Abstract
The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients (n = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph (n = 41) obtained from hearing-impaired patients (n = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.
Highlights
One of the challenges in cochlear implantation is to understand the wide variability in performance amongst users
To determine the biologically significant pathways regulated by Brain derived neurotrophic factor (BDNF) in the cochlea, we determined which components of neurotrophin signaling were present at a high level in the normal inner ear
We have demonstrated that BDNF is expressed in cochlear tissue in normal hearing individuals
Summary
One of the challenges in cochlear implantation is to understand the wide variability in performance amongst users. Candidates with similar history and implanted with the same device can demonstrate outcomes on both ends of the spectrum (Carlson et al, 2012). Since human temporal bone studies have recently shown a link between spiral ganglion population and cochlear implant outcomes (Seyyedi et al, 2014), one of the research targets is to maintain the viable population of spiral ganglion neurons for stimulation. Objective measures of cochlear function suggest that a healthier neuronal population may result in better speech outcomes (Kim et al, 2010). This raises the possibility of modulating spiral ganglion function and health through drug delivery to the inner ear in conjunction with cochlear implantation
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