Rosa T. Branca

Increasing hyperpolarized spin lifetimes through true singlet eigenstates.

The sensitivity limitations for magnetic resonance imaging of organic molecules have recently been addressed by hyperpolarization methods, which prepare excess nuclear spin polarization. This approach can increase sensitivity by orders of magnitude, but the enhanced signal relaxes away in tens of seconds, even in favorable cases. Here we show theoretically that singlet states between strongly coupled spins in molecules can be used to store and retrieve population in very-long-lived disconnected eigenstates, as long as the coupling between the spins substantially exceeds both the couplings to other spins and the resonance frequency difference between them. Experimentally, 2,3-carbon-13–labeled diacetyl has a disconnected eigenstate that can store population for minutes and is read out by hydration to make the two spins inequivalent.

Molecular MRI for sensitive and specific detection of lung metastases

Early and specific detection of metastatic cancer cells in the lung (the most common organ targeted by metastases) could significantly improve cancer treatment outcomes. However, the most widespread lung imaging methods use ionizing radiation and have low sensitivity and/or low specificity for cancer cells. Here we address this problem with an imaging method to detect submillimeter-sized metastases with molecular specificity. Cancer cells are targeted by iron oxide nanoparticles functionalized with cancer-binding ligands, then imaged by high-resolution hyperpolarized 3He MRI. We demonstrate in vivo detection of pulmonary micrometastates in mice injected with breast adenocarcinoma cells. The method not only holds promise for cancer imaging but more generally suggests a fundamentally unique approach to molecular imaging in the lungs.

In vivo brown adipose tissue detection and characterization using water–lipid intermolecular zero-quantum coherences

Brown adipose tissue and white adipose tissue depots are noninvasively characterized in vitro and in vivo in healthy and obese mice using intermolecular zero‐quantum coherence transitions between lipid and water spins. Intermolecular zero‐quantum coherences enable selective detection of spatial correlation between water and lipid spins and thereby the hydration of fatty deposits with subvoxel resolution. At about a 100 mm distance scale, the major observed peaks are between water, methylene protons at 1.3 ppm, and olefinic protons at 5.3 ppm. Our in vitro results show that the methylene–olefinic intermolecular zero‐quantum coherence signal is strong both in brown and white adipose tissues, but that the water–methylene intermolecular zero‐quantum coherence signal is characteristic only of brown adipose tissue. In vivo, the ratio of these peaks is substantially higher in lean or young mice than in old or obese mice. Magn Reson Med, 2011.

Detecting brown adipose tissue activity with BOLD MRI in mice

The recent discovery of active brown adipose tissue (BAT) in adult humans and the correlation found between the activity of this tissue and resting metabolic rate strongly suggest that this tissue may be implicated in the development of obesity in humans, as it is in rodents. Despite the possible physiological role of this tissue in the onset of human obesity, few noninvasive imaging techniques to detect BAT activity in humans exist. The scope of this work is to investigate the possibility of detecting BAT activity using blood‐oxygen‐level‐dependent MRI. Our results show that the strong increase in oxygen consumption and consequent increase in blood deoxyhemoglobin levels following BAT activation lead to a well‐localized signal drop in BAT. This strongly suggests the possibility to use blood‐oxygen‐level‐dependent MRI for the noninvasive detection of BAT activity. Magn Reson Med, 2012.

Accurate Temperature Imaging Based on Intermolecular Coherences in Magnetic Resonance

Conventional magnetic resonance methods that provide interior temperature profiles, which find use in clinical applications such as hyperthermic therapy, can develop inaccuracies caused by the inherently inhomogeneous magnetic field within tissues or by probe dynamics, and work poorly in important applications such as fatty tissues. We present a magnetic resonance method that is suitable for imaging temperature in a wide range of environments. It uses the inherently sharp resonances of intermolecular zero-quantum coherences, in this case flipping up a water spin while flipping down a nearby fat spin. We show that this method can rapidly and accurately assign temperatures in vivo on an absolute scale.

Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI

Significance In recent years, there has been a growing interest in brown adipose tissue (BAT), a tissue specialized in nonshivering thermogenesis and considered to be the next therapeutic target against obesity and diabetes. However, the detection of this very sparse tissue still represents a major challenge. To our knowledge, we report the first in vivo detection of BAT and thermogenic activity by hyperpolarized xenon gas MRI. We show that during thermogenic activity a more than 15-fold enhancement in xenon uptake by BAT enables us to clearly differentiate this tissue from the surrounding tissue and to thereby overcome the major limitations of conventional imaging methods. We also use lipid-dissolved hyperpolarized xenon chemical shift to demonstrate direct in vivo MR thermometry of BAT. The study of brown adipose tissue (BAT) in human weight regulation has been constrained by the lack of a noninvasive tool for measuring this tissue and its function in vivo. Existing imaging modalities are nonspecific and intrinsically insensitive to the less active, lipid-rich BAT of obese subjects, the target population for BAT studies. We demonstrate noninvasive imaging of BAT in mice by hyperpolarized xenon gas MRI. We detect a greater than 15-fold increase in xenon uptake by BAT during stimulation of BAT thermogenesis, which enables us to acquire background-free maps of the tissue in both lean and obese mouse phenotypes. We also demonstrate in vivo MR thermometry of BAT by hyperpolarized xenon gas. Finally, we use the linear temperature dependence of the chemical shift of xenon dissolved in adipose tissue to directly measure BAT temperature and to track thermogenic activity in vivo.

NMR Hyperpolarization Techniques of Gases

Nuclear spin polarization can be significantly increased through the process of hyperpolarization, leading to an increase in the sensitivity of nuclear magnetic resonance (NMR) experiments by 4-8 orders of magnitude. Hyperpolarized gases, unlike liquids and solids, can often be readily separated and purified from the compounds used to mediate the hyperpolarization processes. These pure hyperpolarized gases enabled many novel MRI applications including the visualization of void spaces, imaging of lung function, and remote detection. Additionally, hyperpolarized gases can be dissolved in liquids and can be used as sensitive molecular probes and reporters. This Minireview covers the fundamentals of the preparation of hyperpolarized gases and focuses on selected applications of interest to biomedicine and materials science.

In Vivo Noninvasive Detection of Brown Adipose Tissue through Intermolecular Zero-Quantum MRI

The recent discovery of active Brown Adipose Tissue (BAT) in adult humans has opened new avenues for obesity research and treatment, as reduced BAT activity seem to be implicated in human energy imbalance, diabetes, and hypertension. However, clinical applications are currently limited by the lack of non-invasive tools for measuring mass and function of this tissue in humans. Here we present a new magnetic resonance imaging method based on the normally invisible intermolecular multiple-quantum coherence 1H MR signal. This method, which doesn’t require special hardware modifications, can be used to overcome partial volume effect, the major limitation of MR-based approaches that are currently being investigated for the detection of BAT in humans. With this method we can exploit the characteristic cellular structure of BAT to selectively image it, even when (as in humans) it is intimately mixed with other tissues. We demonstrate and validate this method in mice using PET scans and histology. We compare this methodology with conventional 1H MR fat fraction methods. Finally, we investigate its feasibility for the detection of BAT in humans.

Hyperpolarized carbon–carbon intermolecular multiple quantum coherences

Intermolecular multiple quantum coherences (iMQCs) can provide unique contrast with sub-voxel resolution. However, the characteristic growth rate of iMQCs mostly limits these effects to either hydrogen or hydrogen-coupled systems for thermally polarized samples. Hyperpolarization techniques such as dynamic nuclear polarization (DNP) allow for significant increases in the carbon signal (even more signal than that from hydrogen), making carbon iMQCs achievable. We present the first intermolecular multiple quantum signal between two carbon nuclei.

iDQC anisotropy map imaging for tumor tissue characterization in vivo

Intermolecular double quantum coherences (iDQCs), signals that result from simultaneous transitions of two or more separated spins, are known to produce images that are highly sensitive to subvoxel structure, particularly local anisotropy. Here we demonstrate how iDQCs signal can be used to efficiently detect the anisotropy created in breast tumor tissues and prostate tumor tissues by targeted (LHRH‐conjugated) superparamagnetic nanoparticles (SPIONs), thereby distinguishing the necrotic area from the surrounding tumor tissue. Magn Reson Med, 2009.