Faculty Bibliography

The existence of stem cells in the adult nervous system is well recognized; however, the potential of these cells is still widely debated. We demonstrate that neural stem cells exist within the embryonic and adult cerebellum. Comparing the potential of neural stem cells derived from the forebrain and cerebellum, we find that progeny derived from each of these brain regions retain regional character in vitro as well as after homotopic transplantation. However, when ectopically transplanted, neurosphere-derived cells from either region are largely unable to generate neurons. With regard specifically to embryonic and adult cerebellar stem cells, we observe that they are able to give rise to neurons that resemble different select classes of cerebellar subclasses when grafted into the perinatal host cerebellum. Most notably, upon transplantation to the perinatal cerebellum, cerebellar stem cells from all ages are able to acquire the position and mature electrophysiological properties of cerebellar granule cells

Numerous lines of evidence suggest that Notch signaling plays a pivotal role in controlling the production of neurons from progenitor cells. However, most experiments have relied on gain-of-function approaches because perturbation of Notch signaling results in death prior to the onset of neurogenesis. Here, we examine the requirement for Notch signaling in the development of the striatum through the analysis of different single and compound Notch1 conditional and Notch3 null mutants. We find that normal development of the striatum depends on the presence of appropriate Notch signals in progenitors during a critical window of embryonic development. Early removal of Notch1 prior to neurogenesis alters early-born patch neurons but not late-born matrix neurons in the striatum. We further show that the late-born striatal neurons in these mutants are spared as a result of functional compensation by Notch3. Notably, however, the removal of Notch signaling subsequent to cells leaving the germinal zone has no obvious effect on striatal organization and patterning. These results indicate that Notch signaling is required in neural progenitor cells to control cell fate in the striatum, but is dispensable during subsequent phases of neuronal migration and differentiation

BACKGROUND AND PURPOSE: Because of their invasive nature, high-grade glial tumors are uniformly fatal. The purpose of this study was to quantify MR imaging-occult, glial tumor infiltration beyond its radiologic margin through its consequent neuronal cell damage, assessed by the global concentration decline of the neuronal marker N-acetylaspartate (NAA). METHODS: Seventeen patients (10 men; median age, 39 years; age range, 23-79 years) with radiologically suspected (later pathologically confirmed) supratentorial glial neoplasms, and 17 age- and sex-matched controls were studied. Their whole-brain NAA (WBNAA) amounts were obtained with proton MR spectroscopy: for patients on the day of surgery (n = 17), 1 day postsurgery (n = 15), and once for each control. To convert into concentrations, suitable for intersubject comparison, patients' global NAA amounts were divided by their brain volumes segmented from MR imaging. Least squares regression was used to analyze the data. RESULTS: Pre- and postoperative WBNAA (mean +/- SD) of 9.2 +/- 2.1 and 9.7 +/- 1.8 mmol/L, respectively, in patients were indistinguishable (P = .369) but significantly lower than in controls (12.5 +/- 1.4 mmol/L). Mean resected tumor size (n = 15) was approximately 3% of total brain volume. CONCLUSION: The average 26% WBNAA deficit in the patients, which persisted following surgical resection, cannot be explained merely by depletion within the approximately 3% MR imaging-visible tumor volume or an age-dependent effect. Although there could be several possible causes of such widespread decline--perineuronal satellitosis, neuronal deafferentation, Wallerian and retrograde degeneration, vasogenic edema, functional diaschisis, secondary vascular changes--most are a direct or indirect reflection of extensive, MR imaging-occult, microscopic tumor cell infiltration, diffusely throughout the otherwise 'normal-appearing' brain

We report the findings from whole-brain proton MR spectroscopy, quantifying the neuronal marker N-acetylaspartate (NAA), for 2 presurgical meningioma patients and 10 healthy controls. The patients' whole-brain NAA (WBNAA) concentrations were considerably elevated (3+ SDs) compared with healthy controls when excluding the tumors from brain volume; WBNAA levels normalized following correction to approximate 'preneoplastic' brain size. These results suggest global neuronal preservation in these 2 patients while their brains were compressed by large, slowly growing, extra-axial masses

In this study, we describe prominent perivenular spaces as a sign that is seen on high-resolution (512 x 512) transverse T2-weighted MR images in patients with multiple sclerosis. The observed widening of perivenular space is depicted as a stringlike hyperintensity projecting radially and aligned with multiple sclerosis lesions (usually small), following the course and configuration of deep venular structures. This widening may be an important sign in differentiating primary (ie, in multiple sclerosis) from secondary causes of demyelination

We review how neurons in the principal pathway connecting the retina to the visual cortex represent information about the chromatic and spatial characteristics of the retinal image. Our examination focuses particularly on individual neurons: what are their visual properties, how might these properties arise, what do these properties tell us about visual signal transformations, and how might these properties be expressed in perception? Our discussion is inclined toward studies on old-world monkeys and where possible emphasizes quantitative work that has led to or illuminates models of visual signal processing

A retrospective view of the critical events and advances in the development of criteria, instruments and algorithms in the diagnosis of Alzheimer's disease. The review is from the vantage point of the National Institute on Aging and its role in the development of the national infrastructure, in the US, for clinical research on dementia. The paper discusses future research needs and challenges for developing new diagnostic armamentarium for early and accurate detection of neurodegenerative processes of dementia in the early prodromal stages or during early mild cognitive impairments

Inferior olivary (IO) neurons are electrically coupled through gap junctions and generate synchronous subthreshold oscillations of their membrane potential at a frequency of 1 to 10 Hz. While the ionic mechanisms of these oscillatory responses are well understood, their origin and ensemble properties remain controversial. Here, the role of gap junctions in generating and synchronizing IO oscillations was examined by combining intracellular recordings with high-speed voltage-sensitive dye imaging in rat brainstem slices. Single-cell responses and ensemble synchronized responses of IO neurons were compared in control conditions and in the presence of 18beta-glycyrrhetinic acid (18beta-GA), a pharmacological gap junction blocker. Under our experimental conditions, 18beta-GA had no adverse effects on intrinsic electroresponsive properties of IO neurons, other than the block of gap junction-dependent dye coupling and the resulting change in cells' passive properties. Application of 18beta-GA did not abolish single-cell oscillations. Pharmacologically uncoupled IO neurons continued to oscillate with a frequency and amplitude that were similar to those recorded in control conditions. However, these oscillations were no longer synchronized across a population of IO neurons. Our optical recordings did not detect any clusters of synchronous oscillatory activity in the presence of the blocker. These results indicate that gap junctions are not necessary for generating subthreshold oscillations, rather, they are required for clustering of coherent oscillatory activity in the IO. The findings support the view that oscillatory properties of single IO neurons endow the system with important reset dynamics, while gap junctions are mainly required for synchronized neuronal ensemble activity

A generalized method for phase-constrained parallel MR image reconstruction is presented that combines and extends the concepts of partial-Fourier reconstruction and parallel imaging. It provides a framework for reconstructing images employing either or both techniques and for comparing image quality achieved by varying k-space sampling schemes. The method can be used as a parallel image reconstruction with a partial-Fourier reconstruction built in. It can also be used with trajectories not readily handled by straightforward combinations of partial-Fourier and SENSE-like parallel reconstructions, including variable-density, and non-Cartesian trajectories. The phase constraint specifies a better-conditioned inverse problem compared to unconstrained parallel MR reconstruction alone. This phase-constrained parallel MRI reconstruction offers a one-step alternative to the standard combination of homodyne and SENSE reconstructions with the added benefit of flexibility of sampling trajectory. The theory of the phase-constrained approach is outlined, and its calibration requirements and limitations are discussed. Simulations, phantom experiments, and in vivo experiments are presented