Name: quantitative mapping of specific ventilation in the human lung using proton magnetic resonance imaging and oxygen as a contrast agent
Uploaded: 2019-06-05T14:00:00
Description: Watch this Scientific Journal Video about Quantitative Mapping of Specific Ventilation in the Human Lung using Proton Magnetic Resonance Imaging and Oxygen as a Contrast Agent at JoVE.com

This work was supported by the National Heart, Lung and Blood Institute (NHLBI) (grants R01 HL-080203, R01 HL-081171, R01 HL-104118 and R01-HL119263) and the National Space Biomedical Research Institute (National Aeronautics and Space Administration grant NCC 9-58). E.T. Geier was supported by NHLBI grant F30 HL127980.

The University of California, San Diego Human Research Protection Program has approved this protocol.
1. Subject Safety and Training
<ol>
	<li>Obtain written, informed consent from the subject. Describe the potential risks presented by exposure to rapidly changing magnetic fields, and the potential discomfort of using facial mask and breathing dry gas.</li>
	<li>Ensure that the subject can safely undergo MR scanning, utilizing the locally approved MRI safety screening questionnaire.</li>
	<l...

<ol>
	<li>S&#225;, R. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Vertical+distribution+of+specific+ventilation+in+normal+supine+humans+measured+by+oxygen-enhanced+proton+MRI.">Vertical distribution of specific ventilation in normal supine humans measured by oxygen-enhanced proton MRI.</a> Journal of Applied Physiology. 109 (6), 1950-1959 (2010).</li><li>Henderson, A. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+gravitational+distribution+of+ventilation-perfusion+ratio+is+more+uniform+in+prone+than+supine+posture+in+the+normal+human+lung.">The gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung.</a> Journal of Applied Physiology. 115 (3), 313-324 (2013).</li><li>Geier, E. T., Neuhart, I., Theilmann, R. J., Prisk, G. K., S&#225;, R. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Spatial+persistence+of+reduced+specific+ventilation+following+methacholine+challenge+in+the+healthy+human+lung.">Spatial persistence of reduced specific ventilation following methacholine challenge in the healthy human lung.</a> Journal of Applied Physiology. 124 (5), 1222-1232 (2018).</li><li>Tedjasaputra, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+heterogeneity+of+regional+specific+ventilation+is+unchanged+following+heavy+exercise+in+athletes.">The heterogeneity of regional specific ventilation is unchanged following heavy exercise in athletes.</a> Journal of Applied Physiology. 115 (1), 126-135 (2013).</li><li>Fowler, W. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lung+Function+Studies.+III.+Uneven+Pulmonary+Ventilation+in+Normal+Subjects+and+in+Patients+with+Pulmonary+Disease.">Lung Function Studies. III. Uneven Pulmonary Ventilation in Normal Subjects and in Patients with Pulmonary Disease.</a> Journal of Applied Physiology. 2 (6), 283-299 (1949).</li><li>Robertson, J. S., Siri, W. E., Jones, H. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lung+ventilation+patterns+determined+by+analysis+of+nitrogen+elimination+rates;+use+of+mass+spectrometer+as+a+continuous+gas+analyzer.">Lung ventilation patterns determined by analysis of nitrogen elimination rates; use of mass spectrometer as a continuous gas analyzer.</a> Journal of Clinical Investigation. 29 (5), 577-590 (1950).</li><li>S&#225;, R. C., Asadi, A. K., Theilmann, R. J., Hopkins, S. R., Prisk, G. K., Darquenne, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Validating+the+distribution+of+specific+ventilation+in+healthy+humans+measured+using+proton+MR+imaging.">Validating the distribution of specific ventilation in healthy humans measured using proton MR imaging.</a> Journal of Applied Physiology. 116 (8), 1048-1056 (2014).</li><li>Musch, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Topographical+distribution+of+pulmonary+perfusion+and+ventilation,+assessed+by+PET+in+supine+and+prone+humans.">Topographical distribution of pulmonary perfusion and ventilation, assessed by PET in supine and prone humans.</a> Journal of Applied Physiology. 93 (5), 1841-1851 (2002).</li><li>Venegas, J. G., Schroeder, T., Harris, R. S., Winkler, R. T., Melo, M. F. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+distribution+of+ventilation+during+bronchoconstriction+is+patchy+and+bimodal:+a+PET+imaging+study.">The distribution of ventilation during bronchoconstriction is patchy and bimodal: a PET imaging study.</a> Respiratory Physiology &amp; Neurobiology. 148 (1-2), 57-64 (2005).</li><li>Orphanidou, D., Hughes, J. M., Myers, M. J., Al-Suhali, A. R., Henderson, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tomography+of+regional+ventilation+and+perfusion+using+krypton+81m+in+normal+subjects+and+asthmatic+patients.">Tomography of regional ventilation and perfusion using krypton 81m in normal subjects and asthmatic patients.</a> Thorax. 41 (7), 542-551 (1986).</li><li>King, G. G., Eberl, S., Salome, C. M., Meikle, S. R., Woolcock, A. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Airway+closure+measured+by+a+technegas+bolus+and+SPECT.">Airway closure measured by a technegas bolus and SPECT.</a> American Journal of Respiratory and Critical Care Medicine. 155 (2), 682-688 (1997).</li><li>Horn, F. C., Deppe, M. H., Marshall, H., Parra-Robles, J., Wild, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantification+of+regional+fractional+ventilation+in+human+subjects+by+measurement+of+hyperpolarized+3He+washout+with+2D+and+3D+MRI.">Quantification of regional fractional ventilation in human subjects by measurement of hyperpolarized 3He washout with 2D and 3D MRI.</a> Journal of Applied Physiology. 116 (2), 129-139 (2014).</li><li>Hamedani, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+hybrid+multibreath+wash-in+wash-out+lung+function+quantification+scheme+in+human+subjects+using+hyperpolarized+3+He+MRI+for+simultaneous+assessment+of+specific+ventilation,+alveolar+oxygen+tension,+oxygen+uptake,+and+air+trapping.">A hybrid multibreath wash-in wash-out lung function quantification scheme in human subjects using hyperpolarized 3 He MRI for simultaneous assessment of specific ventilation, alveolar oxygen tension, oxygen uptake, and air trapping.</a> Magnetic Resonance in Medicine. 78 (2), 611-624 (2017).</li><li>Hall, E. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effect+of+supine+exercise+on+the+distribution+of+regional+pulmonary+blood+flow+measured+using+proton+MRI.">The effect of supine exercise on the distribution of regional pulmonary blood flow measured using proton MRI.</a> Journal of Applied Physiology. 116 (4), 451-461 (2014).</li><li>Henderson, A. C., S&#225;, R. C., Barash, I. A., Holverda, S., Buxton, R. B., Prisk, G. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+intravenous+infusion+of+20mL/kg+saline+alters+the+distribution+of+perfusion+in+healthy+supine+humans.">Rapid intravenous infusion of 20mL/kg saline alters the distribution of perfusion in healthy supine humans.</a> Respiratory Physiology &amp; Neurobiology. 180 (2-3), 331-341 (2012).</li><li>Arai, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+quantitative+multiple-breath+specific+ventilation+imaging+using+colocalized+2D+oxygen-enhanced+MRI+and+hyperpolarized+3He+MRI.">Comparison of quantitative multiple-breath specific ventilation imaging using colocalized 2D oxygen-enhanced MRI and hyperpolarized 3He MRI.</a> Journal of Applied Physiology. 125 (5), 1526-1535 (2018).</li><li>Chen, Q., Jakob, P. M., Griswold, M. A., Levin, D. L., Hatabu, H., Edelman, R. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oxygen+enhanced+MR+ventilation+imaging+of+the+lung.">Oxygen enhanced MR ventilation imaging of the lung.</a> Magma: Magnetic Resonance Materials in Physics, Biology, and Medicine. 7 (3), 153-161 (1998).</li><li>. Deforminator: Projective transformation to register small scale Lung deformation Available from: <a target="_blank" href="https://github.com/UCSDPulmonaryImaging/Deforminator">https://github.com/UCSDPulmonaryImaging/Deforminator</a> (2019)</li><li>Yang, G., Stewart, C. V., Sofka, M., Tsai, C. -. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Registration+of+Challenging+Image+Pairs:+Initialization,+Estimation,+and+Decision.">Registration of Challenging Image Pairs: Initialization, Estimation, and Decision.</a> IEEE Transactions on Pattern Analysis and Machine Intelligence. 29 (11), 1973-1989 (2007).</li><li>Arai, T. J., Villongco, C. T., Villongco, M. T., Hopkins, S. R., Theilmann, R. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Affine+transformation+registers+small+scale+lung+deformation.">Affine transformation registers small scale lung deformation.</a> Conf Proc IEEE Eng Med Biol Soc. 2012, 5298-5301 (2012).</li><li>Theilmann, R. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+MRI+measurement+of+lung+density+must+account+for+the+change+in+T(2)+(*)+with+lung+inflation.">Quantitative MRI measurement of lung density must account for the change in T(2) (*) with lung inflation.</a> Journal of Magnetic Resonance Imaging. 30 (2), 527-534 (2009).</li><li>Arai, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Magnetic+Resonance+Imaging+Quantification+of+Pulmonary+Perfusion+using+Calibrated+Arterial+Spin+Labeling.">Magnetic Resonance Imaging Quantification of Pulmonary Perfusion using Calibrated Arterial Spin Labeling.</a> Journal of Visualized Experiments. 51 (51), e2712 (2011).</li><li>Lewis, S. M., Evans, J. W., Jalowayski, A. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Continuous+Distributions+of+Specific+Ventilation+Recovered+From+Inert-Gas+Washout.">Continuous Distributions of Specific Ventilation Recovered From Inert-Gas Washout.</a> Journal of Applied Physiology. 44 (3), 416-423 (1978).</li><li>Cook, F. R., Geier, E. T., Asadi, A. K., S&#225;, R. C., Prisk, G. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+Prototyping+of+Inspired+Gas+Delivery+System+for+Pulmonary+MRI+Research.">Rapid Prototyping of Inspired Gas Delivery System for Pulmonary MRI Research.</a> 3D Printing and Additive Manufacturing. 2 (4), 196-203 (2015).</li><li>Zapol, W. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pulmonary+Delivery+of+Therapeutic+and+Diagnostic+Gases.">Pulmonary Delivery of Therapeutic and Diagnostic Gases.</a> Journal of Aerosol Medicine and Pulmonary Drug Delivery. 31 (2), 78-87 (2018).</li><li>Kang, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+silico+modeling+of+oxygen-enhanced+MRI+of+specific+ventilation.">In silico modeling of oxygen-enhanced MRI of specific ventilation.</a> Physiological Reports. 6 (7), e13659 (2018).</li></ol>

Specific ventilation imaging allows quantitative mapping of the spatial distribution of specific ventilation in the human lung. Alternatives to SVI exist but are limited in some manner: Multiple breath washout provides a measure of heterogeneity but lacks spatial information23. Alternative imaging methods expose patients to ionizing radiation (e.g., SPECT, PET, CT, gamma scintigraphy) or are not widely available (hyperpolarized gas imaging using MRI). Specific ventilation imaging provides spatial ...

The overall goal of specific ventilation imaging (SVI) &#8213; a proton magnetic resonance imaging (MRI) technique that uses oxygen as a contrast agent1 &#8213; is to quantitatively map specific ventilation in the human lung. Specific ventilation is the ratio of fresh gas delivered to a lung region in one breath divided by the end expiratory volume of the same lung region1. In conjunction with measurements of local lung density, specific ventilation can be used to compute regional ventilation2. Measurements of local ventilation and ventilation heterogeneity that are provided by SVI have the potential to enrich the understanding of how the lung functions, both normally and abnormally3,4.
Specific ventilation imaging is an extension of the classical physiology test, multiple breath washout (MBW), a technique first introduced in the 1950s5,6. Both techniques use gas washin/washout to measure heterogeneity of specific ventilation, but SVI provides spatially-localized information while MBW provides only global measures of heterogeneity. In MBW, a mass spectrometer is used to measure the mixed expired concentration of an insoluble gas (nitrogen, helium, sulfur hexafluoride, etc.) over many breaths during a washout of that gas, as depicted in Figure 1. Along with the expired volume per breath during the washout period, this information can be used to compute the overall distribution of specific ventilation in the lung. In SVI, an MRI scanner is used to measure the T1-weighted signal &#8213; which is a surrogate for the amount of oxygen in solution in lung tissue, a direct indicator of local oxygen concentration &#8213; in each lung voxel over many breaths during several washin/washouts of oxygen. In a way that is directly analogous to MBW, this information allows us to compute the specific ventilation of each lung voxel. In other words, the technique performs thousands of parallel MBW-like experiments, one for each voxel, during an SVI experiment. Indeed, the spatial maps of specific ventilation thus produced can be compiled to recover the specific ventilation heterogeneity output of MBW. A validation study7 showed that the two methodologies produced comparable results when performed in series on the same subjects.
Other imaging modalities exist that, like SVI, provide spatial measures of ventilation heterogeneity. Positron emission tomography (PET)8,9, single-photon emission computed tomography (SPECT)10,11, and hyperpolarized gas MRI12,13 techniques have been used to create a substantial body of literature regarding the spatial pattern of ventilation in healthy and abnormal subjects. In general, these techniques have at least one distinct advantage over SVI, in that their signal-to-noise ratio is characteristically higher. However, each technique also has a characteristic disadvantage: PET and SPECT involve exposure to ionizing radiation, and hyperpolarized MRI requires the use of highly specialized hyperpolarized gas and a MR scanner with non-standard multi-nuclei hardware.
SVI, a proton-MRI technique, typically uses 1.5 Tesla MR hardware with inhaled oxygen as a contrast agent (both elements are readily available in healthcare), making it potentially more generalizable to the clinical environment. SVI leverages the fact that oxygen shortens the longitudinal relaxation time (T1) of lung tissues1, which in turn translates to a change in signal intensity in a T1-weighted image. Thus, changes in the concentration of inspired oxygen induce change in signal intensity of appropriately timed MRI images. The rate of this change following an abrupt change in inspired oxygen concentration, typically air and 100% oxygen, reflects the rate at which resident gas is replaced by the inhaled gas. This replacement rate is determined by specific ventilation.
As SVI involves no ionizing radiation, it has no contraindications for longitudinal and interventional studies that follow patients over time. Thus, it is ideally suited for studying disease progression or evaluating how individual patients responds to treatment. Due to its relative ease and safe repeatability, specific ventilation imaging is, in general, an ideal technique for those who wish to study large effects and/or a large number of people over time or in several different clinical locations.
Following the original publication describing the technique1, specific ventilation imaging (SVI) has been used in studies focused on the effect of rapid saline infusion, posture, exercise, and bronchoconstriction2,3,4,14,15. The technique&#8217;s ability to estimate whole lung heterogeneity of specific ventilation has been validated using the well-established multiple breath washout test7 and more recently, a regional a cross-validation was performed, by comparing SVI and hyperpolarized gas multiple breath specific ventilation imaging16. This reliable and readily deployable technique, capable of quantitatively mapping specific ventilation in the human lung, has the potential to significantly contribute to early detection and diagnosis of respiratory disease. It also presents new opportunities to quantify regional lung abnormalities and follow changes induced by therapy. These changes in region-specific lung function, which SVI enables us to measure for the first time, have the potential to become biomarkers for assessing the impact of drugs and inhaled therapies, and could be an extremely useful tool in clinical trials.
The purpose of this article is to present the methodology of specific ventilation imaging in detail and in a visual form, thus contributing to the dissemination of the technique to more centers.

<table>
	<tbody>
		<tr>
			<td>3D-printed flow bypass system</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Face mask</td>
			<td>Hans Rudolph</td>
			<td></td>
			<td>7400 series Oro-nasal mask, different sizes</td>
		</tr>
		<tr>
			<td>Gas/oxygen regulator</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Mask head set</td>
			<td>Hans Rudolph</td>
			<td></td>
			<td>7400 compatible head set</td>
		</tr>
		<tr>
			<td>Matlab</td>
			<td>Mathworks</td>
			<td></td>
			<td>analysis software developed locally</td>
		</tr>
		<tr>
			<td>Medical oxygen</td>
			<td>Air Liquide/Linde</td>
			<td></td>
			<td>Oxygen to be delivered to the subject</td>
		</tr>
		<tr>
			<td>MRI</td>
			<td>GE healthcare</td>
			<td></td>
			<td>1.5 T GE HDx Excite twin-speed scanner</td>
		</tr>
		<tr>
			<td>Plastic tubing</td>
			<td></td>
			<td></td>
			<td>&#188;&#8221;, 3/8&#8221; and 1/2&#8221; tubing and connectors</td>
		</tr>
		<tr>
			<td>Pulse oximeter</td>
			<td>Nonin</td>
			<td></td>
			<td>7500 FO (MR compatible)</td>
		</tr>
		<tr>
			<td>Switch valve</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Torso coil</td>
			<td>GE healthcare</td>
			<td></td>
			<td>High gain torso coil for GE scanner</td>
		</tr>
	</tbody>
</table>

quantitative mapping of specific ventilation in the human lung using proton magnetic resonance imaging and oxygen as a contrast agent

Specific ventilation imaging (SVI) is a functional magnetic resonance imaging technique capable of quantifying specific ventilation &#8213; the ratio of the fresh gas entering a lung region divided by the region&#8217;s end-expiratory volume &#8213; in the human lung, using only inhaled oxygen as a contrast agent. Regional quantification of specific ventilation has the potential to help identify areas of pathologic lung function. Oxygen in solution in tissue shortens the tissue&#8217;s longitudinal relaxation time (T1), and thus a change in tissue oxygenation can be detected as a change in T1-weighted signal with an inversion recovery acquired image. Following an abrupt change between two concentrations of inspired oxygen, the rate at which lung tissue within a voxel equilibrates to a new steady-state reflects the rate at which resident gas is being replaced by inhaled gas. This rate is determined by specific ventilation. To elicit this sudden change in oxygenation, subjects alternately breathe 20-breath blocks of air (21% oxygen) and 100% oxygen while in the MRI scanner. A stepwise change in inspired oxygen fraction is achieved through use of a custom three-dimensional (3D)-printed flow bypass system with a manual switch during a short end-expiratory breath hold. To detect the corresponding change in T1, a global inversion pulse followed by a single shot fast spin echo sequence was used to acquire two-dimensional T1-weighted images in a 1.5&#160;T MRI scanner, using an eight-element torso coil. Both single slice and multi-slice imaging are possible, with slightly different imaging parameters. Quantification of specific ventilation is achieved by correlating the time-course of signal intensity for each lung voxel with a library of simulated responses to the air/oxygen stimulus. SVI estimations of specific ventilation heterogeneity have been validated against multiple breath washout and proved to accurately determine the heterogeneity of the specific ventilation distribution.

Single slice SVI in a healthy subject 
Specific ventilation imaging produces quantitative maps of specific ventilation as shown in Figure 3A, which depicts a single slice in the right lung of a 39-year-old healthy female. Note the presence of the expected vertical gradient in specific ventilation; the dependent portion of the lung presents higher specific ventilation than the non-dependent portion of the lung. A histogram of the mapped specific vent...

Watch this Scientific Journal Video about Quantitative Mapping of Specific Ventilation in the Human Lung using Proton Magnetic Resonance Imaging and Oxygen as a Contrast Agent at JoVE.com

Quantitative Mapping of Specific Ventilation in the Human Lung using Proton Magnetic Resonance Imaging and Oxygen as a Contrast Agent

Specific ventilation imaging is a functional magnetic resonance imaging technique that allows for quantification of regional specific ventilation in the human lung, using inhaled oxygen as a contrast agent. Here, we present a protocol to collect and analyze specific ventilation imaging data.

Specific ventilation imaging (SVI) is a functional magnetic resonance imaging technique capable of quantifying specific ventilation &#8213; the ratio of ...

Specific Ventilation Imaging, or SVI, is a qualitative lung imaging technique that will help us further our fundamental understanding of physiology and the management of respiratory diseases. SVI is radiation-free and requires only commonly available equipment, an MRI scanner and medical oxygen. This makes it safe for children and ideal for repeat studies in adults.The translation of SVI to clinical practice may improve the management of asthma because it will allow us to identify areas that are most affected by the disease. The ability to map changes within the lung in response to therapy may help optimize inhale therapy and inform individualized therapeutic choices. Helping demonstrate this procedure is Vincent Tedjasaputra, a post-doctoral fellow in the Department of Medicine.Begin beginning the procedure, obtain written informed consent from the subject and describe the potential risks presented by the exposure to rapidly changing magnetic fields and the potential discomfort of using a facial mask and breathing dry gas. Confirm that the subject can safely undergo magnetic resonance scanning utilizing the locally approved Magnetic Resonance Imaging or MRI safety screening questionnaire. Train the subject to breathe in time with the MR scan sequence and measure the subject's nose to chin dimensions to determine the size of the face mask that will best fit the subject.Then verify that the subject's pockets and clothing are free from magnetic-based credit cards and iron-containing metal pieces. To prepare the MR scanner, connect a torso coil to the appropriate connector in the scanner table to configure the scanner for use and place sheets, pads, and pillows on the scanner table so that the subject will be comfortable for at least 30 minutes of imaging. To assemble the oxygen delivery system, place a two-way switch valve within reach of the scanner operator and use a piece of eight meter length one-quarter inch diameter plastic tubing to connect the oxygen supply to one inlet of the switch valve.Connect the outlet of the switch valve in the control room to the one-quarter plastic tubing and feed the tubing through the pass through of the control room to the scanner room taking care that the tubing reaches the middle of the scanner bore. Secure the flow bypass attachment to the face mask for the subject. Connect the half-inch brass end of the tubing to the flow bypass mask attachment.Set the pressure on the oxygen supply outlet regulator to a value that produces a flow of oxygen greater than the expected peak inspiratory flow according to the nature of the study and the overall resistance of the gas delivery system. Then activate the flow of oxygen to test the switch valve, making sure an adequate flow is present at the outlet of the flow bypass attachment and that no leaks are present in the plastic tubing. To prepare the subject for the imaging, have the subject lie on the scanner table making sure that the top of the lower coil element is higher than the subject's shoulders to ensure that the top of the lower coil element provides an adequate coverage of the lung apices.Have the subject insert ear plugs and verify that sound is being blocked. Tape a safety mechanism to the subject's wrist so that it can be easily accessed and attach the mask and flow bypass system to the subject's face. Briefly occlude the expiratory side of the flow bypass attachment and ask the subject to attempt a normal inspiration and expiration to check for leaks.Now load the subject into the scanner using the light centering tool to make sure that the torso coil occupies the center of the bore and guide the flow bypass line to assure subject comfort while moving the subject towards the center of the scanner. After selecting the lung location for imaging slices, acquire a localizer sequence to obtain an anatomical map that will be used to prescribe the rest of the exam. Use the scanner graphical user interface to click and drag the imaging slice centered in the lung field targeting the region of interest to the desired location to select up to four sagittal lung slices to be studied.Then make a note of the location of the imaging slices with respect to the location of the spinal column so that the same volume can be re-imaged for longitudinal studies. For specific ventilation imaging, set the inversion time in the MR computer for the most medial slice to 1100 milliseconds to maximum the air oxygen contrast, the number of repetitions to 220, and the repetition time to five seconds. Monitor the consistency of the subject's lung volume and expiration during subsequent acquisitions and provide feedback to improve the quality if necessary.Switch the subject's inspired gas mixture every 20 breaths during the acquisition breath hold for the subject's comfort, alternating between the room air and medical oxygen. Check the pulse oximeter regularly to verify the heart rate and oxygen saturation and check in with the subject frequently to give regular updates of the time remaining. After breath 220, the imaging is complete.Return the subject to room air and remove them from the scanner. To create a specific ventilation map, import the images for registration into the image analysis software and visually inspect the entire 220 image stack to select the image for each slice that best represents the functional residual capacity. Using the mode image as a reference, use projective or a fine registration to register all of the images to the functional residual capacity reference and quantify the specific ventilation in the lung from the registered stack using an appropriate algorithm.A map of the specific ventilation will be created. SVI produces quantitative maps of specific ventilation, for example as shown in this single slice image in the right lung of a 39-year-old healthy female. Note the presence of the expected vertical gradient in the specific ventilation with the dependent portion of the lung presenting a higher specific ventilation than the non-dependent portion of the lung.A histogram of the map specific ventilation values with a best fit log normal probability distribution function allows the width of the best fit distribution to be used as a metric of specific ventilation heterogeneity. Here, a multiple breath washout acquired in the same subject in the same posture is shown. The temporal recording of nitrogen concentration was measured at the mouth following a shift from inspired air to inspired 100%oxygen.In this distribution of specific ventilation as estimated from the washout for both specific ventilation imaging and multiple breath washout, the width of the distribution was found to be within healthy normal range. Training the subjects to breath in time with the scanner and giving them feedback during acquisition can help to ensure good quality data. Combined with measurements of density and perfusion, SVI can be used to map the local ratio of ventilation to perfusion and measure of gas exchange efficiency.This technique has been used to understand distribution of ventilation after strenuous exercise and a special panel of repeated bronchial restriction in asthma. The MRI environment requires attention to safety as a strong magnetic field is always on and ferromagnetic objects can become projectile resulting in injury.

quantitative-mapping-specific-ventilation-human-lung-using-proton

Research

JoVE Journal

Medicine

Magnetic Resonance Derived Myocardial Strain Assessment Using Feature Tracking

Purpose: An accurate and practical method to measure parameters like strain in myocardial tissue is of great clinical value, since it has been shown, that strain is a more sensitive and earlier marker for contractile dysfunction than the frequently used parameter EF. Current technologies for CMR are time consuming and difficult to implement in clinical practice. Feature tracking is a technology that can lead to more automization and robustness of quantitative analysis of medical images with less time consumption than comparable methods.
Methods: An automatic or manual input in a single phase serves as an initialization from which the system starts to track the displacement of individual patterns representing anatomical structures over time. The specialty of this method is that the images do not need to be manipulated in any way beforehand like e.g. tagging of CMR images.
Results: The method is very well suited for tracking muscular tissue and with this allowing quantitative elaboration of myocardium and also blood flow.
Conclusions: This new method offers a robust and time saving procedure to quantify myocardial tissue and blood with displacement, velocity and deformation parameters on regular sequences of CMR imaging. It therefore can be implemented in clinical practice.

An accurate and practical method to measure parameters like strain in myocardial tissue is of great clinical value, since it has been shown, that strain is a more sensitive and earlier marker for contractile dysfunction than the frequently used parameter EF.

Purpose: An accurate and practical method to measure parameters like strain in myocardial tissue is of great clinical value, since it has been shown, that ...

Magnetic Resonance Imaging Quantification of Pulmonary Perfusion using Calibrated Arterial Spin Labeling

This demonstrates a MR imaging method to measure the spatial distribution of pulmonary blood flow in healthy subjects 
during normoxia (inspired O2, fraction (FIO2) = 0.21) hypoxia (FIO2 = 0.125), and hyperoxia 
(FIO2 = 1.00). In addition, the physiological responses of the subject are monitored in the MR scan environment. MR images 
were obtained on a 1.5 T GE MRI scanner during a breath hold from a sagittal slice in the right lung at functional residual capacity. An arterial 
spin labeling sequence (ASL-FAIRER) was used to measure the spatial distribution of pulmonary blood flow 1,2 and a multi-echo fast 
gradient echo (mGRE) sequence 3 was used to quantify the regional proton (i.e. H2O) density, allowing the quantification 
of density-normalized perfusion for each voxel (milliliters blood per minute per gram lung tissue). 
With a pneumatic switching valve and facemask equipped with a 2-way non-rebreathing valve, different oxygen concentrations 
were introduced to the subject in the MR scanner through the inspired gas tubing. A metabolic cart collected expiratory gas via expiratory tubing. Mixed expiratory O2 and CO2 concentrations, oxygen consumption, carbon dioxide production, respiratory exchange ratio, 
respiratory frequency and tidal volume were measured. Heart rate and oxygen saturation were monitored using pulse-oximetry. 
Data obtained from a normal subject showed that, as expected, heart rate was higher in hypoxia (60 bpm) than during normoxia (51) or hyperoxia (50) and the arterial oxygen saturation (SpO2) was reduced during hypoxia to 86%. Mean ventilation was 8.31 L/min BTPS during hypoxia, 7.04 L/min during normoxia, and 6.64 L/min during hyperoxia. Tidal volume was 0.76 L during hypoxia, 0.69 L during normoxia, and 0.67 L during hyperoxia. 
Representative quantified ASL data showed that the mean density normalized perfusion was 8.86 ml/min/g during hypoxia, 8.26 ml/min/g during normoxia and 8.46 ml/min/g during hyperoxia, respectively. In this subject, the relative dispersion4, an index of global heterogeneity, was increased in hypoxia (1.07 during hypoxia, 0.85 during normoxia, and 0.87 during hyperoxia) while the fractal dimension (Ds), another index of heterogeneity reflecting vascular branching structure, was unchanged (1.24 during hypoxia, 1.26 during normoxia, and 1.26 during hyperoxia). 
Overview. This protocol will demonstrate the acquisition of data to measure the distribution of pulmonary perfusion noninvasively under conditions of normoxia, hypoxia, and hyperoxia using a magnetic resonance imaging technique known as arterial spin labeling (ASL). 
Rationale: Measurement of pulmonary blood flow and lung proton density using MR technique offers high spatial resolution images which can be quantified and the ability to perform repeated measurements under several different physiological conditions. In human studies, PET, SPECT, and CT are commonly used as the alternative techniques. However, these techniques involve exposure to ionizing radiation, and thus are not suitable for repeated measurements in human subjects.

A MR imaging method to study the distribution of pulmonary blood flow under a variety of physiological conditions, in this case exposure to three different inspired oxygen concentrations: hypoxia, normoxia, and hyperoxia, is described. This technique utilizes human pulmonary physiology research techniques in an MR scanning environment.

This demonstrates a MR imaging method to measure the spatial distribution of pulmonary blood flow in healthy subjects 
during normoxia (inspired O2, ...

Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.
For this purpose, we injected 105 MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg1. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula1. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US).
MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified2-4. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions5,6. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles7.
In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions.

In the pathogenesis of bone metastasis, angiogenesis is a crucial process and therefore represents a target for imaging and therapy. Here, we present a rat model of site-specific breast cancer bone metastasis and describe strategies to non-invasively image angiogenesis in vivo using magnetic resonance imaging, volumetric computed tomography and ultrasound.

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell ...

In vivo Macrophage Imaging Using MR Targeted Contrast Agent for Longitudinal Evaluation of Septic Arthritis

Macrophages are key-cells in the initiation, the development and the regulation of the inflammatory response to bacterial infection. Macrophages are intensively and increasingly recruited in septic joints from the early phases of infection and the infiltration is supposed to regress once efficient removal of the pathogens is obtained. The ability to identify in vivo macrophage activity in an infected joint can therefore provide two main applications: early detection of acute synovitis and monitoring of therapy.
In vivo noninvasive detection of macrophages can be performed with magnetic resonance imaging using iron nanoparticles such as ultrasmall superparamagnetic iron oxide (USPIO). After intravascular or intraarticular administration, USPIO are specifically phagocytized by activated macrophages, and, due to their magnetic properties, induce signal changes in tissues presenting macrophage infiltration. A quantitative evaluation of the infiltrate is feasible, as the area with signal loss (number of dark pixels) observed on gradient echo MR images after particles injection is correlated with the amount of iron within the tissue and therefore reflects the number of USPIO-loaded cells.
We present here a protocol to perform macrophage imaging using USPIO-enhanced MR imaging in an animal model of septic arthritis, allowing an initial and longitudinal in vivo noninvasive evaluation of macrophages infiltration and an assessment of therapy action.

In vivo Macrophage Imaging Using MR Targeted Contrast Agent for Longitudinal Evaluation of Septic Arthritis

We demonstrate how to perform macrophage MR imaging using ultrasmall superparamagnetic contrast agent (USPIO) in septic arthritis, allowing an initial and longitudinal in vivo non-invasive evaluation of macrophages infiltration and an assessment of therapy efficacy.

Macrophages are key-cells in the initiation, the development and the regulation of the inflammatory response to bacterial infection. Macrophages are ...

Quantitative Magnetic Resonance Imaging of Skeletal Muscle Disease

Quantitative magnetic resonance imaging (qMRI) describes the development and use of MRI to quantify physical, chemical, and/or biological properties of living systems. Neuromuscular diseases often exhibit a temporally varying, spatially heterogeneous, and multi-faceted pathology. The goal of this protocol is to characterize this pathology using qMRI methods. The MRI acquisition protocol begins with localizer images (used to locate the position of the body and tissue of interest within the MRI system), quality control measurements of relevant magnetic field distributions, and structural imaging for general anatomical characterization. The qMRI portion of the protocol includes measurements of the longitudinal and transverse relaxation time constants (T1 and T2, respectively). Also acquired are diffusion-tensor MRI data, in which water diffusivity is measured and used to infer pathological processes such as edema. Quantitative magnetization transfer imaging is used to characterize the relative tissue content of macromolecular and free water protons. Lastly, fat-water MRI methods are used to characterize fibro-adipose tissue replacement of muscle. In addition to describing the data acquisition and analysis procedures, this paper also discusses the potential problems associated with these methods, the analysis and interpretation of the data, MRI safety, and strategies for artifact reduction and protocol optimization.

Neuromuscular diseases often exhibit a temporally varying, spatially heterogeneous, and multi-faceted pathology. The goal of this protocol is to characterize this pathology using non-invasive magnetic resonance imaging methods.

Quantitative magnetic resonance imaging (qMRI) describes the development and use of MRI to quantify physical, chemical, and/or biological properties of ...

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neovascularization, and tumor cell invasion. We have recently established a protocol of DCE-MRI of orthotopic pancreatic tumor xenografts in mouse models by securing tumors with an orthogonally bent plastic board to prevent motion transfer from the chest region during imaging. The pressure by this board was localized on the abdominal area, and has not resulted in respiratory difficulty of the animals. This article demonstrates the detailed procedure of orthotopic pancreatic tumor modeling using small animals and DCE-MRI of the tumor xenografts. Quantification method of pharmacokinetic parameters in DCE-MRI is also introduced. The procedure described in this article will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.

The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy.

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe ...

Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle

Skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, which is critically important in health and disease, can be measured in vivo and noninvasively in humans via phosphorus-31 magnetic resonance spectroscopy (31PMRS). However, the approach has not been widely adopted in translational and clinical research, with variations in methodology and limited guidance from the literature. Increased optimization, standardization, and dissemination of methods for in vivo 31PMRS would facilitate the development of targeted therapies to improve OXPHOS capacity and could ultimately favorably impact cardiovascular health. 31PMRS produces a noninvasive, in vivo measure of OXPHOS capacity in human skeletal muscle, as opposed to alternative measures obtained from explanted and potentially altered mitochondria via muscle biopsy. It relies upon only modest additional instrumentation beyond what is already in place on magnetic resonance scanners available for clinical and translational research at most institutions. In this work, we outline a method to measure in vivo skeletal muscle OXPHOS. The technique is demonstrated using a 1.5 Tesla whole-body MR scanner equipped with the suitable hardware and software for 31PMRS, and we explain a simple and robust protocol for in-magnet resistive exercise to rapidly fatigue the quadriceps muscle. Reproducibility and feasibility are demonstrated in volunteers as well as subjects over a wide range of functional capacities.

Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle

This work demonstrates the feasibility of an in vivo phosphorus-31 magnetic resonance spectroscopy (31PMRS) technique to quantify mitochondrial oxidative phosphorylation (OXPHOS) capacity in human skeletal muscle.

Skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, which is critically important in health and disease, can be measured in vivo ...

Cardiac Magnetic Resonance Imaging at 7 Tesla

CMR at an ultra-high field (magnetic field strength B0&#160;&#8805; 7 Tesla) benefits from the signal-to-noise ratio (SNR) advantage inherent at higher magnetic field strengths and potentially provides improved signal contrast and spatial resolution. While promising results have been achieved, ultra-high field CMR is challenging due to energy deposition constraints and physical phenomena such as transmission field non-uniformities and magnetic field inhomogeneities. In addition, the magneto-hydrodynamic effect renders the synchronization of the data acquisition with the cardiac motion difficult. The challenges are currently addressed by explorations into novel magnetic resonance technology. If all impediments can be overcome, ultra-high field CMR may generate new opportunities for functional CMR, myocardial tissue characterization, microstructure imaging or metabolic imaging. Recognizing this potential, we show that multi-channel radio frequency (RF) coil technology tailored for CMR at 7 Tesla together with higher order B0 shimming and a backup signal for cardiac triggering facilitates high fidelity functional CMR. With the proposed setup, cardiac chamber quantification can be accomplished in examination times similar to those achieved at lower field strengths. To share this experience and to support the dissemination of this expertise, this work describes our setup and protocol tailored for functional CMR at 7 Tesla.

The sensitivity gain inherent to ultrahigh field magnetic resonance holds promise for high spatial resolution imaging of the heart. Here, we describe a protocol customized for functional cardiovascular magnetic resonance (CMR) at 7 Tesla using an advanced multi-channel radio-frequency coil, magnetic field shimming and a triggering concept.

CMR at an ultra-high field (magnetic field strength B0&#160;&#8805; 7 Tesla) benefits from the signal-to-noise ratio (SNR) advantage inherent at higher ...

In Vivo Morphometric Analysis of Human Cranial Nerves Using Magnetic Resonance Imaging in Meni&#232;re's Disease Ears and Normal Hearing Ears

Analysis of neural structures in Meni&#232;re's Disease (MD) is of importance, since a loss of such structures has previously been proposed for this patient group but has yet to be confirmed. This protocol describes a method of in vivo evaluation of neural changes especially well suitable for cranial nerve analysis using magnetic resonance imaging (MRI). MD-patients and normal hearing persons were examined in a 3-T MR-scanner using a scan protocol including strongly T2-weighted 3D gradient-echo-sequence (3D-CISS). In the patient group, MD was additionally confirmed using MRI-based assessment of endolymphatic hydrops. Morphometric analysis was performed using a freeware DICOM viewer. Evaluation of cranial nerves included measurements of cross-sectional areas (CSAs) of the nerves at different levels as well as orthogonal diametric measurements.

&lt;em&gt;In Vivo&lt;/em&gt; Morphometric Analysis of Human Cranial Nerves Using Magnetic Resonance Imaging in Meni&amp;#232;re&#039;s Disease Ears and Normal Hearing Ears

To evaluate morphological changes of cranial nerves such as loss of neural structures or swelling of cranial nerves in Meni&#232;re&#39;s Disease (MD) or in healthy persons in vivo, a protocol of evaluation has been developed using magnetic resonance imaging (MRI). Additional MRI-based confirmation of MD was performed.

Analysis of neural structures in Meni&#232;re's Disease (MD) is of importance, since a loss of such structures has previously been proposed for this ...

Phase Contrast Magnetic Resonance Imaging in the Rat Common Carotid Artery

Phase contrast magnetic resonance imaging (PC-MRI) is a noninvasive approach that can quantify flow-related parameters such as blood flow. Previous studies have shown that abnormal blood flow may be associated with systemic vascular risk. Thus, PC-MRI can facilitate the translation of data obtained from animal models of cardiovascular diseases to pertinent clinical investigations. In this report, we describe the procedure for measuring blood flow in the common carotid artery (CCA) of rats using cine-gated PC-MRI and discuss relevant analysis methods. This procedure can be performed in a live, anesthetized animal and does not require euthanasia after the procedure. The proposed scanning parameters yield repeatable measurements for blood flow, indicating excellent reproducibility of the results. The PC-MRI procedure described in this article can be used for pharmacological testing, pathophysiological assessment, and cerebral hemodynamics evaluation.

The overall goal of this procedure is to measure the blood flow in the rat common carotid artery by using noninvasive phase contrast magnetic resonance imaging.

Phase contrast magnetic resonance imaging (PC-MRI) is a noninvasive approach that can quantify flow-related parameters such as blood flow. Previous ...