The objective of the proposed work is to determine and characterize the spatio-temporal limits of the metabolic and hemodynamic responses that result from evoked neural activity. For this purpose a genetically enhanced mouse model expressing the light-sensitive protein Channelrhodopsin-2 will be used whereby the neuronal activity can be controlled through the modulation of the diameter and intensity of a light stimulus delivered directly onto the surface of the brain (photo-stimulus). First, the minimum neuronal activity that elicits a blood flow response will be determined using two-photon microscopy with sub-micrometer resolution. The size and strength of the neuronal activity will be characterized using a calcium indicator. Then, an intra-vascular fluorescent dye will be used to measure corresponding changes in blood velocity and vessel diameter in capillaries. Second, the consistency of these findings and the effect of resolution will be investigated by measuring the functional cerebral blood flow, metabolic and overall hemodynamic responses using larger- scale optical imaging with resolution of tens of micrometers. Specifically, the following optical methods will be used to measure blood flow, metabolic and overall hemodynamic responses to neural activity: laser speckle imaging, intrinsic auto-fluorescence imaging and optical imaging of intrinsic signal, respectively. The latter is a direct analog of blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI). As a result of this project, the spatio-temporal limits of the metabolic and hemodynamic responses will be uncovered with unparalleled resolution. In addition, sufficient knowledge will be obtained to elucidate the theoretical and practical requirements of current brain research tools like fMRI to detect activities encoded in the hemodynamic response that may be thought to be undetectable. This work will have a tremendous impact in brain imaging studies of function in animals and humans, including clinical and basic science research. To perform the proposed studies I will undergo training in two-photon imaging of brain function and complementary optical imaging methods, and in electrophysiological recording of neuronal activity. A unique combination of local and national experts will provide and oversee the necessary training. This proposal is vital in fulfilling my ultimate career goal of attaining an independent and successful research program that focuses on imaging normal and pathological brain function.

Public Health Relevance

The hemodynamic response induced by neural activity is, and has been, the principal means of studying brain function in animals and humans. Methods like functional magnetic resonance imaging are now essential in basic science, developmental, cognitive and clinical studies of normal and impaired brain function. This proposal will reveal the fundamental limits of hemodynamic-based methods to image and detect brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01NS066131-05
Application #
8662324
Study Section
NST-2 Subcommittee (NST)
Program Officer
Babcock, Debra J
Project Start
2010-06-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$123,377
Indirect Cost
$9,139
Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kozai, Takashi D Y; Eles, James R; Vazquez, Alberto L et al. (2016) Two-photon imaging of chronically implanted neural electrodes: Sealing methods and new insights. J Neurosci Methods 258:46-55
Kozai, Takashi D Y; Jaquins-Gerstl, Andrea S; Vazquez, Alberto L et al. (2016) Dexamethasone retrodialysis attenuates microglial response to implanted probes in vivo. Biomaterials 87:157-69
Kozai, Takashi D Y; Catt, Kasey; Li, Xia et al. (2015) Mechanical failure modes of chronically implanted planar silicon-based neural probes for laminar recording. Biomaterials 37:25-39
Iordanova, Bistra; Vazquez, Alberto L; Poplawsky, Alexander J et al. (2015) Neural and hemodynamic responses to optogenetic and sensory stimulation in the rat somatosensory cortex. J Cereb Blood Flow Metab 35:922-32
Kozai, Takashi D Y; Jaquins-Gerstl, Andrea S; Vazquez, Alberto L et al. (2015) Brain tissue responses to neural implants impact signal sensitivity and intervention strategies. ACS Chem Neurosci 6:48-67
Kozai, Takashi D Y; Vazquez, Alberto L (2015) Photoelectric artefact from optogenetics and imaging on microelectrodes and bioelectronics: New Challenges and Opportunities. J Mater Chem B Mater Biol Med 3:4965-4978
Vazquez, Alberto L; Murphy, Matthew C; Kim, Seong-Gi (2014) Neuronal and physiological correlation to hemodynamic resting-state fluctuations in health and disease. Brain Connect 4:727-40
Vazquez, Alberto L; Fukuda, Mitsuhiro; Crowley, Justin C et al. (2014) Neural and hemodynamic responses elicited by forelimb- and photo-stimulation in channelrhodopsin-2 mice: insights into the hemodynamic point spread function. Cereb Cortex 24:2908-19
Fukuda, Mitsuhiro; Vazquez, Alberto L; Zong, Xiaopeng et al. (2013) Effects of the α₂-adrenergic receptor agonist dexmedetomidine on neural, vascular and BOLD fMRI responses in the somatosensory cortex. Eur J Neurosci 37:80-95
Kozai, Takashi D Yoshida; Vazquez, Alberto L; Weaver, Cassandra L et al. (2012) In vivo two-photon microscopy reveals immediate microglial reaction to implantation of microelectrode through extension of processes. J Neural Eng 9:066001

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