Gregg Recanzone - US grants

sensory disorders; nervous system; deafness; hearing; ear; Mammalia;

sensory disorders; nervous system; deafness; hearing; ear; Mammalia;

DESCRIPTION (Adapted from Applicant's abstract): The long term objectives of this research program are to elucidate the cortical contributions to spatial perception. The experiments of this proposal specifically address the cortical processing of visual, auditory, and combined visual and auditory stimuli in the primate. The visual system strongly modulates the perception of spatially and temporally disparate visual and auditory stimuli. Under some circumstances, for example when spatial and temporal disparities are small, visual stimuli are able to 'capture' the perceived location of auditory stimuli, giving rise to a unified percept of the multi-stimulus object. Under different circumstances, for example when the spatial and temporal disparities are large, the visual system is not able to capture the perceived location of the auditory stimulus, and therefore the percept is of two distinct objects. Although these perceptual illusions have been known and studied extensively, the neural basis of these perceptions is currently poorly understood. Neurons throughout the cerebral cortex and the superior colliculus have been described to respond to more than one stimulus modality. However, how these poly-sensory neurons contribute to spatial perception of multi-modal stimuli is also unclear. This is due largely to the lack of investigation of these neural responses with respect to the spatial perceptions elicited by them. A clearer understanding of how the different stimulus attributes of real world objects are integrated by the central nervous system, and ultimately process information that result in a unified percept of the real world, is critical to our understanding of the cortical mechanisms of sensory processing in general. These experiments will directly address the neuronal mechanisms of spatial perception of multi-modal stimuli by taking advantage of the interactions between visual and auditory stimuli in these perceptions. Single neuron activity will be defined under conditions where visual and auditory stimuli are simultaneously presented from the same location, as well as under conditions where the two stimulus modalities are disparate in space and/or time. These neuronal responses will be correlated with the resulting perception of the stimulus location. By using stimulus disparities that lead to both unified percepts of single bi-sensory objects, as well as perceptions of two distinct locations, a direct relationship between the neuronal activity and perception can be derived. These experiments will therefore directly address this fundamental process of sensory perception.

[unreadable] DESCRIPTION (provided by applicant): In real world situations, objects and event comprise multiple stimulus attributes. They emit or reflect light, make sounds, and have characteristic mass and tactile properties. While the nervous system initially processes each sensory modality independently by transducing a restricted portion of energy by specialized receptors, this information is ultimately combined at higher stations of the nervous system to generate unified percepts. Even though this is a fundamental process of sensory systems, very little is understood how information from different sensory systems is combined, and how this integrations results in the perception of single objects and events. One way in which the processes of multi-sensory integration can be explored is to compare the responses of single neurons to the perceptions generated by combined sensory stimuli. By comparing the neuronal responses between the physical stimuli and the resulting perceptions, one can begin to elucidate the underlying neuronal mechanisms of that perception. One can further test these hypotheses by taking advantage of stimuli that generate faulty perceptions, i.e. illusions. The goals of this research project are to explore how single neurons in the cerebral cortex combine visual and auditory information. Specifically, we wish to determine if multi-sensory stimuli are processed in regions of the cerebral cortex that are traditionally considered to be 'unimodal', or if multi-sensory integration does not occur until the traditionally considered 'multi-modal' areas. We will use combined auditory and visual stimuli that generate perceptual illusions in both the temporal and spatial domain to explore where neurons respond best to the physical characteristics of the stimuli (such as in the sensory receptors) and where neurons respond best to the resulting perceptions that we all experience. By tracking these responses throughout the cortical hierarchy we will begin to understand how and where these integrative processes take place. These insights will provide a cornerstone for understanding complex perceptions and cognitive ability. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Hearing deficits are the third leading cause of disability in the aged. Over half of all people in the US over seventy suffer some form of age-related hearing deficits. This is a ubiquitous problem with many sources, and the peripheral contributions to age-related deficits, particularly high frequency hearing loss, have been explored and have revealed several important features of these disorders. However, there remains relatively little understood about the consequences of age-related hearing loss and normal aging on central auditory structures, particularly the neocortex, and how age-related changes in either anatomical or physiological processes in central structures give rise to perceptual deficits. Our lack of understanding of these central effects is due in large part to the lack of an effective animal model that (1) shares many organizational features of auditory cortex with humans, (2) has a reasonably long life span such that age-related hearing deficits progress over the course of several years as in the human, and (3) are not prohibitively expensive. I have a unique opportunity to develop such an animal model as I have access to a large geriatric colony of macaque monkeys that satisfy these three criteria. The goals of this proposal are to determine which auditory cortical response properties are most influenced by normal aging and age-related hearing loss. Two normal young animals, two older animals with age- related high frequency hearing loss, and two older age-matched animals without age-related hearing loss will be used in these experiments. Spectral, spatial, and temporal response properties of single neurons in primary and secondary auditory cortical fields will be defined in each, monkey. Comparisons between neurons in different monkeys, as well as in auditory cortical fields that have been reorganized due to the high frequency hearing loss, will be compared to determine which aspects of auditory information processing are most susceptible to aging and age-related hearing loss. The results of this study will provide the foundation for future research programs aimed at the development of remedial treatments and therapies, as well as in hearing aid design, for individuals suffering from age-related hearing deficits. [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this project is to study the cortical correlates of auditory and visual integration in the spatial and temporal domains.

DESCRIPTION (provided by applicant): Hearing deficits are the third leading cause of disability in the aged. Over half of all people in the US over seventy suffer some form of age-related hearing deficits. This is a ubiquitous problem with many sources, and the peripheral contributions to age-related deficits, particularly high frequency hearing loss, have been explored and have revealed several important features of these disorders. However, there remains relatively little understood about the consequences of age-related hearing loss and normal aging on central auditory structures, particularly the neocortex, and how age-related changes in either anatomical or physiological processes in central structures give rise to perceptual deficits. Our lack of understanding of these central effects is due in large part to the lack of an effective animal model that (1) shares many organizational features of auditory cortex with humans, (2) has a reasonably long life span such that age-related hearing deficits progress over the course of several years as in the human, and (3) are not prohibitively expensive. The goals of this proposal are to fill this gap by correlating hearing deficits related to either age or hearing loss with single neuron activity in core and belt areas of auditory cortex as well as the perceptual abilities and the cochlear morphology of the same individuals. Experimental groups will include young animals with no hearing loss, young animals with hearing loss, geriatric animals with minimal hearing loss and geriatric animals with hearing loss. Animals will be trained on spatial and temporal discrimination tasks and cortical activity will be directly correlated with this behavioral performance, hearing thresholds, and cochlear morphology. Comparisons between neurons in different animals, as well as in auditory cortical fields that have been reorganized due to the high frequency hearing loss, will be compared to determine which aspects of auditory information processing are most susceptible to aging and age-related hearing loss. The results of this study are a critical step in the development of new remedial treatments and therapies, as well as in hearing aid design, for individuals suffering from age-related hearing deficits.

DESCRIPTION (provided by applicant): Selective auditory attention allows individuals to selectively attend to a dining companion's voice in a loud, noisy restaurant or toward the location of different musicians in a band. Attentional dysfunction is one of the hallmarks of human aging. Indeed, whereas aging's effect on hearing can often be characterized by changes in the audiogram, nearly half of all humans over 75 years of age suffer from dysfunction in perceptual and cognitive components of audition, such as selective auditory attention, even in cases where the audiogram is normal. These deficits lead to social isolation, depression, and other types of cognitive dysfunction. The neural mechanisms underlying auditory attention, the causal role that different brain areas play in attention, and the effect that aging has on attentio are not known. In the auditory system, stimuli are hypothesized to be processed by two cortical pathways: (1) a dorsal pathway from the auditory cortex to the prefrontal cortex (dPFC) that mediates spatial components of audition and (2) an analogous ventral pathway that mediates non-spatial components of audition in adjacent regions of the prefrontal cortex (vPFC). This anatomical segregation leads us to our hypothesis that the PFC is a major participant in the top-down control of selectively attending to different auditory features (spatial and non-spatial. Further, we also hypothesize that natural aging reduces the effectiveness of this top-down control, giving rise to age-related auditory attention deficits. Aim #1 tests the causal role of th PFC in auditory attention. Young adult animals participate in a spatial or non-spatial auditory attention task while either the vPFC or the dPFC is selectively inactivated by cortical cooling. We hypothesize that inactivation of the dorsal pathway will cause selective behavioral deficits on the spatial task, whereas inactivation of the ventral pathway will cause selective behavioral deficits on the non-spatial task. Aim #2 tests the effect of aging on auditory attention by comparing the results of cortical cooling in young vs. aged animals. We hypothesize that, in the geriatric monkeys, the ability of directed attention to improve behavioral performance will be impaired relative to young adult monkeys. Second, we hypothesize that the PFC activity in geriatric monkeys is diminished and, as a consequence, inactivation of either pathway will impair performance less in geriatric monkeys relative to younger adult monkeys. These results will provide the foundation of knowledge necessary to develop remedial therapies to limit or reverse attention deficits in the aged.

? DESCRIPTION (provided by applicant): The ability to process complex sounds is critical for identifying and localizing most real-world objects and events, understanding speech, and producing and appreciating music. Individuals with hearing deficits can be devastated by this dysfunction which can leave them socially isolated, depressed, and even suicidal. Some forms of hearing deficits are the result of problems in the auditory periphery, in which case hearing aids and cochlear implants can be beneficial. However, these interventions have limited if any effect for those with hearing deficits due to central causes, such as strokes, brain injury, and especially natural aging. Unfortunately there are currently no established remedial therapies or treatments for hearing deficits that are caused by central dysfunction. Similarly, attention to auditory stimuli is critical for the perception of those features, although we again have very litte understanding of the neural mechanisms of these attentional influences. A better understanding of the normal cortical processes that underlie auditory perception and selective auditory attention is necessary to develop effective treatments for centrally-mediated hearing deficits. Previous research has indicated that the primate auditory cortex processes spatial and non-spatial (temporal) information independently. Specifically, it is believed that in the lateral belt auditory cortex, the anterolateral field (AL) processes temporal information while the caudolateral field (CL) processes spatial information, with the middle-lateral field (ML) processing both features in an intermediate way. To date, however, there has been no direct evidence that the activity of neurons in the lateral belt is correlated with the perception of temporal or spatial acoustic features. In the proposed study we will record single neuron activity in the lateral belt while non-human subjects attend to and actively discriminate the temporal or spatial features of identical acoustic stimuli. We will use psychophysical tasks that will engage feature-based attention in order to determine how top-down attention influences the activity of cortical neurons believed to be processing the different acoustic features, and the subject's perception of those features. These results will provide the first direct test, at the single neuro level, of the long- held hypothesis that the primate auditory cortex is composed of at least two parallel processing streams. They will also provide the first investigation of how top-down attention influences neuronal activity in the auditory cortex at the single neuron level. These experiments will distinguish between two competing hypotheses: whether attentional effects are global across auditory cortical areas regardless of which acoustic feature is being attended vs the attentional effects are selective to only those neurons processing the attended acoustic feature. Finally, these results will also provide the first test of whether attention mechanisms in the auditory system fit into the current framework of top- down attentional influences on single neuron activity that are largely based on a plethora of studies in the visual cortex.

PROJECT SUMMARY/ABSTRACT Age-related hearing loss is a ubiquitous problem, estimated to affect up to one third of the population. This condition is much more detrimental than ?hard of hearing?, rather, it has been implicated in a host of co-morbidities such as cognitive deficits, and other mental illness. It remains unclear if this is a cause and effect situation or an epiphenomenon. If the former, simple interventions may well lead to much better mental health among the elderly. The long-term goal of the proposed research program is to identify the neural coding principles that allow listeners to make sense of, and focus on, particular sounds (i.e. what you are listening to) when they occur mixed with other sounds (i.e. the background), something that is common in many listening situations. Although this is an extremely difficult computational problem, people with normal hearing solve it effortlessly. Unfortunately, this remarkable ability almost always declines with age, leaving individuals struggling to understand speech in noisy environments. In order to develop assistive technologies or therapies to restore this critical function, we need to understand how the brain processes sounds in complex acoustic scenes, and, in particular, exactly how it fails to do so in aged individuals. Age-related shifts in the coding strategy employed at different stages of the auditory pathway are believed to involve compensatory changes related to attenuated input from more peripheral stages, and recent research in older animals has demonstrated quantitative and qualitative changes in central neural representation of complex sounds. Crucially, these changes appear to involve changes in how information is transformed along the cortical hierarchy. For this reason, a rigorous study of the effects of age-related hearing loss must include a comparison of cortical areas, such as core versus belt, that function at different levels of the processing hierarchy in normal hearing. Moreover, these central changes impact not only ?bottom-up? sound processing along the ascending auditory pathway, but also ?top-down? modulation by attention. The proposed studies will therefore contrast how complex sounds in challenging listening environments are processed in young versus old animals while those animals are performing perceptual tasks that either do or do not require auditory attention. These studies will be the first to track changes in how multiple complex sounds are encoded across hierarchical levels of processing in the auditory pathway in a primate model of aging, while allowing direct comparisons between cortical response changes and auditory perceptual deficits.