This project aims to use advanced in-vivo optical imaging and microscopy techniques to study blood flow variations in the resting brain, and the meaning of synchronizations in blood flow fluctuations in different brain regions. Functional connectivity mapping (FCM) is an increasingly popular tool in functional magnetic resonance imaging (fMRI), which harnesses synchronous fluctuations in blood flow throughout the resting brain to infer connectivity between different regions. FCM is widely thought to capture a fundamental property of the brain's networks, and is rapidly being adopted for studies of complex conditions such as autism, Alzheimer's, depression and schizophrenia. However, while FCM is increasingly being applied in preference to traditional stimulation-based fMRI studies, very little is understood about the mechanisms causing the fluctuations in cerebral blood, nor the underlying meaning of hemodynamic synchrony in different brain areas. In fact, there is mounting evidence that baseline fluctuations in blood flow have a range of origins that may not all be related to the presence of neuronal activity, nor represent genuine connectivity between brain regions. In this project, we will optimize and extend the suite of advanced in-vivo exposed-cortex optical imaging and microscopy tools that we have developed to date to address the primary challenge of baseline imaging;that data must be acquired without averaging over multiple trials and therefore must have high signal to noise, and all parameters must be recorded in parallel. To this end, we will develop high-speed, high resolution parallel imaging of both hemodynamics and bulk-loaded calcium sensitive dyes over large bilateral cranial windows in rats to map the relations between baseline blood flow and neuronal activity. We will also map fluctuations in flavoprotein (FAD) autofluorescence with spontaneous hemodynamics as a measure of local oxidative metabolism, both complemented with simultaneous electrophysiology. These studies will be performed under a range of anesthesia states as well as in a small subset of awake animals (aim 1). To relate our findings directly to fMRI data in the whole brain, we will develop a system for simultaneous acquisition of exposed cortex optical imaging and fMRI data in rats, elucidating the metabolic (FAD) and neuronal (Ca2+) basis of fMRI signal fluctuations and their relation to fluctuations in the rest of the brain (aim 2). We will further use in-vivo two-photon microscopy for cellular-level metabolic imaging of FAD and NADH fluorescence, and of calcium sensitive dyes to explore the cellular correlates of spontaneous hemodynamic activity, with simultaneous wide-field reflectance imaging of hemoglobin oxygenation dynamics (aim 3). These innovative studies will allow us to determine whether spontaneous hemodynamic fluctuations have the same underlying basis as stimulus-evoked responses, and to explore the nature of the connectivity that FCM infers. Our results will be highly significant, as they will provide insight into the meaning of clinical fMRI FCM results, while also providing guidance for FCM researchers in how to avoid potential neurovascular coupling-related confounds.
This proposal aims to use advanced in-vivo optical imaging and microscopy to study the way that blood flow varies in the resting brain, and the meaning of synchronizations in blood flow fluctuations in different brain regions. Fluctuations in blood flow are currently being used in human magnetic resonance imaging studies to infer connectivity between brain regions, and the popularity of this technique is growing rapidly for studies of diseases such as autism, Alzheimer's and schizophrenia. This project will study the underlying basis of this connectivity mapping, both helping researchers to better understand their clinical results, while also providing new guidance for collection and analysis of data acquired from the resting brain.
|Kozberg, Mariel G; Ma, Ying; Shaik, Mohammed A et al. (2016) Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling. J Neurosci 36:6704-17|
|Akassoglou, Katerina; Agalliu, Dritan; Chang, Christopher J et al. (2016) Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium. Front Neurosci 10:46|
|Chow, Daniel S; Horenstein, Craig I; Canoll, Peter et al. (2016) Glioblastoma Induces Vascular Dysregulation in Nonenhancing Peritumoral Regions in Humans. AJR Am J Roentgenol 206:1073-81|
|Ma, Ying; Shaik, Mohammed A; Kim, Sharon H et al. (2016) Wide-field optical mapping of neural activity and brain haemodynamics: considerations and novel approaches. Philos Trans R Soc Lond B Biol Sci 371:|
|Ma, Ying; Shaik, Mohammed A; Kozberg, Mariel G et al. (2016) Resting-state hemodynamics are spatiotemporally coupled to synchronized and symmetric neural activity in excitatory neurons. Proc Natl Acad Sci U S A :|
|Kozberg, M; Hillman, E (2016) Neurovascular coupling and energy metabolism in the developing brain. Prog Brain Res 225:213-42|
|Bouchard, Matthew B; Voleti, Venkatakaushik; Mendes, CÃ©sar S et al. (2015) Swept confocally-aligned planar excitation (SCAPE) microscopy for high speed volumetric imaging of behaving organisms. Nat Photonics 9:113-119|
|Galwaduge, P T; Kim, S H; Grosberg, L E et al. (2015) Simple wavefront correction framework for two-photon microscopy of in-vivo brain. Biomed Opt Express 6:2997-3013|
|Cayce, Jonathan Matthew; Bouchard, Matthew B; Chernov, Mykyta M et al. (2014) Calcium imaging of infrared-stimulated activity in rodent brain. Cell Calcium 55:183-90|
|Chen, Brenda R; Kozberg, Mariel G; Bouchard, Matthew B et al. (2014) A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc 3:e000787|
Showing the most recent 10 out of 16 publications