Comparison of Single-Shot Rapid Acquisition with Relaxation Enhancement and Echo Planar Current Density MRI Sequences for Monitoring of Electric Pulse Delivery in Irreversible Electroporation I. Serša1, F. Bajd1, M. Kranjc2, H. Busse3, N. Garnov3, R. Trampel4, and D. Miklavčič2 1
Institut “Jozef Stefan”, Jamova cesta 39, SI-1000, Ljubljana, Slovenia University of Ljubljana, Faculty of Electrical Engineering, Tržaška 25, SI-1000, Ljubljana, Slovenia 3 Department of Diagnostic and Interventional Radiology, University of Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany 4 Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstr. 1a, 04103 Leipzig, Germany 2
Abstract— Success of electroporation treatment critically depends on coverage of the target tissue with electric field. The electric field during delivery of the electroporation pulses can be reconstructed by the magnetic resonance electric impedance tomography, a method that uses current density distribution data and electric potentials at the electrodes for reconstruction of electric field in the sample. In this study, two complementary MRI methods for current density imaging during delivery of irreversible electroporation pulses are presented. One of the methods is based on the single-shot rapid acquisition with relaxation enhancement while the other is based on the echo planar imaging MRI method. The methods were compared in terms of their sensitivity and susceptibility to image artifacts by experiments on a liver test sample that were performed on a 2.35 T small bore MRI scanner. In the experiments, a standard protocol for irreversible electroporation where 90 electric pulses of 100 µs, 3000 V are delivered at 1 Hz was performed. Results of the study confirmed that both methods have comparable sensitivity. The RARE-based method was found less susceptible to artifacts while the EPI-based method has lower SAR value and may therefore be a better candidate for use in clinics. Keywords— MRI, current density imaging, electroporation, electric field monitoring.
I. INTRODUCTION Use of electroporation as a clinical method for tumor treatment is expanding. Two varieties of it are used: electrochemo therapy (ECT) and irreversible electroporation (IRE). In ECT [1-4] the used electric field is sufficiently high that for a short time makes cell membranes permeable and thus eases transport of anticancer drugs into the cells, while in IRE [5, 6] the exposure to electric field is higher (number of pulses and amplitude) so that the electric pulses itself without the aid of the anticancer drugs results in a cell death in the electroprated tumor region. For the success of either of the treatment methods, it is very important that the electric field in the treated region is within the specified range or the treatment efficacy is poor [7-9]. Therefore, the use on an efficient method for the electric field monitoring during the delivery of electric pulses is highly demanded. Recently, a
method for reconstruction of electric field distribution during electroporation pulse delivery based on magnetic resonance electrical impedance tomography (MREIT) was suggested [10]. So far, MREIT was primarily used in low voltage/ low current regimes as a method for electrical conductivity mapping [11], while its application in electroporation is relatively new and was used only in a few recent studies. These include agar phantom experiments [10], ex vivo liver tissue experiments [12] and in vivo muse tumor experiments [13]. An essential step in MREIT is an acquisition of current density (CD) distributions during the delivery of electroporation pulses. These can be obtained by current density imaging (CDI) techniques [14], which rely on mapping of the magnetic field change due to application of the electroporation currents and conversion of the maps to CD images using Ampere’s law. In principle, for calculation of the one component of the current density, information on the two components of the magnetic field change is needed. This would impose a rotation of the sample to at least two perpendicular orientations, as the magnetic field change can be recorded only along the direction of the static magnetic field. However, with special orientations of the electrodes with respect to the static magnetic field, the sample rotation may be avoided and CD maps can be calculated just from a magnetic field change map acquired in one sample orientation [10, 13]. Standard CDI sequence [14, 15] is designed for long low voltage electric pulses that are used in a combination with a standard spin-echo imaging sequence. The sequence is inappropriate for its use in electroporation as it requires delivery of typically more than 100 electric pulses for acquisition of one CD image. As the pulses have high voltage, they may significantly alter the sample during image data acquisition. Therefore, electric pulses can be repeated only very limited times for acquisition of one image, ideally application of only one electroporation pulse should be sufficient for acquisition of one CD image. Possible candidates as imaging methods for electroporation monitoring are therefore from the family of single-shot MR imaging methods. Specifically, in this study two such methods were employed
© Springer Science+Business Media Singapore 2016 T. Jarm and P. Kramar (eds.), 1st World Congress on Electroporation and Pulsed Electric Fields in Biology, Medicine and Food & Environmental Technologies (WC 2015), IFMBE Proceedings 53, DOI: 10.1007/978-981-287-817-5_19
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forr CDI and com mpared in their performance on o ex vivo liverr tisssue sample im maging. The seequences are CDI modifications of the singgle-shot rapidd acquisition with w relaxationn RARE) methodd [16] and thhe echo planarr enhhancement (R im maging (EPI) [17]. II. MATERIAL AN ND METHOD DS A. CDI Sequencees for IRE Monnitoring Current densitties were imagged by two typpes of CDI sequences that are shown in Fig.. 1. Both sequeences are spinechho based and have h in their innitial part a shoort (typically tc = 100 µs long) electroporation e n electric pulsee, while signaal acqquisition is in the second paart of the sequuence. The sequences differ inn the signal acqquisition part, which w is in thee firsst case equal to the single-sshot RARE accquisition (Figg. 1a)), while in the second case, it i is equal to thhe EPI acquisi-tion (Fig. 1b). The T electric pullse alters the static s magneticc field due to curreents flowing thhrough the sam mple. Result of thee currents is a signal phase shhift. The shift is proportionaal to the electric puulse duration annd to the static magnetic fieldd chaange. Thereforre, the phase shift s can be ussed for calculation of the magneetic field changge and ultimateely for calculation of the currennt density distriibution image.
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refocusing radiofrequenncy (RF) pulses (0°and 900°), and subsequen nt signal co-adddition. Therefore, we nameed it the two-shot RARE CDI seequence [18]. The T two repetittions are o avoid artefaacts from elecctric currents flowing needed to through the t sample annd with them m associated auxiliary a phase shiift miss registrration. Such problems p are not n common to th he EPI-type off the CDI sequeence, which giives nice results wiith only one seequence run annd is therefore twice as fast as thee two-shot RAR RE CDI sequennce. B. Samplle Preparationn and CDI expeeriment The peerformance of both CDI sequuences was tessted on a beef liverr tissue samplee, which was exxposed to highh voltage electric pulses p that are typically usedd in IRE. Liveer tissue was obtained from a slaughterhouse s , as meat product for human co onsumption. Thhe slaughterhoouse operates in accordance to Slovenian law w and the proccess of slaughttering is regulated by Rules onn animal proteection and weelfare at slaughter (Ur. l. RS, N. 5/2006), whicch ensures ethiccal standards of slaughtering procedure p and is in compliannce with European n Union Counccil directive onn the protectionn of animals at th he time of slauughter or killinng (93/119/EC C). Temperature of the liver tiissue was mainntained at 4°C C before beginning g of the experriment and thenn allowed to warm w to the room m temperature. The tissue was sectioned to t cylindrical and d flat shaped samples with a diameter off 21 mm and heigh ht of 10 mm annd then placedd in a plastic coontainer. Two need dle platinum-irridium electroddes with a diam meter of 1 mm were inserted at a distance of 144 mm betweenn them in the samplle perpendiculaarly to it and in i parallel to each e other. Altogeether 90 pulses of 3000 V amplitude, a 1 Hzz repetition rate and 100 µs (R RARE-type off sequence) orr 300 µs (EPI-typee of sequence) duration and were delivereed to the sample. Electric E pulses were deliveered by a cusstomized Cliniporaator Vitae (IGE EA, Carpi, Italyy) pulse generaator.
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Fig. 1 Two complem mentary CDI pulsee sequences designned for irreversiblee eleectroporation moniitoring: a) two-shoot RARE CDI pulsse sequence and b)) EPI CDI pulsee sequence. The RARE-tyype pulse sequuence consists of two repetitions of the sequuence, each with w a differennt phase of thee
Fig. 2 Seqquential vs. centricc signal acquisitionn line ordering in k-space. k
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Comparison of Single-Shot Rapid Acquisition with Relaxation Enhancement and Echo Planar Current Density MRI Sequences
Both CDI sequences for IRE monitoring were performed on a 2.35 T horizontal bore small animal MRI scanner. The scanner was based on an Oxford superconducting magnet (Oxford Instruments, Abingdon, UK), an Apollo NMR/MRI spectrometer (Tecmag Inc., Houston TX, USA) and MRI probes for MR microscopy (Bruker, Ettlingen, Germany). The sequences were run with identical geometric and resolution parameters: field of view 30 mm, imaging matrix 64 by 64, slice thickness 4 mm and repetition time 1 s, while echo-time parameters were different: inter-echo time in the two-shot RARE CDI sequence was 2.64 ms and spin-echo time in the EPI CDI sequence was 35 ms. To maximize CDI sensitivity, signal acquisition ordering of lines in the kspace was centric for the RARE-type of sequence and was sequential for the EPI-type of sequence.
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image sets (Fig. 3, top row vs. Fig. 3 bottom row) clearly shows tissue alteration as a result of its exposure to high voltage electric pulses, i.e. electroporation. Moreover, conductivity of the tissue increased which resulted in a higher current density between the electrodes. CDI results shown in Fig. 4 confirmed that a CD distribution can be imaged also by the EPI CDI sequence. Figure 4 shows the magnitude CD image of an identical tissue sample to the previous experiment. As expected, current density was the highest next to the electrodes and then decreased as distance from the electrodes increased. However, trajectory of the highest current was not a straight line connecting the electrodes, but was shifted sideways. In the experiment 90 electroporation pulses were delivered and the same number of CD images was obtained. The one shown corresponds to CD distribution at the end of the experiment.
III. RESULTS Figure 3 depicts results of the CDI experiment on the liver sample from data acquired by the two-shot RARE CDI sequence. By the sequence vector maps of current distribution as well as the corresponding maps of current density magnitude were obtained. In the experiment 90 electroporation pulses were delivered and 45 CD images were calculated as delivery of two electroporation pulses was needed for calculation of one CD image.
Fig. 4 Current density distribution image of a liver sample calculated from data obtained by the EPI-based CDI sequence.
IV. DISCUSSION
Fig. 3 Calculated current distribution vector field maps (left) and the corresponding current density magnitude images (right) at the beginning of electroporation experiment (1st row) and at the end of it when 90 highvoltage electric pulses were already delivered to the liver sample (2nd row). CDI data were acquired by the two-shot RARE CDI sequence. In Fig. 3, the CD images corresponding to the first two electroporation pulses and to the last two (89th and 90th) electroporation pulses are shown. Comparison of these two
Results of CDI on the liver test sample confirmed that both tested CDI sequences, the two-shot RARE CDI sequence as well as the EPI CDI sequence, enable clear visualization of current distribution in the electroporated tissue region and are therefore appropriate for tissue electroporation monitoring. However, there are distinctions between both CDI sequences used here. As already pointed in the materials section, the twoshot RARE CDI sequence requires two repetitions of the sequence for acquisition of one image, while the EPI CDI sequence does not have such a limitation and enables image acquisition already after only one sequence run, i.e. after a single electroporation pulse. Therefore, it is a true single-shot sequence. Unfortunately, the EPI CDI sequence has also its drawback. As all EPI sequences are prone to susceptibility (magnetic field inhomogeneity) artefacts, the EPI CDI sequence is no exception. Therefore, it is not very clear if the unusual current distribution in Fig. 4 is true or it is an EPI artifact. If it is true then it could be attributed to the void in the middle of the sample, perhaps due to liver tissue folding. The two-shot RARE CDI sequence is more robust in this respect and can produce nice artifact free images also with samples of poor magnetic field homogeneity. The EPI CDI sequence has also an important advantage over to the two-shot RARE CDI sequence and that is low specific absorption rate (SAR). SAR
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is a measure of the rate at which energy is absorbed by the human body when exposed to a radio frequency (RF) electromagnetic radiation. Namely, in the two-shot RARE CDI sequence there are many RF refocusing pulses that may contribute to a significant tissue RF irradiation. As there are strict regulations regarding SAR in clinical MRI, the performance of two-shot RARE CDI sequence may be impeded when used in human MRI. For comparison, in the presented study, for acquisition of one CD image 130 RF refocusing pulses were delivered to the sample with the two-shot RARE CDI sequence, while only one RF refocusing pulse was delivered to the sample with the EPI CDI sequence. V. CONCLUSION
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In our study a comparison between two two-shot RARE CDI sequence and the EPI CDI sequence is presented. Results on the liver tissue test sample ex vivo confirmed that both sequences could be used for monitoring of irreversible tissue electroporation, but with different limitations. The two-shot RARE CDI sequence was found very robust and can produce good results also with samples in conditions of poor magnetic field homogeneity, while the EPI CDI sequence is prone to susceptibility artifacts. However, the EPI CDI sequence has considerably lower SAR than the twoshot RARE CDI sequence and may therefore be more appropriate for electroporation monitoring in clinical MRI.
ACKNOWLEDGMENT
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This study was supported by the Slovenian Research Agency (ARRS) and conducted within the scope of the Electroporation in Biology and Medicine European Associated Laboratory (LEA-EBAM). This manuscript is a result of the networking efforts of the COST Action TD1104 (www.electroporation.net).
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CONFLICT OF INTEREST
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The authors declare that they have no conflict of interest.
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Igor Serša Jozef Stefan Institute Jamova 39 Ljubljana Slovenia
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