Faculty Bibliography

Echocardiography is the preferred initial imaging method for assessment of cardiac masses. Cardiac magnetic resonance (CMR) imaging, with its excellent tissue characterization and wide field of view, may provide additional unique information. We evaluated the predictive value of echocardiography and CMR imaging parameters to identify tumors and malignancy and to provide histopathologic diagnosis of cardiac masses. Fifty patients who underwent CMR evaluation of a cardiac mass with subsequent histopathologic diagnosis were identified. Echocardiography was available in 44 of 50 cases (88%). Echocardiographic and CMR characteristics were evaluated for predictive value in distinguishing tumor versus nontumor and malignant versus nonmalignant lesions using histopathology as the gold standard. The Wilcoxon rank-sum test was used to compare the 2 imaging methods' ability to provide the correct histopathologic diagnosis. Parameters associated with tumor included location outside the right atrium, T2 hyperintensity, and contrast enhancement. Parameters associated with malignancy included location outside the cardiac chambers, nonmobility, pericardial effusion, myocardial invasion, and contrast enhancement. CMR identified 6 masses missed on transthoracic echocardiography (4 of which were outside the heart) and provided significantly more correct histopathologic diagnoses compared to echocardiography (77% vs 43%, p <0.0001). In conclusion, CMR offers the advantage of identifying paracardiac masses and providing crucial information on histopathology of cardiac masses.

The control of deep cerebellar nuclear (DCN) neuronal firing is central to cerebellar function but is not well understood. The large majority of synapses onto DCN neurons derive from Purkinje cells (PCs), suggesting that PC activity is an important determinant of DCN firing; however, PCs fire both simple and complex spikes (CSs), and little is known about how the latter's action affects DCN activity. Thus, here, we explored the effects of CSs on DCN activity. CSs were recorded from PC arrays along with individual DCN neurons. Presumed synaptically connected PC-DCN cell pairs were identified using CS-triggered correlograms of DCN activity, which also showed that CS activity was associated with a predominantly inhibitory effect on DCN activity. The strength of the CS effect varied as a function of synchrony, such that isolated CSs produced only weak inhibition of DCN activity, whereas highly synchronous CSs caused a larger drop in firing levels. Although the present findings were obtained in anesthetized animals, similar CS synchrony levels exist in awake animals, and changes in synchrony level have been observed in association with movements in awake animals. Thus, the present data suggest that synchronous CS activity may be a mechanism for shaping DCN output related to motor commands.

In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-beta (Abeta) pathology, greater clinical efficacy may be achieved by clearing tau than Abeta aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.

Tumor necrosis factor-alpha (TNF-alpha) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-alpha expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-alpha and inflammatory pain, we identified its increased expression in the teeth of patients affected with caries and pulpitis. We generated a transgenic mouse model (TNF-alphaglo) that could be used to conditionally overexpress TNF-alpha. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-alpha in both the tooth pulp and bone to study oral pain that would result from subsequent development of pulpitis and bone loss. The resulting DMP1/TNF-alphaglo mice show inflammation in the tooth pulp that resembles pulpitis while also displaying periodontal bone loss. Inflammatory infiltrates and enlarged blood vessels were observed in the tooth pulp. Pulpitis and osteitis affected the nociceptive neurons innervating the orofacial region by causing increased expression of inflammatory cytokines within the trigeminal ganglia. With this new mouse model morphologically mimicking pulpitis and osteitis, we tested it for signs of oral pain with an oral function assay (dolognawmeter). This assay/device records the time required by a mouse to complete a discrete gnawing task. The duration of gnawing required by the DMP1/TNF-alphaglo mice to complete the task was greater than that for the controls; extended gnaw time in a dolognawmeter indicates reduced orofacial function. With the DMP1/TNF-alphaglo mice, we have shown that TNF-alpha expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain.

PURPOSE: We describe a 2 x 6 channel sodium/proton array for knee MRI at 3T. Multielement coil arrays are desirable because of well-known signal-to-noise ratio advantages over volume and single-element coils. However, low tissue-coil coupling that is characteristic of coils operating at low frequency can make the potential gains from a phased array difficult to realize. METHODS: The issue of low tissue-coil coupling in the developed six-channel sodium receive array was addressed by implementing 1) a mechanically flexible former to minimize the coil-to-tissue distance and reduce the overall diameter of the array and 2) a wideband matching scheme that counteracts preamplifier noise degradation caused by coil coupling and a high-quality factor. The sodium array was complemented with a nested proton array to enable standard MRI. RESULTS: The wideband matching scheme and tight-fitting mechanical design contributed to >30% central signal-to-noise ratio gain on the sodium module over a mononuclear sodium birdcage coil, and the performance of the proton module was sufficient for clinical imaging. CONCLUSION: We expect the strategies presented in this study to be generally relevant in high-density receive arrays, particularly in x-nuclei or small animal applications. Magn Reson Med, 2015. (c) 2015 Wiley Periodicals, Inc.

Response inhibition deficits are widely believed to be at the core of Attention-Deficit Hyperactivity Disorder (ADHD). Several studies have examined neural architectural correlates of ADHD, but research directly examining structural correlates of response inhibition is lacking. Here we examine the relationship between response inhibition as measured by a Go/No Go task, and cortical surface area and thickness of the caudal inferior frontal gyrus (cIFG), a region implicated in functional imaging studies of response inhibition, in a sample of 114 young adults with and without ADHD diagnosed initially during childhood. We used multiple linear regression models to test the hypothesis that Go/No Go performance would be associated with cIFG surface area or thickness. Results showed that poorer Go/No Go performance was associated with thicker cIFG cortex, and this effect was not mediated by ADHD status or history of substance use. However, independent of Go/No Go performance, persistence of ADHD symptoms and more frequent cannabis use were associated with thinner cIFG. Go/No Go performance was not associated with cortical surface area. The association between poor inhibitory functioning and thicker cIFG suggests that maturation of this region may differ in low performing participants. An independent association of persistent ADHD symptoms and frequent cannabis use with thinner cIFG cortex suggests that distinct neural mechanisms within this region may play a role in inhibitory function, broader ADHD symptomatology, and cannabis use. These results contribute to Research Domain Criteria (RDoC) by revealing novel associations between neural architectural phenotypes and basic neurobehavioral processes measured dimensionally.

Noise-band vocoders are often used to simulate the signal processing algorithms used in cochlear implants (CIs), producing acoustic stimuli that may be presented to normal hearing (NH) subjects. Such evaluations may obviate the heterogeneity of CI user populations, achieving greater experimental control than when testing on CI subjects. However, it remains an open question whether advancements in algorithms developed on NH subjects using a simulator will necessarily improve performance in CI users. This study assessed the similarity in vowel identification of CI subjects and NH subjects using an 8-channel noise-band vocoder simulator configured to match input and output frequencies or to mimic output after a basalward shift of input frequencies. Under each stimulus condition, NH subjects performed the task both with and without feedback/training. Similarity of NH subjects to CI users was evaluated using correct identification rates and information theoretic approaches. Feedback/training produced higher rates of correct identification, as expected, but also resulted in error patterns that were closer to those of the CI users. Further evaluation remains necessary to determine how patterns of confusion at the token level are affected by the various parameters in CI simulators, providing insight into how a true CI simulation may be developed to facilitate more rapid prototyping and testing of novel CI signal processing and electrical stimulation strategies.

The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell 'backprojections' play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance - 'mossy fiber variance' - which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become 'dominant,' one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of 'dominant' GCs - subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network.

PURPOSE: To evaluate the performance of an edge-based registration technique in correcting for respiratory motion artifacts in magnetic resonance renographic (MRR) data and to examine the efficiency of a semiautomatic software package in processing renographic data from a cohort of clinical patients. MATERIALS AND METHODS: The developed software incorporates an image-registration algorithm based on the generalized Hough transform of edge maps. It was used to estimate glomerular filtration rate (GFR), renal plasma flow (RPF), and mean transit time (MTT) from 36 patients who underwent free-breathing MRR at 3T using saturation-recovery turbo-FLASH. The processing time required for each patient was recorded. Renal parameter estimates and model-fitting residues from the software were compared to those from a previously reported technique. Interreader variability in the software was quantified by the standard deviation of parameter estimates among three readers. GFR estimates from our software were also compared to a reference standard from nuclear medicine. RESULTS: The time taken to process one patient's data with the software averaged 12 +/- 4 minutes. The applied image registration effectively reduced motion artifacts in dynamic images by providing renal tracer-retention curves with significantly smaller fitting residues (P < 0.01) than unregistered data or data registered by the previously reported technique. Interreader variability was less than 10% for all parameters. GFR estimates from the proposed method showed greater concordance with reference values (P < 0.05). CONCLUSION: These results suggest that the proposed software can process MRR data efficiently and accurately. Its incorporated registration technique based on the generalized Hough transform effectively reduces respiratory motion artifacts in free-breathing renographic acquisitions. J. Magn. Reson. Imaging 2015.