Elevated Acoustic Startle Responses in Humans: Relationship to Reduced Loudness Discomfort Level, but not Self-Report of Hyperacusis.

Increases in the acoustic startle response (ASR) of animals have been reported following experimental manipulations to induce tinnitus, an auditory disorder defined by phantom perception of sound. The increases in ASR have been proposed to signify the development of hyperacusis, a clinical condition defined by intolerance of normally tolerable sound levels. To test this proposal, the present study compared ASR amplitude to measures of sound-level tolerance (SLT) in humans, the only species in which SLT can be directly assessed. Participants had clinically normal/near-normal hearing thresholds, were free of psychotropic medications, and comprised people with tinnitus and without. ASR was measured as eyeblink-related electromyographic activity in response to a noise pulse presented at a range of levels and in two background conditions (noise and quiet). SLT was measured as loudness discomfort level (LDL), the lowest level of sound deemed uncomfortable, and via a questionnaire on the loudness of sounds in everyday life. Regardless of tinnitus status, ASR amplitude at a given stimulus level increased with decreasing LDL, but showed no relationship to SLT self-reported via the questionnaire. These relationships (or lack thereof) could not be attributed to hearing threshold, age, anxiety, or depression. The results imply that increases in ASR in the animal work signify decreases in LDL specifically and may not correspond to the development of hyperacusis as would be self-reported by a clinic patient.

Increased contralateral suppression of otoacoustic emissions indicates a hyperresponsive medial olivocochlear system in humans with tinnitus and hyperacusis.

Atypical medial olivocochlear (MOC) feedback from brain stem to cochlea has been proposed to play a role in tinnitus, but even well-constructed tests of this idea have yielded inconsistent results. In the present study, it was hypothesized that low sound tolerance (mild to moderate hyperacusis), which can accompany tinnitus or occur on its own, might contribute to the inconsistency. Sound-level tolerance (SLT) was assessed in subjects (all men) with clinically normal or near-normal thresholds to form threshold-, age-, and sex-matched groups: 1) no tinnitus/high SLT, 2) no tinnitus/low SLT, 3) tinnitus/high SLT, and 4) tinnitus/low SLT. MOC function was measured from the ear canal as the change in magnitude of distortion-product otoacoustic emissions (DPOAE) elicited by broadband noise presented to the contralateral ear. The noise reduced DPOAE magnitude in all groups ("contralateral suppression"), but significantly more reduction occurred in groups with tinnitus and/or low SLT, indicating hyperresponsiveness of the MOC system compared with the group with no tinnitus/high SLT. The results suggest hyperresponsiveness of the interneurons of the MOC system residing in the cochlear nucleus and/or MOC neurons themselves. The present data, combined with previous human and animal data, indicate that neural pathways involving every major division of the cochlear nucleus manifest hyperactivity and/or hyperresponsiveness in tinnitus and/or low SLT. The overactivation may develop in each pathway separately. However, a more parsimonious hypothesis is that top-down neuromodulation is the driving force behind ubiquitous overactivation of the auditory brain stem and may correspond to attentional spotlighting on the auditory domain in tinnitus and hyperacusis.

Subcallosal brain structure: correlation with hearing threshold at supra-clinical frequencies (>8 kHz), but not with tinnitus.

This study tested for differences in brain structure between tinnitus and control subjects, focusing on a subcallosal brain region where striking differences have been inconsistently found previously. Voxel-based morphometry (VBM) was used to compare structural MRIs of tinnitus subjects and non-tinnitus controls. Audiograms of all subjects were normal or near-normal at standard clinical frequencies (≤8 kHz). Mean threshold through 14 kHz, age, sex and handedness were matched between groups. There were no definitive differences between tinnitus and control groups in modulated or unmodulated maps of gray matter (GM) probability (i.e., GM volume and concentration, respectively). However, when the image data were tested for correlations with parameters that were either not measured or not matched between the tinnitus and control groups of previous studies, a notable correlation was found: Threshold at supra-clinical frequencies (above 8 kHz) was negatively correlated with modulated GM probability in ventral posterior cingulate cortex, dorsomedial prefrontal cortex, and a subcallosal region that included ventromedial prefrontal cortex and coincided with previously-reported differences between tinnitus and control subjects. The results suggest an explanation for the discrepant findings in subcallosal brain: threshold at supra-clinical frequencies may have differed systematically between tinnitus and control groups in some studies but not others. The observed correlation between (1) brain structure in regions engaged in cognitive and attentional processes and (2) hearing sensitivity at frequencies generally considered unnecessary for normal human auditory behavior is surprising and worthy of follow up.

Brainstem auditory evoked potentials suggest a role for the ventral cochlear nucleus in tinnitus.

Numerous studies have demonstrated elevated spontaneous and sound-evoked brainstem activity in animal models of tinnitus, but data on brainstem function in people with this common clinical condition are sparse. Here, auditory nerve and brainstem function in response to sound was assessed via auditory brainstem responses (ABR) in humans with tinnitus and without. Tinnitus subjects showed reduced wave I amplitude (indicating reduced auditory nerve activity) but enhanced wave V (reflecting elevated input to the inferior colliculi) compared with non-tinnitus subjects matched in age, sex, and pure-tone threshold. The transformation from reduced peripheral activity to central hyperactivity in the tinnitus group was especially apparent in the V/I and III/I amplitude ratios. Compared with a third cohort of younger, non-tinnitus subjects, both tinnitus, and matched, non-tinnitus groups showed elevated thresholds above 4 kHz and reduced wave I amplitude, indicating that the differences between tinnitus and matched non-tinnitus subjects occurred against a backdrop of shared peripheral dysfunction that, while not tinnitus specific, cannot be discounted as a factor in tinnitus development. Animal lesion and human neuroanatomical data combine to indicate that waves III and V in humans reflect activity in a pathway originating in the ventral cochlear nucleus (VCN) and with spherical bushy cells (SBC) in particular. We conclude that the elevated III/I and V/I amplitude ratios in tinnitus subjects reflect disproportionately high activity in the SBC pathway for a given amount of peripheral input. The results imply a role for the VCN in tinnitus and suggest the SBC pathway as a target for tinnitus treatment.

Hearing without listening: functional connectivity reveals the engagement of multiple nonauditory networks during basic sound processing.

The present functional magnetic resonance imaging (fMRI) study presents data challenging the traditional view that sound is processed almost exclusively in the classical auditory pathway unless imbued with behavioral significance. In a first experiment, subjects were presented with broadband noise in on/off fashion as they performed an unrelated visual task. A conventional analysis assuming predictable sound-evoked responses demonstrated a typical activation pattern that was confined to classical auditory centers. In contrast, spatial independent component analysis (sICA) disclosed multiple networks of acoustically responsive brain centers. One network comprised classical auditory centers, but four others included nominally "nonauditory" areas: cingulo-insular cortex, mediotemporal limbic lobe, basal ganglia, and posterior orbitofrontal cortex, respectively. Functional connectivity analyses confirmed the sICA results by demonstrating coordinated activity between the involved brain structures. In a second experiment, fMRI data obtained from unstimulated (i.e., resting) subjects revealed largely similar networks. Together, these two experiments suggest the existence of a coordinated system of multiple acoustically responsive intrinsic brain networks, comprising classical auditory centers but also other brain areas. Our results suggest that nonauditory centers play a role in sound processing at a very basic level, even when the sound is not intertwined with behaviors requiring the well-known functionality of these regions.

Ringing ears: the neuroscience of tinnitus.

Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved. A brain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing.

Tinnitus, diminished sound-level tolerance, and elevated auditory activity in humans with clinically normal hearing sensitivity.

Phantom sensations and sensory hypersensitivity are disordered perceptions that characterize a variety of intractable conditions involving the somatosensory, visual, and auditory modalities. We report physiological correlates of two perceptual abnormalities in the auditory domain: tinnitus, the phantom perception of sound, and hyperacusis, a decreased tolerance of sound based on loudness. Here, subjects with and without tinnitus, all with clinically normal hearing thresholds, underwent 1) behavioral testing to assess sound-level tolerance and 2) functional MRI to measure sound-evoked activation of central auditory centers. Despite receiving identical sound stimulation levels, subjects with diminished sound-level tolerance (i.e., hyperacusis) showed elevated activation in the auditory midbrain, thalamus, and primary auditory cortex compared with subjects with normal tolerance. Primary auditory cortex, but not subcortical centers, showed elevated activation specifically related to tinnitus. The results directly link hyperacusis and tinnitus to hyperactivity within the central auditory system. We hypothesize that the tinnitus-related elevations in cortical activation may reflect undue attention drawn to the auditory domain, an interpretation consistent with the lack of tinnitus-related effects subcortically where activation is less potently modulated by attentional state. The data strengthen, at a mechanistic level, analogies drawn previously between tinnitus/hyperacusis and other, nonauditory disordered perceptions thought to arise from neural hyperactivity such as chronic neuropathic pain and photophobia.

BOLD responses in human auditory cortex are more closely related to transient MEG responses than to sustained ones.

Blood oxygen level dependent-functional magnetic resonance imaging (BOLD-fMRI) and magnetoencephalographic (MEG) signals are both coupled to postsynaptic potentials, although their relationship is incompletely understood. Here, the wide range of BOLD-fMRI and MEG responses produced by auditory cortex was exploited to better understand the BOLD-fMRI/MEG relationship. Measurements of BOLD and MEG responses were made in the same subjects using the same stimuli for both modalities. The stimuli, 24-s sequences of click trains, had duty cycles of 2.5, 25, 72, and 100%. For the 2.5% sequence, the BOLD response was elevated throughout the sequence, whereas for 100%, it peaked after sequence onset and offset and showed a diminished elevation in between. On the finer timescale of MEG, responses at 2.5% consisted of a complex of transients, including N(1)m, to each click train of the sequence, whereas for 100% the only transients occurred at sequence onset and offset between which there was a sustained elevation in the MEG signal (a sustained field). A model that separately estimated the contributions of transient and sustained MEG signals to the BOLD response best fit BOLD measurements when the transient contribution was weighted 8- to 10-fold more than the sustained one. The findings suggest that BOLD responses in the auditory cortex are tightly coupled to the neural activity underlying transient, not sustained, MEG signals.

The auditory midbrain of people with tinnitus: abnormal sound-evoked activity revisited.

Sound-evoked fMRI activation of the inferior colliculi (IC) was compared between tinnitus and non-tinnitus subjects matched in threshold (normal), age, depression, and anxiety. Subjects were stimulated with broadband sound in an "on/off" fMRI paradigm with and without on-going sound from the scanner coolant pump. (1) With pump sounds off, the tinnitus group showed greater stimulus-evoked activation of the IC than the non-tinnitus group, suggesting abnormal gain within the auditory pathway of tinnitus subjects. (2) Having pump sounds on reduced activation in the tinnitus, but not the non-tinnitus group. This result suggests response saturation in tinnitus subjects, possibly occurring because abnormal gain increased response amplitude to an upper limit. (3) In contrast to Melcher et al. (2000), the ratio of activation between right and left IC did not differ significantly between tinnitus and non-tinnitus subjects or in a manner dependent on tinnitus laterality. However, new data from subjects imaged previously by Melcher et al. suggest a possible tinnitus subgroup with abnormally asymmetric function of the IC. The present and previous data together suggest elevated responses to sound in the IC are common among those with tinnitus and normal thresholds, while abnormally asymmetric activation is not, even among those with lateralized tinnitus.

Human cortical activity during streaming without spectral cues suggests a general neural substrate for auditory stream segregation.

The brain continuously disentangles competing sounds, such as two people speaking, and assigns them to distinct streams. Neural mechanisms have been proposed for streaming based on gross spectral differences between sounds, but not for streaming based on other nonspectral features. Here, human listeners were presented with sequences of harmonic complex tones that had identical spectral envelopes, and unresolved spectral fine structure, but one of two fundamental frequencies (f0) and pitches. As the f0 difference between tones increased, listeners perceived the tones as being segregated into two streams (one stream for each f0) and cortical activity measured with functional magnetic resonance imaging and magnetoencephalography increased. This trend was seen in primary cortex of Heschl's gyrus and in surrounding nonprimary areas. The results strongly resemble those for pure tones. Both the present and pure tone results may reflect neuronal forward suppression that diminishes as one or more features of successive sounds become increasingly different. We hypothesize that feature-specific forward suppression subserves streaming based on diverse perceptual cues and results in explicit neural representations for auditory streams within auditory cortex.

The role of auditory cortex in the formation of auditory streams.

Auditory streaming refers to the perceptual parsing of acoustic sequences into "streams", which makes it possible for a listener to follow the sounds from a given source amidst other sounds. Streaming is currently regarded as an important function of the auditory system in both humans and animals, crucial for survival in environments that typically contain multiple sound sources. This article reviews recent findings concerning the possible neural mechanisms behind this perceptual phenomenon at the level of the auditory cortex. The first part is devoted to intra-cortical recordings, which provide insight into the neural "micromechanisms" of auditory streaming in the primary auditory cortex (A1). In the second part, recent results obtained using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in humans, which suggest a contribution from cortical areas other than A1, are presented. Overall, the findings concur to demonstrate that many important features of sequential streaming can be explained relatively simply based on neural responses in the auditory cortex.

Cortical FMRI activation to sequences of tones alternating in frequency: relationship to perceived rate and streaming.

Human listeners were functionally imaged while reporting their perception of sequences of alternating-frequency tone bursts separated by 0, 1/8, 1, or 20 semitones. Our goal was to determine whether functional magnetic resonance imaging (fMRI) activation of auditory cortex changes with frequency separation in a manner predictable from the perceived rate of the stimulus. At the null and small separations, the tones were generally heard as a single stream with a perceived rate equal to the physical tone presentation rate. fMRI activation in auditory cortex was appreciably phasic, showing prominent peaks at the sequence onset and offset. At larger-frequency separations, the higher- and lower-frequency tones perceptually separated into two streams, each with a rate equal to half the overall tone presentation rate. Under those conditions, fMRI activation in auditory cortex was more sustained throughout the sequence duration and was larger in magnitude and extent. Phasic to sustained changes in fMRI activation with changes in frequency separation and perceived rate are comparable to, and consistent with, those produced by changes in the physical rate of a sequence and are far greater than the effects produced by changing other physical stimulus variables, such as sound level or bandwidth. We suggest that the neural activity underlying the changes in fMRI activation with frequency separation contribute to the coding of the co-occurring changes in perceived rate and perceptual organization of the sound sequences into auditory streams.

Mapping an intrinsic MR property of gray matter in auditory cortex of living humans: a possible marker for primary cortex and hemispheric differences.

Recently, magnetic resonance properties of cerebral gray matter have been spatially mapped--in vivo--over the cortical surface. In one of the first neuroscientific applications of this approach, this study explores what can be learned about auditory cortex in living humans by mapping longitudinal relaxation rate (R1), a property related to myelin content. Gray matter R1 (and thickness) showed repeatable trends, including the following: (1) Regions of high R1 were always found overlapping posteromedial Heschl's gyrus. They also sometimes occurred in planum temporale and never in other parts of the superior temporal lobe. We hypothesize that the high R1 overlapping Heschl's gyrus (which likely indicates dense gray matter myelination) reflects auditory koniocortex (i.e., primary cortex), a heavily myelinated area that shows comparable overlap with the gyrus. High R1 overlapping Heschl's gyrus was identified in every instance suggesting that R1 may ultimately provide a marker for koniocortex in individuals. Such a marker would be significant for auditory neuroimaging, which has no standard means (anatomic or physiologic) for localizing cortical areas in individual subjects. (2) Inter-hemispheric comparisons revealed greater R1 on the left on Heschl's gyrus, planum temporale, superior temporal gyrus and superior temporal sulcus. This asymmetry suggests greater gray matter myelination in left auditory cortex, which may be a substrate for the left hemisphere's specialized processing of speech, language, and rapid acoustic changes. These results indicate that in vivo R1 mapping can provide new insights into the structure of human cortical gray matter and its relation to function.

Effects of sound level on fMRI activation in human brainstem, thalamic and cortical centers.

The dependence of fMRI activation on sound level was examined throughout the auditory pathway of normal human listeners using continuous broadband noise, a stimulus widely used in neuroscientific investigations of auditory processing, but largely neglected in neuro-imaging. Several specialized techniques were combined here for the first time to enhance detection of brainstem activation, mitigate scanner noise, and recover temporal resolution lost by the mitigation technique. The main finding was increased activation with increasing level in cochlear nucleus, superior olive, inferior colliculus, medial geniculate body and auditory cortical areas. We suggest that these increases reflect monotonically increasing activity in a preponderance of individual auditory neurons responsive to broadband noise. While the time-course of activation changed with level, the change was subtle and only significant in a part of the cortex. To our knowledge, these are the first fMRI data showing the effects of sound level in subcortical centers or for a non-tonal, non-speech stimulus at any stage of the pathway. The present results add to the body of parametric data in normal human listeners and are fundamental to the design of any fMRI experiment employing continuous noise.

Effects of sound bandwidth on fMRI activation in human auditory brainstem nuclei.

Few neuro-imaging studies of the auditory system have examined the dependence of brain activation on sound bandwidth, a fundamental stimulus parameter, and none have examined bandwidth dependencies in the brainstem. The present study examined the effect of bandwidth on human brainstem activation using fMRI, an indicator of population neural activity. The studied stimuli (broadband, two-, one-, and third-octave continuous noise) activated three brainstem centers: cochlear nucleus, superior olivary complex, and inferior colliculus. Activation could be confidently attributed to these nuclei because it was appropriately punctate (given the small size of the imaged nuclei) and appropriately located (as determined from histological atlases). Activation in all three imaged centers increased monotonically with increasing bandwidth when either stimulus spectrum level or energy was held constant. Supplementary experiments indicated that the measured bandwidth dependencies were not contaminated by the extraneous sounds produced by the scanner. Increases in fMRI activation with increasing bandwidth would be expected from populations of neurons having a single best frequency and only excitatory responses to sound, but not necessarily from lower auditory system neurons with their often more complex responses. Our results provide basic information for designing auditory neuro-imaging studies that need to control for, or manipulate sound bandwidth.

Neuromagnetic correlates of streaming in human auditory cortex.

The brain is constantly faced with the challenge of organizing acoustic input from multiple sound sources into meaningful auditory objects or perceptual streams. The present study examines the neural bases of auditory stream formation using neuromagnetic and behavioral measures. The stimuli were sequences of alternating pure tones, which can be perceived as either one or two streams. In the first experiment, physical stimulus parameters were varied between values that promoted the perceptual grouping of the tone sequence into one coherent stream and values that promoted its segregation into two streams. In the second experiment, an ambiguous tone sequence produced a bistable percept that switched spontaneously between one- and two-stream percepts. The first experiment demonstrated a strong correlation between listeners' perception and long-latency (>60 ms) activity that likely arises in nonprimary auditory cortex. The second demonstrated a covariation between this activity and listeners' perception in the absence of physical stimulus changes. Overall, the results indicate a tight coupling between auditory cortical activity and streaming perception, suggesting that an explicit representation of auditory streams may be maintained within nonprimary auditory areas.

Short-term sound temporal envelope characteristics determine multisecond time patterns of activity in human auditory cortex as shown by fMRI.

Functional magnetic resonance imaging (fMRI) of human auditory cortex has demonstrated a striking range of temporal waveshapes in responses to sound. Prolonged (30 s) low-rate (2/s) noise burst trains elicit "sustained" responses, whereas high-rate (35/s) trains elicit "phasic" responses with peaks just after train onset and offset. As a step toward understanding the significance of these responses for auditory processing, the present fMRI study sought to resolve exactly which features of sound determine cortical response waveshape. The results indicate that sound temporal envelope characteristics, but not sound level or bandwidth, strongly influence response waveshapes, and thus the underlying time patterns of neural activity. The results show that sensitivity to sound temporal envelope holds in both primary and nonprimary cortical areas, but nonprimary areas show more pronounced phasic responses for some types of stimuli (higher-rate trains, continuous noise), indicating more prominent neural activity at sound onset and offset. It has been hypothesized that the neural activity underlying the onset and offset peaks reflects the beginning and end of auditory perceptual events. The present data support this idea because sound temporal envelope, the sound characteristic that most strongly influences whether fMRI responses are phasic, also strongly influences whether successive stimuli (e.g., the bursts of a train) are perceptually grouped into a single auditory event. Thus fMRI waveshape may provide a window onto neural activity patterns that reflect the segmentation of our auditory environment into distinct, meaningful events.

A neural representation of pitch salience in nonprimary human auditory cortex revealed with functional magnetic resonance imaging.

Pitch, one of the primary auditory percepts, is related to the temporal regularity or periodicity of a sound. Previous functional brain imaging work in humans has shown that the level of population neural activity in centers throughout the auditory system is related to the temporal regularity of a sound, suggesting a possible relationship to pitch. In the current study, functional magnetic resonance imaging was used to measure activation in response to harmonic tone complexes whose temporal regularity was identical, but whose pitch salience (or perceptual pitch strength) differed, across conditions. Cochlear nucleus, inferior colliculus, and primary auditory cortex did not show significant differences in activation level between conditions. Instead, a correlate of pitch salience was found in the neural activity levels of a small, spatially localized region of nonprimary auditory cortex, overlapping the anterolateral end of Heschl's gyrus. The present data contribute to converging evidence that anterior areas of nonprimary auditory cortex play an important role in processing pitch.

Tonotopic organization in human auditory cortex revealed by progressions of frequency sensitivity.

Functional neuroimaging experiments have revealed an organization of frequency-dependent responses in human auditory cortex suggestive of multiple tonotopically organized areas. Numerous studies have sampled cortical responses to isolated narrow-band stimuli, revealing multiple locations in auditory cortex at which the position of response varies systematically with frequency content. Because appropriate anatomical or functional grouping of these distinct frequency-dependent responses is uncertain, the number and location of tonotopic mappings within human auditory cortex remains unclear. Further, sampling does not address whether the observed mappings exhibit continuity as a function of position. This functional magnetic resonance imaging study used frequency-swept stimuli to identify progressions of frequency sensitivity across the cortical surface. The center-frequency of narrow-band, amplitude-modulated noise was slowly swept between 125 and 8,000 Hz. The latency of response relative to sweep onset was determined for each cortical surface location. Because frequency varied systematically with time, response latency indicated the frequency to which a location was maximally sensitive. Areas of cortex exhibiting a progressive change in response latency with position were considered tonotopically organized. There exist two main findings. First, six progressions of frequency sensitivity (i.e., tonotopic mappings) were repeatably observed in the superior temporal plane. Second, the locations of the higher- and lower-frequency endpoints of these progressions were approximately congruent with regions reported to be most responsive to discrete higher- and lower-frequency stimuli. Based on these findings and previous anatomical work, we propose a correspondence between these progressions and anatomically defined cortical areas, suggesting that five areas in human auditory cortex exhibit at least six tonotopic organizations.