Study of Laser Ablation in the In Vivo Rabbit Brain With MR Thermometry

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1 JOURNAL OF MAGNETIC RESONANCE IMAGING 16: (2002) Original Research Study of Laser Ablation in the In Vivo Rabbit Brain With MR Thermometry Lili Chen, PhD, 1 Janaka P. Wansapura, PhD, 1 Gary Heit, PhD, 2 and Kim Butts, PhD 1 * Purpose: To investigate the peak temperature and thermal dose (T 43 ) as tissue damage indicators for thermal therapy. Materials and Methods: The proton resonant frequency (PRF) shift thermal coefficient was calibrated on six in vivo rabbit brains during interstitial laser ablation. The peak temperature and T 43 were correlated with the lesion observed on T2-weighted spin-echo (SE) MRI at 4 hours post-heating in seven thermal lesions using direct MR measurement and analysis based on a binary discriminate model. Results: The peak temperature and T 43 were C and minutes, respectively, from the direct MR measurement. The values derived by the binary discriminate analysis were C and minutes, respectively. Conclusion: Our results suggest that tissue damage in rabbit brain 4 hours after thermal ablation can be predicted reliably from a threshold temperature of approximately 48 C. Key Words: laser ablation; interventional MRI; thermal dose; thermometry; in vivo rabbit brain J. Magn. Reson. Imaging 2002;16: Wiley-Liss, Inc. IMAGE-GUIDED THERMAL THERAPY is very promising for the minimally invasive and noninvasive treatment of benign and malignant tumors. Image guidance can be used to monitor the procedure to ensure the safety and efficacy of the treatment. MRI is particularly promising as a guidance modality because of its excellent soft-tissue contrast, sensitivity to temperature, and ability to evaluate tissue damage after therapy. Many studies have shown that thermal lesions can be clearly visualized on MR images (1 16). In our previous 1 Department of Radiology, Stanford University, Stanford, California. 2 Department of Neurosurgery, Stanford University, Stanford, California. Contract grant sponsor: Whitaker Foundation; Contract grant sponsor: NIH; Contract grant numbers: R21 CA 79931; RR *Address reprint requests to: K.B., Department of Radiology, Stanford University, 1201 Welch Rd., Stanford, CA Kim@s-word.stanford.edu Received August 21, 2001; Accepted March 29, DOI /jmri Published online in Wiley InterScience ( studies (15,16) we demonstrated that T2-weighted MRI correlated within 0.5 mm with the cell death zone using cell viability staining with triphenyl tetrazolium chloride (TTC) in rabbit brain 4 hours after focused ultrasound ablation. Although T2-weighted MRI accurately depicts thermal lesions post-treatment, it cannot be used for real-time monitoring in the brain due to a time delay of more than 15 minutes before the lesion appears (15). Real-time MR thermal mapping can provide an indication of tissue damage if a measure of tissue damage is known. Several studies have elucidated specific values of peak temperature, thermal dose, and a temperature-time product for thermal indicators of tissue damage in various tissue types, such as in the thigh muscle and the prostate (17,18). However, much work needs to be done before values for thermal indicators can be determined for all tissue types and cancers. This is especially true since initial studies on different tissues have resulted in different values for these parameters (17,18). For example, the threshold temperature of 51 C and the T 43 of 200 minutes in the in vivo canine prostate were reported by Peters et al (18), while 47 C and T 43 of 4.7 minutes in the in vivo rabbit muscle were reported by McDannold et al (17). The purposes of this work were to investigate the threshold temperature and thermal dose, T 43 (19), as indicators of tissue damage in the in vivo rabbit brain, and to determine a practical approach for in vivo thermal monitoring on an interventional MRI scanner. MATERIALS AND METHODS Laser System and MR Scanner Custom-made, conical-tipped laser fibers (30 feet long) manufactured by Surgical Laser Technologies (Montgomeryville, PA) were used. The fibers were 0.6 mm in diameter, with a 5-mm-long tip and 0.2-mm diameter (laser diffusion region). The wavelength was 1064 nm. The laser power source was located outside the scan room. All the MR images were performed using a standard 0.5 T Signa SP open MRI system (GE Medical Systems, Milwaukee, WI). PRF Thermal Coefficient Calibration Six New Zealand white rabbits ( kg) were used. The animal experiments were approved by the Admin Wiley-Liss, Inc. 147

2 148 Chen et al. istrative Panel on Laboratory Animal Care (APLAC) at Stanford University. Each rabbit was anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg) administered subcutaneously. After induction, the rabbit was intubated and anesthesia was maintained with isoflurane (2% to 3%) and oxygen (1%). Prior to laser ablation, a piece of skull (approximately mm) was surgically removed. The dura mater was carefully ruptured without injury to the brain. The rabbit was placed in the bore of the 0.5 T MR scanner in a prone position. An extremity coil was placed above the brain. A warm plastic blanket was placed between the scanner table and the rabbit to aid in thermoregulation. A laser fiber was inserted 8 mm into the brain and was placed between two Luxtron fiberoptic temperature sensors (Luxtron Corporation, Santa Clara, CA). The Luxtron sensors were 8 mm apart and 8 mm into the brain. All three fibers were placed in one hemisphere in a sagittal MRI plane, approximately 3 mm away from the longitudinal fissure. T1-weighted fast spin-echo (FSE) images (TR/ TE 500/17 msec, FOV cm, matrix , slice thickness 3.0 mm) were performed to check the registration between the MRI scan plane and the two Luxtron temperature sensors. Gradient-echo (GE) MR phase images with three TE settings in separate experiments (TR/TE 77.2/38.9, 21.5, 13.3 msec; FOV cm; matrix ; slice thickness 3.0 mm; flip angle 30 ; image time 10 seconds) were continuously obtained before, during, and after heating. A reference phantom, separated from the animal by 2 cm, was used for correction of any scalar phase drift during imaging. After heating, the procedure was repeated for the other hemisphere. The brains were heated with 2 W laser power. The heating time ranged from 1 to 8 minutes. The maximum temperatures measured by the Luxtron temperature sensors ranged from 45 C to 83 C ( T C). All animals were euthanized with intravenous injection of euthanasia solution at 1 ml/4.5 kg immediately after heating. Thermal Ablation Techniques Seven rabbits were used to study the correlation between maximum (threshold) temperature, thermal dose, and lesion on T2 SE-weighted MRI. Each animal was anesthetized and prepared as described above. The rabbit was placed in the bore of the 0.5 T Signa SP MR scanner in a prone position. A laser fiber was inserted approximately 8 mm into the brain and 3 mm lateral to the longitudinal fissure. Two rice noodles (approximate 1 mm in diameter) were inserted approximately 8 mm into the brain, on both sides of the laser fiber, as fiducial markers. The laser fiber and the two rice noodles were located within a sagittal MR scan plane. A Luxtron temperature sensor was inserted 8 mm into the brain and approximately 4 mm lateral to the laser fiber, and baseline temperature was measured. A reference phantom separated from the animal by 2 cm above the animal was used for correction of phase drift during imaging. T1-weighted FSE (TR/TE 500/17 msec, FOV cm, matrix , slice thickness 3.0 mm) images were used to check Table 1 Heating Parameters Used to Make Seven Lesions in Seven Animals for Temperature and T 43 Measurements Lesion no. Laser power (W) Baseline temperature ( C) Heating duration (s) Lesion diameter (mm) the registration between the MR scan plane and the fiducial markers. The brains were heated with 2 W laser power. The heating time ranged from 30 to 581 seconds (Table 1). To ensure that a thermal lesion was created in each experiment, heating was applied until a temperature of at least 55 C was measured by Luxtron temperature sensor. GE MR phase images were continuously acquired (TR/TE 77.2/38.9 msec; FOV cm; matrix ; slice thickness 3.0 mm; flip angle 30 ; image time 10 seconds) before, during, and after heating. One pixel resolution was mm. Based on our previous studies, in which the thermal lesion on MRI correlated well with the cell death zone at 4 hours post-treatment (16), the animals were kept in the magnet under general anesthesia for 4 hours. A set of T2-weighted SE MR images were then acquired (TR/TE 4000 msec; matrix ; FOV cm; slice thickness 2 mm; number of excitations 4). One pixel resolution was mm. The animals were then euthanized. Data Analysis Image Processing MR temperature maps were processed in near real time to provide immediate assessment of the heating. Baseline phase maps acquired before heating were subtracted from the remaining phase maps. This was done by multiplying each image by the complex conjugate of the baseline image on a pixel-by-pixel basis. In addition, the phase measured in the separate phantom was similarly subtracted from the phase maps. This was done to correct for any scalar phase drift during the course of the heating. This processing was repeated retrospectively at the time of image analysis. PRF Thermal Coefficient Calibration A region of interest (ROI) for MR temperature measurement was taken at the tip of the thermal sensor (2 2 pixels). Paired data (MR, Luxtron) were obtained from 1140 time-points. Lines were fitted to the phase shift ( ) vs. temperature elevation ( T) for each TE, and to / T vs. TE, respectively. The thermal coefficient was found from the fitted line. The data analysis indicated an interaction between the laser beam and the Luxtron temperature sensors. As a result, our calibrations only

3 MR Thermometry for Thermal Therapy 149 Figure 1. T2-weighted MRI 4 hours after laser ablation, showing the thermal lesion and two fiducial markers. used the data points that were taken when the laser was turned off. Measurement of Peak Temperature and T 43 on the Lesion Boundary Using Direct MR Measurement Seven lesions were used for data analysis. The fiducial and anatomical markers were used for registration between T2 and GE-MRI. The exterior margin of the bright ring on T2-weighted SE-MRI was defined as the thermal lesion (Fig. 1). T2-weighted images were magnified 4 times ( ) using a bilinear interpolation in order to trace the accurately. The lesion boundaries were then manually traced, as were the fiducial markers and the outline of the brain. The fiducial markers and outline of the brain were registered to the GE images used for the temperature mapping. The manually traced lesion was then superimposed on MR temperature maps. For each pixel in the lesion, the maximum temperature reached through the entire heating was measured. The peak temperatures from the lesion were then averaged, yielding a single average value for each lesion. For each lesion, the cumulative thermal dose (T 43 ) was calculated on each pixel over the lesion based on the Arrhenius-damage integral (19). The thermal doses from each pixel on the lesion were averaged, yielding a single average value of T 43 for each lesion. The uncertainty of the T 43 for each lesion was the difference between the maximum and minimum values on the lesion. Determination of Critical (Maximum) and T 43 Using the Binary Discrimination Model The values of critical temperature and T 43 that discriminate the pixels just inside the lesion from these just outside the were determined using receiver operating characteristic (ROC) curves (5). Two ROIs were chosen: one at the location of one pixel inside the lesion, and the other at the location of one pixel outside the lesion. The peak value of each pixel during the course of the heating was used for the analysis. The threshold temperature/t 43 is given by the point geometrically nearest to the upper left corner of the ROC curve, which corresponds to the threshold value that maximizes the fraction of pixels just inside the exceeding the threshold, and minimizes the fraction of pixels just outside the that are misclassified by exceeding the threshold. RESULTS Calibration of Thermal Coefficient In this study we found the phase change, / T (in degrees/ C), as a function of TE by / T B o TE 0.48 (1) where is the gyromagnetic ratio, B o the magnetic field strength, and 0.48 a phase offset (see Discussion).

4 150 Chen et al. Table 2 Direct Measurement of Maximum Temperature and T 43 on Lesion Boundary Lesion no. Maximum T ( C) a T 43 (minutes) b ( ) ( ) ( ) ( ) (0.5 92) (0.1 77) ( ) Average ( ) a The error is the standard deviation. b These values in brackets are the variations from pixel to pixel. Direct Measurement of Critical Temperature and T 43 on the Lesion Boundary in MRI Table 2 shows averaged values of threshold temperature and T 43 on the lesion for seven lesions. The averaged value over all seven lesions is C, and the averaged T 43 is minutes. The range of the T 43 value is minutes. Measurement of Critical Temperature and T 43 Using a Discrimination Model Figure 2a is a typical graph showing the number of pixels in percent above a temperature threshold on the inside ROI vs. the number of pixels above that threshold on the outside ROI from lesion 1. A point on the curve is chosen which is geometrically closest to the Table 3 Threshold Temperature on Lesion Boundary Measured From Discriminate Model Lesion no. Threshold T ( C) % pixels inside threshold T % pixels outside threshold T Average The error is the standard deviation. upper left corner. This point corresponds to a threshold temperature of 48 C. At this temperature, 66% of pixels on the inside ROI were above the threshold value, while only 27% of pixels on the outside ROI were above this threshold temperature. These ROI data are again plotted in Figure 2b as the number of pixels above the threshold temperature vs. threshold temperature. The threshold temperature of 48 C is plotted as a vertical bar, nicely differentiating the two ROIs. Table 3 summarized the threshold temperature derived from the discriminate model over all seven lesions. On average, the threshold temperature is C. At this temperature, 73% of pixels on the inside ROI were above the threshold temperature while only 30% of pixels on the outside ROI were above this threshold. Figure 2. a: Plot of the number of pixels in percent above a threshold temperature on the inside ROI vs. the number of pixels above that threshold on the outside ROI from lesion 1. The point on the curve geometrically closest to the upper left corner corresponds to a critical temperature of 48 C. At this temperature, 66% of pixels in the inside ROI were above the threshold value, while only 27% of pixels in the outside ROI were above this threshold temperature. b: Plot of the number pixels above the threshold temperature vs. threshold temperature. The critical temperature of 48 C is indicated as a vertical line, nicely differentiating the two ROIs.

5 MR Thermometry for Thermal Therapy 151 Figure 3. a: Plot of the number of pixels in percent above a threshold T 43 on the inside ROI vs. the number of pixels above that threshold on the outside ROI from lesion 1. The point on the curve geometrically closest to the upper left corner corresponds to a critical T 43 of 13 minutes. At this T 43, 52% of pixels in the inside ROI were above the threshold value, while only 14% pixels in the outside ROI were above this threshold T 43. b: Plot of the number pixels above the threshold T 43 vs. threshold T 43. The critical T 43 of 13 minutes is indicated as a vertical line, nicely differentiating the two ROIs. Similarly, the threshold T 43 from lesion 1 was also plotted in Figure 3. The threshold T 43 was found to be 13 minutes. Figure 3a shows that 52% of pixels on the inside ROI were above the threshold while only 14% of pixels on the outside ROI were above this threshold. These ROI data are again plotted in Figure 3b as the number of pixels above the threshold T 43 vs. threshold T 43. The threshold T 43 of 13 minutes was also plotted as a vertical bar, differentiating the two ROIs. Table 4 shows the values of threshold T 43 over all seven lesions. On average, the threshold T 43 was 28 41min. At this T 43, 67% of pixels on the inside ROI were above the threshold T 43 while only 25% of pixels on the outside ROI were above the threshold. From Figures 2 and 3, we can see that the threshold temperature and T 43 models Table 4 Threshold T 43 on Lesion Boundary Measured From Discriminate Model Lesion no. T 43 (minutes) % pixels inside threshold T 43 % pixels outside threshold T Average The error is the standard deviation. provide similar discrimination values, although there is a large variation in T 43. DISCUSSION The thermal coefficient of ppm/ C obtained from this study in rabbit brain in vivo is in good agreement with that of ppm/ C in pig brain ex vivo reported by Harth et al (20). Peters et al (21) reported that the thermal coefficient is independent of tissue type ex vivo. The value of the thermal coefficient obtained from this study is consistent with the findings of Harth et al (20) in ex vivo brain, as well as with our own previous study on ex vivo bovine liver (22). A phase offset of 0.48 degrees/ C was found in our calibration study (see Eq. [1]). In an electrically conductive media, B 1 (t) experiences a phase lag dependent on the temperature-sensitive electrical conductivity of the media. This phase lag does not subtract away with subtraction of baseline images and does not depend on the TE. In our experiments, the phase offset was substantial and not completely explained by the offset described by Peters and Henkelman (23). The exact reason for the apparent phase offset in our experiments remains to be investigated. It is evident from Eq. [1] that the effect of the phase offset on / T will be smaller with longer TE. For example, with a shorter TE of 13 msec, there will be a 48% error in / T if the phase offset is not taken into account. With a longer TE of 38 msec, there will be only a 17% error in / T if the offset is not taken into

6 152 Chen et al. account. Therefore, we recommend the use of longer TE to reduce the effect of the phase offset if it will not be explicitly measured. Alternatively, a two-echo sequence can be used to obtain an initial phase at an early TE for subtraction of the phase offset. Detailed data analysis showed that on the temperature vs. time curve, the maximum temperature for individual pixels could be reached at different times (or images) during heating. In this study, the peak temperature for each pixel on the lesion was selected over the entire heating time. In this way we ensured that the maximum temperature reached from each pixel was measured as accurately as possible. The results of our data suggest that in vivo calculations of T 43 are quite variable, more so than the calculations of the critical temperature. This variability may be in part due to the fact that our temporal resolution was relatively low at 10 seconds per image. Even an error of a few seconds in measurement of the time at the peak temperature can result in large variations in the calculated T 43. However, temporal resolution can only be gained at the expense of the signal-to-noise ratio (SNR) and/or spatial resolution. Graham et al (5) also found large variations in calculations of T 43 ex vivo. We would agree with their assessment that from a practical standpoint it may be better and simpler to state the time required at a particular temperature to achieve the desired effect (5). The results of this study are of significance to the clinical application of MRI guidance for thermal therapy. However, the parameters (critical temperature and T 43 ) derived from this study are different from those in canine prostate reported by Peters et al (18) and in rabbit muscle reported by McDannold et al (17). It appears that different organs may have different thresholds of temperature and T 43 for tissue damage. It is not clear whether different cancers have different thresholds for tissue damage. Therefore, measurements in various tissues and species are required before clinical application of this technique. In summary, we have validated thermal coefficients in MRI in the in vivo normal rabbit brain using the PRF shift method. The threshold temperature and T 43 as a thermal dose from the thermal lesion in MRI were measured, yielding a value of 48 C for the threshold temperature. The value for T 43 was highly inconsistent, which led us to conclude that in practice this parameter would be difficult to use to monitor thermal ablations that are similar to our experimental setup. ACKNOWLEDGMENTS We thank Dr. Karl Vigen for comments on the manuscript. We are grateful to Diane Howard and Wendy Baumgardner for their expert technical assistance. REFERENCES 1. Cline HE, Schenck JF, Watkins RD, et al. Magnetic resonanceguided thermal surgery. 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