Contrast-enhanced magnetic resonance imaging (MRI) is the cornerstone for brain tumor diagnosis and treatment planning. While its sensitivity for metastases is superior to that of CT or PET-CT, small lesions (<5- mm) and leptomeningeal spread may still be missed, which can have a major impact on prognosis and planning for stereotactic radiosurgery, as well as on the use of targeted biologics that cross the blood-brain barrier. A method that could further improve the sensitivity and specificity of MRI for brain tumors would be of great clinical benefit. Towards this end, we have developed a new class of pulse sequences, called T1 Relaxation-Enhanced Steady-State (T1RESS), that greatly improves the visibility of tumors in contrast- enhanced MRI. Compared with existing neuroimaging techniques, T1RESS at least doubles the tumor-to- background contrast while significantly improving the tumor-to-background contrast-to-noise ratio. An “unbalanced” version (uT1RESS) renders blood vessel dark and is the focus of our proposal. In a preliminary study of 54 adult patients that was published in Science Advances, uT1RESS provided a remarkable twofold or greater improvement in tumor-to-brain contrast along with a marked improvement in lesion-to-brain contrast-to-noise in comparison to standard-of-care MPRAGE and other pulse sequences that are commonly used to image brain tumors. We found that even small metastatic tumor deposits and leptomeningeal lesions that were difficult to distinguish from small blood vessels with standard imaging techniques could be unambiguously identified. The primary hypothesis of this five-year grant proposal is that T1RESS will significantly improve the sensitivity for small brain metastases compared with existing MRI pulse sequences, while also reducing scan times. A secondary hypothesis is that the twofold improvement in tumor-to-brain contrast obtained with uT1RESS can be used to enable a substantial twofold reduction in gadolinium-based contrast agent (GBCA) dosage. Studies of phantoms, healthy volunteers, and patients with brain tumors along with Bloch equation modeling will be used to guide sequence optimization. These optimization efforts will be followed by a two- institution study to determine the accuracy of the technique. Our specific aims are as follows: 1. To apply uT1RESS in healthy subjects and patients with brain tumors to systematically evaluate the impact of various sequence parameters on image appearance, contrast, SNR, and lesion sharpness, and to optimize the technique to maximize tumor visibility while minimizing scan time and image artifacts. 2. To perform a pilot study to determine whether metrics of tumor visibility using uT1RESS and a twofold reduced GBCA contrast agent dosage are noninferior to MPRAGE with a standard contrast agent dosage. 3. To perform a two-site research trial at 3T to characterize the appearance of brain metastases with uT1RESS, and to determine its accuracy for small brain metastases ...