John S. Oghalai

Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome

About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We previously reported that mice carrying a multigene deletion (Df1) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Df1 and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Df1/+ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l. Mutation of either gene is sufficient to cause reduced PPI. Tbx1 is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral/psychiatric phenotype. A likely role for Tbx1 haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, Tbx1 and Gnb1l are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.

Unrecognized benign paroxysmal positional vertigo in elderly patients

Balance disorders in elderly patients are associated with an increased risk of falls but are often difficult to diagnose because of comorbid chronic medical problems. We performed a cross-sectional study to determine the prevalence of unrecognized benign paroxysmal positional vertigo (BPPV) and associated lifestyle sequelae in a public, inner-city geriatric population. Dizziness was found in 61% of patients, whereas balance disorders were found in 77% of patients. Nine percent were found to have unrecognized BPPV. Multivariate analysis demonstrated that the presence of a spinning sensation and the absence of a lightheadedness sensation predicted the presence of unrecognized BPPV. Patients with unrecognized BPPV were more likely to have reduced activities of daily living scores, to have sustained a fall in the previous 3 months, and to have depression. These data indicate that unrecognized BPPV is common within the elderly population and has associated morbidity. Further prospective studies are warranted.

Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea

Inner ear hair cells are specialized sensory cells essential for auditory function. Previous studies have shown that the sensory epithelium is postmitotic, but it harbors cells that can behave as progenitor cells in vitro, including the ability to form new hair cells. Lgr5, a Wnt target gene, marks distinct supporting cell types in the neonatal cochlea. Here, we tested the hypothesis that Lgr5+ cells are Wnt-responsive sensory precursor cells. In contrast to their quiescent in vivo behavior, Lgr5+ cells isolated by flow cytometry from neonatal Lgr5EGFP-CreERT2/+ mice proliferated and formed clonal colonies. After 10 d in culture, new sensory cells formed and displayed specific hair cell markers (myo7a, calretinin, parvalbumin, myo6) and stereocilia-like structures expressing F-actin and espin. In comparison with other supporting cells, Lgr5+ cells were enriched precursors to myo7a+ cells, most of which formed without mitotic division. Treatment with Wnt agonists increased proliferation and colony-formation capacity. Conversely, small-molecule inhibitors of Wnt signaling suppressed proliferation without compromising the myo7a+ cells formed by direct differentiation. In vivo lineage tracing supported the idea that Lgr5+ cells give rise to myo7a+ hair cells in the neonatal Lgr5EGFP-CreERT2/+ cochlea. In addition, overexpression of β-catenin initiated proliferation and led to transient expansion of Lgr5+ cells within the cochlear sensory epithelium. These results suggest that Lgr5 marks sensory precursors and that Wnt signaling can promote their proliferation and provide mechanistic insights into Wnt-responsive progenitor cells during sensory organ development.

Hearing loss in children with very low birth weight: current review of epidemiology and pathophysiology

An association between birth weight <1500 g (very low birth weight (VLBW)) and hearing loss has been long recognised. As universal hearing screening programmes have become widely implemented and the survival rate of VLBW babies in modern intensive care units has increased, we have gained a substantially better understanding of the nature of this problem. However, many gaps in our knowledge base exist. This review describes recent data on hearing loss in the VLBW population and explains the current level of understanding about the physiological basis underlying the auditory deficits in these patients. Although VLBW alone may not have a severe impact on hearing, it is commonly associated with multiple other risk factors that can alter hearing in a synergistic fashion. Therefore, the risk of hearing loss is substantially higher than in the general newborn population. Also, it is important to perform a more comprehensive audiometric evaluation than standard otoacoustic emission screening for infants who are in the neonatal intensive care unit in order not to miss hearing loss due to retrocochlear pathology. Furthermore, children with VLBW are also at increased risk of experiencing progressive or delayed-onset hearing loss, and thus should continue to have serial hearing evaluations after discharge from the neonatal intensive care unit.

The Fate of the Tumor Remnant after Less-than-Complete Acoustic Neuroma Resection

OBJECTIVES: We sought to determine the recurrence rate after near-total and subtotal resection of acoustic neuroma. STUDY DESIGN, SETTING, AND PATIENTS: We conducted a retrospective chart review of a total of 79 patients: 50 with near-total resections (remnant ≤ 25 mm 2 and ≤ 2 mm thick) and 29 with subtotal resections (any larger remnant). Surgical approach included 5 middle fossa, 17 retrosigmoid, and 57 translabyrinthine. MAIN OUTCOME MEASURES: Recurrence was defined as documented tumor growth by serial imaging or the recommendation for further treatment after a single scan. No recurrence was defined as no visible tumor on imaging for a minimum follow-up time of 3 years or tumor remnants that remained unchanged on serial scans (mean, 5-year follow-up). RESULTS: Fifty-two patients were included in the study group. Recurrences were seen in 1 (3%) of 33 patients who had a near-total resection compared with 6 (32%) of 19 patients who had a subtotal resection. After adjustment for follow-up time and large tumor size, the odds ratio for recurrence was 12 times larger for subtotal than for near-total resections (P = 0.033). All recurrences were seen following the translabyrinthine approach in the mid-cerebellopontine angle. None were encountered in the internal auditory canal. The mean time interval from surgery to the detection of a recurrence was 3 years (range, 1 to 5 years). CONCLUSIONS: The recurrence rate when performing a near-total resection is low but is substantially higher with a subtotal resection. Recurrences can be detected within the first 5 postoperative years. We recommend near-total resection in any patient if needed to preserve neural integrity. Subtotal resection is best avoided whenever possible; however, adjunctive treatment with stereotactic radiotherapy may be considered.

Noninvasive in vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the mouse cochlea.

Significance The membranes within the cochlea vibrate in response to sound. However, measuring these vibrations to study the sense of hearing has been a technological challenge because invasive techniques have been required. Herein, we describe a new technique capable of depth-resolved displacement measurements in 3D space with picometer sensitivity within the unopened mouse cochlea. We used this technique to make, to our knowledge, the first measurements of the tectorial membrane, the structure that overlies the sensory hair cell stereociliary bundles, within a healthy cochlea. We found that the tectorial membrane sustains traveling wave propagation differently than the more commonly measured basilar membrane. This finding provides a clearer understanding of the mechanical stimulus at the level of the inner hair cell responsible for non-linear sound encoding. Sound is encoded within the auditory portion of the inner ear, the cochlea, after propagating down its length as a traveling wave. For over half a century, vibratory measurements to study cochlear traveling waves have been made using invasive approaches such as laser Doppler vibrometry. Although these studies have provided critical information regarding the nonlinear processes within the living cochlea that increase the amplitude of vibration and sharpen frequency tuning, the data have typically been limited to point measurements of basilar membrane vibration. In addition, opening the cochlea may alter its function and affect the findings. Here we describe volumetric optical coherence tomography vibrometry, a technique that overcomes these limitations by providing depth-resolved displacement measurements at 200 kHz inside a 3D volume of tissue with picometer sensitivity. We studied the mouse cochlea by imaging noninvasively through the surrounding bone to measure sound-induced vibrations of the sensory structures in vivo, and report, to our knowledge, the first measures of tectorial membrane vibration within the unopened cochlea. We found that the tectorial membrane sustains traveling wave propagation. Compared with basilar membrane traveling waves, tectorial membrane traveling waves have larger dynamic ranges, sharper frequency tuning, and apically shifted positions of peak vibration. These findings explain discrepancies between previously published basilar membrane vibration and auditory nerve single unit data. Because the tectorial membrane directly overlies the inner hair cell stereociliary bundles, these data provide the most accurate characterization of the stimulus shaping the afferent auditory response available to date.

Tuning of the outer hair cell motor by membrane cholesterol

Cholesterol affects diverse biological processes, in many cases by modulating the function of integral membrane proteins. We observed that alterations of cochlear cholesterol modulate hearing in mice. Mammalian hearing is powered by outer hair cell (OHC) electromotility, a membrane-based motor mechanism that resides in the OHC lateral wall. We show that membrane cholesterol decreases during maturation of OHCs. To study the effects of cholesterol on hearing at the molecular level, we altered cholesterol levels in the OHC wall, which contains the membrane protein prestin. We show a dynamic and reversible relationship between membrane cholesterol levels and voltage dependence of prestin-associated charge movement in both OHCs and prestin-transfected HEK 293 cells. Cholesterol levels also modulate the distribution of prestin within plasma membrane microdomains and affect prestin self-association in HEK 293 cells. These findings indicate that alterations in membrane cholesterol affect prestin function and functionally tune the outer hair cell.

Atoh1-lineal neurons are required for hearing and for the survival of neurons in the spiral ganglion and brainstem accessory auditory nuclei

Atoh1 is a basic helix–loop–helix transcription factor necessary for the specification of inner ear hair cells and central auditory system neurons derived from the rhombic lip. We used the Cre–loxP system and two Cre-driver lines (Egr2Cre and Hoxb1Cre ) to delete Atoh1 from different regions of the cochlear nucleus (CN) and accessory auditory nuclei (AAN). Adult Atoh1-conditional knock-out mice (Atoh1CKO ) are behaviorally deaf, have diminished auditory brainstem evoked responses, and have disrupted CN and AAN morphology and connectivity. In addition, Egr2; Atoh1CKO mice lose spiral ganglion neurons in the cochlea and AAN neurons during the first 3 d of life, revealing a novel critical period in the development of these neurons. These new mouse models of predominantly central deafness illuminate the importance of the CN for support of a subset of peripheral and central auditory neurons.

Predicting the effect of post-implant cochlear fibrosis on residual hearing.

Intracochlear scarring is a well-described sequela of cochlear implantation. We developed a mathematical model of passive cochlear mechanics to predict the impact that this might have upon residual acoustical hearing after implantation. The cochlea was modeled using lumped impedance terms for scala vestibuli (SV), scala tympani (ST), and the cochlear partition (CP). The damping of ST and CP was increased in the basal one half of the cochlea to simulate the effect of scar tissue. We found that increasing the damping of the ST predominantly reduced basilar membrane vibrations in the apex of the cochlea while increasing the damping of the CP predominantly reduced basilar membrane vibrations in the base of the cochlea. As long as intracochlear scarring continues to occur with cochlear implantation, there will be limitations on hearing preservation. Newer surgical techniques and electrode technologies that do not result in as much scar tissue formation will permit improved hearing preservation.

Transjugular craniotomy for the management of jugular foramen tumors with intracranial extension.

Objectives: To elucidate indications and outcomes with the transjugular craniotomy for resection of jugular foramen tumors with intracranial extension. The transjugular approach is a lateral craniotomy conducted through a partial petrosectomy traversing the jugular fossa combined with resection of the sigmoid sinus and jugular bulb, which often have been occluded by disease. Study Design: Retrospective review. Setting: University medical center. Patients: Twenty-eight patients with intracranial jugular foramen tumors who underwent a total of 30 surgical procedures. Main Outcome Measures: Pathologic findings, surgical approach, extent of tumor resection, rate of facial nerve mobilization and ear canal closure, facial and lower cranial nerve outcomes, and hearing preservation. Results: Tumors included schwannoma (37%), meningioma (33%), glomus jugulare (23%), and chordoma (7%). The surgical approaches were tailored to maximize functional preservation, and included the transjugular (53%), translabyrinthine (17%), retrosigmoid (10%), and far lateral (7%) craniotomies. Translabyrinthine (3%) or transcondylarfar lateral (3%) approaches were occasionally used in combination with the trans-jugular approach. Most procedures were managed in a single stage (90%), but three patients with massive tumor in the neck required two stages. Microsurgical gross total and near-total tumor removal (37% each) were commonly achieved, although subtotal resections (27%) were occasionally performed. In only a minority of cases was facial nerve mobilization (7%) or ear canal closure (21%) required. If present preoperatively, Grade I facial nerve function was usually maintained (22 of 24 [92%]) and Hearing Class A or B could always be maintained (9 of 9 [100%]). As expected, new lower cranial nerve dysfunction was common (8 of 30 [27%]), although over half of the patients had complete lower nerve palsy preoperatively (16 of 30 [53%]). Conclusion: Most patients with jugular foramen tumors with intracranial extension can be managed with a single-stage transjugular craniotomy. Facial nerve mobilization or ear canal closure is usually not required, permitting conservation of facial function and hearing, when present preoperatively.