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>
	<li>If the subject is a female of childbearing age, and uncertain of her pregnancy status, ask her to self-administer an over-the-counter pregnancy test. If the subject is pregnant, exclude the subject from the remainder of the study.</li>
	<li>Measure the subject&#8217;s weight. Scanner safety parameters that limit the amount of radio frequency (RF) energy delivered to the subject require input of this characteristic. Verify that the subject&#8217;s weight is below the maximal weight limit of the MRI table (in this case, 136 kg).</li>
	<li>Train the subject to breathe in time with the MR scan sequence. Preferably, play an audio recording of a previous scan and instruct the subject to breathe normally and complete a breath every 5 s, using the audio cues from the scanner as guide; breathe along with the subject for the purpose of training.</li>
	<li>Determine the size of the face mask (sizes range from petite to extra-large [XL]) that best fits the subject by measuring the subject&#8217;s nose-to-chin dimensions. An appropriately-sized mask will fit comfortably yet will prevent air from leaking in between the mask and the subject&#8217;s skin at any point. Try on other sizes if necessary.</li>
	<li>Verify that the subject&#8217;s pockets and clothing are free from magnetic-based credit cards and iron-containing metal pieces. If required, have the subject change into the medical gown provided by the MRI facility. 
	NOTE: Metal can be hazardous in the MRI environment, and metallic objects such as clips (typically in bras), metal rings (bras and hoodies), metal button or zippers (shirts, sweaters), hair extension and wigs have the potential to create imaging artifacts.</li>
</ol>
2. Preparation of the MRI Environment
<ol>
	<li>Only allow personnel trained in MRI safety to the standards of the imaging facility to enter the scanner room or assist in performing this experiment.</li>
	<li>Configure the MR scanner for use with a torso coil by connecting the coil to the appropriate connector in the scanner table.</li>
	<li>Prepare the scanner table with sheets, pads, and pillows so that the subject will be comfortable for at least 30 min during imaging.</li>
	<li>Assemble the oxygen delivery system. 
	NOTE: A schematic diagram of the tubing is presented in Figure 2.
	<ol>
		<li>Place a two/three-way switching valve within reach of the scanner operator or person performing the SVI experiment.</li>
		<li>Connect either the tank of medical oxygen (outside the scanner room) or the oxygen wall supply (if available) to one inlet of the switching valve using &#188;-inch plastic tubing.</li>
		<li>Connect the outlet of the switch valve located in the control room to the 8 m (sufficient length for the scanner) &#188;-inch plastic tubing. Feed the tubing through the pass-through, from the control room to the scanner room, and ensure that it will reach the middle of the scanner bore. 
		NOTE: The plastic tubing connecting the switching valve outlet to the flow-bypass mask included a step up in diameter in the last 2 m, from &#188; inch to 3/8 inch to &#189; inch, in order to decrease the noise produced by air flowing into the flow bypass system.</li>
		<li>Connect the &#189; inch end of the tubing to the flow-bypass mask attachment.</li>
		<li>Secure the flow-bypass attachment to the face mask that fits the subject.</li>
		<li>Set the pressure on the gas tank or wall outlet regulator to a value that produces a flow of oxygen greater than the expected peak inspiratory flow. The pressure needed depends on the nature of the study (rest, exercise, etc.) and the overall resistance of the gas delivery system (typically ~70 psi for the delivery system described in step 2.4.3 for studies at rest).</li>
		<li>Test the switch valve by activating the flow of oxygen, making sure adequate flow is present at the outlet of the flow-bypass attachment and that no leaks are present in the plastic tubing.</li>
	</ol>
	</li>
</ol>
3. Instrumenting and Preparing the Subject for Imaging
<ol>
	<li>Have the subject lie on the MRI table. Make sure the top of the lower-coil element provides adequate coverage of the lung apices, by making sure the top of the lower-coil element is higher than the subject&#8217;s shoulders.</li>
	<li>Have the subject insert earplugs and verify that sound is being blocked.</li>
	<li>Tape the squeeze ball (or an alternate safety mechanism) to the subject&#8217;s wrist so that it can be easily accessed.</li>
	<li>Attach the mask and flow-bypass system to the subject&#8217;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.</li>
	<li>Place the subject into the scanner, using the light centering tool to make sure that the torso coil occupies the center of the bore.</li>
	<li>Connect the flow bypass line to the 3D printed flow-bypass mask attachment using the tight-fitting brass nut to the inlet.</li>
</ol>
4. MRI Imaging
<ol>
	<li>Select the anatomical location for imaging slices.
	<ol>
		<li>Acquire a localizer sequence to obtain an anatomical map that will be used to prescribe the rest of the exam.</li>
		<li>Select up to 4 sagittal lung slices to be studied by clicking and dragging the imaging slice to the desired location using the scanner graphical user interface. Typically, the field of view is set to 40 x 40 cm and slice thickness to 1.5 cm. Select slices centered in the lung field targeting the region of interest for the study, typically minimizing the intrusion of large pulmonary vessels medially and chest wall laterally to maximize the sampled lung volume. 
		NOTE: Slice selection can be done in any plane; up to 4 slices can be selected. For the purpose of demonstration, one slice will be acquired.</li>
		<li>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 reimaged for longitudinal studies.</li>
	</ol>
	</li>
	<li>Specific ventilation imaging 
	NOTE: A list of typical MRI parameters is presented in Table 1.
	<ol>
		<li>Set the inversion time in the MR computer for the most medial slice to 1,100 ms to maximize air-oxygen contrast17.</li>
		<li>Set the acquisition parameters (Table 1) for imaging acquisition. For multi slice acquisition, each additional slice is acquired after the first, at intervals of 235 ms (1,335 ms, 1,570 ms, 1,805 ms). 
		NOTE: Following the inversion recovery pulse and a time interval (described by the inversion time), each slice image is acquired using a half-Fourier single-shot turbo spin-echo (HASTE), at 128 x 128 resolution (70-lines of k-space sampled); images are reconstructed to 256 x 256 resolution.</li>
		<li>Set the number of repetitions to 220 and the repetition time (TR) to 5 s. This will result in repeating 4.2.1 and 4.2.2 for a total of 220 consecutive breaths, 5 s apart. Ask the subject to voluntarily gate his or her breathing in time with the image acquisition. 
		NOTE: Images are acquired at the end of a normal expiration in a short voluntary breathing interruption at functional residual capacity (FRC). It is important that a similar lung volume is reached consistently during each of these consecutive acquisitions.</li>
		<li>Monitor the consistency of the subject&#8217;s lung volume (end expiration) during subsequent acquisitions and provide feedback to improve quality if necessary. Increase TR (the time interval between successive acquisitions) if the subject finds it difficult to reach a consistent lung volume every 5 s.</li>
		<li>Switch the subject&#8217;s inspired gas mixture every 20 breaths (during the acquisition breath hold for the subject&#8217;s comfort), alternating between room air and medical oxygen. Make note of when the switches occurred, and the intervals during which the subject was breathing each gas. Allow the subject to breath 100% oxygen for 40 consecutive breaths at some point in the experiment (typically breaths 20-60 or 180-220) to increase sensitivity to low ventilation lung regions.</li>
		<li>Regularly verify heart rate (40&#8722;80 for normal subjects at rest) and oxygen saturation (typically 98&#8722;100%) by looking at the pulse oximeter (Figure 2); deviations from the norm can signal distress or anxiety.</li>
		<li>Talk to the subject frequently by pressing the scanner keyboard push-to-talk button, giving regular updates of time remaining.</li>
		<li>After breath 220, imaging is complete. Return the subject to room air and remove him or her from the scanner.</li>
	</ol>
	</li>
</ol>
5. Creating a Specific Ventilation Map from a Time Series of Images
<ol>
	<li>Verify that a stack of 220 consecutive MR images for each lung slice were acquired.</li>
	<li>Import the images for registration into the image analysis software (e.g., MATLAB).</li>
	<li>Of the 220 images, choose, by visual inspection of the entire image stack, for each slice one that best represents functional residual capacity. Functional residual capacity is identified as the &#8220;mode&#8221; of lung volumes in the stack.</li>
	<li>Using the &#8220;mode&#8221; image as reference, use projective or affine registration to register all images to the functional residual capacity reference. 
	NOTE: Registration is typically performed using an algorithm developed in house18 or a publicly-available generalized-dual bootstrap iterative closest point algorithm (GDB-ICP19).</li>
	<li>Use the output of the registration algorithm to compute the area change of each image. Discard images whose registration step required &#62;10% area change from the image stack, and treat them as missing data20.</li>
	<li>Quantify specific ventilation in the lung from the registered stack using an algorithm developed in house1,7. Perform quantification by comparing the time response of each voxel to the consecutive oxygen washin and washout series, to a library of 50 simulated, noise free, responses, corresponding to specific ventilations ranging from 0.01 to 10, in 15% increments. Each voxel is assigned a value of specific ventilation corresponding to the specific ventilation of the simulated ideal presenting maximal correlation with each voxel&#8217;s time series, as originally presented in1.</li>
	<li>The output of the previous step is a map of specific ventilation. Create a histogram of the distribution, and compute the width of the specific ventilation distribution, a measure of the specific ventilation heterogeneity, independent of tidal volume.</li>
</ol>
6. Combining Specific Ventilation and Density Maps to Compute Regional Alveolar Ventilation
<ol>
	<li>In addition to SVI, acquire lung proton density images21, as described in a previous study22 (sections 4.4 and 5.1 in reference22). Obtain the proton density images in the same lung slice(s), at the same lung volume (FRC, end of a normal expiration); set the resolution to 64 x 64, corresponding to a voxel size of ~6.3 mm x 6.3 mm x 15 mm (~0.6 cm3).</li>
	<li>Align specific ventilation and proton density images.
	<ol>
		<li>Smooth both the specific ventilation and proton density images using a gaussian filter with a kernel size of ~1 cm3.</li>
		<li>Perform rigid registration (translation and rotation) between the map of specific ventilation and the map of density using a mutual information-based algorithm.</li>
	</ol>
	</li>
	<li>Compute alveolar ventilation from co-registered specific ventilation and proton density data.
	<ol>
		<li>Compute a map of (1-Density), which is the fraction of air in the sampled volume at the end of a normal expiration, assuming that the lung is composed of air and tissue and that tissue density is ~1 g/cm3.</li>
		<li>Compute a regional ventilation map as the product (1-Density) x SV (natural units). Multiply this product by the volume of a voxel (or other region of interest) and the breathing frequency (imposed, typically 12 breaths/min), to obtain a map of ventilation in the more familiar units of ml/min. 
		NOTE: For each lung region, SV = &#916;V/V0 and (1 &#8211; Density) &#8776; V0. Thus, the product (1-Density) x SV = regional ventilation, expressed in natural units.</li>
	</ol>
	</li>
</ol>

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The authors have nothing to disclose.

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 ...

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6.3K Views.  University of California, San Diego. 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.

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

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 ...

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 ...

Human Fetal Blood Flow Quantification with Magnetic Resonance Imaging and Motion Compensation

Magnetic resonance imaging (MRI) is an important tool for the clinical assessment of cardiovascular morphology and heart function. It is also the recognized standard-of-care for blood flow quantification based on phase contrast MRI. While such measurement of blood flow has been possible in adults for decades, methods to extend this capability to fetal blood flow have only recently been developed.
Fetal blood flow quantification in major vessels is important for monitoring fetal pathologies such as congenital heart disease (CHD) and fetal growth restriction (FGR). CHD causes alterations in the cardiac structure and vasculature that change the course of blood in the fetus. In FGR, the path of blood flow is altered through the dilation of shunts such that the oxygenated blood supply to the brain is increased. Blood flow quantification enables assessment of the severity of the fetal pathology, which in turn allows for suitable&#160;in utero&#160;patient management and planning for postnatal care.
The primary challenges of applying phase contrast MRI to the human fetus include small blood vessel size, high fetal heart rate, potential MRI data corruption due to maternal respiration, unpredictable fetal movements, and lack of conventional cardiac gating methods to synchronize data acquisition. Here, we describe recent technical developments from our lab that have enabled the quantification of fetal blood flow using phase contrast MRI, including advances in accelerated imaging, motion compensation, and cardiac gating.

Here we present a protocol for measuring fetal blood flow rapidly with MRI and retrospectively performing motion correction and cardiac gating.