Faculty Bibliography

Background: Oxytocin is essential for social interactions and maternal behavior. However, little is known about how oxytocin modulates neural circuits to improve social and maternal outcomes. We describe a synaptic mechanism by which oxytocin enhances signal-to-noise ratio in left primary auditory cortex to improve mouse maternal behavior. Methods: We performed electrophysiological recordings, and used anatomical, optogenetic and behavioral techniques to examine the role of oxytocin in maternal behavior in wild-type C57BL/6 and Oxytocin-IRES-Cre mice. Results: Virgins females, who do not initially retrieve distressed pups, rapidly expressed retrieval behavior after receiving oxytocin under dam and pups co-housing conditions. Retrieval onset was accelerated in 20/36 mice receiving systemic oxytocin and in 5/7 mice receiving optogenetic stimulation (P=0.03, 0.05, respectively; Fisher's two-tailed exact test). To confirm regional sites of action subserving improved maternal behavior, we generated novel antibodies that bind to the mouse oxytocin receptor. Oxytocin receptors were preferentially expressed in the left auditory cortex (19% left cells, 14% right cells, n=21, P=0.001). Finally, we utilitzed in vivo whole-cell recordings to measure spiking/synaptic responses to pup calls. Pup call responses were lateralized, with co-tuned/temporally-precise responses in left auditory cortex of maternally-experienced but not maternal-naive adults. Pairing calls with oxytocin enhanced call-evoked responses in virgin dams by balancing the magnitude/ timing of inhibition with excitation, transitioning the auditory cortex from a virgin-like state to a maternal state. Conclusions: Our study provides a biological basis for the lateralization of vocal processing and emergence of experience-based social learning. These studies inform behavioral therapies involving oxytocin administration

The aim of this study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. We prospectively collected treatment parameters and outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Univariate and multivariate analyses were performed to identify predictors of overall survival. The median overall survival from first SRS procedure was 6.7, 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54 % at 6 months and 41 % at 12 months from the time of SRS. In contrast, BRAF-WT had overall survival rates of 28 % at 6 months and 19 % at 12 months. Overall survival was extended for patients on a BRAF inhibitor at or after the first SRS. The median time to intracranial progression was 3.9 months on a BRAF inhibitor and 1.7 months without. The local control rate for all treated tumors was 92.5 %, with no difference based on BRAF status. Patients with higher KPS, fewer treated intracranial metastases, controlled systemic disease, RPA Class 1 and BRAF-M patients had extended overall survival. Overall, patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival from the time of SRS. As patients live longer as a result of more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

OBJECTIVES: Although it has been shown previously that changes in temporal coding produce changes in pitch in all cochlear regions, research has suggested that temporal coding might be best encoded in relatively apical locations. The authors hypothesized that although temporal coding may provide useable information at any cochlear location, low rates of stimulation might provide better sound quality in apical regions that are more likely to encode temporal information in the normal ear. In the present study, sound qualities of single electrode pulse trains were scaled to provide insight into the combined effects of cochlear location and stimulation rate on sound quality. DESIGN: Ten long-term users of MED-EL cochlear implants with 31-mm electrode arrays (Standard or FLEX) were asked to scale the sound quality of single electrode pulse trains in terms of how "Clean," "Noisy," "High," and "Annoying" they sounded. Pulse trains were presented on most electrodes between 1 and 12 representing the entire range of the long electrode array at stimulation rates of 100, 150, 200, 400, or 1500 pulses per second. RESULTS: Although high rates of stimulation are scaled as having a Clean sound quality across the entire array, only the most apical electrodes (typically 1 through 3) were considered Clean at low rates. Low rates on electrodes 6 through 12 were not rated as Clean, whereas the low-rate quality of electrodes 4 and 5 were typically in between. Scaling of Noisy responses provided an approximately inverse pattern as Clean responses. High responses show the trade-off between rate and place of stimulation on pitch. Because High responses did not correlate with Clean responses, subjects were not rating sound quality based on pitch. CONCLUSIONS: If explicit temporal coding is to be provided in a cochlear implant, it is likely to sound better when provided apically. In addition, the finding that low rates sound clean only at apical places of stimulation is consistent with previous findings that a change in rate of stimulation corresponds to an equivalent change in perceived pitch at apical locations. Collectively, the data strongly suggest that temporal coding with a cochlear implant is optimally provided by electrodes placed well into the second cochlear turn.

Treatment for intracranial germ cell tumors includes platinum-based chemotherapy and external beam radiation therapy, which are risk factors for hearing loss. In patients who experience significant sensorineural ototoxicity due to cochlear hair cell injury, dose reduction of chemotherapy may be necessary. This report describes an adolescent male, with excellent treatment response for an intracranial nongerminomatous germ cell tumor, who developed sensorineural hearing loss, which was central rather than cochlear in origin and unrelated to carboplatin. This patient highlights the need to carefully differentiate the type and etiology of sensorineural hearing loss in patients with brain tumors receiving ototoxic chemotherapy.

OBJECTIVES/HYPOTHESIS:Although salvage total laryngectomy remains the definitive approach to recurrent/persistent glottic cancer following failed radiation therapy for favorable early-stage disease, it comes at the price of a permanent laryngostome and an impact on quality of life. We describe a three-stage method of laryngeal reconstruction for salvage partial laryngectomy to address the unique challenges of operating on radiation recurrent/persistent cancer. STUDY DESIGN:This was a single-surgeon retrospective case series of patients who underwent a three-stage laryngeal reconstruction for salvage partial laryngectomy. METHODS:We performed a comprehensive review of the clinical, pathologic, and radiologic files of all patients who underwent a three-stage laryngeal reconstruction for salvage partial laryngectomy. RESULTS:Seven male patients underwent a three-stage laryngeal reconstruction following open partial salvage laryngectomy. The average follow-up time since salvage surgery was 55 months. All patients were without evidence of recurrence and demonstrated satisfactory functional outcomes. CONCLUSION:Staged reconstruction provides a more controlled assessment of wound healing and valuable pathologic information regarding the specific disease virulence and adequacy of the margins. LEVEL OF EVIDENCE:4. Laryngoscope, 126:1061-1070, 2016.

BACKGROUND: The application of aesthetic, craniofacial, and microsurgical principles in the execution of face transplantation may improve outcomes. Optimal soft-tissue face transplantation can be achieved by incorporating subunit facial skeletal replacement and subsequent tissue resuspension. The purpose of this study was to establish a reconstructive solution for a full face and scalp burn and to evaluate outcome precision and consistency. METHODS: Seven mock face transplants (14 cadavers) were completed in the span of 1 year. Components of the vascularized composite allograft included the eyelids, nose, lips, facial muscles, oral mucosa, total scalp, and ears; and skeletal subunits of the zygoma, nasal bone, and genial segment. Virtual surgical planning was used for osteotomy selection, and to evaluate postoperative precision of hard- and soft-tissue elements. RESULTS: Each transplant experience decreased each subsequent transplant surgical time. Prefabricated cutting guides facilitated a faster dissection of both donor and recipient tissue, requiring minimal alteration to the allograft for proper fixation of bony segments during inset. Regardless of donor-to-recipient size discrepancy, ample soft tissue was available to achieve tension-free allograft inset. Differences between virtual transplant simulation and posttransplant measurements were minimal or insignificant, supporting replicable and precise outcomes. CONCLUSIONS: This facial transplant model was designed to optimize reconstruction of extensive soft-tissue defects of the craniofacial region representative of electrical, thermal, and chemical burns, by incorporating skeletal subunits within the allograft. The implementation of aesthetic, craniofacial, and microsurgical principles and computer-assisted technology improves surgical precision, decreases operative time, and may optimize function.

OBJECTIVES: Based on our laboratory's newly confirmed motor pathway for glottic closure, we measured the glottic closing force (GCF) during isolated stimulation of the external branch of the superior laryngeal nerve (eSLN) in the porcine model. Glottic closure is 1 of the primary mechanisms for prevention of aspiration during deglutition. METHODS: The recurrent laryngeal nerve (RLN) and eSLN were identified bilaterally in 4 porcine necks. Subsequently, GCF was measured with a pressure transducer as the distal ends of individual nerves were stimulated in 4 animals. The RLN mediated GCF was measured first, followed by isolated eSLN mediated GCF, followed by transection of the RLN and repeat measurement of the eSLN GCF. Ultimately, the cricothyroid (CT) muscle attachment was released and the GCF measured. RESULTS: The GCF during isolated eSLN stimulation before and after RLN transection is approximately 89% of the RLN mediated GCF in each animal. The GCF after CT release is approximately 84% of the RLN perceived GCF. Transection of the RLN did not alter the eSLN observed GCF. CONCLUSIONS: The GCF obtained during isolated eSLN stimulation is adequate for delivery of an appropriate laryngeal protective response and may be considered a target motor nerve for augmenting GCF in selected rehab settings.

BACKGROUND: The classic form of Chediak-Higashi syndrome (CHS), an autosomal recessive disorder of lysosomal trafficking with childhood onset caused by mutations in LYST, is typified ophthalmologically by ocular albinism with vision loss attributed to foveal hypoplasia or nystagmus. Optic nerve involvement and ophthalmological manifestations of the late-onset neurodegenerative form of CHS are rarely reported and poorly detailed. METHODS: Case series detailing ophthalmological and neurological findings in three adult siblings with the late-onset form of CHS. RESULTS: All three affected siblings lacked features of ocular albinism and demonstrated significant optic nerve involvement as evidenced by loss of colour and contrast vision, central visual field loss, optic nerve pallor, retinal nerve fibre layer thinning by optical coherence tomography (OCT) and abnormal visual evoked potential, with severity corresponding linearly to age of the sibling and severity of neurological disease. Further, unusual prominence of a 'third line' on macular OCT that may be due to abnormal melanosomes was seen in all three siblings and in their father. Neurological involvement included parkinsonism, cerebellar ataxia and spastic paraparesis. CONCLUSIONS: This report expands the ophthalmological phenotype of the late-onset neurodegenerative form of CHS to include optic neuropathy with progressive vision loss, even in the absence of ocular albinism, and abnormal prominence of the interdigitation zone between cone outer segment tips and apical processes of retinal pigment epithelium cells on macular OCT.

OBJECTIVE:To perform the translation, cross-cultural adaptation, and validation of the Sino-Nasal Outcome Test-22 (SNOT-22) questionnaire to the Hebrew language. STUDY DESIGN AND SETTING:A single-center prospective cross-sectional study. SUBJECTS AND METHODS:Seventy-three chronic rhinosinusitis (CRS) patients and 73 patients without sinonasal disease filled the Hebrew version of the SNOT-22 questionnaire. Fifty-one CRS patients underwent endoscopic sinus surgery, out of which 28 filled a postoperative questionnaire. Seventy-three healthy volunteers without sinonasal disease also answered the questionnaire. Internal consistency, test-retest reproducibility, validity, and responsiveness of the questionnaire were evaluated. RESULTS:Questionnaire reliability was excellent, with a high internal consistency (Cronbach's alpha coefficient, 0.91-0.936) and test-retest reproducibility (Spearman's coefficient, 0.962). Mean scores for the preoperative, postoperative, and control groups were 50.44, 29.64, and 13.15, respectively (P < .0001 for CRS vs controls, P < .001 for preoperative vs postoperative), showing validity and responsiveness of the questionnaire. CONCLUSION:The Hebrew version of SNOT-22 questionnaire is a valid outcome measure for patients with CRS with or without nasal polyps.

BACKGROUND:The purpose of this study was to evaluate the efficacy of postoperative intense pulsed light therapy on patients who undergo bilateral eyelid surgery. METHODS:Patients presenting over a 3-month period for bilateral eyelid surgery were asked to participate in an institutional review board-approved study. Intense pulsed light therapy was administered three times to the same randomly assigned side on postoperative days 1 to 2, 5 to 7, and 10 to 12. Sham light therapy was administered to the contralateral side. Patient surveys and physician ratings were obtained based on photographic evaluation of ecchymosis, edema, and erythema. Three physicians, including the senior author (A.E.W.), submitted ratings, and these ratings were assessed for interobserver reliability. RESULTS:Twenty-eight patients who underwent bilateral eyelid surgery followed by intense pulsed light therapy were enrolled. The mean age of the patients was 66 years (range, 44 to 81 years). Eighty-six percent of patients were female. The change in ratings between postoperative days 1 to 2 and 10 to 12, in the treatment and control groups, was statistically significant for severity of bruising by both patient and physician assessment and for color of bruising only by patient assessment. The interobserver reliability reached the greatest agreement in the ecchymosis category at each time point for the treatment group. CONCLUSION:In a series of patients who underwent eyelid surgery, intense pulsed light therapy decreased the degree of ecchymosis compared with sham treatment in postoperative eyelid surgery patients. CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, II.