Transformative low-cost "purpose-built" MRI systems for brain imaging

Magnetic resonance imaging (MRI) is a powerful non-invasive technology that provides a unique window to the structure and the function of the body, with high resolution, speed, and biological contrast. For the brain, MRI provides the undisputed standard of care for the diagnosis and monitoring of neurological disorders and injuries including traumatic brain injury (TBI). MRI is not widely deployable because high-strength magnetic fields (of order 1 T) are necessary to obtain useful brain images. These systems involve large, heavy, fragile, and expensive equipment (such as superconducting magnets) that is incompatible with operation in field hospitals and other forward sites, and as a result high-field MRI instruments offer limited utility for imaging in these contexts. We contend that non-cryogenic low-magnetic-field implementations of MRI can be developed to allow robust, transportable imaging modalities well suited to diagnose the types of injuries prevalent in TBI, and practical for field operation.

We have been leading a program to develop tools and techniques for low-magnetic-field implementations of MRI focused on brain imaging. This program has been rethinking conventional approaches to MRI scanner construction, and thus far has shown potential to create transformative non-cyrogenic low-field deployable MRI scanners with high diagnostic impact and low power and siting requirements. These scanners, by their ubiquity, will lead to entirely new ways of informing and practicing field/forward medicine. Our research program develops tools and techniques to revolutionize conventional MRI scanner construction and create transformative and widely deployable low-field scanners with high diagnostic impact. The potential ubiquity of these inexpensive instruments would democratize MRI, and lead to entirely new ways of informing and practicing medicine. Toward this goal, the LFI is now a “high-performance” low-field scanner and challenges the presuppositions about what is indeed possible at low field. Our recent results at 6.5 mT have demonstrated heretofore unattainable speed and resolution, and result from a program of advanced hardware and high efficiency pulse sequence development combined with state of the art undersampling and compressed sensing techniques. This work has established a proof of principle of high performance, robust, and potentially clinically relevant techniques and technologies, and opens up doors to transformational and revolutionary robust applications of MRI.

Advanced compute-based methods for quantitative image acquisition and reconstruction

The availability of inexpensive GPU-based compute has opened the door to new quantitative model-based strategies for the acquisition and the reconstruction of highly-undersampled imaging data. We have been developing neural network deep learning based approaches such as AUTOMAP and other DRNs to leverage scalable-compute and signficiantly deburden the need for precision hardware.

Nanodiamond-enhanced MRI using in situ Overhauser hyperpolarization

Nanodiamonds are of interest as nontoxic substrates for targeted drug delivery and as highly biostable fluorescent markers for cellular tracking. Beyond optical techniques, however, options for noninvasive imaging of nanodiamonds in vivo are severely limited. We have demonstrated that the Overhauser effect, a proton–electron polarization transfer technique, can enable high-contrast magnetic resonance imaging (MRI) of nanodiamonds in water at room temperature and ultra-low magnetic field. The technique transfers spin polarization from paramagnetic impurities at nanodiamond surfaces to 1H spins in the surrounding water solution, creating MRI contrast on-demand. We examine the conditions required for maximum enhancement as well as the ultimate sensitivity of the technique. The ability to perform continuous in situ hyperpolarization via the Overhauser mechanism, in combination with the excellent in vivo stability of nanodiamond, raises the possibility of performing noninvasive in vivo tracking of nanodiamond over indefinitely long periods of time.

Molecular imaging using continuous SABRE induced hyperpolarization

Current hyperpolarized imaging with dissolution DNP and superconducting MRI scanners is very powerful because of its unique ability to track chemical transformations in vivo. However, the experiments are relatively cumbersome, slow and expensive. We have been working in collaboration with Warren Warren and Thomas Theis at Duke to develop a milliTesla (mT) approach to hyperpolarized MRI that is simple, fast, and attaiable at modest cost with high sensitivity. In addition, the mT approach promises biomolecular imaging of more biological processes by taking advantage of significantly extended relaxation times attainable at ultra-low fields.

We have combined low-cost, ULF MRI with parahydrogen based hyperpolarization. Specifically, we combine our 6.5 mT ULF MRI scanner with SABRE (Signal Amplification By Reversible Exchange) which hyperpolarizes substrates directly in room temperature liquids. SABRE uses an Iridium based catalyst which reversibly binds parahydrogen and substrate to enable hyperpolarization transfer. This process allows for continuous re-hyperpolarization of substrates even after detection.SABRE hyperpolarization is optimized at 6.5 mT because of nuclear spin energy level mixing of parahydrogen derived hydrides and substrate protons at exactly this field. Our initial experiemnts in this realm are compelling: SABRE enhacements of 1,650,000-fold of a 100 mM pyridine solution compared to thermal (at 6.5 mT) are easily attainable!

New MRI methods for "injury imaging"—MRI of free radicals

We have recently demonstrated a a high-resolution approach for imaging free radicals with low field MRI that offers new perspectives for the non-invasive measurement of free radicals in living organisms: free radical sensitive Overhauser-enhanced MRI (OMRI). An in vivo implementation in which endogenous free-radical injury markers provide an unambiguous non-invasive marker for ischemia reperfusion injury has potential to transform the field of hyperacute stroke and transient ischemic attack diagnosis and management, and clarify the mechanisms involved in reperfusion injury and the local effects of novel therapies.

Similarly, free radical imaging may transform diagnosis and treatment of secondary injury following TBI. The use of technology in vivo has the potential to become a powerful tool to obtain pathophysiologic insight into the spatiotemporal kinetics of free radical generation following brain injury, monitor the impact of therapies directed to alleviate free radical-mediated cell damage, and ultimately aid in clinical evaluation and treatment of acute TBI. Indeed, timely and non-invasive tomographic detection of free radical production and oxidative stress can guide therapeutic interventions to be tailored for each patient.

Hyperpolarization and Spin-exchange physics

Ultra-low field MRI is made practical by the process of noble gas "hyperpolarization". In this laser optical pumping process, the NMR signal of noble gases such as 3He and 129Xe can be increased by four to five orders of magnitude by increasing the atoms' nuclear spin polarization. This field of research continues to be of great importance as NMR and MRI applications for spin-polarized noble gases are myriad. Research by investigators outside the small community of spin-physicists has, however, been critically hampered by an almost complete lack of access to polarized gas by the community of end users. As a way to tackle this problem, our group is part of a multi-institution collaboration (Brigham and Women’s Hospital, Harvard, SIU Carbondale, University of Nottingham, and Vanderbilt) to further improve the performance and to aid in the dissemination of noble gas polarizers. Our Consortium has constructed a large-scale (>1 L/hr) 129Xe polarizer for clinical, pre-clinical, and materials NMR/MRI applications and attained near-unity nuclear polarization with it. Comprised of mostly off-the-shelf components, our automated, modular polarizer is easy to use and employs a simplified “open-source” design, readily implementable in other laboratories. This first “consortium polarizer” is installed at BWH and collaborators there are using it to acquire images on clinical scanners, including measurements of human pulmonary septal thickness in vivo.

Of present interest are experimental aspects of clinical-scale production of hyperpolarized (HP) xenon by stopped-flow SEOP,3,4 specifically SEOP cell design (including the use of alternative materials, coatings, and geometries), laser technology, and ultra-low field versus high-field polarimetry of 129Xe and 131Xe.

Long lived nuclear singlet states as a new contrast mechanism in NMR and MRI

In collaboration with Ron Walsworth's group at Harvard, have been investigating novel and efficient ways to create and manipulate nuclear-spin singlet states and related dressed states in naturally-occurring molecules as powerful tools for nuclear NMR spectroscopy and MRI. Such novel spin states have wide applicability in chemistry, physics, biology, and materials science, e.g., to improve the detection of NMR signals in crowded spectra, to measure and image weak magnetic couplings in molecules, and to perform high-resolution NMR spectroscopy at very low magnetic fields. This work has led to the development of a new quantum filter utilizing nuclear spin singlet states which allows undesired NMR spectral background to be removed and target spectral peaks to be revealed. This new NMR contrast mechanism is named SUCCESS, or “Suppression of Undesired Chemicals using Contrast-Enhancing Singlet States," and has been demonstrated in vitro for three target molecules relevant to neuroscience: aspartate, threonine, and glutamine. We are working to develop SUCCESS into a robust, widely-applicable technique for NMR and MRI, with particular emphasis on brain biomolecules (such as GABA) for application to neurology and neuroscience.

Shot noise limited optical detection of NMR

High-field NMR and MRI systems are noise-limited by the induced voltages in the sample, and not by coil losses or amplifier noise—this is the classic “body noise dominated” regime of high-frequency operation. Although no gains are likely to be had from improving coil Q, or by reducing the coil or amplifier noise temperature in this regime, improved B sensitivity could allow for more flexibility in the placement of the receive sensor for a fixed detection SNR. Compared to a resistive coil, optical shot-noise (not Johnson noise) would fundamentally limit a magnetofluorescence-based sensor. Similarly, consideration of the noise-scaling laws of optical-based detection devices might allow the high filling-factor requirement manifestly engineered into close-fitting MRI probes to be significantly relaxed, culminating in more open geometry detectors, for example an massive array (N>512) of small, high Q, optical sensors around a sample. Potential great gains in SNR and acceleration could be obtained from such a massively parallel detector system. Continued work on this project is ideally suited for a graduate student interested in the overlap of coherent electron spin dynamics, quantum optics, and NMR.

Molecular imaging with OMRI using targeted free-radical probes

NMR relaxation-based targeted probes that recognize important biomarkers of atherosclerosis, apoptosis, necrosis, angiogenesis, thrombosis and inflammation have been developed, and manifest themselves in changes in local relaxation. Once injected and bound this targeted molecular-contrast may not be “turned off”. A new idea that we are working on in collaboration with Peter Caravan’s Molecular Imaging Contrast Agent Lab at the Martinos Center is to leverage the high-resolution and high speed OMRI attainable in the LFI with TEMPOL towards a new paradigm of molecular imaging, one based on hyperpolarized radical-based injected targeted agents, where the hyperpolarization is done via in vivo DNP at low field. Unlike relaxation-based MRI molecular imaging agents, this new approach using the Overhauser effect not only can enhance the signal at the site of the functional agent, but also proves a way to modulate this enhancement at will via applied RF, allowing for a more clean background-free detection and potentially lowering the detection sensitivity using narrow-band lock-in techniques. This could lead to purpose-built portable very specific molecular-imaging based high-resolution and low cost screening systems. This would allow targeted- and anatomical imaging to be performed in the same system, at the same time, as a new deployable tool for transforming diagnosis based on molecular imaging.

Open-Access, Low Magnetic Field Polarized gas Pulmonary MRI

We have developed a novel biomedical imaging technology: magnetic resonance imaging (MRI) at low magnetic fields (less than 10 mT) of hyperpolarized noble gas (3He) inhaled into human lungs. This technology enables MRI studies of human ventilation in a simple, low-cost system with an open geometry (i.e., with a person standing, sitting, or lying down), without the problems of high magnetic fields for people with implants such as pacemakers, and free of magnetic succeptibility artifacts that arise from air-tissue interfaces.

We use this system to study pulmonary physiology by mapping ventilation and pulmonary oxygen concentration as a function of body orientation in the gravitational field. This technology may enable small, portable, low-field MRI systems with important uses such as imaging the underdeveloped lungs of premature infants, who often suffer from pulmonary problems and cannot be moved from the neonatal intensive care unit to a conventional MRI scanner.

Overhauser-enhanced magnetic resonance elastography (OMRE)

MR elastography (MRE) is a powerful technique to assess the mechanical properties of living tissues but its sensitivity is reduced in areas exhibiting short T2, and longer acquisition times are required to mitigate the lower signal. The longer T2s inherent to very-low-field MRI can be exploited of to perform high-speed MRE in combination with Overhauser dynamic nuclear polarization. Indeed, OMRE at very low magnetic field can be used to detect mechanical waves over short acquisition times, and this new modality can extend the usefulness of low cost, portable MRI systems to detect elasticity changes in patients with implanted devices or iron overload.

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