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

Abstract

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 ∼ 5 mm anterior and ∼ 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.

Introduction

Tinnitus is an auditory phantom sensation usually accompanied by hearing loss consequent on noise exposure or the aging process. Tinnitus sensations are variable but typically consist of continuous tonal or hissing sounds with center frequencies of 3–8 kHz, which overlap the measured region of hearing impairment in the audiogram (Norena et al., 2002). Neural changes induced by noise exposure in this frequency region have been identified by animal models of hearing loss and include (1) increased spontaneous firing rates of neurons in auditory cortical and subcortical structures although not in auditory nerve fibers; (2) increased synchronization of the spontaneous activity of cortical neurons in the affected frequency region; and (3) a change in the frequency representation of auditory cortex, such that frequencies bordering the edge of hearing loss are over-represented in the cortical tonotopic map (for reviews, see Eggermont and Roberts, 2004; Kaltenbach, 2000; Irvine et al., 2000). Decreased inhibition in central auditory structures consequent on hearing injuries or damaged input from non-auditory pathways may underlie these effects, which point to a central rather than peripheral origin of tinnitus sensations. Positron emission tomography (PET) studies of human tinnitus sufferers have documented increased neural activity in subcortical auditory nuclei (Melcher et al., 2000), in limbic structures associated with emotion (Lockwood et al., 1998), and in the auditory cortex (Lockwood et al., 1998, Lockwood et al., 2001) where lemniscal and extralemniscal inputs converge and the sensation of tinnitus may be generated.

In principle, functional brain activity related to tinnitus should be expressed in auditory-evoked potentials (AEPs) and magnetic fields (AEFs), which reflect current sinks and sources generated by neural activity in the superficial neocortical laminae (Fishman et al., 2000). Studies comparing N1 transient responses of the AEP/AEF between tinnitus and normal hearing subjects have produced an inconsistent picture with some studies reporting increases in N1 amplitude and N1 slope/intensity functions in tinnitus for tones presented near or below the tinnitus frequency (Dietrich et al., 2001, Norena et al., 1999, Hoke et al., 1989, Weisz et al., 2005), and other studies reporting either decreases in these variables at frequencies near the edge of the tinnitus pitch (P2/N1 intensity function at 2 kHz; Kadner et al., 2002) or no changes at all in N1 amplitude in tinnitus (Jacobson et al., 1991). Most of these studies have been guided by the idea that expansion of the cortical representation for edge frequencies after hearing loss modulates neural activity in cortical tonotopic map just below the edge of the deafferented region (edge of normal hearing in the audiogram). The expected modulations may be complex, however, with AEP enhancements predicted when edge frequencies are over-represented in the tonotopic map (Dietrich et al., 2001) and AEP diminution when surround inhibition is deployed from the enhanced representation to frequencies below the region of hearing impairment (Kadner et al., 2002).

A different approach to the study of neural correlates of tinnitus has investigated cortical tonotopic map reorganization in tinnitus sufferers. Following this approach, Mühlnickel et al. (1998) found that the cortical source of the N1m magnetic field evoked by the tinnitus frequency in tinnitus subjects was shifted on average by 2.7 mm from its location in the cortical place map of normal hearing controls. The extent of the deviation correlated the subjective degree of tinnitus, implicating map reorganization as a contributing factor. A broadened tuning response of neurons to spectral frequency in the tinnitus frequency region could explain these findings, if it is assumed that excitation of a larger population of neurons shifted the center of activation from its expected location in the cortical representation. Whether the deviations recorded by Mühlnickel et al. reflect changes in the PAC is uncertain, however, because the cortical generators of the N1m typically localize outside of the PAC (Picton et al., 1999, Bosnyak et al., 2004, Engelien et al., 2000) and may reflect interactions occurring between the PAC and belt regions of the auditory cortex. An alternative approach is to investigate auditory “middle latency responses” (MLRs) and the closely related 40-Hz “steady-state response” (SSR) in tinnitus subjects. MLRs generate a 19- to 30-ms waveform with a wave period of about 25 ms that localizes to the region of Heschl’s gyrus (Schneider et al., 2002). Neural sources underlying the waveform appear to stabilize into an oscillating network with repetitive stimulation and summate to yield a prominent SSR when carrier frequencies are amplitude modulated (AM) near 40 Hz (Galambos et al., 1981, Gutschalk et al., 1999, Ross et al., 2005). Accordingly, the cortical sources of the 40-Hz SSR overlap those of the 19- to 30-ms MLR waveform and are tonotopically organized in the region of PAC (Pantev et al., 1996, Ross et al., 2000). Diesch et al. (2004) probed cortical representations in tinnitus subjects using 40-Hz SSRs at six carrier frequencies spanning the edge frequency of hearing loss in the subject’s audiogram. SSR amplitude increased relative to previously published transfer functions relating SSR amplitude to carrier frequency (Ross et al., 2000) when carrier frequencies entered the tinnitus frequency region, suggesting altered neuronal excitability in this region. In addition, no evidence for a tonotopic gradient was found, pointing to possible map reorganization in tinnitus subjects. While the findings of Diesch et al. (2004) are suggestive, they could not be linked conclusively with tinnitus, because normal hearing controls were not tested. Gerken et al. (2001) studied MLRs in tinnitus and normal hearing subjects. In agreement with the suggestion of Diesch et al. (2004), Gerken et al. (2001) found evidence of enhanced MLRs in tinnitus compared to normal hearing controls. However, tonotopic organization was not investigated in this study.

The present experiment investigated tonotopic organization and neural dynamics in the PAC associated with tinnitus, in a large sample of tinnitus subjects and normal hearing controls. Our first goal was to compare frequency gradients measured by the SSR in normal hearing subjects with the results of fMRI studies of tonotopy (Wessinger et al., 2001, Schönwiesner et al., 2002, Formisano et al., 2003, Talavage et al., 2004) and to assess hemispheric differences in the 3D location of SSR maps in relation to cytoarchitectural (Rademacher et al., 2001) and morphometric (Penhune et al., 1996) studies of the PAC. Previous studies of tonotopic organization assessed by the magnetic SSR have not distinguished maps in the two hemispheres or considered their relation to functional and structural features of the PAC assessed by other brain imaging methods. Our second goal was to use our assessments of the frequency organization of the SSR in normal hearing subjects as a baseline for evaluating tonotopic reorganization in tinnitus and for detecting changes in the amplitude and phase of SSRs which could signal a loss of intracortical inhibition thought to underlie neural dynamics associated with this condition.