Faculty Bibliography

Rapid temporal modulation of acoustic signals among several vertebrate lineages has recently been shown to depend on the actions of superfast muscles. We hypothesized that such fast events, known to require synchronous activation of muscle fibers, would rely upon motoneuronal properties adapted to generating a highly synchronous output to sonic muscles. Using intracellular in vivo recordings, we identified a suite of premotor network inputs and intrinsic motoneuronal properties synchronizing the oscillatory-like, simultaneous activation of superfast muscles at high-gamma frequencies in fish. Motoneurons lacked spontaneous activity, firing synchronously only at the frequency of premotor excitatory input. Population-level motoneuronal output generated a spike-like, vocal nerve volley that directly determines muscle contraction rate and, in turn, natural call frequency. In the absence of vocal output, motoneurons showed low excitability and a weak afterhyperpolarization leading to rapid accomodation in firing rate. By contrast, vocal activity was accompanied by a prominent afterhyperpolarization, indicating a dependency on network activity. Local injection of a GABAA receptor antagonist demonstrated the necessity of electrophysiologically- and immunohistochemically-confirmed inhibitory GABAergic input for motoneuronal synchrony and vocalization. Numerous transneuronally labeled motoneurons following single cell neurobiotin injection together with electrophysiological collision experiments confirmed gap junctional coupling, known to contribute to synchronous activity in other neural networks. Motoneuronal synchrony at the premotor input frequency was maintained during differential recruitment of variably sized motoneurons. Differential motoneuron recruitment led, however, to amplitude modulation (AM) of vocal output and, hence, natural call AM. In sum, motoneuronal intrinsic properties, in particular low excitability, predisposed vocal motoneurons to the synchronizing influences of premotor inputs to translate a temporal input code into a coincident and extremely synchronous, but variable amplitude, output code. We propose an analogous suite of neuronal properties as a key innovation underlying similarly rapid acoustic events observed among amphibians, reptiles, birds and mammals.

Cancer patients often suffer from pain and most will be prescribed mu-opioids. mu-opioids are not satisfactory in treating cancer pain and are associated with multiple debilitating side effects. Recent studies show that mu and delta opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which control thermal and mechanical pain, respectively. In this study we investigated IB4 (+) and IB4 (-) neurons in mechanical and thermal hypersensitivity in an orthotopic mouse oral cancer model. We used a delta opioid receptor agonist and a P2X(3) antagonist to target IB4 (+) neurons and to demonstrate that this subset plays a key role in cancer-induced mechanical allodynia, but not in thermal hyperalgesia. Moreover, selective removal of IB4 (+) neurons using IB4-saporin impacts cancer-induced mechanical but not thermal hypersensitivity. Our results demonstrate that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective delta-opioid receptor agonist or P2X(3) antagonist, might be useful in treating oral cancer pain. PERSPECTIVE: To clarify the mechanisms of oral cancer pain, we examined the differential role of IB4 (+) and IB4 (-) neurons. Characterization of these 2 subsets of putative nociceptors is important for further development of effective clinical cancer pain relief.

Because multiple symptoms associated with "sickness behavior" have a negative impact on functional status and quality of life, increased information on the mechanisms that underlie inter-individual variability in this symptom experience is needed. The purposes of this study were to determine: if distinct classes of individuals could be identified based on their experience with pain, fatigue, sleep disturbance, and depression; if these classes differed on demographic and clinical characteristics; and if variations in pro- and anti- inflammatory cytokine genes were associated with latent class membership. Self-report measures of pain, fatigue, sleep disturbance, and depression were completed by 168 oncology outpatients and 85 family caregivers (FCs). Using latent class profile analysis (LCPA), three relatively distinct classes were identified: those who reported low depression and low pain (83%), those who reported high depression and low pain (4.7%), and those who reported high levels of all four symptoms (12.3%). The minor allele of IL4 rs2243248 was associated with membership in the "All high" class along with younger age, being White, being a patient (versus a FC), having a lower functional status score, and having a higher number of comorbid conditions. Findings suggest that LPCA can be used to differentiate distinct phenotypes based on a symptom cluster associated with sickness behavior. Identification of distinct phenotypes provides new evidence for the role of IL4 in the modulation of a sickness behavior symptom cluster in oncology patients and their FCs.

Oculodentodigital dysplasia (ODDD) is a rare developmental disease resulting from germline mutations in the GJA1 gene that encodes the gap junction protein connexin43 (Cx43). In addition to the classical ODDD symptoms that affect the eyes, teeth, bone and digits, in some cases ODDD patients have reported bladder impairments. Thus, we chose to characterize the bladder in mutant mouse models of ODDD that harbor two distinct Cx43 mutations, G60S and I130T. Histological assessment revealed no difference in bladder detrusor wall thickness in mutant compared to littermate control mice. The overall localization of Cx43 in the lamina propria and detrusor also appeared to be similar in the bladders of mutant mice with the exception that the G60S mice had more instances of intracellular Cx43. However, both mutant mouse lines exhibited a significant reduction in the phosphorylated P1 and P2 isoforms of Cx43, while only the I130T mice exhibited a reduction in total Cx43 levels. Interestingly, Cx26 levels and distribution were not altered in mutant mice as it was localized to intracellular compartments and restricted to the basal cell layers of the urothelium. Our studies suggest that these two distinct genetically modified mouse models of ODDD probably mimic patients who lack bladder defects or other factors, such as aging or co-morbidities, are necessary to reveal a bladder phenotype.

OBJECTIVE: Many older adults have decreased kidney function. Practitioners should be informed that no single clinical assessment method is validated in predicting their kidney function. DATA SOURCES: Primary literature identified through MEDLINE/PubMed (1950-2010) and EMBASE (1980-2010) databases. The search was limited to English language, human subjects, and individuals 65 years of age and older. STUDY SELECTION AND DATA EXTRACTION: Research, review articles, and additional publications related to geriatric, elderly, kidney function assessment, and cystatin C. DATA SYNTHESIS: Screening and diagnosing chronic kidney disease are a challenge in older adults partially because of muscle loss and frailty. The various tools used to estimate creatinine clearance (Clcr) are not validated and may lead to under- or overdiagnosis of kidney function. The clinician must be cautious when using and interpreting results from these values. RESULTS: Estimating the glomerular filtration rate (eGFR) with either the Modification of Diet in Renal Disease (MDRD) or Cockcroft-Gault (Clcr) formulae yielded better predictions of kidney function when compared with creatinine alone, or to measured Clcr. These estimation methods should be used in clinical practice to provide a better estimation of kidney function in older adults until a more valid assessment tool becomes available. CONCLUSIONS: There is no proven valid method for eGFR in older adults; however, the CG and MDRD equations are routinely applied in clinical practice. Kidney function assessment in older adults remains a challenge, and practitioners should know their limitations.

Sudden cardiac death is responsible for several hundred thousand deaths each year in the United States. Multiple lines of evidence suggest that perturbation of gap junction expression and function in the heart, or what has come to be known as cardiac gap junction remodeling, plays a key mechanistic role in the pathophysiology of clinically significant cardiac arrhythmias. Here we review recent studies from our laboratory using genetically engineered murine models to explore mechanisms implicated in pathologic gap junction remodeling and their proarrhythmic consequences, with a particular focus on aberrant posttranslational phosphorylation of connexin43.

The dentate gyrus is one of two main areas of the mammalian brain where neurons are born throughout adulthood, a phenomenon called postnatal neurogenesis. Most of the neurons that are generated are granule cells (GCs), the major principal cell type in the dentate gyrus. Some adult-born granule cells develop in ectopic locations, such as the dentate hilus. The generation of hilar ectopic granule cells (HEGCs) is greatly increased in several animal models of epilepsy and has also been demonstrated in surgical specimens from patients with intractable temporal lobe epilepsy (TLE). Herein we review the results of our quantitative neuroanatomic analysis of HEGCs that were filled with Neurobiotin following electrophysiologic characterization in hippocampal slices. The data suggest that two types of HEGCs exist, based on a proximal or distal location of the cell body relative to the granule cell layer, and based on the location of most of the dendrites, in the molecular layer or hilus. Three-dimensional reconstruction revealed that the dendrites of distal HEGCs can extend along the transverse and longitudinal axis of the hippocampus. Analysis of axons demonstrated that HEGCs have projections that contribute to the normal mossy fiber innervation of CA3 as well as the abnormal sprouted fibers in the inner molecular layer of epileptic rodents (mossy fiber sprouting). These data support the idea that HEGCs could function as a "hub" cell in the dentate gyrus and play a critical role in network excitability.

The Laboratory of Translational Auditory Research (LTAR/NYUSM) is part of the Department of Otolaryngology at the New York University School of Medicine and has close ties to the New York University Cochlear Implant Center. LTAR investigators have expertise in multiple related disciplines including speech and hearing science, audiology, engineering, and physiology. The lines of research in the laboratory deal mostly with speech perception by hearing impaired listeners, and particularly those who use cochlear implants (CIs) or hearing aids (HAs). Although the laboratory's research interests are diverse, there are common threads that permeate and tie all of its work. In particular, a strong interest in translational research underlies even the most basic studies carried out in the laboratory. Another important element is the development of engineering and computational tools, which range from mathematical models of speech perception to software and hardware that bypass clinical speech processors and stimulate cochlear implants directly, to novel ways of analyzing clinical outcomes data. If the appropriate tool to conduct an important experiment does not exist, we may work to develop it, either in house or in collaboration with academic or industrial partners. Another notable characteristic of the laboratory is its interdisciplinary nature where, for example, an audiologist and an engineer might work closely to develop an approach that would not have been feasible if each had worked singly on the project. Similarly, investigators with expertise in hearing aids and cochlear implants might join forces to study how human listeners integrate information provided by a CI and a HA. The following pages provide a flavor of the diversity and the commonalities of our research interests.

Although there have been many advancements in cancer research, much is still unknown about the heterogeneous tumor microenvironment. Diffusion-weighted MRI has proven to be a viable and versatile microstructural probe. Diffusion-weighted sequences specifically sensitive to intravoxel incoherent motion (IVIM) have seen a recent resurgence of interest as they promise to provide a valuable window on the vascular microenvironment. To understand, test, and optimize IVIM-sensitive approaches, a complex flow phantom was constructed to mimic certain characteristics of the tumor microenvironment such as tortuous microvasculature, heterogeneous vascular permeability, and interstitial fluid pressure buildup. Results using this phantom on a clinical scanner platform confirmed IVIM sensitivity to microscopic flow effects. Biexponential fitting of signal decay curves enabled quantitative extraction of perfusion fraction, IVIM-related pseudodiffusivity, and tissue diffusivity. Parametric maps were also generated, illustrating the potential utility of IVIM-sensitive imaging in clinical settings. The flow phantom proved to be an effective test-bed for validating and optimizing the IVIM-MRI technique to provide surrogate markers for microvascular properties. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc

Purpose:To assess the reproducibility and the distribution of intravoxel incoherent motion (IVIM) and diffusion-tensor (DT) imaging parameters in healthy renal cortex and medulla at baseline and after hydration or furosemide challenges.Materials and Methods:Using an institutional review board-approved HIPAA-compliant protocol with written informed consent, IVIM and DT imaging were performed at 3 T in 10 volunteers before and after water loading or furosemide administration. IVIM (apparent diffusion coefficient [ADC], tissue diffusivity [D(t)], perfusion fraction [f(p)], pseudodiffusivity [D(p)]) and DT (mean diffusivity [MD], fractional anisotropy [FA], eigenvalues [lambda(i)]) imaging parameters and urine output from serial bladder volumes were calculated. (a) Reproducibility was quantified with coefficient of variation, intraclass correlation coefficient, and Bland-Altman limits of agreement; (b) contrast and challenge response were quantified with analysis of variance; and (c) Pearson correlations were quantified with urine output.Results:Good reproducibility was found for ADC, D(t), MD, FA, and lambda(i) (average coefficient of variation, 3.7% [cortex] and 5.0% [medulla]), and moderate reproducibility was found for D(p), f(p), and f(p) . D(p) (average coefficient of variation, 18.7% [cortex] and 25.9% [medulla]). Baseline cortical diffusivities significantly exceeded medullary values except D(p), for which medullary values significantly exceeded cortical values, and lambda(1,) which showed no contrast. ADC, D(t), MD, and lambda(i) increased significantly for both challenges. Medullary diffusivity increases were dominated by transverse diffusion (1.72 +/- 0.09 [baseline] to 1.79 +/- 0.10 [hydration] mum(2)/msec, P = .0059; or 1.86 +/- 0.07 [furosemide] mum(2)/msec, P = .0094). Urine output correlated with cortical ADC with furosemide (r = 0.7, P = .034) and with medullary lambda(1) (r = 0.83, P = .0418), lambda(2) (r = 0.85, P = .0301), and MD (r = 0.82, P = .045) with hydration.Conclusion:Diffusion MR metrics are sensitive to flow changes in kidney induced by diuretic challenges. The results of this study suggest that vascular flow, tubular dilation, water reabsorption, and intratubular flow all play important roles in diffusion-weighted imaging contrast.(c) RSNA, 2012.