Faculty Bibliography

OBJECTIVE: Micro-electrocorticography (muECoG) offers a minimally invasive neural interface with high spatial resolution over large areas of cortex. However, electrode arrays with many contacts that are individually wired to external recording systems are cumbersome and make recordings in freely behaving rodents challenging. We report a novel high-density 60-electrode system for muECoG recording in freely moving rats. APPROACH: Multiplexed headstages overcome the problem of wiring complexity by combining signals from many electrodes to a smaller number of connections. We have developed a low-cost, multiplexed recording system with 60 contacts at 406 mum spacing. We characterized the quality of the electrode signals using multiple metrics that tracked spatial variation, evoked-response detectability, and decoding value. Performance of the system was validated both in anesthetized animals and freely moving awake animals. MAIN RESULTS: We recorded muECoG signals over the primary auditory cortex, measuring responses to acoustic stimuli across all channels. Single-trial responses had high signal-to-noise ratios (SNR) (up to 25 dB under anesthesia), and were used to rapidly measure network topography within approximately 10 s by constructing all single-channel receptive fields in parallel. We characterized evoked potential amplitudes and spatial correlations across the array in the anesthetized and awake animals. Recording quality in awake animals was stable for at least 30 days. Finally, we used these responses to accurately decode auditory stimuli on single trials. SIGNIFICANCE: This study introduces (1) a muECoG recording system based on practical hardware design and (2) a rigorous analytical method for characterizing the signal characteristics of muECoG electrode arrays. This methodology can be applied to evaluate the fidelity and lifetime of any muECoG electrode array. Our muECoG-based recording system is accessible and will be useful for studies of perception and decision-making in rodents, particularly over the entire time course of behavioral training and learning.

Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-beta, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-beta elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.

PURPOSE: The diffusion orientation distribution function (dODF) is primarily used for white matter fiber tractography. Here the resolving power of the dODF is investigated for a simple diffusion model of two intersecting axonal fiber bundles. METHODS: The resolving power for the dODF is evaluated using the Sparrow criterion. This is determined for the exact dODF and also for q-space imaging (QSI), q-ball, and kurtosis approximations. RESULTS: Based on theoretical and numerical calculations, the resolving power is found to depend on the eigenvalues of the diffusion model and on the degree of radial weighting for the dODF. The resolving powers of the QSI and q-ball dODFs improve with increased b-value. The kurtosis dODF has a resolving power similar to that of the exact dODF. CONCLUSION: The dODFs, whether exact or approximate, have finite resolving powers that limit their sensitivity to fiber crossings. The resolving powers for the different dODFs considered here provide convenient benchmarks for assessing and comparing their performance. Magn Reson Med, 2015. (c) 2015 Wiley Periodicals, Inc.

Online imaging requires that the reconstruction of current frame only depends on the previous frames, and real time imaging is the desired case. In this work, we propose a novel scheme for real time dynamic magnetic resonance imaging (dMRI) reconstruction. Different from previous methods, the reconstructions of the second frame to the last frame are independent in our scheme, which only require the first frame as the reference image. Therefore, this scheme can be naturally implemented in parallel. After the first frame is reconstructed, all the later frames can be processed as soon as the k-space data are acquired. As an extension of the conventional spatial total variation, a new online model called dynamic total variation is used to exploit the sparsity on both spatial and temporal domains in dMRI. In real time dMRI, each frame is required to be reconstructed very fast. We then design a novel reweighted least squares algorithm to solve the challenging problem. Motivated by the special structure of partial Fourier transform in sparse MRI, this algorithm is accelerated by the preconditioned conjugate gradient descent method. The proposed method is compared with 4 state-of-the-art online and offline methods on two in-vivo cardiac dMRI datasets. The experimental results show that our method significantly outperforms previous online methods, and is comparable to the offline methods in terms of reconstruction accuracy.

The human monoclonal antibody denosumab inhibits osteoclast-mediated bone resorption by binding to receptor activator of nuclear factor kappaB ligand (RANKL), which is upregulated by tumor cells. Denosumab is indicated to prevent skeletal-related events (SREs) from osteoporosis and metastatic bone disease. We report a case of denosumab-induced hypocalcemia to highlight potential toxicity and treatment considerations. A 66-year-old man with prostate cancer, small cell lung cancer, and bone metastases presented with fatigue, weakness, and muscle spasm. Sixteen days prior, he received cycle 6 of cisplatin and etoposide, leuprolide, and denosumab (120 mg subcutaneously). His examination demonstrated a slight resting tremor, normal strength, and negative Chvostek sign. Laboratory analysis revealed hemoglobin, 8.0 g/dL; total calcium, 5.2 mg/dL (pre-denosumab, 8.9 mg/dL); and magnesium, 0.7 mg/dL. He initially received two units packed red blood cells, intravenous calcium and magnesium, and vitamin D. During his hospitalization, he required multiple doses of intravenous and oral calcium, magnesium, and vitamin D. Despite ongoing oral supplementation, his post-discharge serum calcium fluctuated significantly, requiring close monitoring and frequent dose adjustments. Denosumab's unique antiresorptive properties yield fewer SREs. The trade-off is increased hypocalcemia risk, which may be severe and require aggressive, prolonged supplementation and monitoring.

By modeling axons as thin cylinders, it is shown that the inverse Funk transform of the diffusion MRI (dMRI) signal intensity obtained on a spherical shell in q-space gives an estimate for a fiber orientation density function (fODF), where the accuracy improves with increasing b-value provided the signal-to-noise ratio is sufficient. The method is similar to q-ball imaging, except that the Funk transform of q-ball imaging is replaced by its inverse. We call this new approach fiber ball imaging. The fiber ball method is demonstrated for healthy human brain, and fODF estimates are compared to diffusion orientation distribution function (dODF) approximations obtained with q-ball imaging. The fODFs are seen to have sharper features than the dODFs, reflecting an enhancement of the higher degree angular frequencies. The inverse Funk transform of the dMRI signal intensity data provides a simple and direct method of estimating a fODF. In addition, fiber ball imaging leads to an estimate for the ratio of the fraction of MRI visible water confined to the intra-axonal space divided by the square root of the intra-axonal diffusivity. This technique may be useful for white matter fiber tractography, as well as other types of microstructural modeling of brain tissue.

Developments in microfabrication technology have enabled the production of neural electrode arrays with hundreds of closely spaced recording sites, and electrodes with thousands of sites are under development. These probes in principle allow the simultaneous recording of very large numbers of neurons. However, use of this technology requires the development of techniques for decoding the spike times of the recorded neurons from the raw data captured from the probes. Here we present a set of tools to solve this problem, implemented in a suite of practical, user-friendly, open-source software. We validate these methods on data from the cortex, hippocampus and thalamus of rat, mouse, macaque and marmoset, demonstrating error rates as low as 5%.

We describe a 21-year-old woman who presented with chest pain and dyspnea on exertion and who was found to have a large pericardial mass. Multimodality imaging was instrumental in narrowing the differential diagnosis and planning surgical treatment, which included coronary artery bypass and right-sided heart reconstruction. The final pathologic diagnosis was lymphohemangioma; to our knowledge, this was the largest cardiac/pericardial vascular tumor ever to be reported in the literature.

The varepsilon4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of varepsilon4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were varepsilon4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in varepsilon4-carriers was episodic memory decline associated with odor identification impairment. In individuals without varepsilon4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by varepsilon4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the varepsilon4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that varepsilon4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the varepsilon4 should be considered when using olfactory assessment as an early-stage indicator.

In many vertebrate species, certain individuals will seek out opportunities for aggression, even in the absence of threat-provoking cues. Although several brain areas have been implicated in the generation of attack in response to social threat, little is known about the neural mechanisms that promote self-initiated or 'voluntary' aggression-seeking when no threat is present. To explore this directly, we utilized an aggression-seeking task in which male mice self-initiated aggression trials to gain brief and repeated access to a weaker male that they could attack. In males that exhibited rapid task learning, we found that the ventrolateral part of the ventromedial hypothalamus (VMHvl), an area with a known role in attack, was essential for aggression-seeking. Using both single-unit electrophysiology and population optical recording, we found that VMHvl neurons became active during aggression-seeking and that their activity tracked changes in task learning and extinction. Inactivation of the VMHvl reduced aggression-seeking behavior, whereas optogenetic stimulation of the VMHvl accelerated moment-to-moment aggression-seeking and intensified future attack. These data demonstrate that the VMHvl can mediate both acute attack and flexible seeking actions that precede attack.