Project Summary / Abstract Magnetic Particle Imaging (MPI) is a novel tomographic imaging modality, with unprecedented contrast, depth of penetration and sensitivity (1 micromolar sensitivity today; 100 nM soon). MPI is only being actively researched in a few labs in North America, and in a dozen labs in the EU. Still, MPI already competes with nuclear medicine in terms of dose-limited sensitivity, and already surpasses scintigraphy in terms of safety (zero radiation), convenience (no “hot” labeling) and reporter persistence (infinite duration magnetization instead of half life limited to hours or days). Prof. Conolly's lab at UC Berkeley and his lab's startup company (Magnetic Insight, Alameda CA) have designed and built nearly all the high-resolution MPI scanners now in North America. MPI tracers (superparamagnetic iron oxides, SPIOs) are safe for human use, and some are already approved for human use by the FDA. It is believed that SPIO tracers are safer for chronic kidney disease (CKD) patients than the standard angiographic tracers, Iodine (X-ray and X-ray CT) and Gadolinium (MRI). This proposal is in response to the BRAIN initiative goal to develop new imaging systems that use disruptive, new approaches to dramatically improve spatiotemporal resolution of current human neuroimaging. The physics of MPI offers unprecedented vascular contrast at the capillary level with no background tissue clutter, because human tissues produce zero MPI signal and are completely transpar- ent. The absence of a background signal could reduce physiologic noise significantly. We have already studied the brain vascular response to hypercapnia, neuro-inflammatory processes in traumatic brain injury (TBI), and performed the world's first (unpublished) CBF/CBV measurements in a rodent model. The only significant physical weakness holding MPI back from human translation is its poor spatial reso- lution, now about 1.4 mm in a small animal. The resolution in MPI is determined entirely by two parameters: the tracer magnetic resolution (typically 10 mT), and the selection field gradient (roughly 7 T/m), leading to roughly 10 mT/(7 T/m) ⇡ 1.4 mm resolution. FDA electromagnetic safety constraints (dB/dt and SAR) preclude us from increasing the gradient strength further. Hence, to make MPI safe and high resolution, we must develop far higher resolution MPI tracers. Here we introduce a dramatic advance in MPI technology, which we call strong interacting MPI (siMPI), which has experimentally demonstrated 10-fold resolution im- provement, with 1 mT magnetic resolution. The impact of the tracer resolution improvement will be nothing short of revolutionary: siMPI could reduce the cost of human MPI scanners by 100-fold and improve sensitivity per gram of tracer by 10-fold! Moreover, siMPI will permit MPI scanning with dramatically mit- igated FDA electromagnetic safety concerns (dB/dt and SAR). In short, siMPI is precisely disruptive new approach to dramatically improve spatiotemporal resolution of a current neuroimaging method. 2

Narrative A novel medical imaging technique called Magnetic Particle Imaging (MPI) has shown extraordinary promise for imaging functional activation through changes in Cerebral Blood Volume (CBV). The PI's lab at UC Berkeley has pioneered MPI scanner and application development; here we plan to develop transforma- tive advances in neuroscience by improving MPIs inherent resolution 10-fold (that is, up to 1000-fold voxel volume reduction) which could enable the first human functional MPI scanner with high spatio-temporal resolution.