Variations of dynamic contrast-enhanced magnetic resonance imaging in evaluation of breast cancer therapy response: a multicenter data analysis challenge.

Pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time-course data allows estimation of quantitative parameters such as K (trans) (rate constant for plasma/interstitium contrast agent transfer), v e (extravascular extracellular volume fraction), and v p (plasma volume fraction). A plethora of factors in DCE-MRI data acquisition and analysis can affect accuracy and precision of these parameters and, consequently, the utility of quantitative DCE-MRI for assessing therapy response. In this multicenter data analysis challenge, DCE-MRI data acquired at one center from 10 patients with breast cancer before and after the first cycle of neoadjuvant chemotherapy were shared and processed with 12 software tools based on the Tofts model (TM), extended TM, and Shutter-Speed model. Inputs of tumor region of interest definition, pre-contrast T1, and arterial input function were controlled to focus on the variations in parameter value and response prediction capability caused by differences in models and associated algorithms. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) values for K (trans) and v p being as high as 0.59 and 0.82, respectively. Parameter agreement improved when only algorithms based on the same model were compared, e.g., the K (trans) intraclass correlation coefficient increased to as high as 0.84. Agreement in parameter percentage change was much better than that in absolute parameter value, e.g., the pairwise concordance correlation coefficient improved from 0.047 (for K (trans)) to 0.92 (for K (trans) percentage change) in comparing two TM algorithms. Nearly all algorithms provided good to excellent (univariate logistic regression c-statistic value ranging from 0.8 to 1.0) early prediction of therapy response using the metrics of mean tumor K (trans) and k ep (=K (trans)/v e, intravasation rate constant) after the first therapy cycle and the corresponding percentage changes. The results suggest that the interalgorithm parameter variations are largely systematic, which are not likely to significantly affect the utility of DCE-MRI for assessment of therapy response.

Synthetic signal injection using a single radiofrequency channel.

PURPOSE: To demonstrate that, when injecting an artificial reference signal for quantitation purposes, the real and artificial signals can be acquired separately, using a single radiofrequency (RF) channel, with no loss of fidelity. Conversion of MR signals to units of concentration can be simplified by injection of a precalibrated, artificial reference signal, or pseudo-signal. In previous implementations, the pseudo-signal was acquired simultaneously with the real signals arising from the sample and this requires a second, integrated RF channel. MATERIALS AND METHODS: We used in vivo spectroscopy and in vitro imaging measurements to test the validity of the separate acquisition method. RESULTS: There was very strong correlation (r = 0.94; P = 0.02) between the in vivo concentrations determined with separate and simultaneous acquisition methods. The in vitro measurements validated that the separate acquisition method compensates for differences in coil loading conditions as well as the simultaneous acquisition method. CONCLUSION: Separate acquisition eliminates the need for a second RF channel, which allows easier implementation at sites that have only one channel available, and relaxes the constraints on the number and amplitude of pseudo-signals. This flexibility can be exploited to increase the signal to noise ratio of the pseudo-signal and reduce variability when making the conversion to units of concentration.

Quantitative in vivo magnetic resonance spectroscopy using synthetic signal injection.

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment.

Magnetic resonance imaging of boiling induced by high intensity focused ultrasound.

Both mechanically induced acoustic cavitation and thermally induced boiling can occur during high intensity focused ultrasound (HIFU) medical therapy. The goal was to monitor the temperature as boiling was approached using magnetic resonance imaging (MRI). Tissue phantoms were heated for 20 s in a 4.7-T magnet using a 2-MHz HIFU source with an aperture and radius of curvature of 44 mm. The peak focal pressure was 27.5 MPa with corresponding beam width of 0.5 mm. The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73 degrees C after 7 s of continuous HIFU exposure when boiling started. Boiling was detected by visual observation, by appearance on the MR images, and by a marked change in the HIFU source power. Nonlinear modeling of the acoustic field combined with a heat transfer equation predicted 100 degrees C after 7 s of exposure. Averaging of the calculated temperature field over the volume of the MRI voxel (0.3 x 0.5 x 2 mm(3)) yielded a maximum of 73 degrees C that agreed with the MR thermometry measurement. These results have implications for the use of MRI-determined temperature values to guide treatments with clinical HIFU systems.

Synthetic signal injection using inductive coupling.

Conversion of MR signals into units of metabolite concentration requires a very high level of diligence to account for the numerous parameters and transformations that affect the proportionality between the quantity of excited nuclei in the acquisition volume and the integrated area of the corresponding peak in the spectrum. We describe a method that eases this burden with respect to the transformations that occur during and following data acquisition. The conceptual approach is similar to the ERETIC method, which uses a pre-calibrated, artificial reference signal as a calibration factor to accomplish the conversion. The distinguishing feature of our method is that the artificial signal is introduced strictly via induction, rather than radiation. We tested a prototype probe that includes a second RF coil rigidly positioned close to the receive coil so that there was constant mutual inductance between them. The artificial signal was transmitted through the second RF coil and acquired by the receive coil in parallel with the real signal. Our results demonstrate that the calibration factor is immune to changes in sample resistance. This is a key advantage because it removes the cumbersome requirement that coil loading conditions be the same for the calibration sample as for experimental samples. The method should be adaptable to human studies and could allow more practical and accurate quantification of metabolite content.

Time-courses of perfusion and phosphocreatine in rat leg during low-level exercise and recovery.

PURPOSE: To develop a noninvasive protocol for measuring local perfusion and metabolic demand in muscle tissue with sufficient sensitivity and time resolution to monitor kinetics at the onset of low-level exercise and during recovery. MATERIALS AND METHODS: Capillary-level perfusion, the critical factor that determines oxygen and substrate delivery to active muscle, was measured by an arterial spin labeling (ASL) technique optimized for skeletal muscle. Phosphocreatine (PCr) kinetics, which signal the flux of oxidative phosphorylation, were measured by (31)P MR spectroscopy. Perfusion and PCr measurements were made in parallel studies before, during, and after three different intensities of low-level, stimulated exercise in rat hind limb. RESULTS: The data reveal close coupling between the perfusion response and PCr changes. The onset and recovery time constants for PCr changes were independent of contractile force over the range of forces studied. Perfusion time constants during both onset of exercise and recovery tended to increase with contractile force. CONCLUSION: These results demonstrate that the protocol implemented can be useful for probing the mechanisms that control skeletal muscle blood flow, the physiological limits to muscle performance, and the causes for the attenuated exercise-induced hyperemia observed in disease states.

Nonlinear magnetic field gradients can reduce SAR in flow-driven arterial spin labeling measurements.

This work describes how custom-built gradient coils, designed to generate magnetic fields with amplitudes that vary nonlinearly with position, can be used to reduce the potential for unsafe tissue heating during flow-driven arterial spin labeling processes. A model was developed to allow detailed analysis of the adiabatic excitation process used for flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS) an arterial spin labeling method developed specifically for use in skeletal muscle. The model predicted that, by adjusting the amplitude of the gradient field, the specific absorption rate could be reduced by more than a factor of 6 while still achieving effective labeling. Flow phantom measurements and in vivo measurements from exercising rat hind limb confirmed the accuracy of the model's predictions. The modeling tools were also applied to the more widely used continuous arterial spin labeling (CASL) method and predicted that specially shaped gradients could allow similar reductions in SAR.

FAWSETS perfusion measurements in exercising skeletal muscle.

Arterial spin labeling (ASL) techniques are now recognized as valid tools for providing accurate measurements of cerebral and cardiac perfusion. The labeling process used with most ASL techniques creates two problems, magnetization transfer (MT) effects and arterial transit time effects, that require compensation. The compensation process limits time resolution and hinders absolute quantification. MT effects are particularly problematic in skeletal muscle because they are large and change rapidly during exercise. The protocol presented here was developed specifically for quantification of perfusion in exercising skeletal muscle. The ASL technique that was implemented, FAWSETS, eliminates MT effects and arterial transit times. Localized, single-voxel perfusion measurements were acquired from rat hind limbs at rest, during ischemia and during three different levels of stimulated exercise. The results demonstrate sufficient sensitivity to determine the time constants for perfusion changes at onset of, and during recovery from, exercise and to distinguish the differences in the amplitude of the perfusion response to different levels of exercise. Additional measurements were conducted to demonstrate insensitivity to MT effects. The exercise protocol is easily adaptable to phosphorous magnetic resonance measurements, allowing the possibility to acquire local measurements of perfusion and metabolism from the same tissue in future experiments.

Gradient-enhanced FAWSETS perfusion measurements.

This work describes the use of custom-built gradients to enhance skeletal muscle perfusion measurements acquired with a previously described arterial spin labeling technique known as FAWSETS (flow-driven arterial water stimulation with elimination of tissue signal). Custom-built gradients provide active control of the static magnetic field gradient on which FAWSETS relies for labeling. This allows selective, 180 degrees modulations of the phase of the perfusion component of the signal. Phase cycling can then be implemented to eliminate all extraneous components leaving a signal that exclusively reflects capillary-level perfusion. Gradient-enhancement substantially reduces acquisition time and eliminates the need to acquire an ischemic signal to quantify perfusion. This removes critical obstacles to application of FAWSETS in organs other than skeletal muscle and makes the measurements more desirable for clinical environments. The basic physical principles of gradient-enhancement are demonstrated in flow phantom experiments and in vivo utility is demonstrated in rat hind limb during stimulated exercise.

Validation and advantages of FAWSETS perfusion measurements in skeletal muscle.

This work discusses the strengths, limitations and validity of a novel arterial spin labeling technique when used specifically to measure perfusion in limb skeletal muscle. The technique, flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS), offers several advantages over existing arterial spin labeling techniques. The primary goal of this study was to determine the perfusion signal response to changes in net hind limb flow that were independently verifiable. The range of perfusate flow was relevant to skeletal muscle during mild to moderate exercise. Localized, single voxel measurements were acquired from a 5 mm-thick slice in the isolated perfused rat hind limb at variable net flow rates. The results show that the perfusion signal is linearly proportional to net hind limb flow with a correlation coefficient of 0.974 (p = 0.0013). FAWSETS is especially well suited for studies of skeletal muscle perfusion, where it eliminates the need to compensate for magnetization transfer and arterial transit time effects. A conceptual discussion of the basic principles underlying these advantages is presented.