David Feinberg, Ph.D., M.D. - US grants

Sub-second MRI has enhanced our understanding of brain structure and function in normal and disease states. Functional MRI studies of cerebral activation have better spatial and temporal resolution than positron emission tomography (PET). For detection of brain disease, MR diffusion and perfusion imaging serve as sensitive indicators of hyperacute stroke. These applications differ markedly yet share a common theme, they benefit from sub-second MRI. The most widely used approach to sub-second MRI, echo planar imaging (EPI), suffers from severe limitations. EPI shows artifacts, distortions and blurring, with complete brain signal loss near bone/air interfaces. Futhermore, rapid signal decay during EPI data acquisition limits spatial resolution and signal-to-noise ratio (SNR). These limitations become more severe with stronger magnetic fields, desirable for improving MR functional image contrast and signal strength. In this proposal, novel sub-second MRI technology will be developed and will overcome the limitations of three-dimensional (3D) EPI. Without major distortions or signal loss artifacts, this new technology will image the entire brain in a fraction of a second. These advances will be applied at high field strength to study the recently discovered "fast response" in the functional MR signal time course. This new 3D imaging technology will move MRI brain activation studies much closer to the temporal resolution of magnetoencephalography (MEG) which is limited in spatial resolution and localization. Specific aims: 1) To develop single-shot 3D gradient-and-spin echo (GRASE) technique. The following aims are to achieve interchangable improvements in SNR, resolution and data acquisition speed in sub-second images: 2) to implement variable signal encoding time (VET) in 2D and 3D single-shot sequences, 3) to encode k-space more efficiently using cylindrical and spherical coverage and 4) to optimize and test the new pulse sequence techniques with high performance gradient hardware specifically designed for brain imaging. The methods detailed in this proposal will speed the transformation of MRI from a static, two-dimensional diagnostic imaging modality to a dynamic four-dimensional brain probe, with time the fourth dimension. Ultimately, the tools developed herein will allow more detailed study of brain structure, function and dynamic physiology.

DESCRIPTION (provided by applicant): We are proposing the development of a family of 3D single-slab MRI pulse sequences based on interleaved cylindrical k-space trajectories. Spin-echo-train and gradient-echo versions will be implemented on a state-of-the-art commercially available whole-body MR scanner equipped with high-performance gradients. This trajectory type features a rare combination of beneficial characteristics: high sampling efficiency, excellent off-resonance behavior, low diffusion and flow sensitivity as well as drastically reduced RF radiation exposure of the examined subject. Various optimized sequence variants will be incorporated into 3D product sequences that will benefit such diverse research areas as high-speed, high-resolution brain MRJ, contrast-enhanced MRA, high-field MRI and hyperpolarized-gas MRI, The success of each developmental step will be ensured by a stringent image quality control that ensures that the signal-to-noise and the overall image artifact load for a given set of sequence parameters is equal to or better than the competing conventional MRI pulse sequences based on rectilinear or spiral trajectories. During the commercialization phase the developed set of pulse sequences will be ported for suitable hardware and software platforms of all major MR hardware manufacturers.

DESCRIPTION (provided by applicant): Despite new rapid image acquisition techniques high-quality MRI data requires data collection times of several seconds or minutes. Any kind of uncompensated object movement on this time scale will lead to blurring, ghosting or other artifacts in the resulting images. All currently available motion correction schemes employ triggering, gating or some sort of navigator echo, which frequently give rise to large amounts of rejected data, compromised image quality or a significant amount of residual blurring. We are proposing a hybrid approach that employs ultrasound images to monitor the position of the target organ. The spatial information is then passed along to the MRI scanner, which adjusts the slice orientation accordingly. This method effectively allows MR image acquisition in the reference frame of the moving organ and not that of the stationary MRI scanner. Ultrasound-guided MRI should permit dramatic improvements in imaging the heart or abdominal organs that are affected by physiological motion.

[unreadable] DESCRIPTION (provided by applicant): Arterial spin labeling (ASL) has proven its ability to non-invasively measure cerebral blood flow (CBF). However, widespread use of this promising technique has been prevented by its long acquisition time due to the inherently image low signal-to-noise ratio (SNR). Recently, it has been shown that the use of 3D instead of 2D 'single-shot' sub-second imaging sequences greatly improve SNR and slice coverage of the brain. The new generation of MRI scanners equipped with improved magnetic gradient systems, phased array multi-channel receiver systems and high magnetic field strengths (3T and 4T) greatly enhance the performance of the ASL pulse sequences. Clinical use of state-of-the-art ASL techniques is very limited since no major MR scanner manufacturer supports this type of perfusion imaging, with currently no commercial ASL products available on any MRI scanners. We are proposing the development of a family of highly efficient 3D MRI pulse sequences for perfusion imaging using ASL and CPMG spin echo pulse sequences, gradient-and-spin-echo (GRASE). This pulse sequence set will consist of single-shot (one set of repeatedly refocused signals) and multi-shot acquisitions using advanced variants of ASL blood labeling preparation schemes. The sequences will be designed and implemented on a 1.5T MR scanner equipped with a 40 mT/m high performance gradients. The new imaging sequences will be ported to 3T and 4T high field scanners at different universities, Washington University, University of Pennsylvania, University of California San Francisco and Harvard where the new imaging technology will undergo further optimization and testing. The availability of these highly efficient pulse sequences to researchers and clinicians will give the capability to perform 3D perfusion imaging of the whole brain at conventional high resolution 256 x 256 matrix images and to perform time averaged sub-second 3D perfusion maps which differentiate different vascular territories. The resulting quantitative measures of blood perfusion will be useful for studies of neurodegenerative diseases, drug trials and identifying perfusion abnormalities in stroke and cerebrovascular disease. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): MRI is a proven non-invasive technique to make functional MRI (fMRI) by measuring changes in "blood oxygen level dependent" (BOLD) contrast in different regions of the brain resulting from the neurovascular coupling of neuronal activity. Echo planar imaging (EPI) is the most widely used fMRI pulse sequence, due to its speed and BOLD contrast, however EPI has relatively poor image quality due to distortions and signal missing from brain regions of high susceptibility near bone and air interfaces. In high spatial resolution (sub-millimeter) fMRI at 7T to explore the functional organization of the cortex, EPI is limited to single 2D image slice that cannot reveal the true 3D distribution of neuronal activity. We are proposing of the development of a family of highly efficient 3D fMRI pulse sequences which obtain sub-second 3D images of the brain, optimized for BOLD contrast in fMRI. The sequences will utilize gradient-and-spin-echo (GRASE) pulse sequence which is hybridized and modified to obtain BOLD contrast in high spatial resolution and minimal artifacts. The new 3D fMRI sequences will be designed and implemented to reduce or eliminate the susceptibility related artifacts of distortion and signal loss in EPI. The availability of these 3D fMRI pulse sequences will give researchers and clinicians the capability of performing fMRI of the brain with improvements over current 2D fMRI methodology. The sequence will be designed and implemented on a 1.5T MR scanner. The new sequences will be ported to 3T and 7T high field scanners at University of California Berkeley, University of Minnesota and UCSF where the new imaging technology will undergo further optimization and testing in neuroscience studies. PUBLIC HEALTH RELEVANCE: Functional MRI (fMRI) is a widely used method to study the brain while it is performing thinking tasks and to map out regions of brain activity. We are proposing a sub-second 3D imaging technology to be supplement or replace the current use of sub-second 2D imaging for fMRI. The 3D fMRI will be useful for revealing the basic organization of the brain's activity which could lead to new discoveries of how the brain works. The resulting measurements obtained in the brain with 3D fMRI will be useful for studies of neurodegenerative diseases including Alzheimer's disease, drug trials and for evaluating people with stroke and cerebrovascular diseases. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Development of high resolution functional MRI (fMRI) capabilities for mapping cortical columns is 3D. fMRI is a widely used method to study the brain while it is performing thinking tasks and to map out regions of brain activity. We are proposing a sub-second 3D imaging technology to be supplement or replace the current use of sub-second 2D imaging for fMRI. The 3D fMRI will be useful for revealing the basic organization of the brain's activity which could lead to new discoveries of how the brain works. The resulting measurements obtained in the brain with 3D fMRI will be useful for studies of neurodegenerative diseases including Alzheimer's disease, drug trials and for evaluating people with stroke and cerebrovascular diseases.

DESCRIPTION (provided by applicant): MRI is a proven non-invasive technique that makes high resolution image of the brain. Echo planar imaging (EPI) is the most widely used MRI technique used for neurosciences due to its extremely fast imaging speed and unique contrast mechanisms. EPI combined with diffusion sensitive gradient pulses provides 3D visualization of axonal fibers, which reveals the connectional anatomy of the human brain. EPI is also nearly exclusively used for functional MRI (fMRI) given its extremely high sensitivity to changes in blood oxygen level dependent (BOLD) contrast in different regions of the brain, revealing maps of neuronal activity. We are proposing to develop a family of highly efficient new EPI sequences for diffusion and fMRI providing several times faster imaging of the brain. This new faster imaging technique works by multiplexing several images within the single-shot echo train, to produce several images instead of a single EPI image from a each train of signals, whereas only a single image is produced in the normal EPI pulse sequence. The new Multiplexed EPI imaging sequence will largely replace the use of the original EPI sequence invented by Peter Mansfield in 1978 that to date has been used for all neuroscience and clinical brain imaging. The availability of these Multiplexed EPI techniques will give researchers and clinicians the capability of performing high angular resolution diffusion imaging (HARDI) in scan times reduced from 25 minutes to 8 or 12 minutes scans and these scan times will be more tolerable by both patients and research subjects. The multiplexed EPI can scan many times faster or instead be used to provide more images that are thinner for higher resolution and reduced artifacts. The greatly accelerated scan times of the whole brain will enable new experiments in functional MRI at 7 Tesla and 3 Tesla. The sequence will be designed, implemented and evaluated on MRI scanners operating at 3T at University of California Berkeley and San Francisco and at 7T and 10.5T at University of Minnesota. Once the Multiplexed EPI sequence is fully evaluated and optimized, it will be made into a useful tool for basic and clinical neuroscience research, and for clinical diagnostic imaging.

DESCRIPTION (provided by applicant): MRI cerebral perfusion imaging is a widely disseminated technique on nearly all MRI scanners used for clinical diagnosis of brain disease and for neuroscience research. Over the last five years there has been considerably increased use of arterial spin labeling (ASL) for clinical diagnosis, while still i.v. injections of a gadoliium based contrast bolus are widely used clinically. Both brain perfusion methods, ASL and DSC techniques, involve making images very fast to identify the passage of blood through the capillary compartment. The image signal-to-noise ratio (SNR) is limited by the small (e.g., 3%) fraction of blood in tissue volumes. This is proportionately small but a second limitation is the time window of imaging, which is constrained to about 500-700 milliseconds for the capillary phase of blood passage. Therefore, rapid imaging of blood inflow is essential. For this reason DSC contrast based methods and ASL with multi-slice 2D EPI have not been able to satisfactorily image perfusion in the entire brain except with thick slices hence reduced spatial resolution. 3D imaging has therefore been developed as an alternative to 2D EPI. However, 2D images have certain desirable characteristics compared with 3D if there are patient motion artifacts. To overcome these limitations we propose to develop novel technology to acquire images simultaneously instead of separately. This approach called simultaneous multi-slice imaging ASL (SMS ASL) and SMS DSC increases by several fold the number of images that are acquired during the limited time window of capillary perfusion phase so the whole brain can be imaged. Another benefit of SMS-ASL is that the time to scan the brain can be greatly reduced by avoiding repeated scans of different brain areas, thus, reducing motion artifacts. A second major innovation in this project is the Hadamard encoded ASL, which is highly useful in clinical studies where the blood arterial transit time (ATT) is not known as in normal aging of people. The Hadamard-ASL acquires images at several different inflow times (TI) to be sure to capture the capillary perfusion phase of blood in at least one set of images. By acquiring the different TI values in a well-defined sub-bolus partitioning of the labeling period, their combination gives separated images at the distinct TI with essentially 2x the SNR and half the net scan time as required by current methodology which acquires each TI data set independently and sequentially. Both the Hadamard and the SMS can be combined for further improvements in SNR, speed and spatial resolution. This will highly impact the accessibility to patients and the robustness of the perfusion technology in clinical use. The availability of the new simultaneous perfusion imaging technology will give clinicians and researchers the capability of performing significantly improved MRI perfusion measurements in patients and these improvements will impact the diagnosis of many different brain diseases, including stroke, leukoencephalopathies and degenerative diseases; i.e., Alzheimer's disease and Parkinson's disease. Perfusion measurements of quantitative cerebral blood flow (CBF) and ATT are important quantitative biomarkers useful as physiological imaging in evaluating new drug therapies for brain diseases. This family of new perfusion imaging techniques utilizes more efficient pulse sequences that provide major advantages in resolution, slice coverage, SNR and speed. The new simultaneous imaging will have high utility and be highly desirable for use on clinical scanners worldwide. The improved quantitative MRI perfusion imaging offers overall increased efficiency that is highly commercializable given they provide improved diagnostic approaches to evaluate brain disease and further improve specificity and sensitivity in MRI neuroradiological exams. The new sequences will be designed, implemented and evaluated on MRI scanners operating at 1.5 Tesla at AMRIT, at 3T at University of California Berkeley and at 3T and 7T at University of California, San Francisco Medical Center and at Martinos Center for Biomedical Imaging, Massachusetts General Hospital, and Harvard Medical School. Once the new perfusion sequences are optimized they will be further evaluated and optimized in collaborative clinical test sites of UCSF Medical Center, UCLA and University of Pennsylvania. In addition to establishing their value in neuroradiology exams, they will be made into useful tools for basic and clinical neuroscience research.

DESCRIPTION (provided by applicant): The goal of this project is to investigate two fundamental visual processing streams in the human brain, the magnocellular and parvocellular pathways. These pathways are physically segregated in subdivisions of the lateral geniculate nucleus (LGN) of the thalamus, a subcortical visual structure that connects the retina to the visual cortex. The magnocellular and parvocellular subdivisions of the LGN have different and complementary visual functions but have been difficult to study in humans due to their small size and subcortical location deep within the brain. A better understanding of the functional specialization of these pathways is important for public health, because deficits in specific subdivisions have been associated with human disorders such as dyslexia and schizophrenia. Further, it has been proposed that the magnocellular and parvocellular subdivisions preferentially provide input to large-scale visual pathways in dorsal and ventral cortex, respectively, but the precise relationships between subcortical and cortical pathway organization in the human brain remain unknown. We propose to use functional magnetic resonance imaging (fMRI) with high spatial and temporal resolution to noninvasively characterize responses to visual stimulation in human LGN. By presenting visual stimuli known to preferentially drive activity within a single subdivision, we will localize the magnocellular and parvocellular subdivisions within the LGN in each participant based on their patterns of visual responses. The localization technique we will develop may be used in the future to characterize the functional properties of the magnocellular and parvocellular subdivisions in both healthy and diseased brains. We will then investigate the functional relationships among large-scale visual cortical networks and the magnocellular and parvocellular LGN subdivisions. To do this, we will employ recent advances in imaging technology for fMRI to obtain measures of connectivity between each subdivision and each of many objectively defined cortical areas, based on correlated fMRI activity in pairs of brain regions. This investigation will help to precisely characterize relationships between subcortical and cortical visual pathways and will assess an influential but incompletely tested theory about the relative contributions of magnocellular and parvocellular pathways to visual processing in dorsal and ventral cortex. A more complete understanding of the normal functional organization of subcortical and cortical visual pathways is critical for developing treatments for multiple diseases, disorders, and injuries that affect visual areas of the brain.

? DESCRIPTION (provided by applicant): MRI is the only technology that can image the connectivity of the human brain in vivo and non-invasively. However, neither BOLD fMRI nor diffusion-based fiber tracking has been able to break the barrier of 1-mm voxel spatial resolution. Yet, 1-mm voxel contains roughly 50,000 neuronal cells and the human cortex is less than 5 mm thick. The disparity between the spatial scales has thus created a large gap between MRI studies of the whole brain and optical imaging and cell recordings of groups of neurons. The overarching objective of this proposal is to bring noninvasive human brain imaging into the microscale resolution and begin to bridge studies of neuronal circuitry and network organization in the human brain. Our breakthrough technology, termed MR Corticography (MRCoG), will achieve dramatic gains in spatial and temporal resolutions by focusing exclusively to the cortex. Higher-sensitivity coil sensors will be designed that tailor to the superficial volume of the brain MRCoG will also be used to map intracortical axonal connectivity, overcoming a fundamental resolution limit inherent to all in vivo human neuronal fiber tractography to date by replacing diffusion imaging with a novel susceptibility contrast mapping of axon fibers. Innovative imaging pulse sequences will be designed to complement the high-sensitivity coil arrays to achieve higher spatial resolution in the neocortex. The improved capabilities of these sensors will be further exploited using new, vastly more efficient spatial multiplexed and temporal multiplexed image acquisition to further accelerate scanning by taking advantage of spatiotemporal sparsity. In summary, the proposed research will create a novel technology for imaging the human brain's neocortex with barrier-breaking resolution and contrast. MRCoG will facilitate the integration between in vivo non-invasive human-brain MRI and cellular and genetic imaging techniques. If successful, it will fundamentally transform our ability to study the human brain. Because it is based on MRI, MRCoG can be readily translated to patient care, providing potential high impact in the care of mental health, traumatic brain injuries, epilepsy among many other debilitating brain diseases and disorders.

PROJECT SUMMARY Functional MRI (fMRI) is performed at a macroscopic scale of 1 to 3 millimeters spatial resolution. The term `mesoscale' has come to denote the resolution of a finer granularity of neuronal organization, to show functional organization across the depth and along the surface of the cortex. Mesoscale fMRI representation of neural activity, however, is not firmly established. A primary objective of this research is to evaluate fMRI's ability to accurately differentiate neuronal activity in cortical layers and columns. This will allow studies of local circuitry in columnar organization and layers with fiber projections to and from distant brain regions, so that hierarchical and directional connectivity between hundreds of human brain regions may eventually be routinely studied non-invasively in the human brain. This project will leverage state-of-the-art MRI hardware and pulse sequences specifically designed for high- resolution imaging of human cortex in a BRAIN Initiative project for next generation human brain imaging (NIH R24MH106096 ?MRI Corticography? (MRCoG)). It will also use several cutting-edge neuroscience technologies, including CLARITY, optogenetic fMRI (ofMRI), transcranial magnetic stimulation (TMS) and electrocorticography (ECoG), to identify and manipulate neuronal activity underlying the fMRI signal. To determine the spatial specificity and laminar profile of BOLD activity, we will use optogenetic stimulation of neuronal populations in different cortical layers of mouse brain while simultaneously imaging with BOLD fMRI. Secondly, variations of vascular and neuronal density will be disambiguated from variations of co-localized fMRI activity using CLARITY and 3D fluorescence microscopy. In humans, the microscale to mesoscale fMRI mapping will be validated using direct electrophysiological mapping with ultra-high-density ECoG grids and advanced computational modeling. To elucidate whole brain mesoscale circuit interactions in humans, MRCoG will be combined with TMS to test hierarchical organization of frontal cortex and transhemispheric motor connections. In humans, pharmacologically modulated brain circuits will be evaluated using an FDA-approved cholinesterase inhibitor, to determine the laminar profile of mesoscale fMRI when feedforward processing is increased.

? DESCRIPTION (provided by applicant): MRI phase contrast velocity imaging is a widely disseminated on nearly all MRI scanners used for clinical diagnosis of brain disease, cardiac and cardiovascular disease and for neuroscience research. Currently phase contrast imaging of blood flow and CSF motion requires longer scan times with each 2D slice or 3D spatial image requiring additional dimension of velocity encoding requiring greater acquisition time. Given the physiological variation in heart rate, cardiac stroke output and respiratory motion effects on blood and CSF velocity, no less the need to greatly reduce the patients time in the scanner, there is a need to reduce the scan time of phase contrast imaging. To achieve several times faster imaging we propose to develop novel technology to acquire velocity phase images simultaneously instead of seperately. Our new technique called simultaneous multi-slice imaging (SMS) phase contrast (PC) imaging is innovated to obtain 2 -10 phase contrast images recorded simultaneously resulting in nearly this factor of reciprocal reduction in scan time. The availability of the new simultaneous phase contrast imaging technology will give clinicians and researchers the capability of performing significantly improved MRI perfusion measurements in the and these improvements will impact the diagnosis of many different diseases, including stroke, cardiac, cardiovascular diseases. Additionally blood flow and CSF flows which are important quantitative biomarkers useful as physiological imaging in evaluating new drug therapies for diseases. This family of new phase contrast imaging techniques utilizes more efficient pulse sequences that provide major advantages in resolution, slice coverage, SNR and speed. The new simultaneous imaging will have high utility and be highly desirable for use on clinical scanners worldwide. The improved quantitative MRI blood flow imaging offers overall increased speed that is highly commercializable given they provide improved diagnostic approaches to evaluate diseases and further improve specificity and sensitivity in MRI exams. The new technology will be designed, implemented and evaluated on MRI scanners at University of California Berkeley, University of California San Francisco (UCSF) Medical Center, Harvard Medical School, and Cedar-Sinai Medical Center. Once imaging protocols are optimized they will be further evaluated and optimized in collaborative clinical test sites in Europe, including the major cardiovascular hospital in London, the Royal Brompton Hospital and elsewhere. In addition to establishing their value in medical exams, the simultaneous phase contrast imaging will be made into useful tools for basic and clinical research.

SUMMARY The overarching objective of our proposal is to bring noninvasive human brain imaging into the microscale (50-500 micron isotropic) resolution in order to create a tool for studies of neuronal circuitry and network organization in the human brain. Our breakthrough technology, MR Corticography (MRCoG), represents substantial advances over existing MRI approaches. MRCoG achieves dramatic gains in spatial and temporal resolutions by focusing several different types of coil arrays on the cerebral cortex of the live human brain. These optimized high-density receiver arrays with 128 coils also serve as a shim array and thereby obtain much higher quality imaging. High-performance magnetic field gradients will be combined with state-of-the-art pulse sequences to produce over 30-times acceleration in echo planar imaging. This will enable us to reach 0.4 mm resolution in fMRI studies of the entire cerebral cortex. This unprecedented spatial resolution in human fMRI is sufficient to identify functional activity at different depth in the cortex corresponding to different cortical layers. MRCoG will also be used to achieve 100-200 micron resolution susceptibility contrast images and this enables us to map intra-cortical axon connections and the cytoarchitecture of human cortex. With over 10 times higher resolution than current 7T scanners, MRCoG will overcome current scale limitations in imaging the function and structure of cortical layers and columns. The evaluation and refinement of MRCoG will entail using advanced computational models of brain circuitry, feedforward and feedback neuronal circuit models and computational models for decoding the brain using data from layer specific and column specific fMRI. Functional and structural MRI performed with MRCoG will generate new avenues to explore human brain circuitry at an order of magnitude higher spatial resolution, while importantly image the entire cortex rather than by current approaches (e.g. zoomed imaging) that measure only small areas of cortex. Many existing 7T MRI scanners will be able to incorporate MRCoG high-resolution technology; therefore, MRCoG can be rapidly disseminated to neuroscience research centers and used to advance medical discoveries. We will evaluate MRCoG ability to resolve currently unobservable cortex abnormalities in epilepsy and autism spectrum disorder (ASD) and to improve localization and mapping of abnormal circuitry in the brain.