Contributions of Rod and Cone Pathways to Retinal Direction Selectivity Through Development.

UNLABELLED: Direction selectivity is a robust computation across a broad stimulus space that is mediated by activity of both rod and cone photoreceptors through the ON and OFF pathways. However, rods, S-cones, and M-cones activate the ON and OFF circuits via distinct pathways and the relative contribution of each to direction selectivity is unknown. Using a variety of stimulation paradigms, pharmacological agents, and knockout mice that lack rod transduction, we found that inputs from the ON pathway were critical for strong direction-selective (DS) tuning in the OFF pathway. For UV light stimulation, the ON pathway inputs to the OFF pathway originated with rod signaling, whereas for visible stimulation, the ON pathway inputs to the OFF pathway originated with both rod and M-cone signaling. Whole-cell voltage-clamp recordings revealed that blocking the ON pathway reduced directional tuning in the OFF pathway via a reduction in null-side inhibition, which is provided by OFF starburst amacrine cells (SACs). Consistent with this, our recordings from OFF SACs confirmed that signals originating in the ON pathway contribute to their excitation. Finally, we observed that, for UV stimulation, ON contributions to OFF DS tuning matured earlier than direct signaling via the OFF pathway. These data indicate that the retina uses multiple strategies for computing DS responses across different colors and stages of development. SIGNIFICANCE STATEMENT: The retina uses parallel pathways to encode different features of the visual scene. In some cases, these distinct pathways converge on circuits that mediate a distinct computation. For example, rod and cone pathways enable direction-selective (DS) ganglion cells to encode motion over a wide range of light intensities. Here, we show that although direction selectivity is robust across light intensities, motion discrimination for OFF signals is dependent upon ON signaling. At eye opening, ON directional tuning is mature, whereas OFF DS tuning is significantly reduced due to a delayed maturation of S-cone to OFF cone bipolar signaling. These results provide evidence that the retina uses multiple strategies for computing DS responses across different stimulus conditions.

Neurophysiology of the Superior Laryngeal Nerve in an In Vivo Rat Model.

OBJECTIVE: The superior laryngeal nerve (SLN) is fundamental in laryngeal sensation, cough reflex, and pitch control. SLN injury has substantial consequences including altered sensation, aspiration, and dysphonia. To date, in vivo measurement of the SLN remains elusive. The purpose of this study was to assess the feasibility of recording motor and sensory evoked potentials in a rat SLN model. METHODS: Twenty-two rat hemi-laryngeal preparations (n = 11) were obtained from 4-month-old Sprague-Dawley rats and included in this study. Compound motor action potentials (CMAPs) and motor unit number estimation (MUNE) were calculated by stimulating the SLN at the point of medial extension near the carotid artery and by placing a recording electrode on the cricothyroid muscle. Sensory response was determined through stimulation of the SLN and laryngoscopic visualization of a laryngeal adductor reflex (LAR). SLN and cricothyroid muscle cross-sections were stained and histologic morphometrics were quantified. RESULTS: Laryngeal evoked potentials were successfully obtained in all trials. Mean CMAP latency and negative durations were 0.99 ± 0.57 ms and 1.49 ± 0.57 ms, respectively. The median MUNE was 2.06 (IQR 1.88, 3.51). LAR was induced with a mean intensity of 0.69 ± 0.20 mV. Mean axon count, myelin thickness, and g-ratio were 681 ± 192.2, 1.72 ± 0.26, and 0.45 ± 0.04, respectively. CONCLUSIONS: This study demonstrates the feasibility of recording evoked response potentials following SLN stimulation. We hypothesize that this work will provide a tractable animal model to study changes in laryngeal sensation and cricothyroid motor function with aging, neurodegenerative disease, aspiration, or nerve injury. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1778-1784, 2024.

Quantitative Evaluation of Vocal Bowing Following Bilateral Thyroplasty in Age-Related Vocal Atrophy.

OBJECTIVE: Age-related vocal atrophy (ARVA) is associated with vocal fold bowing, persistent glottal gap during phonation, and dysphonia. Bilateral medialization thyroplasty is sometimes performed in patients with ARVA to improve vocal fold closure and voice. We set out to quantify stroboscopic changes in vocal fold bowing, glottal closure, and abduction angle following bilateral thyroplasty and determine how these changes affect voice quality among patients with ARVA. METHODS: Fifteen individuals with ARVA who underwent bilateral medialization thyroplasty were included in this study. Two independent investigators calculated bowing index (BI), normalized glottal gap area (NGGA), and maximum abduction angle from laryngostroboscopic exams using ImageJ™. Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) and patient-reported measures were collected before and after thyroplasty. RESULTS: Thyroplasty resulted in a 10-point improvement in overall CAPE-V (Mean dif -10; 95% CI -17, -3.3, p < 0.01) and VHI-10 (mean dif -3.8; 95% CI -9.8, 2.3, p = 0.19, n = 8). NGGA and BI significantly decreased following surgery (mean dif -78; 95% CI -155, -1.5, p = 0.05; and mean dif -2.1; 95% CI -2.4, -0.84, p < 0.01, respectively). BI correlated with CAPE-V scores (r = 0.66, 95% CI 0.22, 0.87, p < 0.01). When considering the normalized combined contributions of both NGGA and BI, there was a stronger correlation in CAPE-V scores (r = 0.87, 95% CI 0.50, 0.97, p < 0.01) compared with either measure alone. CONCLUSIONS: Thyroplasty resulted in a decrease in vocal fold bowing, glottal gap area, and CAPE-V scores in patients with ARVA. Correction of vocal bowing and glottal gap, following bilateral thyroplasty, improved voice measures following surgery. Quantitative evaluation of vocal fold morphology may be valuable when assessing the severity and treatment-response in patients with ARVA following bilateral thyroplasty. Laryngoscope, 134:835-841, 2024.

Utilizing novel recurrent laryngeal motor nerve conduction studies to characterize the aging larynx: A pilot study.

Objectives: Age-related changes to the larynx are associated with dysphonia and contribute to reduced quality of life. This study utilizes recurrent laryngeal motor nerve conduction studies (rlMNCS) to determine if neurophysiologic changes occur in the aging larynx using an aging rat model. Study Design: Animal study. Methods: In vivo rlMNCS were performed in 10 young hemi-larynges (3-4 months) and 10 aged hemi-larynges (18-19 months) rats (Fischer 344 × Brown Norway F344BN). Recording electrodes were placed into the thyroarytenoid (TA) muscle through direct laryngoscopy. Recurrent laryngeal nerves (RLNs) were directly stimulated with bipolar electrodes. Compound motor action potentials (CMAPs) were obtained. RLN cross-sections were stained with toluidine blue. Axon count, myelination, and g-ratio were quantified utilizing AxonDeepSeg analysis software. Results: rlMNCS were successfully obtained in all animals. Mean CMAP amplitude and negative durations in young rats were 3.58 ± 2.20 mV and 0.93 ± 0.14 mS (mean dif: 0.17; 95% CI: -2.21 to 2.54), respectively, and 3.74 ± 2.81 mV and 0.98 ± 0.11 mS (mean dif: 0.050; 95% CI: -0.07 to 0.17). No significant differences in onset latency or negative area were observed. Mean axon count in young rats (176 ± 35) was comparable to that in old rats (173 ± 31). Myelin thickness and g-ratio did not differ between groups. Conclusions: There were no statistically significant differences in RLN conduction or axon histology between young and aged rats in this pilot study. This work provides a basis for future, adequately powered studies, and may lead to a tractable animal model to study the aging larynx. Level of Evidence: 5.

Quantification of Vocal Fold Atrophy in Age-Related and Parkinson's Disease-Related Vocal Atrophy.

OBJECTIVE: Vocal fold atrophy (VFA) is associated with aging and Parkinson's disease (PD). Clinical diagnosis of VFA depends on several visual-perceptual laryngostroboscopy findings that are inherently subjective. The purpose of this study was to use quantitative measurements to; (1) examine the relationships between VFA and dysphonia severity and (2) evaluate differences in VFA in patients with age-related VFA versus PD. METHODS: Thirty-six patients >60 years of age with VFA were included in this retrospective cohort study. Demographic information, medical history, Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), Voice Handicap Index-10 (VHI-10), and still images from the stroboscopic exam were obtained. Image J™ was used to measure VFA, including bowing index (BI), normalized glottal gap area, and normalized mucosal wave amplitude. Pearson's correlation was used to evaluate the relationship between VFA, CAPE-V, and VHI-10. t-Tests and multivariate linear regression were used to compare VFA measures by dysphonia severity (CAPE-V <30 vs. >30) and diagnosis (age-related vocal atrophy [ARVA] and PD). RESULTS: BI was positively correlated with CAPE-V. Patients with CAPE-V >30 had a significantly larger BI compared to those with CAPE-V <30. Patients with PD had significantly larger BI than those with ARVA. Diagnosis of PD also predicted a larger BI after controlling for age and CAPE-V. CONCLUSION: Quantitative measures supported an association between bowing severity and dysphonia severity in patients with PD and ARVA. A PD diagnosis significantly predicted more severe BI. These findings demonstrate the potential utility of BI. Quantitative VFA measures might also provide insight into the mechanisms of ARVA and dysphonia. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1462-1469, 2023.

Postmarketing Reporting of Paxlovid-Related Dysgeusia: A Real-World Pharmacovigilance Study.

OBJECTIVE: A novel COVID-19 therapeutic, nirmatrelvir/ritonavir (Paxlovid), is commonly associated with reports of dysgeusia. The Food and Drug Administration Adverse Event Reporting System (FAERS) database was used to determine the real-world reporting of Paxlovid-associated dysgeusia (PAD), identify associated factors, and describe the relative reporting rates of dysgeusia for Paxlovid compared to other COVID-19 therapeutics (OCT), ritonavir alone, and other protease inhibitors (OPI). STUDY DESIGN: Observational retrospective. SETTING: Tertiary academic medical center. METHODS: We collected patient and adverse event characteristics reported in the FAERS database between January 1968 and September 2022. Disproportionality analyses were used to compare the reporting of PAD to dysgeusia reported for OCT, ritonavir, and OPI. RESULTS: 345,229 adverse events were included in the present study. Dysgeusia was a frequently reported Paxlovid-associated adverse event (17.5%) and was associated with nonserious COVID-19 infection (reporting odds ratio [ROR] 1.4; 95% confidence interval [CI] 1.2, 1.7) and female sex (ROR = 1.7; 95% CI 1.6, 1.9). Paxlovid was more likely to be associated with the reporting of dysgeusia compared to OCT (ROR 305.4; 95% CI 164.1, 568.5), ritonavir (ROR 28.0; 95% CI 24.1, 32.7), and OPI (ROR 49.0; 95% CI 42.8, 56.1). CONCLUSION: Dysgeusia is much more likely to be reported by patients receiving Paxlovid than those receiving OCT, ritonavir alone, or OPI. These findings suggest a potential mechanism of dysgeusia that causes distorted taste out of proportion to the background effects of COVID-19 infection and specific to nirmatrelvir. Future studies are needed to determine the underlying pathophysiology and long-term clinical implications for patients who report dysgeusia with Paxlovid.

Long-term outcomes with the pulmonary autograft inclusion technique in adults with bicuspid aortic valves undergoing the Ross procedure.

OBJECTIVE: To compare outcomes with wrapped (pulmonary autograft inclusion) versus unwrapped techniques in adults with bicuspid aortic valves undergoing the Ross procedure. METHODS: Between 1992 and 2019, 129 adults with bicuspid aortic valves (aged ≥18 years) underwent the Ross procedure by a single surgeon. Patients were divided into those without autograft inclusion (unwrapped, n = 71) and those with autograft inclusion (wrapped, n = 58). Median follow-up was 10.3 years (interquartile range, 3.0-16.8 years). Need for autograft reintervention was analyzed using competing risks. RESULTS: Pre- and intraoperative characteristics as well as 30-day morbidity or mortality did not differ between cohorts. Survival at 1, 5, and 10 years, respectively, was 97.2%, 97.2%, and 95.6% in the unwrapped cohort and 100%, 100%, and 100% in the wrapped cohort (P = .15). Autograft valve failure occurred in 25 (35.2%) of the unwrapped and 3 (5.2%) of the wrapped patients. Competing risks analysis demonstrated the wrapped cohort to have a lower need for autograft reintervention (subhazard ratio, 0.28, 95% confidence interval, 0.08-0.91; P = .035). The cumulative incidence of autograft reintervention (death as a competing outcome) at 1, 5, and 10 years, respectively, was 10.2%, 14.9%, and 26.8% in the unwrapped cohort and 4.0%, 4.0%, and 4.0% in the wrapped cohort. CONCLUSIONS: In adults with bicuspid aortic valves, the Ross procedure with pulmonary autograft inclusion stabilizes the aortic root preventing dilatation and reduces the need for reoperation. The autograft inclusion technique allows the Ross procedure to be performed in this population with excellent long-term outcomes.