Networks of small nuclei in the meso and diencephalon (thalamus, hypothalamus, brainstem, etc.) and their connections to the cortex are critical to understanding consciousness and the onset of sedation during anesthesia. Yet despite their importance for daily survival, the functional connections among nuclei and between nuclei and cortex remain poorly understood. Ultra high field MRI at or above 7 Tesla (7T) provides several benefits for studying deep brain nuclei in humans, including improved image Signal to Noise Ratio (SNR) and improved contrast (CNR) for susceptibility based structural (SWI) and functional (BOLD) imaging as well as greater T1-dispersion. In addition to problems stemming from their small size, the study of nuclei at 7T is impeded by both static and dynamic variations in the background magnet field (B0) at these locations. These B0 variations cause image artifacts such as ghosting, signals voids, blurring, and geometric distortion. ?B0 order and cannot compensate dynamic ?B0. In the current project, we propose a comprehensive field Innovation: Standard B0 shim coils on commercial MRI scanners can only compensate static up to 2nd monitoring and control system to null high spatial order static and dynamic field variations at 7T. The system will use integrated RF-shim coil elements for maximum shimming and RF efficiency, NMR field probes for field monitoring, and feedback control for real-time shim updating. We are the first to combine these technologies in a unified system capable of largely overcoming the obstacle of ?B0 in 7T MR imaging. Validation: We use the proposed system to (a.) reduce the standard deviation of B0 inhomogeneity on a slice-optimized basis over the whole brain; (b.) stabilize the phase of EPI time-series data; (c.) mitigate ghosting in multi-shot EPI; (d.) image and identify known functional networks between the brainstem and cortex in single subjects; and (e.) test a hypothesis based on animal models about the action of the anesthetic dexmedotomidine on a brainstem circuit involving three specific nuclei. Clinical benefit: By providing a new tool for studying the activity of brainstem nuclei during sedation, this project paves the way for future efforts to improve our understanding of neural circuits, develop safer site-specific anesthetic drugs, and potentially reduce post-operative delirium and cognitive impairment. Training: I am fortunate to be a part of the exceptionally rich neuroimaging environment at the MGH Martinos Center, one of the premier environments in the world for developing and validating the proposed field control technology. My K99/R00 proposal is designed to help me pivot from a MRI physicist into an independent investigator with enough background in neurobiology to ask clinically significant questions involving deep brain circuits and then develop targeted high-field MRI technology to answer them. To this end, I will require additional training, coursework, and mentorship in the K99 phase focusing on fMRI, neuroscience, physiology, and pharmacology. Structured training will include coursework, tutorials, workshops, neuroimaging seminars, and clinical exposure. The training plan includes the following: 1. Continued MR physics and hardware mentorship from Dr. Lawrence Wald 2. Training in functional MRI data acquisition and analysis, guidance by Drs. Jonathan Polimeni and Marta Bianciardi on ultra-high field fMRI data, and help from Drs. Randy Buckner and Vitaly Napadow in functional connectivity analysis. 3. Courses on neuroscience and physiology as well as guided study of brainstem nuclei and associated circuits in the arousal pathway, led by Drs. Emery Brown, Brian Edlow, and Vitaly Napadow. 4. Coursework in pharmacology and mentorship by Dr. Brown in designing and conducting anesthesia studies and understanding drug action on the brainstem in the broader context of human physiology. 5. Annual conference attendance including ISMRM and HBM. 6. Participation in the BrainMap neuroimaging seminar series and MGH Radiology Grand Rounds. 7. Career guidance from my primary mentors, including advice on grant-writing and the faculty job search. I am confident that this foundation will enable me to collaborate effectively with neuroscientists and clinicians in neuroimaging studies that depict brainstem anatomy and function in unprecedented detail. Transition to independence: My strong background in hardware and MRI physics, combined with my training and mentorship plan, will enable the success of this project and my subsequent transition to independence. I will emerge from the K99 phase with a combination of engineering and neurophysiology knowledge that neither of my mentors possesses, allowing me to separate from them and occupy a niche bridging technology and brainstem neurophysiology. Using technology developed and validated in Aims 1, 2 and 3.2, and leveraging early clinical findings of Aim 3.2, I will submit an R01 grant during the R00 phase. The grant is expected to be a more in-depth use of sedative drugs with neuroimaging to probe the role of deep brain nuclei in supporting consciousness. Given the compelling need to better understand these nuclei, and the enormous potential of 7T MRI for enabling this understanding, I anticipate that I will emerge in the R00 phase a highly competitive candidate for faculty positions either at MGH or elsewhere.

Public Health Relevance

(No more than 2-3 Sentences) Ultra-high field magnetic resonance imaging offers unparalleled signal-to-noise ratio and contrast for resolving small brainstem nuclei that support consciousness and are implicated in numerous neurological disorders, but our ability to image these structures has been impeded by static and dynamic distortions of the background magnetic field due to tissue heterogeneity and respiration. This project will develop a comprehensive field monitoring and compensation system to mitigate this field distortion, allowing us to image in much finer detail the activity of brainstem nuclei during altered states of arousal in anesthesia. Improved understanding of brainstem circuits will aid in developing safer, site-specific anesthetic drugs and potentially help reduce the incidence of post-operative delirium and cognitive impairment.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Wang, Shumin
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Massachusetts General Hospital
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Stockmann, Jason P; Wald, Lawrence L (2018) In vivo B0 field shimming methods for MRI at 7T. Neuroimage 168:71-87
Setsompop, Kawin; Fan, Qiuyun; Stockmann, Jason et al. (2018) High-resolution in vivo diffusion imaging of the human brain with generalized slice dithered enhanced resolution: Simultaneous multislice (gSlider-SMS). Magn Reson Med 79:141-151