Different bimodal neuromodulation settings reduce tinnitus symptoms in a large randomized trial.

More than 10% of the population suffers from tinnitus, which is a phantom auditory condition that is coded within the brain. A new neuromodulation approach to treat tinnitus has emerged that combines sound with electrical stimulation of somatosensory pathways, supported by multiple animal studies demonstrating that bimodal stimulation can elicit extensive neural plasticity within the auditory brain. More recently, in a large-scale clinical trial, bimodal neuromodulation combining sound and tongue stimulation drove significant reductions in tinnitus symptom severity during the first 6 weeks of treatment, followed by diminishing improvements during the second 6 weeks of treatment. The primary objective of the large-scale randomized and double-blinded study presented in this paper was to determine if background wideband noise as used in the previous clinical trial was necessary for bimodal treatment efficacy. An additional objective was to determine if adjusting the parameter settings after 6 weeks of treatment could overcome treatment habituation effects observed in the previous study. The primary endpoint at 6-weeks involved within-arm and between-arm comparisons for two treatment arms with different bimodal neuromodulation settings based on two widely used and validated outcome instruments, Tinnitus Handicap Inventory and Tinnitus Functional Index. Both treatment arms exhibited a statistically significant reduction in tinnitus symptoms during the first 6-weeks, which was further reduced significantly during the second 6-weeks by changing the parameter settings (Cohen's d effect size for full treatment period per arm and outcome measure ranged from - 0.7 to - 1.4). There were no significant differences between arms, in which tongue stimulation combined with only pure tones and without background wideband noise was sufficient to reduce tinnitus symptoms. These therapeutic effects were sustained up to 12 months after the treatment ended. The study included two additional exploratory arms, including one arm that presented only sound stimuli during the first 6 weeks of treatment and bimodal stimulation in the second 6 weeks of treatment. This arm revealed the criticality of combining tongue stimulation with sound for treatment efficacy. Overall, there were no treatment-related serious adverse events and a high compliance rate (83.8%) with 70.3% of participants indicating benefit. The discovery that adjusting stimulation parameters overcomes previously observed treatment habituation can be used to drive greater therapeutic effects and opens up new opportunities for optimizing stimuli and enhancing clinical outcomes for tinnitus patients with bimodal neuromodulation.

Positron Emission Tomography Imaging Reveals Auditory and Frontal Cortical Regions Involved with Speech Perception and Loudness Adaptation.

Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi-tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up-regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus.

Auditory midbrain implant: research and development towards a second clinical trial.

The cochlear implant is considered one of the most successful neural prostheses to date, which was made possible by visionaries who continued to develop the cochlear implant through multiple technological and clinical challenges. However, patients without a functional auditory nerve or implantable cochlea cannot benefit from a cochlear implant. The focus of the paper is to review the development and translation of a new type of central auditory prosthesis for this group of patients that is known as the auditory midbrain implant (AMI) and is designed for electrical stimulation within the inferior colliculus. The rationale and results for the first AMI clinical study using a multi-site single-shank array will be presented initially. Although the AMI has achieved encouraging results in terms of safety and improvements in lip-reading capabilities and environmental awareness, it has not yet provided sufficient speech perception. Animal and human data will then be presented to show that a two-shank AMI array can potentially improve hearing performance by targeting specific neurons of the inferior colliculus. A new two-shank array, stimulation strategy, and surgical approach are planned for the AMI that are expected to improve hearing performance in the patients who will be implanted in an upcoming clinical trial funded by the National Institutes of Health. Positive outcomes from this clinical trial will motivate new efforts and developments toward improving central auditory prostheses for those who cannot sufficiently benefit from cochlear implants. This article is part of a Special Issue entitled .

Electrical stimulation of the midbrain for hearing restoration: insight into the functional organization of the human central auditory system.

The cochlear implant can restore speech perception in patients with sensorineural hearing loss. However, it is ineffective for those without an implantable cochlea or a functional auditory nerve. These patients can be implanted with the auditory brainstem implant (ABI), which stimulates the surface of the cochlear nucleus. Unfortunately, the ABI has achieved limited success in its main patient group [i.e., those with neurofibromatosis type 2 (NF2)] and requires a difficult surgical procedure. These limitations have motivated us to develop a new hearing prosthesis that stimulates the midbrain with a penetrating electrode array. We recently implanted three patients with the auditory midbrain implant (AMI), and it has proven to be safe with minimal movement over time. The AMI provides loudness, pitch, temporal, and directional cues, features that have shown to be important for speech perception and more complex sound processing. Thus far, all three patients obtain enhancements in lip reading capabilities and environmental awareness and some improvements in speech perception comparable with that of NF2 ABI patients. Considering that our midbrain target is more surgically exposable than the cochlear nucleus, this argues for the use of the AMI as an alternative to the ABI. Fortunately, we were able to stimulate different midbrain regions in our patients and investigate the functional organization of the human central auditory system. These findings provide some insight into how we may need to stimulate the midbrain to improve hearing performance with the AMI.

Antidromic activation reveals tonotopically organized projections from primary auditory cortex to the central nucleus of the inferior colliculus in guinea pig.

The inferior colliculus (IC) is highly modulated by descending projections from higher auditory and nonauditory centers. Traditionally, corticofugal fibers were believed to project mainly to the extralemniscal IC regions. However, there is some anatomical evidence suggesting that a substantial number of fibers from the primary auditory cortex (A1) project into the IC central nucleus (ICC) and appear to be tonotopically organized. In this study, we used antidromic stimulation combined with other electrophysiological techniques to further investigate the spatial organization of descending fibers from A1 to the ICC in ketamine-anesthetized guinea pigs. Based on our findings, corticofugal fibers originate predominantly from layer V of A1, are amply scattered throughout the ICC and only project to ICC neurons with a similar best frequency (BF). This strict tonotopic pattern suggests that these corticofugal projections are involved with modulating spectral features of sound. Along the isofrequency dimension of the ICC, there appears to be some differences in projection patterns that depend on BF region and possibly isofrequency location within A1 and may be indicative of different descending coding strategies. Furthermore, the success of the antidromic stimulation method in our study demonstrates that it can be used to investigate some of the functional properties associated with corticofugal projections to the ICC as well as to other regions (e.g., medial geniculate body, cochlear nucleus). Such a method can address some of the limitations with current anatomical techniques for studying the auditory corticofugal system.