Joseph P. Walton

Age-Related Alteration in Processing of Temporal Sound Features in the Auditory Midbrain of the CBA Mouse

The perception of complex sounds, such as speech and animal vocalizations, requires the central auditory system to analyze rapid, ongoing fluctuations in sound frequency and intensity. A decline in temporal acuity has been identified as one component of age-related hearing loss. The detection of short, silent gaps is thought to reflect an important fundamental dimension of temporal resolution. In this study we compared the neural response elicited by silent gaps imbedded in noise of single neurons in the inferior colliculus (IC) of young and old CBA mice. IC neurons were classified by their temporal discharge patterns. Phasic units, which accounted for the majority of response types encountered, tended to have the shortest minimal gap thresholds (MGTs), regardless of age. We report three age-related changes in neural processing of silent gaps. First, although the shortest MGTs (1–2 msec) were observed in phasic units from both young and old animals, the number of neurons exhibiting the shortest MGTs was much lower in old mice, regardless of the presentation level. Second, in the majority of phasic units, recovery of response to the stimulus after the silent gap was of a lower magnitude and much slower in units from old mice. Finally, the neuronal map representing response latency versus best frequency was found to be altered in the old IC. These results demonstrate a central auditory system correlate for age-related decline in temporal processing at the level of the auditory midbrain.

Neural correlates of behavioral gap detection in the inferior colliculus of the young CBA mouse

Abstract The gap detection paradigm is frequently used in psychoacoustics to characterize the temporal acuity of the auditory system. Neural responses to silent gaps embedded in white-noise carriers, were obtained from mouse inferior colliculus (IC) neurons and the results compared to behavioral estimates of gap detection. Neural correlates of gap detection were obtained from 78 single neurons located in the central nucleus of the IC. Minimal gap thresholds (MGTs) were computed from single-unit gap functions and were found to be comparable, 1–2 ms, to the behavioral gap threshold (2 ms). There was no difference in MGTs for units in which both carrier intensities were collected. Single unit responses were classified based on temporal discharge patterns to steady-state noise bursts. Onset and primary-like units had the shortest mean MGTs (2.0 ms), followed by sustained units (4.0 ms) and phasic-off units (4.2 ms). The longest MGTs were obtained for inhibitory neurons (x¯ = 14 ms). Finally, the time-course of behavioral and neurophysiological gap functions were found to be in good agreement. The results of the present study indicate the neural code necessary for behavioral gap detection is present in the temporal discharge patterns of the majority of IC neurons.

Timing is everything: temporal processing deficits in the aged auditory brainstem.

This summary article reviews the literature on neural correlates of age-related changes in temporal processing in the auditory brainstem. Two types of temporal processing dimensions are considered, (i) static, which can be measured using a gap detection or forward masking paradigms, and (ii) dynamic, which can be measured using amplitude and frequency modulation. Corresponding data from physiological studies comparing neural responses from young and old animals using acoustic stimuli as silent gaps-in-noise, amplitude modulation, and frequency modulation are considered in relation to speech perception. Evidence from numerous investigations indicates an age-related decline in encoding of temporal sound features which may be a contributing factor to the deficits observed in speech recognition in many elderly listeners.

Behavioral and neural measures of auditory temporal acuity in aging humans and mice.

Three experiments compared auditory temporal acuity in humans and in the behavior and single cells in the inferior colliculus (IC) of mice, to establish the comparability of aging effects on temporal acuity across species, and to suggest a neural foundation. The thresholds for silent gaps placed in white noise (MGTs) were similar in young mice and young humans, and increased in some but not all old humans and old mice. Neural MGT in the most sensitive cells of both young and old mice was comparable to behavioral MGT in the young of both species, but older mice had more cells with very high MGT. Human listeners were selected to have minimal absolute hearing loss. Older mice had significant hearing loss that was correlated with MGT in behavioral, but not in neural, measures. Some old mice and some old IC cells, however, had low MGTs coupled with elevated absolute hearing thresholds. Age-related changes in temporal acuity appear comparable in humans and mice. The data suggest a common deficit in neural mechanisms.

Neural processing of musical timbre by musicians, nonmusicians, and musicians possessing absolute pitch.

Cognitive event-related potentials (ERPs) were measured during a timbre discrimination task from three subject groups varying in musical experience. The P3 component of the ERP was recorded from musicians with absolute pitch, musicians without absolute pitch, and nonmusicians during a task comprising timbres of varying difficulty. The three-timbre series, all of which consisted of the same pitch, were (1) string instruments in the same family (cello and viola), (2) flutes made of different materials (silver and wood), and (3) instruments of slightly different size (B-flat versus F tubas). The amplitude and latency of the P3 component varied systematically as a function of musical experience and type of timbre discrimination. The difficult timbre task resulted in mean P3 amplitudes which were larger for musicians relative to nonmusicians, however P3 amplitudes were similar for the two additional timbre series. The mean P3 latencies for musicians were shorter when compared to nonmusicians across all three series. In comparison, the AP subjects displayed the shortest mean P3 latencies, but had smaller P3 amplitudes relative to both musicians and nonmusicians. The implications of these findings suggest that perceptual tasks involving one of the fundamental building blocks of music, namely timbre, does elicit differential brain activity from memory or information processing systems from subjects with varying degrees of musical training.

Age-related structural and functional changes in the cochlear nucleus

Presbycusis - age-related hearing loss - is a key communication disorder and chronic medical condition of our aged population. The cochlear nucleus is the major site of projections from the auditory portion of the inner ear. Relative to other levels of the peripheral and central auditory systems, relatively few studies have been conducted examining age-related changes in the cochlear nucleus. The neurophysiological investigations suggest declines in glycine-mediated inhibition, reflected in increased firing rates in cochlear nucleus neurons from old animals relative to young adults. Biochemical investigations of glycine inhibition in the cochlear nucleus are consistent with the functional aging declines of this inhibitory neurotransmitter system that affect complex sound processing. Anatomical reductions in neurons of the cochlear nucleus and their output pathways can occur due to aging changes in the brain, as well as due to age-dependent plasticity of the cochlear nucleus in response to the age-related loss of inputs from the cochlea, particularly from the basal, high-frequency regions. Novel preventative and curative biomedical interventions in the future aimed at alleviating the hearing loss that comes with age, will likely emanate from increasing our knowledge and understanding of its neural and molecular bases. To the extent that this sensory deficit resides in the central auditory system, including the cochlear nucleus, future neural therapies will be able to improve hearing in the elderly.

Lead exposure during development results in increased neurofilament phosphorylation, neuritic beading, and temporal processing deficits within the murine auditory brainstem

Low‐level lead (Pb) exposure is a risk factor for learning disabilities, attention deficit hyperactivity disorder (ADHD), and other neurological dysfunction. It is not known how Pb produces these behavioral deficits, but low‐level exposure during development is associated with auditory temporal processing deficits in an avian model, while hearing thresholds remain normal. Similar auditory processing deficits are found in children with learning disabilities and ADHD. To identify cellular changes underlying this functional deficit, Pb‐induced alterations of neurons and glia within the mammalian auditory brainstem nuclei were quantified in control and Pb‐exposed mice at postnatal day 21 by using immunohistochemistry, Western blotting, and 2D gel electrophoresis. Pb‐treated mice were exposed to either 0.1 mM (low) or 2 mM (high) Pb acetate throughout gestation and through 21 days postnatally. Pb exposure results in little change in glial proteins such as glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or F4/80 as determined by Western blot analysis and immunohistochemistry. In contrast, Pb exposure alters neuronal structural proteins by inducing increased phosphorylation of both the medium (NFM) and high‐weight (NFH) forms of neurofilament within auditory brainstem nuclei. Axons immunolabeled for neurofilament protein show neuritic beading following Pb exposure both in vivo and in vitro, suggesting that Pb exposure also impairs axonal transport. Functional assessment shows no significant loss of peripheral function, but does reveal impairments in brainstem conduction time and temporal processing within the brainstem. These results provide evidence that Pb exposure during development alters axonal structure and function within brainstem auditory nuclei. J. Comp. Neurol. 506:1003–1017, 2008.

39 – Auditory Temporal Processing during Aging

This chapter presents results of a thematic interdisciplinary approach to characterizing and determining the neural bases of presbycusis. Research audiology, psychoacoustics, behavior and experimental psychology, neuroimaging and neurology, single-cell neurophysiology, neuroanatomy and neurochemistry, and evoked potential neurophysiology contributed to cross-project experiments in humans and animals. By using psychoacoustic and evoked potential neurophysiological paradigms such as forward and backward masking (gaps), interstimulus intervals and rates, and by manipulating naturally occurring pauses and voice-onset times in speech, we were able to gain insights into age-related slowing of central nervous system timing mechanisms. The peripheral auditory system with its extensive bank of filters is responsible for the spectral analysis of simple and complex environmental sounds. Thus, inner ear dysfunction is characterized principally and initially by deficiencies in frequency analysis and sensitivity. In contrast, most sounds, and especially suprathreshold complex sounds such as speech, vary over time. Therefore, measures of temporal resolution that can reflect the integrity of the central auditory system have become especially useful in our research seeking to determine the effects of age, per se, on hearing. Here we present results of our temporal resolution research utilizing human and animal subjects aimed at determining neural sites of hearing loss due to aging. This chapter also reinforces how findings from animal models can assist in understanding the human condition and thus lead to future interventions.

Synaptic loss in the central nucleus of the inferior colliculus correlates with sensorineural hearing loss in the C57BL/6 mouse model of presbycusis

Between 3 and 25 months of age, light and electron microscopic features of principal neurons in the central nucleus of the inferior colliculus of the C57BL/6 mouse were quantitated. This mouse strain has a genetic defect producing progressive sensorineural hearing loss which starts during young adulthood (2 months of age) with high-frequency sounds. During the second year of life, hearing is severely impaired, progressively involving all frequencies. The hearing loss was documented in the present study by auditory brainstem recordings of the mice at various ages. The cochleas from many of the same animals showed massive loss of both inner and outer hair cells beginning at the base (high-frequency region) and progressing with age along the entire length to the apex (low-frequency region). In the inferior colliculi, there was a significant decrease in the size of principal neurons in the central nucleus. There was a dramatic decrease in the number of synapses of all morphologic types on principal neuronal somas. The percentage of somatic membrane covered by synapses decreased by 67%. A ventral (high frequency) to dorsal (low frequency) gradient of synaptic loss could not be identified within the central nucleus. These synaptic changes may be related to the equally dramatic physiologic changes which have been noted in the central nucleus of the inferior colliculus, in which response properties of neurons normally sensitive to high-frequency sounds become more sensitive to low-frequency sounds. The synaptic loss noted in this study may be due to more than the loss of primary afferent pathways. It may represent alterations of the complex synaptic circuitry related to the central deficits of presbycusis.

Effects of Musical Training and Absolute Pitch on the Neural Processing of Melodic Intervals: A P3 Event-Related Potential Study

During perceptual tasks involving the discrimination of musical intervals, event-related potentials, specifically the P3, were measured for three subject groups: musicians without absolute pitch, musicians with absolute pitch, and nonmusicians. The two interval-discrimination tasks were a simple two-note contour task and a difficult interval-size discrimination task. Clear effects on the neural waveforms were found for both training and the presence of the absolute pitch ability. In general, training increases the amplitude and shortens the latency of the P3, while the absolute pitch ability reduces the amplitude and shortens the latency, or eliminates the P3 altogether. The absolute pitch effect may be due to the use of a long-term memory strategy involved in the correct performance of the discrimination task rather than performing the task by updating working memory each time a target occurs. Finally, these data are contrasted with those from studies involving sine tones and timbrediscrimination tasks.