Functional Magnetic Resonance Imaging (fMRI) has become a method of choice for human functional neuroimaging studies, and is beginning to make inroads into clinical applications such as monitoring of stroke rehabilitation. However, in current practice, fMRI suffers from the uncertain relation of the imaged hemodynamic responses to the underlying neuroglial activity and quantitative hemodynamic parameters. Interpretation of fMRI studies in disease states are even more ambiguous since it requires not only understanding the mechanisms of neurovascular coupling but the impact of altered cerebrovascular dynamics on the BOLD signal under conditions of neurovascular deficit. As a result, the analysis of fMRI data has so far been largely correlational and descriptive. In order to gain a mechanistic understanding of the relationship between BOLD contrast and the underlying neuroglial activity, one has to consider multiple physiological processes, from macroscopic hemodynamic changes to the microscopic neurovascular communication. To this end, we will combine direct and quantitative measurement of hemodynamic and neuronal parameters simultaneously with fMRI aiming to understand the relationship between the BOLD response and the underlying neuroglial activity. We then will establish microscopic correlates of large-scale (populational) hemodynamic and neuroglial signals and will integrate macro- and microscopic measurements. Specifically, in Aim1 we will characterize BOLD signals in hemodynamic terms by employing simultaneous optical imaging of blood oxygenation and blood flow.
In Aim2 we will establish a correlation between stimulus-induced BOLD response and the underlying neuronal and astrocytic activity by performing simultaneous calcium imaging (using fluorescent calcium indicators) and voltage-sensitive dyes imaging. Our choice of calcium as an indicator of neuroglial activity is based on its recognized role as an important second messenger in multiple molecular signal transduction pathways, including those intimately involved in neurovascular communication. Finally, we will establish microscopic correlates of the large-scale hemodynamic and calcium signals by using 2-photon microscopy (Aim 3). Integration of macroscopic fMRI and calcium measurements with 2-photon data will allow a mechanistic interpretation of BOLD signals in terms of activity of underlying single cells and single blood vessels. 1

Public Health Relevance

The relationship between functional MRI (fMRI) signals and the underlying microscopic neurovascular unit (NVU) physiology is a central unresolved issue in the interpretation of human functional neuroimaging data. The main goal of this proposal is to combine quantitative optical measurements of hemodynamic and neuroglial signals directly with BOLD fMRI aiming for a mechanistic interpretation of BOLD signals in terms of activity of the underlying single cells and single blood vessels. The proposed project will provide a mechanistic framework for understanding of fMRI signals and ultimately will guide the development of novel therapeutic, preventative, and diagnostic approaches. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057198-05
Application #
8461189
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Babcock, Debra J
Project Start
2009-05-15
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$312,493
Indirect Cost
$105,621
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sakadžić, Sava; Yaseen, Mohammad A; Jaswal, Rajeshwer et al. (2016) Two-photon microscopy measurement of cerebral metabolic rate of oxygen using periarteriolar oxygen concentration gradients. Neurophotonics 3:045005
GÅ‚Ä…bska, Helena T; Norheim, Eivind; Devor, Anna et al. (2016) Generalized Laminar Population Analysis (gLPA) for Interpretation of Multielectrode Data from Cortex. Front Neuroinform 10:1
Uhlirova, Hana; Kılıç, Kıvılcım; Tian, Peifang et al. (2016) The roadmap for estimation of cell-type-specific neuronal activity from non-invasive measurements. Philos Trans R Soc Lond B Biol Sci 371:
Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna et al. (2016) Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study. Biol Psychiatry Cogn Neurosci Neuroimaging 1:49-59
Gagnon, Louis; Sakadžić, Sava; Lesage, Frédéric et al. (2016) Validation and optimization of hypercapnic-calibrated fMRI from oxygen-sensitive two-photon microscopy. Philos Trans R Soc Lond B Biol Sci 371:
Gagnon, Louis; Smith, Amy F; Boas, David A et al. (2016) Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation. Front Comput Neurosci 10:82
Uhlirova, Hana; Kılıç, Kıvılcım; Tian, Peifang et al. (2016) Cell type specificity of neurovascular coupling in cerebral cortex. Elife 5:
Shih, Andy Y; Rühlmann, Charlotta; Blinder, Pablo et al. (2015) Robust and fragile aspects of cortical blood flow in relation to the underlying angioarchitecture. Microcirculation 22:204-18
Gagnon, Louis; Sakadžić, Sava; Lesage, Frédéric et al. (2015) Quantifying the microvascular origin of BOLD-fMRI from first principles with two-photon microscopy and an oxygen-sensitive nanoprobe. J Neurosci 35:3663-75
Devor, Anna; Roe, Anna W; Mahadevan-Jansen, Anita et al. (2014) The BRAIN Initiative. Neurophotonics 1:011001

Showing the most recent 10 out of 25 publications