Malcolm J. Avison - US grants

technology /technique development; diabetes mellitus; nuclear magnetic resonance spectroscopy; methylamines; hyperglycemia; cerebrum; magnetic resonance imaging; tertiary amine; glucose; creatine phosphate; creatine; laboratory rat;

It has been suggested that age related decline in motor skills may be due at least in part to loss of dopaminergic neurons in the nigrostriatal system. The long term objective of this project is to use functional Magnetic Resonance Imaging (fMRI) to map patterns of neuronal activation in the nigrostriatal system of female rhesus monkeys in response to specific well defined dopaminergic stimuli, and to examine the age related changes in these responses. Once these age related changes have been characterized, the ability of neurotrophic factors to arrest and/or reverse them will be examined. If age related changes in nigrostriatal activity can be identified in this monkey model, the non-invasive nature of the fMRI measurement will be easily applicable to studies in humans. The specific aims of the project are to test the following hypotheses: 1) Dopamine and dopamine receptor agonist induced nigrostriatal activation in the rhesus monkey is correlated in an age dependent manner with motor performance and dopaminergic status. FMIR will be used to measure the spatial and temporal patterns of neural activation in the nigrostriatal system of Adult Female Rhesus monkeys (5-24 years) in response to the dopamine precursor levodopa, the D1 + D2 agonist apomorphine, and the D2 agonist quinpirole. 2) Tropic factors directly administered to the nigrostriatal system of older rhesus monkeys will cause changes in the spatial and temporal patterns of neural activation consistent with improved nigrostriatal function. FMRI will be used to compare spatial and temporal patterns of dopaminergic activation in elderly female rhesus given trophic factor with the activation in age-matched animals given vehicle alone. 3) Specific age related changes in cerebral anatomy of the rhesus monkey correlate with age related decline in motor skill. MRI data obtained for coregistration of functional changes with anatomy, and for planning of stereotaxic surgery will be used to generate an 'average' brain for animals in three age groups (Young Adults (5-9 years); Middle Age Adults (14-17 years); Late Middle Age Adults (20-24 years)). The 'average' brains will be compared statistically, with particular emphasis being placed on identifying changes in nigrostriatal anatomy.

Monoamine Regulation of Cortical Circuitry. The studies in this project are directed equally at examining structural deficits in schizophrenic prefrontal cortex at the cellular level and at elucidating prefrontal neural circuits that have been implicated in schizophrenia. The proposed studies will test the hypothesis that dysregulation of modulatory neurotransmitters, particularly dopamine and serotonin, produce dystrophic changes in cortical pyramidal and/or non-pyramidal neurons related to those observed in schizophrenia. To enhance our understanding of the neuropathology of schizophrenia at the cellular level, in Specific Aim 1 we propose to take a new approach-intracellular injection of selected neurons in fixed slices of postmortem tissue from patients and controls. After filling with Lucifer Yellow, double-label immunohistochemical procedures will be applied to visualize the dendritic arbors of selected pyramidal cells and their modulatory inputs (dopamine, serotonin and Substance P). Results from the immunohistochemical approach will be supplemented by stereological morphometry and the Golgi technique in the same blocks of tissue to correlate changes in dendritic morphology, cell size and packing density and modulatory inputs in supragranular layers of postmortem prefrontal cortex in schizophrenic brains. The second aim will conduct corollary studies in non-human primates with experimentally induced neurotransmitter dysregulation (EIND) and normal control monkeys, designed to elucidate the mechanisms for specific abnormalities observed in schizophrenic brain. This aim will employ same methods and quantitative approaches used in the postmortem studies. Specific Aims 2 will employ a "living-then-fixed" slice preparation developed in this laboratory to study local circuit interactions between selected pyramidal and non- pyramidal neurons in the supragranular layers of prefrontal cortex, where pathology has been demonstrated in schizophrenia. Finally, in Specific Aim 4, we will examine electron-microscopically the source of intrinsic and extrinsic afferents that interact with the D1 receptor and related signaling proteins. This receptor which is located predominantly in dendritic spines has been reported to be decreased in schizophrenia and is regulated by both the typical and atypical drugs that are used to treat schizophrenia. Collectively, the proposed studies are designed to be directly relevant to the issues of neuropathology in schizophrenia and, in addition, expand fundamental knowledge about cortical circuitry in association cortex.

Among the most common and debilitating neurological complications of HIV infection is HIV associated dementia (HAD) or AIDS dementia complex (ADC). The exact pathogenesis of this disorder remains a conundrum, but trafficking of HIV-infected peripheral macrophages across the blood-brain barrier (BBB) appears to be an important route of entry of HIV, and the rate at which this occurs may be a determinant of HAD onset and/or progression. BBB breakdown is known to increase the rate of macrophage trafficking into CNS, and there is evidence for microvascular abnormalities, including increased regional blood volume (RCBV) and BBB disruption in HIV seropositive and particularly in HAD patients. Indeed preliminary results suggest that the severity of these microvascular changes is correlated with the severity of HAD. Zidovudine monotherapy and, more recently, highly active anti-retroviral therapy (HAART) may reduce the incidence of HAD. Furthermore, zidovudine or HAART may arrest or even reverse the dementing process, at least temporarily, in many but not all patients. The means by which HAART might slow the progression of HAD is unclear, but may include reduced trafficking of infected and/or activated macrophage into the CNS both as a result of a reduced serum viral load, and also by reversing the damage to the BBB. In this study employing patients with HAD of varying severity, carefully studied by clinical examination, neuropsychological test battery, and contrast-enhanced magnetic resonance imaging (MRI), we propose to test the over-arching hypothesis that disruption of cerebral microvascular integrity is a key event in progression to HAD, (with the severity of HAD correlated with the degree of microvascular disruption) and that therapies which reverse these microvascular defects lead to improvement in RAD.

DESCRIPTION (provided by applicant):This application from Vanderbilt University seeks partial funding for the acquisition of a state-of-the-art high field (4.7T) wide bore (60cm) vertical Magnetic Resonance Imaging/Spectroscopy system optimized for studies of the CNS in non-human primates (NHP). This system is essential for several current NIH-funded projects of the structural and functional neuroanatomy of the NHP brain. It is also essential for several projects addressing the fundamental biophysical origins of the fMRI BOLD response. The proposed facility will provide a major new capability for in vivo imaging and spectroscopy in NHPs, thereby permitting current NIH-funded investigators to undertake studies, which are beyond the scope and/or capabilities of existing equipment. MR studies in NHPs at Vanderbilt are currently restricted to a clinical 3T system, and are limited in scope to brief pre-operative stereotaxic studies to guide electrode placement. The new instrument will acquire structural and functional images and spectra that have inherently higher signal to noise ratios, greater spatial and spectral resolution, and images that are more sensitive to some contrast mechanisms. The proposed system will have shim, gradient, and r.f. coils and other associated hardware that are optimized for NHP studies, and will be based upon a modem console and spectrometer capable of a wide array of modem experiments. These new capabilities will include fast and 3D imaging at very high resolution, improved diffusion weighting and diffusion tensor imaging for white matter tractography, and broad-band multi-nuclear (1H, 31P, 13C etc.) in vivo MR spectroscopy for studies of regional metabolism. The system will be an integral part of the newly created Vanderbilt University Institute of Imaging Science (VUIIS), and will be housed in a newly constructed building with a bay already dedicated to and designed for a high field NHP scanner. It will be supported by a large and experienced group of physicists, engineers and computer scientists, and a well trained and qualified support staff, including electronic engineers and animal technologists. These technical experts will assist users in experimental design, data acquisition and data analysis. The proposed instrument will be a multi-user facility, supervised by a director and a core staff, developed and managed via an operating committee, and with oversight by an advisory committee charged with the responsibility of assuring appropriate access to NIH funded investigators. The proposed instrument will significantly increase the number and quality of investigations using NHPs, and will help Vanderbilt University meet its commitment to enhancing basic and clinical neuroscience research.

Prenatal cocaine (PNCE) and alcohol exposure (PNAE) result in sustained behavioral deficits similar in many respects to attention deficit hyperactivity disorder (ADHD). While this similarity suggests the involvement of similar or overlapping neural circuits in all three groups, subtle differences in the specific deficits and their differential responsiveness to stimulants suggest differences in the nature of the disruptions within a specific circuit and/or disruptions in non-overlapping circuits. Studies in animals suggest that PNCE results in a post-synaptic defect in dopamine (DA) neurotransmission that is refractory to stimulants, such as amphetamine (AMPH) or methylphenidate (MPH). In human studies, the data are less clear, reflecting, at least in part, the difficulty of identifying subjects with pure PNCE or PNAE, and, in part, the fact that tools for measuring circuit function have only recently become available. This project will bring together three groups of researchers with expertise in developmental consequences of alcohol and cocaine exposure in utero, functional and structural neuroimaging, and ADHD, with the overarching goal of characterizing the neural correlates of ADHD behaviors in PNCE and PNAE individuals, using a combination of detailed neurocognitive testing, ERP, and functional, structural, and diffusion tensor (DTI) MRI. We will study a well characterized cohort of 18-year-old, African American adolescents, whose PNCE and PNAE were ascertained prospectively during gestation. This cohort is unique in that recruitment was stratified to minimize the confounding of alcohol and cocaine. The study has the following Specific Aims: 1) To use fMRI to confirm that individuals with PNCE, PNAE, and idiopathic ADHD have a functional impairment in fronto-striatal circuits and that additional circuit dysfunctions contribute to behavioral deficits in PNAE; 2) To test the hypothesis that the circuit defect in PNCE-associated ADHD is postsynaptic and, therefore, unresponsive to MPH; 3) To use structural MRI and DTI to examine the contribution of structural abnormalities to the functional impairment in neural circuitry linked to ADHD-related deficits; 4) To identify the neural correlates of dyscalculia in individuals with PNAE and test the hypothesis that PNAE is characterized by a specific deficit in activation of parietal networks subserving number processing.

The long term goal of the proposed research is to develop, validate and disseminate a set of generalizable methods for non-invasive mapping of the spatio-temporal dynamics of functional and structural plastic changes in the primate CNS using MRI. It outlines a strategy for improving MRI methods for measuring CNS plasticity, together with tools that allow the high resolution MRI observations to link changes in local and cellular electrophysiological properties on the one hand, to plastic changes in distributed brain circuits on the other, providing a methodological bridge across scales. The specific tools include optimized, translational, MR approaches for multiscale structural and functional brain imaging and high precision (sub-millimeter) methods for MRI and multi-modality intra- and inter-subject co-registration. The methods will be developed and tested using a well-characterized non-human primate model, and will be validated using "gold standard" highresolution mapping tools including functional optical imaging of intrinsic signal (OIS), dense array electrode mapping, and tissue histology. With these goals in mind, the proposal's Specific Aims are: Aim 1) To refine and test the limits of MRI for mapping and characterizing functional and structural plasticity with sub-millimeter resolution in intact animals. Aim 2) To develop integrated imaging and post-processing tools that allow high precision coregistration of MR images in the same animal longitudinally and across multiple modalities.