ABSTRACT The increased availability of ultra-high field scanners provides an opportunity to perform fMRI at sub-millimeter spatial scales and enables in vivo probing of laminar function in the human brain. Investigations at this new mesoscopic spatial scale in neuroscience not only advance our understanding of the cortical micro-circuitry in vivo in health and disease, but also help bridge the gap between macroscopic (e.g., conventional fMRI, behavior) and microscopic (e.g., extracellular recordings) measures of brain function. However, despite promising potentials, critical barriers remain in achieving adequate sensitivity, specificity, accuracy, coverage at this scale. Until recently, most layer-fMRI studies have been confined to one of the primary cortices using a task design with a small brain coverage together with macro-vascular-contaminated sequence contrasts for functional measurement and defining cortical layers roughly based on distortion mis-matched anatomical reference. In this project proposal, we will develop a whole-brain layer-specific imaging sequence tool in humans, for achieving fMRI at high resolution (£800 µm isotropic), high specificity (not being spatially biased with unspecific vein signals as in BOLD), high sensitivity (robust measurement at layer-level resolution), high spatial accuracy (layer fMRI analysis in native fMRI space to avoid blurring and errors arising from registration), whole brain coverage, and eventually extending layer fMRI to more flexible connectivity-based experiment designs. We will adapt two sequence methods, one is an integrated blood volume and perfusion (VAPER) contrast method to improve layer fMRI specificity, and the other is a magnetization transfer (MT) weighted anatomical EPI imaging technique to facilitate determination of cortical depth in native fMRI space. We will improve the pulse design of the VAPER/MT preparation and incorporate them with a skipped-CAIPI 3D-EPI (segmented acquisition with CAIPIRINHA sampling) acquisition, as a new method we will call VAPER/MT-3D-EPI. We will develop the sequence and optimize its design for a whole-brain 0.8-mm isotropic imaging, and demonstrate its sensitivity and specificity through measuring layer-dependent activity. We will use this new sequence to collect a whole- brain submillimeter functional image dataset in humans at both resting state and during movie-watching, establish the layer-specific functional connectivity analysis pipeline, and investigate the involvement of different cortical layers in the maintenance of the brain networks. We will publicly share the data and analysis code to facilitate development of layer fMRI methods and demonstrate VAPER/MT-3D-EPI as a user-friendly layer fMRI tool for network neuroscience.

NARRATIVE Investigations at cortical layer level in neuroscience not only advance our understanding of the cortical micro-circuitry in vivo in health and disease, but also help bridge the gap between macroscopic (e.g., conventional fMRI, behavior) and microscopic (e.g., extracellular recordings) measures of brain function. In this project, we will develop a whole-brain layer-specific imaging sequence tool in humans, for achieving fMRI at high resolution (£800 µm isotropic), high specificity (not being spatially biased with unspecific vein signals as in BOLD), high sensitivity (robust measurement at layer-level resolution), high spatial accuracy (layer fMRI analysis in native fMRI space to avoid blurring and errors arising from registration), whole brain coverage, and eventually extending layer fMRI to more flexible connectivity- based experiment designs.