Intra-cochlear Flushing Reduces Tissue Response to Cochlear Implantation.

INTRODUCTION: Intraoperative trauma leading to bleeding during cochlear implantation negatively impacts residual hearing of cochlear implant recipients. There are no clinical protocols for the removal of blood during implantation, to reduce the consequential effects such as inflammation and fibrosis which adversely affect cochlear health and residual hearing. This preclinical study investigated the implementation of an intra-cochlear flushing protocol for the removal of blood. METHODS: Three groups of guinea pigs were studied for 28 days after cochlear implantation; cochlear implant-only (control group); cochlear implant with blood injected into the cochlea (blood group); and cochlear implant, blood injection, and flushing of the blood from the cochlea intraoperatively (flush group). Auditory brainstem responses (ABRs) in addition to tissue response volumes were analyzed and compared between groups. RESULTS: After implantation, the blood group exhibited the highest ABR thresholds when compared to the control and flush group, particularly in the high frequencies. On the final day, the control and blood group had similar ABR thresholds across all frequencies tested, whereas the flush group had the lowest thresholds, significantly lower at 24 kHz than the blood and control group. Analysis of the tissue response showed the flush group had significantly lower tissue responses in the basal half of the array when compared with the blood and control group. CONCLUSIONS: Flushing intra-cochlear blood during surgery resulted in better auditory function and reduced subsequent fibrosis in the basal region of the cochlea. This finding prompts the implementation of a flushing protocol in clinical cochlear implantation. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1410-1416, 2024.

Cochlear implant surgery facilitates intracochlear distribution of perioperative systemic steroids.

BACKGROUND: Systemically administered steroids are widely utilised for hearing preservation therapies. More recently, steroids have been administered to achieve hearing protection after cochlear implant surgery. Currently there is a lack of understanding as to which administration route offers most therapeutic efficacy, local or systemic administration. Paramount to this are observations in animal studies that systemic administration following implantation offers hearing protection and reduced cochlear fibrosis, despite observations that perilymphatic levels are up to 10-fold higher after local administration in non-implanted cochleae. AIMS/OBJECTIVES: This paper explores the impact that cochlear implantation and associated acute inflammation has on steroid distribution and uptake following systemic administration of dexamethasone. MATERIAL AND METHODS: Eight guinea pigs received systemic dexamethasone 60 min prior to cochlear implantation. Implanted and contralateral non-implanted cochlea were harvested for tissue immunohistochemistry and detection of dexamethasone. RESULTS: Cochleostomy with scala tympani implantation resulted in a significant increase in cochlear dexamethasone signal. This was most notable at the organ of Corti, stria vascularis, and blood product in the scala tympani. CONCLUSIONS AND SIGNIFICANCE: This study demonstrates that the inner ear distribution of systemically administered steroids is enhanced following surgery for cochlear implantation and provides rationale for systemic perioperative steroids in hearing preservation surgery.

Spironolactone Ameliorates Cochlear Implant Induced Endolymphatic Hydrops.

BACKGROUND: Endolymphatic hydrops (EH) has been observed in both animal and human cochleae following cochlear implant (CI) surgery. We tested whether EH could be eliminated by administration of mineralocorticoid steroid antagonist spironolactone and explored the electrophysiological consequences of this. METHODS: Sixty-four adult guinea pigs underwent cochlear implantation with a dummy electrode. Animals then survived either 2, 7, or 28 days. Auditory function was monitored by recording electrocochleography from the round window membrane preimplantation, and on the last day of the experiment. Spironolactone or control solution was added to animals' feed for 7 days (if they survived that long) beginning immediately prior to surgery. The presence of EH was determined using thin-sheet laser imaging microscopy. RESULTS: Treatment with spironolactone resulted in significant reduction in EH in the second cochlear turn 7 days postimplantation. In all animals, the compound action potential (CAP) threshold was elevated 2 days postimplantation, but for most frequencies had recovered substantially by 28 days. There was no treatment effect on CAP thresholds. SP/AP ratios were elevated at day 2. The amplitude growth of the CAP did not differ between test and control groups at any time after implantation. CONCLUSIONS: EH can be suppressed by antagonism of mineralocorticoid receptors in the week after cochlear implantation. Reduction in EH did not lead to any change in hearing, and there was no indication of synaptopathy signalled by reduced CAP amplitude at high sound intensities. We found no electrophysiological evidence that EH early after implantation impacts negatively upon preservation of residual hearing.

The Effect of Different Round Window Sealants on Cochlear Mechanics Over Time.

BACKGROUND: This project investigated the effects of round window membrane (RWM) sealants after surgical incision, with a focus on audiological thresholds, ossicular mechanics, and the impact upon cochlear function and pathology. METHODS: Twenty-eight guinea pigs were randomly allocated to one of three sealant groups (muscle, n = 7; fascia, n = 7, Tisseel, n = 8) or an unsealed control group (n = 6). Preoperative hearing was measured using auditory brainstem responses (ABRs). The ossicular chain and RWM were exposed surgically, and Laser Doppler Vibrometry (LDV) measurements were obtained from the long process of the incus. The RWM was incised then sealed (or left unsealed) according to group. ABR testing and LDV measurements were repeated 4 and 12 weeks after surgery. At 12 weeks all cochleae were harvested. RESULTS: ABR thresholds deteriorated over time in all groups. Overall, group was not statistically significant (p = 0.064). There was no significant effect by group on LDV measurements (p = 0.798). Histopathological analyses of the RWM showed that the fascia group had more extensive fibrosis than other groups (Independent-Samples Median Test, p = 0.001). However, there were minimal differences in the outer hair cell counts between the different intervention groups. CONCLUSIONS: All the interventions appeared to be safe while none affected the cochlear mechanics or hearing thresholds in a statistically significant manner.

The role of URO17™ biomarker to enhance diagnosis of urothelial cancer in new hematuria patients-First European Data.

Introduction and objectives: Novel biomarker research is vital for the progression of safe and thorough diagnostic medicine. There is now a need to improve the diagnosis of bladder cancer via a noninvasive urine test while balancing the risks of harm from investigational procedures, such as cystoscopy and radiological tests, against the likelihood of malignancy. We evaluate the diagnostic accuracy and sensitivity of Uro17™ urinary biomarker for the detection of urothelial cancer in hematuria patients in a prospective blinded validation study. Uro17™ is an immunobiomarker which binds to the oncoprotein Keratin 17, which is involved in the replication cycle of malignant cells. This study compared cystoscopic and histological investigations against Uro17™ results in patients being investigated for symptoms of urothelial cancer. Materials and methods: After receiving both local and national ethics/protocol approval, 71 patients were consented and recruited into the study. All patients were scheduled to undergo cystoscopic investigation, and following recruitment, a urine sample was collected. Urine samples were anonymized and processed as per standard cytology protocols and stained using Uro17™ immunobiomarker. The pathologists assessing the results were blinded to the patient and background history, and the results were compared to the biopsy histology. Results: The full cohort of enrolled patients consisted of 71 participants included. There were 55 males and 16 females, with an average age of 70. Thirteen were current smokers, 42 ex-smokers, and 16 nonsmokers. The malignancies detected included both muscle-invasive (n = 6) and non-muscle-invasive tumors (n = 38), and tumors of all grades and carcinoma in situ. Uro17™ was shown to have an overall sensitivity of 100% and a specificity of 92.6%, with a positive predictive value of 0.957 and negative predictive value of 1. Uro17™ investigation was positive in every case of urothelial malignancy. Conclusions: Our current data indicates Uro17™ is a highly sensitive noninvasive bladder cancer urine detection test that can improve the diagnosis of Bladder cancer. This can further improve diagnostic capabilities in primary care, reduce the number of referrals to Urology department, and reduce the number of unnecessary invasive procedures for new patients with a suspected urinary bladder cancer.

Cochlear microphonic latency predicts outer hair cell function in animal models and clinical populations.

As recently reported, electrocochleography recorded in cochlear implant recipients showed reduced amplitude and shorter latency in patients with more severe high-frequency hearing loss compared with those with some residual hearing. As the response is generated primarily by receptor currents in outer hair cells, these variations in amplitude and latency may indicate outer hair cell function after cochlear implantation. We propose that an absence of latency shift when the cochlear microphonic is measured on two adjacent electrodes indicates an absence or dysfunction of outer hair cells between these electrodes. We test this preclinically in noise deafened guinea pigs (2 h of a 124 dB HL, 16-24 kHz narrow-band noise), and clinically, in electrocochleographic recordings made in cochlear implant recipients immediately after implantation. We found that normal hearing guinea pigs showed a progressive increase in latency from basal to apical electrodes. In contrast, guinea pigs with significantly elevated high-frequency hearing thresholds showed no change in cochlear microphonic latency measured on basal electrodes (located approximately at the 16-24 kHz location in the cochlea).. In the clinical cohort, a significant negative correlation existed between cochlear microphonic latency shifts and hearing thresholds at 1-, 2-, & 4 kHz when tested on electrodes located at the relevant cochlear tonotopic place. This reduction in latency shift was such that patients with no measurable hearing also had no detectable latency shift (place assessed by CT scan, r's of -.70 to -.83). These findings suggest that electrocochleography can be used as a diagnostic tool to detect cochlear regions with functioning hair cells, which may be important for defining cross-over point for electro-acoustic stimulation.

A new method for three-dimensional immunofluorescence study of the cochlea.

Visualisation of cochlear histopathology in three-dimensions has been long desired in the field of hearing research. This paper outlines a technique that has made this possible and shows a research application in the field of hearing protection after cochlear implantation. The technique utilises robust immunofluorescent labelling followed by effective tissue clearing and fast image acquisition using Light Sheet Microscopy. We can access the health of individual components by immunofluorescent detection of proteins such as myosin VIIa to look at cochlear hair cells, NaKATPase alpha 3 to look at spiral ganglion neurons, and IBA1 to look at macrophages within a single cochlea, whilst maintaining the integrity of fine membranous structures and keeping the cochlear implant in place. This allows the tissue response to cochlear implantation to be studied in detail, including the immune reaction to the implant and the impact on the structure and health of neural components such as hair cells. This technique reduces time and labour required for sectioning of cochleae and can allow visualisation of cellular detail. Use of image analysis software allows conversion of high-resolution image stacks into three-dimensional interactive data sets so volumes and numbers of surfaces can be measured. Immunofluorescent whole cochlea labelling and Light Sheet Microscopy have the capacity to be applied to many questions in hearing research of both the cochlea and vestibular system.

Nanomechanical mapping reveals localized stiffening of the basilar membrane after cochlear implantation.

Cochlear implantation leads to many structural changes within the cochlea which can impair residual hearing. In patients with preserved low-frequency hearing, a delayed hearing loss can occur weeks-to-years post-implantation. We explore whether stiffening of the basilar membrane (BM) may be a contributory factor in an animal model. Our objective is to map changes in morphology and Young's modulus of basal and apical areas of the BM after cochlear implantation, using quantitative nanomechanical atomic force microscopy (QNM-AFM) after cochlear implant surgery. Cochlear implantation was undertaken in the guinea pig, and the BM was harvested at four time-points: 1 day, 14 days, 28 days and 84 days post-implantation for QNM-AFM analysis. Auditory brainstem response thresholds were determined prior to implantation and termination. BM tissue showed altered morphology and a progressive increase in Young's modulus, mainly in the apex, over time after implantation. BM tissue from the cochlear base demonstrated areas of extreme stiffness which are likely due to micro-calcification on the BM. In conclusion, stiffening of the BM after cochlear implantation occurs over time, even at sites far apical to a cochlear implant.

Intracochlear tPA infusion may reduce fibrosis caused by cochlear implantation surgery.

BACKGROUND: Experiments show that the extent of ongoing fibrotic change within the cochlea can be determined by the volume and pattern of bleeding within the first 24 h following cochlear implantation. Tissue-type plasminogen activator (tPA) is effective at reducing thrombus volume when administered both within and external to the systemic circulation. AIMS/OBJECTIVES: To determine if tPA delivered into the scala tympani immediately following implantation will reduce thrombus volume within the lower basal turn of the cochlea. MATERIALS AND METHODS: Guinea pigs were implanted with either 'soft' or 'hard' arrays and administered tPA or saline via an intra-cochlear infusion immediately after implantation. Hearing was checked prior to, and 2 weeks after implantation. Cochleae were then harvested and imaged. RESULTS: Animals implanted with 'soft' arrays had 4.2% less tissue response compared with animals implanted with 'hard' arrays. In animals receiving 'soft' arrays, tPA reduced the volume of tissue response (measured by the percentage of the lower basal turn of the scala tympani occupied by tissue response) compared with saline. CONCLUSIONS AND SIGNIFICANCE: tPA may be effective in reducing the overall volume of tissue response in routine 'soft' cochlear implantation and may have a greater effect in the event of significant surgical trauma.

Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients.

Glucocorticoids have direct anti-inflammatory, anti-oxidant and anti-apoptotic effects on cochlear hair cells. Cochlear glucocorticoid therapy has gained particular attention for its ability to enhance the protection of residual hearing following hearing preservation cochlear implantation. Local drug delivery methods achieve high drug concentrations within the inner ear fluids but are reliant upon diffusion across the round window membrane. Diffusion has been shown to demonstrate large individual variability. This study explores the role of "adjuvant agents", which when administered with glucocorticoids, enhance inner ear absorption and distribution. Guinea pig cochleae were administered either dexamethasone alone or in combination with hyaluronic acid, histamine, or combination histamine and hyaluronic acid, targeted at the round window membrane. Control subjects received saline. Perilymph was sampled from the cochlear apex, and basal to apical dexamethasone concentrations recorded with mass spectroscopy. Cochleae were harvested, and immunohistochemistry employed to explore dexamethasone tissue penetration and distribution. Basal to apical gradients were observed along the scala tympani, with higher dexamethasone concentrations observed at the cochlear base. Gradients were more pronounced and uniform when administered on a hyaluronic acid sponge, while histamine increased absolute concentrations reaching the inner ear. Tissue penetration correlated with perilymph concentration. Our results demonstrate that adjuvant agents can be employed to enhance dexamethasone absorption and distribution in the inner ear, thus proposing therapeutic strategies that may enhance steroid facilitated hearing protection.

A comparison of cochlear distribution and glucocorticoid receptor activation in local and systemic dexamethasone drug delivery regimes.

Local and systemically delivered glucocorticoids are commonly administered to protect the cochlea against damage associated with a variety of insults. There is reason to believe that dexamethasone administered by these routes may arrive at cochlear target sites via different pathways. Clinically, there is a lack of clarity as to which route is more effective in any specific circumstance. This study explores dexamethasone distribution within the guinea pig cochlea following local and systemic delivery methods. A combination of mass spectroscopy and immunohistochemistry were employed to compare both perilymph distribution, tissue uptake and receptor activation. Local administration of dexamethasone to the round window membrane resulted in greater perilymph concentrations, with a basal to apical gradient that favours the cochlear base. Tissue immunofluorescence was intimately related to perilymph concentration following local administration. Systemic administration resulted in much lower perilymph concentrations, with an inverse basal to apical gradient favouring the cochlear apex. Lower perilymph concentrations following systemic administration were associated with minimal tissue immunofluorescence. Despite this, GR activation of the SGNs was equivalent in both administration regimes. These results bring into question the efficacy of measuring perilymph concentrations alone as a surrogacy for dexamethasone distribution and activity in the cochlea, suggesting that the steroid ligand may arrive at its target receptor via alternative pathways. Our results suggest an equivalence in efficacy between local and systemic administration routes early after drug delivery, when the ultimate outcome of GR activation is the goal.

Effect of cochlear implantation on middle ear function: A three-month prospective study.

OBJECTIVES/HYPOTHESIS: To determine if cochlear implantation has a delayed effect on the middle ear conductive hearing mechanism by measuring laser Doppler vibrometry (LDV) of the tympanic membrane (TM) in both implanted and contralateral control ears preoperatively and 3 months postoperatively, and then comparing the relative change in LDV outcome measures between implanted and control ears. STUDY DESIGN: Prospective cohort study. METHODS: Eleven preoperative adult unilateral cochlear implant recipients in previously unoperated ears with normal anatomy and aerated temporal bones were included in this study. The magnitude and phase angle of umbo velocity transfer function in response to air- conduction (AC) stimulus, and the magnitude of umbo velocity in response to bone- conduction (BC) stimulus were measured in the implant ear and the contralateral control ear preoperatively and 3 months postoperatively and compared. RESULTS: No significant changes in the magnitude or phase angle of TM velocity in response to either AC or BC stimulus were observed in the implanted ear relative to the contralateral control ear 3 months following cochlear implantation. CONCLUSIONS: From the results of LDV measurements, it can be said that cochlear implantation has no significant delayed effect on the middle ear conductive mechanism. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1207-1212, 2018.

Cannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF.

Sustained local delivery of drugs to the inner ear may be required for future regenerative and protective strategies. The round window is surgically accessible and a promising delivery route. To be viable, a delivery system should not cause hearing loss. This study determined the effect on hearing of placing a drug-delivery microcatheter on to the round window, and delivering either artificial perilymph (AP) or brain-derived neurotrophic factor (BDNF) via this catheter with a mini-osmotic pump. Auditory brainstem responses (ABRs) were monitored for 4 months after surgery, while the AP or BDNF was administered for the first month. The presence of the microcatheter - whether dry or when delivering AP or BDNF for 4 weeks - was associated with an increase in ABR thresholds of up to 15 dB, 16 weeks after implantation. This threshold shift was, in part, delayed by the delivery of BDNF. We conclude that the chronic presence of a microcatheter in the round window niche causes hearing loss, and that this is exacerbated by delivery of AP, and ameliorated temporarily by delivery of BDNF.

The Role of Preoperative Steroids in Atraumatic Cochlear Implantation Surgery.

HYPOTHESIS: Depth of insertion is related to the extent of tissue response and low frequency hearing loss. Intravenous steroids have greatest effect in reducing postimplantation fibrosis and hearing loss in the presence of significant electrode insertion trauma, when compared with saline treatment. BACKGROUND: Experiments exploring the enhancement of cochlear implantation (CI) outcomes with glucocorticosteroids have produced mixed results, possibly due to lack of standardization of the CI model. METHODS: Forty-eight normal-hearing guinea pigs were randomly implanted with a highly flexible electrode to a depth of 1.5, 3.0, or 5.0 mm. For each insertion depth, sub-cohorts received either intravenous saline ("saline") or dexamethasone ("steroid") 60 minutes before implantation. Shifts in electrocochleography thresholds at 2 to 32 kHz were determined before and 4 weeks after implantation. Cochleae were harvested and imaged. RESULTS: Low-frequency hearing loss was greatest with 5.0 mm insertions. Fracture of the osseous spiral lamina and/or fibrotic involvement of the round window membrane exacerbated hearing loss. The extent of intracochlear fibrosis was directly related to the depth of insertion. Steroids reduced the intracochlear tissue response for deepest insertions and in apical regions of the cochlea where basilar membrane contact was prevalent. Steroids preserved no more hearing than saline at all insertion depths. CONCLUSION: Cochlear trauma influenced postimplantation hearing loss and steroid effect on fibrosis. Fibrosis, and to a lesser extent, postimplantation hearing loss increased proportionally to the depth of insertion. Steroids did not influence fibrosis relating to the cochleostomy, but could reduce scarring as the electrode negotiated the hook region or near the electrode tip.

The Effect of Round Window Sealants on Delayed Hearing Loss in a Guinea Pig Model of Cochlear Implantation.

AIM: To determine whether the type of material used to seal the cochlea after round window cochlear implantation influences delayed hearing loss. BACKGROUND: Cochlear implants are now prescribed to patients with residual, low-frequency hearing. This hearing-which provides perceptual benefits for the implanted ear-is frequently lost for unknown reasons weeks to months after surgery in a proportion of patients. A post-surgical change in cochlear mechanics, related to the material used to seal the cochlea after round window implantation, may contribute to this loss. METHODS: An electrode array was implanted in guinea pigs via the round window, which was then sealed with muscle, periosteum, or fibrin glue. Auditory brainstem responses (ABRs) to pure tones (2, 8, 16, 24, and 32 kHz) were recorded before surgery and 1, 4, and 12 weeks after surgery, with subjects then euthanized and their cochleae harvested for histological analysis. RESULTS: Muscle and periosteum, but not fibrin glue, exhibited delayed threshold rises at 2 kHz. Twelve weeks after implantation, 2 kHz threshold shifts differed significantly between muscle (mean, 27.1 dB) and fibrin glue (9.3 dB), but not between these groups and periosteum (19.3 dB). Muscle was sometimes associated with much greater tissue reactions than the other sealants. Most cochleae had injuries to the basilar membrane and/or osseous spiral lamina, regardless of sealant. Hair cell counts did not differ significantly among sealants. CONCLUSION: Delayed, low-frequency hearing loss was observed when cochleae were sealed with muscle or periosteum, but not when cochleae were sealed with fibrin glue.

Delayed low frequency hearing loss caused by cochlear implantation interventions via the round window but not cochleostomy.

Cochlear implant recipients show improved speech perception and music appreciation when residual acoustic hearing is combined with the cochlear implant. However, up to one third of patients lose their pre-operative residual hearing weeks to months after implantation, for reasons that are not well understood. This study tested whether this "delayed" hearing loss was influenced by the route of electrode array insertion and/or position of the electrode array within scala tympani in a guinea pig model of cochlear implantation. Five treatment groups were monitored over 12 weeks: (1) round window implant; (2) round window incised with no implant; (3) cochleostomy with medially-oriented implant; (4) cochleostomy with laterally-oriented implant; and (5) cochleostomy with no implant. Hearing was measured at selected time points by the auditory brainstem response. Cochlear condition was assessed histologically, with cochleae three-dimensionally reconstructed to plot electrode paths and estimate tissue response. Electrode array trajectories matched their intended paths. Arrays inserted via the round window were situated nearer to the basilar membrane and organ of Corti over the majority of their intrascalar path compared with arrays inserted via cochleostomy. Round window interventions exhibited delayed, low frequency hearing loss that was not seen after cochleostomy. This hearing loss appeared unrelated to the extent of tissue reaction or injury within scala tympani, although round window insertion was histologically the most traumatic mode of implantation. We speculate that delayed hearing loss was related not to the electrode position as postulated, but rather to the muscle graft used to seal the round window post-intervention, by altering cochlear mechanics via round window fibrosis.

Effect of both local and systemically administered dexamethasone on long-term hearing and tissue response in a Guinea pig model of cochlear implantation.

Dexamethasone administered prior to cochlear implantation has been shown to reduce the loss of residual hearing in experimental settings. However, its effect on the tissue response around the implant has not been extensively studied. In this study dexamethasone sodium phosphate was administered to guinea pigs via local delivery to the round window (2% dexamethasone for 120 min prior to surgery, 'local 2/120', or 20% dexamethasone for 30 min prior to surgery) or intravenously (2 mg/kg dexamethasone for 60 min) prior to implantation. Auditory brainstem responses (ABR) were monitored for 3 months, after which the cochleae were embedded in Spurr's resin and sectioned. The extent of the tissue response and the survival of the neurosensory structures were analysed. Both local 2/120 and systemically delivered dexamethasone improved ABR thresholds when compared with control animals. Systemic dexamethasone also reduced the tissue response around the electrode. This suggests that whilst both locally and systemically administered dexamethasone can protect residual hearing after cochlear implantation, their effects upon the tissue response to implantation may differ.

Brain-derived neurotrophic factor modulates auditory function in the hearing cochlea.

Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and click-evoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.

Sustained attention in children with two etiologies of early hydrocephalus.

Several studies have shown that children with spina bifida meningomyelocele (SBM) and hydrocephalus have attention problems on parent ratings and difficulties in stimulus orienting associated with a posterior brain attention system. Less is known about response control and inhibition associated with an anterior brain attention system. Using the Gordon Vigilance Task (Gordon, 1983), we studied error rate, reaction time, and performance over time for sustained attention, a key anterior attention function, in 101 children with SBM, 17 with aqueductal stenosis (AS; another condition involving congenital hydrocephalus), and 40 typically developing controls (NC). In SBM, we investigated the relation between cognitive attention and parent ratings of inattention and hyperactivity and explored the impact of medical variables. Children with SBM did not differ from AS or NC groups on measures of sustained attention, but they committed more errors and responded more slowly. Approximately one-third of the SBM group had attention symptoms, although parent attention ratings were not associated with task performance. Hydrocephalus does not account for the attention profile of children with SBM, which also reflects the distinctive brain dysmorphologies associated with this condition.

Characteristics of a spina bifida population including North American Caucasian and Hispanic individuals.

BACKGROUND: Meningomyelocele (MM) is a common human birth defect. MM is a disorder of neural development caused by contributions from genes and environmental factors that result in the NTD and lead to a spectrum of physical and neurocognitive phenotypes. METHODS: A multidisciplinary approach has been taken to develop a comprehensive understanding of MM through collaborative efforts from investigators specializing in genetics, development, brain imaging, and neurocognitive outcome. Patients have been recruited from five different sites: Houston and the Texas-Mexico border area; Toronto, Canada; Los Angeles, California; and Lexington, Kentucky. Genetic risk factors for MM have been assessed by genotyping and association testing using the transmission disequilibrium test. RESULTS: A total of 509 affected child/parent trios and 309 affected child/parent duos have been enrolled to date for genetic association studies. Subsets of the patients have also been enrolled for studies assessing development, brain imaging, and neurocognitive outcomes. The study recruited two major ethnic groups, with 45.9% Hispanics of Mexican descent and 36.2% North American Caucasians of European descent. The remaining patients are African-American, South and Central American, Native American, and Asian. Studies of this group of patients have already discovered distinct corpus callosum morphology and neurocognitive deficits that associate with MM. We have identified maternal MTHFR 667T allele as a risk factor for MM. In addition, we also found that several genes for glucose transport and metabolism are potential risk factors for MM. CONCLUSIONS: The enrolled patient population provides a valuable resource for elucidating the disease characteristics and mechanisms for MM development.