Functional magnetic resonance imaging investigation of brain connectivity

Abstract

Brain connectivity describes the structural, functional and causal connections between distinct neuronal regions. Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a noninvasive technique that can indirectly monitor neuronal activities via neurovascular coupling with high spatial and temporal resolution. The objectives of this doctoral work were to develop and apply novel fMRI methods on the rat brain, for in vivo and global assessments of brain connectivity. Firstly, high resolution and high signal-to-noise resting-state fMRI (rsfMRI) was applied to examine the intracortical laminar functional connectivity. The radial functional connectivity between supragranular layers (L2/3) and infragranular layers (L5/6) was higher. For tangential functional connectivity, the cortical layers were more connected in supragranular and internal granular layers. These findings possess great potential for the understanding of basic functional connectivity among different layers during development, disease, injury and aging in future studies. Secondly, the synergetic use of optogenetic and fMRI was applied to investigate the temporospatial dynamics of distinct cortical and subcortical networks revealed by frequency and layer specific stimulation. Low frequency stimulation of the excitatory neurons in both the superficial (L5b) and deep (L6b) infragranular cortical layers evoked activations in the contralateral cortex. Stimulation in L5b evoked strong subcortical activations, but not in L6b. Local deactivation and activation were observed during high frequency stimulation in L5b and L6b, respectively. Overall, frequency and layer specific optogenetic stimulation recruited distinct widespread and long-range cortical and subcortical activities. Spatiotemporally varying optogenetic stimulation in combination with fMRI presents unique opportunities in studying neural circuits and brain networks. Thirdly, in light of recent findings, it was hypothesized that low frequency signals elicited by the excitatory neurons in the dentate gyrus would propagate to the sensory cortices and alter their functions. Optogenetic stimulation with fMRI readout was utilized to demonstrate for the first time that low frequency stimulation of excitatory neurons in the dorsal dentate gyrus evoked long-range responses in the cortex. The functional consequences of low frequency stimulation were further investigated with rsfMRI and visual fMRI. It was found that brain functional connectivity as well as responses towards visual stimuli increased after low frequency stimulation of the dorsal dentate gyrus, which may be associated with changes in memory and perception. Hence, it is proposed that low frequency oscillations in the hippocampal-neocortical pathway can alter memory consolidation and subsequently perception. Lastly, diffusion tensor imaging and rsfMRI were employed to investigate and document the effects of pregnancy on the structure and function of the brain tissues. Diffusivity was found to generally increase in the whole brain during pregnancy. Regionally, diffusivity increased more pronouncedly in the dorsal hippocampus while fractional anisotropy in the dorsal dentate gyrus increased significantly during pregnancy. For rsfMRI, bilateral hippocampal functional connectivity increased significantly during pregnancy. Moreover, the fractional anisotropy increase appeared to correlate with the bilateral functional connectivity. These findings revealed tissue structural modifications in the whole brain during pregnancy, and that the hippocampus was structurally and functionally remodeled.