This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Clinical imaging studies still mainly rely on qualitative assessment of image features. When pediatric patients or neurodegenerative diseases are studied, this issue may become problematic, because changing brain features need not necessarily reflect changes in metabolic or physiological status. Conversely, pathological processes may on occasion manifest only as physiological changes without associated structural or anatomical abnormalities. The availability of quantitative absolute measures of physiological parameters, including metabolite concentrations, will therefore be extremely useful. Populations such as children or patients with dementia have reduced compliance for MRI exams, and it is crucial that imaging information can be obtained in a short period of time. Towards this goal, TRD2 was structured to develop techniques for fast quantitative MR spectroscopy (MRS) and spectroscopic imaging (MRSI), as reflected in the previous title "Brain Chemistry by MR Spectroscopic Imaging". During the first grant period, we designed new approaches for rapid, quantitative spectroscopic imaging, using the SENSE parallel acquisition technique. We have succeeded in reducing the scan time for multi-slice MRSI from 30 minutes to about 10 min. However, there is still much to be improved, both in terms of the spatial resolution and speed of MRSI. In addition, the information content of MRSI is relatively limited, so there is a need for other, physiological imaging parameters that may provide additional data on disease pathophysiology, diagnosis or prognosis. For instance, our collaborators investigating demyelinating diseases such as Multiple Sclerosis (MS), adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) have a need for imaging methodologies that provide more information on tissue myelin status and axonal integrity. Such information is also important for the study of normal and abnormal neurodevelopment in children, especially in the first years of life when the majority of myelination occurs. For instance, our clinical collaborators studying Cerebral Palsy (CP) and traumatic brain injury (TBI) in children would gain important information if they are able to judge white matter injury and development, in terms of both axonal integrity and myelin status. Spinal cord pathology is recognized to play an important role in clinical disability in diseases such as MS and ALD/ AMN, in some cases being the sole or primary site of involvement. Noninvasive measures of the integrity of axons and myelin in the spinal cord would be invaluable for assessing disease burden, tissue damage, and monitoring the effects of therapeutic interventions. However, the development of physiological neuroimaging techniques for the spine has lagged behind that in the brain. Our new KKI collaborator, Dr. McDonald, is setting up a spinal trauma program for children and his work would benefit tremendously from the capability to image spine metabolism and physiology. These and other collaborators have also wish to measure other physiological quantities in the spine, such as of blood flow, blood volume, and pH. As reflected in our new title, the overall goal of this TRD is therefore the design of such quantitative physiological MRI methodologies in both the brain and spine. AIM 1: Quantitative proton MRSI of the brain and spine at 3.0 Tesla and 7.0 Tesla Proton spectroscopy of the spine is in its infancy, and proton MRS of the brain at very high fields has to date been limited to single voxel studies. We will develop techniques for quantitative proton MRSI of the brain and cervical spinal cord at 3T and 7T. Much more than single-voxel MRS, multi-voxel approaches introduce technical challenges related to increased magnetic susceptibility effects and chemical shift displacement errors. Metabolite quantification suffers from B0 and B1 inhomogeneity. To address these issues, technique development is required in several respects. One area where we will focus is to exploit the synergy between parallel MR and high field acquisitions;we will explore self-calibrating parallel-MRSI schemes for improved SENSE-MRSI performance and reduced scan times. We will also develop MRSI processing software for use by the service and collaboration projects. AIM 2: Quantitative Magnetization Transfer Spectroscopy and Imaging of the brain and spine at 3.0 and 7.0 Tesla We will work on two types of magnetization transfer: 2A) Conventional MT imaging. We will implement high-resolution MT imaging at 7T and we will design imaging approaches for quantifying exchanges rates between the macromolecular phase and the free water pool. 2B) Amide Proton Transfer (APT) Imaging. We recently developed a new method capable of detecting mobile proteins and peptides in situ through the exchange between their amide protons and water protons. Animal studies using this APT contrast showed that the signal intensities in these images reflect pH and protein/peptide content. The goal is to implement this technology on the clinical scanners and explore its utility for the different diseases studies by our collaborators, including stroke, cancer, demyelination, and inflammation. Based on the type of contrast mechanism, this approach is expected to be more successful at high field. AIM 3: Development of novel non-invasive blood volume and blood flow imaging for clinical use at 1.5T, 3.0T, and 7.0T We will develop the use of blood-nulling techniques for the study of blood volume and blood flow imaging in situ. We will start out with the vascular-space occupancy (VASO) approach that we recently originated for fMRI, and implement practical multi-slice approaches for medical application with our collaborators. Recent calculations and subsequent data acquisitions show that the VASO contrast also contains a perfusion contribution, which we will call VAscular Space Labeling (VASL). The aim is to develop VASO and VASL to allow quantification of blood flow and blood volume in patients. These methods, which have relatively low signal-to-noise ratio (SNR) because of the low blood volume of normal brain, will become especially relevant at higher field where improved SNR is expected.