Chunlei Liu, Ph.D. - US grants

Diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI) are important magnetic resonance imaging (MRI) tools with significant clinical utility. However, current available spatial resolution for DWI is typically around 2mm per pixel, which is substantially lower than the submilimeter resolution of anatomical MRI. Such low spatial resolution severely limits the ability of diffusion MRI in investigating white matter structure and integrity, for example. Ultra high field strengths and emerging applications of DWI and DTI in pediatric neuroimaging, small animal neuroimaging, surgical planning and neural fiber tractography have created a strong demand for 1) higher image spatial resolution and 2) larger number of diffusion gradient directions. The overall goal of this proposal is to develop and refine advanced image formation techniques and novel diffusion analysis models. Towards this end, we propose to employ an array of novel techniques including motion navigated multi-shot sequences, parallel imaging with multiple coils, at high (3T) and ultra high magnetic field strengths (7T). Inherent advantages are that multi-shot sequences allow for improved data acquistion schemes with better SNR and reduced artifacts, which also alleviates the problem of rapid signal decay;parallel imaging provides a method for shortening the total scan time and further reducing image artifacts, while ultra high field offers stronger SNR and T2* sensitivity at the expense of potential artifacts. Although the synergy of these techniques holds great potential for high resolution DWI and DTI, many technical challenges remain. The specific aims of this research are to meet these challenges by: 1) developing multi-shot DW sequences with efficient volumetric imaging with 3D motion navigation and;2) developing multi-shot parallel imaging acquistion techniques and fast image reconstruction algorithms that can efficiently and rapidly post-process thousands of images in a clinical setting, and finally;3) measuring higher order diffusion tensor parameters to resolve multi-modal white matter structures. These advanced techniques will not only allow better visualization and quantitation of in vivo water proton diffusion processes on the scale of a few hundred microns, but will also significantly improve the quality and speed of the image acquistions. These techniques will eventually result better diagnostic potential for diffusion-weighted images, and, ultimately, more accurate quantification of complex tissue diffusion properties.

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. We are interested in imaging and quantifying the constrast generated by suceptibility variations in the mouse brain at high magnetic field. The work is based on the observations by Duyn et al that cytoarchitectural details of the brain can become much more apparent in phase contrast images than with more traditional contrast metrics (e.g. T1,T2, diffusion) . We believe this is a fundamentally enabling project that will allow extension into many different areas. The project has several different phases: Phase 1: We will establish the method for phase contrast imaging based upon work done previously at the Lucas Center (Stanford). This will involve measuring and correcting for Bo inhomogenities in the 7T MR system and measuring and correcting for B1 inhomogenoty of the M2M 35 mm quadrature coil. Phase 2: We will image live C57BL/6J mice using a 3D implementation of the phase contrast method at spatial resolution of <100 microns. We will compare the contrast seen in specific regions of the brain to more traditional imaging protocols (SPGR, FSE, and FIESTA) Phase 3: We will export the method to the 9.4T system to allow imaging of perfusion fixed brains at 21 microns where distribution of the active stain (ProHance) may provide more dramatic phase contrast. Phase 4: We will look toward to possibility of detecting small concentrations of SPIO contrast agent[unreadable]initally in phantoms to determine the potential sensitivity enhancement for molecular imaging.

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. Sepsis is a potentially life-threatening condition, in which immune system's reaction to an infection may injure body tissues far from the original infection. Neonatal sepsis is particularly dangerous in very low birth weight (VLBW) infants. Studies have shown that about 21% of VLBW infants who survied beyond 3 days have blood culture proven late-onset sepsis. Even if the infant survives, the adverse effect of sepsis can be long lasting, resulting in abnormal brain development. However, accurate early diagnosis in the neonates is difficult because there is no definitive diagnostic test;even blood cultures have an unacceptably low sensitivity. Therefore, the clinician must accept that a number of neonates will have treatment initiated for sepsis who do not have the disease. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection, improved technology is needed for detecting the onset of sepsis and studying its long-term effect on development. This pilot project will test and idetify MRI based methods for detecting brain injuries caused by stool infection using a newly developed mouse model. Aim 1: we will quantify changes in myelination caused by sepsis using high-resolution quantitative susceptibility imaging. Aim 2: we will quantify degradations in white-matter integrity and connectivity with high-resolution diffusion tensor imaging. The project will evaluate two promissing MRI methods for the early diagnosis of white matter injuries caused by neonatal sepsis. Successful early dedection of infection allows early intervention and prevents potential damages to neural development.

DESCRIPTION (provided by applicant): One in four adult Americans experiences a mental health disorder in a given year. About 2.4 million Americans live with schizophrenia. There are considerable and growing evidences suggesting schizophrenia may originate from early neurodevelopment involving abnormal neuronal circuits. However, schizophrenia still cannot be diagnosed until young adulthood at the earliest when the most rapid phase of neurodevelopment has already completed. The lack of earlier risk assessment has severely limited our understanding of the developmental trajectory of the disease thus preventing more effective intervention before symptom onset. This project will develop a novel non-invasive MRI technique that will provide the necessary sensitivity and resolution (10 micron) to detect potential developmental abnormalities associated with neuronal circuits. Our preliminary studies have demonstrated a markedly improved sensitivity and resolution compared to state-of- the-art MRI techniques. We will further develop this novel technique and determine its molecular basis of the improved sensitivity. We will test the technique on transgenic mouse models of schizophrenia and investigate its ability to detect abnormalities in neuronal circuits before symptoms occur. In particular, we will determine the relationship between the new image contrast and abnormalities of myelination and synapses associated with corticostriatal and corticohippocampal connectivity. The rationale of the research is that the proposed multidisciplinary imaging-genetics study would help us to better understand the genetic and developmental components of the disease, to detect circuit abnormalities before behavioral symptoms, and to eventually guide treatment strategies.

? 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.

DESCRIPTION (provided by applicant): The objective of the International Workshop on MRI Phase Contrast and Quantitative Susceptibility Mapping (QSM) is to provide a forum for researchers and clinicians interested in MRI signal phase and QSM. Magnetic susceptibility is a physical property that reflects how a substance changes the magnetic field. Magnetic susceptibility of tissue has recently been shown to be affected by organ function, disease state, and intervention. Until very recently, susceptibility has been primarily treated as a source of image artifacts and has not been systematically explored as tissue contrast in MRI. Several recent breakthroughs in reconstructing tissue phase and susceptibility have started to change the status quo. For example, phase contrast has revealed unprecedented spatial details of brain anatomy in vivo. QSM is enabling noninvasive and in vivo measurements of oxygen saturation and iron deposition in stroke, multiple sclerosis, Parkinson's and Alzheimer's diseases, and other neurological disorders and diseases. Further, QSM offers a new contrast mechanism for studying properties of nerve bundles including myelination and fiber tract orientation. Following these findings, there has been an exploding interest in phase and QSM from the MRI, diagnostic Radiology and Neuroscience communities. Given this rapid growth, there is a pressing need to facilitate the education and dissemination of knowledge and conduct a dialogue of unmet needs and future directions. We plan to meet this demand through the following three specific aims: 1) to bring together scientists from varied backgrounds including physics, engineering, biology and medicine to promote cross-fertilization of ideas on technical developments and clinical applications and to identify and emphasize the methodologies that bear the potential to innovate QSM technology and its future clinical uses; 2) to foster collaborative relationships among researchers from multi-centers to critically evaluate existing phase and QSM technology and assess unresolved issues and unmet needs; 3) to educate young scientists (trainees and junior investigators) and scientists from different backgrounds on the fundamentals and state-of-the-art of MRI phase and QSM technology. The proposed QSM workshop will facilitate the education, innovation and translational applications of an emerging medical imaging technology.

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic and disabling disease. Worldwide, there are over 2.5 million people suffering from it, with more than 400,000 in the US alone. Although there is no known cure for MS, there are therapies that can effectively slow down the disease. These therapeutic regimens mainly aim to control symptoms and prevent further damages. For this strategy to be effective, we need to diagnose the disease early and characterize it accurately. However, at its early stage, MS is difficult to diagnose as is symptoms can mimic those of many other nervous system disorders. In the past decade, the use of brain and spinal MRI has greatly improved the diagnostic accuracy. However, it has also become increasingly clear that current clinical MRI protocols show only part of MS pathology, failing to reveal important changes occurring at the microscopic level. Furthermore, it is now recognized that standard MRI protocols do not reflect the severity of clinical symptoms. For example, we often see no change in MR findings even though clinical worsening has occurred. At the same time, clinical trials and emerging treatments are focusing increasingly on prevention of CNS injury and promotion of recovery from damages already occurred. Therefore, there is an urgent need for improved diagnostic and prognostic imaging tools that can evaluate the disease status more accurately. The hallmark of MS is loss of myelin which protects the axons and facilitates the transmission of nerve signals. Recent studies suggested that myelin has a unique magnetic susceptibility that can be measured by MRI. This unique magnetic property reduces the rate of MRI signal decay (R2*) and causes a positive frequency shift when demyelination occurs. If this magnetic property can be quantified accurately, it can be used as a powerful marker to initiate early treatment and to monitor treatment outcome. We are developing novel, accurate and clinical feasible techniques to image and quantify tissue magnetic susceptibility with high spatial resolution. In the proposed project, we will further develop and optimize this novel technique; we will determine the relationship between susceptibility and MS pathology; we will characterize susceptibility properties of MS brains in lesions and normal appearing white matter and gray matter; we will determine if susceptibility can be used as a marker for predicting disease progression and clinical disability. The expected outcome will facilitate the translation o this novel technique to the clinical management of MS. In addition to MS, the technique has a broad applicability in the imaging of many other neurological diseases and disorders.

DESCRIPTION (provided by applicant): One in every four deaths in the US is caused by heart disease. Heart disease is the leading cause of death for both men and women and for people of most ethnicities including African Americans, Hispanics and Whites. Besides common preventive measures, detecting early signs of cardiac abnormalities is the key for preventing death caused by heart disease. While we have a range of non-invasive MRI techniques to detect brain abnormalities, techniques for imaging the heart are still underdeveloped and often inadequate. In particular, it has been extremely challenging, if not entirely impossible, to image and track myocardial fibers in vivo. Myocardial fiber forms a unique helical spiral from base to apex of the heart. This structure is a key determinant of the mechanical and electric properties of the myocardium. While diffusion tensor imaging (DTI) has been the only technique that allows the mapping of myocardial fibers non-invasively, it has been applied primarily ex vivo. In vivo DTI of live human hearts has been only performed in a limited few studies. There are currently no clinically accepted techniques for imaging and tracking the myocardial fibers. The objective of this application is to develop and validate a radically new way to image myocardial fibers in vivo based on the technique of susceptibility tensor imaging (STI) and tractography. STI measures the interaction between magnetic fields and myocardium. It utilizes this interaction to quantify tissue property and reconstruct fiber structures. The proposed technique is fast, high resolution, non-invasive and quantitative. If successful, STI will allow the routine examination of the microstructure and connectivity of myocardium with high spatial details. It will fill in a majo gap in our capability to evaluate the myocardial conditions of both healthy and diseased hearts.

Iron concentration in deep gray matter (DGM) regions is associated with neurodegenerative disease, but DGM iron also increases with adult age, in the absence of disease. Previous studies have reported association between age-related DGM iron accumulation and decline in some aspects of neurocognitive function. However, previous studies have typically focused on a limited number of neurocognitive outcome measures, often biased towards motor functioning, and have relied on less than optimal MRI methods to estimate iron concentration, such as MRI relaxometry. Further, although decline in structural and functional brain connectivity appears to contribute to neurocognitive decline in healthy aging, the role of iron in this decline is not clear. In this project we test a model of the influence of age-related DGM iron accumulation on neurocognitive function, proposing that age-related DGM iron contributes to oxidative stress and consequently to a decline in network connectivity. The research will investigate the effects of DGM iron using Quantitative Susceptibility Mapping (QSM), a novel and validated technique that has several advantages over previous methods for estimating GM iron (e.g., relaxometry). This research comprises imaging and neurocognitive testing of 270 healthy, community-dwelling individuals, with 45 individuals in each of six age decades: 20s, 30s, 40s, 50s, 60s, and 70s. The participants in their 60s and 70s will be tested at two time points, approximately 3 years apart. Aim 1 will test the hypothesis that iron in the head of the caudate will have a greater mediating or moderating influence, on the relation between age and the neurocognitive measures, relative to other DGM regions, and that this influence will extend to measures of the efficiency of decision processes (drift rate). Aim 2 will test the hypothesis that age-related increase in DGM iron, particularly in the head of the caudate, influences structural and functional connectivity in a serial manner, with regionally specific associations among DGM iron, the white matter (WM) integrity of frontostriatal circuits, and the functional connectivity of associated resting-state networks (RSNs). Aim 3 will test the hypothesis that the age-related influences of DGM iron identified in Aims 1 and 2, in cross-sectional analyses, can be confirmed longitudinally, across a three-year interval. The project will consequently contribute to a more comprehensive theoretical model, than presently available, of the influence of DGM iron on the relation between age and neurocognitive performance. The findings will also be relevant to assessing the potential role of DGM iron as a biomarker of neurodegenerative disease.

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.

Abstract Magnetogenetics is a recently proposed method for stimulating cells using electromagnetic fields. In one approach, radio-frequency (RF) electromagnetic fields are applied to stimulate membrane channel proteins such as TRPV1 and TRPV4 that are attached to ferritins. The concept is highly attractive as it enables wireless neural stimulation without limitation on penetration depth or the requirement of invasive surgeries. If successful, RF- based magnetogenetics can provide a non-invasive approach for large-scale neural stimulation that can reach anywhere in the brain and achieve cellular specificity. This capability overcomes a significant limitation in other techniques such as electrical stimulation and optogenetics where stimulation is spatially restricted. However, while there have been several independent reports of experimental evidences for magnetogenetic effects using RF waves, the physical and neurobiological underpinnings of such effects remain unclear and controversial. Reported experiments have been conducted only in a few selected frequencies and amplitudes and the responses were mostly measured indirectly based on downstream physiological effects. The objective of the proposed project is to systematically characterize, model and validate the neurobiological and cellular responses upon RF stimulation in neurons expressing ferritin-attached TRPV1 and TRPV4 channels. Specifically, we aim to characterize these magnetogenetic channels of their: 1) neuronal responses to electrical and chemical stimuli and to RF stimulation over a wide range of frequencies and amplitudes; 2) temperature responses to RF stimulation at the protein, cytoplasmic membrane and cellular level; 3) cellular metabolic processes upon RF stimulation. We will systematically evaluate two novel working hypotheses of the underlying mechanisms. If successful, the project will characterize the cellular responses to RF stimulation, quantify activation thresholds and safety limits, establish standard protocols and elucidate the biophysical underpinnings of this reported RF- based magnetogenetic phenomenon. It would resolve a fundamental challenge in advancing this technology and guide a more rationale design and improvement of the techniques. Understanding the mechanisms of the initial reports of magnetogenetics would be a significant addition to the present ensemble of neuro-stimulation technologies such as electrical stimulation and optogenetics and contribute to one central goal of the BRAIN Initiative that is to develop new and improved perturbation technologies suitable for controlling specified cell types and circuits to modulate function in the central nervous system.

Abstract The ability to noninvasively modulate and image the brain with spatial and temporal precision is highly desirable for understanding brain circuits in health and disease. Transcranial magnetic stimulation (TMS) is a method for stimulating the superficial cortex with high spatial and temporal precision, and its effects can be aimed at deeper targets by leveraging the trans-synaptic connectivity of brain circuits. Functional magnetic resonance imaging (fMRI) has high spatial resolution but limited temporal precision, and the opposite holds for electroencephalography (EEG). These three noninvasive electromagnetic methods have recently been combined to achieve high spatial and temporal precision of concurrent modulation and imaging of the brain. This approach, however, has various significant technical limitations, including mutual electromagnetic artifacts decreasing the signal-to-noise ratio and delaying the acquisition of imaging/EEG data, TMS acoustic noise co- activating auditory pathways, and the inability to adaptively adjust the TMS coil position within the MRI scanner for optimal targeting. The overarching objective of this project is to address these limitations by developing and integrating an array of novel technologies. We will develop a compact, energy efficient, quiet, as well as MRI- and EEG-compatible TMS coil. The TMS coil will be actuated with a custom MRI-compatible robotic system, allowing adaptive optimization of the coil position and orientation based on imaging feedback. The neural circuit responses to the stimulation will be imaged with a newly developed a flexible, head-conforming array of MRI coils combining local magnetic field shimming and RF receiving to achieve high signal-to-noise ratio and fast image acquisition. The brain activity will be simultaneously recorded both before and after TMS with high temporal resolution and low noise using a novel wireless EEG system. To meet the technical challenges of creating such as a system operating inside MRI scanners, our team has developed several breakthrough technologies that will work synergistically to reduce or eliminate couplings between system components and enhance the stimulation precision and imaging speed and sensitivity. Once developed, the robotically-actuated TMS-EEG-fMRI system will enable systematic interrogation of human brain circuits inside an MRI scanner with spatial and temporal flexibility and precision that are impossible to achieve with current technology. The integrated system will be easy-to-use, and platform-agonistic thus having the potential for immediate and scalable impact. First-time adaptive optimization of the TMS coil placement in the MRI scanner will be demonstrated for brain-state-triggered engagement of a deep brain target. In summary, the proposed robotically- actuated TMS-EEG-fMRI system will enable modulation and imaging of brain circuits with enhanced anatomical and functional precision that can lead to advances in neuroscience research and therapeutic interventions.

Abstract Alzheimer?s disease (AD) affects over 5 million Americans and is expected to affect 2-3-fold more in the next few decades. AD is associated with aggregation of amyloid-beta (Ab) and phosphorylated tau proteins. Curiously, burden of A?, classically considered the most important AD pathological hallmark is not enough to indicate clinical decline or progression. For example, cognitive-normal elders may also carry high levels of A? and recent clinical trials aiming to reduce A? have generally failed to improve patients? conditions. Therefore, developing biomarkers that can better predict clinical outcome and progression are needed. Confluent evidence shows that regional brain magnetic susceptibility measured by MRI differs between AD patients and healthy controls, and importantly such changes may predict cognitive decline. However, it is unclear what causes these susceptibility changes in AD. While iron deposition has been widely suspected as the underlying cause, our recent study has discovered that aggregation of Ab and tau by itself produces strong diamagnetic susceptibility, opposite of the paramagnetic susceptibility generated by iron deposition. The opposing magnetic susceptibility of iron and aggregated pathological proteins poses a significant challenge as current MRI-based magnetic susceptibility mapping algorithms cannot differentiate iron from other colocalizing diamagnetic susceptibility sources within the same voxel. Our goal is to develop a novel technique that can differentially quantify molecular sources of magnetic susceptibility and test whether the resulting susceptibility components can serve as markers of progressive AD pathology. We will test our techniques and hypothesis utilizing a unique capability that combines in cranio MRI at autopsy with histological examinations. We have developed innovative histological processing methods that allow voxel-to-voxel matching between MRI and histology in 3D, thus permitting the examination of the relationship between magnetic susceptibility components and the neuropathology underlying AD. If successful, our techniques and findings might ultimately allow the detection of AD-related neuropathology at much earlier stages, permit intervention before neurons become irretrievably damaged and non-invasively assess disease progression. These techniques, once standardized, will be highly cost-effective, widely accessible and readily implementable in non-specialized clinical imaging centers, thus better serving the growing population of AD patients.

Abstract Magnetic resonance imaging (MRI) is an indispensable non-invasive imaging technology for diagnostic medicine and basic research. Today?s MRI assumes single-photon excitation. More specifically, for each nuclear spin, a single photon accompanies the transition between energy states which creates MRI signal. This photon must resonate near the Larmor frequency. The goal of this project is to explore and develop an entire new class of MRI that utilizes multiphoton excitation. That is, instead of the usual single-photon resonance, the proposed technique can excite multiphoton resonances to generate signal for MRI by using multiple magnetic field frequencies, none of which are near the Larmor frequency. Only the total energy absorbed by a spin must correspond to the Larmor frequency. Multiphoton MRI is a radical new way to perform MRI. It introduces new flexibilities for excitation, encoding, contrast generation and reception. The project will explore and develop the essential hardware, pulse sequences, excitation and receiving techniques for clinically feasible multiphoton MRI. If successful, multiphoton MRI will pave the road for many new avenues to generate novel MRI images and benefit human health.