Faculty Bibliography

Diffusion within the extracellular space (ECS) of the brain is necessary for chemical signaling and for neurons and glia to access nutrients and therapeutics; however, the width of the ECS in living tissue remains unknown. We used integrative optical imaging to show that dextrans and water-soluble quantum dots with Stokes-Einstein diameters as large as 35 nm diffuse within the ECS of adult rat neocortex in vivo. Modeling the ECS as fluid-filled 'pores' predicts a normal width of 38-64 nm, at least 2-fold greater than estimates from EM of fixed tissue. ECS width falls below 10 nm after terminal ischemia, a likely explanation for the small ECS visualized in electron micrographs. Our results will improve modeling of neurotransmitter spread after spillover and ectopic release and establish size limits for diffusion of drug delivery vectors such as viruses, liposomes, and nanoparticles in brain ECS

The author's laboratory studies the neural basis of learning and decision-making using a combination of techniques from neuroscience, economics and psychology. Behavioral studies of decision-making in both human and non-human primates guide physiological experiments using single neuron recording and functional magnetic resonance imaging. The goal of the laboratory is to achieve an interdisciplinary understanding of choice behavior that transcends the understanding of this phenomenon available to any single scholarly discipline.

Conventional diffusion tensor imaging (DTI) measures water diffusion parameters based on the assumption that the spin displacement distribution is a Gaussian function. However, water movement in biological tissue is often non-Gaussian and this non-Gaussian behavior may contain useful information related to tissue structure and pathophysiology. Here we propose an approach to directly measure the non-Gaussian property of water diffusion, characterized by a four-dimensional matrix referred to as the diffusion kurtosis tensor. This approach does not require the complete measurement of the displacement distribution function and, therefore, is more time efficient compared with the q-space imaging technique. A theoretical framework of the DK calculation is established, and experimental results are presented for humans obtained within a clinically feasible time of about 10 min. The resulting kurtosis maps are shown to be robust and reproducible. Directionally-averaged apparent kurtosis coefficients (AKC, a unitless parameter) are 0.74 +/- 0.03, 1.09 +/- 0.01 and 0.84 +/- 0.02 for gray matter, white matter and thalamus, respectively. The three-dimensional kurtosis angular plots show tissue-specific geometry for different brain regions and demonstrate the potential of identifying multiple fiber structures in a single voxel. Diffusion kurtosis imaging is a useful method to study non-Gaussian diffusion behavior and can provide complementary information to that of DTI

Advances in cognitive neuroscience now allow us to use physiological techniques to measure and assess mental states under a growing set of circumstances. The implication of this growing ability has not been lost on the western legal community. If biologists can accurately measure mental state, then legal conflicts that turn on the true mental states of individuals might well be resolvable with techniques ranging from electroencephalography to functional magnetic resonance imaging. Therefore, legal practitioners have increasingly sought to employ cognitive neuroscientific methods and data as evidence to influence legal proceedings. This poses a risk, because these scientific methodologies have largely been designed and validated for experimental use only. Their subsequent use in legal proceedings is an application for which they were not intended, and for which those methods are inadequately tested. We propose that neurobiologists, who might inadvertently contribute to this situation, should be aware of how their papers will be read by the legal community and should play a more active role in educating and engaging with that community.

OBJECTIVE: The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. STUDY DESIGN: Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. RESULTS: After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p=.025) and 5.7 stairs per minute more 3MSC (p=.053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227+/-18 microg/mg more with rhASB than placebo (p<.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. CONCLUSION: rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile

Human visual speed perception is qualitatively consistent with a Bayesian observer that optimally combines noisy measurements with a prior preference for lower speeds. Quantitative validation of this model, however, is difficult because the precise noise characteristics and prior expectations are unknown. Here, we present an augmented observer model that accounts for the variability of subjective responses in a speed discrimination task. This allowed us to infer the shape of the prior probability as well as the internal noise characteristics directly from psychophysical data. For all subjects, we found that the fitted model provides an accurate description of the data across a wide range of stimulus parameters. The inferred prior distribution shows significantly heavier tails than a Gaussian, and the amplitude of the internal noise is approximately proportional to stimulus speed and depends inversely on stimulus contrast. The framework is general and should prove applicable to other experiments and perceptual modalities

Dysfunction of cholinergic basal forebrain (CBF) neurons of the nucleus basalis (NB) is a cardinal feature of Alzheimer's disease (AD) and correlates with cognitive decline. Survival of CBF neurons depends upon binding of nerve growth factor (NGF) with high-affinity (trkA) and low-affinity (p75(NTR)) neurotrophin receptors produced within CBF neurons. Since trkA and p75(NTR) protein levels are reduced within CBF neurons of people with mild cognitive impairment (MCI) and mild AD, trkA and/or p75(NTR) gene expression deficits may drive NB degeneration. Using single cell expression profiling methods coupled with custom-designed cDNA arrays and validation with real-time quantitative PCR (qPCR) and in situ hybridization, individual cholinergic NB neurons displayed a significant down regulation of trkA, trkB, and trkC expression during the progression of AD. An intermediate reduction was observed in MCI, with the greatest decrement in mild to moderate AD as compared to controls. Importantly, trk down regulation is associated with cognitive decline measured by the Global Cognitive Score (GCS) and the Mini-Mental State Examination (MMSE). In contrast, there is a lack of regulation of p75(NTR) expression. Thus, trk defects may be a molecular marker for the transition from no cognitive impairment (NCI) to MCI, and from MCI to frank AD