Project Summary Abnormalities in brain energy metabolism are strongly linked to a variety of pathologies including Alzheimer's disease, traumatic brain injury, cancer, and ischemia. Magnetic resonance spectroscopy (MRS) and imaging (MRI) allow non-invasive observation of nuclei (proton 1H, phosphorus 31P, sodium 23Na, and deuterium 2H) present in many metabolites and ions that play key roles in various stages of this metabolic process. Up to this point, technical challenges have prevented more than two nuclei from being studied simultaneously, which can conceal causality and temporal relationships between metabolic functions. In this project, we propose to engi- neer a quadri-nuclear MRI (4X-MRI) hardware system, acquisition method, and processing pipeline to enable proton, sodium, phosphorus, and deuterium simultaneous or interleaved measurements within the same scan protocol. Given its signal strength advantage, ultra-high-field MRI (7 T) is a natural fit for multinuclear MRI. How- ever, custom hardware and acquisition methods are nonetheless required to interact with spins that resonate at different frequencies (at 7 Tesla, 297 MHz for 1H, 120 MHz for 31P, 79 MHz for 23Na, 46 MHz for 2H) and efficiently accommodate a range of spin dynamics. We will implement a quadruple-tuned radiofrequency (RF) coil and hardware platform to excite and detect signals from 1H, 31P, 23Na, and 2H. The new hardware will be paired with custom pulse sequences that exploit the significant differences between spin relaxation times to enable multinuclear acquisitions in a single examination. Together, the tools developed in this study will enable dynamic metabolic neuroimaging and will provide sufficient proof-of-principle to support a wide range of in vivo studies in health, disease, and challenge paradigms. Specific aims of this pilot project are: (1) Data acquisition: 1H/31P/23Na/2H MRI at 7 T. (1.a) To build a quadruple-tuned 32-channel RF coil. (1.b) To develop a flexible 4X-MRI protocol with interleaved multinuclear acquisitions. (2) Data processing: Modeling the quantitative infor- mation from the 4X-MRI data. (2.a) To optimize methods of quantification from all multinuclear acquisitions, such as relaxation times from 1H data, intracellular sodium concentration from 23Na data, metabolite concentration (glucose, glutamate/glutamine, lactate) from labeled 2H-glucose uptake, metabolite concentration (ATP, phospho- creatine) from 31P. (2.b) Precision and accuracy in phantoms. (3) Application in vivo: (3.a) To assess repeatability and reproducibility of 4X-MRI in healthy subjects. (3.b) To assess sensitivity and specificity of 4X-MRI in patients with steno-occlusive disease (SOD). We will scan patients with SOD with 4X-MRI to measure differences in brain metabolism between ischemic and normal tissues. This new 4X-MRI tool could help researchers and clinicians interested in measuring multiple parameters related to brain energy in vivo, for both diagnosis or prognosis of diseas...