Faculty Bibliography

The utilization of parallel imaging permits increased MR acquisition speed and efficiency; however, parallel MRI usually leads to a deterioration in the signal-to-noise ratio when compared with otherwise equivalent unaccelerated acquisitions. At high accelerations, the parallel image reconstruction matrix tends to become dominated by one principal component. This has been utilized to enable substantial reductions in g-factor-related noise. A previously published technique achieved noise reductions via a computationally intensive search for multiples of the dominant singular vector which, when subtracted from the image, minimized joint entropy between the accelerated image and a reference image. We describe a simple algorithm that can accomplish similar results without a time-consuming search. Significant reductions in g-factor-related noise were achieved using this new algorithm with in vivo acquisitions at 1.5 T with an eight-element array.

Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.

Myelinating Schwann cells regulate the localization of ion channels on the surface of the axons they ensheath. This function depends on adhesion complexes that are positioned at specific membrane domains along the myelin unit. Here we show that the precise localization of internodal proteins depends on the expression of the cytoskeletal adapter protein 4.1G in Schwann cells. Deletion of 4.1G in mice resulted in aberrant distribution of both glial adhesion molecules and axonal proteins that were present along the internodes. In wild-type nerves, juxtaparanodal proteins (i.e., Kv1 channels, Caspr2, and TAG-1) were concentrated throughout the internodes in a double strand that flanked paranodal junction components (i.e., Caspr, contactin, and NF155), and apposes the inner mesaxon of the myelin sheath. In contrast, in 4.1G(-/-) mice, these proteins "piled up" at the juxtaparanodal region or aggregated along the internodes. These findings suggest that protein 4.1G contributes to the organization of the internodal axolemma by targeting and/or maintaining glial transmembrane proteins along the axoglial interface.

Numerous brain structures are composed of distinct layers and such stratification has a profound effect on extracellular diffusion transport in these structures. We have derived a more general form of diffusion equation incorporating inhomogeneities in both the extracellular volume fraction (alpha) and diffusion permeability (theta). A numerical solution of this equation for a special case of layered environment was employed to analyze diffusion in the CA1 region of hippocampus where stratum pyramidale occupied by the bodies of principal neurons is flanked by stratum radiatum and stratum oriens. Extracellular diffusion in the CA1 region was measured in vitro by real-time iontophoretic and real-time pressure methods, and numerical analysis found that stratum pyramidale had a significantly smaller extracellular volume fraction (alpha=0.127) and lower diffusion permeability (theta=0.327) than the other two layers (alpha=0.218, theta=0.447). Stratum pyramidale thus functioned as a diffusion barrier for molecules attempting to cross it. We also demonstrate that unless the detailed properties of all layers are taken into account when diffusion experiments are interpreted, the extracted apparent parameters of the extracellular space lose their physical meaning and capacity to describe any individual layer. Such apparent parameters depend on diffusion distance and direction, giving a false impression of microscopic anisotropy and non-Gaussian behavior. This finding has implications for all diffusion mediated physiological processes as well as for other diffusion methods including integrative optical imaging and diffusion-weighted magnetic resonance imaging.

Posterior tongue defects present a unique reconstructive challenge. The various reconstructive options available for treating the defect created by a posterior hemiglossectomy frequently result in a distorted tongue and functional impairment. This paper describes a novel sliding anterior hemitongue flap to allow reconstruction of moderate resection defects (i.e. for T1-T2 tongue squamous cell carcinomas) of the posterior tongue. By mobilizing the anterior tongue, near normal mobility and tongue length are maintained. This surgical technique may be performed alone intraorally or in combination with a neck dissection.

Cancer pain is an ever-present public health concern. With innovations in treatment, cancer patients are surviving longer, but uncontrollable pain creates a poor quality of life for these patients. Oral cancer is unique in that it causes intense pain at the primary site and significantly impairs speech, swallowing, and masticatory functions. We propose that oral cancer pain has underlying biologic mechanisms that are generated within the cancer microenvironment. A comprehensive understanding of key mediators that control cross-talk between the cancer and peripheral nervous system, and possible interventions, underlies effective cancer pain management. The purpose of this review is to explore the current studies on oral cancer pain and their implications in clinical management for cancer pain in general. Furthermore, we will explore the endogenous opioid systems and novel cancer pain therapeutics that target these systems, which could solve the issue of opiate tolerance and improve quality of life in oral cancer patients.

BACKGROUND: Mandibular osteoradionecrosis is the most devastating complication after radiation therapy for head and neck malignancies. Quality of life (QOL) after surgical treatment is unclear. METHODS: A retrospective cohort analysis (1997-2007) was conducted of all patients treated at our institution for stage II and III mandibular osteoradionecrosis. Nineteen of 35 patients responded to a modified University of Washington QOL questionnaire. Twenty had undergone reconstruction using free flaps, and the remainder with plates, plates and local flaps, or debridement alone. RESULTS: Complications included 3 infections, 5 with hardware, 5 flap-specific, and 1 nonunion. Four patients had recurrent squamous cell carcinoma (SCC). The factors of greatest concern to patients were appearance, swallowing, and chewing. Average overall QOL was good to very good, and very good compared to preoperative. CONCLUSION: Despite a 37% complication rate, a multidisciplinary team approach with adequate debridement, resection, and reconstruction can greatly improve QOL. (c) 2011 Wiley Periodicals, Inc. Head Neck, 2012.

Conventional imaging is unable to detect damage that accounts for permanent cognitive impairment in patients with mild traumatic brain injury (MTBI). While diffusion tensor imaging (DTI) can help to detect diffuse axonal injury (DAI), it is a limited indicator of tissue complexity. It has also been suggested that the thalamus may play an important role in the development of clinical sequelae in MTBI. The purpose of this study was to determine if diffusional kurtosis imaging (DKI), a novel quantitative magnetic resonance imaging (MRI) technique, can provide early detection of damage in the thalamus and white matter (WM) of MTBI patients and if thalamic injury is associated with cognitive impairment. Twenty-two MTBI patients and 14 controls underwent MRI and neuropsychological testing. Mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) were measured in the thalamus and several WM regions classically identified with DAI. Compared to controls, patients examined within one year after injury exhibited variously altered DTI and DKI derived measures in the thalamus and the internal capsule while, in addition to these regions, patients examined more than one year after injury also showed similar differences in the splenium of the corpus callosum and the centrum semiovale. Cognitive impairment was correlated to MK in the thalamus and the internal capsule. These findings suggest that combined use of DTI and DKI provides a more sensitive tool for identifying brain injury. In addition, MK in the thalamus might be useful for early prediction of permanent brain damage and cognitive outcome

Noncontrast techniques for peripheral MR angiography are receiving renewed interest because of safety concerns about the use of gadolinium in patients with renal insufficiency. One class of techniques involves subtraction of dark-blood images acquired during fast systolic flow from bright-blood images obtained during slow diastolic flow. The goal of this work was to determine whether the inherent sparsity of the difference images could be exploited to achieve greater acceleration without loss of image quality in the context of generalized autocalibrating partially parallel acquisition (GRAPPA). It is shown that noise amplification at high acceleration factors can be reduced by performing subtraction on the raw data, before calculation of the GRAPPA weights, rather than on the final magnitude images. Use of the difference data to calculate the GRAPPA weights decreases the geometry factor (g-factor), because the difference data represent a sparse image set. This demonstrates an inherent property of GRAPPA and does not require the use of compressed sensing. Application of this approach to highly accelerated data from healthy volunteers resulted in similar depiction of large arteries to that obtained with low acceleration and standard reconstruction. However, visualization of very small vessels and arterial branches was compromised. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

Lipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD (LOAD) patients, as well as the forebrain of three transgenic familial AD (FAD) mouse models. Although the cerebellum lacked major alterations in lipid composition, we found an elevation of a signaling pool of diacylglycerol as well as sphingolipids in the prefrontal cortex of AD patients. Furthermore, the diseased entorhinal cortex showed specific enrichment of lysobisphosphatidic acid, sphingomyelin, the ganglioside GM3, and cholesterol esters, all of which suggest common pathogenic mechanisms associated with endolysosomal storage disorders. Importantly, a significant increase in cholesterol esters and GM3 was recapitulated in the transgenic FAD models, suggesting that these mice are relevant tools to study aberrant lipid metabolism of endolysosomal dysfunction associated with AD. Finally, genetic ablation of phospholipase D(2), which rescues the synaptic and behavioral deficits of an FAD mouse model, fully normalizes GM3 levels. These data thus unmask a cross-talk between the metabolism of phosphatidic acid, the product of phospholipase D(2), and gangliosides, and point to a central role of ganglioside anomalies in AD pathogenesis. Overall, our study highlights the hypothesis generating potential of lipidomics and identifies novel region-specific lipid anomalies potentially linked to AD pathogenesis