Anatomy of superior olivary complex and lateral lemniscus in Etruscan shrew.

Based on the auditory periphery and the small head size, Etruscan shrews (Suncus etruscus) approximate ancestral mammalian conditions. The auditory brainstem in this insectivore has not been investigated. Using labelling techniques, we assessed the structures of their superior olivary complex (SOC) and the nuclei of the lateral lemniscus (NLL). There, we identified the position of the major nuclei, their input pattern, transmitter content, expression of calcium binding proteins (CaBPs) and two voltage-gated ion channels. The most prominent SOC structures were the medial nucleus of the trapezoid body (MNTB), the lateral nucleus of the trapezoid body (LNTB), the lateral superior olive (LSO) and the superior paraolivary nucleus (SPN). In the NLL, the ventral (VNLL), a specific ventrolateral VNLL (VNLLvl) cell population, the intermediate (INLL) and dorsal (DNLL) nucleus, as well as the inferior colliculus's central aspect were discerned. INLL and VNLL were clearly separated by the differential distribution of various marker proteins. Most labelled proteins showed expression patterns comparable to rodents. However, SPN neurons were glycinergic and not GABAergic and the overall CaBPs expression was low. Next to the characterisation of the Etruscan shrew's auditory brainstem, our work identifies conserved nuclei and indicates variable structures in a species that approximates ancestral conditions.

Medial superior olive in the rat: Anatomy, sources of input and axonal projections.

Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential aspect of binaural hearing: the ability of animals to localize the sources of low-frequency sounds by detecting the interaural time difference (ITD), that is the difference in the time at which the sound arrives at each ear. In mammals, ITDs are mostly encoded in the medial superior olive (MSO), one of the main nuclei of the superior olivary complex (SOC). Because of their small heads and high frequency hearing range, rats and mice are often considered unable to use ITDs for sound localization. Moreover, their MSO is frequently viewed as too small or insignificant compared to that of mammals that use ITDs to localize sounds, including cats and gerbils. However, recent research has demonstrated remarkable similarities between most morphological and physiological features of mouse MSO neurons and those of MSO neurons of mammals that use ITDs. In this context, we have analyzed the structure and neural afferent and efferent connections of the rat MSO, which had never been studied by injecting neuroanatomical tracers into the nucleus. The rat MSO spans the SOC longitudinally. It is relatively small caudally, but grows rostrally into a well-developed column of stacked bipolar neurons. By placing small, precise injections of the bidirectional tracer biotinylated dextran amine (BDA) into the MSO, we show that this nucleus is innervated mainly by the most ventral and rostral spherical bushy cells of the anteroventral cochlear nucleus of both sides, and by the most ventrolateral principal neurons of the ipsilateral medial nucleus of the trapezoid body. The same experiments reveal that the MSO densely innervates the most dorsolateral region of the central nucleus of the inferior colliculus, the central region of the dorsal nucleus of the lateral lemniscus, and the most lateral region of the intermediate nucleus of the lateral lemniscus of its own side. Therefore, the MSO is selectively innervated by, and sends projections to, neurons that process low-frequency sounds. The structural and hodological features of the rat MSO are notably similar to those of the MSO of cats and gerbils. While these similarities raise the question of what functions other than ITD coding the MSO performs, they also suggest that the rat MSO is an appropriate model for future MSO-centered research.

GABAB receptor-mediated modulation in the developing dorsal nucleus of the lateral lemniscus.

The dorsal nucleus of the lateral lemniscus (DNLL) is a GABAergic, reciprocally connected auditory brainstem structure that continues to develop postnatally in rodents. One key feature of the DNLL is the generation of a strong, prolonged, ionotropic, GABAA receptor-mediated inhibition. Possible GABAB receptor-mediated signalling is unexplored in the DNLL. Here, we used Mongolian gerbils of either sex to describe GABAB receptor-mediated modulation of postsynaptic potassium currents and synaptic inputs in postnatal (P) animals of days 10/11 and 23-28. Throughout development, we observed the presence of a Baclofen-activated GABAB receptor-enhanced potassium outward conductance that is capable of suppressing action potential generation. In P10/11, old gerbils GABAB receptor activation enhances glutamatergic and suppresses ionotropic GABAergic synaptic transmission. During development, this differential modulation becomes less distinct, because in P22-28, old animals Baclofen-activated GABAB receptors rather enhance ionotropic GABAergic synaptic transmission, whereas glutamatergic transmission is both enhanced and suppressed. Blocking GABAB receptors causes an increase in ionotropic GABAergic transmission in P10/11 old gerbils that was independent on stimulation frequency but depended on the type of short-term plasticity. Together with the lack of Baclofen-induced changes in the synaptic paired-pulse ratio of either input type, we suggest that GABAB receptor-mediated modulation is predominantly postsynaptic and activates different signalling cascades. Thus, we argue that in DNLL neurons, the GABAB receptor is a post-synaptically located signalling hub that alters signalling cascades during development for distinct targets.

Structural arrangement of auditory brainstem nuclei in the bats Phyllostomus discolor and Carollia perspicillata.

The structure of the mammalian auditory brainstem is evolutionarily highly plastic, and distinct nuclei arrange in a species-dependent manner. Such anatomical variability is present in the superior olivary complex (SOC) and the nuclei of the lateral lemniscus (LL). Due to the structure-function relationship in the auditory brainstem, the identification of individual nuclei supports the understanding of sound processing. Here, we comparatively describe the nucleus arrangement and the expression of functional markers in the auditory brainstem of the two bat species Phyllostomus discolor and Carollia perspicillata. Using immunofluorescent labeling, we describe the arrangement and identity of the SOC and LL nuclei based on the expression of synaptic markers (vesicular glutamate transporter 1 and glycine transporter 2), calcium-binding proteins, as well as the voltage-gated ion channel subunits Kv1.1 and HCN1. The distribution of excitatory and inhibitory synaptic labeling appears similar between both species and matches with that of other mammals. The detection of calcium-binding proteins indicates species-dependent differences and deviations from other mammals. Kv1.1 and HCN1 show largely the same expression pattern in both species, which diverges from other mammals, indicating functional adaptations in the cellular physiology of bat neurons.

Hearing abnormalities in multiple sclerosis: clinical semiology and pathophysiologic mechanisms.

Auditory manifestations from multiple sclerosis (MS) are not as common as the well-recognized sentinel exacerbations of optic neuritis, partial myelitis, motor weakness, vertiginous episodes, heat intolerance, and eye movement abnormalities. This paper discusses four cases of auditory changes, secondary to MS, and describes the first case, to our knowledge, of palinacousis, the perseveration of hearing, despite cessation of the sound stimulus. For each we characterize the initial complaint, the diagnostic work up, and ultimately, underscore the individualized treatment interventions, that allowed us to achieve a remission in all four cases. Individually codifying the treatment regimens served to mitigate, if not to abolish, the clinical derangements in hearing. Special attention is focused upon examination of the clinical manifestations and the pathophysiologic mechanisms which are responsible for them. We further emphasize the differential diagnostic considerations, and physical exam findings, along with the results of laboratory testing, neuro-imaging sequences, and lesion localization. Taken together, such information is germane to organizing cogently coherent strategic treatment plan(s). We believe that this small case series represents a clinically pragmatic example of 'precision medicine'; a principal theme and goal throughout this paper, the achievement of such in MS, but also as an illustration for the assessment and management schema for neuroimmunologic disorders in general.

Dopamine in Auditory Nuclei and Lemniscal Projections is Poised to Influence Acoustic Integration in the Inferior Colliculus.

Dopamine (DA) modulates the activity of nuclei within the ascending and descending auditory pathway. Previous studies have identified neurons and fibers in the inferior colliculus (IC) which are positively labeled for tyrosine hydroxylase (TH), a key enzyme in the synthesis of dopamine. However, the origins of the tyrosine hydroxylase positive projections to the inferior colliculus have not been fully explored. The lateral lemniscus (LL) provides a robust inhibitory projection to the inferior colliculus and plays a role in the temporal processing of sound. In the present study, immunoreactivity for tyrosine hydroxylase was examined in animals with and without 6-hydroxydopamine (6-OHDA) lesions. Lesioning, with 6-OHDA placed in the inferior colliculus, led to a significant reduction in tyrosine hydroxylase immuno-positive labeling in the lateral lemniscus and inferior colliculus. Immunolabeling for dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT), enzymes responsible for the synthesis of norepinephrine (NE) and epinephrine (E), respectively, were evaluated. Very little immunoreactivity for DBH and no immunoreactivity for PNMT was found within the cell bodies of the dorsal, intermediate, or ventral nucleus of the lateral lemniscus. The results indicate that catecholaminergic neurons of the lateral lemniscus are likely dopaminergic and not noradrenergic or adrenergic. Next, high-pressure liquid chromatography (HPLC) analysis was used to confirm that dopamine is present in the inferior colliculus and nuclei that send projections to the inferior colliculus, including the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus, and auditory cortex (AC). Finally, fluorogold, a retrograde tracer, was injected into the inferior colliculus of adult rats. Each subdivision of the lateral lemniscus contained fluorogold within the somata, with the dorsal nucleus of the lateral lemniscus showing the most robust projections to the inferior colliculus. Fluorogold-tyrosine hydroxylase colocalization within the lateral lemniscus was assessed. The dorsal and intermediate nuclei neurons exhibiting similar degrees of colocalization, while neurons of the ventral nucleus had significantly fewer colocalized fluorogold-tyrosine hydroxylase labeled neurons. These results suggest that several auditory nuclei that project to the inferior colliculus contain dopamine, dopaminergic neurons in the lateral lemniscus project to the inferior colliculus and that dopaminergic neurotransmission is poised to play a pivotal role in the function of the inferior colliculus.

Intrinsic properties of avian interaural level difference sound localizing neurons.

Intrinsic properties of neurons are one major determinant for how neurons respond to their synaptic inputs and shape their outputs in neural circuits. Here, we studied the intrinsic properties of neurons in the chicken posterior portion of the dorsal nucleus of the lateral lemniscus (LLDp), the first interaural level difference (ILD) encoder of the avian auditory pathway. Using whole-cell recordings in brain slices, we revealed that the LLDp is composed of a heterogeneous neuron population based on their firing patterns. LLDp neurons were broadly classified as either phasic or tonic firing neurons, with further classification applied to tonic firing neurons, such as regular (most dominant, n = 82 out of 125 cells, 65.6%), pauser, or adaptive firing. Neurons with different firing patterns were distributed about evenly across the dorsoventral as well as mediolateral axis of LLDp. Phasic firing neurons were of faster membrane time constant, and lower excitability than tonic firing neurons. The action potentials (APs) elicited at the current thresholds displayed significant differences in first spike latency, AP peak amplitude, half-width, and maximal rising and falling rates. Interestingly, for APs elicited at suprathreshold currents (400 pA above thresholds), some of the differences diminished while a few others emerged. Remarkably, most parameters of the APs at thresholds were significantly different from those of APs at suprathresholds. Combined with our previous study (Curry and Lu, 2016), the results lend support to the two-cell type model for ILD coding in the avian system.

Minimal Number of Required Inputs for Temporally Precise Action Potential Generation in Auditory Brainstem Nuclei.

The auditory system relies on temporal precise information transfer, requiring an interplay of synchronously activated inputs and rapid postsynaptic integration. During late postnatal development synaptic, biophysical, and morphological features change to enable mature auditory neurons to perform their appropriate function. How the number of minimal required input fibers and the relevant EPSC time course integrated for action potential generation changes during late postnatal development is unclear. To answer these questions, we used in vitro electrophysiology in auditory brainstem structures from pre-hearing onset and mature Mongolian gerbils of either sex. Synaptic and biophysical parameters changed distinctively during development in the medial nucleus of the trapezoid body (MNTB), the medial superior olive (MSO), and the ventral and dorsal nucleus of the lateral lemniscus (VNLL and DNLL). Despite a reduction in input resistance in most cell types, all required fewer inputs in the mature stage to drive action potentials. Moreover, the EPSC decay time constant is a good predictor of the EPSC time used for action potential generation in all nuclei but the VNLL. Only in MSO neurons, the full EPSC time course is integrated by the neuron's resistive element, while otherwise, the relevant EPSC time matches only 5-10% of the membrane time constant, indicating membrane charging as a dominant role for output generation. We conclude, that distinct developmental programs lead to a general increase in temporal precision and integration accuracy matched to the information relaying properties of the investigated nuclei.

Information Processing by Onset Neurons in the Cat Auditory Brainstem.

Octopus cells in the ventral cochlear nucleus (VCN) have been difficult to study because of the very features that distinguish them from other VCN neurons. We performed in vivo recordings in cats on well-isolated units, some of which were intracellularly labeled and histologically reconstructed. We found that responses to low-frequency tones with frequencies < 1 kHz reveal higher levels of neural synchrony and entrainment to the stimulus than the auditory nerve. In responses to higher frequency tones, the neural discharges occur mostly near the stimulus onset. These neurons also respond in a unique way to 100 % amplitude-modulated (AM) tones with discharges exhibiting a bandpass tuning. Responses to frequency-modulated sounds (FM) are unusual: Octopus cells react more vigorously during the ascending than the descending parts of the FM stimulus. We examined responses of neurons in the ventral nucleus of the lateral lemniscus (VNLL) whose discharges to tones and AM sounds are similar to octopus cells. Repeated stimulation with short tone pips of VCN and VNLL onset neurons evokes trains of action potentials with gradual shifts toward later times in their first spike latency. This behavior parallels short-term post-synaptic depression observed by other authors in in vitro VCN recordings of octopus cells. VCN and VNLL onset units in cats respond to frozen noise stimuli with gaps as narrow as 1 ms with a robust discharge near the stimulus onset following the gap. This finding suggests that VCN and VNLL onset cells play a role in gap detection, which is of great importance to speech perception.

Nicotinic acetylcholine receptor subunit α7-knockout mice exhibit degraded auditory temporal processing.

The CHRNA7 gene that encodes the α7-subunit of the nicotinic acetylcholine receptor (α7-nAChR) has been associated with some autism spectrum disorders and other neurodevelopmental conditions characterized, in part, by auditory and language impairment. These conditions may include auditory processing disorders that represent impaired timing of neural activity, often accompanied by problems understanding speech. Here, we measure timing properties of sound-evoked activity via the auditory brainstem response (ABR) of α7-nAChR knockout mice of both sexes and wild-type colony controls. We find a significant timing delay in evoked ABR signals that represents midbrain activity in knockouts. We also examine spike-timing properties of neurons in the inferior colliculus, a midbrain nucleus that exhibits high levels of α7-nAChR during development. We find delays of evoked responses along with degraded spiking precision in knockout animals. We find similar timing deficits in responses of neurons in the superior paraolivary nucleus and ventral nucleus of the lateral lemniscus, which are brainstem nuclei thought to shape temporal precision in the midbrain. In addition, we find that other measures of temporal acuity including forward masking and gap detection are impaired for knockout animals. We conclude that altered temporal processing at the level of the brainstem in α7-nAChR-deficient mice may contribute to degraded spike timing in the midbrain, which may underlie the observed timing delay in the ABR signals. Our findings are consistent with a role for the α7-nAChR in types of neurodevelopmental and auditory processing disorders and we identify potential neural targets for intervention.NEW & NOTEWORTHY Disrupted signaling via the α7-nicotinic acetylcholine receptor (α7-nAChR) is associated with neurodevelopmental disorders that include impaired auditory processing. The underlying causes of dysfunction are not known but a common feature is abnormal timing of neural activity. We examined temporal processing of α7-nAChR knockout mice and wild-type controls. We found degraded spike timing of neurons in knockout animals, which manifests at the level of the auditory brainstem and midbrain.

A Temporal Filter for Binaural Hearing Is Dynamically Adjusted by Sound Pressure Level.

In natural environments our auditory system is exposed to multiple and diverse signals of fluctuating amplitudes. Therefore, to detect, localize, and single out individual sounds the auditory system has to process and filter spectral and temporal information from both ears. It is known that the overall sound pressure level affects sensory signal transduction and therefore the temporal response pattern of auditory neurons. We hypothesize that the mammalian binaural system utilizes a dynamic mechanism to adjust the temporal filters in neuronal circuits to different overall sound pressure levels. Previous studies proposed an inhibitory mechanism generated by the reciprocally coupled dorsal nuclei of the lateral lemniscus (DNLL) as a temporal neuronal-network filter that suppresses rapid binaural fluctuations. Here we investigated the consequence of different sound levels on this filter during binaural processing. Our in vivo and in vitro electrophysiology in Mongolian gerbils shows that the integration of ascending excitation and contralateral inhibition defines the temporal properties of this inhibitory filter. The time course of this filter depends on the synaptic drive, which is modulated by the overall sound pressure level and N-methyl-D-aspartate receptor (NMDAR) signaling. In psychophysical experiments we tested the temporal perception of humans and show that detection and localization of two subsequent tones changes with the sound pressure level consistent with our physiological results. Together our data support the hypothesis that mammals dynamically adjust their time window for sound detection and localization within the binaural system in a sound level dependent manner.

Focal electrical stimulation of dorsal nucleus of the lateral lemniscus modulates auditory response properties of inferior collicular neurons in the albino mouse.

The inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from many bilateral lower auditory nuclei, intrinsic projections within IC, contralateral IC through the commissure of IC and from the auditory cortex (AC). These excitatory and inhibitory inputs from both ascending and descending auditory pathways contribute significantly to auditory response properties and temporal signal processing in IC. The present study examines the contribution of gamma-aminobutyric acid-ergic (GABAergic) inhibition of dorsal nucleus of the lateral lemniscus (DNLL) in influencing the response properties and amplitude sensitivity of contralateral IC neurons using focal electrical stimulation of contralateral DNLL and by the application of bicuculline to the recording site of modulated IC neurons. Focal electrical stimulation of contralateral DNLL produces inhibition (78.1%), facilitation (7.1%) or no effect (14.8%) in the number of spikes, firing duration and the first-spike latency of modulated IC neurons. The degree of modulation is inversely correlated to the difference in best frequency (BF) between electrically stimulated DNLL neurons and modulated IC neurons (p < 0.01). The application of bicuculline to the recording site of modulated IC neurons abolishes the inhibitory effect of focal electrical stimulation of DNLL neurons. DNLL inhibition also modulates the amplitude sensitivity of IC neurons by changing the dynamic range (DR) and the slope of rate-amplitude function (RAF) of modulated IC neurons. Possible biological significance of these findings in relation to auditory signal processing is discussed.

Relationship between auditory pathway fractional anisotropy and audibility in patients with cerebellopontine angle tumors on diffusion tensor imaging.

OBJECTIVE: Recent reports demonstrated that acoustic nerve disorders affect the auditory pathway on diffusion tensor imaging (DTI). The aim was to investigate whether auditory pathway fractional anisotropy (FA) values are associated with audibility in patients with cerebellopontine angle tumors. PATIENTS AND METHODS: Patients with cerebellopontine angle tumors were included in this retrospective study. Preoperatively, all patients underwent magnetic resonance imaging (MRI) including DTI. Two regions of interest on the lateral lemniscus (LL) and inferior colliculus (IC) were set bilaterally on DTI. FA values were calculated using software. Correlations between FA values and audibility were evaluated using Spearman's rank correlation coefficient. Statistical significance was defined as p < 0.05. RESULTS: Seventeen patients with cerebellopontine angle tumors were included in this study. FA values in the bilateral LL showed a significant negative correlation with hearing impairment severity (r = -0.758, -0.600, p < 0.05). FA values on the ipsilateral side of the IC showed a significant negative correlation with hearing impairment severity (r = -0.477, p < 0.05). FA values on the contralateral side of the IC did not correlate with hearing impairment severity (r = -0.201, p > 0.05). One patient with a low FA value on the contralateral side of the IC had postoperative hearing impairment despite good preoperative hearing ability. CONCLUSIONS: FA values in the bilateral LL and on the ipsilateral side of the IC reflected hearing impairment severity. Decreased FA values on the contralateral side of the IC might predict hearing impairment postoperatively.

Auditory Midbrain Hypoplasia and Dysmorphology after Prenatal Valproic Acid Exposure.

Prenatal exposure to the antiepileptic valproic acid (VPA) is associated with an increased risk of autism spectrum disorder (ASD) in humans and is used as an animal model of ASD. The majority of individuals with ASD exhibit adverse reactions to sensory stimuli and auditory dysfunction. Previous studies of animals exposed to VPA reveal abnormal neuronal responses to sound and mapping of sound frequency in the cerebral cortex and hyperactivation, hypoplasia and abnormal neuronal morphology in the cochlear nuclei (CN) and superior olivary complex (SOC). Herein, we examine the neuronal populations in the lateral lemniscus and inferior colliculus in animals exposed in utero to VPA. We used a combination of morphometric techniques, histochemistry and immunofluorescence to examine the nuclei of the lateral lemniscus (NLL) and the central nucleus of the inferior colliculus (CNIC). We found that the VPA exposure resulted in larger neurons in the CNIC and the dorsal nucleus of the lateral lemniscus (DNLL). However, we found that there were significantly fewer neurons throughout all nuclei examined in the auditory brainstem of VPA-exposed animals. Additionally, we found significantly fewer calbindin-immunopositive neurons in the DNLL. VPA exposure had no impact on the proportions of perineuronal nets in the NLL or CNIC. Finally, consistent with our observations in the CN and SOC, VPA exposure resulted in fewer dopaminergic terminals in the CNIC. Together, these results indicate that in utero VPA exposure significantly impacts structure and function of nearly the entire central auditory pathway.

The Role of the Dorsal Nucleus of the Lateral Lemniscus in Shaping the Auditory Response Properties of the Central Nucleus of the Inferior Collicular Neurons in the Albino Mouse.

In the ascending auditory pathway, the central nucleus of the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from many bilateral lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and from the auditory cortex. All these presynaptic excitatory and inhibitory inputs dynamically shape and modulate the auditory response properties of individual IC neurons. For this reason, acoustic response properties vary among individual IC neurons due to different activity pattern of presynaptic inputs. The present study examines modulation of auditory response properties of IC neurons by combining sound stimulation with focal electrical stimulation of the contralateral dorsal nucleus of the lateral lemniscus (referred to as ESDNLL) in the albino mouse. Brief ESDNLL produces variation (increase or decrease) in the number of impulses, response latency and discharge duration of modulated IC neurons. Additionally, 30-minute short-term ESDNLL alone produces variation in the best frequency (BF) and minimum threshold (MT) of modulated IC neurons. These varied response parameters recover in different manner and time course among individual modulated IC neurons. Possible pathways and neural mechanisms underlying these findings are discussed.

Value and mechanisms of EEG reactivity in the prognosis of patients with impaired consciousness: a systematic review.

BACKGROUND: Electroencephalography (EEG) is a well-established tool for assessing brain function that is available at the bedside in the intensive care unit (ICU). This review aims to discuss the relevance of electroencephalographic reactivity (EEG-R) in patients with impaired consciousness and to describe the neurophysiological mechanisms involved. METHODS: We conducted a systematic search of the term "EEG reactivity and coma" using the PubMed database. The search encompassed articles published from inception to March 2018 and produced 202 articles, of which 42 were deemed relevant, assessing the importance of EEG-R in relationship to outcomes in patients with impaired consciousness, and were therefore included in this review. RESULTS: Although definitions, characteristics and methods used to assess EEG-R are heterogeneous, several studies underline that a lack of EEG-R is associated with mortality and unfavorable outcome in patients with impaired consciousness. However, preserved EEG-R is linked to better odds of survival. Exploring EEG-R to nociceptive, auditory, and visual stimuli enables a noninvasive trimodal functional assessment of peripheral and central sensory ascending pathways that project to the brainstem, the thalamus and the cerebral cortex. A lack of EEG-R in patients with impaired consciousness may result from altered modulation of thalamocortical loop activity by afferent sensory input due to neural impairment. Assessing EEG-R is a valuable tool for the diagnosis and outcome prediction of severe brain dysfunction in critically ill patients. CONCLUSIONS: This review emphasizes that whatever the etiology, patients with impaired consciousness featuring a reactive electroencephalogram are more likely to have a favorable outcome, whereas those with a nonreactive electroencephalogram are prone to having an unfavorable outcome. EEG-R is therefore a valuable prognostic parameter and warrants a rigorous assessment. However, current assessment methods are heterogeneous, and no consensus exists. Standardization of stimulation and interpretation methods is needed.

Neural Processing of Acoustic and Electric Interaural Time Differences in Normal-Hearing Gerbils.

Bilateral cochlear implants (CIs) provide benefits for speech perception in noise and directional hearing, but users typically show poor sensitivity to interaural time differences (ITDs). Possible explanations for this deficit are deafness-induced degradations in neural ITD sensitivity, between-ear mismatches in electrode positions or activation sites, or differences in binaural brain circuits activated by electric versus acoustic stimulation. To identify potential limitations of electric ITD coding in the normal-hearing system, responses of single neurons in the dorsal nucleus of the lateral lemniscus and in the inferior colliculus to ITDs of electric (biphasic pulses) and acoustic (noise, clicks, chirps, and tones) stimuli were recorded in normal-hearing gerbils of either sex. To maintain acoustic sensitivity, electric stimuli were delivered to the round window. ITD tuning metrics (e.g., best ITD) and ITD discrimination thresholds for electric versus transient acoustic stimuli (clicks, chirps) obtained from the same neurons were not significantly correlated. Across populations of neurons with similar characteristic frequencies, however, ITD tuning metrics and ITD discrimination thresholds were similar for electric and acoustic stimuli and largely independent of the spectrotemporal properties of the acoustic stimuli when measured in the central range of ITDs. The similarity of acoustic and electric ITD coding on the population level in animals with normal hearing experience suggests that poorer ITD sensitivity in bilateral CI users compared with normal-hearing listeners is likely due to deprivation-induced changes in neural ITD coding rather than to differences in the binaural brain circuits involved in the processing of electric and acoustic ITDs.SIGNIFICANCE STATEMENT Small differences in the arrival time of sound at the two ears (interaural time differences, ITDs) provide important cues for speech understanding in noise and directional hearing. Deaf subjects with bilateral cochlear implants obtain only little benefit from ITDs. It is unclear whether these limitations are due to between-ear mismatches in activation sites, differences in binaural brain circuits activated by electric versus acoustic stimulation, or deafness-induced degradations in neural ITD processing. This study is the first to directly compare electric and acoustic ITD coding in neurons of known characteristic frequencies. In animals with normal hearing, populations of auditory brainstem and midbrain neurons demonstrate general similarities in electric and acoustic ITD coding, suggesting similar underlying central auditory processing mechanisms.

Electrogenic N-methyl-D-aspartate receptor signaling enhances binaural responses in the adult brainstem.

In sensory systems, the neuronal representation of external stimuli is enhanced along the sensory pathway. In the auditory system, strong enhancement of binaural information takes place between the brainstem and the midbrain; however, the underlying cellular mechanisms are unknown. Here we investigated the transformation of binaural information in the dorsal nucleus of the lateral lemniscus (DNLL), a nucleus that connects the binaural nuclei in the brainstem and the inferior colliculus in the midbrain. We used in vitro and in vivo electrophysiology in adult Mongolian gerbils to show that N-methyl-D-aspartate receptor (NMDARs) play a critical role in neuronal encoding of stimulus properties in the DNLL. While NMDARs increase firing rates, the timing and the accuracy of the neuronal responses remain unchanged. NMDAR-mediated excitation increases the information about the acoustic stimulus. Taken together, our results show that NMDARs in the DNLL enhance the auditory information content in adult mammal brainstem.

The Medial and Lateral Lemnisci: Anatomically Adjoined But Functionally Distinct Fiber Tracts.

OBJECTIVE: The dense and complex distribution of neural structures in the brainstem makes it challenging to understand their real configuration. We used the fiber microdissection technique to show the course of the medial and lateral lemnisci within the brainstem. Although these structures seem anatomically alike, they are functionally distinct. METHODS: Fifteen human brainstems and 8 brain hemispheres (formalin-fixed and previously frozen) were dissected and studied under the operating microscope by applying the fiber microdissection technique. RESULTS: We delineated and described the medial and lateral lemnisci, noting their gross elaborate arrangement. These structures are intimately compact and closely related to one another in their common trajectory through the tegmenta of the pons and midbrain. However, we were not able to identify the exact origin and termination of their fibers or the accurate delimitation between the medial lemniscus, spinothalamic tract, and lateral lemniscus along their course in the brainstem. CONCLUSIONS: Using the fiber microdissection technique, we were able to define a general perspective of the topography and architecture of the medial and lateral lemnisci in the brainstem. This perspective should be incorporated into interpretations of magnetic resonance imaging techniques, recognizing both their benefits and limitations. It should also be applied to surgical planning and strategies to achieve a safer and more precise microsurgical procedure.

Synaptic Inhibition in Avian Interaural Level Difference Sound Localizing Neurons.

Synaptic inhibition plays a fundamental role in the neural computation of the interaural level difference (ILD), an important cue for the localization of high-frequency sound. Here, we studied the inhibitory synaptic currents in the chicken posterior portion of the dorsal nucleus of the lateral lemniscus (LLDp), the first binaural level difference encoder of the avian auditory pathway. Using whole-cell recordings in brain slices, we provide the first evidence confirming a monosynaptic inhibition driven by direct electrical and chemical stimulation of the contralateral LLDp, establishing the reciprocal inhibitory connection between the two LLDps, a long-standing assumption in the field. This inhibition was largely mediated by GABAA receptors; however, functional glycine receptors were also identified. The reversal potential for the Cl- channels measured with gramicidin-perforated patch recordings was hyperpolarizing (-88 mV), corresponding to a low intracellular Cl- concentration (5.2 mm). Pharmacological manipulations of KCC2 (outwardly Cl- transporter) activity demonstrate that LLDp neurons can maintain a low intracellular Cl- concentration under a high Cl- load, allowing for the maintenance of hyperpolarizing inhibition. We further demonstrate that hyperpolarizing inhibition was more effective at regulating cellular excitability than depolarizing inhibition in LLDp neurons.