Michael Moseley - US grants

DESCRIPTION (Applicant's Abstract): The overall goal of this research is to assess the utility of T2- and diffusion-weighted MR in aiding the clinical diagnosis of human stroke. At present, identification of stroke relies primarily on neurological assessment rather than physiological measurement, since the ability to study ischemic pathophysiology in humans has been limited. Rapid identification of all strokes represents a particularly difficult challenge. We believe that diffusion-sensitive MRI techniques can improve the management of stroke in these regions by noninvasively and rapidly providing diagnostic information that is not available from neurological assessments and that cannot be obtained by presently-used CT, conventional spin-echo, FLAIR T2, and single-shot diffusion-weighted MRI methods. We will focus on diffusion-weighted MR imaging (DWI) because of its inherent sensitivity to cellular energy failure and to cellular necrosis. During the first year of funding, we will test a battery of advanced DWI methods that build on single- and multi-shot spin-echo and echo-planar imaging (EPI) methods with presently-used and improved navigation for motion reduction. We will determine the optimal method based upon a composite index of signal-to-noise, resolution, scan time, and artifact minimization. This evaluation will be done by two blinded neuroradiologists on a population of 48 stroke patients. During the second and third years of funding, we will pursue our ultimate goal of improving diagnosis of stroke patients (n=96) by evaluating the performance of the optimal DWI method together with T2 to 1): depict the relevant lesion responsible for the clinical history and 2): better augment the neurological assessment than dose the conventional (T2-weighted) MR exam alone. We will test the hypotheses that DWI will identify acute lesions not seen with T2 at presentation, will identify acute lesions in patients with multiple ischemic lesions not readily differentiated by T2, and will predict the T2-weighted MR depiction of acute lesion at chronic timepoints and thereby eliminate the need for follow-up radiological studies. The successful completion of this work will provide objective criteria beyond the neurological exam and a rapid, non-invasive tool for the neurologist to improve the diagnosis and management of patients with acute stroke.

The overall goal of this research is to evaluate diffusion- and perfusion-weighted MR methodologies for the diagnostic advantages and predictive value they bring to the management of clinical stroke. At present, identification of stroke relies primarily on neurological assessment rather than physiological measurement, since the ability to study ischemic pathophysiology in humans has been limited. Rapid identification of the relevant lesions represents a particularly difficult challenge. We believe that diffusion- and perfusion-sensitive MRI techniques can improve the management of stroke in these regions by rapidly providing diagnostic information that is not available from neurological assessments and that cannot be obtained by presently-used CT or conventional MRI methods. We will focus on diffusion-weighted (DWI), perfusion-weighted MR (PWI), and time-resolved vascular MR imaging because of its inherent sensitivity to cellular energy failure and to the underlying hemodynamic behaviors. During all years of funding, parameters of stroke severity (volume, location, and circulation) measured by MR will be correlated to acute and chronic stroke severity measured by neurological assessments based on the National Institutes of Health Stroke Scale Scores (NIHSSS) and the Bamford Classification, and to the final T2-weighted images. We will build a comprehensive database of stroke severity (volume, location, and circulation) from both large and small strokes (anterior and posterior) from 24 patients per year. Our aims are to determine the correlation of diffusion- and perfusion-weighted MR parameters of stroke severity with clinical assessment of stroke severity at the acute timepoint, identify diagnostic predictors of the clinical outcome of stroke, and to derive the relationship between vascular risk and metabolic status. The successful completion of this work will deliver an integrated battery of MR measurements best predictive of stroke severity and clinical outcome. It will also provide objective criteria beyond the neurological exam and a rapid, non-invasive tool for the neurologist to improve the diagnosis and management of patients with acute stroke.

Introduction: Diffusion- and perfusion-weighted MRI (DWI and PWI) provides unique diagnostic information not available from neurological or CT assessments. To implement these new methodologies in the clinical setting, a 20-minute DWI/PWI protocol has been used to evaluate these new MR methodologies for the diagnostic advantages and predictive value they bring to the management of clinical stroke and to longitudinally monitor the progression of ischemia to infarction. Methods: Patients presenting with new neurologic symptoms within 6 hours of onset were studied over the past 8 months. These patients were imaged at presentation following neurological and CT exams and again at 3-6 hours, 9-12 hours, 36-48 hours and finally at 30 days. Cases were excluded if the time of onset was not clearly established. Because the time of ischemic onset within the first few hours is often difficult to determine accurately, eight patients were included in this study. An in-patient GE Signa Horizon (gradient strengths 22 mT/m) was used for all studies. Results: The ASE-EPI sequence was chosen over corresponding SE-EPI and the GRE-EPI options as the best balance between susceptibility sensitivity (FR2*) and background image artifacts at a single-dose injection. All patients showed regional DW hyperintensity in anatomic locations appropriate to the clinical symptoms. ADC values were lower than normal at acute timepoints and elevated above normal beyond 10 days, in agreement with earlier studies. Depiction of the acute ischemic lesions from normal brain or pre-exiting chronic lesions was significantly improved using the IR-ADC maps over the conventional ADC maps. The DW and IR-ADC maps were superior over the conventional and FLAIR T2-wt images in depiction of hyperacute lesions and the differentiation of acute from chronic lesions. Averaged ("trace") ADC maps were superior in lesion conspicuity to the anisotropic ADC maps for all lesions. The PWI exam was superior to the DWI and T2 exams in the depiction of hyperacute events. Conclusions: DWI/PWI protocols provide rapid identification of the extent, location, and circulation of the relevant lesion(s) and the underlying hemodynamic behaviors responsible for the clinical symptoms.

Under the direction of Dr. Michael Moseley, MS Donna Nash will collect data for her doctoral dissertation. Her archaeological research will focus on the region surrounding the site of Cerro Baul which is located in the Osmore drainage in Southern Peru. During the period from ca. 500 - 1000 AD two states, termed "Wari" and "Tiwanaku" arose in the Southern Andes and this situation provides a rare opportunity to study the interactions between early simple state level societies. The Osmore drainage appears to mark a boundary between the two and archaeological remains of both are found in this region. While it is often possible to assign sites to one state or the other based on ceramic remains, in other cases such determinations are more difficult because distinctively decorated sherds are lacking. MS Nash plans to approach the problem through an analysis of household organization. Based on work at large high status sites a distinctive Wari pattern which combines domestic and ritual/administrative activities within single structures has been observed. Although it has been postulated to be the case, it is not certain whether this same pattern also exists in the more numerous lower status dwellings. In prior work MS Nash and her collaborators have located a number of small Wari structures and with NSF support she will excavate ten of them. From the distribution of ceramics, lithics and other remains recovered she will determine both the nature and placement of activities. Because some sites will likely contain little habitation debris MS Nash will collect soil samples and determine chemical signatures which are activity related.

This research is important for several reasons. It will provide insight into the political and social organization of an early state society. It will also develop a spatial signature which will help to define the Wari presence in other regions of Peru. Finally it will assist in training a promising young scientist.

Introduction: The apparent diffusion coefficient (ADC) of water in gray and white matter decreases significantly (~35%) after global ischemia. However, the effects of ischemia on water diffusion and its anisotropy in nerve are unknown. The purpose of this study was to measure water diffusion and its anisotropy in the optic and trigeminal nerve after cardiac arrest in the rat. Methods: Cardiac arrest was induced in anesthetized Sprague-Dawley rats (n=7) by an i.v. injection of potassium chloride. Core temperature was maintained at 3711!C by warm air circulation. MRI diffusion measurements were performed on a GE CSI 2 T spectrometer prior to cardiac arrest and at 20, 40, 60, and 90 min after cardiac arrest. In order to investigate anisotropic diffusion and since the nerves are in approximate alignment with the Z direction, the ADC values parallel (//) and perpendicular (^) to the length of the nerve were obtained with the diffusion gradients applied along Z and X (or Y), respectively. Results and Conclusion: ADC(//) and ADC(^) decreased by 44 and 46%, respectively, in the optic nerve, and by 24 and 26%, respectively, in the trigeminal nerve at 90 min post cardiac arrest, relative to the ADCs prior to cardiac arrest. Interestingly, the rate of approach to the minimum ADC was slower than in the cortex. This is in agreement with the slower decrease of the ADC in white matter relative to gray matter after cardiac arrest. Despite the absolute reductions in ADC, anisotropy {ADC(//)/ADC(^)} was preserved throughout the 90 min after cardiac arrest and it remained at ~2.9 for both the optic and trigeminal nerves. Therefore, changes in diffusional anisotropy would not be expected at the acute stage of ischemia.

Under the direction of Dr. Michael Moseley, Mr. Richard Smailes will collect data for his doctoral dissertation. Mr. Smailes has a background in construction contracting and is familiar with modern computer assisted techniques to aid in design, cost estimation and scheduling. These provide the framework within which modern building takes place. In this highly innovative project he will take this set of techniques, adapt them and apply the retrospectively to the construction of a prehistoric royal compound at the site of Chan Chan Peru. This ancient city located on Peru's arid North Coast contains a number of monumental structures consisting of walled enclosures which surround multiple buildings and storerooms. Archaeologists believe that early compounds were occupied by multiple successive rules while later ones served only one: each king constructed his own which was abandoned after his death. It is unclear however how long such a compound took to build given available construction techniques and methods of labor organization. Previous attempts in both Peru and other regions of the world to estimate labor involved in monumental construction have been rudimentary and based solely on amount of earth and other material involved in construction. Issues of the types of tasks involved, crew size and scheduling have not been considered. Modern contractors have computer based techniques which assist in planning and managing construction and in estimating costs. Mr. Smailes will use these to analyze a Chan Chan royal compound. The site has been carefully mapped and Mr. Smailes will use these data to construct a three dimensional computer model of the compound. This will provide the basis from which estimation will proceed. He will also conduct ethnoarchaeological research in Peru to gain insight into traditional construction practices such as adobe brick making.

Archaeologists not unreasonably assume that a correlation exists between the size and complexity of a construction and the level of complexity and social organization of the society which built it. Therefore they often attempt to estimate the amount of labor required for a particular monumental structure and use this to speculate about other aspects of the society. Mr. Smailes' research will constitute a significant improvement to the methodologies employed to date and, if successful will likely be applied in many archaeological situations in many parts of the world. Thus its methodological impact will likely be significant. This research will increase our understanding of one of the cradles of civilization and assist in training a promising young scientist.

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall aim of this project is to map the potential pathways of cognitive and motor activation. This has progressed in the last year to add several improvements in the DTI image reconstruction and processing software (?Tensorcalc?) that we wrote and maintain for the P41 RR09784. Diffusion tensor imaging (DTI) is a promising new technique for the assessment of white matter (WM) structural integrity and connectivity. We have written and refined 3 key core DTI map tracking algorithms that are being used to track white matter fibers for determining the potential white matter trafficking patterns. One of the more exciting methods to arise from the noninvasive mapping of white matter tracks is the potential of tracking the white matter fibers from one region of brain to another. This in essence, reveals the underlying ?wiring? of the activated brain. Our algorithm allows for real-time connectivity maps that can be generated from planting a seed in one white matter tract region. We have constructed software ?phantoms? to check the algorithms for accuracy and reproducibility. Our diffusion tensor imaging protocol is performed using a spin echo EPI technique and we have added a host of new spiral methods. The vector maps hold the orientation of the fibers as well as the magnitude of the orientation. From the fiber maps, one can compose several general approaches to finding connectivity from fiber to fiber from a variety of model algorithms that we have built.

DESCRIPTION (provided by applicant): The overall goal of this new submission is to temporally differentiate subclinical oligemia above the threshold for clinical impairment (reduced CBF yet above a critical diffusion ADC threshold) from brain below thresholds of viability and at risk for hemorrhage. For each year of this 4-year study, 24 consecutive inpatients presenting with stroke-like symptoms between 6-24 hours of symptom onset will be studied. These patients will display a wide range of blood flow values and physiological states over which to determine the temporal dependences of perfusion on segmented ADC measures, yet be stable enough to undergo both the CT and MR studies needed to test the hypotheses. One important aspect of this study is to establish MR bolus-tracking as a quantitative perfusion method. We will improve the ability of perfusion-weighted MRI (PWI) to quantitatively map perfusion (Specific Aim 1) in order to establish temporal diffusion and flow thresholds in the setting of evolving acute clinical stroke (Specific Aim 2). To do this, we will acquire quantitative cerebral blood flow (CBF) maps derived from dualecho/ dual-shot gradient-echo GRE-EPI bolus tracking arterial input AIF-derived PWI images. We will test the hypothesis that CBF values measured from our automated AIF selection deconvolution routines will better correlate with the "gold standard" XeCT values (acquired from the same patients at presentation) than will user-defined AIF selections. We will then co-register the MR perfusion (CBF, MTT, and CBV) and XeCT CBF values onto segmented gray and white matter diffusion (traceADC, 11-13 eigenvalues, and fractional anisotropy FA) distributions in these patients. Upon successful completion of these studies, we will have established a number of highly accurate predictive tools for evaluating brain ischemia using MRI by providing a snap-shot of the regional physiological status of evolving infarcts. We believe that this information will lead to new measures for clinical management and will eventually allow management decisions to be made within an individual patient's therapeutic time window as opposed to current conceptions of a rigid time window.

DESCRIPTION (provided by applicant): This proposal is in response to NCRR "HIGH END INSTRUMENTATION PROGRAM (RFA: RR-03-009) to reinforce our investment in improved instrumentation for the advancement of biomedical research in Stanford's interdisciplinary approach. The acquisition of the proposed General Electric "microSigna 7.0" 7T High-Field Small-Bore MR Signa LX scanner will address our needs for a high-end MR experimental scanner to support and drive the research of our community of basic and clinical scientists within the multimodality imaging facility for laboratory animal imaging called the Stanford Center for Innovation in In-vivo Imaging (SCI3). This resource has been successfully established as an integral part of the Medical School and larger Stanford community. The SCI3 is supported by the Stanford NCRR P41 (Glover, PI), the Stanford NCI Small Animal Imaging Research Proposal (SAIRP, Contag, Moseley, Co-PI's), and the newly-created Molecular Imaging Program at Stanford (MIPS, Gambhir, PI). The advanced MR scanner to be acquired will together with our microPET, microCT, and microSPECT platforms permit us to better monitor both structural and functional changes in small animal models non-invasively and in real-time. State of the art MR imaging within the SCI3 is necessary to enhance detection sensitivity and resolution; our strong MR-oriented faculty within the P41 will help develop new MR adaptations to support a growing number of crucial biomedical experimental studies now being done on our 1.5T and 3T whole-body GE Signa LX scanners. The acquisition of this new high-field, small bore (310mm bore) experimental scanner that brings the best in clinical consoles (the LX 11, EXCITE2, 8-channel multi-coil platform) and all GE and Stanford-derived LX pulse sequences together with a new design in high-speed gradients (25cm, 500mT/m) with 8-channel multi-coil RF arrays will greatly enhance our MR program at Stanford by providing a route for translational research from the top down, that is, by bringing all the powerful scanning tools available on clinical research scanners to our routine-to-advanced animal MR scanning. The result will be improved imaging technologies that push the limits of currently available bioimaging MR methods combined with the easy-to-use yet powerful LX console that will greatly facilitate the introduction of researchers and young investigators to state-of-the-art MR imaging, and also support a strong multi-modality Stanford Center for Innovation in In-vivo Imaging (SCI3).

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With National Science Foundation support, Drs. Charles Stanish, Michael Moseley, Ryan Williams, and an international team of scholars will conduct an archaeological survey between the coast and highlands of southern Peru. The team is constituted of U.S. and Peruvian researchers with expertise in archaeology, ethnohistory, and GIS who will assess the nature of trade and exchange in the earliest Andean states. The survey will examine the little known region between the best-documented colony of the ancient Tiwanaku state in Moquegua, Peru and its capital in the Titicaca Basin of Bolivia. This 250 kilometer zone crosses some of the most rugged terrain in the Americas, climbing over 5000 meters in elevation. The research will focus on how ancient states maintained trade routes with far flung outposts in the period between 500 and 1000 AD when these polities first emerged. It will also be poised to compare investments in state infrastructure like roads and way stations from the early state period with the better-known Inca empire as well as preceding cultural groups like Pukara and the archaic hunter-gatherers.

The team will conduct full-scale archaeological survey around two areas with extensive pasture resources and at historical crossroads. They will also survey extensive portions of paths detected from aerial imagery to identify settlements and features that date their use. Their goal is to determine whether formal roads and way stations were part of the earliest state infrastructure, or if only informal paths connecting dispersed settlements was the norm during the Tiwanaku Period. The results of the survey will tell us how the earliest archaic states managed to expand beyond their heartlands and how they maintained connections with distant colonies over the course of hundreds of years.

The research program will yield new insights into the ties that bind colonial enterprises to their heartlands. It innovates a new methodology that uses computer models and geographic network analysis to survey large archaeological regions. The intellectual merit of the program will thus enable researchers to examine how archaic states integrate their territories and maintain the flow of goods and services over long distances.

The broader impacts of the study include fostering international collaboration between U.S. and Peruvian scholars, training students from both countries, and building scientific understanding through museums and public outreach in both nations. It will focus on a poorly understood area in the highlands of Peru that may yield many new research programs and questions to be answered. It will also help us to better understand the relationship between large-scale human societies and their impacts on environment.

DESCRIPTION (provided by applicant): The recanalization of brain following ischemic stroke is the best means of recovering brain. However, restoration of flow is often accompanied by brain injury and tissue death. A reliable depiction of restoration of flow together with salvageable brain is of clinical significance. Imaging with MRI offers diagnostically useful depictions of stroke injury from T2, DWI, and perfusion imaging. However, we need improved methods of perfusion in order to best map and differentiate flow from tissue status. The clinical hypothesis that reperfusion of brain is a process of restoration of flow in the time window of salvaging brain, and being able to depict both aspects of that reperfusion process are crucial to the hundreds of reperfusion procedures done daily worldwide. The overall goal of this new submission is to identify and improve cerebral blood flow (CBF) techniques from dynamic susceptibility contrast (DSC) perfusion-weighted MRI (PWI) methods that can depict both restoration of flow together with the microvascular status that would optimally compare with DWI to form a clinically useful DWI-PWI mismatch representing brain tissue-at-risk or salvageable brain. To do this, we will assess the value of mapping perfusion with a gradient- echo (GRE) and a spin-echo (SE) signal acquired together in a multi-shot, multi- echo, and DSC first-pass bolus contrast agent MRI technique. The perfusion maps will be compared with a gold-standard xenon CT (xeCT) value of CBF. We aim to show equivalence between GRE- and SE-DSC to the gold-standard in order to visualize vascular and microvascular status in 120 stroke patients having had recanalization procedures. We will obtain T1, T2, T2*, diffusion-weighted imaging (DWI), and bolus PWI in 120 patients presenting at 6-48 hours following reperfusion and obtain a second follow-up study at 30 days as a measure of tissue outcome together with clinical assessments. We believe successful attainment of these aims promises to markedly improve acute stroke care by validating a MRI-based perfusion methods sensitive to both vascular status and tissue microvascular status. This study will lead to better understanding of mapping flow and microvascular status in patients with severe cerebrovascular disease and greatly enhance the already significant diagnostic power of MRI in acute ischemic stroke by better mapping metabolic- perfusion mismatches after reperfusion. PUBLIC HEALTH RELEVANCE: In the early hours following large vessel occlusion, the ultimate severity of the stroke will be greatly determined by how long the occlusion has gone on and how soon the vessels can be opened and flow restored to the brain. One question however, is how to depict the regions of the brain suffering from the stroke that will be recovered by restoration of flow and which parts will eventually die. This proposal assesses whether a rapid means of acquiring blood flow data from MRI can accurately and reliably measure the blood flow in various parts of the brain and whether this MR method can see recoverable brain from regions of the brain destined to die. The do this, we will compare various MRI methods of mapping blood flow with known standards in radiology. These MRI-based methods use an injected contrast agent that can give maps of blood flow, blood volume, transit time of the blood, arrival times of the blood flow and other measures of vascular status. They can also depict flow that is sensitive to all vessels including the larger feeding arteries to the stroked region as well as the small capillary beds necessary for delivering oxygen to the brain tissue. We will include 120 stroke patients into this study that have had reperfusion procedures done within a time window of 6 to 48 hours. For all patients, we will validate the MRI cerebral blood flow measurements using a gold-standard, stable xenon-enhanced CT exam. Successful completion of this project will lead to better understanding of how well MRI can measure blood flow and which MRI measurement will give us the best view of brain regions that have had flow restored after recanalization (or reperfusion) and which regions are likely to die even after restoration of flow. This will greatly enhance the already significant diagnostic power of MRI in acute ischemic stroke.

DESCRIPTION (provided by applicant): This proposal is in response to the NCRR "SHARED INSTRUMENTATION PROGRAM S10" (RFA: PAR-09- 028) to reinforce our investment in improved instrumentation for the advancement of biomedical research in Stanford's interdisciplinary programs. Translational biomedical research is of the utmost importance today and with the rapid advances in molecular medicine and stem cells, plays a vital role in the relevance to public health. We are requesting funds for an upgrade of our General Electric Healthcare "MicroSigna" 7 Tesla/310mm animal MRI scanner to the recently-announced GE-Varian product, the MR901. The Stanford 7T MicroSigna was purchased in 2005 from a funded NCRR NIH High-End Shared Instrumentation Grant (1 S10 RR019887-01) entitled "High Field GE Experimental MR Scanner". The existing MicroSigna 7T purchased from the S10 mechanism was in essence a commercial prototype of the now product MR901. The acquisition of the proposed General Electric-Varian MR901 7Tesla High-Field Small-Bore MR scanner upgrade will complete our needs for an MR experimental scanner to support and drive the research of our community of basic and clinical scientists within the multimodality imaging facility, the Stanford Small Animal Imaging Center (SAIC). The SAIC is supported by the Stanford NCRR P41 (Glover, PI), the Stanford Molecular Imaging Program at Stanford (MIPS, Contag, PI), and the Stanford In Vivo Cellular and Molecular Imaging Center (ICMIC, Gambhir, PI). The MR upgrade to be acquired will permit us to better monitor both structural and functional changes in small animal models non-invasively. State of the art MR imaging within the SAIC is necessary to enhance detection sensitivity and resolution;our strong MR-oriented faculty within the P41 has helped us develop new MR applications to support a growing number of crucial biomedical experimental studies now being done on our 3T and 7T whole-body GE Signa LX scanners. The acquisition of this new experimental scanner upgrade will bring the best in clinical consoles (the Signa HDx 20x, multi-coil platform) and all Stanford-derived Signa pulse sequences together into the recently announced GE-Varian MR901 MR scanner commercial product line. The current GE 7T animal scanner (the "MicroSigna") has no doubt enhanced our MR program at Stanford by providing a route for translational research from the top down, that is, by bringing all the MR tools available on clinical research scanners to our routine animal scanning. The upgrade is needed to further improve our imaging technology and bring our MR scanner to a product fully supported by GE and Varian and thus greatly facilitate the introduction of researchers and young investigators to state-of-the-art MR imaging, and also support a strong multi-modality Stanford Small Animal Imaging Facility (SAIC). PUBLIC HEALTH RELEVANCE: This proposal seeks the acquisition of the General Electric-Varian MR901 7Tesla High-Field Small-Bore MR scanner upgrade for the Stanford Small Animal Imaging Facility (SAIC) and the Stanford research community. The current GE 7T animal scanner (the "MicroSigna") housed within the SAIC, while having allowed our many major and minor groups to initiate MR research programs, is limited by several factors which this upgrade will address. The MRI scanner and gradient coil upgrade will permit us to better monitor both structural and functional changes in our various experimental models non-invasively. The upgrade will also bring our MRI scanner to the current commercial product potential necessary for any and all future enhancements. State of the art MR imaging at Stanford is necessary to enhance detection sensitivity and resolution over what we can achieve today on our present system.

? DESCRIPTION (provided by applicant): The main disadvantage of MRI is its long scan time, taking up to one hour at our institution. For children, MRI can be particularly frightening because of long scan times within a noisy and confined space that can increase anxiety and risk of motion artifacts in the acquired images. In cases of excessive motion, MRI sequences are often repeated, further increasing scan time, or requiring patient revisit to the MRI suite. Alternativel, general anesthesia (GA) is used - which reduces the overall patient comfort, safety, throughput, and adding to the cost of care. As a result of these major issues, there is an immediate need for a fast MRI protocol that parallels the diagnostic capacity of the standard MRI. The methods here will overcome a set of well-known problems with the use of fast imaging using Echo Planar Imaging (EPI) through the use of a family of `short axis EPI' motion-correctable MRI methods. The 5minute exam we will develop based on these methods will reduce the scan failure rate through a rapid non-sedated brain exam with high diagnostic quality - potentially leading to detecting abnormalities in patients who otherwise cannot be reliably scanned with MRI. By obviating the need for patient sedation, improving patient comfort and reducing the scan time by up to 35min per patient, we propose to dramatically increase patient throughput, comfort, reduce scan failure rate, and the cost of healthcare.