Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans.

The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve inputs from the cochlea with somatosensory inputs from the head and neck. In previous work, we developed a guinea pig model of tinnitus induced by noise exposure and showed that the fusiform cells in these animals exhibited increased spontaneous activity and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term depression (LTD). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold promise for suppressing chronic tinnitus, which reduces quality of life for millions of tinnitus sufferers worldwide.

Subcortical amplitude modulation encoding deficits suggest evidence of cochlear synaptopathy in normal-hearing 18-19 year olds with higher lifetime noise exposure.

Noise exposure and aging can damage cochlear synapses required for suprathreshold listening, even when cochlear structures needed for hearing at threshold remain unaffected. To control for effects of aging, behavioral amplitude modulation (AM) detection and subcortical envelope following responses (EFRs) to AM tones in 25 age-restricted (18-19 years) participants with normal thresholds, but different self-reported noise exposure histories were studied. Participants with more noise exposure had smaller EFRs and tended to have poorer AM detection than less-exposed individuals. Simulations of the EFR using a well-established cochlear model were consistent with more synaptopathy in participants reporting greater noise exposure.

Evidence that hidden hearing loss underlies amplitude modulation encoding deficits in individuals with and without tinnitus.

Damage to auditory nerve fibers that expresses with suprathreshold sounds but is hidden from the audiogram has been proposed to underlie deficits in temporal coding ability observed among individuals with otherwise normal hearing, and to be present in individuals experiencing chronic tinnitus with clinically normal audiograms. We tested whether these individuals may have hidden synaptic losses on auditory nerve fibers with low spontaneous rates of firing (low-SR fibers) that are important for coding suprathreshold sounds in noise while high-SR fibers determining threshold responses in quiet remain relatively unaffected. Tinnitus and control subjects were required to detect the presence of amplitude modulation (AM) in a 5 kHz, suprathreshold tone (a frequency in the tinnitus frequency region of the tinnitus subjects, whose audiometric thresholds were normal to 12 kHz). The AM tone was embedded within background noise intended to degrade the contribution of high-SR fibers, such that AM coding was preferentially reliant on low-SR fibers. We also recorded by electroencephalography the "envelope following response" (EFR, generated in the auditory midbrain) to a 5 kHz, 85 Hz AM tone presented in the same background noise, and also in quiet (both low-SR and high-SR fibers contributing to AM coding in the latter condition). Control subjects with EFRs that were comparatively resistant to the addition of background noise had better AM detection thresholds than controls whose EFRs were more affected by noise. Simulated auditory nerve responses to our stimulus conditions using a well-established peripheral model suggested that low-SR fibers were better preserved in the former cases. Tinnitus subjects had worse AM detection thresholds and reduced EFRs overall compared to controls. Simulated auditory nerve responses found that in addition to severe low-SR fiber loss, a degree of high-SR fiber loss that would not be expected to affect audiometric thresholds was needed to explain the results in tinnitus subjects. The results indicate that hidden hearing loss could be sufficient to account for impaired temporal coding in individuals with normal audiograms as well as for cases of tinnitus without audiometric hearing loss.

Tinnitus is associated with reduced sound level tolerance in adolescents with normal audiograms and otoacoustic emissions.

Recent neuroscience research suggests that tinnitus may reflect synaptic loss in the cochlea that does not express in the audiogram but leads to neural changes in auditory pathways that reduce sound level tolerance (SLT). Adolescents (N = 170) completed a questionnaire addressing their prior experience with tinnitus, potentially risky listening habits, and sensitivity to ordinary sounds, followed by psychoacoustic measurements in a sound booth. Among all adolescents 54.7% reported by questionnaire that they had previously experienced tinnitus, while 28.8% heard tinnitus in the booth. Psychoacoustic properties of tinnitus measured in the sound booth corresponded with those of chronic adult tinnitus sufferers. Neither hearing thresholds (≤15 dB HL to 16 kHz) nor otoacoustic emissions discriminated between adolescents reporting or not reporting tinnitus in the sound booth, but loudness discomfort levels (a psychoacoustic measure of SLT) did so, averaging 11.3 dB lower in adolescents experiencing tinnitus in the acoustic chamber. Although risky listening habits were near universal, the teenagers experiencing tinnitus and reduced SLT tended to be more protective of their hearing. Tinnitus and reduced SLT could be early indications of a vulnerability to hidden synaptic injury that is prevalent among adolescents and expressed following exposure to high level environmental sounds.

Evidence for differential modulation of primary and nonprimary auditory cortex by forward masking in tinnitus.

It has been proposed that tinnitus is generated by aberrant neural activity that develops among neurons in tonotopic of regions of primary auditory cortex (A1) affected by hearing loss, which is also the frequency region where tinnitus percepts localize (Eggermont and Roberts 2004; Roberts et al., 2010, 2013). These models suggest (1) that differences between tinnitus and control groups of similar age and audiometric function should depend on whether A1 is probed in tinnitus frequency region (TFR) or below it, and (2) that brain responses evoked from A1 should track changes in the tinnitus percept when residual inhibition (RI) is induced by forward masking. We tested these predictions by measuring (128-channel EEG) the sound-evoked 40-Hz auditory steady-state response (ASSR) known to localize tonotopically to neural sources in A1. For comparison the N1 transient response localizing to distributed neural sources in nonprimary cortex (A2) was also studied. When tested under baseline conditions where tinnitus subjects would have heard their tinnitus, ASSR responses were larger in a tinnitus group than in controls when evoked by 500 Hz probes while the reverse was true for tinnitus and control groups tested with 5 kHz probes, confirming frequency-dependent group differences in this measure. On subsequent trials where RI was induced by masking (narrow band noise centered at 5 kHz), ASSR amplitude increased in the tinnitus group probed at 5 kHz but not in the tinnitus group probed at 500 Hz. When collapsed into a single sample tinnitus subjects reporting comparatively greater RI depth and duration showed comparatively larger ASSR increases after masking regardless of probe frequency. Effects of masking on ASSR amplitude in the control groups were completely reversed from those in the tinnitus groups, with no change seen to 5 kHz probes but ASSR increases to 500 Hz probes even though the masking sound contained no energy at 500 Hz (an "off-frequency" masking effect). In contrast to these findings for the ASSR, N1 amplitude was larger in tinnitus than control groups at both probe frequencies under baseline conditions, decreased after masking in all conditions, and did not relate to RI. These results suggest that aberrant neural activity occurring in the TFR of A1 underlies tinnitus and its modulation during RI. They indicate further that while neural changes occur in A2 in tinnitus, these changes do not reflect the tinnitus percept. Models for tinnitus and forward masking are described that integrate these findings within a common framework.

Modulation of electrocortical brain activity by attention in individuals with and without tinnitus.

Age and hearing-level matched tinnitus and control groups were presented with a 40 Hz AM sound using a carrier frequency of either 5 kHz (in the tinnitus frequency region of the tinnitus subjects) or 500 Hz (below this region). On attended blocks subjects pressed a button after each sound indicating whether a single 40 Hz AM pulse of variable increased amplitude (target, probability 0.67) had or had not occurred. On passive blocks subjects rested and ignored the sounds. The amplitude of the 40 Hz auditory steady-state response (ASSR) localizing to primary auditory cortex (A1) increased with attention in control groups probed at 500 Hz and 5 kHz and in the tinnitus group probed at 500 Hz, but not in the tinnitus group probed at 5 kHz (128 channel EEG). N1 amplitude (this response localizing to nonprimary cortex, A2) increased with attention at both sound frequencies in controls but at neither frequency in tinnitus. We suggest that tinnitus-related neural activity occurring in the 5 kHz but not the 500 Hz region of tonotopic A1 disrupted attentional modulation of the 5 kHz ASSR in tinnitus subjects, while tinnitus-related activity in A1 distributing nontonotopically in A2 impaired modulation of N1 at both sound frequencies.

Development of auditory phase-locked activity for music sounds.

The auditory cortex undergoes functional and anatomical development that reflects specialization for learned sounds. In humans, auditory maturation is evident in transient auditory-evoked potentials (AEPs) elicited by speech or music. However, neural oscillations at specific frequencies are also known to play an important role in perceptual processing. We hypothesized that, if oscillatory activity in different frequency bands reflects different aspects of sound processing, the development of phase-locking to stimulus attributes at these frequencies may have different trajectories. We examined the development of phase-locking of oscillatory responses to music sounds and to pure tones matched to the fundamental frequency of the music sounds. Phase-locking for theta (4-8 Hz), alpha (8-14 Hz), lower-to-mid beta (14-25 Hz), and upper-beta and gamma (25-70 Hz) bands strengthened with age. Phase-locking in the upper-beta and gamma range matured later than in lower frequencies and was stronger for music sounds than for pure tones, likely reflecting the maturation of neural networks that code spectral complexity. Phase-locking for theta, alpha, and lower-to-mid beta was sensitive to temporal onset (rise time) sound characteristics. The data were also consistent with phase-locked oscillatory effects of acoustic (spectrotemporal) complexity and timbre familiarity. Future studies are called for to evaluate developmental trajectories for oscillatory activity, using stimuli selected to address hypotheses related to familiarity and spectral and temporal encoding suggested by the current findings.

Frequency-specific modulation of population-level frequency tuning in human auditory cortex.

BACKGROUND: Under natural circumstances, attention plays an important role in extracting relevant auditory signals from simultaneously present, irrelevant noises. Excitatory and inhibitory neural activity, enhanced by attentional processes, seems to sharpen frequency tuning, contributing to improved auditory performance especially in noisy environments. In the present study, we investigated auditory magnetic fields in humans that were evoked by pure tones embedded in band-eliminated noises during two different stimulus sequencing conditions (constant vs. random) under auditory focused attention by means of magnetoencephalography (MEG). RESULTS: In total, we used identical auditory stimuli between conditions, but presented them in a different order, thereby manipulating the neural processing and the auditory performance of the listeners. Constant stimulus sequencing blocks were characterized by the simultaneous presentation of pure tones of identical frequency with band-eliminated noises, whereas random sequencing blocks were characterized by the simultaneous presentation of pure tones of random frequencies and band-eliminated noises. We demonstrated that auditory evoked neural responses were larger in the constant sequencing compared to the random sequencing condition, particularly when the simultaneously presented noises contained narrow stop-bands. CONCLUSION: The present study confirmed that population-level frequency tuning in human auditory cortex can be sharpened in a frequency-specific manner. This frequency-specific sharpening may contribute to improved auditory performance during detection and processing of relevant sound inputs characterized by specific frequency distributions in noisy environments.

Music training leads to the development of timbre-specific gamma band activity.

Oscillatory gamma band activity (GBA, 30-100 Hz) has been shown to correlate with perceptual and cognitive phenomena including feature binding, template matching, and learning and memory formation. We hypothesized that if GBA reflects highly learned perceptual template matching, we should observe its development in musicians specific to the timbre of their instrument of practice. EEG was recorded in adult professional violinists and amateur pianists as well as in 4- and 5-year-old children studying piano in the Suzuki method before they commenced music lessons and 1 year later. The adult musicians showed robust enhancement of induced (non-time-locked) GBA, specifically to their instrument of practice, with the strongest effect in professional violinists. Consistent with this result, the children receiving piano lessons exhibited increased power of induced GBA for piano tones with 1 year of training, while children not taking lessons showed no effect. In comparison to induced GBA, evoked (time-locked) gamma band activity (30-90 Hz, approximately 80 ms latency) was present only in adult groups. Evoked GBA was more pronounced in musicians than non-musicians, with synchronization equally exhibited for violin and piano tones but enhanced for these tones compared to pure tones. Evoked gamma activity may index the physical properties of a sound and is modulated by acoustical training, while induced GBA may reflect higher perceptual learning and is shaped by specific auditory experiences.

Sensitivity of EEG and MEG to the N1 and P2 auditory evoked responses modulated by spectral complexity of sounds.

Acoustic complexity of a stimulus has been shown to modulate the electromagnetic N1 (latency approximately 110 ms) and P2 (latency 190 ms) auditory evoked responses. We compared the relative sensitivity of electroencephalography (EEG) and magnetoencephalography (MEG) to these neural correlates of sensation. Simultaneous EEG and MEG were recorded while participants listened to three variants of a piano tone. The piano stimuli differed in their number of harmonics: the fundamental frequency (f ( 0 )), only, or f ( 0 ) and the first two or eight harmonics. The root mean square (RMS) of the amplitude of P2 but not N1 increased with spectral complexity of the piano tones in EEG and MEG. The RMS increase for P2 was more prominent in EEG than MEG, suggesting important radial sources contributing to the P2 only in EEG. Source analysis revealing contributions from radial and tangential sources was conducted to test this hypothesis. Source waveforms revealed a significant increase in the P2 radial source amplitude in EEG with increased spectral complexity of piano tones. The P2 of the tangential source waveforms also increased in amplitude with increased spectral complexity in EEG and MEG. The P2 auditory evoked response is thus represented by both tangential (gyri) and radial (sulci) activities. The radial contribution is expressed preferentially in EEG, highlighting the importance of combining EEG with MEG where complex source configurations are suspected.

Enhanced anterior-temporal processing for complex tones in musicians.

OBJECTIVE: To examine how auditory brain responses change with increased spectral complexity of sounds in musicians and non-musicians. METHODS: Event-related potentials (ERPs) and fields (ERFs) to binaural piano tones were measured in musicians and non-musicians. The stimuli were C4 piano tones and a pure sine tone of the C4 fundamental frequency (f0). The first piano tone contained f0 and the first eight harmonics, the second piano tone consisted of f0 and the first two harmonics and the third piano tone consisted of f0. RESULTS: Subtraction of ERPs of the piano tone with only the fundamental from ERPs of the harmonically rich piano tones yielded positive difference waves peaking at 130 ms (DP130) and 300 ms (DP300). The DP130 was larger in musicians than non-musicians and both waves were maximally recorded over the right anterior scalp. ERP source analysis indicated anterior temporal sources with greater strength in the right hemisphere for both waves. Arbitrarily using these anterior sources to analyze the MEG signals showed a DP130m in musicians but not in non-musicians. CONCLUSIONS: Auditory responses in the anterior temporal cortex to complex musical tones are larger in musicians than non-musicians. SIGNIFICANCE: Neural networks in the anterior temporal cortex are activated during the processing of complex sounds. Their greater activation in musicians may index either underlying cortical differences related to musical aptitude or cortical modification by acoustical training.

Frequency organization of the 40-Hz auditory steady-state response in normal hearing and in tinnitus.

We used the 40-Hz auditory steady-state response (SSR) to compare for the first time tonotopic frequency representations in the region of primary auditory cortex (PAC) between subjects with chronic tinnitus and hearing impairment and normal hearing controls. Frequency representations were measured in normal hearing (n=17) and tinnitus (n=28) subjects using eight carrier frequencies between 384 and 6561 Hz, each amplitude modulated (AM) at 40-Hz on trials of 3 min duration under passive attention. In normal hearing subjects, frequency gradients were observed in the medial-lateral, anterior-posterior, and inferior-superior axes, which were consistent with the orientation of Heschl's gyrus and with functional organization revealed by fMRI investigations. The frequency representation in the right hemisphere was approximately 5 mm anterior and approximately 7 mm lateral to that in the left hemisphere, corroborating with MEG measurements hemispheric asymmetries reported by cytoarchitectonic studies of the PAC and by MRI morphometry. In the left hemisphere, frequency gradients were inflected near 2 kHz in normal hearing subjects. These SSR frequency gradients were attenuated in both hemispheres in tinnitus subjects. Dipole power was also elevated in tinnitus, suggesting that more neurons were entrained synchronously by the AM envelope. These findings are consistent with animal experiments reporting altered tonotopy and changes in the response properties of auditory cortical neurons after hearing loss induced by noise exposure. Degraded frequency representations in tinnitus may reflect a loss of intracortical inhibition in deafferented frequency regions of the PAC after hearing injury.

Modulation of P2 auditory-evoked responses by the spectral complexity of musical sounds.

We investigated whether N1 and P2 auditory-evoked responses are modulated by the spectral complexity of musical sounds in pianists and non-musicians. Study participants were presented with three variants of a C4 piano tone equated for temporal envelope but differing in the number of harmonics contained in the stimulus. A fourth tone was a pure tone matched to the fundamental frequency of the piano tones. A simultaneous electroencephalographic/magnetoencephalographic recording was made. P2 amplitude was larger in musicians and increased with spectral complexity preferentially in this group, but N1 did not. The results suggest that P2 reflects the specific features of acoustic stimuli experienced during musical practice and point to functional differences in P2 and N1 that relate to their underlying mechanisms.

Enhancement of auditory cortical development by musical experience in children.

Auditory evoked potentials (AEPs) express the development of mature synaptic connections in the upper neocortical laminae known to occur between 4 and 15 years of age. AEPs evoked by piano, violin, and pure tones were measured twice in a group of 4- to 5-year-old children enrolled in Suzuki music lessons and in non-musician controls. P1 was larger in the Suzuki pupils for all tones whereas P2 was enhanced specifically for the instrument of practice (piano or violin). AEPs observed for the instrument of practice were comparable to those of non-musician children about 3 years older in chronological age. The findings set into relief a general process by which the neocortical synaptic matrix is shaped by an accumulation of specific auditory experiences.

Distributed auditory cortical representations are modified when non-musicians are trained at pitch discrimination with 40 Hz amplitude modulated tones.

Several functional brain attributes reflecting neocortical activity have been found to be enhanced in musicians compared to non-musicians. Included are the N1m evoked magnetic field, P2 and right-hemispheric N1c auditory evoked potentials, and the source waveform of the magnetically recorded 40 Hz auditory steady state response (SSR). We investigated whether these functional brain attributes measured by EEG are sensitive to neuroplastic remodeling in non-musician subjects. Adult non-musicians were trained for 15 sessions to discriminate small changes in the carrier frequency of 40 Hz amplitude modulated pure tones. P2 and N1c auditory evoked potentials were separated from the SSR by signal processing and found to localize to spatially differentiable sources in the secondary auditory cortex (A2). Training enhanced the P2 bilaterally and the N1c in the right hemisphere where auditory neurons may be specialized for processing of spectral information. The SSR localized to sources in the region of Heschl's gyrus in primary auditory cortex (A1). The amplitude of the SSR (assessed by bivariate T2 in 100 ms moving windows) was not augmented by training although the phase of the response was modified for the trained stimuli. The P2 and N1c enhancements observed here and reported previously in musicians may reflect new tunings on A2 neurons whose establishment and expression are gated by input converging from other regions of the brain. The SSR localizing to A1 was more resistant to remodeling, suggesting that its amplitude enhancement in musicians may be an intrinsic marker for musical skill or an early experience effect.

Enhancement of neuroplastic P2 and N1c auditory evoked potentials in musicians.

P2 and N1c components of the auditory evoked potential (AEP) have been shown to be sensitive to remodeling of the auditory cortex by training at pitch discrimination in nonmusician subjects. Here, we investigated whether these neuroplastic components of the AEP are enhanced in musicians in accordance with their musical training histories. Highly skilled violinists and pianists and nonmusician controls listened under conditions of passive attention to violin tones, piano tones, and pure tones matched in fundamental frequency to the musical tones. Compared with nonmusician controls, both musician groups evidenced larger N1c (latency, 138 msec) and P2 (latency, 185 msec) responses to the three types of tonal stimuli. As in training studies with nonmusicians, N1c enhancement was expressed preferentially in the right hemisphere, where auditory neurons may be specialized for processing of spectral pitch. Equivalent current dipoles fitted to the N1c and P2 field patterns localized to spatially differentiable regions of the secondary auditory cortex, in agreement with previous findings. These results suggest that the tuning properties of neurons are modified in distributed regions of the auditory cortex in accordance with the acoustic training history (musical- or laboratory-based) of the subject. Enhanced P2 and N1c responses in musicians need not be considered genetic or prenatal markers for musical skill.