Project Summary The proposed technologies effectively address a significant shortcoming in current MRI protocolsthat is the incapability of existing protocols to acquire a complete set of high-resolution artifact-free multi-contrast and quantitative MR images from challenging patients (e.g. Parkinsons disease (PD) patients;stroke patients; pediatric populations) within clinically-feasible time. Here we will develop and integratemultidisciplinary approaches to maximize the translatability of advanced MRI technologies to clinical uses forchallenging patients. Aim 1A) We will incorporate fast scan strategies motion-correction and distortion-correction modules into our recently developed multiplexed sensitivity encoded (MUSE) DTI and fMRI in anovel way to enable high-resolution connectivity mapping (at 0.85 mm isotropic resolution in contrast to1.5mm to 4mm that are standard with conventional DTI and fMRI protocols). At this resolution criticalnetwork nodes (e.g. motor and non-motor subregions of subthalamic nucleus (STN)) and pathways that areimportant for patient care (e.g. improved MRI guidance for deep brain stimulation) can be much more reliablyresolved. Aim 1B) We will develop an innovative multi-echo-pathway MRI method to significantly reduce thescan time of multi-contrast MRI and parametric imaging (e.g. achieving simultaneous T1 and T2 parametricmapping within 3 min: ~ 4-fold improvement than conventional protocols). Aim 1C) We will develop motionartifact correction schemes that are suitable for high-resolution multi-contrast MRI in challenging patients.Aim 2A) We plan to first evaluate the MRI technologies in healthy adult volunteers in two ways. First dataobtained with our methods and conventional more time-consuming protocols will be quantitatively compared.Second new knowledge that can only be produced from our high-resolution data (e.g. imaging motor-subregions of STN) will be confirmed with theta-burst transcranial magnetic simulation (TMS) neuro-modulation of motor networks. Aim 2B) We plan to evaluate the proposed imaging technologies in PDpatients in three ways. First in a cross-sectional study we will acquire and compare imaging data from 1)those who are at high risk of PD conversion (with positive family history hyposmia rapid eye movementsleep behavior disorder constipation and impairments in instrumental daily activities) 2) early-stage PDpatients (Hoehn and Yahr scale 1 and 2) and 3) advanced-stage PD patients (Hoehn and Yahr scale 3 and4). Difference in brain structure and function across three populations will be assessed. Second in alongitudinal study imaging data obtained from subjects with high risk of conversion to PD in year 2 and year5 of the project will be compared to measure prodromal brain signal abnormalities and their correlation withlongitudinal behavioral and MRI signal changes. Third we will compare imaging data obtained from PDpatients and non-PD patients (mainly essential tremor) to evaluate the differential diagnosis accuracy of theproposed imaging technologies.