Patent Publication Number: US-2021177503-A1

Title: Regulating delivery of irreversible electroporation pulses according to transferred energy

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to medical equipment, and particularly to methods and devices for monitoring the total electrical energy injected in an irreversible electroporation (IRE) procedure. 
     BACKGROUND 
     Irreversible electroporation (IRE) is a soft tissue ablation technique that applies short pulses of strong electrical fields to create permanent and hence lethal nanopores in the cell membrane, thus disrupting the cellular homeostasis (internal physical and chemical conditions). Cell death following IRE results from apoptosis (programmed cell death) and not necrosis (cell injury, which results in the destruction of a cell through the action of its own enzymes) as in all other thermal or radiation based ablation techniques. IRE is commonly used in tumor ablation in regions where precision and conservation of the extracellular matrix, blood flow and nerves are of importance. 
     SUMMARY 
     Exemplary embodiments of the present invention that are described hereinbelow provide improved methods and devices for performing an IRE procedure. 
     There is therefore provided, in accordance with an exemplary embodiment of the invention, medical apparatus, including a probe configured for insertion into a body of a patient and including a plurality of electrodes configured to contact tissue within the body. An electrical signal generator is coupled to apply bipolar trains of pulses having a voltage amplitude of at least 200 V and having a duration of each of the bipolar pulses less than 20 μs between at least one pair of the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of the electrodes. One or more electrical sensors are coupled to an output of the electrical signal generator and configured to sense the energy dissipated between the at least one pair of the electrodes during the trains of the pulses. A controller is coupled to control electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator, responsively to the one or more electrical sensors, so that the dissipated energy satisfies a predefined criterion. 
     In one exemplary embodiment, the electrical parameters controlled by the controller include a voltage. Alternatively or additionally, the electrical parameters controlled by the controller include a current. 
     In some exemplary embodiments, the controller is configured to control the electrical parameters so that the dissipated energy between each pair of the electrodes meets a specified target value. In one exemplary embodiment, the controller is configured to adjust a peak amplitude of the pulses that are applied between the at least one pair of the electrodes so that the dissipated energy satisfies the predefined criterion. 
     Typically, the one or more electrical sensors are configured to measure a voltage and a current flowing between the at least one pair of the electrodes in a sequence of time intervals, and the controller is configured to measure the dissipated energy by computing a sum of a product of the voltage and the current over the sequence of the time intervals. 
     In further exemplary embodiments, the controller is configured to control the temporal parameters# so that the dissipated energy between each pair of the electrodes meets a specified target value. In one exemplary embodiment, the controller is configured to adjust a number of the pulses that are applied between the at least one pair of the electrodes so that the dissipated energy satisfies the predefined criterion. Alternatively or additionally, the controller is configured to adjust a duration of the pulses that are applied between the at least one pair of the electrodes so that the dissipated energy satisfies the predefined criterion. 
     There is also provided, in accordance with an exemplary embodiment of the invention, a method for ablating tissue within a body of a patient. The method includes inserting a probe into the body, wherein the probe includes a plurality of electrodes configured to contact the tissue. Bipolar trains of pulses having a voltage amplitude of at least 200 V and having a duration of each of the bipolar pulses less than 20 μs are applied between at least one pair of the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of the electrodes. the energy dissipated between the at least one pair of the electrodes during the trains of the pulses is measured, and electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator are controlled, responsively to the measured energy, so that the dissipated energy satisfies a predefined criterion. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The present invention will be more fully understood from the following detailed description of the embodiments thereof, taken together with the drawings in which: 
         FIG. 1  is a schematic pictorial illustration of a multi-channel IRE system used in an IRE ablation procedure, in accordance with exemplary embodiments of the invention; 
         FIG. 2  is a schematic illustration of a bipolar IRE pulse, in accordance with an exemplary embodiment of the invention; 
         FIG. 3  is a schematic illustration of a burst of bipolar pulses, in accordance with an exemplary embodiment of the invention; 
         FIGS. 4A-B  are schematic illustrations of IRE signals with an incorporated RF signal, in accordance with an exemplary embodiment of the invention; 
         FIG. 5  is a block diagram that schematically illustrates an IRE module and its connections to other modules, in accordance with an exemplary embodiment of the invention; 
         FIG. 6  is an electrical schematic diagram of a pulse routing and metrology assembly in the IRE module of FIG.  5 , in accordance with an exemplary embodiment of the illustration; 
         FIG. 7  is an electrical schematic diagram of two adjacent modules in the pulse routing and metrology assembly of  FIG. 6 , in accordance with an exemplary embodiment of the invention; 
         FIG. 8  is an electrical schematic diagram of a pulse generating circuit, a transformer, and a high-voltage supply, in accordance with an exemplary embodiment of the invention; 
         FIG. 9  is an electrical schematic diagram of a switch, in accordance with an exemplary embodiment of the invention; and 
         FIG. 10  is a flowchart that schematically illustrates a method for controlling an IRE procedure, in accordance with an exemplary embodiment of the invention. 
     
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
     Overview 
     IRE is a predominantly non-thermal process, which causes an increase of the tissue temperature by, at most, a few degrees for a few milliseconds. It thus differs from RF (radio frequency) ablation, which raises the tissue temperature by between 20 and 70° C. and destroys cells through heating. IRE utilizes bipolar pulses, i.e., combinations of positive and negative pulses, in order to avoid muscle contraction from a DC voltage. The pulses are applied, for example, between two bipolar electrodes of a catheter. 
     In order for the IRE-pulses to generate the required nanopores in tissue, the field strength E of the pulses must exceed a tissue-dependent threshold E th . Thus, for example, for heart cells the threshold is approximately 500 V/cm, whereas for bone it is 3000 V/cm. These differences in threshold field strengths enable IRE to be applied selectively to different tissues. In order to achieve the required field strength, the voltage to be applied to a pair of electrodes depends both on the targeted tissue and on the separation between the electrodes. The applied voltages may reach up to 2000 V, which is much higher than the typical voltage of 10-200 V in thermal RF ablation. 
     A bipolar IRE-pulse comprises a positive and a negative pulse applied between two electrodes with pulse widths of 0.5-5 μs and a separation between the positive and negative pulses of 0.1-5 μs. (Herein the terms “positive” and “negative” refer to an arbitrarily chosen polarity between the two electrodes.) The bipolar pulses are assembled into pulse trains, each train comprising between one and a hundred bipolar pulses, with a pulse-to-pulse period of 1-20 μs. To perform IRE ablation at a given location, between one and a hundred pulse trains are applied between a pair of electrodes at the location, with a spacing between consecutive pulse trains of 0.3-1000 ms. The total energy per channel (electrode-pair) delivered in one IRE ablation is typically less than 60 J, and an ablation may last up to 10 s. 
     When a multi-electrode catheter is used in an IRE procedure, successive pairs of electrodes may be cycled through during the procedure. Taking as an example a 10-electrode catheter, the electrode pairs may be energized in an adjacent fashion (1-2, 2-3, . . . 9-10) or in an interleaved fashion (1-3, 2-4, . . . 8-10). Energizing, for example, adjacent pairs is done in two stages, first energizing the odd-even electrodes 1-2, 3-4, 5-6, 7-8 and 9-10, and then the even-odd electrodes 2-3, 4-5, 6-7, and 8-9. 
     Before starting the IRE procedure, the physician sets the parameters of the procedure based on, for example, the volume of the tissue to be ablated, required field strength within the tissue, catheter configuration, and the energy to be delivered during the procedure. 
     Once the procedure has started, the IRE ablation pulses may, in addition to the desired effect of electroporation itself, also affect the impedance of the tissue and/or the contact impedance between the electrodes and the tissue. For a fixed duration and amplitude of a pulse, a change in any of these impedances will affect the current delivered by the pulse, and thus the energy transferred from each pulse into the tissue. This, in turn, will cause the total energy dissipated in the tissue during the procedure to deviate from the amount of energy preset by the physician. Consequently, the effect of the IRE ablation may be different than expected. Moreover, two procedures that have the same energy settings for the IRE ablation may in reality have different amounts of energy transferred to the tissue, thus possibly affecting the repeatability of these kinds of procedures. Specifically, exceeding a preset level of energy may lead to unwanted thermal effects, such as formation of bubbles around the electrodes or charring of the tissue. 
     The exemplary embodiments of the present invention that are described herein address the problem of controlling the amount of energy that is delivered to the tissue in an IRE procedure by measuring the actual dissipation of energy between the electrodes. Based on this measurement, the pulses delivered by the catheter to the tissue are controlled so that the amount of dissipated energy satisfies a predefined criterion. For example, the criterion may specify that the amount of dissipated energy meets a certain target value (i.e., that the cumulative energy dissipated in each location in the tissue is equal to the target value to within a certain error bound, such as ±5 percent or ±10 percent). Alternatively or additionally, other criteria may be defined. 
     For these purposes, the exemplary embodiments that are described herein provide a medical apparatus comprising an electrical signal generator and a controller. The medical apparatus further comprises a probe, which is inserted into a body of a patient and which comprises multiple electrodes that contact tissue within the body and are used in applying the electrical signals for the IRE procedure to the tissue. The controller receives setup parameters for implementing an IRE ablation protocol. The parameters may be preset, or they may be adjusted by an operator of the apparatus, such as a physician. The controller transmits to the signal generator instructions to apply trains of bipolar pulses between selected electrodes on the probe. For IRE, these pulses typically have a voltage amplitude of at least 200 V and a duration of each bipolar pulse pair that is less than 20 μs, so as to cause irreversible electroporation of the tissue between the selected electrodes. Alternatively, other suitable pulse parameters may be chosen for this purpose. 
     To measure the pulse energy that is dissipated in the tissue, electrical sensors are coupled to the outputs of the electrical signal generator. These sensors continuously sense the energy dissipated between the bipolar pairs of electrodes, and convey the measured results to the controller. The controller computes the dissipated energy, and controls the electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator, so that the dissipated energy meets a target value or satisfies some other criterion. The electrical signal generator may be configured either as a voltage source or a current source. In the former case, the electrical parameters controlled by the controller are primarily the voltages of the pulses, whereas in the latter case, the electrical parameters are primarily the currents of the pulses. 
     To measure the dissipated energy, the controller receives measurements of the voltages between the electrodes, as well as the currents passing through the electrodes, in successive intervals during the ablation procedure. From these measurements the controller estimates the instantaneous power delivered to the tissue, and thus finds the cumulative energy dissipated in the tissue during the IRE procedure. The controller computes possible adjustments required in the trains of the bipolar pulses so that the total energy dissipated in the procedure satisfies the applicable criteria. For this purpose, the controller typically adjusts one or more of the following parameters: pulse amplitude (either voltage amplitude or current amplitude, depending on whether the signal generator is a voltage source or a current source), pulse width (duration), number of pulses per pulse train, and number of pulse trains during the procedure. Alternatively or additionally, the controller may compute adjustments for individual bipolar pulses or pulse trains so that individual pulses or pulse trains will dissipate a preset amount of energy in the tissue. 
     In some exemplary embodiments, the electrical signal generator used for the IRE procedure is capable of applying, in addition to bipolar pulses for IRE ablation, radio-frequency (RF) signals for thermal RF ablation of the tissue. The measurement of energy dissipation by the electrical sensors can also be used in monitoring and controller the thermal RF ablation process. 
     IRE Ablation System and Ire Pulses# 
       FIG. 1  is a schematic pictorial illustration of a multi-channel IRE system  20  used in an IRE ablation procedure, in accordance with exemplary embodiments of the present invention. In the following description, the IRE ablation procedure will also be referred to as “IRE ablation” or “IRE procedure.” In the illustrated exemplary embodiment, a physician  22  is performing a multi-channel IRE ablation procedure using IRE system  20 . Physician  22  is performing the procedure on a subject  24 , using an ablation catheter  26  whose distal end  28  comprises multiple ablation electrodes  30  arrayed along the length of the catheter  26 . 
     IRE system  20  comprises a processor  32  and an IRE module  34 , wherein the IRE module comprises an IRE generator  36  and an IRE controller  38 . As will be further detailed below, IRE generator  36  generates trains of electrical pulses, which are directed to selected electrodes  30  for performing an IRE procedure. The waveforms (timing and amplitude) of the trains of electrical pulses are controlled by IRE controller  38 . Processor  32 , as will also be detailed below, handles the input and output interface between IRE system  20  and physician  22 . 
     Processor  32  and IRE controller  38  each typically comprises a programmable processor, which is programmed in software and/or firmware to carry out the functions that are described herein. Alternatively or additionally, each of them may comprise hard-wired and/or programmable hardware logic circuits, which carry out at least some of these functions. Although processor  32  and IRE controller  38  are shown in the figures, for the sake of simplicity, as separate, monolithic functional blocks, in practice some of these functions may be combined in a single processing and control unit, with suitable interfaces for receiving and outputting the signals that are illustrated in the figures and are described in the text. In some exemplary embodiments, IRE controller  38  resides within IRE module  34 , as high-speed control signals are transmitted from the IRE controller to IRE generator  36 . However, provided that signals at sufficiently high speeds may be transmitted from processor  32  to IRE generator  36 , IRE controller  38  may reside within the processor. 
     Processor  32  and IRE module  34  typically reside within a console  40 . Console  40  comprises input devices  42 , such as a keyboard and a mouse. A display screen  44  is located in proximity to (or integral to) console  40 . Display screen  44  may optionally comprise a touch screen, thus providing another input device. 
     IRE system  20  may additionally comprise one or more of the following modules (typically residing within console  40 ), connected to suitable interfaces and devices in system  20 :
         An electrocardiogram (ECG) module  46  is coupled through a cable  48  to ECG electrodes  50 , which are attached to subject  24 . ECG module  46  is configured to measure the electrical activity of a heart  52  of subject  24 .   A temperature module  54  is coupled to optional temperature sensors, such as thermocouples  56  located adjacent to each electrode  30  on distal end  28  of catheter  26 , and is configured to measure the temperature of adjacent tissue  58 .   A tracking module  60  is coupled to one or more electromagnetic position sensors (not shown) in distal end  28 . In the presence of an external magnetic field generated by one or more magnetic-field generators  62 , the electromagnetic position sensors output signals that vary with the positions of the sensors. Based on these signals, tracking module  60  may ascertain the positions of electrodes  30  in heart  52 .       

     The above modules  46 ,  54 , and  60  typically comprise both analog and digital components, and are configured to receive analog signals and transmit digital signals. Each module may additionally comprise hard-wired and/or programmable hardware logic circuits, which carry out at least some of the functions of the module. 
     Catheter  26  is coupled to console  40  via an electrical interface  64 , such as a port or socket. IRE signals are thus carried to distal end  28  via interface  64 . Similarly, signals for tracking the position of distal end  28 , and/or signals for tracking the temperature of tissue  58 , may be received by processor  32  via interface  64  and applied by IRE controller  38  in controlling the pulses generated by IRE generator  36 . 
     An external electrode  65 , or “return patch”, may be additionally coupled externally between subject  24 , typically on the skin of the subject&#39;s torso, and IRE generator  36 . 
     Processor  32  receives from physician  22  (or from other user), prior to and/or during the IRE procedure, setup parameters  66  for the procedure. Using one or more suitable input devices  42 , physician  22  sets the parameters of the IRE pulse train, as explained below with reference to  FIGS. 2-4  and Table 1. Physician  22  further selects pairs of ablation electrodes  30  for activation (for receiving the IRE pulse trains) and the order in which they are activated. 
     In setting up the IRE ablation, physician  22  may also choose the mode of synchronization of the burst of IRE pulses with respect to the cycle of heart  52 . A first option, which is called a “synchronous mode,” is to synchronize the IRE pulse burst to take place during the refractory state of heart  52 , when the heart is recharging and will not respond to external electrical pulses. The burst is timed to take place after the QRS-complex of heart  52 , wherein the delay is approximately 50 percent of the cycle time of the heart, so that the burst takes place during the T-wave of heart  52 , before the P-wave. In order to implement synchronous mode, IRE controller  38  times the burst or bursts of IRE pulses based on ECG signals  414  from ECG module  46 , shown in  FIG. 5 , below. 
     A second synchronization option is an asynchronous mode, wherein the burst of IRE pulses is launched independently of the timing of heart  52 . This option is possible, since the IRE burst, typically of a length of 200 ms, with a maximal length of 500 ms, is felt by the heart as one short pulse, to which the heart does not react. Asynchronous operation of this sort can be useful in simplifying and streamlining the IRE procedure. 
     In response to receiving setup parameters  66 , processor  32  communicates these parameters to IRE controller  38 , which commands IRE generator  36  to generate IRE signals in accordance with the setup requested by physician  22 . Additionally, processor  32  may display setup parameters  66  on display screen  44 . 
     In some exemplary embodiments, processor  32  displays on display  44 , based on signals received from tracking module  60 , a relevant image  68  of the subject&#39;s anatomy, annotated, for example, to show the current position and orientation of distal end  28 . Alternatively or additionally, based on signals received from temperature module  54  and ECG module  46 , processor  32  may display on display screen  44  the temperatures of tissue  58  at each electrode  30  and the electrical activity of heart  52 . 
     To begin the procedure, physician  22  inserts catheter  26  into subject  24 , and then navigates the catheter, using a control handle  70 , to an appropriate site within, or external to, heart  52 . Subsequently, physician  22  brings distal end  28  into contact with tissue  58 , such as myocardial or epicardial tissue, of heart  52 . Next, IRE generator  36  generates multiple IRE signals, as explained below with reference to  FIG. 3 . The IRE signals are carried through catheter  26 , over different respective channels, to pairs of ablation electrodes  30 , such that currents  72  generated by the IRE pulses flow between the electrodes of each pair (bipolar ablation), and perform the requested irreversible electroporation on tissue  58 . 
       FIG. 2  is a schematic illustration of a bipolar IRE pulse  100 , in accordance with an exemplary embodiment of the invention. 
     A curve  102  depicts the voltage V of bipolar IRE pulse  100  as a function of time t in an IRE ablation procedure. The present exemplary embodiments relate to IRE generator  36 , which is configured as a voltage source. Consequently, IRE signals are here described in terms of their voltages. As will be described below, IRE generator  36  may alternatively be configured as a current source, in which case the IRE pulses would be described in terms of their currents. The bipolar IRE pulse comprises a positive pulse  104  and a negative pulse  106 , wherein the terms “positive” and “negative” refer to an arbitrarily chosen polarity of the two electrodes  30  between which the bipolar pulse is applied. The amplitude of positive pulse  104  is labeled as V+, and the temporal width of the pulse is labeled as t+. Similarly, the amplitude of negative pulse  106  is labeled as V−, and the temporal width of the pulse is labeled as t−. The temporal width between positive pulse  104  and negative pulse  106  is labeled as t SPACE . Typical values for the parameters of bipolar pulse  100  are given in Table 1, below. 
       FIG. 3  is a schematic illustration of a burst  200  of bipolar pulses, in accordance with an embodiment of the invention. 
     In an IRE procedure, the IRE signals are delivered to electrodes  30  as one or more bursts  200 , depicted by a curve  202 . Burst  200  comprises N T  pulse trains  204 , wherein each train comprises N p  bipolar pulses  100 . The length of pulse train  204  is labeled as t T . The period of bipolar pulses  100  within a pulse train  204  is labeled as t PP , and the interval between consecutive trains is labeled as Δ T , during which the signals are not applied. Typical values for the parameters of burst  200  are given in Table 1, below. 
       FIGS. 4A-B  are schematic illustrations of IRE signals  302  and  304  with an incorporated RF signal, in accordance with exemplary embodiments of the present invention. In the exemplary embodiments shown in  FIGS. 4A-B , RF ablation is combined with IRE ablation in order to benefit from both of these ablation modalities. 
     In  FIG. 4A , a curve  306  depicts the voltage V as a function of time t of an RF signal  308  between two bipolar pulses  310  and  312 , similar to bipolar pulse  100  of  FIG. 2 . The amplitude of RF signal  308  is labeled as V RF  and its frequency is labeled as f RF , and the separation between bipolar pulses  310  and  312  is labeled as A RF . Typically the frequency f RF  is between 350 and 500 kHz, and the amplitude V RF  is between 10 and 200 V, but higher or lower frequencies and amplitudes may alternatively be used. 
     In  FIG. 4B , a curve  314  depicts the voltage V as a function of time t of an RF signal  316  between a positive IRE pulse  318  and a negative IRE pulse  320 . IRE pulses  318  and  320  are similar to pulses  104  and  106  of  FIG. 2 . In this exemplary embodiment, the spacing t SPACE  between positive and negative pulses  318  and  320  has been stretched, as indicated in Table 1. 
     Typical values of the amplitude and frequency of RF signals  308  and  316  are given in Table 1. When an RF signal is inserted into the IRE signal, as depicted either in  FIG. 4A  or  FIG. 4B , the combination of the two signals is repeated to the end of the ablation procedure. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Typical values for the parameters of IRE signals 
               
            
           
           
               
               
               
               
            
               
                   
                 Parameter 
                 Symbol 
                 Typical values 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Pulse amplitudes 
                 V+, V− 
                 200-2000 
                 V 
               
               
                   
                 Pulse currents 
                 I 
                 1-26 
                 A 
               
               
                   
                 Pulse widths 
                 t+, t− 
                 0.5-5 
                 μs 
               
               
                   
                 Spacing between 
                 t SPACE   
                 0.1-5 
                 μs 
               
            
           
           
               
               
               
               
            
               
                   
                 positive and 
                   
                 (1-10 ms when an optional RF 
               
               
                   
                 negative pulse 
                   
                 signal is inserted between the 
               
               
                   
                   
                   
                 positive and negative pulses) 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Period of bipolar 
                 t PP   
                 1-20 
                 μs 
               
               
                   
                 pulses in a pulse 
                   
                   
                   
               
               
                   
                 train 
                   
                   
                   
               
               
                   
                 Length of pulse 
                 t T   
                 100 
                 μs 
               
               
                   
                 train 
                   
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Number of bipolar 
                 N P   
                 1-100 
               
               
                   
                 pulses in a pulse 
                   
                   
               
               
                   
                 train 
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Spacing between 
                 Δ T   
                 0.3-1000 
                 ms 
               
               
                   
                 consecutive pulse 
                   
                   
                   
               
               
                   
                 trains 
                   
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Number of pulse 
                 N T   
                 1-100 
               
               
                   
                 trains in a burst 
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Length of a burst 
                   
                 0-500 
                 ms 
               
               
                   
                 Energy per channel 
                   
                 ≤60 
                 J 
               
               
                   
                 Total time for IRE 
                   
                 ≤10 
                 s 
               
               
                   
                 signal delivery 
                   
                   
                   
               
               
                   
                 Amplitude of 
                 V RF   
                 10-200 
                 V 
               
               
                   
                 optional RF signal 
                   
                   
                   
               
               
                   
                 Frequency of 
                 f RF   
                 500 
                 kHz 
               
               
                   
                 optional RF signal 
               
               
                   
               
            
           
         
       
     
     IRE Module 
       FIG. 5  is a block diagram that schematically shows details of IRE module  34  and its connections to other modules in system  20 , in accordance with an exemplary embodiment of the present invention. 
     With reference to  FIG. 1 , IRE module  34  comprises IRE generator  36  and IRE controller  38 . IRE module  34  is delineated in  FIG. 5  by an outer dotted-line frame  402 . Within frame  402 , IRE generator  36  is delineated by an inner dotted-line frame  404 . IRE generator  36  comprises a pulse generation assembly  406  and a pulse routing and metrology assembly  408 , which will both be further detailed in  FIGS. 6-9 , below. 
     IRE generator  36  may be configured either as a voltage source or as a current source. Typical voltages of the IRE pulses vary from 200 V to 2000 V, with the ohmic loads for the pulses varying from 75Ω to 200Ω, and consequently the currents varying from 1 A to 26 A. In the present exemplary embodiments, IRE generator  36  is configured as a voltage source. Configuring IRE generator  36  as a current source will be apparent to those skilled in the art after reading the present description. 
     IRE controller  38  communicates with processor  32  through bi-directional signals  410 , wherein the processor communicates to the IRE controller commands reflecting setup parameters  66 . IRE controller  38  further receives digital voltage and current signals  412  from pulse routing and metrology assembly  408 . The controller utilizes these signals, inter alia, in computing the flow of energy dissipated in tissue  58 . Additionally, IRE controller  38  receives digital ECG signals  414  from ECG module  46 , and digital temperature signals  416  from temperature module  54 , and communicates these signals through bi-directional signals  410  to processor  32 . 
     IRE controller  38  communicates to pulse generation assembly  406  digital command signals  418 , derived from setup parameters  66 , as well as from the computed dissipation of energy. Command signals  418  cause IRE generator  36  to generate IRE pulses, such as those shown in  FIGS. 3-5 , while IRE controller  38  adjusts the properties of the IRE pulses based on the computed dissipation of energy and the required dissipated energy. (Further details of the control process are shown in  FIG. 10 ). These IRE pulses are sent to pulse routing and metrology assembly  408  as analog pulse signals  420 . Pulse routing and metrology assembly  408  is coupled to electrodes  30  through output channels  422 , as well as to return patch  65  through connection  424 .  FIG. 5  shows ten output channels  422 , labelled CH1-CH10. In the following description, a specific electrode is called by the name of the specific channel coupled to it; for example electrode CH5 relates to the electrode that is coupled to CH5 of channels  422 . Although  FIG. 5  refers to ten channels  422 , IRE generator may alternatively comprise a different number of channels, for example 8, 16, or 20 channels, or any other suitable number of channels. 
       FIG. 6  is an electrical schematic diagram of pulse routing and metrology assembly  408  of  FIG. 5 , in accordance with an exemplary embodiment of the invention. For the sake of clarity, the circuits involved in measuring currents and voltages, have been omitted. These circuits will be detailed in  FIG. 7 , below. Output channels  422  and connection  424  are shown in  FIG. 6  using the same labels as in  FIG. 5 . 
     Pulse routing and metrology assembly  408  comprises modules  502 , with one module for each output channel  422 . A pair  504  of adjacent modules  502  is shown in detail in  FIG. 7 , below. 
     Each module  502  comprises switches, labelled as FO i , SO i , N i , and BP i  for the i th  module. Switches FO i  are all fast switches for switching the IRE ablation from channel to channel, whereas switches SO i , N i , and BP i  are slower relays, used to set up pulse routing and metrology assembly  408  for a given mode of IRE ablation. A typical switching time for fast switches FO i  is shorter than 0.3 μs, whereas slow relays SO i , N i , and BP i  require a switching time of only 3 ms. The examples that are given below demonstrate uses of the switches and relays. 
     Example 1 demonstrates the use of the switches and relays for IRE ablation between pairs of electrodes according to an odd-even scheme CH1-CH2, CH3-CH4, CH5-CH6, CH7-CH8, and CH9-CH10. (Here the bipolar pulses are applied between each electrode and a first neighbor.) The settings of the switches and relays are shown in Table 2, below. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Switch and relay settings for Example 1 
               
            
           
           
               
               
               
               
               
            
               
                 Channel 
                 Fast switch 
                 Slow relay 
                 Slow relay 
                 Slow relay 
               
               
                 CH i   
                 FO i   
                 SO i   
                 N i   
                 BPi 
               
               
                   
               
               
                 CH1 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH2 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH3 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH4 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH5 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH6 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH7 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH8 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH9 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH10 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                   
               
            
           
         
       
     
     Example 2 demonstrates the use of the switches and relays for IRE ablation between pairs of electrodes according to an even-odd scheme CH2-CH3, CH4-CH5, CH6-CH7, and CH8-CH9 (in which the bipolar pulses are applied between each electrode and its second neighbor). For a circular catheter  26 , wherein the first and last of electrodes lie side-by-side, the pair CH10-CH1 may be added to the even-odd pairs. The settings of the switches and relays are shown in Table 3, below. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Switch and relay settings for Example 2 
               
            
           
           
               
               
               
               
               
            
               
                 Channel 
                 Fast switch 
                 Slow relay 
                 Slow relay 
                 Slow relay 
               
               
                 CH i   
                 FO i   
                 SO i   
                 N i   
                 BPi 
               
               
                   
               
               
                 CH1 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH2 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH3 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH4 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH5 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH6 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH7 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH8 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH9 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH10 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                   
               
            
           
         
       
     
     Combining Examples 1 and 2, a fast IRE ablation between all pairs of electrodes  30  may be accomplished by first ablating with the even-odd scheme of Example 1, then switching each fast switch FO i  to an opposite state (from ON to OFF and from OFF to ON), and then ablating with the odd-even scheme of Example 2. As slow relays SO i , N i , and BP i  are not required to switch their states, the switching takes place at the speed of the FO i  switches. 
     Example 3 demonstrates IRE ablation between non-adjacent electrodes  30 , in this example CH1-CH3, CH4-CH6, and CH7-CH9. Such a configuration may be utilized to cause deeper lesions in tissue  58 . The settings of the switches and relays are shown in Table 4, below. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Switch and relay settings for Example 3 
               
            
           
           
               
               
               
               
               
            
               
                 Channel 
                 Fast switch 
                 Slow relay 
                 Slow relay 
                 Slow relay 
               
               
                 CH i   
                 FO i   
                 SO i   
                 N i   
                 BPi 
               
               
                   
               
               
                 CH1 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH2 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH3 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH4 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH5 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH6 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH7 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH8 
                 ON 
                 ON 
                 ON 
                 OFF 
               
               
                 CH9 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                 CH10 
                 OFF 
                 ON 
                 ON 
                 OFF 
               
               
                   
               
            
           
         
       
     
     Again, other pairs of electrodes may be rapidly chosen by reconfiguring switches FO i . 
     Example 4 demonstrates an alternative way to perform an ablation between channels CH1 and CH3. In this example, a BP line  506  is utilized to close the ablation circuit. The settings of the switches and relays are shown in Table 5, below. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Switch and relay settings for Example 4 
               
            
           
           
               
               
               
               
               
            
               
                 Channel 
                 Fast switch 
                 Slow relay 
                 Slow relay 
                 Slow relay 
               
               
                 CH i   
                 FO i   
                 SO i   
                 N i   
                 BPi 
               
               
                   
               
               
                 CH1 
                 ON 
                 ON 
                 OFF 
                 ON 
               
               
                 CH2 
                 OFF 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH3 
                 ON 
                 ON 
                 OFF 
                 ON 
               
               
                 CH4 
                 OFF 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH5 
                 ON 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH6 
                 OFF 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH7 
                 ON 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH8 
                 OFF 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH9 
                 ON 
                 ON 
                 OFF 
                 OFF 
               
               
                 CH10 
                 OFF 
                 ON 
                 OFF 
                 OFF 
               
               
                   
               
            
           
         
       
     
     In Example 4, the electrical path in pulse routing and metrology assembly  408  couples transformer secondaries  508  and  510  in series. As the distance between electrodes CH1 and CH3 is double to that between adjacent electrodes (for example CH1 and CH2), the voltage between CH1 and CH3 has to be double the voltage between adjacent electrodes so as to have the same electrical field strength between the respective electrodes. This is accomplished by driving the primaries for these two secondaries in opposite phases. Slow switches SO i  are all left in the ON-state in preparation for the next ablation between another pair of electrodes, for example between CH2 and CH4. 
     As shown in the above examples, the implementation of pulse routing and metrology assembly  408  using relays and fast switches enables a flexible and fast distribution of IRE pulses to electrodes  30 , as well as a flexible re-configuration of the applied IRE pulse amplitudes. 
       FIG. 7  is an electrical schematic diagram of two adjacent modules  601  and  602  of pulse routing and metrology assembly  408 , in accordance with an exemplary embodiment of the invention. 
     Modules  601  and  602  make up pair  504  of  FIG. 6 , as is shown by dash-dot frame with the same label ( 504 ). Modules  601  and  602  are fed by pulse generating circuits  603  and  604 , respectively, which comprise, with reference to  FIG. 5 , parts of pulse generation assembly  406 . Modules  601  and  602 , in turn, feed channels CH1 and CH2, respectively, similarly to modules  502  of pair  504  in  FIG. 6 . Two modules  601  and  602  are shown in  FIG. 7  in order to show a connection  605  between the modules. As the two modules are identical (and identical to the additional modules in pulse routing and metrology assembly  408 ), only module  601  is described in detail below. 
     Further details of pulse generating circuits  603  and  604  are shown in  FIGS. 8-9 , below. Pulse generation assembly  406  comprises one pulse generating circuit similar to circuits  603  and  604  for each channel of IRE generator  36 . Pulse generation assembly  406  further comprises a high-voltage supply  607 , detailed in  FIG. 8 . 
     Pulse generating circuit  603  is coupled to module  601  by a transformer  606 . Fast switch FO 1  and slow relays SO 1 , N 1 , and BP 1  are labelled similarly to  FIG. 6 . A low-pass filter  608  converts a pulse train transmitted by pulse generating circuit  603  via transformer  606  and switch FO 1  to a sinusoidal signal, allowing CH1 to be used for RF ablation. Similarly, each channel of IRE generator  36  may be independently used for RF ablation. The engagement of filter  608  is controlled by a relay  610 . An RF signal having a given frequency f RF  and amplitude V RF  is produced by pulse generating circuit  603  emitting a train of bipolar pulses at the frequency f RF  through low-pass filter  608 , which converts this pulse train to a sinusoidal signal with the frequency f RF . The amplitude of the train of bipolar pulses is adjusted so that the amplitude of the sinusoidal signal is V RF . 
     A voltage V 1  and current I 1  coupled to CH1 are shown in  FIG. 7  as a voltage between channels CH1 and CH2, and a current flowing to CH1 and returning from CH2. 
     V 1  and I 1  are measured by a metrology module  612 , comprising an operational amplifier  614  for measuring the voltage and a differential amplifier  616  measuring the current across a current sense resistor  618 . Voltage V 1  is measured from a voltage divider  620 , comprising resistors R 1 , R 2 , and R 3 , and an analog multiplexer  622 . Analog multiplexer  622  couples in either resistor R 1  or R 2 , so that the voltage dividing ratio of voltage divider  620  is either R 1 /R 3  or R 2 /R 3 . Metrology module  612  further comprises an analog-to-digital converter (ADC)  624  for converting the measured analog voltage V 1  and current I 1  to digital signals DV 1  and DI 1 . These digital signals are sent through a digital isolator  626  to IRE controller  38  as signals  412  ( FIG. 5 ). As further detailed in  FIG. 10 , IRE controller  38  utilizes digital signals DV 1  and DI 1 , as well as the corresponding digital signals from the other modules, to compute the energy dissipated in tissue  58 . Digital isolator  626  protects subject  24  ( FIG. 1 ) from unwanted electrical voltages and currents. 
     Switch FO 1 , relays SO 1 , BP 1 , N 1  and  610 , and analog multiplexer  622  are driven by IRE controller  38 . For the sake of simplicity, the respective control lines are not shown in  FIG. 7 . 
       FIG. 8  is an electrical schematic diagram of pulse generating circuit  603 , transformer  606 , and high-voltage supply  607 , in accordance with an exemplary embodiment of the invention. 
     Pulse generating circuit  603  ( FIG. 7 ) comprises two switches  702  and  704 , whose internal details are further shown in  FIG. 9 , below. Switch  702  comprises a command input  706 , a source  708 , and a drain  710 . Switch  704  comprises a command input  712 , a source  714 , and a drain  716 . Together switches  702  and  704  form a half of an H-bridge (as is known in the art), also called a “half bridge.” 
     High-voltage supply  607  supplies to respective outputs  720  and  722  a positive voltage V+ and a negative voltage V−, adjustable within respective positive and negative ranges of ±(10-2000) V responsively to a signal received by a high-voltage command input  724  from IRE controller  38 . High-voltage supply  607  also provides a ground connection  723 . A single high-voltage supply  607  is coupled to all pulse generating circuits of pulse generation assembly  406 . Alternatively, each pulse generating circuit may be coupled to a separate high-voltage supply. 
     Drain  710  of switch  702  is coupled to positive voltage output  720 , and source  708  of the switch is coupled to an input  726  of transformer  606 . When command input  706  receives a command signal CMD+, positive voltage V+ is coupled from positive voltage output  720  to transformer input  726  via switch  702 . Source  714  of switch  704  is coupled to negative voltage output  722 , and drain  716  of the switch is coupled to transformer input  726 . When command input  712  receives a command signal CMD−, negative voltage V− is coupled from negative voltage output  722  to transformer input  726  via switch  704 . Thus, by alternately activating the two command signals CMD+ and CMD−, positive and negative pulses, respectively, are coupled to transformer input  726 , and then transmitted by transformer  606  to its output  728 . The timing of the pulses (their widths and separation) are controlled by command signals CMD+ and CMD−, and the amplitudes of the pulses are controlled by a high-voltage command signal CMD HV  to high-voltage command input  724 . All three command signals CMD+, CMD−, and CMD HV  are received from IRE controller  38 , which thus controls the pulses fed into the respective channel of pulse routing and metrology assembly  408 . 
     In an alternative exemplary embodiment (not shown in the figures), a full H-bridge is utilized, with a single-polarity high-voltage supply. This configuration may also be used to produce both positive and negative pulses from the single-polarity source, in response to signals controlling the full H-bridge. An advantage of this exemplary embodiment is that it can use a simpler high-voltage supply, whereas the advantage of a half bridge and a dual high-voltage power supply is that it provides a fixed ground potential, as well as independently adjustable positive and negative voltages. 
       FIG. 9  is an electrical schematic diagram of switch  702 , in accordance with an embodiment of the invention. Switch  704  is implemented in a similar fashion to switch  702 . 
     The switching function of switch  702  is implemented by a field-effect transistor (FET)  802 , comprising a gate  804 , source  708 , and drain  710 . Command input  706  is coupled to gate  804 , with source  708  and drain  710  coupled as shown in  FIG. 8 . Additional components  806 , comprising Zener diodes, a diode, a resistor, and a capacitor, function as circuit protectors. 
       FIG. 10  is a flowchart  900  that schematically illustrates a method for controlling an IRE procedure, in accordance with an exemplary embodiment of the present invention. In flowchart  900 , a dotted-line frame  902  indicates schematically the steps of the process that take place within IRE generator  36 , and a dotted-line frame  904  indicates schematically the steps of the process that take place within IRE controller  38 . This particular functional division is described here solely by way of example, however, and the principles of the present method may alternatively be applied in other sorts of IRE module configurations, as well as in other systems for IRE, as will be apparent to those skilled in the art after reading the present description. 
     The IRE procedure starts in a start step  906 . In a setup definition step  908 , physician  22  defines, through input devices  42 , the setup parameters for the procedure. These setup parameters are based, for example, on the required tissue volume, field strength within the tissue, catheter configuration, and the energy to be delivered into the tissue during the procedure. Processor  32  transmits these setup parameters to IRE controller  38  in a parameter transmission step  910 . IRE controller  38  extracts or computes from the setup parameters a requested total dissipated energy in a requested energy step  911 . This step defines a target value (for example in Joules) of the energy that is to be dissipated from the IRE pulses into the tissue at each location where ablation is to take place. 
     In a setup step  912 , IRE controller  38  sets up the IRE ablation parameters for IRE generator  36 , and transmits them to the generator in a modify/transmit step  914 . Once the ablation parameters have been set up in IRE generator  36 , IRE controller  38  initiates the ablation by sending an appropriate command to IRE generator  36  in an ablation start/continue step  916 . In response to the command, IRE generator  36  applies IRE pulses to electrodes  30  in an IRE pulse step  918 . At the same time, metrology module  612  ( FIG. 7 ) within IRE generator  36  measures the voltage V i  and current I i  within each channel i in a V/I measurement step  920 , and transmits their values to IRE controller  38 . 
     Based on the received values of V i  and I i , IRE controller  38  computes continuously, in a dissipated energy step  922 , the energy dissipated in tissue  58 . The computation of the dissipated energy is based on a multiplication of the received values V i  and I i  in each of a sequence of time intervals, and a cumulative summation of the products. In a first comparison step  924 , IRE controller  38  checks whether the cumulative dissipated energy from the start of the procedure computed in dissipated energy step  922  is already equal to (or perhaps exceeds) the requested total dissipated energy recorded in requested energy step  911 . If the result is affirmative, the IRE ablation is terminated in an end step  926 . 
     When the requested total dissipated energy has not yet been reached at step  924 , IRE controller  38  computes, in a prediction step  928 , a predicted total dissipated energy assuming the ablation is continued using the current parameters (such as bipolar pulse amplitudes, pulse widths, and number of remaining pulses) of IRE generator  36 . In a second comparison step  930 , IRE controller  38  compares the predicted total dissipated energy (from step  928 ) to the requested total dissipated energy (from step  911 ). When these two are equal, the ablation continues using the current ablation parameters, and the ablation continues through step  916 . 
     When the predicted total dissipated energy deviates from the requested total dissipated energy at step  930 , IRE controller  38  modifies the IRE ablation parameters in modify/transmit step  914 , and the cycle of  FIG. 10  continues. Thus, the feedback provided by the measurement of ablation voltages V i  and currents I i  by metrology module  612  to IRE controller  38  enables the controller to adjust the ablation parameters of IRE generator  36  so as to achieve the requested total dissipated energy for the ablation procedure. 
     Alternatively or additionally, when the setup parameters specify an energy per pulse or pulse train, the process flow described by flow chart  900  is modified accordingly. 
     It will be appreciated that the embodiments described above are cited by way of example, and that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not disclosed in the prior art.