Faculty Bibliography

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

OBJECTIVES/UNASSIGNED:Early in the COVID-19 pandemic, outpatient visits were adapted for the virtual setting, forcing laryngologists to presume certain diagnoses without the aid of laryngoscopy, solely based on history and the limited physical exam available via video visit. This study aims to examine the accuracy of presumptive diagnoses made via telemedicine, compared to subsequent in-person follow up, where endoscopic examination could confirm or refute suspected diagnoses. METHODS/UNASSIGNED:A retrospective chart review was conducted of 38 patients evaluated for voice-related issues at NYU Langone Health and the University of California-San Francisco. Presumptive diagnoses at the initial telemedicine encounter were noted, along with diagnostic cues used for clinical reasoning and recommended treatment plans. These presumptive diagnoses were compared to diagnoses and plans established following laryngoscopy at follow-up in-person visits. RESULTS/UNASSIGNED:After laryngoscopy at the first in-person visit, 38% of presumptive diagnoses changed, as did 37% of treatment plans. The accuracy varied among conditions. Muscle tension dysphonia and Reinke's edema were accurately diagnosed without laryngoscopy, but other conditions, including vocal fold paralysis and subglottic stenosis, were not initially suspected, relying on laryngoscopy for diagnosis. CONCLUSIONS/UNASSIGNED:While some laryngologic conditions may be reasonably identified without in-person examination, laryngoscopy remains central to definitive diagnosis and treatment. Telemedicine can increase access to care, but it may provide more utility as a screening tool, triaging which patients should present more urgently for in-person laryngoscopy. LEVEL OF EVIDENCE/UNASSIGNED:4.

OBJECTIVE:To assess a series of patients receiving teprotumumab therapy and objectively quantify the rates of otologic adverse events. STUDY DESIGN:A prospective cohort study of adult patients receiving teprotumumab between May 2020 and January 2022. SETTING:Tertiary referral center. METHODS:Prior to treatment initiation, an ototoxicity-specific audiometric battery was completed, which included conventional audiometry (frequencies 250-8000 Hz), ultrahigh-frequency audiometry (9000-20,000 Hz), tympanometry, speech discrimination scores, and distortion product otoacoustic emissions (DPOAEs). Testing was then repeated after treatment completion. RESULTS:In total, 35 patients were recruited, with a median (range) age of 48.5 years (21-74), and 8 (22.8%) were male. The most common subjective symptom reported was a hearing decline (25.7%), followed by aural fullness (17.1%) and tinnitus (14.3%). Fourteen patients had both pre- and posttreatment audiometric data. Among them, 3 patients (21.4%) were found to have changes in standard frequency audiometry, and 10 (71.4%) had changes in high-frequency audiometry, with 2 patients having changes in both. Less than half (n = 5) of the 11 patients with changes in standard or high-frequency pure tone hearing noted subjective hearing decline. Changes in DPOAE were noted in 4 patients out of 13 (30.7%). Two patients discontinued treatment due to hearing decline. Finally, 3 patients (8.6%) were diagnosed with patulous eustachian tube (PET) by an otolaryngologist, and another 3 patients are suspected to have PET based on symptom description during ophthalmologic follow-up. CONCLUSION:In our cohort, a high incidence of otologic symptoms was found to be associated with teprotumumab usage. Subjective hearing decline, changes in ultrahigh-frequency hearing as well as eustachian tube dysfunction may be encountered and suggest the potential ototoxicity of teprotumumab.

Background: Racial/ethnic (R/E) minorities with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. While disparities in patient outcomes for R/E minorities have been well documented, the specific drivers of the inferior outcomes remain poorly understood. Patients and Methods: This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database (NCDB) from 2000"“2016. Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. The main outcome in this study was overall survival (OS). Univariate time-to-event survival analyses were performed using the Kaplan"“Meier product limit estimates and the log-rank test to evaluate the differences between strata. Results: There were 304,138 patients with HNSCC identified in this study, of which 262,762 (86.3%) were White, 32,528 (10.6%) were Black, 6191 were Asian (2.0%), and 2657 were Native American/Other (0.9%). Black R/E minorities were more likely to be uninsured (9% vs. 5%, p < 0.0001), have Medicaid insurance (22% vs. 8%, p < 0.0001), be in a lower income quartile (<30,000, 42% vs. 13%, p < 0.0001), have metastatic disease (5% vs. 2%, p < 0.001), and have a total treatment time 6 days longer than White patients (median 107 vs. 101 days, p < 0.001). The 5-year OS for White, Black, Native American/Other, and Asian patients was 50.8%, 38.6%, 51.1%, and 55.8%, respectively. Among the oropharynx HNSCC patients, the 5-year OS rates in p16+ White, Black, and Asian patients were 65.7%, 39.4%%, and 55%, respectively. After a multivariate analysis, Black race was still associated with an inferior OS (HR:1.09, 95% CI: 1.03"“1.15, p = 0.002). Conclusions: This large cohort study of HNSCC patients demonstrates that Black race is independently associated with worse OS, in part due to socioeconomic, clinical, and treatment-related factors.

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. Collectively, we find that development reveals previously hidden organization to the input, processing, and output layers of a highly conserved vertebrate sensorimotor circuit. The spatial and temporal attributes we uncover constrain the developmental mechanisms that may specify the fate, function, and organization of vestibulo-ocular reflex neurons. More broadly, our data suggest that, like invertebrates, temporal mechanisms may assemble vertebrate sensorimotor architecture.

While motor cortical circuits contain information related to specific movement parameters¹, long-range inputs also have a critical role in action execution^2,3. Thalamic projections can shape premotor activity^2-6 and have been suggested⁷ to mediate the selection of short, stereotyped actions comprising more complex behaviours⁸. However, the mechanisms by which thalamus interacts with motor cortical circuits to execute such movement sequences remain unknown. Here we find that thalamic drive engages a specific subpopulation of premotor neurons within the zebra finch song nucleus HVC (proper name) and that these inputs are critical for the progression between vocal motor elements (that is, 'syllables'). In vivo two-photon imaging of thalamic axons in HVC showed robust song-related activity, and online perturbations of thalamic function caused song to be truncated at syllable boundaries. We used thalamic stimulation to identify a sparse set of thalamically driven neurons within HVC, representing ~15% of the premotor neurons within that network. Unexpectedly, this population of putative thalamorecipient neurons is robustly active immediately preceding syllable onset, leading to the possibility that thalamic input can initiate individual song components through selectively targeting these 'starter cells'. Our findings highlight the motor thalamus as a director of cortical dynamics in the context of an ethologically relevant behavioural sequence.

Objective: We conducted a qualitative study of patients"™ perspectives on dry mouth outcomes to explore their personal experiences and investigate which outcomes are most important to them. This work was part of the WONDER initiative (World Workshop on Oral Medicine Outcomes Initiative for the Direction of Research) exploring Core Outcome Measures in Effectiveness Trials. Study Design: Using a study-specific topic guide, we conducted digitally recorded, semi-structured interviews of focus groups of patients with dry mouth secondary to Sjogren syndrome and head and neck radiotherapy. We conducted interviews until data saturation had been achieved and evaluated all transcripts for accuracy before we anonymized the data. Results: Two focus groups consisting of 4 participants per group identified 4 distinct themes: (1) impact on oral health and function, (2) social isolation and withdrawal, (3) frustration with dry mouth management, and (4) limited knowledge of the medical community and lack of understanding of family and friends. Conclusions: The diversity of self-reported outcomes and the complexity of patient perceptions identified in our work may represent additional barriers to successful dry mouth management that should be considered in the design of future clinical trials.

PURPOSE/OBJECTIVE:Head and neck cancer (HNC) treatment results in morbidity impacting quality of life (QOL) in survivorship. This analysis evaluated changes in oral health-related QOL (OH-QOL) up to 2 years after curative intent radiation therapy (RT) for HNC patients and factors associated with these changes. METHODS:572 HNC patients participated in a multicenter, prospective observational study (OraRad). Data collected included sociodemographic, tumor, and treatment variables. Ten single-item questions and 2 composite scales of swallowing problems and senses problems (taste and smell) from a standard QOL instrument were assessed before RT and at 6-month intervals after RT. RESULTS:The most persistently impacted OH-QOL variables at 24 months included: dry mouth; sticky saliva, and senses problems. These measures were most elevated at the 6-month visit. Aspects of swallowing were most impacted by oropharyngeal tumor site, chemotherapy, and non-Hispanic ethnicity. Problems with senses and dry mouth were worse with older age. Dry mouth and sticky saliva increased more among men and those with oropharyngeal cancer, nodal involvement, and use of chemotherapy. Problems with mouth opening were increased by chemotherapy and were more common among non-White and Hispanic individuals. A 1000 cGy increase in RT dose was associated with a clinically meaningful change in difficulty swallowing solid food, dry mouth, sticky saliva, sense of taste, and senses problems. CONCLUSIONS:Demographic, tumor, and treatment variables impacted OH-QOL for HNC patients up to 2 years after RT. Dry mouth is the most intense and sustained toxicity of RT that negatively impacts OH-QOL of HNC survivors. GOV IDENTIFIER/UNASSIGNED:NCT02057510; first posted February 7, 2014.