-frequency and similarity of the frequency tuning curves. The presence of a distributed code would imply that the interplay of several multi-units leads to better representation of the complex sound. We have tested this by comparing neural discrimination between pooled sets of simultaneously recorded responses to non-simultaneously recorded ones. The latter was obtained by randomly shuffling the trials. We used linear discriminant analysis for the classification. The extracted features were firing rates of time windows over the duration of the longest vocalizations. We found that the averaged correlation of single spike-trains is much lower than correlation of poststimulus time histograms (PSTH). This is partly due to the high trial-trial variability which is averaged out in the PSTHs. Correlation decreases with distance ( 'μm' and 'best frequency') along the tonotopic gradient, see Figure ​Figure1.1. Within an iso-frequency lamina though it does not decrease with μm-distance. This redundancy within the iso-frequency laminae but not along the tonotopic gradient has implications for arrays to electrically stimulate the ICC. Figure 1 Correlation for multi-units along the tonotopic gradient versus logarithmically scaled difference in best frequency. Correlation decreases with BF-distance. There is no significant difference in neural discrimination performance for simultaneous and non-simultaneous responses which could be found from the multi-unit responses.

Neural integration and enhancement from the inferior colliculus up to different layers of auditory cortex

While the cochlear implant has successfully restored hearing to many deaf patients, it cannot benefit those without a functional auditory nerve or an implantable cochlea. As an alternative, the auditory midbrain implant (AMI) has been developed and implanted into deaf patients. Consisting of a single-shank array, the AMI is designed for stimulation along the tonotopic gradient of the inferior colliculus (ICC). Although the AMI can provide frequency cues, it appears to insufficiently transmit temporal cues for speech understanding because repeated stimulation of a single site causes strong suppressive and refractory effects. Applying the electrical stimulation to at least two sites within an isofrequency lamina can circumvent these refractory processes. Moreover, coactivation with short intersite delays (<5 ms) can elicit cortical activation which is enhanced beyond the summation of activity induced by the individual sites. The goal of our study was to further investigate the role of the auditory cortex in this enhancement effect. In guinea pigs, we electrically stimulated two locations within an ICC lamina or along different laminae with varying interpulse intervals (0-10 ms) and recorded activity in different locations and layers of primary auditory cortex (A1). Our findings reveal a neural mechanism that integrates activity only from neurons located within the same ICC lamina for short spiking intervals (<6 ms). This mechanism leads to enhanced activity into layers III-V of A1 that is further magnified in supragranular layers. This integration mechanism may contribute to perceptual coding of different sound features that are relevant for improving AMI performance.

3D model of frequency representation in the cochlear nucleus of the CBA/J mouse.

The relationship between structure and function is an invaluable context with which to explore biological mechanisms of normal and dysfunctional hearing. The systematic and topographic representation of frequency originates at the cochlea, and is retained throughout much of the central auditory system. The cochlear nucleus (CN), which initiates all ascending auditory pathways, represents an essential link for understanding frequency organization. A model of the CN that maps frequency representation in 3D would facilitate investigations of possible frequency specializations and pathologic changes that disturb frequency organization. Toward this goal, we reconstructed in 3D the trajectories of labeled auditory nerve (AN) fibers following multiunit recordings and dye injections in the anteroventral CN of the CBA/J mouse. We observed that each injection produced a continuous sheet of labeled AN fibers. Individual cases were normalized to a template using 3D alignment procedures that revealed a systematic and tonotopic arrangement of AN fibers in each subdivision with a clear indication of isofrequency laminae. The combined dataset was used to mathematically derive a 3D quantitative map of frequency organization throughout the entire volume of the CN. This model, available online (http://3D.ryugolab.com/), can serve as a tool for quantitatively testing hypotheses concerning frequency and location in the CN.

Tonotopic and localized pathways from primary auditory cortex to the central nucleus of the inferior colliculus

Descending projections from the cortex to subcortical structures are critical for auditory plasticity, including the ability for central neurons to adjust their frequency tuning to relevant and meaningful stimuli. We show that focal electrical stimulation of primary auditory cortex in guinea pigs produces excitatory responses in the central nucleus of the inferior colliculus (CNIC) with two tonotopic patterns: a narrow tuned pattern that is consistent with previous findings showing direct frequency-aligned projections; and a broad tuned pattern in which the auditory cortex can influence multiple frequency regions. Moreover, excitatory responses could be elicited in the caudomedial portion along the isofrequency laminae of the CNIC but not in the rostrolateral portion. This descending organization may underlie or contribute to the ability of the auditory cortex to induce changes in frequency tuning of subcortical neurons as shown extensively in previous studies.

Classification of vocalizations by recordings from the auditory midbrain

The temporal and spatial properties of responses to complex stimuli in the central nucleus of the inferior colliculus (ICC), the main converging station in the auditory midbrain, can provide evidence for coding principles in the auditory system and are relevant for the design of neuroprosthesis. We study responses from guinea pigs to a set of eleven species-specific vocalizations which show a wide range of spectral contents, envelope types, frequency and amplitude modulations. The envelopes of the acoustically presented stimuli are characterized as complex or periodic impulses and have various degrees of periodicity. The frequency content ranges from harmonic strucutres to broad spectral distributions. The data analyzed were multi-unit recordings taken simultaneously from 32 positions in the ICC of guinea pigs using a double shank electrode. Peristimulus time histograms (PSTHs) of the high dimensional recordings were classified by linear discriminant analysis in order to evaluate the spatial and temporal distribution of stimulus-related information without the assumption of a specific coding scheme. Neighboring neural populations respond in a similar manner and have highly correlated PSTHs. Combining responses from different positions improves the classification performance for distant postions which do not show correlation, but not for adjacent positions. Separability of responses along the tonotopic gradient of the ICC to vocalizations shows great variation according to their spectral properties. Low-frequency stimuli are found to be better separable in low characteristic frequency (CF) lamina than complex envelope or broad spectral stimuli. Some stimuli of the latter type (squeal, whistle) are nearly perfectly discriminated in multi-units with high CF whereas discrimination for low-frequency stimuli is less good (60 - 70 %) in this region, see Figure ​Figure1.1. For multi-units positioned in the mid-frequency range along the tonotopic axis all stimuli can be separated at a level similar to the result obtained in the low/high CF regions for the respective preferred stimuli. Figure 1 Confusion matrix for the classification of neural responses to periodic low-frequency stimuli (low chutter, drr) and complex-envelope broad-spectrum stimuli (squeal, low whistle) for a multi-unit in an iso-frequency lamina with a characteristic frequency ... We interpret the results as a consequence of the combination of several frequencies in the vocalizations that are better covered by the widely tuned receptive fields of the neurons in the mid-frequency range than by the receptive fields of the units with CFs in the extreme frequency ranges.

Coactivation of different neurons within an isofrequency lamina of the inferior colliculus elicits enhanced auditory cortical activation

The phenomenal success of the cochlear implant (CI) is attributed to its ability to provide sufficient temporal and spectral cues for speech understanding. Unfortunately, the CI is ineffective for those without a functional auditory nerve or an implantable cochlea required for CI implementation. As an alternative, our group developed and implanted in deaf patients a new auditory midbrain implant (AMI) to stimulate the central nucleus of the inferior colliculus (ICC). Although the AMI can provide frequency cues, it appears to insufficiently transmit temporal cues for speech understanding. The three-dimensional ICC consists of two-dimensional isofrequency laminae. The single-shank AMI only stimulates one site in any given ICC lamina and does not exhibit enhanced activity (i.e., louder percepts or lower thresholds) for repeated pulses on the same site with intervals <2-5 ms, as occurs for CI pulse or acoustic click stimulation. This enhanced activation, related to short-term temporal integration, is important for tracking the rapid temporal fluctuations of a speech signal. Therefore, we investigated the effects of coactivation of different regions within an ICC lamina on primary auditory cortex activity in ketamine-anesthetized guinea pigs. Interestingly, our findings reveal an enhancement mechanism for integrating converging inputs from an ICC lamina on a fast scale (<6-ms window) that is compromised when stimulating just a single ICC location. Coactivation of two ICC regions also reduces the strong and long-term (>100 ms) suppressive effects induced by repeated stimulation of just a single location. Improving AMI performance may require at least two shanks implanted along the tonotopic gradient of the ICC that enables coactivation of multiple regions along an ICC lamina with the appropriate interstimulus delays.

Inferior colliculus responses to dual-site intralamina stimulation in the ventral cochlear nucleus

A major limitation of the present auditory brainstem implant (ABI) is its inability to access the tonotopic organization of the ventral cochlear nucleus (VCN). A previous study by our group indicated that stimulation of single sites within a given VCN frequency region did not always elicit frequency-specific responses within the central nucleus of the inferior colliculus (CIC) and in some cases did not elicit a response at all. For this study, we hypothesized that sequential stimulation (with a short interpulse delay of 320 μsec) of two VCN sites in similar frequency regions would enhance responsiveness in CIC neurons. Multiunit neural recordings in response to pure tones were obtained at 58 VCN and 164 CIC sites in anesthetized rats. Among the 58 VCN sites, 39 pairs of sites with similar characteristic frequencies were chosen for electrical stimulation. Each member of a VCN pair was electrically stimulated individually, followed by sequential stimulation of the pair, while recording CIC responses. On average, CIC sites were found to respond to dual-site VCN stimulation with significantly lower thresholds, wider dynamic ranges, a greater extent of activation with increasing current levels, and a higher degree of frequency specificity compared with single-site stimulation. Although these effects were positive for the most part, in some cases dual-site stimulation resulted in increased CIC thresholds and decreased dynamic ranges, extent of activation, and frequency specificity. The results suggest that multisite stimulation within VCN isofrequency laminae using penetrating electrodes could significantly improve ABI stimulation strategies and implant performance.

Spectral and Temporal Modulation Tradeoff in the Inferior Colliculus

The cochlea encodes sounds through frequency-selective channels that exhibit low-pass modulation sensitivity. Unlike the cochlea, neurons in the auditory midbrain are tuned for spectral and temporal modulations found in natural sounds, yet the role of this transformation is not known. We report a distinct tradeoff in modulation sensitivity and tuning that is topographically ordered within the central nucleus of the inferior colliculus (CNIC). Spectrotemporal receptive fields (STRFs) were obtained with 16-channel electrodes inserted orthogonal to the isofrequency lamina. Surprisingly, temporal and spectral characteristics exhibited an opposing relationship along the tonotopic axis. For low best frequencies (BFs), units were selective for fast temporal and broad spectral modulations. A systematic progression was observed toward slower temporal and finer spectral modulation sensitivity at high BF. This tradeoff was strongly reflected in the arrangement of excitation and inhibition and, consequently, in the modulation tuning characteristics. Comparisons with auditory nerve fibers show that these trends oppose the pattern imposed by the peripheral filters. These results suggest that spectrotemporal preferences are reordered within the tonotopic axis of the CNIC. This topographic organization has profound implications for the coding of spectrotemporal features in natural sounds and could underlie a number of perceptual phenomena.

Cytoarchitecture of the human superior olivary complex: Medial and lateral superior olive

The superior olivary complex is a group of brainstem nuclei involved in hearing and includes the medial superior olive (MSO) and the lateral superior olive (LSO), surrounded by periolivary cell groups. The structure and functional roles of the MSO and LSO have been the subject of many investigations in laboratory animals and it has largely been assumed that these findings are directly transferable to humans. However, little is known conclusively regarding the detailed organization of the human superior olivary complex. The goal of this study is to provide a detailed analysis of the cytoarchitecture of the human MSO and LSO. Results from the examination of eight human brainstems confirm the existence of a conserved MSO and provide evidence of a prominent and highly ordered LSO. Unbiased stereological estimates of neuronal number indicate approximately 15,500 neurons in the MSO and 5600 neurons in the LSO. Additionally, a three-dimensional model of the MSO and LSO was constructed and provides evidence that the human LSO is composed of medial and lateral segments. Finally, an analysis of neuronal morphology, in Nissl stained and Golgi impregnated tissue, provides evidence of multiple neuronal classes within each nucleus and further that these neurons demonstrate a precise geometric arrangement (depending on the nucleus) that is suggestive of isofrequency laminae.