Medical Imaging of Hyperpolarized Noble Gases Perspectives and

Medical Imaging of Hyperpolarized Noble Gases Perspectives and Prospects at the Quarter Century Mark Wilson Miller University of Virginia Department of Radiology & Medical Imaging SPIN 2018 Conference, Ferrara Italy September 13, 2018

Nuclear Magnetic Resonance (NMR) l RF pulse B l Receive RF coil NMR signal in RF coil

Magnetic Resonance Imaging (MRI) · NMR frequency is proportional to the magnetic field strength: l B Large magnetic field 1. 5 ~ 3. 0 Tesla 1 H: f = 63~126 MHz

Magnetic Resonance Imaging (MRI) · NMR frequency is proportional to the magnetic field strength: l · If we apply a magnetic field gradient G across the subject, this creates a linear mapping between frequency and position: B l G ~ 40 m. T/m · This is the physical basis of MRI ! 2003 Nobel Prize in Medicine Large magnetic field 1. 5 ~ 3. 0 Tesla 1 H: f = 63~126 MHz

Magnetic Resonance Imaging (MRI) · Clinical MRI scanners image the 1 H nuclei (protons) in water and fat Boltzmann distribution at 1. 5 T Thermal-equilibrium polarization: ~ 0. 0005 % at 1. 5 T (5 parts per million) B Large magnetic field 1. 5 ~ 3. 0 Tesla 1 H: f = 63~126 MHz

Magnetic Resonance Imaging (MRI) · Clinical MRI scanners image the 1 H nuclei (protons) in water and fat Boltzmann distribution at 1. 5 T Thermal-equilibrium polarization: ~ 0. 0005 % at 1. 5 T (5 parts per million) B Excellent signal nonetheless, since 2/3 of the atoms in your body are hydrogen !

“Hyper”polarization Spin-Exchange Optical Pumping (SEOP) of noble gases SEOP is a 2 -step process: Helmholtz coil 1. Optical pumping: Circularly polarized laser light transfers spin angular momentum to the valence electron of a rubidium atom Oven T > 100°C Glass cell containing 3 He, Rb e l. Rbv B ~20 G (2 m. T) 795 nm laser

“Hyper”polarization Spin-Exchange Optical Pumping (SEOP) of noble gases SEOP is a 2 -step process: Helmholtz coil 1. Optical pumping: Circularly polarized laser light transfers spin angular momentum to the valence electron of a rubidium atom p en p Oven T > 100°C Glass cell containing 3 He, Rb l. Rbv ~20 G (2 m. T) 2. Spin Exchange: Rubidium electron transfers spin to noble gas nucleus The only nonradioactive spin-1/2 noble gases are 3 He and 129 Xe. B 795 nm laser

Early Hyperpolarized-Gas MRI 1994: First hyperpolarized gas images published in Nature Excised mouse lung/heart 129 Xe in lung 1 H in heart · ~1 m. L 129 Xe, polarized to >25% using rubidium SEOP with 2 W Ti-Sapphire laser “We note that 3 He is also an attractive candidate for imaging; it can be produced with comparable polarization, and has a larger magnetic moment and longer relaxation times. ” Albert MS, Cates GD, Driehuys B, Happer W, Saam B, Springer Jr CS, Wishnia A. Biological magnetic resonance imaging using laser-polarized 129 Xe. Nature 370: 199 -200 (1994).

Early Hyperpolarized-Gas MRI 1996: First hyperpolarized gas images in a human (3 He) Posterior slice Central slice · Clinical 1. 5 T human scanner, but with custom RF coil tuned to the 3 He resonance frequency · 1. 2 L 3 He, polarized to ~15% using rubidium spin-exchange optical pumping · 100 W diode laser array (Key advancement !) Mac. Fall JR, Charles HC, Black RD, Middleton H, Swartz JC, Saam B, Driehuys B, Erickson C, Happer W, Cates GD, Johnson GA, Ravin CE. Human Lung Airspaces: Potential for MR Imaging with Hyperpolarized He-3. Radiology (1996). Anterior slice Loop RF coil (too small)

Early Hyperpolarized-Gas MRI 1997: First hyperpolarized 129 Xe images in a human Central slice Anterior slice More-anterior slice · Clinical 1. 5 T human scanner, but with custom RF coil tuned to the 129 Xe resonance frequency · 0. 5 L 3 He, polarized to ~2 -3% with rubidium SEOP using newly developed flow-freeze-thaw method · Same 100 W diode laser array Mugler JP, Driehuys B, Brookeman JR, Cates GD, Berr SS, Bryant RG, Daniel TM, de Lange EE, Downs JH, Erickson CJ, Happer W, Hinton DP, Kassel NF, Maier T, Phillips CD, Saam BT, Sauer KL, Wagshul ME. MR Imaging with Hyperpolarized 129 Xe Gas: Preliminary Human Results. MRM 37: 809 -815 (1997).

Rise of 3 He Image quality much better with 3 He (in late ‘ 90 s) 3 He MRI (1996) 129 Xe MRI (1997) · Inherent signal-to-noise advantage: 3 -fold greater gyromagnetic ratio → 3 -fold greater signal per nuclear spin · Easy to hyperpolarize liter quantities of 3 He with up to 40% polarization

First Commercial Polarizer (ca. 1997) Dispense into bag for inhalation Can do 129 Xe: 500 m. L @ 5~10% or 3 He: 1 L @ 30~40%

1. 5 Tesla Clinical MRI Scanner Vest-type RF coil (48. 5 MHz for 3 He) Inhale gas from bag

High-Resolution 3 D Lung MRI Chest radiograph 3 He MRI Pneumatocele (very unusual)

High-Resolution 3 D Lung MRI Coronal (front) view Sagittal (side) view Axial (top) view isotropic 3 mm resolution Amazingly detailed image of lung airspaces, but most interesting part of the image is where there isn’t any 3 He !

Lung Function and Structure The main function of the lung is gas exchange · The structure of the lung is designed to bring oxygenated air into close contact with deoxygenated capillary blood so that gas exchange can occur. · Fundamental unit of gas exchange is the alveolus. air → O 2 → ← CO 2 ← blood

Lung Function and Structure The main function of the lung is gas exchange VENTILATION BLOOD FLOW

Airways Structure Conducting airways Starting with trachea, bifurcate for 15 generations

Airways Structure acinus ~3 mm transitional bronchioles Alveoli ~250 µm Gas-exchange airways Starting with trans. bronchioles, bifurcate another 8 generations

Airways Structure · 215 transitional bronchioles implies ~30, 000 acini · ~10, 000 alveoli per transitional acinus bronchioles · ~300 million alveoli Total volume: 3 -6 L · Total surface area available for gas Alveoli ~250 µm exchange: 50~100 m 2 · Volume of conducting Gas-exchange airways: 150 m. L Starting with trans. bronchioles, acinus ~3 mm bifurcate another 8 generations

Obstructive Lung Diseases Conducting airways become blocked, so downstream alveoli don’t ventilate · Asthma · Chronic Obstructive Pulmonary Disease (COPD): Emphysema + Chronic Bronchitis · Alpha− 1 Antitrypsin Deficiency · Cystic Fibrosis

Obstructive Lung Diseases

3 He Ventilation Imaging Healthy Subject Asthmatic EE de Lange et al. Lung air spaces: MR imaging evaluation with hyperpolarized 3 He gas. Radiology 1999; 210: 851 -857.

3 He Ventilation Imaging · Severe-persistent asthmatic Pre Albuterol Post Albuterol TA Altes et al. Hyperpolarized 3 He MR Lung Ventilation Imaging in Asthmatics—Preliminary Findings. JMRI 2001; 13: 378 -84

3 He MRI of Obstructive Lung Disease Functional Imaging: Ventilation 129 Xe in lung Healthy normal Smoker COPD Asthma Cystic Fibrosis a 1 antitrypsin def.

Obstructive Lung Diseases

Lung Structure · Fine alveolar structure cannot be resolved with any clinical imaging modality (except microscope!) · CT (computed tomography) resolution limit: 0. 5 mm

Diffusion-Weighted MRI · Simulated Brownian motion

3 He Diffusion in Emphysema Normal Acinus Emphysema High ADC Low ADC Normal lung microstructure Enlarged airspaces

3 He Diffusion: Lung Transplant Computed Tomography (CT) Native Lung Transplanted Lung 3 He ADC map Native ~ 0. 8 cm 2/s Transplant ~ 0. 2 cm 2/s · 3 He free diffusion coefficient: ~0. 9 cm 2/s in air

Fall of 3 He Kramer D. DOE begins rationing helium-3. Physics Today 63 (2010).

Rise of 129 Xe High-volume, high-polarization commercial polarizers started becoming available in late ‘ 00 s Polarean ~2014 Polarization “cell” l There is even an “open source” Xe. Med ~2008 movement underway (BYO)

129 Xe versus 3 He today 1 L 129 Xe yields similar image quality as 0. 3 L 3 He Cystic Fibrosis Mugler JP and Altes TA. Hyperpolarized 129 Xe MRI of the human lung. JMRI 37: 313– 331 (2013).

Xenon Gas Exchange 129 Xe 3 He remains confined to the lung airspaces, follows same uptake pathways as O 2 and · Inhaled but 129 Xe dissolves into lung tissue and blood thus can be used to study gas exchange directly ! · In addition to simple dissolution into tissue membranes and blood plasma, 129 Xe also binds to the hemoglobin in red blood cells

129 Xe NMR spectrum in the lung · Resonance frequency of dissolved-phase 129 Xe is shifted by about 200 ppm with respect to gas phase. frequency-selective RF excitation · Within the dissolved phase, the resonance frequency of 129 Xe bound to hemoglobin is shifted by about 20 ppm with respect to 129 Xe dissolved in tissues and blood plasma. dissolved phase gas phase

129 Xe NMR spectrum in the lung · Resonance frequency of dissolved-phase 129 Xe is shifted by about 200 ppm with respect to gas phase. · Within the dissolved phase, the resonance frequency of 129 Xe bound to hemoglobin is shifted by about 20 ppm with respect to 129 Xe dissolved in tissues and blood plasma. These so-called “chemical shifts” allow us to image gas and dissolved phases separately. non-selective RF excitation Equilibrium dissolved-phase concentration is only ~2% of gas-phase concentration dissolved phase gas phase

MRI of Dissolved-Phase 129 Xe frequency-selective RF excitation Clever way to image both gas and dissolved phases simultaneously yet separately: · As before, use frequency- selective RF pulse to preferentially excite dissolved-phase spins · Make use of “frequencymaps-to-position” nature of MRI to make dissolvedphase 129 Xe appear at different location than gas phase. dissolved phase gas phase

MRI of Dissolved-Phase 129 Xe Simultaneous imaging of gas and dissolved phases Clever way to image both gas and dissolved phases simultaneously yet separately: frequency-selective RF excitation · As before, use frequency- selective RF pulse to preferentially excite dissolved-phase spins · Normal volunteer Make use of “frequency- maps-to-position” nature of MRI to make dissolvedphase 129 Xe appear at different location than gas phase. dissolved phase gas phase

3 D MRI of Dissolved-Phase 129 Xe Healthy volunteer with benign pulmonary nodule Coronal (front) view Sagittal (side) view Axial (top) view Conventional 1 H MRI Mugler JP et al. Simultaneous MRI of ventilation distribution and gas uptake in the human lung using hyperpolarized Xenon -129. Proc Natl Acad Sci 107: 21707 -12 (2010).

MRI of Dissolved-Phase 129 Xe · Can also separately image tissue and red blood cell (RBC) compartments. Healthy Volunteer heart Qing K, Ruppert K, Jiang Y, Mata JF, Miller GW, Shim YM, Wang C, Ruset IC, Hersman FW, Altes TA, Mugler JP. Regional Mapping of Gas Uptake by Blood and Tissue in the Human Lung Using Hyperpolarized Xenon-129 MRI. JMRI 39: 346 -359 (2014).

So is hyperpolarized-gas MRI useful? · For research: Absolutely! Ø Has given us a better understand of basic lung function and disease processes, especially in obstructive lung diseases. · For drug development: Probably. Ø Allows us to see what is going on under the surface. · In the clinic: Hopefully someday. To be useful in the practice of medicine, must provide superior capabilities for either disease diagnosis or informing treatment decisions. (e. g. Earlier detection? ) Ø There are currently no drugs that can reverse or otherwise change the course of chronic obstructive lung disease! Ø Still looking for “killer app”. Might be outside the lung… Ø

A preview of things to come? · Inhaled xenon taken up by the bloodstream gets transported throughout the body Lungs Human kidneys Hamedani H et al. ISMRM 2018.