Proc. Natl. Acad. Sci. USA Vol. 95, pp. 10340–10343, August 1998 Psychology Reorganization of auditory cortex in tinnitus (plasticityymagnetic source imaging) WERNER MU¨HLNICKEL*, THOMAS ELBERT†,EDWARD TAUB‡, AND HERTA FLOR*§ *Department of Psychology, Clinical Psychology and Behavioral Neuroscience, Humboldt University, Hausvogteiplatz 5-7, D-10117 Berlin, Germany; †Department of Psychology, University of Konstanz, Postfach 5560-D23, D-78434 Konstanz, Germany; and ‡Department of Psychology, University of Alabama, 415 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294 Edited by Mortimer Mishkin, National Institute of Mental Health, Bethesda, MD, and approved June 9, 1998 (received for review November 14, 1997) ABSTRACT Magnetic source imaging was used to deter- subjects and controls were of comparable age [t 5 1.81, not mine whether tonotopy in auditory cortex of individuals with significant (n.s.)] and gender (x2 5 0.03, n.s; see Table 1). tinnitus diverges from normative functional organization. Ten Auditory Testing. Hearing loss and tinnitus frequency were tinnitus subjects and 15 healthy controls were exposed to four assessed by an audiogram. Only subjects with simple tonal sets of tones while magnetoencephalographic recordings were tinnitus were included. A standard audiogram procedure was obtained from the two cortical hemispheres in sequence. A used where sounds of various intensities and frequencies were marked shift of the cortical representation of the tinnitus delivered and the tinnitus sound was identified by matching it frequency into an area adjacent to the expected tonotopic to the sounds that were presented. In an additional procedure, location was observed. The Euclidean distance of the tinnitus the subjects self-produced the tinnitus sound by moving a frequency from the trajectory of the tonotopic map was 5.3 cursor on a video screen that varied frequency and intensity of mm (SD 5 3.1) compared with a distance of 2.5 mm (SD 5 1.3) a sound until it matched the tinnitus sound. The maximum of a corresponding frequency in the healthy controls (t 5 3.13, deviation of the two procedures was 50 Hz and 4 db; thus the P < 0.01). In addition, a strong positive correlation was found determination of the tinnitus sound was very reliable. Four between the subjective strength of the tinnitus and the amount tinnitus subjects had right ear, two subjects had left ear, and of cortical reorganization (r 5 0.82, P < 0.01). These results four subjects had bilateral tinnitus. Subjectively experienced demonstrate that tinnitus is related to plastic alterations in tinnitus strength was assessed by the German version of the auditory cortex. Similarities between these data and the West Haven-Yale Multidimensional Pain Inventory (12, 13), previous demonstrations that phantom limb pain is highly which was modified so that sounds instead of pain were correlated with cortical reorganization suggest that tinnitus assessed (thus comprising the Multidimensional Tinnitus In- may be an auditory phantom phenomenon. ventory or MIT). Its convergent validity, assessed by correlat- ing it with the commonly used visual analogue scale, yielded a Subjective tinnitus is characterized by the perception of audi- high (for validity studies) correlation coefficient of 0.53. The stability and internal consistency of the MTI scale is also tory signals experienced in the absence of any internal or 5 5 external source of sound. This very disturbing phenomenon is excellent: Cronbach’s alpha 0.93; test-retest reliability r experienced by 35% of the population at some point in their 0.91. Informed consent was obtained after the nature and lives, and in about 1% of the population it seriously interferes possible consequences of the study were explained. with a person’s life (1–4). A central nervous system correlate Auditory Stimulation. Four sets of 200 pure tone pulses of of subjective tinnitus has long been sought, but has not been 500 msec duration and 70 dB above the individual hearing level found (5–7). Based on previous findings from our group were presented sequentially to each ear with an interstimulus reporting a close association of phantom limb pain and reor- interval of 2 sec. The sequence of sets of tones and order of ganization of primary somatosensory cortex (8, 9), we hypoth- initial side of stimulation were determined by a random esized that tinnitus might be a phantom phenomenon (10) process. In the healthy controls, standard carrier frequencies related to alterations of the tonotopic map in auditory cortex. of 1,000, 2,000, 4,000, and 8,000 Hz were used. In the tinnitus To evaluate this possibility, magnetic source imaging was used group, the three standard frequencies that were most distant to determine the tonotopic organization of the auditory cortex from the tinnitus frequency were used as standard stimuli. The in groups of tinnitus subjects and healthy controls. fourth tone was chosen to match the tinnitus frequency (mean 5 4,500 Hz, SD 5 1,100) and the standard tone that was closest to this frequency (4,000 Hz in all cases) was deleted MATERIALS AND METHODS from the tone series. Study Patients. Ten right-handed tinnitus subjects with Neuromagnetic Source Imaging. During auditory stimula- tonal tinnitus between 2,000 and 8,000 Hz and a maximal tion, magnetoencephalographic recordings were carried out in hearing loss of 25 dB below the normative hearing level and 15 a magnetically shielded room by using a 37-channel neuro- right-handed controls with normal hearing and without tinni- magnetometer (Magnes Biomagnetic Technologies, San Di- tus participated in the study. In the samples we have studied ego, CA). The stimulus-related fields were recorded from an thus far, 80% of the patients complained of tonal as compared area under a circular sensor array 14.4 cm in diameter centered over the auditory cortex of the two hemispheres in an order with noisiform tinnitus. This incidence is in accordance with counterbalanced between subjects. The magnetic signals were that reported in the literature (11). The present data are thus sampled at a rate of 296 Hz, digitally filtered by using 0.1 Hz relevant to the majority of tinnitus sufferers. The tinnitus high-pass and 20 Hz low-pass filters and selectively averaged The publication costs of this article were defrayed in part by page charge This paper was submitted directly (Track II) to the Proceedings office. payment. This article must therefore be hereby marked ‘‘advertisement’’ in Abbreviations: n.s., not significant; MTI, Multidimensional Tinnitus accordance with 18 U.S.C. §1734 solely to indicate this fact. Inventory. © 1998 by The National Academy of Sciences 0027-8424y98y9510340-4$2.00y0 §To whom reprint requests should be addressed. e-mail: [email protected] PNAS is available online at www.pnas.org. berlin.de. 10340 Downloaded by guest on September 24, 2021 Psychology: Mu¨hlnickel et al. Proc. Natl. Acad. Sci. USA 95 (1998) 10341 Table 1. Demographic and clinical aspects of the tinnitus group Hearing loss at the Tinnitus tinnitus Tinnitus Subject Age, Affected strength, frequency, frequency, Duration, # yr Gender ear MTI dB Hz yr 2 31 M Left 1.0 15 4,200 6 3 38 M Right 5.3 10 4,000 2 5 32 M Both 4.3 10 5,900 3 6 35 M Both 4.0 14 6,000 1 7 18 F Right 3.3 13 4,000 1 11 36 F Right 2.0 6 4,200 6 13 31 F Both 4.6 10 6,000 2 15 29 M Right 3.6 25 3,000 7 17 32 M Both 4.6 20 4,000 5 18 20 M Left 4.3 15 3,700 1 Mean 32.4 3.7 4,500 3.4 Tinnitus strength was assessed by the tinnitus severity scale of the MTI, which is composed of three items referring to the severity of the sounds at the present time, during the previous week, and the amount of suffering related to the sounds on a seven-point scale ranging from 0 5 none to 6 5 extreme. for each stimulus frequency. The location of the peak of the 4,000 Hz was chosen as the corresponding ‘‘tinnitus frequency’’ N1m component of the stimulus-related field was identified of the healthy controls. The mean Euclidean distance between within the range of 50–160 msec by using a single equivalent this frequency and the trajectory formed by the three remain- current dipole (ECD) model in a homogeneous spherical ing standard frequencies was 2.5 mm (SD 5 1.3) for the two volume conductor. N1m has been shown to be tonotopically hemispheres of the healthy controls. Thus, this distance was represented in primary auditory cortex, mainly Brodman’s more than twice as large in the contralateral hemisphere of the area 41. Actual latencies varied between 77 and 138 msec tinnitus subjects as in both hemispheres of the healthy controls across subjects with a mean latency of 97 msec; there were no (t 5 3.13, P , 0.01), indicating that there was an expansion of significant differences between the tinnitus subjects and the tonotopic map in the tinnitus subjects. The Euclidean healthy controls. The dipole locations were computed from a distance measure in the ipsilateral hemisphere of the tinnitus selection of points within a 50-msec time segment around the subjects was not significantly different from this measure in maximum rms amplitude across the 37 channels. Points were both hemispheres of the controls (t 5 1.05, n.s.) nor were the selected if they met the following requirements: (i)rms distances in the contralateral and ipsilateral hemispheres in the indicating a signal-to-noise ratio .3, (ii) goodness of fit of the tinnitus subjects significantly different from each other (t 5 ECD model to the measured field .0.90, and (iii) a minimal 0.96, n.s.).