Modern functional neuroimaging methods, such as Positron Emission Tomography (PET), and functional Magnetic Resonance Imaging (fMRI), rely on the coupling of neuronal electrical activity to changes in local metabolic demands--called """"""""cerebrometabolic coupling""""""""--and to the hemodynamic regulation of energy supply and waste removal--called """"""""cerebrovascular coupling""""""""--to measure brain activity through indirect surrogate markers of such activity. Understanding the relationship between local brain activity and the major physiological markers that are measured is of paramount importance for the correct interpretation and quantification of functional neuroimaging data. My main research interests are to understand and elucidate the mechanisms of regulation of cerebral blood flow during normal and stimulation induced brain activity. Amongst the several key aspects of this magnificently broad task, I have directed research efforts in the first year on investigating two major signaling pathways - the nitric oxide (NO)pathway, and the prostaglandin (PGE2) pathway, known to be involved in translating a change in brain activity into a vascular response. The first experiments have focused on the use of rats and mice and functional MRI, combined with simultaneous electrophysiological recordings, to measure the hemodynamic response and the increased electrical activity to stimulation of the somatosensory cortex, before and after the use of potent and specific inhibitors of nitric oxide synthase (NOS) and of cyclooxygenase-2 (COX-2). Preliminary results show a significant decrease (50-90%) of the hemodynamic response to somatosensory stimulation after inhibition of either COX-2 or NOS, respectively, with minimal decrease of electrical activity. Such results confirm the hypothesis that NO and PGE2 are important mediators of the cerebrovascular coupling. These results have been submitted for publication. A few collaborators have been of essential help in this project. Prof. Mathias Hoehn, of the Max-Planck Institute for Neurological Research, Cologne, Germany, has helped develop the protocol for somatosensory stimulation of the rat and for recording of SEPs in the magnet. In NINDS, Dr. Leonardo Belluscio in NINDS has been collaborating in developing 2-photon confocal techniques to directly visualize the cortical microvasculature. And Dr. Francesca Bosetti, NIA, has helped with assays to measure COX-2 activity. For example, in the lab of Dr. Francesca Bosetti, basal activity of COX-2 was measured in control and experimental rats showing at least 64% inhibition of COX-2 by meloxicam.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS003012-01
Application #
7143928
Study Section
(CMU)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2005
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Stefanovic, Bojana; Schwindt, Wolfram; Hoehn, Mathias et al. (2007) Functional uncoupling of hemodynamic from neuronal response by inhibition of neuronal nitric oxide synthase. J Cereb Blood Flow Metab 27:741-54
Aoki, Ichio; Takahashi, Yoshiyuki; Chuang, Kai-Hsiang et al. (2006) Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride. NMR Biomed 19:50-9
Keilholz, Shella D; Silva, Afonso C; Raman, Mira et al. (2006) BOLD and CBV-weighted functional magnetic resonance imaging of the rat somatosensory system. Magn Reson Med 55:316-24
Gsell, Willy; Burke, Michael; Wiedermann, Dirk et al. (2006) Differential effects of NMDA and AMPA glutamate receptors on functional magnetic resonance imaging signals and evoked neuronal activity during forepaw stimulation of the rat. J Neurosci 26:8409-16
Stefanovic, Bojana; Bosetti, Francesca; Silva, Afonso C (2006) Modulatory role of cyclooxygenase-2 in cerebrovascular coupling. Neuroimage 32:23-32
Hutchinson, Elizabeth B; Stefanovic, Bojana; Koretsky, Alan P et al. (2006) Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia. Neuroimage 32:520-30
Chen, Zhengguang; Silva, Afonso C; Yang, Jehoon et al. (2005) Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminase. J Neurosci Res 79:383-91
Lee, Jung Hee; Silva, Afonso C; Merkle, Hellmut et al. (2005) Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: dose-dependent and temporal evolution of T1 contrast. Magn Reson Med 53:640-8
de Zwart, Jacco A; Silva, Afonso C; van Gelderen, Peter et al. (2005) Temporal dynamics of the BOLD fMRI impulse response. Neuroimage 24:667-77
Silva, Afonso C; Lee, Jung Hee; Aoki, Ichio et al. (2004) Manganese-enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations. NMR Biomed 17:532-43

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