Faculty Bibliography

OBJECTIVES/HYPOTHESIS: To determine the prevalence of otologic complaints in subjects with dysphonia and traumatic brain injury (TBI) in a sample population of the US Army. STUDY DESIGN: Cross-sectional study. METHODS: A total of 292 subjects were identified with a new diagnosis of voice disorder during a 3.5-year period at three large military medical centers. Of them, 70 subjects were also identified with TBI and had no history of dysphonia before this time period. In those with voice disorders and TBI, documentation of hearing complaints, hearing loss, tinnitus, or vertigo was recorded. Time to visit an otolaryngologist and audiologist were also recorded. RESULTS: A total of 70 soldiers were identified with a diagnosis of a voice disorder and TBI. Of these soldiers, 83% had at least one otologic complaint and 50% had more than one. Approximately 60%, 39%, and 44% of the subjects reported tinnitus, hearing loss, or vertigo, respectively. A total of 62% of the subjects with otologic complaints, TBI, and dysphonia were seen by an otolaryngologist. Time until an otolaryngologist evaluated these soldiers varied widely, with an average of 17 months and standard deviation of 12.5 months. CONCLUSIONS: Otologic manifestations are common in soldiers with dysphonia and TBI. Careful consideration of communication impairment from otologic dysfunction in those with speech disorders after TBI is warranted.

Micro-Electrocorticography (muECoG) offers a minimally invasive, high resolution interface with large areas of cortex. However, large arrays of electrodes with many contacts that are individually wired to external recording systems are cumbersome and make chronic recording in freely behaving small animals challenging. Multiplexed headstages overcome this limitation by combining the signals from many electrodes to a smaller number of connections directly on the animal's head. Commercially available multiplexed headstages provide high performance integrated amplification, multiplexing and analog to digital conversion. However, the cost of these systems can be prohibitive for small labs or for experiments that require a large number of animals to be continuously recorded at the same time. Here we have developed a multiplexed 60-channel headstage amplifier optimized to chronically record electrophysiological signals from high-density muECoG electrode arrays. A single, ultraflexible (2 mm thickness) microHDMI cable provided the data interface. Using low cost components, we have reduced the cost of the multiplexed headstage to ~$125. Paired with a custom interface printed circuit board (PCB) and a general purpose data acquisition system (M-series DAQ, National Instruments), an inexpensive and customizable electrophysiology system is assembled. Open source LabVIEW software that we have previously released controlled the system. It can also be used with other open source neural data acquisition packages. Combined, we have presented a scalable, low-cost platform for high-channel count electrophysiology.

Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL-Ecad-RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival.

This study investigates the feasibility of using binaural dichotic presentation of speech components decomposed using a recently proposed resonance-based decomposition method to release listeners from intra-speech masking and yield better perceived sound quality. Resonance-based decomposition is a nonlinear signal analysis method based not on frequency or scale but on resonance. We decomposed different categories of speech stimuli (vowels, consonants, and sentences) into low-and high-resonance component using various combination of low-and high-Q-factors {Q1,Q2}. 10 normal hearing listeners were asked to rate the perceived quality of each individual decomposed component presented diotically, and in pair presented dichotically. We found that the perceived quality rating of these resonance components when presented in pair was higher than the mean of perceived quality ratings of these resonance components when presented individually. Our result suggests that listeners were able to fuse binaural dichotic presentation of high-and low-resonance components and perceived better sound quality.

Principal neurons of the lateral superior olivary nucleus (LSO) respond selectively to interaural level differences (ILD). To perform this computation, LSO neurons integrate excitatory synaptic drive from the ipsilateral ear with inhibitory synaptic drive from the contralateral ear via the medial nucleus of the trapezoid body (MNTB). Previous research demonstrated that inhibitory terminals from the MNTB to the LSO are eliminated during development. Furthermore, MNTB synapses display an activity- and age-dependent long-term depression (iLTD) that may contribute to inhibitory synapse elimination. However, inhibitory synapses that are stabilized become stronger. Here, we asked whether MNTB synapses displayed activity-dependent strengthening. Whole-cell recordings were obtained from LSO neurons in a gerbil brain slice before and after hearing onset. The inhibitory MNTB afferents were stimulated at a low rate, similar to spontaneous discharge rates observed in vivo. The MNTB-evoked inhibitory responses were strengthened by 40-300% when synaptic activity was coupled with postsynaptic membrane depolarization, exogenous glutamate application, or activation of ipsilateral excitatory synaptic inputs. This inhibitory long-term potentiation (iLTP) was associated with increased spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. One hour after iLTP induction, IPSCs could not be de-potentiated by the MNTB stimulation pattern that induces iLTD in control slices. iLTP could only be induced after hearing onset (>P12), and was blocked in the presence of a GABAB receptor antagonist. Together, these results suggest a developmental period during which the induction of iLTP depends on the conjoint activation of GABAB receptors and postsynaptic depolarization. We propose that iLTP may support stabilization of un-pruned MNTB connections and contribute to the emergence of ILD processing in the mature LSO.

HYPOTHESIS: Pretreatment with antiherpetic medications and steroids decreases likelihood of development of delayed facial paralysis (DFP) after otologic surgery. BACKGROUND: Heat-induced reactivation of herpes simplex virus type 1 (HSV1) in geniculate ganglion neurons (GGNs) is thought to cause of DFP after otologic surgery. Antiherpetic medications and dexamethasone are used to treat DFP. Pretreatment with these medications has been proposed to prevent development of DFP. METHODS: Rat GGN cultures were latently infected with HSV1 expressing a lytic protein-GFP chimera. Cultures were divided into pretreatment groups receiving acyclovir (ACV), acyclovir-plus-dexamethasone (ACV + DEX), dexamethasone alone (DEX), or untreated media (control). After pretreatment, all cultures were heated 43 degrees C for 2 hours. Cultures were monitored daily for reactivation with fluorescent microscopy. Viral titers were determined from culture media. RESULTS: Heating cultures to 43 degrees C for 2 hours leads to HSV1 reactivation and production of infectious virus particles (59 +/- 6.8%); heating cultures to 41 degrees C showed a more variable frequency of reactivation (60 +/- 40%), compared with baseline rates of 14.4 +/- 5%. Cultures pretreated with ACV showed lower reactivation rates (ACV = 3.7%, ACV + DEX = 1.04%) compared with 44% for DEX alone. Viral titers were lowest for cultures treated with ACV or ACV + DEX. CONCLUSION: GGN cultures harboring latent HSV1 infection reactivate when exposed to increased temperatures that can occur during otologic surgery. Pretreatment with ACV before heat provides prophylaxis against heat-induced HSV reactivation, whereas DEX alone is associated with higher viral reactivation rates. This study provides evidence supporting the use of prophylactic antivirals for otologic surgeries associated with high rates of DFP.

IMPORTANCE: There continues to be a paucity of data regarding the pharyngeal plexus (PP) and its interconnectivity with the laryngeal nerves and function. OBJECTIVE: To identify the specific neural pathways involved in the glottic closure reflex (GCR)-like pathway of the PP and other pathways to the thyroarytenoid (TA) muscle in the porcine model. DESIGN, SETTING, AND ANIMAL SUBJECTS: Animal experimental study from September 2013 to June 2014 conducted in a tertiary academic medical center on male Yorkshire pigs. INTERVENTIONS: Contraction of the TA was detected with electromyography (EMG) during electrical stimulation of the PP in 7 porcine necks. Subsequently, the external branch of the superior laryngeal nerve (eSLN), communicating nerve of Galen (NG), and the recurrent laryngeal nerve (RLN) were sequentially transected to help elucidate the path of neural conduction. MAIN OUTCOMES AND MEASURES: Confirmation of TA muscle contraction by EMG. RESULTS: Stimulation of the PP evoked a response from the TA muscle in 6 of 7 subject animals. In 3 of 7 subjects, a long latency response (mean, 14.62 milliseconds) was identified, which was eliminated only after transection of the RLN. In 3 of 7 subjects, a short latency response (mean 3.05 milliseconds) was identified, which disappeared in 1 subject each by eSLN, RLN, and NG transection. CONCLUSIONS AND RELEVANCE: We identified the specific neural pathway involved in the PP's GCR-like pathway. We also noted a variable direct pattern of innervation to the TA.

Quantitative levels of harmful oral microbes present following complex surgical excisions of head and neck cancer are important since wounds are often contaminated through direct connection to the oral cavity and its flora. This possibility is especially important in irradiated patients who have decreased protective salivary function. In addition, high oral microbial levels increase and intensify oral mucositis leading to significant morbidity in patients treated with radiation therapy. One previously untested surgical teaching to decrease the bacterial inoculum present in the oral cavity is to counsel patients against consuming otherwise nutritious dairy products, as they are thought to coat the oral cavity with rate-limiting nutrients vital for bacterial growth. This risk may extend to individuals with chronic laryngeal penetration or aspiration, since salivary bacterial load might represent a lethal threat in the presence of marginal pulmonary reserve. A crossover study using six healthy adult volunteers and six patients who had previously undergone radiation therapy to an oropharyngeal primary site was performed. Saliva samples were quantitatively cultured in both groups with and without the consumption of dairy products at 1-h and 5-h intervals. Analysis of quantitative cultures demonstrated that the consumption of dairy products had no influence on bacterial levels present in previously radiated subjects and nonirradiated controls. Additionally, the consumption of dairy did not affect the composition of microbes present. Due to the lack of changes in both quantity and composition of oral bacteria seen in this study, patients would not benefit from the avoidance of dairy products.