TRD3 Addressing biological barriers in in vivo human brain MRI acquisitions Abstract In this project, we propose a program of bioengineering development to improve human functional and anatomical MRI at its acquisition stage. We aim to bridge the macro and micro scales of brain architecture by improving the spatio-temporal resolution of fMRI down to its biological limits. The barriers we face in acquisition encoding and then again in the ability of MRI to perform anatomical imaging at the meso scale (500 um or less) and finally the spatial fidelity of fMRI maps themselves are primarily biological. Firstly, we impact MRI encoding broadly by focusing on methods to address the Peripheral Nerve Stimulation (PNS) barrier in application of fast gradient coils. We will improve gradient coil technology through utilizing a detailed peripheral nerve stimulation model to predict nerve stimulation and optimize reduction strategies. In Aim 2 we address the confounds of respiratory and patient motion in anatomical imaging through motion robust image reconstruction of anatomical MR images using a data-consistency driven approach. We jointly estimate biological nuisance modulations from respiration and patient motion within the multi-channel kspace data. Successful joint estimate of the image and the nuisance variables within a comprehensive forward model effectively removes these confounds from the image yielding a motion and respiratory robust acquisition. Finally, in aim 3 we develop methods to address spatial resolution limits imposed on fMRI by large vasculature by predicting and removing them from the activation maps on the flattened cortical surface by models incorporating prior knowledge from high resolution vascular maps. Overall, our tools will broadly advance the study of human brain circuits at the mesoscopic scale while retaining the whole- brain and non-invasive features of MRI.