Mark S. Conradi

New, compensated Carr-Purcell sequences

Abstract New, compensated Carr-Purcell pulse sequences are reported, all based on x and y phase alternation of the π pulses. The sequences compensate cumulative pulse errors for all three components of magnetization. Applications include the measurement of homonuclear dipole coupling in the presence of chemical shifts and the measurement of heteronuclear dipole coupling in magic-angle spinning experiments (REDOR). The performance of the new pulse sequences is compared experimentally to previously reported schemes.

Quantitative in vivo assessment of lung microstructure at the alveolar level with hyperpolarized 3He diffusion MRI

The study of lung emphysema dates back to the beginning of the 17th century. Nevertheless, a number of important questions remain unanswered because a quantitative localized characterization of emphysema requires knowledge of lung structure at the alveolar level in the intact living lung. This information is not available from traditional imaging modalities and pulmonary function tests. Herein, we report the first in vivo measurements of lung geometrical parameters at the alveolar level obtained with 3He diffusion MRI in healthy human subjects and patients with severe emphysema. We also provide the first experimental data demonstrating that 3He gas diffusivity in the acinus of human lung is highly anisotropic. A theory of anisotropic diffusion is presented. Our results clearly demonstrate substantial differences between healthy and emphysematous lung at the acinar level and may provide new insights into emphysema progression. The technique offers promise as a clinical tool for early diagnosis of emphysema.

MR imaging of diffusion of 3He gas in healthy and diseased lungs

Hyperpolarized 3He gas MRI was used to form maps of the effective diffusivity of gas in human lungs. Images of diffusion as well as spin density are presented from a study of 11 healthy volunteers and 5 patients with severe emphysema. The effective rate of diffusion, De, of the gas is reduced by the alveolar walls; tissue destruction in emphysema is hypothesized to result in larger De. Indeed, the mean value of De in the emphysematous lungs is found here to be about 2.5 times that of healthy lungs, although still smaller than the unrestricted diffusivity of 3He in free air. Histograms of De values across coronal slices are presented. The results are discussed in terms of spatial variations, variations among individuals, healthy and diseased, and variations due to changes in lung volume. Magn Reson Med 44:174–179, 2000.

Hyperpolarized 3He diffusion MRI and histology in pulmonary emphysema.

Diffusion MRI of hyperpolarized 3He shows that the apparent diffusion coefficient (ADC) of 3He gas is highly restricted in the normal lung and becomes nearly unrestricted in severe emphysema. The nature of this restricted diffusion provides information about lung structure; however, no direct comparison with histology in human lungs has been reported. The purpose of this study is to provide information about 3He gas diffusivity in explanted human lungs, and describe the relationship between 3He diffusivity and the surface area to lung volume ratio (SA/V) and mean linear intercept (Lm) measurements—the gold standard for diagnosis of emphysema. Explanted lungs from patients who were undergoing lung transplantation for advanced COPD, and donor lungs that were not used for transplantation were imaged via 3He diffusion MRI. Histological measurements were made on the same specimens after they were frozen in the position of study. There is an inverse correlation between diffusivity and SA/V (and a positive correlation between diffusivity and Lm). An important result is that restricted 3He diffusivity separated normal from emphysematous lung tissue more clearly than the morphometric analyses. This effect may be due to the smaller histologic sampling size compared to the MRI voxel sizes. Magn Reson Med, 2006.

Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized (3)He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii-parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lungs gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials.

Rapid Imaging of Hyperpolarized Gas Using EPI

Rapid repetitive MRI of hyperpolarized (HP) gases using echo‐planar imaging (EPI) has been theoretically investigated and experimentally demonstrated for 3He in human lung. A quantitative treatment of signal attenuation and magnetization consumption for the unique circumstance of a rapidly diffusing nonrenewable magnetization source has been performed. Rapid (compared to the human respiratory cycle) and repetitive imaging of the lung gas space with EPI and a single delivered bolus of HP‐3He is feasible using low flip angles, provided the voxels are not too small. A coarse‐grid (32 × 64) EPI pulse sequence has been developed and implemented to image the lungs of healthy volunteers during rebreathing of a HP‐3He/N2 gas mixture. A set of three 10‐mm axial slices was imaged every 0.12 sec for the 36 sec duration of rebreathing, yielding a real‐time visualization of ventilation. Despite some mild artifacts, the images are of good quality and show changes in gas density related to respiratory physiology. Magn Reson Med 42:507–514, 1999.

Dynamic echo planar MR imaging of lung ventilation with hyperpolarized 3 He in normal subjects and patients with severe emphysema

We applied the rapid imaging capability of echo planar MR pulse sequences and hyperpolarized 3He ventilation imaging to observe the dynamic distribution of gas in the lungs during breathing. Findings in five normal volunteers (age 19–53 years) and four patients with severe smoking‐related emphysema (age 56–71 years) were compared. All studies were performed on a 1.5 T whole body scanner using a 30 cm Helmholtz surface coil and 0.5 l of 20–40% polarized 3He mixed with 1–2 l nitrogen. Our echo planar imaging pulse sequence allowed acquisition of each image in 0.04 s, with a pixel size of 7 mm2 (TR = 40.5 ms, TE = 12.1 ms, flip angle = 22°, echo train length = 32, matrix = 32 × 64, field of view = 225 × 450 mm, slice thickness = 10 mm). Imaging was performed in the transaxial plane repeatedly at 3, 10 or 20 evenly spaced levels, immediately before and during breathing of the gas mixture. In normal subjects during the first breath, 3He appeared throughout each slice first in the mid lungs, then in the lower lungs, then in the upper lungs, with slightly greater signal in the dependent posterior regions. In patients with emphysema, sequential filling of different lung regions was seen during the first breath, with delayed filling of other regions observed during rebreathing and room air washout. We conclude that subsecond dynamic 3He MR ventilation imaging can reveal normal and abnormal ventilation phenomena not seen with conventional scintigraphic methods, and offers another approach to the study of ventilation physiology and pathophysiology. Copyright

Sensitivity enhancement for NMR of the central transition of quadrupolar nuclei

Abstract A sensitivity enchancement technique for the central transition of half-integer nuclear spins is reported. For a spin-I the largest and smallest thermal equilibrium populations, in the m = ± I levels, are transferred to the m = − 1 2 . The resulting signal enhancement of the central transition is of maximum value 2I. The population transfer is accomplished by frequency or field sweeping, resulting in sequential adiabatic inversions of the satellite transitions. Thus, the technique works on powder and amorphous samples as well as on single crystals, as demonstrated in experiments on 27Al in Al2O3.

Hyperpolarized 3He MR Imaging: Physiologic Monitoring Observations and Safety Considerations in 100 Consecutive Subjects

PURPOSE To evaluate the safety of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging. MATERIALS AND METHODS Local institutional review board approval and informed consent were obtained. Physiologic monitoring data were obtained before, during, and after hyperpolarized (3)He MR imaging in 100 consecutive subjects (57 men, 43 women; mean age, 52 years +/- 14 [standard deviation]). The subjects inhaled 1-3 L of a gas mixture containing 300-500 mL (3)He and 0-2700 mL N(2) and held their breath for up to 15 seconds during MR imaging. Heart rate and rhythm and oxygen saturation of hemoglobin as measured by pulse oximetry (Spo(2)) were monitored continuously throughout each study. The effects of (3)He MR imaging on vital signs and Spo(2) and the relationship between pulmonary function, number of doses, and clinical classification (healthy volunteers, patients with asthma, heavy smokers, patients undergoing lung volume reduction surgery for severe emphysema, and patients with lung cancer) and the lowest observed Spo(2) were assessed. Any subjective symptoms were noted. RESULTS Except for a small postimaging decrease in mean heart rate (from 78 beats per minute +/- 13 to 73 beats per minute +/- 11, P < .001), there was no effect on vital signs. A mean transient decrease in Spo(2) of 4% +/- 3 was observed during the first minute after gas inhalation (P < .001) in 77 subjects who inhaled a dose of 1 L for 10 seconds or less, reaching a nadir of less than 90% at least once in 20 subjects and of less than 85% in four subjects. There was no correlation between the lowest Spo(2) and pulmonary function parameters other than baseline Spo(2) (r = 0.36, P = .001). The lowest mean Spo(2) varied by 1% between the first and second and second and third doses (P < .001) and was unrelated to clinical classification (P = .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred. CONCLUSION Hyperpolarized (3)He MR imaging can be safely performed in healthy subjects, heavy smokers, and those with severe obstructive airflow limitation, although unpredictable transient desaturation suggests that potential subjects should be carefully screened for comorbidities.

Hyperpolarized 3He MRI of mouse lung

Hyperpolarized 3He images of mouse lung are presented. Ventilation images and measurements of 3He apparent diffusion coefficient (ADC) are reported in healthy mice, and preliminary studies of emphysema and lung cancer in mice are described using these techniques. The design and operation of an electronically controlled small‐animal ventilator to deliver the hyperpolarized gas and control animal respiration are described. Images are acquired using an asymmetric gradient echo imaging method to enhance the signal‐to‐noise ratio of the rapidly diffusing 3He. In mice with elastase‐induced emphysema, the whole‐lung average ADC is greater by approximately 25%, a statistically significant difference, compared to healthy animals. By contrast, mice exposed to cigarette smoke for up to 12 months reveal no statistically relevant increases in ADC, although emphysema was not confirmed in these mice. A study of lung cancer (melanoma) in mice is also presented. While tumors are shown to cause substantial ventilation defects in the lung, these defects appear confined to the cancerous regions and do not extend to large‐scale regions of the lung distal to the tumors. Magn Reson Med 52:1310–1317, 2004.