Stable long-term outcomes after cochlear implantation in subjects with TMPRSS3 associated hearing loss: a retrospective multicentre study.

BACKGROUND: The spiral ganglion hypothesis suggests that pathogenic variants in genes preferentially expressed in the spiral ganglion nerves (SGN), may lead to poor cochlear implant (CI) performance. It was long thought that TMPRSS3 was particularly expressed in the SGNs. However, this is not in line with recent reviews evaluating CI performance in subjects with TMPRSS3-associated sensorineural hearing loss (SNHL) reporting overall beneficial outcomes. These outcomes are, however, based on variable follow-up times of, in general, 1 year or less. Therefore, we aimed to 1. evaluate long-term outcomes after CI implantation of speech recognition in quiet in subjects with TMPRSS3-associated SNHL, and 2. test the spiral ganglion hypothesis using the TMPRSS3-group. METHODS: This retrospective, multicentre study evaluated long-term CI performance in a Dutch population with TMPRSS3-associated SNHL. The phoneme scores at 70 dB with CI in the TMPRSS3-group were compared to a control group of fully genotyped cochlear implant users with post-lingual SNHL without genes affecting the SGN, or severe anatomical inner ear malformations. CI-recipients with a phoneme score ≤ 70% at least 1-year post-implantation were considered poor performers and were evaluated in more detail. RESULTS: The TMPRSS3 group consisted of 29 subjects (N = 33 ears), and the control group of 62 subjects (N = 67 ears). For the TMPRSS3-group, we found an average phoneme score of 89% after 5 years, which remained stable up to 10 years post-implantation. At both 5 and 10-year follow-up, no difference was found in speech recognition in quiet between both groups (p = 0.830 and p = 0.987, respectively). Despite these overall adequate CI outcomes, six CI recipients had a phoneme score of ≤ 70% and were considered poor performers. The latter was observed in subjects with residual hearing post-implantation or older age at implantation. CONCLUSION: Subjects with TMPRSS3-associated SNHL have adequate and stable long-term outcomes after cochlear implantation, equal to the performance of genotyped patient with affected genes not expressed in the SGN. These findings are not in line with the spiral ganglion hypothesis. However, more recent studies showed that TMPRSS3 is mainly expressed in the hair cells with only limited SGN expression. Therefore, we cannot confirm nor refute the spiral ganglion hypothesis.

Neural correlates of human somatosensory integration in tinnitus.

Possible neural correlates of somatosensory modulation of tinnitus were assessed. Functional magnetic resonance imaging (fMRI) was used to investigate differences in neural activity between subjects that can modulate their tinnitus by jaw protrusion and normal hearing controls. We measured responses to bilateral sound and responses to jaw protrusion. Additionally we studied multimodal integration of somatosensory jaw protrusion and sound. The auditory system responded to both sound and jaw protrusion. Jaw responses were enhanced in the cochlear nucleus (CN) and the inferior colliculus (IC) in tinnitus patients. The responses of the auditory brain areas to jaw protrusion presumable account for the modulation of tinnitus as described by the patients. The somatosensory system responded to jaw protrusion and not to sound. These responses occurred both in subjects with tinnitus and controls. Unexpectedly, the cerebellum responded to sound in normal hearing subjects, but not in tinnitus patients. Together, these results provide a neurophysiological basis for the effect of jaw protrusion on tinnitus.

Neural activity underlying tinnitus generation: results from PET and fMRI.

Tinnitus is the percept of sound that is not related to an acoustic source outside the body. For many forms of tinnitus, mechanisms in the central nervous system are believed to play an important role in the pathology. Specifically, three mechanisms have been proposed to underlie tinnitus: (1) changes in the level of spontaneous neural activity in the central auditory system, (2) changes in the temporal pattern of neural activity, and (3) reorganization of tonotopic maps. The neuroimaging methods fMRI and PET measure signals that presumably reflect the firing rates of multiple neurons and are assumed to be sensitive to changes in the level of neural activity. There are two basic paradigms that have been applied in functional neuroimaging of tinnitus. Firstly, sound-evoked responses as well as steady state neural activity have been measured to compare tinnitus patients to healthy controls. Secondly, paradigms that involve modulation of tinnitus by a controlled stimulus allow for a within-subject comparison that identifies neural activity that may be correlated to the tinnitus percept. Even though there are many differences across studies, the general trend emerging from the neuroimaging studies, is that tinnitus in humans may correspond to enhanced neural activity across several centers of the central auditory system. Also, neural activity in non-auditory areas including the frontal areas, the limbic system and the cerebellum seems associated with the perception of tinnitus. These results indicate that in addition to the auditory system, non-auditory systems may represent a neural correlate of tinnitus. Although the currently published neuroimaging studies typically show a correspondence between tinnitus and enhanced neural activity, it will be important to perform future studies on subject groups that are closely matched for characteristics such as age, gender and hearing loss in order to rule out the contribution of these factors to the abnormalities specifically ascribed to tinnitus.

Functional imaging of unilateral tinnitus using fMRI.

CONCLUSIONS: This article shows that the inferior colliculus plays a key role in unilateral subjective tinnitus. OBJECTIVES: The major aim of this study was to determine tinnitus-related neural activity in the central auditory system of unilateral tinnitus subjects and compare this to control subjects without tinnitus. SUBJECTS AND METHODS: Functional MRI (fMRI) was performed in 10 patients (5 males) with unilateral tinnitus (5 left-sided, 5 right-sided) and 12 healthy subjects (6 males); both groups had normal hearing or mild hearing loss. fMRI experiments were performed using a 3T Philips Intera Scanner. Auditory stimuli were presented left or right and consisted of dynamically rippled broadband noise with a sound pressure level of 40 or 70 dB SPL. The responses of the inferior colliculus and the auditory cortex to the stimuli were measured. RESULTS: The response to sound in the inferior colliculus was elevated in tinnitus patients compared with controls without tinnitus.