Rationale: The overall goal of this 2017 Neurofibromatosis Research Program research proposal is to improve hearing in deaf patients with neurofibromatosis type 2 (NF-2). The hallmark of NF-2 is the growth of brain tumors that injure the balance and hearing nerves in both ears. These tumors are called vestibular schwannomas and result in permanent hearing loss in all NF-2 patients due to their continued growth and/or surgical removal. NF-2 patients are not candidates for a cochlear implant (CI), as a CI requires intact hearing nerves. The only hearing improvement therapy approved for deaf NF-2 patients in the United States is the auditory brainstem implant (ABI), which was approved in 2000 and is based on technology that is almost three decades old.

The ABI has a flat electrode array that is placed on a specialized group of nerves in the brainstem called the cochlear nucleus. The ABI bypasses the inner ear and damaged hearing nerves to provide hearing sensations to the brain. Most NF-2 ABI patients have meaningful sound perception that improves lip-reading abilities, but only rarely does an NF-2 ABI user experience speech recognition (unlike most CI users). In addition, many patients with the ABI have side effects, resulting in the need to turn off channels to reduce overall sound input to the brain.

Our knowledge of the ABI took a step forward when we developed new computed tomography (CT or CAT scan) methods and showed for the first time that ABI array location on the brainstem varies considerably from patient to patient. These observations may be explained by the challenging nature of ABI surgery. The surgeon must place the ABI blindly using surrounding brainstem landmarks and electrical recordings because the target of the electrode array (the cochlear nucleus) is not directly seen. Thus, one goal of this proposal is to use our new imaging methods to improve targeting of ABI placement and thereby improve hearing outcomes for recipients. Additionally, existing ABI electrode arrays are rigid and flat and do not sit well on the curved surface of the brainstem. Thus, a further goal of this proposal is to develop and test new flexible electrode arrays that circumvent this problem by conforming to the brainstem.

Objectives/Aims:

1. All ABI patients receive routine CT scans of the brain several hours to days following craniotomy surgery. Using these standard CT scans, we will perform digital image processing to eliminate the metal artifact of the ABI electrodes and create a three-dimensional (3D) reconstruction of the skull. This exciting new approach will allow our research team to accurately pinpoint the precise position of the ABI electrode array. Unlike CI surgery or deep brain stimulation implant surgery, where CT scans and magnetic resonance imaging (MRI) scans are used routinely to guide the surgeon or confirm appropriate placement, imaging has not been used for ABI surgery until now. Therefore, the ideal ABI array position is not known. We will thus assess how the position of the ABI array varies with clinical responses from implanted patients (such as hearing outcomes and the number of usable electrodes) and identify the ideal positioning.

2. The second surgical guide used during ABI surgery involves the electrical responses recorded by stimulating the brain with the ABI. These responses can vary widely based on ABI array position, and even which individual electrode(s) are used. We will correlate the ideal positioning identified in Aim 1 with these responses to identify the optimal ABI position that is associated with the best electrical recordings.

3. Even with perfect placement of the ABI electrode array using the above techniques, outcomes would still be limited because the flat and rigid ABI array itself does not fit well to the curved surface of the brainstem. This result causes some electrodes, particularly those on the edge of the array, to have insufficient contact with the target. This third part of our proposal focuses on developing flexible electrodes using new materials that can better fit the brainstem, a highly specialized technology invented by our scientific collaborator of 5 years, Professor Stéphanie Lacour at EPFL in Geneva, Switzerland.

Target Population: NF-2 patients who are candidates for or users of the ABI.

Clinical Applications and Timeline: A major strength of our proposal is the immediate potential for clinical translation. The ideal position and optimal waveforms identified in Aims 1 and 2 can readily be used during surgery to guide placement, especially given the availability of surgical CT navigation technology, including at our institution. In addition, though more long-term in perspective, the flexible electrode design and novel biomaterials used in Aim 3 have already been extensively tested in animal models by our research team, and this proposal represents their first translation to humans.

Overall Impact/Contribution: It is extremely disappointing to offer a deaf NF-2 patient a hearing implant that provides modest benefits and little to no speech recognition, unlike the CI or a hearing aid. Despite these limitations, the ABI device and its surgical implantation techniques have remained largely unchanged since its initial development three decades ago. Our proposal brings together a multi-disciplinary, multi-institutional team to address this neglected area of NF2 research and could drastically improve hearing and quality of life for deaf NF-2 patients.