Faculty Bibliography

OBJECTIVE/HYPOTHESIS: We hypothesize that the central response during swallowing rehabilitation is critical and may be exploited to maximize the therapeutic benefit. We seek to provide preliminary data regarding the neural networks associated with commonly employed rehabilitation strategies to increase our understanding of the neural bases underlying these maneuvers. STUDY DESIGN: Case series. METHODS: Ten healthy adults (five males, five females), ranging in age from 20 to 30 years (mean age = 25 years, SD = 2.5 years) with no previous history of neurologic illness or swallowing complaint were subjected to a single-trial functional magnetic resonance imaging (fMRI) paradigm. The experimental tasks consisted of three swallow maneuvers, dry swallow, Effortful swallow, and the Mendelsohn maneuver. RESULTS: Multiple regions including the cingulate gyrus, inferior frontal gyrus, insula, pre- and postcentral gyrus, inferior parietal lobe, superior frontal gyrus, supramarginal gyrus thalamus, were detected. The Effortful swallow, when compared to the dry swallow, elicited significant differential activation in the left superior temporal gyrus, left insula, left inferior parietal lobe, bilateral medial frontal gyrus, and right anterior cingulate. The Mendelsohn maneuver, when compared to the dry swallow, elicited significant activation in the bilateral postcentral gyrus, bilateral precentral gyrus, bilateral cingulate gyrus, bilateral medial frontal gyrus, left inferior parietal lobe, left supramarginal gyrus, and right insula. CONCLUSIONS: Our findings suggest that a single-trial design is sensitive to delineate a widespread neural network of activation in both hemispheres associated with rehabilitation tasks. Both the Effortful swallow and Mendelsohn maneuvers elicited significantly higher responses in regions related to swallowing, suggestive of enhanced cortical activation during these tasks

Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway

OBJECTIVES: To present a rare case of facial nerve paraganglioma and novel use of a processed allograft for facial nerve reconstruction. STUDY DESIGN: Case report and review of the literature. METHODS: A 34 year old female presented with progressive onset right sided facial palsy for 5 months. CT and MRI demonstrated an irregular mass in the right facial nerve canal from the intratympanic segment to the stylomastoid foramen. RESULTS: Following transmastoid resection, the defect was repaired using processed allograft. Pathologic analysis was consistent with a paraganglioma. Facial nerve paraganglioma is a rare entity that has been reported only 10 times in the literature. CONCLUSIONS: Traditional methods of facial nerve reconstruction, including autologous and cadaveric grafting, can lead to significant patient morbidity. Autologous nerve grafts are the 'gold standard' for superior regenerative capability, but are limited by the length and potential neuroma formation at the donor site. Allogenic grafts from donors or cadavers have shown some efficacy, but can require immunosuppression. The Avance nerve graft is a cadaveric graft, processed and decellularized to maintain an extracellular matrix with laminin and intact endoneural tubes, thus providing support for the growing axon without generating an immune response. Initial studies of the Avance graft in animals and humans have examined repair of peripheral nerves, but this is the first reported case of human facial nerve reconstruction

Spike-timing-dependent plasticity (STDP) has attracted considerable experimental and theoretical attention over the last decade. In the most basic formulation, STDP provides a fundamental unit - a spike pair - for quantifying the induction of long-term changes in synaptic strength. However, many factors, both pre- and postsynaptic, can affect synaptic transmission and integration, especially when multiple spikes are considered. Here we review the experimental evidence for multiple types of nonlinear temporal interactions in STDP, focusing on the contributions of individual spike pairs, overall spike rate, and precise spike timing for modification of cortical and hippocampal excitatory synapses. We discuss the underlying processes that determine the specific learning rules at different synapses, such as postsynaptic excitability and short-term depression. Finally, we describe the success of efforts toward building predictive, quantitative models of how complex and natural spike trains induce long-term synaptic modifications

During development, detection for many percepts matures gradually. This provides a natural system in which to investigate the neural mechanisms underlying performance differences: those aspects of neural activity that mature in conjunction with behavioral performance are more likely to subserve detection. In principle, the limitations on performance could be attributable to either immature sensory encoding mechanisms or an immature decoding of an already-mature sensory representation. To evaluate these alternatives in awake gerbil auditory cortex, we measured neural detection of sinusoidally amplitude-modulated (sAM) stimuli, for which behavioral detection thresholds display a prolonged maturation. A comparison of single-unit responses in juveniles and adults revealed that encoding of static tones was adult like in juveniles, but responses to sAM depth were immature. Since perceptual performance may reflect the activity of an animal's most sensitive neurons, we analyzed the d prime curves of single neurons and found an equivalent percentage with highly sensitive thresholds in juvenile and adult animals. In contrast, perceptual performance may reflect the pooling of information from neurons with a range of sensitivities. We evaluated a pooling model that assumes convergence of a population of inputs at a downstream target neuron and found poorer sAM detection thresholds for juveniles. Thus, if sAM detection is based on the most sensitive neurons, then immature behavioral performance is best explained by an immature decoding mechanism. However, if sAM detection is based on a population response, then immature detection thresholds are more likely caused by an inadequate sensory representation

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment

OBJECTIVES: To observe the extent of nasal polyposis endoscopically in a cystic fibrosis population before the first surgical intervention and to grade the extent using a modified Malm scale, to observe patients prospectively and record the need for revision endoscopic sinus surgery (ESS), and to compare this among the individual polyp grading groupings. DESIGN: Retrospective medical record review of data collected prospectively. SETTING: Tertiary care hospital. PATIENTS: Forty-nine consecutive patients with a clinical preoperative diagnosis of cystic fibrosis and sinusitis. MAIN OUTCOME MEASURES: Using a modified Malm scale, the extent of polyps was prospectively graded into 3 groups before the first surgical intervention. The number of patients needing revision ESS and the mean time to revision ESS were compared among the 3 groups. RESULTS: Forty-nine consecutive patients underwent ESS between 1992 and 2007. We used a 3-stage system for extent of polyposis: 16 patients were noted to have no polyps (grade A), 14 had mild polyposis (grade B), and 19 had extensive polyposis (grade C). During the study, 14 patients required revision surgery: 3 with mild polyps and 11 with extensive polyps. Mean time to revision surgery was 39.7 months for those with grade B and 23.8 months for those with grade C. In the overall statistical analysis, the rate of revision ESS was significantly different among the 3 groups (P < .001). In pairwise comparisons, there were significant differences between those with grades A and C (P < .001) and between those with grades B and C (P = .04) and a trend toward significance between those with grades A and B (P = .052). There were no complications from ESS. CONCLUSION: Preoperative grading of nasal polyposis in patients with cystic fibrosis can help assess the future likelihood of revision ESS

PURPOSE: To conduct an evidence-based systematic review and provide an estimate of the effects of oral motor interventions (OMIs) on feeding/swallowing outcomes (both physiological and functional) and pulmonary health in preterm infants. METHOD: A systematic search of the literature published from 1960 to 2007 was conducted. Articles meeting the selection criteria were appraised by 2 reviewers and vetted by a 3rd for methodological quality. RESULTS: Twelve studies were included and focused on 3 OMIs-nonnutritive sucking (NNS), oral/perioral stimulation, and NNS plus oral/perioral stimulation. Six studies addressed the effects of OMI on the feeding/swallowing physiology outcomes of feeding efficiency or sucking pressures. Ten studies addressed the functional feeding/swallowing outcomes of oral feeding or weight gain/growth. No studies reported data on pulmonary health. Methodological quality varied greatly. NNS alone and with oral/perioral stimulation showed strong positive findings for improvement in some feeding/swallowing physiology variables and for reducing transition time to oral feeding. Prefeeding stimulation showed equivocal results across the targeted outcomes. None of the OMIs provided consistent positive results on weight gain/growth. CONCLUSIONS: Although some OMIs show promise for enhancing feeding/swallowing in preterm infants, methodological limitations and variations in results across studies warrant careful consideration of their clinical use

OBJECTIVES: We compared estimated blood loss (EBL) in patients who underwent surgical excision of carotid body tumors (CBTs) after preoperative superselective angiography with embolization (PSE) with that in patients who underwent excision of CBTs without PSE. METHODS: We performed a retrospective chart review of a consecutive case series in a single surgeon's practice within an academic tertiary care medical center. Twenty-five patients underwent surgical resection of a CBT from 1989 to 2009. From 1989 to 1996, 10 consecutive patients had PSE of the CBT, whereas the subsequent 15 patients (1996 to 2009) had no PSE. Demographic data including age, sex, and tumor size were collected. The EBL was obtained from intraoperative records and operative notes dictated at the time of surgery. Tumor size was based on preoperative radiographic measurements by a senior radiologist and the surgeon. RESULTS: In the 10 patients with PSE, the mean age was 41 years (range, 22 to 72 years) and the mean tumor size was 4.8 cm (range, 2.9 to 8.3 cm). The mean EBL was 305 mL (range, 50 to 1,000 mL); 2 patients had an EBL of more than 400 mL. In the 15 patients without PSE, the mean age was 43.7 years (range, 20 to 75 years) and the mean tumor size was 4.4 cm (range, 2.8 to 7.9 cm). The mean EBL was 265.6 mL (range, 40 to 900 mL); 2 patients had an EBL of more than 400 mL. There were no significant differences between the 2 groups with regard to age, tumor size, or EBL. CONCLUSIONS: Preoperative superselective angiography with embolization of a CBT does not lead to a significant reduction in intraoperative EBL