"Transcanal view" computed tomography reformat: Applications for transcanal endoscopic ear surgery.

PURPOSE: Transcanal endoscopic ear surgery (TEES) is an increasingly used surgical approach for otologic surgeries, but no en face preoperative imaging format currently exists. We aim to assess the utility of a transcanal high resolution computed tomography (HRCT) reformat suitable for TEES preoperative planning. MATERIALS AND METHODS: Preoperative HRCTs of patients with middle ear pathologies (cholesteatoma, otosclerosis, and glomus tympanicum) who underwent TEES were obtained. Axial image series were rotated and reformatted -90 or +90 degrees for left and right ear surgeries, respectively, where additional rotation along the left-right axis was performed to align the transcanal series with the plane of the external auditory canal. Quantitative measurements of middle ear structures were recorded. Consecutive transcanal reformatted sections were then reviewed to identify critical middle ear anatomy and pathology with corresponding TEES cases. RESULTS: The aforementioned methodology was used to create three transcanal view HRCTs. The mean left-right axis degree of rotation was 4.0 ± 2.2 degrees. In the cholesteatoma transcanal HRCT, areas of cholesteatoma involvement in middle ear compartments (e.g. epitympanum) and eroded ossicles were successfully identified in the corresponding case. In the otosclerosis transcanal HRCT, areas for potential otosclerotic involvement were visualized such as the round window as well as a low-hanging facial nerve. In the glomus tympanicum transcanal HRCT, the span of the glomus tympanicum was successfully visualized in addition to a high riding jugular bulb. CONCLUSION: A transcanal HRCT reformat may aid preoperative planning for middle ear pathologies. This novel reformat may help highlight patient-specific anatomy.

A proteomic investigation into mechanisms underpinning corticosteroid effects on neural stem cells.

Corticosteroids (CSs) are widely used clinically, for example in pediatric respiratory distress syndrome, and immunosuppression to prevent rejection of stem cell transplant populations in neural cell therapy. However, such treatment can be associated with adverse effects such as impaired neurogenesis and myelination, and increased risk of cerebral palsy. There is increasing evidence that CSs can adversely influence key biological properties of neural stem cells (NSCs) but the molecular mechanisms underpinning such effects are largely unknown. This is an important issue to address given the key roles NSCs play during brain development and as transplant cells for regenerative neurology. Here, we describe the use of label-free quantitative proteomics in conjunction with histological analyses to study CS effects on NSCs at the cellular and molecular levels, following treatment with methylprednisolone (MPRED). Immunocytochemical staining showed that both parent NSCs and newly generated daughter cells expressed the glucocorticoid receptor, with nuclear localisation of the receptor induced by MPRED treatment. MPRED markedly decreased NSC proliferation and neuronal differentiation while accelerating the maturation of oligodendrocytes, without concomitant effects on cell viability and apoptosis. Parallel proteomic analysis revealed that MPRED induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. Our findings support the hypothesis that some neurological deficits associated with CS use may be mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects.

Development of a nanomaterial bio-screening platform for neurological applications.

Nanoparticle platforms are being intensively investigated for neurological applications. Current biological models used to identify clinically relevant materials have major limitations, e.g. technical/ethical issues with live animal experimentation, failure to replicate neural cell diversity, limited control over cellular stoichiometries and poor reproducibility. High-throughput neuro-mimetic screening systems are required to address these challenges. We describe an advanced multicellular neural model comprising the major non-neuronal/glial cells of the central nervous system (CNS), shown to account for ~99.5% of CNS nanoparticle uptake. This model offers critical advantages for neuro-nanomaterials testing while reducing animal use: one primary source and culture medium for all cell types, standardized biomolecular corona formation and defined/reproducible cellular stoichiometry. Using dynamic time-lapse imaging, we demonstrate in real-time that microglia (neural immune cells) dramatically limit particle uptake in other neural subtypes (paralleling post-mortem observations after nanoparticle injection in vivo), highlighting the utility of the system in predicting neural handling of biomaterials.

Increasing magnetite contents of polymeric magnetic particles dramatically improves labeling of neural stem cell transplant populations.

Safe and efficient delivery of therapeutic cells to sites of injury/disease in the central nervous system is a key goal for the translation of clinical cell transplantation therapies. Recently, 'magnetic cell localization strategies' have emerged as a promising and safe approach for targeted delivery of magnetic particle (MP) labeled stem cells to pathology sites. For neuroregenerative applications, this approach is limited by the lack of available neurocompatible MPs, and low cell labeling achieved in neural stem/precursor populations. We demonstrate that high magnetite content, self-sedimenting polymeric MPs [unfunctionalized poly(lactic acid) coated, without a transfecting component] achieve efficient labeling (≥90%) of primary neural stem cells (NSCs)-a 'hard-to-label' transplant population of major clinical relevance. Our protocols showed high safety with respect to key stem cell regenerative parameters. Critically, labeled cells were effectively localized in an in vitro flow system by magnetic force highlighting the translational potential of the methods used.

Alignment of multiple glial cell populations in 3D nanofiber scaffolds: toward the development of multicellular implantable scaffolds for repair of neural injury.

Non-neuronal cells of the central nervous system (CNS), termed "neuroglia," play critical roles in neural regeneration; therefore, replacement of glial populations via implantable nanofabricated devices (providing a growth-permissive niche) is a promising strategy to enhance repair. Most constructs developed to date have lacked three-dimensionality, multiple glial populations and control over spatial orientations, limiting their ability to mimic in vivo neurocytoarchitecture. We describe a facile technique to incorporate multiple glial cell populations [astrocytes, oligodendrocyte precursor cells (OPCs) and oligodendrocytes] within a three-dimensional (3D) nanofabricated construct. Highly aligned nanofibers could induce elongation of astrocytes, while OPC survival, elongation and maturation required pre-aligned astrocytes. The potential to scale-up the numbers of constituent nanofiber layers is demonstrated with astrocytes. Such complex implantable constructs with multiple glial sub-populations in defined 3D orientations could represent an effective approach to reconstruct glial circuitry in neural injury sites. FROM THE CLINICAL EDITOR: Clinically available methods to enhance nervous tissue regeneration remain scarce despite decades of research. In this study, a novel 3D nanofabricated construct is demonstrated, that includes populations of astrocytes, oligodendrocyte precursor cells and oligodendrocytes providing a well-orchestrated glial microenvironment for more efficient central nervous system repair.

In vitro model of neurotrauma using the chick embryo to test regenerative bioimplantation.

Effective repair of spinal cord injury sites remains a major clinical challenge. One promising strategy is the implantation of multifunctional bioscaffolds to enhance nerve fibre growth, guide regenerating tissue and modulate scarring/inflammation processes. Given their multifunctional nature, such implants require testing in models which replicate the complex neuropathological responses of spinal injury sites. This is often achieved using live, adult animal models of spinal injury. However, these have substantial drawbacks for developmental testing, including the requirement for large numbers of animals, costly infrastructure, high levels of expertise and complex ethical processes. As an alternative, we show that organotypic spinal cord slices can be derived from the E14 chick embryo and cultured with high viability for at least 24 days, with major neural cell types detected. A transecting injury could be reproducibly introduced into the slices and characteristic neuropathological responses similar to those in adult spinal cord injury observed at the lesion margin. This included aligned astrocyte morphologies and upregulation of glial fibrillary acidic protein in astrocytes, microglial infiltration into the injury cavity and limited nerve fibre outgrowth. Bioimplantation of a clinical grade scaffold biomaterial was able to modulate these responses, disrupting the astrocyte barrier, enhancing nerve fibre growth and supporting immune cell invasion. Chick embryos are inexpensive and simple, requiring facile methods to generate the neurotrauma model. Our data show the chick embryo spinal cord slice system could be a replacement spinal injury model for laboratories developing new tissue engineering solutions.

Comparative utility of vestibular function tests in patients with peripheral and central vestibular dysfunction.

Background: Bithermal caloric irrigation, video head impulse test (vHIT), and rotational testing are commonly used to assess peripheral vestibular function, but the relative clinical utility of each test in differentiating patients with peripheral vestibulopathy is debated. Objectives: To determine whether (1) the combination of two or more vestibular tests enhances diagnostic utility over a single test; (2) abnormal test results on vestibular tests correlate with one another. Methods: Retrospective analysis of data collected from multidisciplinary vestibular clinics at two academic medical centers from 2016 to 2022. Results: 150 patients (54.10 ± 15.09 years, 88 females) were included. No individual test was significantly better at predicting the presence of peripheral vestibular damage (p > 0.05). vHIT test results improved significantly when combined with either the caloric test (p = 0.007) or rotary chair test (p = 0.039). Caloric and rotational testing had high sensitivity (74.65% and 76.06%, respectively) and specificity (83.54% and 78.48%, respectively). vHIT demonstrated excellent specificity (89.87%) but poor sensitivity (47.89%). Caloric, vHIT, and rotary chair tests results did not correlate with one another (p > 0.05). Conclusions: Vestibular function tests have comparable diagnostic utility, yet each offers unique advantages. Caloric and rotational testing may be best suited for screening peripheral damage and vHIT may function ideally as a confirmatory test.

Reverse Correlation Characterizes More Complete Tinnitus Spectra in Patients.

Goal: We validate a recent reverse correlation approach to tinnitus characterization by applying it to individuals with clinically-diagnosed tinnitus. Methods: Two tinnitus patients assessed the subjective similarity of their non-tonal tinnitus percepts and random auditory stimuli. Regression of the responses onto the stimuli yielded reconstructions which were evaluated qualitatively by playing back resynthesized waveforms to the subjects and quantitatively by response prediction analysis. Results: Subject 1 preferred their resynthesis to white noise; subject 2 did not. Response prediction balanced accuracies were significantly higher than chance across subjects: subject 1: 0.5963, subject 2: 0.6922. Conclusion: Reverse correlation can provide the foundation for reconstructing accurate representations of complex, non-tonal tinnitus in clinically diagnosed subjects. Further refinements may yield highly similar waveforms to individualized tinnitus percepts.

Music Perception in Bone-Anchored Hearing Implant Users.

OBJECTIVE: Music is a highly complex acoustic stimulus in both spectral and temporal contents. Accurate representation and delivery of high-fidelity information are essential for music perception. However, it is unclear how well bone-anchored hearing implants (BAHIs) transmit music. The study objective is to establish music perception performance baselines for BAHI users and normal hearing (NH) listeners and compare outcomes between the cohorts. METHODS: A case-controlled, cross-sectional study was conducted among 18 BAHI users and 11 NH controls. Music perception was assessed via performance on seven major musical element tasks: pitch discrimination, melodic contour identification, rhythmic clocking, basic tempo discrimination, timbre identification, polyphonic pitch detection, and harmonic chord discrimination. RESULTS: BAHI users performed comparably well on all music perception tasks with their device compared with the unilateral condition with their better-hearing ear. BAHI performance was not statistically significantly different from NH listeners' performance. BAHI users performed just as well, if not better than NH listeners when using their control contralateral ear; there was no significant difference between the two groups except for the rhythmic timing (BAHI non-implanted ear 69% [95% CI: 62%-75%], NH 56% [95% CI: 49%-63%], p = 0.02), and basic tempo tasks (BAHI non-implanted ear 80% [95% CI: 65%-95%]; NH 75% [95% CI: 68%-82%, p = 0.03]). CONCLUSIONS: This study represents the first comprehensive study of basic music perception performance in BAHI users. Our results demonstrate that BAHI users perform as well with their implanted ear as with their contralateral better-hearing ear and NH controls in the major elements of music perception. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1381-1387, 2024.

Investigating Internalization of Reporter-Protein-Functionalized Polyhedrin Particles by Brain Immune Cells.

Achieving sustained drug delivery to the central nervous system (CNS) is a major challenge for neurological injury and disease, and various delivery vehicles are being developed to achieve this. Self-assembling polyhedrin crystals (POlyhedrin Delivery System; PODS) are being exploited for the delivery of therapeutic protein cargo, with demonstrated efficacy in vivo. However, to establish the utility of PODS for neural applications, their handling by neural immune cells (microglia) must be documented, as these cells process and degrade many biomaterials, often preventing therapeutic efficacy. Here, primary mouse cortical microglia were cultured with a GFP-functionalized PODS for 24 h. Cell counts, cell morphology and Iba1 expression were all unaltered in treated cultures, indicating a lack of acute toxicity or microglial activation. Microglia exhibited internalisation of the PODS, with both cytosolic and perinuclear localisation. No evidence of adverse effects on cellular morphology was observed. Overall, 20-40% of microglia exhibited uptake of the PODS, but extracellular/non-internalised PODS were routinely present after 24 h, suggesting that extracellular drug delivery may persist for at least 24 h.

Magnetic nanoparticle mediated transfection of neural stem cell suspension cultures is enhanced by applied oscillating magnetic fields.

Safe genetic modification of neural stem cell (NSC) transplant populations is a key goal for regenerative neurology. We describe a technically simple and safe method to increase transfection in NSCs propagated in the neurosphere (suspension culture) model, using magnetic nanoparticles deployed with applied oscillating magnetic fields ('magnetofection technology'). We show that transfection efficiency was enhanced over two-fold by oscillating magnetic fields (frequency=4 Hz). The protocols had no effect on cell viability, cell number, stem cell marker expression and differentiation profiles of 'magnetofected' cultures, highlighting the safety of the technique. As far as we are aware, this is the first successful application of magnetofection technology to suspension cultures of neural cells. The procedures described offer a means to augment the therapeutic potential of NSCs propagated as neurospheres - a culture model of high clinical translational relevance - by safe genetic manipulation, with further potential for incorporation into 'magneto-multifection' (repeat transfection) protocols. FROM THE CLINICAL EDITOR: This team of investigators describe a simple and safe method to increase transfection in neural stem cells using magnetic nanoparticles deployed with oscillating magnetic fields, demonstrating a greater than two-fold transfection efficiency increase by applying low frequency magnetic oscillation.

Labyrinthitis Ossificans in a Post-Splenectomy Patient With Meningitis: A Case Report and Review of Literature.

This report describes a case of cochlear implantation to treat profound deafness three months after a diagnosis of bacterial meningitis in a patient with a remote history of splenectomy. A 71-year-old woman with a remote history of a splenectomy over 20 years before presented with bilateral profound deafness that occurred as sequela from pneumococcal meningitis three months prior. The patient had been vaccinated against the 23-valent polysaccharide pneumococcal vaccine (PPV-23). The audiometric evaluation revealed no response in either ear. Imaging was suggestive of complete ossification of the right cochlea with partial ossification of the basal turn of the left cochlea. She underwent successful left-sided cochlear implantation. Standard post-implantation speech outcomes include consonant-nucleus-consonant (CNC) word and phoneme scores and Az-Bio in quiet and noise. The patient noted subjective improvement in her hearing. Performance measures markedly improved when compared to her pre-operative evaluation, which showed no aided sound detection. This case report highlights the possibility of meningitis many years after splenectomy that can result in profound deafness with labyrinthitis ossificans and the potential for hearing rehabilitation for cochlear implantation.

Simulating traumatic brain injury in vitro: developing high throughput models to test biomaterial based therapies.

Traumatic brain injuries are serious clinical incidents associated with some of the poorest outcomes in neurological practice. Coupled with the limited regenerative capacity of the brain, this has significant implications for patients, carers, and healthcare systems, and the requirement for life-long care in some cases. Clinical treatment currently focuses on limiting the initial neural damage with long-term care/support from multidisciplinary teams. Therapies targeting neuroprotection and neural regeneration are not currently available but are the focus of intensive research. Biomaterial-based interventions are gaining popularity for a range of applications including biomolecule and drug delivery, and to function as cellular scaffolds. Experimental investigations into the development of such novel therapeutics for traumatic brain injury will be critically underpinned by the availability of appropriate high throughput, facile, ethically viable, and pathomimetic biological model systems. This represents a significant challenge for researchers given the pathological complexity of traumatic brain injury. Specifically, there is a concerted post-injury response mounted by multiple neural cell types which includes microglial activation and astroglial scarring with the expression of a range of growth inhibitory molecules and cytokines in the lesion environment. Here, we review common models used for the study of traumatic brain injury (ranging from live animal models to in vitro systems), focusing on penetrating traumatic brain injury models. We discuss their relative advantages and drawbacks for the developmental testing of biomaterial-based therapies.

Influence of listening environment on usage patterns in cochlear implant patients with single-sided deafness.

OBJECTIVE: To compare cochlear implant (CI) data logging of patients with single-sided deafness (SSD) and bilateral sensorineural hearing loss (biSNHL) in various acoustic environments and study the implications of data logging on auditory performance. STUDY DESIGN: Retrospective case control study. METHODS: Adult CI patients with SSD or biSNHL from 2010 to 2021 with usage data collected at 3-, 6-, and 12-months following device activation were identified. The CI listening environment was defined as speech in noise, speech in quiet, quiet, music or noise. Auditory performance was measured using the CNC word, AzBio sentence tests and the Tinnitus Handicap Index (THI). RESULTS: 60 adults with SSD or biSNHL were included. CI patients with biSNHL wore their devices more than those with SSD at 3-months post-activation (11.18 versus 8.97 hours/day, p = 0.04), though there were no significant differences at 6-12 months. Device usage was highest in the speech in quiet environment. In SSD CI users, there was a positive correlation (p = 0.03) between device use and CNC scores at 12-months and an improvement in THI scores at 12-months (p = 0.0004). CONCLUSIONS: CI users with SSD and biSNHL have comparable duration of device usage at longer follow-up periods with greatest device usage recorded in speech in quiet environments.

Evaluating the Feasibility of Hydrogel-Based Neural Cell Sprays.

Neurological injuries have poor prognoses with serious clinical sequelae. Stem cell transplantation enhances neural repair but is hampered by low graft survival (ca. 80%) and marker expression/proliferative potential of hydrogel-sprayed astrocytes was retained. Combining a cell spray format with polymer encapsulation technologies could form the basis of a non-invasive graft delivery method, offering potential advantages over current cell delivery approaches.

Ear, Nose, and Throat Manifestations of Vasculitis and Other Systemic Autoimmune Diseases: Otologic, Sinus, and Airway.

Auricular, nasal, and laryngeal manifestations occur frequently in rheumatic diseases. Inflammatory ear, nose, and throat (ENT) processes often result in organ damage and have profound effects on quality of life. Herein, we review the otologic, nasal, and laryngeal involvement of rheumatic diseases, focusing on their clinical presentation and diagnosis. ENT manifestations generally respond to treatment of the systemic disease, which is outside the scope of this review; however, adjunctive topical and surgical treatment approaches, as well as treatment of idiopathic inflammatory ENT manifestations will be reviewed.

Reverse Correlation Uncovers More Complete Tinnitus Spectra.

Goal: This study validates an approach to characterizing the sounds experienced by tinnitus patients via reverse correlation, with potential for characterizing a wider range of sounds than currently possible. Methods: Ten normal-hearing subjects assessed the subjective similarity of random auditory stimuli and target tinnitus-like sounds ("buzzing" and "roaring"). Reconstructions of the targets were obtained by regressing subject responses on the stimuli, and were compared for accuracy to the frequency spectra of the targets using Pearson's [Formula: see text]. Results: Reconstruction accuracy was significantly higher than chance across subjects: buzzing: [Formula: see text] (mean [Formula: see text] s.d.), [Formula: see text], [Formula: see text]; roaring: [Formula: see text], [Formula: see text], [Formula: see text]; combined: [Formula: see text], [Formula: see text], [Formula: see text]. Conclusion: Reverse correlation can accurately reconstruct non-tonal tinnitus-like sounds in normal-hearing subjects, indicating its potential for characterizing the sounds experienced by patients with non-tonal tinnitus.

A benchtop brain injury model using resected donor tissue from patients with Chiari malformation.

The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation (cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this 'proof-of-concept' study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.

Vestibular damage affects the precision and accuracy of navigation in a virtual visual environment.

Vestibular information is available to the brain during navigation, as are the other self-generated (idiothetic) and external (allothetic) sensorimotor cues that contribute to central estimates of position and motion. Rodent studies provide strong evidence that vestibular information contributes to navigation but human studies have been less conclusive. Furthermore, sex-based differences have been described in human navigation studies performed with the head stationary, a situation where dynamic vestibular (and other idiothetic) information is absent, but sex differences in the utilization of vestibular information have not been described. Here, we studied men and women with severe bilateral vestibular damage as they navigated through a visually barren virtual reality environment and compared their performance to normal men and women. Two navigation protocols were employed, which either activated dynamic idiothetic cues ('dynamic task', navigate by turning, walking in place) or eliminated them ('static task', navigate with key presses, head stationary). For both protocols, we employed a standard 'triangle completion task' in which subjects moved to two visual targets in series and then were required to return to their perceived starting position without localizing visual information. The angular and linear 'accuracy' (derived from response error) and 'precision' (derived from response variability) were calculated. Comparing performance 'within tasks', navigation on the dynamic paradigm was worse in male vestibular-deficient patients than in normal men but vestibular-deficient and normal women were equivalent; on the static paradigm, vestibular-deficient men (but not women) performed better than normal subjects. Comparing performance 'between tasks', normal men performed better on the dynamic than the static paradigm while vestibular-deficient men and both normal and vestibular-deficient women were equivalent on both tasks. Statistical analysis demonstrated that for the angular precision metric, sex had a significant effect on the interaction between vestibular status and the test paradigm. These results provide evidence that humans use vestibular information when they navigate in a virtual visual environment and that men and women may utilize vestibular (and visual) information differently. On our navigation paradigm, men used vestibular information to improve navigation performance, and in the presence of severe vestibular damage, they utilized visual information more effectively. In contrast, we did not find evidence that women used vestibular information while navigating on our virtual task, nor did we find evidence that they improved their utilization of visual information in the presence of severe vestibular damage.

Otolith Membrane Herniation, not Semicircular Canal Duct Dilation, Is Associated with Decreased Caloric Responses in Ménière's Disease.

Ménière's disease (MD) is a debilitating disorder with unclear pathophysiology whose diagnosis often relies on clinical judgment rather than objective testing. To complicate matters further, a dissociation has emerged between two vestibular function tests commonly used in patients with MD to examine the same end-organ (the semicircular canals): the caloric test and video head impulse testing (vHIT). Caloric responses are often abnormal, while vHIT results remain normal. Explaining this dissociation could reveal novel insights into MD pathophysiology. Here, we conduct a histopathological study using temporal bone specimens (N = 58, 21 MD-affected ears and 37 age-matched controls) and their clinical testing data to examine current hypotheses aimed at this dissociation. We find otolith membrane herniation into the horizontal semicircular canal in 69% of MD ears, with 90% of these ears demonstrating a diminished caloric response. No ears with a normal response had this herniation. Moreover, we evaluated the semicircular canals for endolymphatic hydrops, which had been hypothesized to contribute to the dissociation, and found no evidence of duct dilation/hydrops. We did, however, note a potentially novel morphologic finding-smaller bony labyrinth cross-sectional diameters/areas in some MD ear canals compared to controls, suggesting relative size of the membranous duct to the bony canal rather than absolute size may be of importance. Taken together, this study refines hypotheses on the vestibular test dissociation in MD, holding diagnostic implications and expanding our understanding of the mechanisms underlying this enigmatic disease.