Faculty Bibliography

Down Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), while abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Auditory brainstem implants (ABIs) stimulate the auditory system at the cochlear nucleus, bypassing the peripheral auditory system including the auditory nerve. They are used in patients who are not cochlear implant candidates. Current criteria for use in the United States are neurofibromatosis type 2 patients 12 years or older undergoing first- or second-side vestibular schwannoma removal. However, there are other nontumor conditions in which patients may benefit from an ABI, such as bilateral cochlear nerve aplasia and severe cochlear malformation not amendable to cochlear implantation. Recent experience with ABI in the pediatric population demonstrates good safety profile and encouraging results.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Description of a novel use of a submandibular gland (SMG) flap pedicled on the facial vessels to restore facial volume after parotidectomy, and comparison of clinical outcomes with alternative modes of reconstruction. STUDY DESIGN/METHODS:Retrospective chart review. METHODS:The surgical technique for a SMG flap is described. Retrospective chart review of cases of parotidectomy at a single tertiary medical center was conducted (n = 43). Cases were grouped in three cohorts of consecutive patients depending on reconstruction technique: SMG flap (n = 13), sternocleidomastoid muscle (SCM) flap (n = 15), and no flap (n = 15). Cohort characteristics and complication rates are reported. RESULTS:The SMG flap was more often used for a malignant pathology (92%) and in conjunction with a neck dissection (100%), compared to the SCM flap (47% and 15%) or no flap (0% and 0%), respectively. The mean House-Brackmann score in the immediate postoperative period in the SMG-flap group was slightly elevated compared to the other groups: 1.6 (standard deviation [SD] ± 0.5) versus 1.1 (SD ± 0.3) and 1.0 (SD ± 0.0). Otherwise, the complication rate was similar across groups. CONCLUSIONS:The SMG flap is a safe and effective option for volume restoration after parotidectomy. It provides durable volume that will not atrophy and is already exposed in the field of dissection for patients undergoing concurrent level I neck dissection. LEVEL OF EVIDENCE/METHODS:3.

Pathogenic variants in COCH, encoding cochlin, cause DFNA9 deafness disorder with characteristic histopathologic findings of cochlin deposits in the inner and middle ears. Here, we present the first case of deafness associated with bilateral external auditory canal (EAC) cochlin deposits, previously unreported evidence suggestive of cochlin-derived amyloid formation, and a novel COCH variant. A 54-year-old woman presented with progressive sensorineural hearing loss and bilateral EAC narrowing by subcutaneous thickening. Excision and histologic evaluation of tissue from both EACs showed paucicellular eosinophilic aggregates containing multiple Congo red-positive foci with yellow and green birefringence under crossed polarization light microscopy. Mass spectrometry performed on both the Congo red-positive and Congo red-negative areas identified cochlin as the most abundant protein, as well as a low abundance of universal amyloid signature peptides only in the Congo red-positive areas. Peptides indicative of a canonical amyloid type were not detected. Electron microscopy showed haphazard, branched microfibrils (3-7 nm in diameter) consistent with cochlin, as well as swirling fibrils (10-24 nm in diameter) reminiscent of amyloid fibrils. Cochlin immunohistochemical staining showed positivity throughout the aggregates. Sequencing of the entire COCH gene coding region from the patient's blood revealed a novel variant resulting in a non-conservative amino acid substitution of isoleucine to phenylalanine (c.1621A>T, p.I541F) in the vWFA2 domain at the protein's C-terminus. Our findings reveal a new pathologic manifestation of cochlin, raise the possibility of previously undescribed cochlin-derived amyloid formation, and highlight the importance of thoroughly investigating all aggregative tissue findings in the practice of diagnostic pathology.

PURPOSE/OBJECTIVE:Though the use of the pedicled nasoseptal flap (NSF), a reconstructive technique used after endoscopic endonasal approaches (EEA) for resection of craniopharyngiomas, has been shown to reduce the occurrence of post-operative cerebrospinal fluid (CSF) leaks in adults, less is known about its use in pediatric populations, specifically in children under the age of 7. The goal of this retrospective cohort study is to determine the viability of the pedicled NSF for pediatric patients. METHODS:Retrospective review of 12 pediatric patients (ages 2-16) undergoing 13 NSF reconstructions after resection of craniopharyngiomas. Radioanatomic analysis of computed tomography (CT) scans was utilized to classify the pneumatization of the sphenoid sinus depending on the thickness of the sphenoid bone margin. Intercarotid distances were measured from magnetic resonance imaging (MRI) scans to assess the feasibility of this reconstruction technique in pediatric patients. RESULTS:At the time of surgery, all patients were noted to have adequate NSF length and width. No post-operative high-flow CSF leaks were found within the group. Lack of pneumatization of the sphenoid sinus and narrow intercarotid distances in the youngest of patients did not lead to negative clinical outcomes. CONCLUSIONS:Based on our results and experience, the pedicled nasoseptal flap is a viable reconstructive option after EEA in the pediatric population, including even the youngest of patients. In these patients, a narrowed window between the intercarotid arteries and the lack of pneumatization of the sphenoid sinus present a challenge that can be overcome by using stereotactic navigation and advanced endoscopic techniques.

OBJECTIVES/OBJECTIVE:Cochlear implants (CIs) restore speech perception in quiet but they also eliminate or distort many acoustic cues that are important for music enjoyment. Unfortunately, quantifying music enjoyment by CI users has been difficult because comparisons must rely on their recollection of music before they lost their hearing. Here, we aimed to assess music enjoyment in CI users using a readily interpretable reference based on acoustic hearing. The comparison was done by testing "single-sided deafness" (SSD) patients who have normal hearing (NH) in one ear and a CI in the other ear. The study also aimed to assess binaural musical enjoyment, with the reference being the experience of hearing with a single NH ear. Three experiments assessed the effect of adding different kinds of input to the second ear: electrical, vocoded, or unmodified. DESIGN/METHODS:In experiment 1, music enjoyment in SSD-CI users was investigated using a modified version of the MUSHRA (MUltiple Stimuli with Hidden Reference and Anchor) method. Listeners rated their enjoyment of song segments on a scale of 0 to 200, where 100 represented the enjoyment obtained from a song segment presented to the NH ear, 0 represented a highly degraded version of the same song segment presented to the same ear, and 200 represented enjoyment subjectively rated as twice as good as the 100 reference. Stimuli consisted of acoustic only, electric only, acoustic and electric, as well as other conditions with low pass filtered acoustic stimuli. Acoustic stimulation was provided by headphone to the NH ear and electric stimulation was provided by direct audio input to the subject's speech processor. In experiment 2, the task was repeated using NH listeners who received vocoded stimuli instead of electric stimuli. Experiment 3 tested the effect of adding the same unmodified song segment to the second ear, also in NH listeners. RESULTS:Music presented through the CI only was very unpleasant, with an average rating of 20. Surprisingly, the combination of the unpleasant CI signal in one ear with acoustic stimulation in the other ear was rated more enjoyable (mean = 123) than acoustic processing alone. Presentation of the same monaural musical signal to both ears in NH listeners resulted with even greater enhancement of the experience compared with presentation to a single ear (mean = 159). Repeating the experiment using a vocoder to one ear of NH listeners resulted in interference rather than enhancement. CONCLUSIONS:Music enjoyment from electric stimulation is extremely poor relative to a readily interpretable NH baseline for CI-SSD listeners. However, the combination of this unenjoyable signal presented through a CI and an unmodified acoustic signal presented to a NH (or near-NH) contralateral ear results in enhanced music enjoyment with respect to the acoustic signal alone. Remarkably, this two-ear enhancement experienced by CI-SSD listeners represents a substantial fraction of the two-ear enhancement seen in NH listeners. This unexpected benefit of electroacoustic auditory stimulation will have to be considered in theoretical accounts of music enjoyment and may facilitate the quest to enhance music enjoyment in CI users.

OBJECTIVES/OBJECTIVE:To determine whether image guidance improves dissection quality among residents in the temporal bone lab and to gauge their reactions to its use. METHODS:Prospective cohort study of nine otolaryngology residents who dissected cadaveric temporal bones with and without image guidance in the temporal bone laboratory. Quality of dissection was measured with the Welling scale. A survey was administered assessing their interactions with the navigation system. RESULTS:There was no significant difference in quality of dissection for the majority of structures or number of major errors with use of image guidance. Dissection quality of the tegmen (4.67 vs. 5.67, P = .034) and sinodural angle (0.83 vs. 1.56, P = .005) was superior in the non-navigation specimens. The majority of residents reported increased confidence with locating several critical anatomic structures and found the system intuitive to use. Nearly all thought it would be helpful in revision cases or for aural atresia. CONCLUSION/CONCLUSIONS:Image guidance did not improve quality of temporal bone dissection or number of major errors in this cohort of residents, but the majority found it intuitive and increased confidence in finding several structures. Navigation systems may play an important adjunctive role in resident education and further work is required to determine its optimal use. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2019.

PURPOSE/OBJECTIVE:Molecular subgroups of pediatric brain tumors associated with divergent biological, clinical, and prognostic features have been identified. However, data regarding the impact of subgroup affiliation on the outcome of children with malignant brain tumors treated with radiation-sparing protocol is limited. We report long-term clinical outcomes and the molecular subgroups of malignant brain tumors in young children whose first-line treatment was high-dose chemotherapy without irradiation. METHODS:Tumor subclassification was performed using the Illumina HumanMethylation450 BeadChip (450k) genome-wide methylation array profiling platform. Clinical information was obtained from chart review. RESULTS:Methylation array profiling yielded information on molecular subgroups in 22 children. Median age at surgery was 26 months (range 1-119 months). Among medulloblastomas (MB), all 6 children in the infant sonic hedgehog (SHH) subgroup were long-term survivors, whereas all 4 children in subgroup 3 MB died. There was one long-term survivor in subgroup 4 MB. One out of five children with ependymoma was a long-term survivor (RELPOS). Both children with primitive neuroectodermal tumors died. One child with ATRT TYR and one child with choroid plexus carcinoma were long-term survivors. CONCLUSIONS:The efficacy of high-dose chemotherapy radiation-sparing treatment appears to be confined to favorable molecular subgroups of pediatric brain tumors, such as infant SHH MB. Identification of molecular subgroups that benefit from radiation-sparing therapy will aid in the design of prospective, "precision medicine"-driven clinical trials.

OBJECTIVES/OBJECTIVE:Development of novel vocal fold (VF) therapeutics is limited by a lack of standardized, meaningful outcomes. We hypothesize that automated microindentation-based VF biomechanical property mapping matched to histology permits quantitative assessment. STUDY DESIGN/METHODS:Ex vivo. METHODS:Twelve anesthetized New Zealand white rabbits underwent endoscopic right VF injury. Larynges were harvested/bisected day 7, 30, or 60 (n = 4/group), with four uninjured controls. Biomechanical measurements (normal force, structural stiffness, and displacement at 1.96 mN) were calculated using automated microindentation mapping (0.3 mm depth, 1.2 mm/s, 2 mm spherical indenter) with a grid overlay (>50 locations weighted toward VF edge, separated into 14 zones). Specimens were marked/fixed/sectioned, and slides matched to measurement points. RESULTS:In the injury zone, normal force/structural stiffness (mean, standard deviation [SD]/mean, SD) increased from uninjured (2.2 mN, 0.64/7.4 mN/mm, 2.14) and day 7 (2.7 mN, 0.75/9.0 mN/mm, 2.49) to day 30 (4.3 mN, 2.11/14.2 mN/mm, 7.05) and decreased at 60 days (2.7 mN, 0.77/9.1 mN/mm, 2.58). VF displacement decreased from control (0.28 mm, 0.05) and day 7 (0.26 mm, 0.05) to day 30 (0.20 mm, 0.05), increasing at day 60 (0.25 mm, 0.06). A one-way ANOVA was significant; Tukey's post hoc test confirmed day-30 samples differed from other groups (P < 0.05), consistent across adjacent zones. Zones far from injury remained similar across groups (P = 0.143 to 0.551). These measurements matched qualitative histologic variations. CONCLUSION/CONCLUSIONS:Quantifiable VF biomechanical properties can be linked to histology. This technological approach is the first to simultaneously correlate functional biomechanics with histology and is ideal for future preclinical studies. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 2019.

PURPOSE/OBJECTIVE:Current research on the female belt voice has generally been limited to the range of C5, which is not representative of the current requirements on Broadway. Additionally, much belt research uses voice teachers or college students. The goal of this study was to acoustically examine both higher and lower belt ranges in 10 women who have performed belt roles on Broadway during the last decade. METHOD/METHODS:We analyzed the long-term average spectrum of the middle stable portion of three belted pitches, one from a lower, more traditional belt song and two from a higher, more contemporary belt song. The dB levels of the first three peaks in the long-term average spectrum corresponding to the first three harmonics were extracted and compared across tasks. Age, professional roles played on Broadway, and self-perceived belt strategy were obtained via interview to find potential unifying factors in resonance strategies. RESULTS:Overall, the dB level of the peaks closest to the second and third harmonics were higher than the peak close to the fundamental frequency. The difference between peaks was statistically greater in the lower belt compared to both higher belt tasks, indicating these singers relied more on a single harmonic in the lower belt range than the higher belt range. In the higher belt range, there was less variability between peaks. No patterns emerged between resonance strategies and demographic information. CONCLUSIONS:Elite female belters use varying resonance strategies to create commercially viable belt sounds in different belt ranges.