Patent Description:
Thermal ablation either adds or removes heat to destroy undesirable cells. For example, cryoablation kills cells by freezing of the extracellular compartment resulting in cell dehydration beginning at -<NUM> C with membrane rupture occurring at colder temperatures. Cryoablation is known to (beneficially) stimulate an antitumor immune response in the patient.

Heat-based thermal ablation adds heat to destroy tissue. Radio-frequency (RF) thermal, microwave and high intensity focused ultrasound ablation can each be used to raise localized tissue temperatures well above the body's normal <NUM> degrees C. For example, RF thermal ablation uses a high frequency electric field to induce vibrations in the cell membrane that are converted to heat by friction. Cell death occurs in as little as <NUM> seconds once the cell temperature reaches <NUM> degrees C, while at higher temperatures cell death is instantaneous. Heat based ablation, however, may not prompt the desirable immune response associated with cryoablation.

Thermal ablation techniques using heat or cold each suffer from the drawback that they have little or no ability to spare normal structures in the treatment zone. Collateral injury to vascular, neural and other structures is undesirable. For this reason, various researchers have explored non-thermal ablation as well.

Non-thermal ablation techniques include electro-chemotherapy, reversible electroporation, and irreversible electroporation. Electroporation refers to a phenomenon in which the plasma membrane of a cell exposed to high voltage pulsed electric fields becomes temporarily permeable due to destabilization of the lipid bilayer. Pores then form, at least temporarily. Electro-chemotherapy combines pore formation with the introduction of chemicals that cause cell death. Because the chemical molecules used are large, only cells subject to the electric fields will absorb the chemical material and subsequently die, making for useful selectivity in the treatment zone. Irreversible electroporation (IRE) omits the chemicals, and instead uses the electric fields, usually with increased amplitude, to expand pores in the cell membrane beyond the point of recovery, causing cell death for want of a patent cell membrane. The spatial characteristics of the applied field control which cells and tissue will be affected, allowing for better selectivity in the treatment zone than with thermal techniques.

One challenge with the electrical (whether thermal or not) ablation techniques is that of local muscle stimulation. A monophasic waveform is thought to provide better results for IRE in terms of causing certain cell death. However, monophasic waveforms tend to cause muscle stimulation, requiring the use of a paralytic to facilitate surgery, among other problems. A biphasic waveform avoids the muscle stimulation, but may not be as effective at the same energy level and/or amplitude as the monophasic waveform. Simply raising power to make the biphasic waveform more effective runs the risk of causing thermal ablation. Enhancements and alternatives to the state of the art are desired to allow a waveform to be used that is as effective as monophasic stimulus for IRE, while avoiding muscle stimulation and thus obtaining the benefits of both monophasic and biphasic therapy.

<CIT>discloses systems, devices, and methods for electroporation ablation therapy. The system includes a pulse waveform signal generator for medical ablation therapy that may be coupled to an ablation device including at least one electrode for ablation pulse delivery to tissue. The signal generator may generate and deliver voltage pulses to the ablation device in the form of a pulse waveform in a predetermined sequence where the signal generator may independently configure a set of electrodes of an ablation device. The signal generator may further perform active monitoring of a set of electrode channels and discharge excess energy using the set of electrode channels.

<CIT> relates to the problem of how to reduce the cost for and enhance the reliability of equipment, by controlling the connection of capacitors with fewer number of switches. To this end, a power supply device, which stores electrical energy in capacitor banks and supplies a load with power is provided with capacitor banks C1-C3 for output which are charged and discharged within the range of the rated voltage of the load, capacitors banks C4, C5 for adjustment which are charged and discharged within the allowable range of fluctuation in load voltage, switching means S1-S3 which series-connect and disconnect the capacitor banks C1-C3 for output and the capacitor banks C4, C5 for adjustment, and a control means A1, which detects the status of charging and discharging of the capacitor banks C1-C3 for output and controls the switching means.

<CIT>discloses systems, methods and computer-accessible mediums that can establish particular parameters for electric pulses based on a characteristic(s) of the tissue(s), and control an application of the electric pulses to tissue(s) for a plurality of automatically controlled and separated time periods to ablate the tissue(s) through mediation of membrane potential and through inducing the cells through a plurality of charge-discharge cycles.

<CIT> discloses a sub-microsecond pulsed electric field generator. The field generator includes a controller, which generates a power supply control signal and generates a pulse generator control signal, and a power supply, which receives the power supply control signal and generates one or more power voltages based on the received power supply control signal. The field generator also includes a pulse generator which receives the power voltages and the pulse generator control signal, and generates one or more pulses based on the power voltages and based on the pulse generator control signal. The controller receives feedback signals representing a value of a characteristic of or a result of the pulses and generates at least one of the power supply control signal and the pulse generator control signal based on the received feedback signals.

The present inventors have recognized, among other things, that a problem to be solved is the provision of ablation therapy that combines high efficacy and tissue selectivity while avoiding muscle stimulation. A number of examples shown below provide illustrative signal generators, systems and methods directed to such improvements. Methods described hereafter do not form part of the claimed invention, which is defined by independent claim <NUM>.

A first non-limiting example takes the form of a device for generating energy for use in the electrical ablation of tissue comprising a voltage source; a capacitor bank having at least a first capacitor and one or more additional capacitors: and an output stage coupling the capacitor bank to a plurality of output nodes, the output stage comprising: a power selector switch pair coupled to the capacitor stack to enable a first output to be defined including the first capacitor and at least one of the one or more additional capacitors, or a second output excluding the first capacitor and including at least one of the one or more additional capacitors, such that the first output is at a higher voltage than the second output; and a plurality of electrode selector switch pairs each associated with one of the plurality of output nodes, each electrode selector switch pair including a high side switch coupled to the power selector switch pair and a low side switch coupled to reference.

Additionally or alternatively to the first non-limiting example, the device may further comprise a feedback circuit coupled to the plurality of output nodes, the feedback circuit comprising one or more current sensors for sensing and quantifying current through one or more output nodes, and a control node coupled to the feedback circuit, the power selector switch pairs and the plurality of electrode selector switch pairs to use the one or more current sensors to control the electrical ablation. Additionally or alternatively the feedback circuit may be configured to detect peak current of output to prevent damage to device componentry. Additionally or alternatively the feedback circuit may be configured to detect average current of output to determine characteristics of delivered therapy.

Additionally or alternatively to the first non-limiting example. the device may further comprise a feedback circuit coupled to the plurality of output nodes, the feedback circuit comprising one or more voltage sensors for sensing and quantifying voltage at one or more output nodes, and a control node coupled to the feedback circuit, the power selector switch pairs. and the plurality of electrode selector switch pairs to use the one or more voltage sensors to control the electrical ablation.

Additionally or alternatively to the first non-limiting example, the device may further comprise a feedback circuit comprising one or more voltage and/or current sensors for monitoring impedance to track tissue characteristics during therapy delivery.

A second non-limiting example takes the form of a device for generating energy for use in the electrical ablation of tissue comprising: a voltage source: a capacitor bank having at least a first capacitor and one or more additional capacitors, the capacitor bank accessible at a plurality of locations to operate as a plurality of output sources; and an output stage coupling the capacitor bank to a plurality of output nodes, the output stage comprising: a plurality of power selector switches coupled to the capacitor stack at the plurality of locations, the plurality of power selector switches allowing independent and simultaneous access to the capacitor bank to derive a plurality of outputs at the same or different voltage levels; and a plurality of electrode selector switch pairs each associated with one of the plurality of output nodes, each electrode selector switch pair including a high side switch coupled to the power selector switch pair and a low side switch coupled to reference.

Additionally or alternatively to the second non-limiting example, the device may further comprise a feedback circuit coupled to the plurality of output nodes, the feedback circuit comprising one or more current sensors for sensing and quantifying current through one or more output nodes, and a control node coupled to the feedback circuit, the power selector switch pairs and the plurality of electrode selector switch pairs to use the one or more current sensors to control the electrical ablation.

Additionally or altematively to the second non-limiting example, the device may further comprise a feedback circuit coupled to the plurality of output nodes, the feedback circuit comprising one or more voltage sensors for sensing and quantifying current at one or more output nodes, and a control node coupled to the feedback circuit, the power selector switch pairs, and the plurality of electrode selector switch pairs to use the one or more voltage sensors to control the electrical ablation.

Additionally or alternatively to the second non-limiting example, the device may further comprise a feedback circuit comprising one or more voltage and/or current sensors for monitoring impedance to track tissue characteristics during therapy delivery.

Additionally or alternatively to the first or second non-limiting examples, the output stage may define a plurality of paths from the capacitor bank to the output nodes, wherein at least one path comprises a current controlling circuit switchable into and out of the path, wherein switching one of the current controlling circuits into a path configures the device to use a constant current output.

Additionally or alternatively to the first or second non-limiting examples, the output stage may define a plurality of paths from the output nodes to the reference, wherein at least one path comprises a current controlling circuit switchable into and out of the path, wherein switching one of the current controlling circuits into a path configures the device to use a constant current output.

Additionally or alternatively to the first or second non-limiting examples, the control circuitry may be configured to provide a constant power output or, altematively, a constant voltage output.

Another example takes the form of a system for ablating tissue comprising a device as in either the first or second non-limiting examples, and a probe for inserting into or placing in contact with or near tissue to be ablated.

A third illustrative and non-limiting example takes the form of method of treating a patient using an ablation therapy comprises setting output parameters for a biphasic electrical output comprising a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, with an interpulse period defined between the first and second phases: a) delivering the biphasic electrical output to the patient using the output parameters and observing whether a muscle response occurs; b) if no muscle response is observed, modifying the output parameters by extending the interpulse period: repeating steps a) and b) until a muscle response is observed or until a predefined maximum interpulse period is used: and if a muscle response is observed, setting a therapeutic interpulse period as either a fraction of or a reduction of the interpulse period at which muscle response is observed; or if the maximum interpulse period is used, setting the therapeutic interpulse period at the maximum interpulse period; and delivering therapy to the patient using a set of therapy parameters including the therapeutic interpulse period.

A fourth illustrative and non-limiting example takes the form of a method of treating a patient using an ablation therapy comprises setting output parameters for an electrical output having a pulse width and amplitude: delivering the electrical output to the patient using the output parameters; observing whether a muscle response occurs in response to the delivered output; and one of: a) if no muscle response is observed, modifying the output parameters by increasing at least one of pulse width or amplitude of the electrical output; b) if a muscle response is observed, modifying the output parameters by decreasing at least one of pulse width or amplitude the electrical circuit; and again delivering the electrical output to the patient, using output parameters as modified in one of steps a) or b).

A fifth illustrative and non-limiting example takes the form of a method of treating a patient using an ablation therapy comprises: setting output parameters for a biphasic electrical output comprising a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, with an interpulse period defined between the first and second phases: delivering the biphasic electrical output to the patient using the output parameters; observing whether a muscle response occurs: a) if no muscle response is observed, modifying the output parameters by extending the interpulse period; b) if a muscle response is observed, modifying the output parameters by reducing the interpulse period; and again delivering the biphasic electrical output to the patient using the output parameters as modified in one of steps a) and b).

A sixth illustrative and non-limiting example takes the form of a method of treating a patient using an ablation therapy comprising: setting output parameters for a biphasic electrical output comprising a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, with an interpulse period defined between the first and second phases; delivering the biphasic electrical output to the patient using the output parameters: observing whether a muscle response occurs: determining that no muscle response occurs and modifying the output parameters by extending the interpulse period; and again delivering the biphasic electrical output to the patient using the output parameters with the extended interpulse period.

A seventh illustrative and non-limiting example takes the form of a method of treating a patient using an ablation therapy comprising: setting output parameters for a biphasic electrical output comprising a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, with an interpulse period defined between the first and second phases: delivering the biphasic electrical output to the patient using the output parameters; observing whether a muscle response occurs; determining that a muscle response occurred and modifying the output parameters by reducing the interpulse period; and again delivering the biphasic electrical output to the patient using the output parameters with the reduced interpulse period.

Additionally or alternatively to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs may be performed by a system user visually observing whether one of visible motion or migration of therapy probe occurs in response to the delivered biphasic electrical output.

Additionally or alternatively to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs may be performed by monitoring an output of an accelerometer placed in or on the patient.

Additionally or alternatively to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs may include sensing myopotentials of muscle tissue of the patient.

Additionally or alternatively to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs may comprise obtaining a subjective feedback from the patient.

An eighth non-limiting example takes the form of a method of delivering an ablation therapy to a patient comprises delivering a therapy pulse train within a predetermined period of time as follows: delivering a first pulse having first voltage and first duration; sensing current during the first pulse: delivering a second pulse having second voltage and duration, wherein the first voltage does not equal the second voltage, and the first duration does not equal the second duration, but the product of the first voltage and first duration is substantially equal to the product of the second voltage and the second duration: sensing current during the second pulse: determining that a quantity of charge delivered during the first pulse is not equal to a quantity of charge delivered during the second pulse: and delivering at least one additional pulse to remove charge imbalance caused by difference between the quantity of charge of the first pulse and the quantity of charge of the second pulse, before expiration of the predetermined period of time.

Additionally or alternatively to the eighth non-limiting example, the at least one additional pulse may be a voltage controlled pulse having a third voltage and a third duration calculated by determining an impedance encountered by at least one of the first and second pulses.

Additionally or alternatively to the eighth non-limiting example, the at least one additional pulse may be a current controlled pulse, while the first and second pulses are voltage controlled pulses.

A ninth illustrative and non-limiting example takes the form of a device for generating energy for use in the electrical ablation of tissue comprising: a voltage source: a capacitor bank for storing energy from the voltage source to be used in delivering ablation energy; voltage conversion circuitry to deliver energy from the voltage source to the capacitor bank at a higher voltage than the voltage source can provide: an output stage coupling the capacitor bank to a plurality of output nodes: sensing circuitry for receiving a sensed signal from a probe adapted for use with the device: and a control circuit configured to control the capacitor bank, voltage conversion circuitry, and output stage, using feedback from the sensing circuitry; wherein the control circuit is configured to perform a method as in any of the third to eighth non-limiting examples.

Additionally or alternatively to the ninth non-limiting example, the sensing circuitry may be configured for use with a probe having a thermal sensor, and the control circuit is configured to receive data from the sensing circuitry related to temperature sensed by the thermal sensor of the probe and modify one or more parameters of a therapy signal generated by the output stage.

Additionally or alternatively to the ninth non-limiting example. the sensing circuitry may be configured for use with a probe having an optical capability, and the control circuit is configured to receive data from the sensing circuitry related to changes in tissue color observed using the optical capability of the probe and modify one or more parameters of a therapy signal generated by the output stage. In a still further example, the sensing circuitry may comprise an optical source and an optical detector, such that the sensing circuitry can direct an optical signal to the optical capability of the probe and receive an optical signal from the probe indicative of tissue reflectance.

Additionally or alternatively to the ninth non-limiting example. the sensing circuitry may be configured for use with a probe having a transducer, and therefore comprises a driver circuit for driving the probe transducer, and is further adapted to receive a signal from the probe transducer. In a still further example. the driver circuit may be configured to issue ultrasound frequency outputs to an ultrasound transducer in the probe in order to detect changes in fluid density of tissue. In a still further example, the driver circuit may be configured to drive a MEMS based accelerometer, and the sensing circuitry is configured to receive a signal from the MEMS based accelerometer to detect heart sounds. In a still further example, the driver circuit may be configured to drive a MEMS based accelerometer, and the sensing circuitry is configured to receive a signal from the MEMS based accelerometer to detect muscle contractions. In a still further example, the driver circuit may be configured to drive a MEMS based accelerometer, and the sensing circuitry is configured to receive a signal from the MEMS based accelerometer to detect acoustic signals associated with ablation.

This overview is intended to provide an introduction to the subject matter of the present patent application.

In the drawings. which are not necessarily drawn to scale. like numerals may describe similar components in different views.

<FIG> shows an approximation of different biophysical responses dependent on the amplitude-time relationship of delivered electrical pulses. The thresholds between cellular responses (<NUM>, <NUM>. <NUM>) operate generally as a function of the applied field strength and pulse duration. Below a first threshold <NUM>, no effect occurs: between the first threshold <NUM> and a second threshold <NUM>, reversible electroporation occurs. Above the second threshold <NUM>, and below a third threshold <NUM>, primarily irreversible electroporation (IRE) occurs. Above a third threshold <NUM>, the effects begin to be primarily thermal, driven by tissue heating. Thus, for example, at a given field strength and duration there may be no effect (location <NUM>), and extending the duration of the field application can yield reversible electroporation (location <NUM>), irreversible electroporation (location <NUM>), and thermal ablation (location <NUM>).

As described in <CIT>, a transmembrane potential in the range of about one volt is needed to cause reversible electroporation, however the relationship between pulse parameters such as timing and duration and the transmembrane potential required for reversible electroporation remains an actively investigated subject. The required field may vary depending on characteristics of the cells to be treated. At a macro level, reversible electroporation requires a voltage in the level of hundreds of volts per centimeter, with irreversible electroporation requiring a still higher voltage. As an example, when considering in vivo electroporation of liver tissue, the reversible electroporation threshold field strength may be about <NUM> V/cm, and the irreversible electroporation threshold field strength may be about <NUM> V/cm, as described in <CIT>. Generally speaking, a plurality of individual pulses are delivered to obtain such effects across the majority of treated tissue: for example. <NUM>, <NUM>, <NUM>, <NUM>, or more pulses may be delivered. Some embodiments may deliver hundreds of pulses.

The electrical field for electroporation has typically been applied by delivering a series of individual pulses each having a duration in the range of one to hundreds of microseconds. For example, <CIT> describes analysis and experiments performed to illustrate that the area between lines <NUM> and <NUM> in <FIG> actually exists, and that a non-thermal IRE therapy can be achieved. using in several experiments a series of eight <NUM> microsecond pulses delivered at <NUM> second intervals.

The tissue membrane does not return instantaneously from a porated state to rest. As a result. the application of pulses close together in time can have a cumulative effect as described, for example, in <CIT>. In addition, a series of pulses can be used to first porate a cell membrane and then move large molecules through generated, reversible pores, as described in <CIT>.

<FIG> show various impacts of application of electrical field to a cell. At electric field strengths below the threshold for reversible electroporation, as shown in <FIG>, the cell membrane <NUM> of cell <NUM> remains intact and no pores occur. As shown in <FIG>, at a higher electric field strength, above the threshold for reversible electroporation and below the threshold for irreversible electroporation, the membrane <NUM> of cell <NUM> develops pores <NUM>. Depending on the characteristics of the applied field and pulse shapes, larger or smaller pores <NUM> may occur, and the pores developed may last for longer or shorter durations.

As shown in <FIG>, at a still higher electric field strength, above the threshold for irreversible electroporation. the cell <NUM> now has a membrane <NUM> with a number of pores <NUM>, <NUM>. At this higher amplitude or power level, pores <NUM>. <NUM> may become so large and/or numerous that the cell cannot recover. It may be noted as well that the pores are spatially concentrated on the left and right side of the cell <NUM> as depicted in <FIG>, with few or no pores in the region <NUM> where the cell membrane is parallel to the applied field (assuming here that the field is applied between electrodes disposed to the right and left sides of the cell shown in <FIG>). This is because the transmembrane potential in region <NUM> remains low where the field is closer to parallel. rather than orthogonal, to the cell membrane.

<FIG> shows a prior art "Leveen" needle. As described in <CIT>, the device comprises an insertable portion <NUM> having a shaft <NUM> that extends to a plurality of tissue piercing electrodes <NUM> that can be extended or retracted once a target tissue <NUM> of a patient <NUM> is accessed. The proximal end of the apparatus is coupled by an electrical connection <NUM> to a power supply <NUM>, which can be used to supply RF energy.

Conventionally. the Leveen needle would be used to deliver thermal ablation to the target tissue. For example, as described in the '<NUM> patent, a return electrode in the form of a plate or plates may be provided on the patient's skin, a return electrode could be provided as another tissue piercing electrode, or a return electrode may be provided on the shaft <NUM> near its distal end, proximal of the tissue piercing electrodes <NUM>.

Enhancements on the original design can be found, for example, in <CIT>, which discusses independent actuation of the tissue piercing electrodes <NUM>. both in terms of movement of the electrodes as well as separately electrically activating individual ones of the electrodes. The <NUM>,<NUM>,<NUM> and <NUM>,<NUM>,<NUM> patents are incorporated herein by reference for showing various probes. the disclosure of which is showing various therapy delivery probes, discloses updates and enhancements on the Leveen needle concept, allowing flexibility in the spacing, size and selection of electrodes.

<FIG> show various waveform features. Referring to <FIG>. a monophasic waveform is shown at <NUM>. The waveform <NUM> is shown relative to a baseline or equipotential <NUM>. An idealized square wave is shown having an amplitude <NUM>, a pulse width <NUM>, and a cycle length <NUM>. The waveform <NUM> is shown as an ideal square wave, with a vertical upswing from baseline <NUM> to the designated amplitude <NUM>. When describing such a waveform, the frequency typically refers to the inverse of the cycle length <NUM>. So, for example, if a waveform having a one microsecond pulse width <NUM> is delivered at two microsecond intervals <NUM>, the "frequency" of the waveform may be described as <NUM> (the inverse of two microseconds). The waveform <NUM> may be a current controlled or voltage controlled waveform. Either approach may be used in various examples, as further described below.

In any real application the edges of the generated waveform will be rounded and the upswing from baseline <NUM> will be more as shown in <FIG>, where the upward divergence from the baseline, shown at <NUM>, is characterized by a rise time <NUM>. At the end of the output there is also a non-ideal fall <NUM> characterized by fall time <NUM>. Real application of the waveform will also include some variation in the peak amplitude, as shown. which may include for example overshoot of the amplitude if the signal output is underdamped, or rounding off of the edges for a critically damped or overdamped signal.

In some examples, one or more of the rise or fall time <NUM>, <NUM> can be manipulated. In an illustrative example, the output circuitry of a system may include selectable elements, such as resistors, inductors or the like, that can slow the rise time if switched into the circuit. For example, the current through an inductor cannot be instantaneously changed, so switching an inductive element into an output circuit can slow the rise time as the inductor begins to allow current to flow.

Rise and fall time may be manipulated in several different ways. For example, the process settings may be selected to modify the peak voltage target; a higher target can yield a faster rise time as various components respond in exponential fashion to being turned on or switched into an output circuit. By monitoring the output, the system can artificially increase a peak voltage target to reduce rise time, and once the true peak voltage is met, the system may switch voltage sources or use an output regulation (such as by using a rectifier or by redirecting output current through a separate discharge path) to cap the voltage output. In another example, component selection may be used, such as by having a plurality of different HV switches available and selectable to the system, with different HV switch types having different rise and fall times. For example, if three output switches are available, each with a different rise/fall characteristic, the system may respond to a user input requesting longer or shorter rise/fall time by selecting an appropriate output switch for use during a particular therapy output session. High pass or low pass filtering may be switched into the output circuit as well to control slew rate, or may be switched into the control signal circuit; a slow turn-on of an output transistor for example can cause slower rise time for the transistor itself and conversely fast turn-on of the output transistor can speed the rise time. In another example, a digital to analog converter may be used as an output circuit, allowing digitized control of rise or fall time. In still a further example. control signals to the output switches can be generated by a digital to analog converter, thus manipulating the on/off signal to the output circuitry itself. In still a further example, using a capacitor stack output as shown in several examples herein, a fast rise time may be effected by using a single switched output from the top (or desired target level) of the capacitor stack, while a slow rise time may be effected by sequentially turning on an output using less than all of the capacitor stack and then subsequently adding more of the capacitor stack to the output; appropriately placed diodes in the output circuitry will prevent back-current or shorting of the newly added portions of the capacitor stack during such a maneuver.

<FIG> shows further details, this time for a biphasic signal. Here, the waveform is shown at <NUM>. with a first, positive pulse at <NUM> quickly followed by a negative pulse at <NUM>. The positive pulse <NUM> has an amplitude <NUM>, and the negative pulse <NUM> has an amplitude <NUM> which is usually equal in voltage to, but of opposite polarity than, the positive pulse. The positive pulse <NUM> has a pulse width <NUM>, and the negative pulse <NUM> has a pulse width <NUM>; again, typically the two pulse widths <NUM>, <NUM> would be equal to one another. For a signal as shown, the cycle length can be determined as shown at <NUM>, from the start of the positive pulse <NUM> to the initiation of a subsequent cycle; again, frequency is the inverse of the cycle length.

In a typical application or use of biphasic signals, the aim is, in part, to achieve charge balancing at the end of each cycle. For that reason, the pulse widths of the two phases are kept equal, and the amplitudes are also equal though of opposite polarity. Whether using a voltage controlled or current controlled system. charge balance can be reasonably maintained by controlling just the pulse width and amplitude. For example, in a voltage controlled system, the current flow will be more or less constant within a cycle, assuming the cycle length <NUM> is fairly short. That is, while it is known that during ablation procedures the tissue impedance changes as cells are destroyed. expelling cellular media which generally reduces impedance, the impedance does not change so quickly that charge balancing of a simple biphasic waveform, even one that does not control current. would become an issue. In some examples below, however, the delivered energy is not a "simple biphasic" waveform insofar as the period between two phases is extended to a duration that is more than half the duration of either phase. for example, in which case it becomes more likely impedance changes can result in a charge imbalance that triggers or risks muscle stimulation.

An interphase period <NUM> represents a time period spent at baseline between the positive and negative pulses, and is ordinarily minimized in accordance with the physical constraints of the underlying circuitry Thus, for example, if a first switch must turn off to end the positive pulse <NUM>, and a second switch is used to initiate the negative pulse <NUM>, assuming digital control, the system may allow a few digital clock cycles to expire after turning off the first switch before turning on the second switch, to avoid any possible internal shorting. Faster switches can reduce the interphase time, and much engineering effort has gone into reducing this time period <NUM>.

For example, a very short interphase period <NUM> can be achieved using a design as shown in <CIT>. In the <CIT> Patent, an inductor is placed in parallel with the output load. A power source is applied to the load and inductor during an initial phase of therapy delivery. Opening a switch between the power source and the load/inductor causes a near immediate reversal of current through the load as the inductor draws current from the load after the power source is disconnected.

The background to be gathered from <FIG> is that of typical usage. In several embodiments described further below. monophasic pulses are used to achieve biphasic results with respect to charge balancing that prevents muscle stimulation. It should be noted that within the examples herein, the term "without causing muscle stimulation" allows for some muscle stimulation, but only an amount tolerable within the relevant intervention and/or surgical domain. For example, the stimulation that occurs is not so much that the patient is made uncomfortable. In another example, the stimulation that occurs is small enough that surgery to ablate tissue is not subject to interference due to stimulated patient movement. In another example, the muscle stimulation that occurs is insignificant to the surgery and allows surgery to be performed without requiring administration of a paralytic. In some examples, the stimulation that occurs does not affect probe placement and securement, or is small enough that migration of the probe does not occur. As used herein, a meaningful charge imbalance for ablation therapy purposes is one that triggers, either within a single cycle or over a plurality of cycles, muscle stimulation that affects a surgery. In several embodiments the aim is to provide enhanced therapy - mimicking monophasic therapy - while avoiding and/or preventing meaningful charge imbalance.

<FIG> shows a signal generator in block form. A signal generator <NUM> may be a self-contained unit, or it may comprise several discrete components coupled together with wires and/or wireless connections. A control block is shown at <NUM> and may comprise a plurality of logic circuits in the form of a state machine, a microcontroller, a microprocessor, or even an off the shelf computing unit such as a laptop or desktop computer, as desired, and may further include various associated analog and/or digital logic, application specific integrated circuits (ASIC). dedicated hardware circuits, etc. The control block <NUM>. having any of these elements and/or combination of these elements, may be described herein as a control node. In an example, the output energy of the system may be delivered at much higher amplitudes than the operational logic uses (i.e., hundreds or thousands of volts for the outputs. with logic and processing performed at amplitudes generally under ten or even five volts). Thus there may be included isolation circuitry, voltage dividers or the like to reduce the systems operating voltages to levels more readily handled by the control circuitry. Dedicated circuits. such as ASIC circuits, may be used for processing high speed operations or to convert measured voltages or currents to digital outputs by including, for example, dedicated analog-to-digital conversion circuits, dedicating sampling circuits to samples voltages or currents. etc. In addition, optical isolator elements are often used in the art to allow low voltage control over high voltage circuitry, for example.

A memory <NUM>, which may or may not be separate from the control block <NUM>. is included to store executable instruction sets for operation as well as keeping a log of activity of the system and any sensor outputs received during therapy. The memory <NUM> may be a volatile or non-volatile memory, and may include optical or digital media, a Flash drive. a hard drive, ROM. RAM, etc. A Ul or user interface <NUM>, which may also be integrated with the control block (such as when using a laptop for control <NUM>, which would include each of memory <NUM> and a UI <NUM>). The UI <NUM> may include a mouse, keyboard, screen touchscreen, microphone, speakers, etc. as desired.

Power in <NUM> may include a battery or batteries. and/or an electrical coupling to plug into a wall socket to receive line power. A therapy block is shown at <NUM> and includes several stages. An isolation and voltage conversion circuit is shown at <NUM> and may include, for example. one or more transformers or other step-up converters (such as a capacitive step-up conversion circuit) to take a battery or line voltage and increase to a high voltage output that is stored in HV storage <NUM>. The HV storage <NUM> may include batteries. inductors or other circuit elements, but will typically be a capacitive storage block such as a stack of capacitors. HV storage <NUM> may be helpful to take the HV signal from block <NUM> and smooth it out over time to provide a more stable high voltage output that is then delivered by an HV output circuit <NUM>. the HV storage <NUM> may enable a lower power voltage input to generate very high power outputs by storing energy over a longer period of time to be delivered in short bursts.

The HV output circuit <NUM> may include a number of switches and other elements, including for example, high voltage switches such as silicon controlled rectifiers, high power Mosfets. and other elements, allowing selective outputting of the high voltage signal to an IO block shown at <NUM>. In some examples, the HV output circuit may be driven using one or more optical isolators or other isolation circuitry or circuit elements to allow isolation of lower power logic and control circuitry from the higher power/amplitude circuitry. The IO block <NUM> may provide a number of sockets to receive plugs from one or more delivery probes <NUM>, as well as one or more outputs for one or more indifferent electrodes to be placed on the body of a patient, serving as return electrodes or simply grounding the patient and system. For illustrative purposes the drawings show individual outputs as if there are separate plugs for each but embodiments herein also include compound plugs and/or ports that facilitate plural electrical connections via a single mechanical coupling.

In some alternative approaches to the therapy block <NUM>, rather than HV Out <NUM> using sets of switches to directly output a signal from HV storage, a resonant circuit may be powered by the HV signal. with outputs of the resonant circuit used for therapy delivery by selectively switching the output of the resonant circuit. A topology that uses a set of four switches in an "H-bridge" to drive an RF circuit is shown, for example, in <CIT>. In some embodiments. control over the individual pulses is achieved in the present invention by omitting the driven RF circuit and relying on a form of extended H-bridge circuit, as shown below in additional figures and description. Additional details that can be used in some embodiments are shown in additional figures below. Certain user interface features are also highlighted below in additional figures and description.

One or more sensing circuits <NUM> may be included to provide feedback to the control block <NUM>. For example, the sensing circuits may measure voltage at the output nodes to the probe <NUM>, or may measure current going to the output nodes that couple to the probe <NUM>, allowing tissue characteristics to be monitored. For example, voltage measuring circuits are well known in the art, including, for example, direct-conversion. successive approximation, ramp-compare, Wilkinson, integrating, Delta-encoded, pipelined, sigma-delta, and/or time-interleaved ADC, any of which may be used as suited to the application. Current measuring circuitry may use. for example. trace resistance sensing. a current sensor based on Faraday's Law such as a current transformer or Rogowski coil, or the use of magnetic field sensors (Hall effect, Flux gate. and/or a magneto-resistive current sensor) electrically or magnetically coupled to one or more transmission lines.

In another example, the probe <NUM> may include a sensor, such as a temperature sensor, a force sensor, or a chemical or pH sensor, any of which can be used to monitor tissue characteristics during therapy delivery. For example. a temperature sensor may be used to manage a non-thermal therapy such as electroporation by observing whether the temperature in a region is raising above a threshold temperature or showing an increasing trend, in which case one or more elements of power output may be reduced to ensure that the desired therapy type is dominant. If the probe contains such items. the sensing circuits <NUM> may include any suitable amplifier, filter or the like to allow the sensed signal to be conditioned for use by the control block <NUM>.

Sensing circuits <NUM> may include a cardiac rhythm sensor that is adapted for use with one or more electrodes (such as surface electrodes placed on the patient's chest) to capture cardiac rhythms and identify physiological windows for therapy delivery. A cardiac signal for purposes of identifying a physiological window for therapy may be received instead from an in-clinic ECG monitor, an implantable medical device such as a subcutaneous cardiac monitor, or a pacemaker or defibrillator, or from a variety of wearable products that sense cardiac rhythms. Rather than using the ECG, heart sounds, or pulse oximetry may be used to identify cardiac cycles and select therapy windows.

In addition, a probe as shown in <FIG> may include one or more imaging apparatuses, such as a lens coupled to a fiber optic cable to capture images at or near the probe. For example, a combination lens and fiber optic cable may be provided on one or more of the tissue piercing electrodes, at a distal end thereof or proximal thereto. The fiber optic cable may have a single strand to simply receive optical images. In some examples a fiber optic cable may have more than one strand to allow for two "channels", using one to illuminate the vicinity of the lens, and the other to receive reflected light, or a splitter may be used at the proximal end to allow pulsed light output to be provided into a single strand and reflected light to be directed to a feedback channel, which is then routed to an optical sensor. As ambient or reflected light changes, one can observe changes in tissue color indicating blood perfusion ongoing or ceasing. or indicating changes in the local tissue. The sensing circuitry <NUM>, in some illustrative examples, may be adapted for such use by having an optical output generator (an LED, VCSEL, or other suitable light generator) and an optical receiver. A lens may or may not be needed: it may be sufficient to provide a fiber optic strand with a cleaved end placed in contact with tissue that allows light to exit and enter.

In another example, one or more transducers may be placed on a probe as shown in <FIG> to serve a plurality of purposes. An accelerometer may be used both to sense muscle motion, as well as to sense other vibrations such as acoustics. Either by issuing an output acoustic ("ping") and receiving feedback. or simply "listening", the transducer may be used to determine whether any sounds are taking place indicative of physical changes in the region of the therapy electrodes. For example. if arcing occurs between two electrodes this can generate thermal energy that can cause vaporization. which may generate acoustic waves that can be sensed. An ultrasound transducer may be provided as well, allowing the use of ultrasound to measure changes in tissue fluid density. For each such transducer, the sensing circuitry <NUM> may comprise a driver circuit, such as an operational amplifier, to provide energy to the transducer via one or more electrical connections in the I/O circuitry <NUM> and probe <NUM>. As noted above, heart sounds may be obtained for use in timing therapy delivery. such a transducer may also be used to obtain heart sounds. For observing acoustic energy and/or muscle motion, a one, two or three axis micro-electro-mechanical system (MEMS) sensor may be used. Such a transducer typically has a vibrating element that changes an electrical parameter as motion is observed. Filtering the output to different frequency ranges in one or more channels may be useful to separately observe patient motion, heart sounds, and/or thermal ablation sourced sounds. Voltage and/or current sensing circuitry already described for block <NUM> may be used to receive, sample, and/or condition signals returned from the transducer.

Optionally, "other therapy" block <NUM> may be included. "Other" therapy may include, for example, the delivery of a chemical or biological agent to provide additional therapy, to enhance therapy being delivered, or to trigger immune response to facilitate the body healing itself after ablation. Such other therapy <NUM> may comprise a reservoir (which may be refillable) of material to be delivered to a patient via, for example, a syringe or catheter or through a probe. An "other therapy" <NUM> may include introducing a substance that enhances, augments, is synergistic with, or independently adds to the ablation effects of therapy delivered electrically. For example, a substance may be injected to modify or enhance electric field effects, as disclosed in <CIT>, titled IRREVERSIBLE ELECTROPORATION THROUGH A COMBINATION OF SUBSTANCE INJECTION AND ELECTRICAL FIELD APPLICATION.

In some examples. a cryotherapy may be integrated into the system to allow tissue cooling before, during or after electrical ablation, prompting immune response if desired. Cryotherapy may be delivered using, for example, a balloon on a therapy probe <NUM> or provided separately with a nozzle in the balloon coupled to a pressurized fluid source. such as nitrous oxide: the pressurized fluid when expelled through the nozzle will expand or go through a phase change from liquid to gas, which causes localized cooling, as disclosed for example in <CIT>. In another example, a fluid (gas or liquid) may be externally cooled and introduced via a catheter for cryogenic purposes, or, in the altemative, externally heated and introduced via a catheter for heat ablation purposes.

In still other examples, other therapy <NUM> may include delivery of energy such as mechanical energy (ultrasound, for example) or optical energy using, for example, a laser source (such as a vertical cavity surface emitting laser, or other laser source) coupled to an optical fiber that extends through a probe to allow laser energy to be delivered to targeted tissue. In some examples, a secondary or "other" therapy may be used, as noted, to trigger the immune response even if it is not used as a primary approach for destroying targeted tissue. The modality of "other therapy" <NUM> may overlap with some of the features of the sensing circuitry, and so the same circuit elements may be considered as part of each block. For example, a laser therapy output may be provided via the I/O, as well as a coupling for optical interrogation of tissue characteristics via an associated probe. Each may use the same or different optical tranducers. In one example, a VCSEL is provided for use by "other therapy" and is reused as needed to provide a lower energy output for optical tissue interrogation by the sensing circuitry <NUM>.

For safety purposes, current sensors on the output circuitry may be used to limit shorting or overcurrent conditions. For example. the Sense In block <NUM> may detect overcurrent at the I/O <NUM> and signal the control circuitry <NUM>, which may in return cut of power to the voltage conversion circuit <NUM> and/or disable HV Out <NUM> to turn off the output circuit (opening a switch, for example) in response to sensed overcurrent. In some embodiments, the Sense In block <NUM> may capture peak current during any therapy output in order to sense for transient events or trends that pose a risk of component damage. Meanwhile, sensed current for other purposes, such as to determine impedance, may be the peak sensed current during stimulus output or may be defined as an average current during the stimulus and more specifically during a particular one of the output phases or plurality of output phases. If taking average current, the sense circuitry may determine begin and end points in time, relative to a system clock, so that the control circuitry can align sensed current with phases and other characteristics of output stimuli.

Additionally or alternatively, the output circuitry in the I/O block <NUM> and/or HV out <NUM> may include a fuse, if desired. Additional safety features may include the provision of a temperature sensor associated with the voltage conversion circuitry <NUM>. HV storage <NUM>, HV out <NUM> and/or I/O <NUM>; a temperature that is too high may cause the system to shut down. In other examples, one or more temperature sensors may be used to prevent operation if the signal generator <NUM> is too cold, as may happen if it is stored or transported in a vehicle in cold weather prior to use. One or more temperature sensors may be provided on the probe to be used with the system to enable or disable operation. For example, a too cold temperature (for example. well below body temperature) may indicate that the probe <NUM> is not yet applied to tissue, and the control circuit <NUM> may prevent stimulus delivery or may provide a warning on the UI <NUM> to the user that the probe <NUM> is not showing body temperature conditions. A too hot temperature at probe <NUM> may signal thermal damage that is occurring in a manner that will be poorly controlled, as may happen if two contacts of the probe are too close together or shorted: again, the control circuitry <NUM> may be configured to turn off or modulate intensity. A temperature sensor on the probe <NUM> may be used for active feedback as well, as the control circuit <NUM> may modulate therapy amplitude and/or pulse width to attain a desired temperature range during therapy. For example, the temperature may be maintained in a predetermined range for non-thermal effects or for thermal effects, such as by keeping temperature above or below a temperature in the range of <NUM> to <NUM> degrees centigrade.

<FIG> shows a target tissue with electrodes thereabout. As shown in <FIG>, a target tissue <NUM> may be surrounded by a plurality of electrodes <NUM>-<NUM>. A probe as shown above in <FIG> may be readily used to place several electrodes around a target tissue <NUM>, with the individual electrodes <NUM>-<NUM> piercing and advancing through tissue around the target. In conventional biphasic application. the electrodes may be used in pairs or groups or as a complete group relative to a remote return electrode, with a positive phase signal immediately followed by a negative phase signal of generally equal but opposite voltage or current. In contrast to such uses, the present invention instead uses a spatial multiplexing of the therapy outputs to deliver therapy with the effectiveness of monophasic outputs while taking advantage of biphasic therapy's reduced side effects (particularly, muscle stimulus). To do so, in one example, electrodes may be used to deliver monophasic therapy in a round-robin type of fashion as follows:.

For this example, each of the outputs may be a monophasic waveform. Pulse width and amplitude during the sequence may be kept constant or may vary, if desired. In an example, the pulse width is in the range of <NUM> to <NUM> microseconds for each pulse. The amplitude may be determined on a voltage or current basis, or may be determined using, for example. a visualization or distance estimation to provide an output in volts per centimeter. For example, an output amplitude may be selected to account for such a distance while exceeding the threshold for IRE for the target tissue <NUM>. In an example, electrodes <NUM> and <NUM> may be estimated to be <NUM> centimeters apart. a calculation that could be made using radiography or other visualization, or which could be determined by assuming an impedance per unit distance for the tissue in region of probe deployment, measuring the impedance between electrodes <NUM> and <NUM>, and then calculating the distance.

Therapy may be delivered, referring to the above chart, sequentially in any order - that is, A-B-C-D-E-F may be the order. In some examples. the sequence A-D may be avoided, as that would essentially be a biphasic output in form even if not in name and therefore may not be as effective as a monophasic output. In some examples, to avoid back-to-back or immediate reversal of the electrode pairing, a rule may be set requiring at least one electrode be different for any given pulse delivery, from the immediately preceding pulse delivery.

The completed sequence, in some examples, is delivered as a pulse train that is completed within time period(s) that meet each of two rules:.

Regarding the therapy completion rule, using the heart as the driver, the cardiac rhythm contains various components known by convention as the R-wave, QRS complex, P-wave, and T-wave. Stimulus for ablation purposes ought not interfere with the cardiac rhythm, and the heart may be less susceptible to electrical signal interference in an interval between the R-wave peak (or end of the QRS complex) and the T-wave. Sometimes this interval can be called the S-T interval (the S-wave ends the QRS complex); the S-T interval for a given patient is likely to last tens of milliseconds and may range from <NUM> to <NUM> milliseconds. Approximately <NUM> milliseconds is typical for a healthy individual, though it is noted that the therapies discussed herein are not necessarily for healthy or typical people and, therefore, the S-T interval may not be "typical". In any event, in some examples, therapy is started and completed within the S-T interval window. A cardiac signal useful for identifying the S-T interval, or other physiologically useful window, may be obtained from a separate device (external or implantable) or may be sensed by a therapy generator having inputs for receiving cardiac signals from electrodes placed in or on the patient. Other sources may be the drivers; for example, detecting diaphragm movements may be useful as well, to time delivery of therapy for when the patient has inhaled, or exhaled.

In other examples, one, the other, or both of these timing rules may be omitted. In some examples, the windows may be approximated. such as by setting a rule that a pulse train must retum to a balanced charge state in less than one millisecond, or <NUM> microseconds, or <NUM> microseconds.

In another example, plural electrodes can be ganged together as cathode:.

In still another example, plural electrodes may be ganged together as the anode:.

Various such pairings may be used. As noted then, the therapy can be delivered according to a rule set. An apparatus for delivering therapy may incorporate such a rule set into stored instruction sets or hardwiring, as desired.

In light of the above, an illustrative example takes the form of a method of therapy delivery comprising delivering a plurality of monophasic outputs between selected pairs or groupings of electrodes in a pulse train Further the therapy delivery and pulse train may be delivered using a first rule that calls for each successive pulse in the pulse train to use at least one different electrode (whether by omitting a previously used electrode, adding an electrode, or swapping one or more electrodes for one or more other electrodes) than an immediately preceding pulse. A second rule calls for the pulse train to be delivered within a preset period of time, such as less than the time constant of surrounding tissue or less than one millisecond. A third rule calls for the pulse train to be delivered within a specified physiological window, where the physiological window corresponds to time within the cardiac cycle when the heart is refractory to or at least relatively less susceptible to electrical interference. Another illustrative example may take the form of a signal generator as shown above in <FIG> which stores in executable form or which is otherwise configured to incorporate the first, second and third rules. For each of these illustrative examples, output therapy pulses may be. for example, in the range of about <NUM> to <NUM> microseconds per pulse. with a pulse train of any suitable length. such as about <NUM> to about <NUM> pulses, and the pulse train may be repeated.

In some examples, as therapy is delivered using the various electrodes, output current in or out of each electrode may be tracked. At the end of a pulse train, or series of pulse trains, the sum of currents through each electrode may be determined, and one or more corrective outputs generated as by delivering a current or voltage of a predetermined amount that is likely to offset any built-up charge at any one electrode interface. Various illustrative examples may include a combination of monitoring charge delivered and then providing a "corrective" pulse to negate any built up charge on any one or more of the electrode surfaces. A corrective pulse may be useful in particular when a voltage controlled output rather than a current controlled output, is used. Additional examples that build off of, or show alternatives to, <FIG>, can be found in <CIT>, and titled SPATIALLY MULTIPLEXED WAVEFORM FOR SELECTIVE CELL ABLATION.

<FIG> shows an illustrative therapy waveform. This example shows a method of delivering a multiphasic ablation waveform comprising generating a first pulse train <NUM> comprising first pulses <NUM> of a first polarity (negative, in the illustration) having a first amplitude <NUM> and a first pulse width <NUM>, alternating with second pulses <NUM> of a second polarity opposite the first polarity, having a second amplitude <NUM> and having a second pulse width <NUM> less than the first pulse width <NUM>. The example further includes generating a second pulse train <NUM> comprising third pulses <NUM> of the first polarity having a third amplitude <NUM> and a third pulse width <NUM>, alternating with fourth pulses <NUM> of the second polarity having a fourth amplitude <NUM> and a fourth pulse width <NUM> greater than the third pulse width <NUM>. The example method may be performed such that the first pulse train <NUM> yields a first charge imbalance, and the second pulse train <NUM> yields a second charge imbalance that offsets the first charge imbalance to prevent muscle stimulation. The charge imbalance of the first pulse train <NUM> would be proportional to the difference between the product of amplitude <NUM>, pulse width <NUM> and the quantity of first pulses <NUM> of the first pulse train <NUM>, and the product of amplitude <NUM>, pulse width <NUM>, and the quantity of second pulses <NUM> of the first pulse train <NUM>.

In some examples, the first and second amplitudes <NUM>, <NUM> are the same, and the third and fourth amplitudes <NUM>, <NUM> are the same. Further, the method may be performed such that a time <NUM> from the start of the first pulse train <NUM> to the end of the second pulse train <NUM> is short enough to avoid muscle stimulation due to the charge imbalance of the first pulse train <NUM>. For example, time <NUM> may be shorter than one millisecond, or shorter than two milliseconds, or some other duration, as desired.

In some examples, the first and fourth pulse widths <NUM>, <NUM> are equal in duration, and the second and third pulse widths <NUM>, <NUM> are equal in duration. For example, the first and fourth pulse widths <NUM>, <NUM> may be in the range of about <NUM> to about <NUM> microseconds. and the second and third pulse widths <NUM>, <NUM> may be in the range of about <NUM> to about <NUM> microseconds. In some examples, the first pulse width <NUM> is about double the second pulse width <NUM>, and the fourth pulse width <NUM> is about double the third pulse width <NUM>. In other examples, the first, second, third and fourth pulse widths are each in a range of about <NUM> to <NUM> microseconds and may have other suitable ratios.

In general, the concept for <FIG> is to provide two pulse trains, each of which would be imbalanced if delivered alone, with delivery taking place in a short enough period of time to achieve charge balance without muscle stimulation. In other examples a single pulse train with asymmetric outputs within the pulse train may be used instead.

In some examples, the first pulse train <NUM> comprises a first quantity of first pulses <NUM> and a second quantity of second pulses <NUM>, and the second pulse train <NUM> comprises a third quantity of third pulses <NUM> and a fourth quantity of fourth pulses <NUM>, wherein the first, second, third and fourth quantities are all equal. In some examples, the first, second, third and fourth amplitudes each exceed an irreversible electroporation threshold. As noted, the "threshold" may be in part dependent on pulse width as well as the distances between electrodes. In other examples. the first second, third and fourth pulse widths are each in a range of about <NUM> to <NUM> microseconds.

In an alternative formulation, a pulsetrain <NUM> may comprise an odd number of pulses, such as pulses p1 to p5, each having the same amplitude, in which pulses pl, p3 and p5 are of the same polarity and each have a pulse width PW, while pulses p2 and p4 are of opposite polarity and each have pulse width <NUM> × PW, which would yield a charge balanced output even though pulses delivered in each polarity are unequal in charge content. In another example, a pulse train <NUM> may comprise an odd number of pulses each having the same pulse width, such as pulses p1 to p5, in which pulses p1, p3, and p5 are of the same polarity and each have an amplitude V, while pulses p2 and p4 are of opposite polarity and each have an amplitude <NUM> × V, again providing an asymmetric output that, upon conclusion of the pulse train, is also charge balanced. Additional examples that build off of, or show alternatives to, <FIG>, can be found in <CIT>, and titled TIME MULTIPLEXED WAVEFORM FOR SELECTIVE CELL ABLATION.

<FIG> shows a method for configuring and/or testing a therapy. An output configuration is set at <NUM>. An output configuration may be, for example, definition of a therapy or non-therapy waveform to be delivered to a patient. A non-therapy waveform may be one which uses lower amplitude or a different pulse width than may be used during therapy, for example. For purposes of the method of <FIG>, the non-therapy waveform - or therapy waveform, may be defined with a longer pulse width than would otherwise be used in therapy in order to amplify the effect of the waveform on patient muscle tissue, if desired. In the example, the output configuration <NUM> comprises at least first and second signal portions that are separated by an interpulse interval. As part of the output configuration an interpulse interval between two signals of opposing or different polarity can be set.

Next, the interpulse interval is tested as indicated at <NUM>. Testing comprises delivering or outputting the waveform that was configured in <NUM>, as indicated at <NUM>, and then determining or observing whether a muscle response occurs <NUM>. If no muscle response occurs, the method adds to the duration of the interpulse delay, as indicated at <NUM>, and returns to block <NUM> to again deliver or output the waveform. The procedure is repeated in this example until one of two conditions is met - either a maximum or upper threshold interpulse interval is used, without any muscle response being observed, or a muscle response is observed. The aim is to maximize the interpulse interval in order to provide a therapy waveform that mimics a monophasic waveform, preferentially enhancing efficacy in causing cell death, while avoiding the side effect of muscle stimulation.

The interpulse delay can then be set as indicated at <NUM>. For example, the interpulse delay may be set by reducing the last interpulse delay which was tested by some margin or percentage. for example, by <NUM> to <NUM> microseconds. or by a percentage such as <NUM> to <NUM> percent. In some examples, the setting of the interpulse at <NUM> is performed differently depending on the nature of the end of testing at block <NUM>, that is, if testing ends because the maximum interpulse is met without a muscle response, then the interpulse delay can be set to the maximum, or if the testing ends because of observed muscle response, the interpulse delay is set to a duration that is a reduction of the last tested interpulse, using a margin or percentage.

With the interpulse delay set at block <NUM>, the method then proceeds to therapy delivery at <NUM>. Therapy delivery may use the same or different parameters in terms of waveform shape, duration, amplitude or type as that tested in blocks <NUM>/<NUM>. For example, because the aim in blocks <NUM> to <NUM> is to select an interpulse delay, which is largely a function of the surrounding tissue and not necessarily a function of the ablation target, it may not be necessary to perform testing using the parameters needed for ablation, which could confound the test results. In other examples. the interpulse delay is tested as part of therapy delivery itself, by using the actual ablation parameters in a repetitive series while adjusting the interpulse delays. In still further examples, as therapy is applied at block <NUM>, for example, in a repeating series of pulse trains, muscle response may be monitored over time and, if muscle response is observed, the interpulse delay parameter may be modified, such as by reducing interpulse delay.

The step of monitoring for muscle response at <NUM> may use subjective and/or objective measurements or observations. For example, subjective monitoring <NUM> may include querying the patient <NUM> as to whether the patient is feeling any sensation of muscle tightening, twitching or the like, and/or asking if the patient is feeling other sensations such as tingling, buzzing, burning, paresthesia, etc. Subjective monitoring <NUM> may also be based on user or physician observation as indicated at <NUM>. requesting that the user indicate whether motion. tightness or other physical response has been witnessed. In still other examples, objective measures <NUM> may be used including, for example, having a motion sensor <NUM> on a probe or placed in or on a patient at a relevant position to determine whether any motion - whether perceptible or not to the user or a patient, is taking place.

In some examples, muscle response may be observed by capturing electrical signals from the muscle itself (myopotentials <NUM>): as muscle demonstrates an electrical response it would be understood that motion is imminent or likely to take place. In still other examples, during a therapy session, it may be that a gross observation - that is. patient sensation or motion - is used during setting of the interpulse delay. and myopotentials are used to provide feedback during therapy by determining whether electrical signals from the muscle change over time; increasing amplitude of sensed electrical response of the muscle may be used to reduce interpulse delay, or some other feature such as amplitude, to avoid triggering muscle motion: conversely, decreasing electrical response may indicate that changes in the ablated tissue (as cells are destroyed, for example) are reducing the likelihood of muscle response. allowing longer interpulse delay and/or higher amplitude outputs.

<FIG> show illustrative output and feedback circuits for a signal generator. Referring now to <FIG>, an illustrative example may comprise a plurality of sources <NUM>. coupled to a plurality of switches <NUM> which allow multiple independent channels for ablative therapy to be delivered. The plurality of sources may comprise current sources (such as a set of current mirrors which can be summed together as desired), or may comprise plural voltage sources, such as a capacitor stack as illustrated further below in <FIG>. Depending on the nature of the sources <NUM>, the switches <NUM> may be omitted as, for example, if current sources that can be independently disabled are used.

The conduction lines between the sources <NUM> and the output block <NUM> can be considered the "high side" of the output circuit in some examples. The high side conduction lines may be monitored if desired using feedback couplings indicated at <NUM>. A feedback coupling <NUM> may be, for example, a current sensor for measuring current through the conduction line or a voltage sensor for measuring voltage. The above noted list of examples for voltage or current sensors may be used. Both a current sensor and a voltage sensor may be provided, if desired. The feedback coupling <NUM> is coupled to a feedback monitoring circuit <NUM>, which may include, for example, various conditioning. filtering, comparing, sampling and/or storing circuits or circuit elements to capture what happens during a therapy output.

The output block <NUM> may include one or more mechanical ports, plugs or other coupling for mechanical and electrical connection to a therapy delivery probe. While four outputs are shown at <NUM>, it should be understood that the invention is not so limited and any number of outputs may be provided. Two or more output blocks <NUM> may be provided instead.

Another set of conduction lines couples the output block <NUM> to another set of switches <NUM>. Switches <NUM> may enable or disable an output and may link the outputs to a reference or ground for the system. or may couple to a plurality of sources <NUM>. In some examples, ablation stimulus output may be simply coupled to system ground for return purposes. In other examples, one or more voltage or current sources may be used as a negative or sink for output energy, if desired.

The conduction lines between block <NUM> and switches <NUM> may be considered the low side conduction lines in some examples. An additional set of feedback couplings <NUM> may be provided on the low side conduction lines. The feedback couplings <NUM> may comprise voltage or current sensors, or both. as desired, and are again coupled to a feedback monitoring circuit <NUM>, which may be similar to block <NUM>. The high side sources <NUM> and switches <NUM>, feedback circuits <NUM>, <NUM>, and low side sources <NUM> and switches <NUM> are all shown as coupled to the control block <NUM>. which may include the various control elements discussed above relative to block <NUM> of <FIG>.

The feedback monitoring circuits <NUM>. <NUM> may be used to monitor peak current of delivered stimuli in order to identify overcurrent conditions and prevent componentry internal to the device from being harmed by overcurrent. Alternatively, peak or average current may be monitored to determine what the output is likely doing in the tissue, whether causing thermal or non-thermal ablation, for example. In an example, average current is monitored, referenced to a time block. such as by reference to the start and end point of a therapy phase, phases, or pulse train. Average current can be used to monitor for changing physiology as. for example, may be relevant to determining that electroporation is occurring and cell contents are being emptied into the intercellular fluid. In other examples, current feedback may be used to provide a current controlled output.

As noted above, additional feedback may be obtained as well from the probe used for stimulus/therapy delivery, including, for example. thermal sensing, acoustic sensing, visual observation/sensing, ultrasound, and impedance monitoring. Such feedback loops may be used to identify hazards and/or to monitor progress and/or success or failure of the therapy output to ablate tissue.

<FIG> shows another example for coupling a power source to a set of voltage sources (a capacitor stack), with independent outputs available at a plurality of different levels. The example <NUM> uses a voltage or power input <NUM> which is coupled to a step-up converter <NUM> that is used to charge a capacitor stack <NUM>. Block <NUM> may be similar to block <NUM> of <FIG>.

The example shows four capacitors <NUM> in the capacitor stack <NUM>; any suitable number of capacitors can be used for examples using a capacitor stack, for example, from <NUM> to <NUM> capacitors, or more, as desired. The capacitors <NUM> and capacitor stack <NUM> collectively will be sized to allow the delivery of high voltage (kilovolt or higher) outputs of durations up to the millisecond range into loads as small as tens of ohms without significant drop-off in voltage. For example, typical output voltages may range between <NUM> volts to <NUM> kv. or lower or higher, and representative loads may be less than <NUM> ohms, such as <NUM> ohms or <NUM> ohms, or lower or higher. Representative capacitor sizes may be in the range of <NUM> to <NUM>,<NUM> microfarads, or lower or higher, either for individual capacitors or for the entire stack. A reconfigurable capacitor stack may include capacitors capable of being charged in parallel and discharged in series. or both charged and discharged in series or parallel using any suitable quantity and arrangement of switches and diodes to couple the capacitors together.

In an illustrative numeric example, the time constant of the output circuit, taking into account output circuit impedance (including the patient) of about <NUM> ohms, is preferably greater than <NUM> millisecond, and more preferably greater than <NUM> milliseconds. Thus, and for example, a set of four <NUM> microfarad capacitors may be used, giving a stack capacitance of <NUM> microfarads, which would yield a <NUM> millisecond time constant when used with a <NUM> ohm load. Reducing the load to <NUM> ohms would still provide a time constant of <NUM> milliseconds. A larger load of course would provide a longer time constant. Other design parameters may be used, including different capacitor quantities and sizes, different patient load estimates. and a different target minimum time constant.

Sets of switch arrays <NUM> are coupled to nodes within the capacitor stack <NUM> at several different levels including at the top <NUM>, between the top two capacitors <NUM>, between the middle two capacitors <NUM> and between the lowest two capacitors <NUM>. Each switch array separately defines paths A, B and C as selectable outputs that are each capable of tapping the stack at different power/voltage levels; each set <NUM> has one switch dedicated to each output path. As indicated at <NUM>, each of the output paths may include a current monitor I1. I3: in other examples a voltage monitor may be on each path, or both voltage and current may be monitored. The switches may be, for example, relays, high power Mosfets, silicon controlled rectifiers (SCR), other transistors, or may include multi-part switches combining for example. an SCR for enabling a signal with a Mosfet to turn the signal off. A ground or reference node G is highlighted as well.

As can be appreciated by the skilled artisan, <FIG> shows an example with multiple, independently operable channels. Given appropriately sized capacitors each channel generally can operate without affecting other channels. The size of the capacitors may be reflected in ratings of the output of the system as capacitor size, combined with output impedance (including the patient), can be used in combination to determine maximum pulse width and voltage/amplitude ratings. For example, if tapping the capacitor stack at position <NUM>, the maximum output current (or minimum impedance) may be relatively larger than if tapping the capacitor stack at the top <NUM>.

The topology shown omits various diodes and current control apparatuses that may be used to allow capacitor stack charging without directly linking step up voltages from block <NUM> to the actual outputs. In some examples, rather than a single coupling at <NUM> to the top of the capacitor stack, voltage conversion may use a multiple-tapped transformer, with each tap tied to a node <NUM>, <NUM>, <NUM>, <NUM>, effectively charging the capacitor stack in parallel while allowing series discharge. For charging, a primary phase would load the transformer with energy from the voltage source <NUM>, and a secondary phase would discharge the loaded energy into the capacitor stack <NUM>. Whichever of the capacitors carries the least voltage would be charged to the greatest extent during the secondary phase. Appropriately timing the secondary phase would allow charging of the capacitor stack intermittent with therapeutic output. By using a multi-tap charging circuit, the capacitor stack can be refreshed and rebalanced as current is drawn from selected portions thereof.

<FIG> shows an illustrative output configuration. Reusing the A, B. C denominations from <FIG>, a set of output nodes O1, O2, O3 is shown coupled to outputs A, B, C. Switch <NUM> couples node A of the circuit in <FIG> to the output node O1 <NUM>. Switch <NUM> is to some extent redundant, noting that the switches shown in <FIG> within each group <NUM> could be the sole switches. While two switches may add complexity, it also may limit leakage current which could be harmful to the patient. Indeed, in some examples one switch may be an enable switch while the other is used to aid in wave shaping and/or to cut off current flow. Current and/or voltage may be measured using node <NUM>. A grounding switch is shown at <NUM>. During operation, the grounding switch <NUM> may be used to define a return electrode for an output - that is, any output current may be delivered relative to ground. As noted previously, rather than a ground or reference, the return may instead be to a negative voltage source or to a current sink, if desired.

<FIG> shows an alternative configuration which allows an output node to be placed in either voltage or current controlled operation. The circuit <NUM> is shown for coupling a single node A <NUM> to output O1 <NUM>, but may be replicated for a plurality of output nodes. A first switch <NUM> connects the output O1 to a resistor <NUM> and bypass switch <NUM>. For a voltage controlled output, switch <NUM> and transistor <NUM> are simultaneously closed. Opening switch <NUM> while driving transistor <NUM> routes current through the resistor <NUM>. By controlling VDrive, powering transistor <NUM>, the current passing through the circuit can be controlled, since the current through resistor <NUM> is limited by the equation: VDrive > I × R(<NUM>), where R(<NUM>) is the resistance of resistor <NUM>, and I is the current. The configuration is somewhat similar to that shown in <CIT>, where it was used to deliver constant current pacing stimulus in an implantable defibrillator. Other configurations may be used as are known in the art.

In some examples, current control can be performed using a current controlling circuit as in <FIG>. In other examples monitoring circuitry, whether on the high side, low side, or at the input/output circuitry, can be used to monitor voltage and/or current. Then, analog to digital conversion circuitry or other regulators may be used to modify the return reference voltage or the output voltage taken from the capacitor stack to change voltage output and provide a constant current, constant voltage, or constant power (power being the product of voltage and current) output. For example, as current changes are measured and monitored, voltage output may be increased or decreased to maintain constant power. In another example. a constant power circuitry may control current flow as shown in <FIG>. while monitoring output voltage, and may modify the current flow by adjusting the VDrive signal to ensure that the product of current and voltage delivered to the probe is constant.

<FIG> show illustrative pulse generation circuits. Referring now to <FIG>, the circuit <NUM> comprises a capacitor bank or stack shown at <NUM>, having a plurality of capacitors and a number of circuit paths, including at least paths <NUM>, <NUM> exiting it. The capacitor stack <NUM> can be charged using a voltage source (not shown), which may be a battery or a line voltage, as desired, coupled to a voltage convertor to generate voltages in the range of one to several kilovolts: <NUM>, <NUM>, <NUM> and up to <NUM> kilovolts, or more, may be used.

An output stage is then provided including at least one power selector switch pair, shown at <NUM>. The power selector switch pair <NUM> is shown having first and second switches <NUM>, <NUM> which enable selection of all or only a portion of the capacitor stack to power an output signal. More than two switches may be included to enable a plurality of different power levels to be selected if desired. If switch <NUM> is closed while switch <NUM> is open. a higher voltage output can be chosen using the entire capacitor stack <NUM>, while if switch <NUM> is open and switch <NUM> is closed, a lower voltage output can be chosen by using less than the entire capacitor stack, thereby excluding at least one of the capacitors of the capacitor stack.

The output circuit further includes a plurality of output arms <NUM>, <NUM>, <NUM>, <NUM>, each including an electrode selector switch pair. The electrode selector switch pairs control which of the output nodes, marked here as Elec <NUM>, Elec2, Elec3, and Elec4, is active as anode or cathode. Two or more such nodes may be active as anodes or cathodes at once: for example, there may be one anode. one cathode, and two open nodes, or two anodes and one cathode with one open node, or two cathodes and one anode with one open node, or two cathodes and two anodes. etc., in various combinations. Each electrode selector switch pair includes a high side switch coupled to the power selector switch pair and a low side switch coupled to a reference. For example, electrode switch pair <NUM> has a high side switch <NUM> for coupling to the power selector <NUM>. and a low side switch <NUM> for coupling to a reference or system ground. If desired, additional branches may include discharge and/or leak resistors (not shown) allowing for active or passive discharge of the circuit when not in use.

<FIG> shows another topology. This time, the capacitor stack or bank <NUM> is connected by at least two output paths <NUM>, <NUM> to a power selector <NUM> as in <FIG>. Electrode switch pairs in this example include at least first and second overall branches <NUM>, <NUM>. While switch pair <NUM> is similar to the switch pairs shown in <FIG>, switch branch <NUM> is different. A first switch pair <NUM> enables access to a plurality of lower level branches with switch pairs <NUM>, <NUM> allowing selective coupling to a set of four output nodes <NUM>, <NUM>, <NUM>, <NUM>. Thus a plurality of topologies of varying complexity may be used to allow separate selection of both power level (via block <NUM>) as well as the outputs to be used (via branches <NUM>.

<FIG> shows an illustrative user interface. The user interface may be generated on a display screen, such as on a stand-alone screen, a laptop computer, a tablet computer, or any other suitable device. The display screen may be a touch screen. The display <NUM> shows a broad variety of features and diagnostics for the user. A slider bar is shown at <NUM> for displaying. relative to a maximum voltage (VH). the current output maximum amplitude; the user may modify the current output maximum amplitude via touchscreen, rollerball, mouse, touchpad, keyboard, etc. A number of current settings are shown at <NUM> including positive pulse width (PPW), negative pulse width (NPW), and interpulse duration (IPD). Each of PPW. and IPD may be modified using the various embodiments shown herein as well as using the embodiments shown in related <CIT> and <CIT>.

Additional modifiable parameters include the pulses per burst (PPB), which controls how many pulses are delivered in a single burst of ablation energy. The intercycle delay (ICD) defines how much time will pass between two sets of pulses. The number of bursts to be delivered (# Bursts) can also be set, as well as the delay between bursts (BRD). In the example shown. output energy would be delivered as four microsecond positive and negative square waves with a four microsecond delay between the two square waves, with five pairs of positive and negative square waves delivered (PPB) having four microseconds between the end of a negative square wave and the succeeding start of a positive square wave. Each burst of <NUM> cycles is separated from the next burst by <NUM> milliseconds, and one-hundred bursts are to be delivered.

Additional control features are shown at <NUM>, with a trigger set to off. If the trigger is on. a biological feature, such as an identified reference point in a cardiac cycle, may be used to trigger each burst, rather than the BRD. In an alternative, having the trigger on, with a BRD set. may indicate that each burst is to be separated from the next by at least the BRD. with a new burst triggered by a sensed biological feature such as the cardiac cycle reference point. A cardiac cycle reference point may be, for example, the identification of an R-wave or QRS complex, which may be followed by some post-event delay. For example. a triggered output may be delivered by sensing an R-wave and waiting <NUM> to <NUM> milliseconds for the end of the R-wave before therapy delivery, with the above noted goal of finishing the burst before the T-wave occurs. The system may be set up to automatically calculate a delay by subtracting from a known, tested, or estimated S-T duration the length of time needed to complete a burst, if desired.

The additional features <NUM> may also define a time limit for completing the therapy, which could timeout to prevent system hang-up. A current threshold is set as noted as well and may be provided to ensure that current does not exceed a threshold that could present a risk of harm to the patient. For example, it is known that as cells are ablated local impedance may drop: excess current could lead to heating of tissue or damage to components, so setting a limit may be useful to ensure safety or to control spatial characteristics of the ablation effects.

As indicated at <NUM>, a time remaining indicator can be provided, as well as a measurement of impedance <NUM>. Impedance may be reported as an overall impedance for the system output, including impedance of the probe being used, or may be more particular to the impedance of the patient tissue being treated. Graphs may be displayed showing sensed output voltage waveforms <NUM>, overall or for particular or recent cycles or bursts of therapy output. Sensed current may similarly be shown in graphical form <NUM>. A disable signal button <NUM> may be provided to allow pre- or post- therapy display of one or more patient signals; during therapy delivery this button <NUM> may be greyed out, hidden or inaccessible if desired. A stop button is displayed prominently at <NUM> to allow therapy to be turned off whenever needed. Current settings for using levels of the capacitor stack may be displayed at <NUM>. Further diagnostics and statuses are shown at the right side of the display, including a current capacitor stack voltage at <NUM>, history of the capacitor stack voltage at <NUM>, and peak sensed voltages for positive and negative phases of the output signal as well as peak current (positive is indicated but negative could be as well), and peak impedance calculation may be displayed in the block at <NUM>. The history of impedance can be shown on a graph relative to time in the block at <NUM>. The particular set of parameters and diagnostics shown is merely exemplary, and more, less or different parameters and diagnostics may be shown. The organization of the display may be modified if desired as well.

<FIG> show a method for therapy delivery that uses unbalanced waveforms with correction of detected charge imbalance. <FIG> shows the method in block form, while <FIG> shows the method in a graphical format. Starting with the <FIG>, the figure illustrates a method of delivering an ablation therapy to a patient comprising delivering a therapy pulse train within a predetermined period of time. The method includes delivering a first output at <NUM>. The first output may be a first pulse having first voltage and first duration. The method includes sensing at least current during the first pulse. as indicated at <NUM>.

Next, the method comprises delivering a second output as indicated at <NUM>. The second output may include a second pulse having second voltage and duration. In an example, the first voltage does not equal the second voltage, and the first duration does not equal the second duration, but the product of the first voltage and first duration is substantially equal to the product of the second voltage and the second duration. Further the method comprises sensing current during the second pulse, as indicated at <NUM>.

The method then includes making an adjustment, as indicated at <NUM>, to the charge balance that results from the first and second outputs <NUM>, <NUM>. In an example, the adjustment <NUM> comprises determining that a quantity of charge delivered during the first pulse is not equal to a quantity of charge delivered during the second pulse. The adjustment comprises delivering at least one additional pulse to remove charge imbalance caused by difference between the quantity of charge of the first pulse and the quantity of charge of the second pulse, before expiration of the predetermined period of time. The one additional pulse may include a single output or more than one output, as indicated at <NUM>.

<FIG> shows the method in graphic form, as a first pulse <NUM> is delivered having a first amplitude and first pulse width, and a second pulse <NUM> is delivered with a second amplitude and second pulse width. The height and width of the two pulses <NUM>, <NUM> can be seen to be different, but the area beneath the line for the two pulses is approximately equal - that is, generally speaking, equal to within about +/- <NUM>%, or +/-<NUM>%, or +/-<NUM>%. While that combination of voltage and duration may be expected to provide a balanced output in terms of charge, in the real world this may not be the case. Therefore one or more adjustment pulses are delivered at <NUM>.

In further examples, the at least one additional pulse is a voltage controlled pulse having a third voltage and a third duration calculated by determining an impedance encountered by at least one of the first and second pulses. Altematively, a total charge delivered during the first and second pulses, or net charge delivered in the first and second pulses, may be calculated. In another example, the adjustment pulse(s) <NUM> may be delivered as current controlled outputs, while the initially delivered pulses <NUM>. <NUM>, may be delivered as voltage controlled outputs. The adjustment pulses may be delivered at a non-therapy amplitude or duration, if desired.

Rather than single pulses, the operation may be to perform a burst of any number of pulses while tracking total charge delivered, followed by one or more corrective outputs to negate charge imbalance. While a significant charge imbalance may not necessarily occur from a single cycle within a burst, or even from a single burst, the concern may be that over time, as cycles are repeated within bursts, and bursts are repeated within a therapy plan, the charge imbalance could build up to become significant enough that it affects the patient or therapy by, for example, causing muscle stimulation. Thus adjustments may be made after pairs of outputs, after cycles, after bursts, or occasionally within a series of bursts. For example, correction may be periodic and provided after a set number of cycles or bursts, or after a set period of time, or may be occasional and provided when a sensed or calculated imbalance reaches or crosses a threshold.

Claim 1:
A device (<NUM>) for generating energy for use in the electrical ablation of tissue comprising:
a voltage source (<NUM>);
a capacitor bank (<NUM>) having at least a first capacitor and one or more additional capacitors, the capacitor bank (<NUM>) accessible at a plurality of locations (<NUM>, <NUM>, <NUM>) to operate as a plurality of output sources; and
an output stage coupling the capacitor bank (<NUM>) to a plurality of output nodes (A, B, C) with an output path for each output node, the output stage further comprising:
a plurality of power selector switches coupled to the capacitor bank (<NUM>) at the plurality of locations (<NUM>, <NUM>, <NUM>), the plurality of power selector switches arranged as sets of switch arrays (<NUM>) each having a switch dedicated to each output path allowing independent and simultaneous access to the capacitor bank (<NUM>) to derive a plurality of outputs at the same or different voltage levels; and
a plurality of electrode selector switch pairs (<NUM>, <NUM>) each associated with a respective one of the plurality of output nodes (A, B, C), each electrode selector switch pair (<NUM>, <NUM>) including a high side switch (<NUM>) coupled to the respective one of the output nodes (A, B, C) and a low side switch (<NUM>) coupled to a reference.