PROJECT SUMMARY Understanding how neural circuits operate and interconnect at mesoscopic (sub-millimeter) scale, and how neuroenergetic metabolism and neurotransmitters support brain function at resting and working state is essential to brain research and BRAIN Initiative. Magnetic resonance (MR) imaging (MRI), including functional MRI (fMRI) and in vivo MR spectroscopic imaging (MRSI), is the sole modality enabling to imaging neural activity, functional connectivity and brain structure at cortical layer and column level, neuroenergetics and neurotransmitters in human brain. However, it remains challenging to address fundamental neuroscience questions requiring much higher sensitivity and spatiotemporal resolution currently unavailable. Increasing MR field strength has been the prevailing paradigm to tackle the challenge, however, beside high cost, it poses a safety concern from elevated specific absorption rate (SAR) of radiofrequency (RF) power in the brain tissue. To address the technical challenges and limitations faced by the MR-based imaging techniques, we have pioneered an innovative and cost-effective engineering solution by introducing the ultra-high dielectric constant (uHDC) former incorporated with RF coils for large improvements of sensitivity and spatiotemporal resolution for fMRI and MRSI, and synergistically reducing SAR at ultrahigh field (UHF). With the NIH R24 funding support, we have made progress with promising results for proof of concept. In this U01 proposal, we will further develop and integrate three advanced technologies: i) fixed and/or tunable uHDC formers incorporated with advanced RF coil technology for maximizing MR sensitivity and minimizing SAR;; ii) SPectroscopic Imaging by exploiting spatiospectral CorrElation (SPICE) technique for significantly boosting signal-to-noise ratio (SNR) and spatiotemporal resolution;; iii) UHF MR technology for further improving sensitivity and spectral resolution of MRSI. The integration of these technologies will achieve cumulative and unprecedented improvements at UHF and break current barriers of spatiotemporal resolution, ultimately enable i) ultrahigh-resolution fMRI mapping of neural activity, circuits and dynamics, and functional connectivity and networks at mesoscopic scale at 3 and 7 tesla(T);; and ii) very high resolution and whole-brain multinuclear MRSI for functional mapping of neuroenergetic and neurotransmitter changes in response to brain stimulation at ultrahigh fields (7T and 10.5T) with an superior (£5mm isotropic) resolution comparable to conventional fMRI. The technology developments will be carried out by a consortium among interdisciplinary researchers from University of Minnesota, Penn State University and...