Optogenetic Stimulation Combined with High-Field fMRI (Opto-fMRI): A New Method for Examination of Evoked BOLD Responses and Functional Connectivity.
and brain disorders involve neural circuits that are widely distributed in the brain.
The ability to map the functional connectivity of distributed circuits, and to assess
how this connectivity evolves over time, will be facilitated by methods for
characterizing the network impact of activating a specific sub-circuit, cell type, or
projection pathway. In this thesis ... read morehigh-resolution blood oxygenation level-dependent
(BOLD) functional MRI (fMRI) at 9.4 Tesla is used to examine the distributed BOLD
response in primate and rodent brain. In this thesis a high-resolution fMRI method for
tracking activity in the squirrel monkey brain is developed. This method simultaneously
provides sub-millimeter functional resolution and near whole-brain coverage. This method
is used to delineate the effect of state dependent changes, as modeled through
isofluorane anesthesia modulation, on tactile fMRI responses in somatosensory and basal
ganglia regions. This study also examines the changes in functional connectivity between
somatosensory and the basal ganglia region as isoflurane depth is modulated. In this
thesis a novel approach was described that combines optical neural activation of
specific cells in the mammalian brain, with fMRI of resultant BOLD signals, or
"Opto-fMRI.‟ By optically activating channelrhodopsin-2 (ChR2)-expressing
excitatory neurons in the primary somatosensory (SI) barrel cortex of mice during an
optimized high-resolution fMRI protocol. Using this novel method we were able to
reliably identify cortical and subcortical targets of pyramidal cells of the primary
somatosensory cortex (SI), in an anesthetized as well as an awake mouse brain. To
demonstrate the use of Opto-fMRI in characterizing the brain state dependence of
functional connectivity, we assessed the impact of isoflurane anesthesia on activity and
correlation of activity across areas in the barrel cortex, and the network stimulated
due to barrel cortex activation. These collective results suggest opto-fMRI can provide
a controlled means for characterizing the distributed network downstream of a defined
cell class in the awake brain. Opto-fMRI may find use in examining causal links between
defined circuit elements in diverse behaviors and pathologies. In this thesis we also
used opto-fMRI to examine the relation between neural activity and the BOLD response.
Extracellular electrophysiological recordings were used to measure the effects of
stimulation on single-unit, multi-unit, and local field potential activity. Optically
driven stimulation of layer V neocortical pyramidal neurons resulted in a positive local
BOLD response at the stimulated site. Consistent with a linear transform model the BOLD
response summated in response to closely spaced trains of stimulation demonstrating an
equivalent response to a multi-synaptic method of driving cortical activity using
somatosensory stimulation. These results bolster the underlying assumptions of BOLD fMRI
and demonstrate the utility of opto-fMRI for probing the relation of the BOLD response
to the underlying neuronal activity.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Biomedical Engineering.
Advisor: Christopher Moore.
Committee: Mark Cronin-Golomb, Sergio Fantini, and Heather Urry.
Keywords: Biomedical engineering, and Neurosciences.read less
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