Some of our publications are listed below. For a full list of publications click here.

31. Christian McHugh, Michele Kelley, Nicholas Bryden, Rosa T. Branca, In vivo hyperCEST imaging: Experimental considerations for a reliable contrast. Magnetic Resonance in Medicine, 02 October 2021

Purpose: HyperCEST contrast relies on the reduction of the solvent signal after selective saturation of the solute magnetization. The scope of this work is to outline the experimental conditions needed to obtain a reliable hyperCEST contrast in vivo, where the “solvent” signal (ie, the dissolved-phase signal) may change over time due to the increase in xenon (Xe) accumulation into tissue.


30. Nicholas Bryden, Michael Antonacci, Michele Kelley, Rosa T. Branca, An open-source, low-cost NMR spectrometer operating in the mT field regime. Journal of Magnetic Resonance, 27 September 2021

Abstract: In recent years, low field and ultra-low field NMR spectrometers have gained interest due to their portability, lower cost, and reduced subject-induced magnetic field inhomogeneities. Here, we describe the design of a low-cost multinuclear NMR spectrometer operating in the ultra-low field regime (ULF), which possesses high spectral resolution and enables arbitrary pulse programming. An inexpensive multifunction input/output (I/O) device is used to handle waveform generation and digitization in the kHz operating range. A home-built radio frequency (RF) mixing circuit is used to down-mix the NMR signals, allowing for the slower sampling rates and lower memory requirements needed to enable minute-long acquisitions using a standard Windows PC. The LabVIEW code, along with a bill of materials for all components used in the spectrometer, is included. As proof of concept, 1H relaxation measurements and the simultaneous detection of 1H with gas phase and dissolved 129Xe frequencies using the described low field NMR spectrometer are demonstrated.


29. Michele Kelley, Rosa Tamara Branca, Theoretical models of spin-exchange optical pumping: Revisited and reconciled. Journal of Applied Physics, 19 April 2021

Abstract: Theoretical models for continuous-flow and stopped-flow spin-exchange optical pumping of 129Xe have long predicted much higher 129Xe polarization values than are measured experimentally, leading to a search for additional depolarization mechanisms. In this work, we show that a misapplication of the general theory of spin-exchange optical pumping along with the incorrect use of previously measured spin-exchange constants has been perpetuated in the past 20 years and is the main cause of the long-held discrepancy between theoretical and experimental 129Xe polarization values. Following the standard theory of spin-exchange optical pumping developed almost 40 years ago by Happer et al., we outline the common mistake made in the application of this theory in modern theoretical models and derive a simplified expression of the spin-exchange cross section that can be used to correctly predict 129Xe polarization values under any set of experimental conditions. We show that the complete expression of the spin-exchange cross section derived using the work of Happer et al. predicts spin-exchange rates tenfold higher than those previously assumed in theoretical models of continuous-flow and stopped-flow spin-exchange optical pumping and can fully rectify the long-standing discrepancy between theoretical and experimental polarization values.


28. Christian T. McHugh, Phillip G. Durham, Michele Kelley, Paul A. Dayton, Rosa T. Branca, Magnetic Resonance Detection of Gas Microbubbles via HyperCEST: A Path Toward Dual Modality Contrast Agent. ChemPhysChem, 14 April 2021

Abstract: Gas microbubbles are an established clinical ultrasound contrast agent. They could also become a powerful magnetic resonance (MR) intravascular contrast agent, but their low susceptibility-induced contrast requires high circulating concentrations or the addition of exogenous paramagnetic nanoparticles for MR detection. In order to detect clinical in vivo concentrations of raw microbubbles via MR, an alternative detection scheme must be used. HyperCEST is an NMR technique capable of indirectly detecting signals from very dilute molecules (concentrations well below the NMR detection threshold) that exchange hyperpolarized 129Xe. Here, we use quantitative hyperCEST to show that microbubbles are very efficient hyperCEST agents. They can accommodate and saturate millions of 129Xe atoms at a time, allowing for their indirect detection at concentrations as low as 10 femtomolar. The increased MR sensitivity to microbubbles achieved via hyperCEST can bridge the gap for microbubbles to become a dual modality contrast agent.


27. Christian T. McHugh, John Garside, Jared Barkes, Jonathan Frank, Constance Dragicevich, Hong Yuan, Rosa T. Branca Differences in [F]FDG uptake in BAT of UCP1 −/− and UCP1 +/+ during adrenergic stimulation of non-shivering thermogenesis. EJNMMI Research, 07 November 2020

Background: Brown adipose tissue (BAT) is a fat tissue found in most mammals that helps regulate energy balance and core body temperature through a sympathetic process known as non-shivering thermogenesis. BAT activity is commonly detected and quantified in [18F]FDG positron emission tomography/computed tomography (PET/CT) scans, and radiotracer uptake in BAT during adrenergic stimulation is often used as a surrogate measure for identifying thermogenic activity in the tissue. BAT thermogenesis is believed to be contingent upon the expression of the protein UCP1, but conflicting results have been reported in the literature concerning [18F]FDG uptake within BAT of mice with and without UCP1. Differences in animal handling techniques such as feeding status, type of anesthetic, type of BAT stimulation, and estrogen levels were identified as possible confounding variables for [18F]FDG uptake. In this study, we aimed to assess differences in BAT [18F]FDG uptake between wild-type and UCP1-knockout mice using a protocol that minimizes possible variations in BAT stimulation caused by different stress responses to mouse handling.


26. Michele Kelley, Alex Burant, Rosa Tamara Branca, Resolving the discrepancy between theoretical and experimental polarization of hyperpolarized 129 Xe using numerical simulations and in situ optical spectroscopy. Journal of Applied Physics, 14 October 2020.

Abstract: For emerging biomedical applications of hyperpolarized xenon, the ability to obtain reliably high nuclear spin polarization levels is paramount. Yet, experimental nuclear spin polarization levels of xenon are highly variable and, more than often than not, well below what theory predicts. Despite rigorous and well-studied theoretical models for hyperpolarization and continuous-flow spin-exchange optical pumping (SEOP), there remains a substantial discrepancy between the theoretical and experimental polarization of 129Xe; inexplicably, seemingly similar experimental parameters can yield very different polarization values. In this paper, the validity of the assumptions typically made about the thermodynamic state of the Rb vapor inside the optical pumping cell and the gas dynamics are investigated through finite element analysis simulations of realistic optical pumping cell models, while in situ optical and nuclear magnetic resonance spectroscopy measurements are used to validate the results of the simulations. Our results show that shorter xenon gas residence times and lower Rb vapor densities than those predicted by empirical saturated vapor pressure curves, along with incorrect SEOP parameters, are the primary cause of the discrepancy between theoretical and experimental polarization values reported in the literature.

25. Michael Antonacci, Le Zhang, Simone Degan, Detlev Erdmann, Rosa T Branca, Calibration of methylene-referenced lipid-dissolved xenon frequency for absolute MR temperature measurements. Magnetic Resonance in Medicineonline 14 September 2018.

Purpose: Absolute MR temperature measurements are currently difficult because they require precalibration procedures specific for tissue types and conditions. Reference of the lipid‐dissolved 129Xe resonance frequency to temperature‐ insensitive methylene protons (rLDX) has been proposed to remove the effect of macro‐ and microscopic susceptibility gradients to obtain absolute temperature information. The scope of this work is to evaluate the rLDX chemical shift (CS) dependence on lipid composition to estimate the precision of absolute temperature measurements in lipids. Methods: Neat triglycerides, vegetable oils, and samples of freshly excised human and rodent adipose tissue (AT) are prepared under 129Xe atmosphere and studied using high‐resolution NMR. The rLDX CS is measured as a function of temperature.1H spectra are also acquired and the consistency of methylene‐referenced water pro- ton and rLDX CS values are compared in human AT. Results: Although rLDX CS shows a dependence on lipid composition, in human and rodent AT samples the rLDX shows consistent CS values with a similar tempera- ture dependence (–0.2058 ± 0.0010) ppm/°C × T (°C) + (200.15 ± 0.03) ppm, ena- bling absolute temperature measurements with an accuracy of 0.3°C. Methylene‐referenced water CS values present variations of up to 4°C, even under well‐controlled conditions. Conclusions: The rLDX can be used to obtain accurate absolute temperature meas- urements in AT, opening new opportunities for hyperpolarized 129Xe MR to measure tissue absolute temperature.


24. Alex Burant,  Michael Antonacci, Andrew McCallister, Le Zhang, Rosa Tamara Branca, Effects of Superparamagnetic Iron Oxide Nanoparticles on the Longitudinal and Transverse Relaxation of Hyperpolarized Xenon Gas, Journal of Magnetic Resonance

Abstract  SuperParamagnetic Iron Oxide Nanoparticles (SPIONs) are often used in magnetic resonance imaging experiments to enhance Magnetic Resonance (MR) sensitivity and specificity. While the effect of SPIONs on the longitudinal and transverse relaxation time of 1H spins has been well characterized, their effect on highly diffusive spins, like those of hyperpolarized gases, has not. For spins diffusing in linear magnetic field gradients, the behavior of the magnetization is characterized by the relative size of three length scales: the diffusion length, the structural length, and the dephasing length. However, for spins diffusing in non-linear gradients, such as those generated by iron oxide nanoparticles, that is no longer the case, particularly if the diffusing spins experience the non-linearity of the gradient. To this end, 3D Monte Carlo simulations are used to simulate the signal decay and the resulting image contrast of hyperpolarized xenon gas near SPIONs. These simulations reveal that signal loss near SPIONs is dominated by transverse relaxation, with little contribution from T1 relaxation, while simulated image contrast and experiments show that diffusion provides no appreciable sensitivity enhancement to SPIONs.


23. Rosa T. Branca, Andrew McCallister, Hong Yuan, Amir Aghajanian, James E. Faber, Nicholas Weimer, Riley Buchanan, Carlos S. Floyd, Michael Antonacci, Le Zhang, and Alex Burant, Accurate quantification of brown adipose tissue mass
by xenon-enhanced computed tomography, Proc. Natl. Acad. Sci. USA, 115 (1) 174-179 (2018).

Significance The search for new obesity drug targets and the rediscovery of active bown fat (brown adipose tissue; BAT) in adult humans has triggered a BAT renaissance.However, the assumption that this tissue plays a key role in energy balance in humans, as it does in rodents, is still a matter of debate. This is because BAT mass cannot be correctly quantified by current imaging techniques, as these are either nonspecific or lack the necessary sensitivity to detect BAT, especially in obese phenotypes. Here, we show that xenon-enhanced computed tomography can accurately quantify BAT mass, especially in obese mouse phenotypes in which ex- tensive BAT hypertrophy hampers the detection of this tissue by current tomographic imaging techniques. Abstract Detection and quantification of brown adipose tissue (BAT) mass remains a major challenge, as current tomographic imaging techniques are either nonspecific or lack the necessary resolution to quantify BAT mass, especially in obese phenotypes, in which this tissue may be present but inactive. Here, we report quanti- fication of BAT mass by xenon-enhanced computed tomography. We show that, during stimulation of BAT thermogenesis, the lipophilic gas xenon preferentially accumulates in BAT, leading to a radiodensity enhancement comparable to that seen in the lungs. This enhancement is mediated by a selective reduction in BAT vascular resistance, which greatly increases vascular perfusion of BAT. This enhancement enables precise identification and quanti- fication of BAT mass not only in lean, but also in obese, mouse phenotypes, in which this tissue is invisible to conventional tomographic imaging techniques. The method is developed and validated in rodents and then applied in macaques to assess its feasibility in larger species.

Click below for a movie showing how xenon accumulates in BAT      



22. Michael A. Antonacci , Le Zhang , Alex Burant, Drew McCallister, and Rosa T. Branca, Simple and Robust Referencing System Enables Identification of Dissolved-Phase Xenon Spectral Frequencies, Magn. Reson. Med., available online 19 December 2017.

Purpose: To assess the effect of macroscopic susceptibility gradients on the gas-phase referenced dissolved-phase 129Xe (DPXe) chemical shift (CS) and to establish the robustness of a water-based referencing system for in vivo DPXe spectra. Methods: Frequency shifts induced by spatially-varying magnetic susceptibility are calculated by finite-element analysis for the human head and chest. Their effect on traditional gas-phase referenced DPXe CS is then assessed theoretically and experimentally. A water-based referencing system for the DPXe resonances that uses the local water protons as reference is proposed and demonstrated in vivo in rats. Results: Across the human brain, macroscopic susceptibility gradients can induce an apparent variation in the DPXe CS of up to 2.5 ppm. An additional frequency shift as large as 6.5 ppm can exist between DPXe and gas-phase resonances. By using nearby water protons as reference for the DPXe CS, the effect of macroscopic susceptibility gradients is eliminated and consistent CS values are obtained in vivo, regardless of shimming conditions, region of interest analyzed, animal orientation, or lung inflation. Combining in vitro and in vivo spectroscopic measurements finally enables confident assignment of some of the DPXe peaks observed in vivo. Conclusions: In order to use hyperpolarized xenon as a biological probe in tissues, the DPXe CS in specific organs/tissues must be reliably measured. When the gas-phase is used as reference, variable CS values are obtained for DPXe resonances. Reliable peak assignments in DPXe spectra can be obtained by using local water protons as reference.


21. Le Zhang, Drew McCallister, Karl M. Koshlap, Rosa Tamara Branca, Correlation distance dependence of the resonance frequency of intermolecular zero-quantum coherences and its implication for MR thermometry, Magn. Reson. Med., 2017, 10.1002/mrm.26801
Purpose:  Because the resonance frequency of water–fat intermolecular zero-quantum coherences (iZQCs) reflects the water–fat frequency separation at the microscopic scale, these frequencies have been proposed and used as a mean to obtain more accurate temperature information. The purpose of this work was to investigate the dependence of the water–fat iZQC resonance frequency on sample microstructure and on the specific choice of the correlation distance. Methods: The effect of water–fat susceptibility gradients on the water–methylene iZQC resonance frequency was first computed and then measured for different water–fat emulsions and for a mixture of porcine muscle and fat. Similar measurements were also performed for mixed heteronuclear spin systems. Results: A strong dependence of the iZQC resonance frequency on the sample microstructure and on the specific choice of the correlation distance was found for spin systems like water and fat that do not mix, but not for spin systems that mix at the molecular level. Conclusions: Because water and fat spins do not mix at the molecular level, the water–fat iZQC resonance frequency and its temperature coefficient are not only affected by sample microstructure but also by the specific choice of the correlation distance.

20. Eric T. Trexler, Drew McCallister, Abbie E. Smith-Ryan, Rosa Tamara Branca, Incidental finding of low brown adipose tissue activity in endurance-trained individuals: Methodological considerations for positron emission tomography, J. Nat. Sci., 3(3), e335, 2017


19. Michael A. Antonacci, Alex Burant, Wolfgang Wagner, Rosa Tamara Branca, Depolarization of nuclear spin polarized 129Xe gas by dark rubidium during spin-exchange optical pumping, J. Magn. Reson., 279, 60-67, 2017

Synopsis: scienceContinuous -flow spin- exchange optical pumping (SEOP) continues to serve as the most widespread method of polarizing 129Xe for magnetic resonance experiments. Unfortunately, continuous-flow SEOP still suffers from as-yet unidentified inefficiencies that prevent the production of large volumes of xenon with a nuclear spin polarization close to theoretically calculated values. In this work we use a combination of ultra-low field nuclear magnetic resonance spectroscopy and atomic absorption spectroscopy (AAS) measurements to study the effects of dark Rb vapor on hyperpolarized 129Xe in situ during continuous-flow SEOP. We find that dark Rb vapor in the optical cell outlet has negligible impact on the final 129Xe polarization at typical experimental conditions, but can become significant at higher oven temperatures and lower flow rates. Additionally, in the AAS spectra we also look for a signature of paramagnetic Rb clusters, previously identified as a source of xenon depolarization and a cause for SEOP inefficiency, for which we are able to set an upper limit of 8.3×1015 Rb dimers per cm3.


18. Drew McCallister, Le Zhang, Alex Burant, Lawrence Katz, Rosa Tamara Branca, A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI, Magn. Reson. Med., 2017, 10.1002/mrm.26589

Purpose: untitledTo assess the spatial correlation between MRI and FDG-PET maps of human BAT and measure differences in fat fraction between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. Methods: In sixteen healthy volunteers, mean age of 30and BMI of 26, fat fraction, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. Results: Fourteen of the sixteen volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in fat fraction or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT fat fraction was observed during BAT stimulation. Conclusions: MR fat fraction, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects.


17. Le Zhang, M.A. Antonacci, Alex Burant, Karl M. Koshlap and Rosa Tamara BrancaRemote detection of hyperpolarized 129Xe resonances via multiple distant dipolar field interactions with 1H, J. Chem. Phys. 145 (19), 194201 (2016)

Synopsis: A le_ddfremote detection scheme utilizing the distant dipolar field interaction between two different spin species was proposed by Granwhr et al (J. Magn. Reson. 176(2), 125; 2005). In that sequence 1H spins were detected indirectly via their dipolar field interaction with 129Xe spins, which served as the sensing spins. Here we propose a modification of the proposed detection scheme that takes advantage of the longer T1 relaxation time of xenon to create a long lasting dipolar field with which the fast relaxing 1H spins are allowed to interact many times during a single acquisition. This new acquisition scheme improves detection sensitivity, but it also presents some challenges.


16. A. Burant, R. T. Branca, Diffusion-mediated 129Xe Gas Depolarization in Magnetic Field Gradients During Continuous-flow Optical Pumping, J. Magn. Reson., 273, 124-129, 2016

Synopsis: The of large volumes of
highly polarized noble gases like helium and xenon is vital to applications of magnetic resonance imaging and spectroscopy with hyperpolarized (HP) gas in humans. In the past ten years, 129Xe has become the gas of choice due to its lower cost, higher availability, relatively high tissue solubility, and wide range of chemical shift values. Though near unity levels of xenon polarization have been achieved in-cell using stopped-flow Spin Exchange Optical Pumping (SEOP), these levels are currently unmatched by continuous-flow SEOP methods. Among the various mechanisms that cause xenon relaxation, such as persistent and transient xenon dimers, wall collisions, and interactions with oxygen, relaxation due to diffusion in magnetic field gradients, caused by rapidly changing magnetic field strength and direction, is often ignored. However, during continuous-flow SEOP production, magnetic field gradients may not have a negligible contribution, especially considering that this methodology requires the combined use of magnets with very different characteristics (low field for spin exchange optical pumping and high field for the reduction of xenon depolarization in the solid state during the freeze out phase) that, when placed together, inevitably create magnetic field gradients along the gas-flow-path. Here, a combination of finite element analysis and Monte Carlo simulations is used to determine the effect of such magnetic field gradients on xenon gas polarization with applications to a specific, continuous-flow hyperpolarization system.

15. Zhang, L., Burant, A., McCallister, A., Zhao, V., Koshlap, K. M., Degan, S., Antonacci, M.A. and Branca, R. T., Accurate MR thermometry by hyperpolarized 129XeMagn. Reson. Med., 78 (3): 1070-1079 (2017)
le_thermometrySynopsis: A new thermometry method based on the temperature dependence of lipid-dissolved 129Xe was proposed, while its accuracy was assessed by direct comparison with Proton Resonance Frequency (PRF) based MR thermometry methods. The temperature dependences of chemical shifts of lipid-dissolved 129Xe, water and methylene spins were first measured in vitro with high accuracy on various fat-rich tissues. The results were then used to obtain relative temperature maps in vivo in mice acclimated at different temperatures. Lipid-dissolved 129Xe based MR thermometry demonstrated superior accuracy in both in vivo and in vitro results when compared to PRF based MR thermometry in fatty tissues.



14. D.A. Barskiy, A.M. Coffey, P. Nikolaou, D.M. Mikhaylov, B.M. Goodson, R.T. Branca, G.J. Lu, M.G. Shapiro, V.V. Telkki, V.V. Zhivonitko, I.V.  Koptyug IV. NMR Hyperpolarization Techniques of Gases, Chemistry, 23 (4): 725-751 (2017)

13. R.T. Branca, T. He, L. Zhang, C.S. Floyd, M. Freeman, C. White, A. Burant, Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI, Proc. Natl. Acad. Sci. USA, 111: 18001-18006 (2014)

12. R.T. Branca, L. Zhang , W.S. Warren, E. Auerbach, A. Khanna, S. Degan, K. Ugurbil, R. Maronpot, In vivo noninvasive detection of Brown Adipose Tissue through intermolecular zero-quantum MRI, PLoS One, 8(9):e74206 (2013)

11. A. Khanna, R.T. Branca, Detecting brown adipose tissue activity with BOLD MRI in mice, Magn. Reson. Med., 68:4, 1285-1290 (2012)

10. Y.M. Chen, R.T. Branca, W.S. Warren, Revisiting the mean-field picture of dipolar effects in solution NMR, J. Chem. Phys., 136(20):204509 (1-11) (2012)

9. R.T. Branca, MRI using intermolecular multiple-quantum coherences, Methods Mol. Biol., 771:241-52 (2011).

8. R.T. Branca, W.S. Warren, In vivo NMR detection of diet-induced changes in adipose tissue composition, J. Lipid Res., 52(4), 833-9 (2011).

7. R.T. Branca, W.S. Warren, In vivo brown adipose tissue detection and characterization using water-lipid intermolecular zero-quantum coherences, Magn. Reson. Med, 65(2): 313-9 (2011)

6. R.T. Branca, E.R. Jenista, W.S. Warren, Inhomogeneity-free heteronuclear iMQC, J. Magn. Reson., 209(2):347-351 (2011)

5. R.T. Branca, Z.I. Cleveland, B. Fubara, C. Kumar, C. Leuschner, R.R. Maronpot, W.S. Warren, B. Driehuys, Molecular MRI for sensitive and specific detection of lung metastases, Proc. Natl. Acad. Sci. USA, 107(8):3693-7(2010). PMID: 20142483

4. W.S. Warren, E.R. Jenista, R.T. Branca, Increasing hyperpolarized spin lifetimes through true singlet eigenstates, Science, 323(5922), 1711-1714 (2009)

3. G. Galiana, R.T. Branca, E.R. Jenista, W.S. Warren, Accurate Temperature Imaging Based on Intermolecular Coherences in Magnetic Resonance, Science, 322(5900), 421-424 (2008)

2. R.T. Branca, G. Galiana, W.S. Warren, Enhanced Nonlinear Magnetic Resonance signals via Square Wave Dipolar Fields, J. Chem. Phys., 129, 054502 (2008)

1. R.T. Branca, S. Capuani, B. Maraviglia,  About the Crazed Sequence, Concepts Magn. Reson. A, 21A, 1:22-36 (2004)