Ramnarayan Ramachandran - US grants

DESCRIPTION (provided by applicant): The basic functional of the auditory system is to allow listeners to detect signals in quiet as well as noisy environments. The ability to detect sounds in noisy environments is compromised in the elderly and the hearing impaired. The representation of signals in noisy environments in the brain is enhanced by feedback connections, which are not fully functional in anesthetized and decerebrate preparations but are in the awake and behaving condition. The goal of this project is to study the representation of signals in quiet and noisy environments in awake and behaving primates. Primates are the choice for this study due to their phylogenetic similarity with humans, as well as the similarity of the primate and human brainstem, which are different from other mammals. Previous studies in cats have shown that the representation of signals in noise can be correlated with receptive field organization and response properties. If sustained noise causes degradation of signal representation, then rapid adaptation to noise would enhance representation, and basic response properties used to characterize a unit may be a good predictor of signal representation quality in noise. This project proposes to test these hypotheses by recoding single unit responses in the cochlear nucleus and inferior colliculus in awake and behaving primates, whose efferent systems are intact and functional. Overall, this study will help determine some of the mechanisms that preserve our ability to hear in high levels of noise.

DESCRIPTION (provided by applicant): The basic function of the auditory system is to allow listeners to detect signals. This needs to happen in both quiet and noisy environments. The ability to detect sounds in noisy environments is compromised in the elderly and the hearing impaired, even with assistive hearing devices. The goal of this project is to determine the neuronal mechanisms in the cochlear nucleus (CN) and inferior colliculus (IC) of primates that mediate detection in quiet and noisy environments. Detection in noise depends on auditory efferent pathways that are fully functional only in awake and behaving organisms. Primates are the choice for this study due to their phylogenetic similarity with humans, as well as the similarity of the primate and human brainstem, which are different from other mammals. Studies in auditory and other sensory system have shown that responses to signals in noise are enhanced by inhibitory influences that suppress the effects of the noise while allowing the signal response to be expressed. Local processing within the IC increases the inhibition, specially wideband inhibition, which cancels the responses to noise while maintaining responses to signals, and mediating detection, thereby rendering ICC responses better related to IC responses than CN. This project proposes to test these hypotheses by recoding single unit responses in the cochlear nucleus and inferior colliculus in awake and behaving primates, and relating them to simultaneously measured behavioral responses. Overall, this study will help determine some of the mechanisms that allow us to detect and perceive sounds in natural environments. PUBLIC HEALTH RELEVANCE: Experiments described in this proposal are designed to investigate the neurophysiological responses to sounds in noise, and their correlation with simultaneously measured detection performance in awake and behaving primates. These studies will lay the foundation for future studies investigating the response changes in the auditory system after hearing loss, and for those investigating the neurophysiological basis of acoustical scene analysis. Finally, evaluation of response properties and the correlations between neurons and behavior at two connected sub-cortical areas will allow us a better understanding of sub-cortical circuitry in the auditory system, and signal processing strategies used by the brain in general, and will help in the design and placement of sub-cortical assistive hearing implants.

DESCRIPTION (provided by applicant): In the natural environment, the brain is often confronted with the daunting task of interpreting auditory signals that occur in the presence of noise, which can render important auditory events ambiguous and less salient. However, in naturalistic circumstances these auditory cues are typically accompanied by visual information, often from the same events. The presence of such coincident audiovisual cues can greatly amplify the salience of a stimulus of interest. However, although a number of studies have illustrated the behavioral and perceptual benefits of having multisensory (e.g., audiovisual) cues available, and a growing literature on the neural encoding processes that characterize multisensory interactions, very few studies have been able to link multisensory neural changes to their behavioral and perceptual correlates. To more firmly establish these links, we will train rhesus monkeys to detect or localize a target sound (signal), and ignore ongoing or simultaneously occurring non-target sounds (noise). The spatial and temporal relationships between the signal and noise will be varied, to evaluate their effects on how well the monkey detects or localizes the signal. Similar experiments will be performed with the addition of visual stimuli, whose location and/or timing will be varied such that it sometimes matches that of the signal, and sometimes that of the noise. This will allow us to assess the effects of non-auditory (visual) stimuli on auditory behavioral performance and allow us to evaluate brain mechanisms of multisensory integration. Neurophysiological recordings of neurons in the inferior and superior colliculi are expected to reveal their differential role in auditory and audiovisual detection and localization behaviors. The translational and clinical relevance of this work is very high for the hearing impaired and the elderly, in that auditory assistive devices often perform poorly in noisy environments. Greater knowledge of how the brain processes auditory signals within noise, and how visual information can enhance neural and behavior performance in complex environments, will be of great utility for the design of better technologies to deal with hearing loss and its profound impact on quality of life.

ABSTRACT Noise-induced hearing loss affects more than 25 million adults, with the majority of these cases suspected to be the result of exposure to environmental sounds. Importantly, some humans with no overt indications of hearing loss have extraordinary difficulty processing speech in noisy environments, but only recently has a potential explanation emerged. Noise exposure at sound pressure levels that cause a temporary threshold shift but no permanent threshold shift results in a loss of ribbon synapses (synaptopathy) without any hair cell loss, and a reduction in the amplitude of auditory brainstem response (ABR) Wave I. Low spontaneous rate (LSR) auditory nerve fibers (ANFs) seem particularly susceptible to this loss. While these effects are well described in rodents, it is not clear that they occur in humans. It is impossible to demonstrate synaptopathy directly in humans. We propose to bridge this gap by performing parallel experiments in humans and an animal model that shares great similarity, both anatomically and mechanistically, with humans: macaques. Our recently developed macaque model of synaptopathy shares some features with the established rodent model, but also reveals differences in susceptibility, which may also be present in other primates such as humans. We propose parallel experiments in control and noise-exposed macaques (without and with synaptopathy, respectively) and in two groups of humans with normal hearing thresholds: a control group and a noise-exposed human cohort. Our overarching hypothesis is that synaptopathy caused by noise exposure impairs temporal processing, resulting in deficits in physiological (Aim1) and behavioral (Aims 2) metrics of suprathreshold stimulus processing, and these deficits will be correlated with the amount of synaptopathy, which will be verified by histology and ANF recordings in macaques (Aim 3). We predict that physiological measures of processes that involve LSR fibers (including coding of modulation in suprathreshold sounds and masked sounds, middle ear muscle reflexes, and recovery from forward masking) will be impaired in subjects with synaptopathy relative to normal subjects (Aim 1). We predict that behaviors that require temporal cues to process simple stimuli (detection of amplitude modulation, suprathreshold masked detection, forward masking thresholds, and the contribution of temporal cues to the detection of suprathreshold tones in noise) and complex stimuli (speech-in-noise and spatial-attention tasks, and release from masking) will be impaired in subjects with synaptopathy (Aim 2). The synaptopathy will be histologically verified and its ANF correlates (loss of LSR fibers) verified directly in macaques (Aim 3). The results of these studies will reveal sensitive physiological and behavioral markers of synaptopathy, validated by histological and neurophysiological findings in macaques. These parallel studies in humans and macaques will elucidate the functional consequences of synaptopathy on auditory perception. Results of our coordinated research program will be used to develop reliable, clinically viable physiological and behavioral indicators of human synaptopathy.