Functional connectivity MRI (fcMRI) is a powerful tool for deciphering spontaneous network activity within the brain. Changes in functional connectivity have been observed in patients with Alzheimer's disease, schizophrenia, and autism, suggesting that fcMRI is sensitive to clinically relevant alterations in the brain. Despite the growing popularity of this technique, our understanding of the spontaneous neural and hemodynamic fluctuations underlying the variations in the blood oxygenation dependent (BOLD) MRI signal used to map functional connectivity is far from complete. Our lab has pioneered the development of simultaneous fcMRI and multisite microelectrode recording in the rodent in order to determine the neural basis for functional connectivity and the spatiotemporal patterns observed in the BOLD signal. Our preliminary results indicate that the relationship between neural activity and BOLD fluctuations is strongly dependent upon the type and depth of anesthesia used. In addition to their primary action on neural activity, most anesthetics also directly impact hemodynamics, and it can be difficult to uncouple the effects. In this study, we will compare functional connectivity and BOLD spatiotemporal dynamics to microelectrode recordings in both anesthetized and unanesthetized rats. This work will either validate the anesthetized rodent as a model for future multimodality studies to elucidate the neurovascular processes underpinnings fcMRI, or serve as a stepping stone for further experiments in unanesthetized rodents.
The specific aims of this study are: 1. Implement fcMRI for unanesthetized rats and determine how functional connectivity and spatiotemporal dynamics compare to measurements in anesthetized animals. Using a specialized holder for unanesthetized rats now commercially available, rats will be acclimatized to the scanner over several days to minimize stress. fcMRI data will be acquired in the awake rat, under isoflurane, and under medetomidine. Differences between connectivity in four functional networks will be examined. The spatiotemporal dynamics of the BOLD fluctuations will also be mapped using a template-creation algorithm developed by our lab, and the relationship between the templates within rats will be used to characterize the spatiotemporal dynamics for each condition. 2. Determine the neural sources of functional connectivity differences in awake compared to anesthetized rats using electrophysiology. To separate the vascular effects of the anesthetics from neural effects, simultaneous microelectrode recording/fcMRI studies will be first obtained from awake animals, and then they will be transitioned to anesthesia. We will compare band-limited local field potential (LFP) signal coherence to BOLD signal correlation to determine which neural properties are the basis of fcMRI in each state. We will also calculate the transfer function for comparing LFPs and fMRI directly under each condition to identify changes.

Public Health Relevance

The goal of this project is to determine how commonly-used anesthetics affect functional connectivity and the spatiotemporal dynamics of the blood oxygenation level dependent (BOLD) MRI signal. These experiments will either validate the anesthetized rat as a platform for future multimodality studies of the relationship between the BOLD signal, neural activity, and hemodynamics, or will serve as the first steps toward future multimodal experiments in unanesthetized rodents.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-J (80))
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Chen, Daofen
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Emory University
Biomedical Engineering
Schools of Medicine
United States
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Thompson, Garth John; Pan, Wen-Ju; Magnuson, Matthew Evan et al. (2014) Quasi-periodic patterns (QPP): large-scale dynamics in resting state fMRI that correlate with local infraslow electrical activity. Neuroimage 84:1018-31
Thompson, Garth John; Merritt, Michael Donelyn; Pan, Wen-Ju et al. (2013) Neural correlates of time-varying functional connectivity in the rat. Neuroimage 83:826-36
Keilholz, Shella D; Magnuson, Matthew E; Pan, Wen-Ju et al. (2013) Dynamic properties of functional connectivity in the rodent. Brain Connect 3:31-40
Pan, Wen-Ju; Thompson, Garth John; Magnuson, Matthew Evan et al. (2013) Infraslow LFP correlates to resting-state fMRI BOLD signals. Neuroimage 74:288-97