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Beginning in 2006, optical coherence tomography (OCT) has been adapted for use as a vibrometer for hearing research. The application of OCT in this field, particularly for studying cochlear mechanics, represents a revolutionary advance over previous technologies. OCT provides detailed evidence of the motions of components within the organ of Corti, extending beyond the first-encountered surface of observation. By imaging through the bony capsule as well as through the round window membrane, OCT has measured vibration at multiple locations along the cochlear spiral, in vivo, under nearly natural conditions. In this document, we present examples of recent research findings to illustrate the applications of OCT in studying cochlear mechanics in both normal and impaired ears., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Auditory sensation is based in nanoscale vibration of the sensory tissue of the cochlea, the organ of Corti complex (OCC). Motion within the OCC is now observable due to optical coherence tomography. In a previous study (Cooper et al., 2018), the region that includes the electro-motile outer hair cells (OHC) and Deiters cells (DC) was observed to move with larger amplitude than the basilar membrane (BM) and surrounding regions and was termed the "hotspot." In addition to this quantitative distinction, the hotspot moved qualitatively differently than the BM, in that its motion scaled nonlinearly with stimulus level at all frequencies, evincing sub-BF activity. Sub-BF activity enhances non-BF motion; thus the frequency tuning of the OHC/DC region was reduced relative to the BM. In this work we further explore the motion of the gerbil basal OCC and find that regions that lack significant sub-BF activity include the BM, the medial and lateral OCC, and the reticular lamina (RL) region. The observation that the RL region does not move actively sub-BF (already observed in Cho and Puria 2022), suggests that hair cell stereocilia are not exposed to sub-BF activity in the cochlear base. The observation that the lateral and RL regions move approximately linearly sub-BF indicates that linear forces dominate non-linear OHC-based forces on these components at sub-BF frequencies. A complex difference analysis was performed to reveal the internal motion of the OHC/DC region and showed that amplitude structure and phase shifts in the directly measured OHC/DC motion emerge due to the internal OHC/DC motion destructively interfering with BM motion., Competing Interests: Declaration of competing interest The authors declare no financial interests or conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Wentzel-Kramers-Brillouin (WKB) approximation is frequently used to explore the mechanics of the cochlea. As opposed to numerical strategies, the WKB approximation facilitates analysis of model results through interpretable closed-form equations and can be implemented with relative ease. As a result, it has maintained relevance in the study of cochlear mechanics for half of a century. Over this time, it has been employed to study a variety of phenomena, including the limits of frequency tuning, active displacement amplification within the organ of Corti, feedforward mechanisms in the cochlea, and otoacoustic emissions. Despite this ubiquity, it is challenging to find rigorous exposition of the WKB approximation's formulation, derivation, and implementation in cochlear mechanics literature. In this tutorial, the foundations of the WKB approximation are discussed in application to models of one- and two-dimensional cochlear macromechanics. This includes mathematical background, rigorous derivation and details of its implementation in software., (© 2024 Acoustical Society of America.)

Recent investigations of traumatic brain injuries have shown that these injuries can result in conformational changes at the level of individual neurons in the cerebral cortex. Focal axonal swelling is one consequence of such injuries and leads to a variable width along the cell axon. Simulations of the electrical properties of axons impacted in such a way show that this damage may have a nonlinear deleterious effect on spike-encoded signal transmission. The computational cost of these simulations complicates the investigation of the effects of such damage at a network level. We have developed an efficient algorithm that faithfully reproduces the spike train filtering properties seen in physical simulations. We use this algorithm to explore the impact of focal axonal swelling on small networks of integrate and fire neurons. We explore also the effects of architecture modifications to networks impacted in this manner. In all tested networks, our results indicate that the addition of presynaptic inhibitory neurons either increases or leaves unchanged the fidelity, in terms of bandwidth, of the network's processing properties with respect to this damage., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Optical coherence tomography (OCT) is capable of angstrom-scale vibrometry of particular interest to researchers of auditory mechanics. We develop a method for compressed sensing vibrometry using OCT that significantly reduces acquisition time for dense motion maps. Our method, based on total generalized variation with uniform subsampling, can reduce the number of samples needed to measure motion maps by a factor of ten with less than 5% normalized mean square error when tested on a diverse set of in vivo measurements from the gerbil cochlea. This opens up the possibility for more complex in vivo experiments for cochlear mechanics., Competing Interests: The authors declare no conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Optical coherence tomography (OCT) is a common modality for measuring vibrations within the organ of Corti complex (OCC) in vivo. OCT's uniaxial nature leads to limitations that complicate the interpretation of data from cochlear mechanics experiments. The relationship between the optical axis (axis of motion measurement) and anatomically relevant axes in the cochlea varies across experiments, and generally is not known. This leads to characteristically different motion measurements taken from the same structure at different orientations. We present a method that can reconstruct two-dimensional (2-D) motion of intra-OCC structures in the cochlea's longitudinal-transverse plane. The method requires only a single, unmodified OCT system, and does not require any prior knowledge of precise structural locations or measurement angles. It uses the cochlea's traveling wave to register points between measurements taken at multiple viewing angles. We use this method to reconstruct 2-D motion at the outer hair cell/Deiters cell junction in the gerbil base, and show that reconstructed transverse motion resembles directly measured transverse motion, thus validating the method. The technique clarifies the interpretation of OCT measurements, enhancing their utility in probing the micromechanics of the cochlea.

Optical coherence tomography (OCT) has become a powerful tool for measuring vibrations within the organ of Corti complex (OCC) in cochlear mechanics experiments. However, the one-dimensional nature of OCT measurements, combined with experimental and anatomical constraints, make these data ambiguous: Both the relative positions of measured structures and their orientation relative to the direction of measured vibrations are not known a priori. We present a method by which these measurement features can be determined via the use of a volumetric OCT scan to determine the relationship between the imaging/measurement axes and the canonical anatomical axes. We provide evidence that the method is functional by replicating previously measured radial vibration patterns of the basilar membrane (BM). We used the method to compare outer hair cell and BM vibration phase in the same anatomical cross section (but different optical cross sections), and found that outer hair cell region vibrations lead those of the BM across the entire measured frequency range. In contrast, a phase lead is only present at low frequencies in measurements taken within a single optical cross section. Relative phase is critical to the workings of the cochlea, and these results emphasize the importance of anatomically oriented measurement and analysis.

Objective: To determine feasibility of providing a concentrated emulsified long-chain polyunsaturated fatty acids (LCPUFA) supplement to very low birth weight infants, and to evaluate blood LCPUFA concentrations at 2 and 8 weeks of study supplementation., Study Design: This prospective, randomized, double-blind, placebo-controlled trial randomized infants to receive (1) LCPUFA-120 (a supplement of 40 mg/kg/day docosahexaenoic acid [DHA] and 80 mg/kg/day arachidonic acid [ARA]; DHA:ARA at 1:2 ratio), (2) LCPUFA-360 (a supplement of 120 mg/kg/day DHA and 240 mg/kg/day ARA), or (3) sunflower oil (placebo control). Infants received supplement daily for 8 weeks or until discharge, whichever came first. Whole blood LCPUFA levels (wt%; g/100 g) were measured at baseline, 2 weeks, and 8 weeks., Results: Infants were 28 weeks of gestation (IQR, 27-30 weeks of gestation) and weighed 1040 g (IQR, 910-1245 g). At 2 weeks, the change in blood DHA (wt%) from baseline differed significantly among groups (sunflower oil, n = 6; -0.63 [IQR, -0.96 to -0.55]; LCPUFA-120: n = 12; -0.14 [IQR, -0.72 to -0.26]; LCPUFA-360, n = 12; 0.46 [IQR, 0.17-0.81]; P = .002 across groups). Change in blood ARA (wt%) also differed by group (sunflower oil: -2.2 [IQR, -3.9 to -1.7]; LCPUFA-120: 0.1 [IQR, -2.1 to 1.1] vs LCPUFA-360: 2.9 IQR, 1.5 to 4.5]; P = .0002). Change from baseline to 8 weeks significantly differed between groups for DHA (P = .02) and ARA (P = .003)., Conclusions: Enteral LCPUFA supplementation supported higher blood DHA by 2 weeks. LCPUFA supplementation at 360 mg of combined DHA and ARA is likely necessary to reduce declines as well as allow increases in whole blood concentrations in the first 8 weeks of life., Trial Registration: Clinicaltrials.gov: NCT03192839., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Necrotizing enterocolitis (NEC) is a devastating bowel necrosis that predominantly affects preterm infants and is characterized by an imbalance toward a proinflammatory state. Fish oil or omega-3 long-chain polyunsaturated fatty acids have the potential to modulate inflammation. In this article, the authors examine the evidence in support of fish oil supplementation to alter the inflammatory response and potentially reduce the risk of NEC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: Necrotizing enterocolitis (NEC) has long remained a significant cause of morbidity and mortality in neonatal intensive care units. While the mainstay of treatment for this devastating condition remains largely supportive, research efforts continue to be directed toward understanding pathophysiology as well as how best to approach surgical management when indicated., Observations: In this review, we first examine recent medical observations, including overviews on the microbiome and a brief review of the use of probiotics. Next, we discuss the use of biomarkers and how clinicians may be able to use them in the future to predict the course of disease and, perhaps, the need for surgical intervention. We then provide an overview on the use of exclusive human milk feeding and the utility of this approach in preventing NEC. Finally, we discuss recent developments in the surgical management of NEC, beginning with indications for surgery and following with a section on technical surgical considerations, including peritoneal drain vs laparotomy. The review concludes with outcomes from infants with surgically treated NEC., Conclusions and Relevance: Although medical treatment options for NEC are largely unchanged, understanding of the disease continues to evolve. As new research methods are developed, NEC pathophysiology can be more completely understood. In time, it is hoped that data from ongoing and planned clinical trials will allow us to routinely add targeted preventive measures in addition to human milk, such as prebiotics and probiotics, to the management of high-risk infants. In addition, the discovery of novel biomarkers may not only prove useful in predicting severity of illness but also will hopefully allow for identification of the disease prior to onset of clinical signs. Finally, continued investigation into optimizing surgical outcomes is essential in this population of infants, many of whom require long-term parenteral therapy and intestinal rehabilitation.

Human milk contains biologically important amounts of transforming growth factor-β2 isoform (TGF-β2), which is presumed to protect against inflammatory gut mucosal injury in the neonate. In preclinical models, enterally administered TGF-β2 can protect against experimental necrotizing enterocolitis, an inflammatory bowel necrosis of premature infants. In this study, we investigated whether TGF-β bioactivity in human preterm milk could be enhanced for therapeutic purposes by adding recombinant TGF-β2 (rTGF-β2) to milk prior to feeding. Milk-borne TGF-β bioactivity was measured by established luciferase reporter assays. Molecular interactions of TGF-β2 were investigated by nondenaturing gel electrophoresis and immunoblots, computational molecular modeling, and affinity capillary electrophoresis. Addition of rTGF-β2 (20-40 nM) to human preterm milk samples failed to increase TGF-β bioactivity in milk. Milk-borne TGF-β2 was bound to chondroitin sulfate (CS) containing proteoglycan(s) such as biglycan, which are expressed in high concentrations in milk. Chondroitinase treatment of milk increased the bioactivity of both endogenous and rTGF-β2, and consequently, enhanced the ability of preterm milk to suppress LPS-induced NF-κB activation in macrophages. These findings provide a mechanism for the normally low bioavailability of milk-borne TGF-β2 and identify chondroitinase digestion of milk as a potential therapeutic strategy to enhance the anti-inflammatory effects of preterm milk., (Copyright © 2015 the American Physiological Society.)

Background: Feeding intolerance (FI) occurs commonly in the neonatal intensive care unit. Breast milk contains a large pool of transforming growth factor-beta (TGF-β). Few studies describe TGF-β levels in preterm milk, and the relationship to FI remains unexplored. We measured TGF-β levels in preterm breast milk to investigate a correlation with FI in preterm infants., Methods: Prospective observational trial of 100 mother-infant pairs, enrolling infants born below 32 wk gestation and less than 1,500 g, and mothers who planned to provide breast milk. TGF-β levels were measured using enzyme-linked immunosorbent assay. Infant charts were reviewed for outcomes., Results: TGF-β declined postnatally, most elevated in colostrum (P < 0.01). TGF-β2 levels were higher than TGF-β1 at all time points (P < 0.01). Colostrum TGF-β levels correlated inversely with birth weight (P < 0.01) and gestational age (P < 0.05). One-week TGF-β2 levels were reduced in growth-restricted infants with FI (P < 0.01). Of infants with necrotizing enterocolitis (NEC), TGF-β2 levels appeared to be low, but small sample size precluded meaningful statistical comparisons., Conclusion: TGF-β levels decline temporally in preterm milk. TGF-β1 colostrum levels correlate inversely with birth weight and gestational age. TGF-β2 may play a role in FI in growth-restricted infants. The relationship of TGF-β2 and NEC merits future investigation.

Human milk contains substantial amounts of transforming growth factor (TGF)-β, particularly the isoform TGF-β2. We previously showed in preclinical models that enterally administered TGF-β2 can protect against necrotizing enterocolitis (NEC), an inflammatory bowel necrosis of premature infants. In this study we hypothesized that premature infants remain at higher risk of NEC than full-term infants, even when they receive their own mother's milk, because preterm human milk contains less bioactive TGF-β than full-term milk. Our objective was to compare TGF-β bioactivity in preterm vs. full-term milk and identify factors that activate milk-borne TGF-β. Mothers who delivered between 23 0/7 and 31 6/7 wk or at ≥37 wk of gestation provided milk samples at serial time points. TGF-β bioactivity and NF-κB signaling were measured using specific reporter cells and in murine intestinal tissue explants. TGF-β1, TGF-β2, TGF-β3, and various TGF-β activators were measured by real-time PCR, enzyme immunoassays, or established enzymatic activity assays. Preterm human milk showed minimal TGF-β bioactivity in the native state but contained a large pool of latent TGF-β. TGF-β2 was the predominant isoform of TGF-β in preterm milk. Using a combination of several in vitro and ex vivo models, we show that neuraminidase is a key regulator of TGF-β bioactivity in human milk. Finally, we show that addition of bacterial neuraminidase to preterm human milk increased TGF-β bioactivity. Preterm milk contains large quantities of TGF-β, but most of it is in an inactive state. Addition of neuraminidase can increase TGF-β bioactivity in preterm milk and enhance its anti-inflammatory effects.

Although smaller and younger preterm neonates can now survive long term due to advances in neonatal medicine, necrotizing enterocolitis (NEC) continues to plague the clinicians caring for these tiny patients. Research studies have contributed to our understanding of this complex disease, including the role of platelet-activating factor (PAF), but preventative and treatment strategies remain limited. One promising preventative measure in recent years has been enteral supplementation of probiotics, but concerns remain regarding the optimal use of these organisms, and safe administration must be assured. This chapter reviews NEC pathophysiology, including the role of PAF, as well as literature on the use of probiotics in the preterm infant., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose of Review: This review will summarize the clinical trials evaluating the role of prophylactic probiotic supplementation in preterm infants in order to reduce the incidence of necrotizing enterocolitis (NEC)., Recent Findings: Evidence suggests that probiotic supplementation in preterm infants reduces the incidence of NEC. In fact, recent meta-analyses have called for the use of probiotics as preventive therapy in subsets of this population. However, although multiple studies have evaluated the use of probiotics for this indication in preterm infants, these trials have used different formulations of bacteria, at differing doses and using varied protocols for administration; thus many unanswered questions remain. In addition, theoretical safety issues and concerns regarding quality of product still need to be addressed., Summary: As NEC remains a serious problem for preterm neonates, proven therapies for prevention and treatment of this dreaded disease are needed. While the evidence does support a future role for probiotics in the prevention of NEC, it is of utmost importance to first ensure that a safe and high-quality product meeting rigorous standards will be provided to these at-risk infants.

Despite modern medical advances, necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in neonatal intensive care units, affecting 10% of premature neonates born weighing less than 1500 g. Although many advances have been made in the understanding of NEC, the etiology and pathophysiology remain incompletely understood, and treatment is limited to supportive care. In recent years, many studies have evaluated the inflammatory cascade that is central to the disease process, and research is ongoing into strategies to prevent and/or ameliorate neonatal NEC. In this review, we examine the key points in the signaling pathways involved in NEC, and potential strategies for prevention and treatment of this dreaded disease.