Brian K. Rutt

MRI Measures of Middle Cerebral Artery Diameter in Conscious Humans During Simulated Orthostasis

BACKGROUND AND PURPOSE The relationship between middle cerebral artery (MCA) flow velocity (CFV) and cerebral blood flow (CBF) is uncertain because of unknown vessel diameter response to physiological stimuli. The purpose of this study was to directly examine the effect of a simulated orthostatic stress (lower body negative pressure [LBNP]) as well as increased or decreased end-tidal carbon dioxide partial pressure (P(ET)CO(2)) on MCA diameter and CFV. METHODS Twelve subjects participated in a CO(2) manipulation protocol and/or an LBNP protocol. In the CO(2) manipulation protocol, subjects breathed room air (normocapnia) or 6% inspired CO(2) (hypercapnia), or they hyperventilated to approximately 25 mm Hg P(ET)CO(2) (hypocapnia). In the LBNP protocol, subjects experienced 10 minutes each of -20 and -40 mm Hg lower body suction. CFV and diameter of the MCA were measured by transcranial Doppler and MRI, respectively, during the experimental protocols. RESULTS Compared with normocapnia, hypercapnia produced increases in both P(ET)CO(2) (from 36+/-3 to 40+/-4 mm Hg, P<0.05) and CFV (from 63+/-4 to 80+/-6 cm/s, P<0.001) but did not change MCA diameters (from 2.9+/-0.3 to 2.8+/-0.3 mm). Hypocapnia produced decreases in both P(ET)CO(2) (24+/-2 mm Hg, P<0.005) and CFV (43+/-7 cm/s, P<0.001) compared with normocapnia, with no change in MCA diameters (from 2.9+/-0.3 to 2.9+/-0.4 mm). During -40 mm Hg LBNP, P(ET)CO(2) was not changed, but CFV (55+/-4 cm/s) was reduced from baseline (58+/-4 cm/s, P<0.05), with no change in MCA diameter. CONCLUSIONS Under the conditions of this study, changes in MCA diameter were not detected. Therefore, we conclude that relative changes in CFV were representative of changes in CBF during the physiological stimuli of moderate LBNP or changes in P(ET)CO(2).

Rapid combined T1 and T2 mapping using gradient recalled acquisition in the steady state.

A novel, fully 3D, high‐resolution T1 and T2 relaxation time mapping method is presented. The method is based on steady‐state imaging with T1 and T2 information derived from either spoiling or fully refocusing the transverse magnetization following each excitation pulse. T1 is extracted from a pair of spoiled gradient recalled echo (SPGR) images acquired at optimized flip angles. This T1 information is combined with two refocused steady‐state free precession (SSFP) images to determine T2. T1 and T2 accuracy was evaluated against inversion recovery (IR) and spin‐echo (SE) results, respectively. Error within the T1 and T2 maps, determined from both phantom and in vivo measurements, is approximately 7% for T1 between 300 and 2000 ms and 7% for T2 between 30 and 150 ms. The efficiency of the method, defined as the signal‐to‐noise ratio (SNR) of the final map per voxel volume per square root scan time, was evaluated against alternative mapping methods. With an efficiency of three times that of multipoint IR and three times that of multiecho SE, our combined approach represents the most efficient of those examined. Acquisition time for a whole brain T1 map (25 × 25 × 10 cm) is less than 8 min with 1 mm3 isotropic voxels. An additional 7 min is required for an identically sized T2 map and postprocessing time is less than 1 min on a 1 GHz PIII PC. The method therefore permits real‐time clinical acquisition and display of whole brain T1 and T2 maps for the first time. Magn Reson Med 49:515–526, 2003.

High-resolution T1 and T2 mapping of the brain in a clinically acceptable time with DESPOT1 and DESPOT2.

Variations in the intrinsic T1 and T2 relaxation times have been implicated in numerous neurologic conditions. Unfortunately, the low resolution and long imaging time associated with conventional methods have prevented T1 and T2 mapping from becoming part of routine clinical evaluation. In this study, the clinical applicability of the DESPOT1 and DESPOT2 imaging methods for high‐resolution, whole‐brain, T1 and T2 mapping was investigated. In vivo, 1‐mm3 isotropic whole‐brain T1 and T2 maps of six healthy volunteers were acquired at 1.5 T with an imaging time of <17 min each. Isotropic maps (0.34 mm3) of one volunteer were also acquired (time <21 min). Average signal‐to‐noise within the 1‐mm3 T1 and T2 maps was ∼20 and ∼14, respectively, with average repeatability standard deviations of 46.7 ms and 6.7 ms. These results demonstrate the clinical feasibility of the methods in the study of neurologic disease. Magn Reson Med 53:237–241, 2005.

Gleaning Multicomponent T-1 and T-2 Information From Steady-State Imaging Data

The driven‐equilibrium single‐pulse observation of T1 (DESPOT1) and T2 (DESPOT2) are rapid, accurate, and precise methods for voxelwise determination of the longitudinal and transverse relaxation times. A limitation of the methods, however, is the inherent assumption of single‐component relaxation. In a variety of biological tissues, in particular human white matter (WM) and gray matter (GM), the relaxation has been shown to be more completely characterized by a summation of two or more relaxation components, or species, each believed to be associated with unique microanatomical domains or water pools. Unfortunately, characterization of these components on a voxelwise, whole‐brain basis has traditionally been hindered by impractical acquisition times. In this work we extend the conventional DESPOT1 and DESPOT2 approaches to include multicomponent relaxation analysis. Following numerical analysis of the new technique, renamed multicomponent driven equilibrium single pulse observation of T1/T2 (mcDESPOT), whole‐brain multicomponent T1 and T2 quantification is demonstrated in vivo with clinically realistic times of between 16 and 30 min. Results obtained from four healthy individuals and two primary progressive multiple sclerosis (MS) patients demonstrate the future potential of the approach for identifying and assessing tissue changes associated with several neurodegenerative conditions, in particular those associated with WM. Magn Reson Med 60:1372–1387, 2008.

Temporal sampling requirements for the tracer kinetics modeling of breast disease

The physiological parameters measured in the tracer kinetics modeling of data from a dynamic contrast-enhanced magnetic resonance (MR) breast exam (blood flow-extraction fraction product [FE], volume of the extracellular extravascular space [Ve], and blood volume [Vb]) may enable non-invasive diagnosis of breast cancer. One of the factors that compromises the accuracy and precision of the parameter estimates, and therefore their diagnostic potential, is the temporal resolution of the MR scans used to measure contrast agent (gadolinium-diethylenetriamine pentaacetic acid [Gd-DTPA]) concentration in an artery (arterial input function [AIF]) and in the tissue (tissue residue function [TRF]). Using computer simulations, we have examined, for several AIF widths, the errors introduced into estimates of tracer kinetic parameters in breast tissue due to insufficient temporal sampling. Temporal sampling errors can be viewed as uncertainties and biases in the parameter estimates introduced by the uncertainty in the relative alignments of the AIF, TRF, and sampling grid. These effects arise from the models inherent sensitivity to error in either the AIF or TRF, which is dependent on the values of the tracer kinetic parameters and increases with AIF width. Based on the results of the simulations, to ensure that the error in FE and Ve will be under 10% of their true values, we recommend a rapid bolus injection of contrast agent (approximately 10 s), that the AIF be sampled every second, and that the TRF be sampled every 16 s or less. An accurate measurement of Vb requires that the TRF be sampled at least every 4 s. The results of these investigations can be used to set minimum dynamic imaging rates for tracer kinetics modeling of the breast.

In vivo magnetic resonance imaging of single cells in mouse brain with optical validation.

In the current work we demonstrate, for the first time, that single cells can be detected in mouse brain in vivo using magnetic resonance imaging (MRI). Cells were labeled with superparamagnetic iron oxide nanoparticles and injected into the circulation of mice. Individual cells trapped within the microcirculation of the brain could be visualized with high‐resolution MRI using optimized MR hardware and the fast imaging employing steady state acquisition (FIESTA) pulse sequence on a 1.5 T clinical MRI scanner. Single cells appear as discrete signal voids on MR images. Direct optical validation was provided by coregistering signal voids on MRI with single cells visualized using high‐resolution confocal microscopy. This work demonstrates the sensitivity of MRI for detecting single cells in small animals for a wide range of application from stem cell to cancer cell tracking. Magn Reson Med, 2006.

Characterization of common carotid artery blood-flow waveforms in normal human subjects

Knowledge of human blood-flow waveforms is required for in vitro investigations and numerical modelling. Parameters of interest include: velocity and flow waveform shapes, inter- and intra-subject variability and frequency content. We characterized the blood-velocity waveforms in the left and right common carotid arteries (CCAs) of 17 normal volunteers (24 to 34 years), analysing 3560 cardiac cycles in total. Instantaneous peak-velocity (Vpeak) measurements were obtained using pulsed-Doppler ultrasound with simultaneous collection of ECG data. An archetypal Vpeak waveform was created using velocity and timing parameters at waveform feature points. We report the following timing (post-R-wave) and peak-velocity parameters: cardiac interbeat interval (T(RR)) = 0.917 s (intra-subject standard deviation = +/- 0.045 s); cycle-averaged peak-velocity (V(CYC)) = 38.8 cm s(-1) (+/-1.5 cm s(-1)); maximum systolic Vpeak = 108.2 cm s(-1) (+/-3.8 cm s(-1)) at 0.152 s (+/-0.008 s); dicrotic notch Vpeak = 19.4 cm s(-1) (+/-2.9 cm s(-1)) at 0.398 s (+/-0.007 s). Frequency components below 12 Hz constituted 95% of the amplitude spectrum. Flow waveforms were computed from Vpeak by analytical solution of Womersley flow conditions (derived mean flow = 6.0 ml s(-1)). We propose that realistic, pseudo-random flow waveform sequences can be generated for experimental studies by varying, from cycle to cycle, only T(RR) and V(CYC) of a single archetypal waveform.

In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single‐cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single‐cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.

Reconstruction of carotid bifurcation hemodynamics and wall thickness using computational fluid dynamics and MRI

A thorough understanding of the relationship between local hemodynamics and plaque progression has been hindered by an inability to prospectively monitor these factors in vivo in humans. In this study a novel approach for noninvasively reconstructing artery wall thickness and local hemodynamics at the human carotid bifurcation is presented. Three‐dimensional (3D) models of the lumen and wall boundaries, from which wall thickness can be measured, were reconstructed from black‐blood magnetic resonance imaging (MRI). Along with time‐varying inlet/outlet flow rates measured via phase contrast (PC) MRI, the lumen boundary was used as input for computational fluid dynamic (CFD) simulation of the subject‐specific flow patterns and wall shear stresses (WSSs). Results from a 59‐year‐old subject with early, asymptomatic carotid artery disease show good agreement between simulated and measured velocities, and demonstrate a correspondence between wall thickening and low and oscillating shear at the carotid bulb. High shear at the distal internal carotid artery (ICA) was also colocalized with higher WSS; however, a quantitative general relationship between WSS and wall thickness was not found. Similar results were obtained from a 23‐year‐old normal subject. These findings represent the first direct comparison of hemodynamic variables and wall thickness at the carotid bifurcation of human subjects. The noninvasive nature of this image‐based modeling approach makes it ideal for carrying out future prospective studies of hemodynamics and plaque development or progression in otherwise healthy subjects.

Application of the static dephasing regime theory to superparamagnetic iron-oxide loaded cells.

The relaxation rates of iron‐oxide nanoparticles compartmentalized within cells were studied and found to satisfy predictions of the static dephasing (SD) regime theory. THP‐1 cells in cell culture were loaded using two different iron‐oxide nanoparticles (superparamagnetic iron‐oxide (SPIO) and ultrasmall SPIO (USPIO)) with four different iron concentrations (0.05, 0.1, 0.2, and 0.3 mg/ml) and for five different incubation times (6, 12, 24, 36, and 48 hr). Cellular iron‐oxide uptake was assessed using a newly developed imaging version of MR susceptometry, and was found to be linear with both dose and incubation time. R  2* sensitivity to iron‐oxide loaded cells was found to be 70 times greater than for R2, and 3100 times greater than for R1. This differs greatly from uniformly distributed nanoparticles and is consistent with a cellular bulk magnetic susceptibility (BMS) relaxation mechanism. The cellular magnetic moment was large enough that R2′ relaxivity agreed closely with SD regime theory predictions for all cell samples tested where the local magnetic dose (LMD) is the sample magnetization due to the presence of iron‐oxide particles). Uniform suspensions of SPIO and USPIO produced R2′ relaxivities that were a factor of 3 and 8 less, respectively, than SD regime theory predictions. These results are consistent with theoretical estimates of the required mass of iron per compartment needed to guarantee SD‐regime‐dominant relaxivity. For cellular samples, R2 was shown to be dependent on both the concentration and distribution of iron‐oxide particles, while R2′ was sensitive to iron‐oxide concentration alone. This work is an important first step in quantifying cellular iron content and ultimately mapping the density of a targeted cell population. Magn Reson Med 48:52–61, 2002.