Behaviors 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 high-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.