Faculty Bibliography

How do humans make choices between different types of rewards? Economists have long argued on theoretical grounds that humans typically make these choices as if the values of the options they consider have been mapped to a single common scale for comparison. Neuroimaging studies in humans have recently begun to suggest the existence of a small group of specific brain sites that appear to encode the subjective values of different types of rewards on a neural common scale, almost exactly as predicted by theory. We have conducted a meta analysis using data from thirteen different functional magnetic resonance imaging studies published in recent years and we show that the principle brain area associated with this common representation is a subregion of the ventromedial prefrontal cortex (vmPFC)/orbitofrontal cortex (OFC). The data available today suggest that this common valuation path is a core system that participates in day-to-day decision making suggesting both a neurobiological foundation for standard economic theory and a tool for measuring preferences neurobiologically. Perhaps even more exciting is the possibility that our emerging understanding of the neural mechanisms for valuation and choice may provide fundamental insights into pathological choice behaviors like addiction, obesity and gambling.

Fibroblasts play a major role in normal cardiac physiology and in the response of the heart to injury and disease. Cardiac electrophysiological research has primarily focused on the mechanisms of remodeling that accompany cardiac disease with an emphasis on myocyte electrophysiology. Recently, there has been increasing interest in the potential role of fibroblasts in cardiac electrophysiology. This review focuses on the arrhythmia mechanisms involving interactions between myocytes and fibroblasts. We also discuss the available evidence supporting the contribution of intracardiac and extracardiac sources to the fibroblast and myofibroblast populations in diseased hearts.

Purpose: To investigate the integrity of the default-mode network (DMN) by using independent component analysis (ICA) methods in patients shortly after mild traumatic brain injury (MTBI) and healthy control subjects, and to correlate DMN connectivity changes with neurocognitive tests and clinical symptoms. Materials and Methods: This study was approved by the institutional review board and complied with HIPAA regulations. Twenty-three patients with MTBI who had posttraumatic symptoms shortly after injury (<2 months) and 18 age-matched healthy control subjects were included in this study. Resting-state functional magnetic resonance imaging was performed at 3 T to characterize the DMN by using ICA methods, including a single-participant ICA on the basis of a comprehensive template from core seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) nodes. ICA z images of DMN components were compared between the two groups and correlated with neurocognitive tests and clinical performance in patients by using Pearson and Spearman rank correlation. Results: When compared with the control subjects, there was significantly reduced connectivity in the PCC and parietal regions and increased frontal connectivity around the MPFC in patients with MTBI (P < .01). These frontoposterior opposing changes within the DMN were significantly correlated (r = -0.44, P = .03). The reduced posterior connectivity correlated positively with neurocognitive dysfunction (eg, cognitive flexibility), while the increased frontal connectivity correlated negatively with posttraumatic symptoms (ie, depression, anxiety, fatigue, and postconcussion syndrome). Conclusion: These results showed abnormal DMN connectivity patterns in patients with MTBI, which may provide insight into how neuronal communication and information integration are disrupted among DMN key structures after mild head injury. (c) RSNA, 2012.

OBJECTIVE: The purpose of this study was to monitor iron clearance from the liver by means of T2 and T2* mapping after administration of an ultrasmall superparamagnetic iron oxide (USPIO) agent. MATERIALS AND METHODS: The study was performed using ferumoxytol (Feraheme), a USPIO agent that has been approved by the US Food and Drug Administration for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Six healthy human participants without anemia or preexisting iron overload were prospectively included. The cohort comprised 4 men and 2 postmenopausal women, aged 22 to 57 years. T2 and T2* mapping of the liver were performed at 1.5 T using multiple spin echo and multiple gradient echo sequences, respectively. After baseline imaging, ferumoxytol was injected intravenously at a dose of 5 mg Fe/kg body weight. Imaging was repeated at 3 days, 1 month, and every 2 months thereafter for up to 11 months or until liver T2* had recovered to 24 milliseconds, the threshold used to define iron deposition. For each examination, maps of the relaxation rates R2 (= 1/T2) and R2* (= 1/T2*) were generated by fitting the signal intensity data as a function of echo time to a monoexponential decay. RESULTS: No adverse reactions to ferumoxytol injection occurred. The magnetic resonance (MR) responses to ferumoxytol varied widely among the participants. Liver R2* increased from a mean value of 35.6 s (range, 28.7-40.9 s) at baseline to a mean value of 241 s (range, 161-417 s) 3 days after administration. Liver R2 increased from 19.4 s (range, 16.6-23.8 s) at baseline to 45.3 s (range, 34.4-58.5 s) at 3 days. There was also a large variation in iron clearance times. In 1 participant, MR relaxation rates had recovered to baseline by 3 months, whereas, in 3 participants, liver R2* remained elevated at 11 months (R2* > 55 s, ie, T2* < 18 milliseconds). In these 3 participants, liver R2 also remained marginally higher at 11 months than corresponding baseline values. CONCLUSIONS: Iron deposition in the liver after a 5 mg Fe/kg dose of ferumoxytol may alter signal contrast on MR images for several months after administration. This is an important consideration in the use of USPIO agents for diagnostic purposes.

PURPOSE: The aim of this study was to use intravoxel incoherent motion diffusion-weighted imaging to discriminate subtypes of renal neoplasms and to assess agreement between intravoxel incoherent motion (perfusion fraction, fp) and dynamic contrast-enhanced magnetic resonance imaging (MRI) metrics of tumor vascularity. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved prospective study, 26 patients were imaged at 1.5-T MRI using dynamic contrast-enhanced MRI with high temporal resolution and diffusion-weighted imaging using 8 b values (range, 0-800 s/mm). Perfusion fraction (fp), tissue diffusivity (Dt), and pseudodiffusivity (Dp) were calculated using biexponential fitting of the diffusion data. Apparent diffusion coefficient (ADC) was calculated with monoexponential fit using 3 b values of 0, 400, and 800 s/mm. Dynamic contrast-enhanced data were processed with a semiquantitative method to generate model-free parameter cumulative initial area under the curve of gadolinium concentration at 60 seconds (CIAUC60). Perfusion fraction, Dt, Dp, ADC, and CIAUC60 were compared between different subtypes of renal lesions. Perfusion fraction was correlated with CIAUC60. RESULTS: We examined 14 clear cell, 4 papillary, 5 chromophobe, and 3 cystic renal cell carcinomas (RCCs). Although fp had higher accuracy (area under the curve, 0.74) for a diagnosis of clear cell RCC compared with Dt or ADC, the combination of fp and Dt had the highest accuracy (area under the curve, 0.78). The combination of fp and Dt diagnosed papillary RCC and cystic RCC with 100% accuracy, and clear cell RCC and chromophobe RCC, with 86.5% accuracy. There was significant strong correlation between fp and CIAUC60 (r = 0.82; P < 0.001). CONCLUSION: Intravoxel incoherent motion parameters fp and Dt can discriminate renal tumor subtypes. Perfusion fraction demonstrates good correlation with CIAUC60 and can assess degree of tumor vascularity without the use of exogenous contrast agent.

Axons in the vertebrate peripheral nervous system are intimately associated with Schwann cells. Axons regulate the Schwann cell phenotype, determining whether they myelinate individual axons or ensheathe multiple, small axons in Remak bundles. Our current understanding of the axonal signals that drive Schwann cells towards these distinct morphological and phenotypic fates is briefly reviewed here. Elucidation of these signals, and the intracellular pathways they regulate, may lead to new, rational therapies for the treatment of inherited and acquired neuropathies.

Respiration in mammals relies on the rhythmic firing of neurons in the phrenic motor column (PMC), a motor neuron group that provides the sole source of diaphragm innervation. Despite their essential role in breathing, the specific determinants of PMC identity and patterns of connectivity are largely unknown. We show that two Hox genes, Hoxa5 and Hoxc5, control diverse aspects of PMC development including their clustering, intramuscular branching, and survival. In mice lacking Hox5 genes in motor neurons, axons extend to the diaphragm, but fail to arborize, leading to respiratory failure. Genetic rescue of cell death fails to restore columnar organization and branching patterns, indicating these defects are independent of neuronal loss. Unexpectedly, late Hox5 removal preserves columnar organization but depletes PMC number and branches, demonstrating a continuous requirement for Hox function in motor neurons. These findings indicate that Hox5 genes orchestrate PMC development through deployment of temporally distinct wiring programs.

Ventricular ATP-sensitive potassium (K(ATP)) channels link intracellular energy metabolism to membrane excitability and contractility. Our recent proteomics experiments identified plakoglobin and plakophilin-2 (PKP2) as putative K(ATP) channel-associated proteins. We investigated whether the association of K(ATP) channel subunits with junctional proteins translates to heterogeneous subcellular distribution within a cardiac myocyte. Co-immunoprecipitation experiments confirmed physical interaction between K(ATP) channels and PKP2 and plakoglobin in rat heart. Immunolocalization experiments demonstrated that K(ATP) channel subunits (Kir6.2 and SUR2A) are expressed at a higher density at the intercalated disk in mouse and rat hearts, where they co-localized with PKP2 and plakoglobin. Super-resolution microscopy demonstrate that K(ATP) channels are clustered within nanometer distances from junctional proteins. The local K(ATP) channel density, recorded in excised inside-out patches, was larger at the cell end when compared with local currents recorded from the cell center. The K(ATP) channel unitary conductance, block by MgATP and activation by MgADP, did not differ between these two locations. Whole cell K(ATP) channel current density (activated by metabolic inhibition) was approximately 40% smaller in myocytes from mice haploinsufficient for PKP2. Experiments with excised patches demonstrated that the regional heterogeneity of K(ATP) channels was absent in the PKP2 deficient mice, but the K(ATP) channel unitary conductance and nucleotide sensitivities remained unaltered. Our data demonstrate heterogeneity of K(ATP) channel distribution within a cardiac myocyte. The higher K(ATP) channel density at the intercalated disk implies a possible role at the intercellular junctions during cardiac ischemia.

Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation.