WO2020144368A1

WO2020144368A1 - Method and system for monitoring separation between an electrode and a target point

Info

Publication number: WO2020144368A1
Application number: PCT/EP2020/050606
Authority: WO
Inventors: Emmanuel VANDER POORTEN; Laurent SCHOEVAERDTS
Original assignee: Katholieke Universiteit Leuven
Priority date: 2019-01-10
Filing date: 2020-01-10
Publication date: 2020-07-16

Abstract

An apparatus (20) for monitoring a distance between a probe electrode (22) and a target point comprises the probe electrode (22) and a receiving electrode (30) suitable for being positioned relative to the target point such that, in use, current may be driven between the probe electrode (22) and the receiving electrode (30) via the target point. The apparatus (20) further comprises an impedance measuring device (27) coupled to the probe electrode (22) and to the receiving electrode (30); and a processor (40) coupled to the impedance measuring device (27). The processor (40) is configured for receiving at least three probe electrode – receiving electrode impedance measurements for at least three different probe electrode – target point distances, and for determining from the at least three impedance measurements whether a stationary point exists in the impedance. A corresponding method is also provided.

Description

METHOD AND SYSTEM FOR MONITORING SEPARATION BETWEEN AN ELECTRODE AND

A TARGET POINT

Field of the invention

Embodiments of the present invention relate to methods and apparatus for monitoring the distance between an electrode and a target point, for example a target point in a collection of neurons.

Background of the invention

Retinal Vein Occlusion (RVO) is a widespread eye vascular disease leading to vision loss because of clots obstructing a retinal vessel. This vascular disorder first causes black spots in people's eyesight and progressively leads to blindness. Retinal vein cannulation is a treatment for RVO in which a microneedle injects a thrombolytic agent inside the clotted vessel. During this procedure, the surgeon only relies on a microscope, looking through the patient eye's lens to perform the vein cannulation. Such visual feedback gives poor depth perception, with a risk to pierce through the targeted vessel and inject the agent underneath the retina, which is referred to as a double puncture. Such situation endangers the patient's eyesight.

Epi-retinal membranes are avascular, fibrocellular membranes, such as scar tissue that can cause blurred and distorted central vision. These membranes attached to the inner surface of the retina are about 60 micrometer thick. In epi-retinal membrane peeling microsurgeons are to peel off these membranes from the retina while not damaging the retina itself. While peeling, the microsurgeon hovers over the retinal surface with sharp instruments such as a forceps or a retinal pick, making relatively large motions. The combination of limited depth perception and relative gross motions make that unintentional contacts with the retina do occur occasionally. In

resistance of stimulation electrodes as a function of electrode proximity to the retina", Majdi et al., J Neural Eng 2015 Feb 12(1):016006, the use of the electrical impedance as a measure of the proximity of insulated platinum electrodes to the inner surface of the retina is described. An increase in impedance is described with increasing proximity to the retina. However, determining the position of the electrode depends on the magnitude of the impedance which may be affected by particular conditions of the environment, for example the anatomical structures involved in the electrically stimulated zone, the medium in which the electrode or tool is being moved, the excitation frequency at which the tissues are stimulated, the electrode contact surface conducting the current.

To complement the depth perception provided by a stereo-microscope, methods based on optical coherence tomography (OCT) have been developed. When integrated in the stereo-microscope, iOCT (intra-operative OCT) can be used to observe the retina. Aside from the large cost of OCT equipment, sophisticated instrument tracking methods such as those described in Zhou et al., "Needle segmentation in volumetric optical coherence tomography images for ophthalmic microsurgery", Applied Sciences 7(8):748 (2017) are required for computing the distance between the instrument and the retina. To avoid the complex optical path of the OCT signal (when integrated in the overhead stereo microscope) fiber based OCT solutions have been developed where an optical fiber is integrated into the instrument leading the OCT signal up to the instrument tip, as described in Kang et al., "Demonstration ofsubretinal injection using common-path swept source OCT guided microinjector", Applied Sciences 8(8):1287 (2018). The disadvantage of this approach is that dedicated instruments need to be designed in which the optical fiber will take considerable space which cannot be used for other functionality.

GB2335990 describes a sensor for sensing penetration depth of a hypodermic needle. Two electrodes are used and a change of impedance with penetration depth is determined. Whether the proper depth has been reached is determined by the magnitude of the change in impedance or the magnitude of the impedance itself. The sensor requires calibration each time the needle is relocated as the electrical properties of the medium change. In catheter ablation treatment of the heart a method is required for maintaining a distance between the ablating end of an ablation catheter and the heart wall, to avoid excessive damage to the heart wall caused by overshoot of the catheter or sub-optimal ablation treatment caused by the catheter end not being close enough to the heart wall. The heart contains a network of neurons.

Summary of the invention

It is an object of embodiments of the present invention to provide affordable, reliable and easy-to-use methods and devices for determining proximity between an electrode and a target point, for instance a target point in a collection of neurons, which are easily translatable between different situations without the need for extensive calibration.

In a first aspect, the present invention provides an apparatus for monitoring a distance between a probe electrode and a target point, for instance a target point in a collection of neurons. The apparatus comprises the probe electrode and a receiving electrode suitable for being positioned relative to the target point such that, in use, current may be driven between the probe electrode and the receiving electrode via the target point. A power supply for driving the current between the probe electrode and the receiving electrode may be included in the apparatus, or may be external to it, in which case the probe electrode and the receiving electrode are connectable to the power supply. The apparatus further comprises an impedance measuring device coupled to the probe electrode and to the receiving electrode; and a processor coupled to the impedance measuring device. The processor is configured for receiving at least three probe electrode - receiving electrode impedance measurements for at least three different probe electrode - target point distances, and for determining from the at least three impedance measurements whether a stationary point exists in the impedance. In embodiments of the present invention, the processor may be further configured for outputting an output signal in dependence upon the presence or absence of a stationary point. This means that an output signal may be provided upon detection of stationary point, of an output signal may be provided as long as the stationary poin is not yet detected. In particular embodiments, the output signal may be any of an audio signal, a visual signal, a tactile signal or a kinaesthetic signal.

An apparatus according to embodiments of the present invention may further comprise a control system configured for receiving the output signal and for, based on the received output signal, dynamically controlling one or more of the position, velocity or acceleration of one or more devices. Examples of such devices may be, without being limited thereto, probes, catheters or guidewires.

In particular embodiments, the control system may be configured for, based on the received output signal, dynamically controlling one or more of the position, velocity or acceleration of the probe electrode.

In particular embodiments, the probe electrode may be comprised in a cannulation needle.

In embodiments of the present invention, the impedance measuring device may be adapted for measuring the impedance at a frequency such that the magnitude of the phase of the impedance measurements is greater than -25°.

In a second aspect, the present invention provides a method of monitoring a distance between a probe electrode and a target point, for instance a target point in a collection of neurons, in a system wherein the probe electrode and a receiving electrode have been positioned relative to the target point, e.g. the collection of neurons, such that, in use, current is driven between the probe electrode and the receiving electrode via the target point. The method comprises the steps of receiving at least three probe electrode receiving electrode impedance measurements for at least three different probe electrode-target point distances, and determining whether a stationary point exists in the impedance. The probe electrode and the receiving electrode may be brought to place before the actual steps of the method, namely the data capturing (impedance measurements) and data processing (stationary point determination) take place. In that sense, the probe electrode and receiving electrode may be called pre-implanted electrodes. In particularly useful embodiments of the present invention, the method may further comprise outputting a signal in dependence upon the presence or absence of such stationary point. The output signal may be any of an audio signal, a visual signal, a tactile or kinaesthetic signal. A method according to embodiments of the present invention may further comprise using the output signal for dynamically controlling the position, velocity and/or acceleration of one or more devices, for instance a probe, a catheter or a guide wire.

The method according to embodiments of the present invention may include not only receiving at least three probe electrode - receiving electrode impedance measurement results, but also carrying out the corresponding measurements. The impedance measurements may be performed at a frequency selected such that the magnitude of the phase of the impedance measurements is greater than -25°.

The presence of a stationary point in the impedance indicates proximity to the target point and can thus be used as a magnitude-independent signal of proximity to the target point, e.g. to the collection of neurons, which is easily translatable between different situations without the need for extensive calibration. The method can be carried out using an apparatus that is affordable compared to OCT equipment and is easy to use. The method can be carried out using an apparatus according to embodiments of the first aspect of the present invention. Particular applications of the method of the present invention may be where the target point is be comprised in the retina, in the brain or in the heart.

In a third aspect of the present invention, a computer program product is provided containing instructions which, when executed by a computer operatively linked to an apparatus for monitoring a distance between a probe electrode and a target point as in any of the embodiments of the first aspect, cause the apparatus to carry out the steps of a method according to any of the embodiments of the second aspect. Particular and preferred aspects of the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims. For purposes of summarizing the invention and the advantages achieved over the prior art, certain objects and advantages of the invention have been described herein above. Of course, it is to be understood that not necessarily all such objects or advantages may be achieved in accordance with any particular embodiment of the invention. Thus, for example, those skilled in the art will recognize that the invention may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objects or advantages as may be taught or suggested herein.

Brief description of the drawings

Features of the present invention will become apparent from the examples and figures, wherein:

Fig. 1 is a flow chart of a method according to embodiments of the present invention;

Fig. 2 illustrates an experimental setup used to measure the electrical bio-impedance on ex-vivo pig eyes;

Fig. 3a illustrates retinal vessels filled with blood before contact with an electrode for calibrating reference height;

Fig. 3b illustrates flushing of blood away from a retinal vessel when applying pressure on the vessel;

Fig. 4 is a plot of probe electrode-retina distance and measured impedance magnitude as a function of time, as the probe electrode is moved towards and away from the retina, where a distance of zero denotes the position of the retinal vessel; Fig. 5 is a plot of probe electrode-retina distance and measured impedance phase as a function of time, for the same experiment as in Fig. 4;

Fig. 6 is a plot of probe electrode-retina distance and measured impedance magnitude as a function of time, as the probe electrode is repeatedly moved towards and away from the retina, where a distance of zero denotes the position of the retinal vessel;

Fig. 7 is a plot of probe electrode-retina distance and measured impedance phase as a function of time, for the same experiment as in Fig. 6.

Fig.8 is a sketch of a number of possible probe configurations where different portions of the probe are conductive (shaded in the figure) and other parts are non-conductive. Fig.9 is a sketch of a steerable instrument in straight and bended configuration with an integrated electrode. The figure shows how the distal steerable segment bends out, upon actuation, in a particular direction.

Detailed description of preferred embodiments

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. Where the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated. The term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. Thus, the scope of the expression "a device comprising means A and B" should not be limited to devices consisting only of components A and B. It means that with respect to the present invention, the only relevant components of the device are A and B. Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. Moreover, the terms top, bottom, over, underand the like in the description and the claims are used for descriptive purposes and not necessarily for describing relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other orientations than described or illustrated herein. In the drawings, like reference numerals indicate like features; and, a reference numeral appearing in more than one figure refers to the same element.

Referring to Fig. 1, a method 10 of monitoring a distance between a probe electrode and a target point, in particular a target point in a collection of neurons, is illustrated, according to embodiments of the present invention, in a system wherein the probe electrode and a receiving electrode are positioned relative to the target point such that, in use, current is driven between the probe electrode and the receiving electrode via the target point. The method comprises the steps of receiving impedance measurement results between the probe electrode and the receiving electrode for at least three different probe electrode-target point distances (step SI), and determining whether a stationary point exists in the impedance (step S2). Optionally, the method also comprises outputting a signal in dependence upon the presence or absence of a stationary point (step SB). The first step of receiving impedance measurement results may include a step of measuring impedance.

A stationary point in the context of the present invention is a point in a graph representing the impedance in function of probe distance to the target point, where the graph changes direction. In such point or at least the close vicinity thereof the function's derivative is zero. This means that the stationary point is that point at which the impedance, which generally decreases with decreasing distance of the probe electrode to the target point, suddenly starts increasing again when the probe electrode is at a particular distance close to the target point.

By making use of a stationary point in the impedance for control of the probe electrode target point spacing, a more accurate and robust method is provided. Three is the minimal number of impedance measurements needed to determine whether a stationary point is present, but more than three measurements can be made, for example where noise is present. Given an appropriate sampling frequency and low-pass filter on the acquired impedance data, the presence of a stationary point can be determined more reliably.

In a first example configuration wherein the collection of neurons, hence the target point, is comprised in a retina of an eye, the probe electrode can be positioned spaced apart from the retina within the saline solution that fills the eye. The receiving electrode can be positioned at the back side of the head. In use, a current is driven along a path which goes from the probe electrode to the receiving electrode via the neurons.

In a second example configuration wherein the collection of neurons, hence the target point, is comprised in a retina of an eye, the receiving electrode can be positioned on the eye which is not penetrated by the probe electrode. As the optic nerves of both eyes are connected by the optic chiasm, in use a current is driven along a path which goes from the probe electrode to the receiving electrode via the neurons and the optic chiasm.

In an example configuration wherein the collection of neurons, hence the target point, is comprised in a wall of the heart, the probe electrode can be located on a tool meant for operating on the heart and the receiving electrode can be positioned on the opposite side of the heart to the point which is intended to be operated on. In use, a current is driven along a path which goes from the probe electrode to the receiving electrode via the neurons.

By "a collection of neurons" it is meant a group of neurons in an organ of the human or animal body. For example, embodiments of the present invention are applicable in brain neuronal response studies. In such a study, it is important for the accuracy of the measurements to keep a set distance between a probe and a point on the brain which is being monitored. Thus the target point for the method according to embodiments of the present invention is located on the brain surface, and the collection of neurons is the collection of neurons in the brain.

Another application of the present invention is in cardiac ablation treatment. An ablation catheter is positioned within the heart and applies heat to an area of the heart wall with the aim of correcting faulty electrical pathways in the heart. The positioning of the catheter with respect to the heart wall is important in the success of the procedure: overshoot of the optimal position can result in unwanted damage to the heart tissue, and undershoot of the optimal position can result in insufficient ablation being carried out. The target point for the method according to embodiments of the present invention in this case is the point to be ablated on the heart wall, and the collection of neurons is the collection of neurons in the heart.

Another application, which will be described in more detail hereinafter, is in retinal surgical procedures where the point of a needle is to be positioned accurately with respect to a retinal vein. The collection of neurons is the collection of neurons of the retina and the target point is a point in the collection of neurons of the retina. As the distance from the top of a vein to the surrounding retinal neurons is generally small, the method can be used for determining the distance from the needle point to the retinal vein. In use, current is mainly driven through the least electrically resistive path between the probe electrode and the receiving electrode. The path depends on the electrical conductivity of the nearby anatomy. As all anatomical structures in the eye are highly conductive, the least resistive path generally involves a distributed area of the retina including the targeted vein and surrounding retinal neurons located between the probe electrode tip and the receiving electrode. The output signal may be an alert or a stop signal if a transition is detected. The output signal may be a "continue" signal if no transition is detected. Alternatively, no output signal may be provided if no transition is detected. The output signal may be provided to a human operator of the electrode or apparatus which comprises the electrode, for example a visual or audio or tactile feedback signal. The output signal may be provided to a processor or control module, for example a control module of an apparatus for controlling the position of the electrode. The control module may be configured to control the position of the electrode in dependence upon the output signal.

Setup to measure the electrical bio-impedance and distance

In RVO, the cannulation of the clotted vessel usually takes place in 0.9% saline solution. This means that the eyeball is filled with an electrically conductive liquid, namely an electrolyte. The surrounding organic tissue is also electrically conductive. Such properties allow a current to flow. The measured electrical bioimpedance will depend mainly on the tissue properties, the distance into the saline solution, the electrode geometry and the contact surface driving the electrical current.

Referring to Fig. 2, in an experimental setup 20 for measuring the electrical bio impedance, part of the setup is placed under a microscope (not shown), for instance a stereoscopic microscope, to target precisely, in the embodiment explained, the retinal vessels, which are the anatomical structures of interest for cannulation. A probe 21 having a conductive electrode 22, for instance a stainless steel 100 pm outer diameter electrode, is used as the probe electrode. In embodiments of the present invention, the conductive electrode 22 may be present all around the probe 21. In alternative embodiments, the conductive electrode 22 may be present at one side of the probe 21 only. Different embodiments of probe and conductive electrode configurations are illustrated in FIG. 8. In the embodiment illustrated in FIG. 2, the tip 38 of the probe 21 forms the conductive probe electrode 22. The probe electrode 22, for instance the electrode tip 38, may be insulated from the remainder of the probe 21, for instance with a Teflon tube, to provide a dedicated tip length, for instance a tip length of 10 mm. The dedicated tip length limits impedance measurement over the selected tip surface. Alternatively, as illustrated in Fig. 2, the probe 21 may be conductive over a longer length; it may even be completely conductive. Alternatively, the conductive part of the probe may be offset with a certain distance from the tip 38 of the probe 21. In the setup illustrated, the probe with its probe electrode 22 is attached to a vertical linear micro-manipulator 23 (e.g. M-423, Newport company, California), which is mounted, via a rigid L-profile 35, on a horizontally positioned linear micro-manipulator 24 (e.g. M-423, Newport company, California). In the setup illustrated the attachment is realized by sandwiching the probe between a nonconductive plexi acrylic plate 32 which is screwed with four screws 34 onto the vertical linear micro-manipulator 23 and a second nonconductive plexi acrylic plate 33 that is screwed on the first nonconductive plexi acrylic plate and the vertical linear micro-manipulator 23 with two of the same 34 screws. Thanks to this layout there is no low-resistance path between the probe 21 and the micro manipulators 23 or 24. The micro-manipulators 23, 24 are equipped with accurate measurement devices, e.g. Vernier Micrometers 25, in their manipulation directions (SM- 25, Newport company, California) so that dedicated step changes, e.g. 1 pm step changes, can be made in the position of the probe electrode 22. In the displayed embodiment precise vertical displacement is realized by adjusting the vertical measurement device Vernier Micrometer. The movable portion of the micro-manipulator 23 onto which the non-conductive plexi acryl plates 32 and 33 and probe 21 are clamped will then move relative to L profile 35. Below this stage, in the embodiment illustrated, ex-vivo enucleated pig eyes (not shown, and an example only) are positioned on a frame 26 such that the probe electrode 22 can vertically approach a targeted retinal vessel of the ex-vivo enucleated pig eyes. The probe electrode 22 is wired, via a e.g. a crocodile clamp 31 and an electrical cable 36 to a real-time impedance measurement device 27 (Quadra, Eliko company, Estonia). This device 27 measures impedance magnitude and phase at 15 different excitation frequencies at 1kHz sampling frequency, measuring impedance magnitudes from 1 kQ to 100 kQ with 0.5 % accuracy. The data is acquired e.g. with a processing system 40 or by USB communication with a computer. At the same time, a distance sensor 28 (e.g. Laser OADM12I6460 S35A, Baumer company, Switzerland) that is mounted on the non- conductive plexi acryl plate 33 and therefore also fixed to the vertical micro-manipulator 23 measures the vertical displacement of the probe electrode 22 relative to a reflective plate 29, for instance a reflecting metallic plate, fixed on a common base plate 50 upon which the micro-manipulator 24 and the frame 26 are mounted. The sensor 28, in the embodiment illustrated, is positioned to work in its most accurate range with a resolution of about 2 pm and measures at 100 Hz sampling frequency. The laser position is acquired via an Ethercat communication by the processing device 40 or the computer. Hence, synchronous acquisition of both types of data allows deriving any correlation that exists between the impedance magnitude/phase and the electrode tip 38 to target point, e.g. retinal vessel of the pig eye, spacing.

Electrical model of the measurement setup in the eyeball

A crocodile clip 30 as receiving electrode is clamped to the optic nerve of the eye. This receiving electrode is connected via an electrical cable 37 to the real-time impedance measurement device 27. The probe electrode 22 is brought into contact with the saline solution that fills the eye (not shown). It is expected that a resistive behavior prevails at high excitation frequencies, while lower frequencies undergo more a capacitive behavior. This behavior is equivalent to a resistor in series with a capacitor. At high frequencies, the capacitance (imaginary part) becomes negligible compared to the resistance (real part). The resistor represents the intrinsic resistive behavior of the saline solution and tissue but depends also on the electrode geometry and contact surface. The capacitance originates from a phenomenon known as double layer capacitance. When applying a voltage difference, charges accumulate at the probe electrode 22 interface with the saline

solution creating a layer involving a parasitic capacitive effect. The electrical model is therefore according to equation 1: where R_s is the resistance of the tissue and saline solution,) represents the imaginary part, w is the excitation frequency and C_s is the double layer capacitance. Preferably the excitation frequency w is set to a value which results in a relatively small contribution from the parasitic capacitance effect due to less time for charges to accumulate at the probe electrode/ electrolyte interface. For example, the excitation frequency is preferably set to a value which results in impedance phases having a magnitude higher than -45°, more preferably higher than -25°, still more preferably higher than -10°.

It can also be seen from equation 1 that the imaginary part tends to zero as w increases. This means that the probe electrode will mainly measure the resistive behavior of the electrolyte.

Impedance-distance profile

To measure the relation between impedance and distance, ex-vivo enucleated pig eyes were cut half open to access the retinal vessels. The vitreous humour was removed and replaced by 0.9 % saline solution. The eye was then placed on a stand 26 (see Fig. 2). A crocodile clip 30 as receiving electrode was attached to the optic nerve of the eye. Another crocodile clip 31 was attached to the backside of the probe electrode 22. Hence, the voltage difference is applied between the outer shell of the eye via the optic nerve and the probe electrode 22. In in-vivo conditions, the receiving electrode is attached to a point which is in conductive contact with the optic nerve, such that the excitation voltage is established between the probe electrode and the receiving electrode via the optic nerve. For example, the receiving electrode may be attached to the other eye and the conductive contact occurs via the optic nerve of the other eye through the optic chiasm to the optic nerve of the eye being monitored. The receiving electrode may be attached to the backside of the head, since the visual processing takes place in the occipital lobe of the brain. The patient's hair could be shaved so as to allow placement of a receiving electrode on the skin.

The electrical impedance varies as a function of the distance between the probe electrode 22 and the targeted retinal vessel. In order to determine the actual height of the vessel relatively to the setup, a first contact was established with the targeted retinal vessel. This offset was recorded by the laser 28. This calibration step was for characterization purposes and may not be applicable for in-vivo surgery. By touching the vessel V slightly, the blood is pushed away and the vessel V turns white in colour, establishing the contact with the probe electrode tip T as shown in Fig. 3a (before contact) and Fig. 3b (after contact). Such a contact provides an approximate estimate of the vessel depth, as the operator chooses when the vessel is sufficiently indented. The variation on this registration step is estimated to be on average 100 pm given the visual feedback and the reading of the Vernier Micrometer 25. Experiments with 10 pig eyes were conducted according to the above described setup and procedure. The impedance was characterized for a range of probe electrode-vessel distances from 0 to 5 mm. Different excitation frequencies were investigated. Fig. 4 and Fig. 5 show the magnitude and phase under the largest excitation frequency of the impedance measurement device 27 (Quadra, in the embodiment illustrated), namely 349 kHz. Fig. 5 shows a superposition of the distance to the vessel measured by the laser 28 and the impedance phase measurement. Fig. 4 shows how the impedance magnitude decreases with the distance until it rises at a distance close to the vessel. This transition was observed consistently over all the tests. From the experiments, it was found that the transition takes place at a distance of 775pm ± 275pm. In Fig. 5, the minimum impedance phase is approximately -6.5°. A purely capacitive behavior would imply a phase of -90° vs a purely resistive behavior with 0°. Thus the experiment operates with close to purely resistive behavior.

According to embodiments of the present invention this stationary point in the impedance as a function of probe electrode-retina spacing can be used to control the spacing of the electrode and the retina by providing a signal of retinal proximity.

Transition detection

The transition, or stationary point, observed in Fig. 4 is a specific pattern in impedance magnitude that allows an active boundary to be established, for example by providing an alert to a surgeon when the probe electrode passes the transition point, thus signaling the proximity to the retina. This is in contrast to the impedance magnitude which depends on many parameters such as the eye condition, the anatomical structures involved in the electrically stimulated zone, the medium in which the electrode or tool is being moved, the excitation frequency at which the tissues are stimulated, the electrode contact surface conducting the current. The transitional pattern described herein is common to all the measurements.

In order to detect this transition, a detection algorithm was designed that combines the impedance magnitude at 349 kHz with the measured electrode speed. The transition is symmetric with probe electrode-retina distance as shown in Fig. 4. When approaching the vessel , the electrode may issue a stop signal alerting the operator to the proximity to the retina if a transition is detected. The motion direction of the electrode relative to the retina may be used to differentiate when the practitioner is aiming at the vessel or retracting it, respectively when the speed is negative and positive. The detection algorithm for detecting the transition, in embodiments of the present invention may proceed as follows:

The distance d_ei,i does not necessarily need to be measured by a laser, for example the distance could be measured by encoders embedded on a system manipulating the electrode or any kind of distance sensing allowing to report the insertion depth of the probe electrode.

In the algorithm, a_t is a gain that determines a threshold based on which the algorithm determines that there is movement in a particular direction. The value of a_t is typically a positive value that is determined in advance e.g. by relying on prior knowledge on the noise of the velocity measurements, that can be derived e.g. based on prior experience in similar settings or by any other means.

In the algorithm, the

is considered negative when approaching the surface. In other cases where the speed is considered positive when approaching the surface the condition for detecting a transition in the algorithm would be

The impedance magnitude derivative d | Z | ,-i can be measured at time step i-1 or it can be estimated by applying any suitable kind of filter on the data that is obtained up to and including time step i-1.

The impedance magnitude derivative d | Z | , can be measured at time step i or it can be estimated by applying any suitable kind of filter on the data that is obtained up to and including time step i.

The above algorithm was tested over 5 ex-vivo enucleated pig eyes prepared as described hereinbefore. The raw data from the distance sensor (laser sensor 28) and the impedance measurement device (Quadra 27) were filtered with a low-pass filter, for instance a Butterworth low-pass filter. Once a retinal vessel was chosen, 10 round-trips were conducted starting at a distance of 4 or 5 mm away from the vessels. 50 round-trips were performed in total. Fig. 6 displays the measured impedance magnitude and the probe electrode-retina distance over time. A binary value overlays the graph reporting when the algorithm detects the transition close to the retina vessel, namely 0 for no detection and 1 if the transition is detected. The initial region of constant impedance follows from calibration of at the start of each cycle. a_t was experimentally determined to be 0.08

on one of the eyes and was kept constant at this value for the 4 other pig eye experiments. Over the 50 round-trips, 49 out of 50 transitions close to the vessels were detected. No transition was reported outside the expected probe electrode-retina distance range of 775±225pm . Thus the algorithm automatically detected the transitions with a sensitivity of 98% and a specificity of 100%. The single undetected transition exhibits noise that is significantly higher than in the other round trips.

The transitions in impedance magnitude were seen in all experiments. This measure can thus be used to assess proximity of the retinal vessel. In Fig. 6, a drift over time in the impedance magnitude can be seen. The drift was found to be in the range of 3 to 30 mQ/s over the experimental timespan. The total drift over each experiment was measured as 5% to 66 % of the peak to peak magnitude (ranging from 15 to 20 W) of a round-trip. To mitigate this drift, for example noble metal electrodes could be used in place of stainless steel electrodes to remove possible galvanic currents, allowing use of the impedance magnitude as well as the transition detection for distance control. Another way to tackle this problem would be to measure the electrical bio-impedance with a four-electrodes systems (two electrodes sensing the voltage and two electrodes exciting the system with a controlled current) instead of a two-electrodes system.

The impedance magnitude is strongly dependent on the contact surface of the electrode 22 and the crocodile clip 30. In the experiments described herein, the electrically conductive tip 22 of the probe 21 is fully plunged inside the saline solution up to the insulator edge of the electrode. This helps to prevent variations in currents as the tip is aiming at the retinal vessel. It is possible that the crocodile clip 30, acting as receiving electrode, clamped to the optic nerve may not be applying the same contact from one experiment to another. The measured magnitude minima and maxima over the 50 round- trips was 388 W ± 39 W at the minima and 410 W ± 38 W at the maxima. Advantageously, distance monitoring according to embodiments of the present invention is not affected by variations in impedance magnitude between sets of impedance measurements for a particular approach or retreat from the retina, as the detection of a possible transition is independent of any impedance magnitude offset due to variations in electrode contact conditions. However, the change in impedance magnitude between sets of impedance measurements may be decreased by reducing and scaling down the contact surface of the receiving electrode relative to the scale of the supporting structure which is the optic nerve in this case.

Impedance phase

Forthe same 50 round trips, the impedance phase was also computed. Forthe round-trips shown in Fig. 6, the impedance phase is shown in Fig. 7. Over the 5 pig eyes, the range of the impedance phase peak to peak values was estimated to be 0.92° ± 0.24°.

The impedance phase ranged over the experiments over [-9.78° ± 0.5°; -9.25° ± 0.5°]. The fastest observed drift was 5*10⁴ degrees per second. The total drift over each experiment varied from 0% to 19 % of the peak to peak phase range for a roundtrip (which ranged from 0.6 to 1.1°). The impedance phase may be less sensitive to drift than the impedance magnitude. At a sufficiently high frequency excitation voltage, parasitic capacitance effects can be significantly reduced such that the impedance is substantially resistive, for example where the magnitude of the impedance phase is less than 10°. As a matter of fact, equation 1 suggests that the phase tends to 0 as the pulsation frequency w increases. It can be seen that the phase becomes more capacitive when approaching the retinal vessel, or equivalently the phase becomes more negative. As the electrode approaches the vessel, the resistance of the saline solution path decreases whereas the capacitance is mainly unaffected. From equation 1, the phase can be computed as shown in equation 2:

confirming that the phase decreases as R_s decreases. Thus the phase may additionally or alternatively be used to give position feedback. The probe electrode may be incorporated into a needle to sense vessel proximity during cannulation. The needle may be mounted on a co-manipulation system such as that described in (Andy Gijbels, Niels Wouters, Peter Stalmans, Hendrik Van Brussel, Dominiek Reynaerts, and Emmanuel Vander Poorten. Design and realisation of a novel robotic manipulator for retinal surgery, 2013 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS), pp. 3598-3603) allowing a surgeon to damp out tremors and accurately puncture a retinal vessel. The system may be used for active damping control using a method according to embodiments of the present invention, based on impedance magnitude alone or on a combination of impedance phase and magnitude. A possible control strategy would be to increase the damping applied to the instrument to maximum damping when detecting the transition in impedance magnitude. In this case, the encoders from the co-manipulation system could be used to estimate the speed of the instrument. A second relevant strategy could be simply to inform the practitioner of the vessel proximity with any suitable kind of feedback, for instance some kind of audio feedback. The surgeon could then adapt the robot damping himself. Humans can react to an audio feedback within 200 ms. Nominal instrument speeds can be considered at 500 pm/s. This means the practitioner could stop the needle within 100 pm. This is reasonable considering that the transition happens at 775pm ± 275pm from the retinal vessel. In addition, such an approach can be beneficial in retinal membrane peeling. The surgeon has to approach the retina, grab the retinal layer and peel it off by circling the instrument within the workspace of the eyeball. Proximity sensing methods according to embodiments of the present invention are an easy and affordable way to set up a virtual bound. Embodiments of the present invention provide a computer program product comprising instructions which, when the program is executed by a computer operatively linked to an apparatus for monitoring a distance between a probe electrode and a target point as in an aspect of the present invention, cause the apparatus to carry out the steps of a method as described herein. The computer may comprise a processor, means for receiving inputs, for example signals or data, and means for providing outputs, for example signals or data. For example, the means for receiving inputs and the means for providing outputs may comprise one or more of a USB or Ethernet port or other wired connection port, a wireless or Bluetooth antenna or card. The computer may be configured to connect through the means for receiving inputs to one or more other devices, such as an impedance measurement device. The computer may be configured to connect through the means for providing outputs to one or more other devices, such as a device for providing auditory alerts, visual cues, haptic cues or any other communication means, based on a signal received from the computer.

Modifications It will be appreciated that many modifications may be made to the embodiments hereinbefore described. The probe electrode may be a cannulation needle comprising a glass pipette sputtered with an electrically conductive coating. A stainless steel protective sleeve can be slid over the needle tip to protect it during insertion, for example insertion into an eyeball.

The output signal could be displayed by haptic or tactile feedback which could be applied to and felt by the practitioner.

The algorithm explains how the results from Fig. 4 to Fig. 7 were obtained. In practice the distance, filtered distance or electrode speed can be obtained from other sensors, such as from OCT, from optical tracking systems, from proprioceptive sensors such as resolvers, encoders, galvanometers or accelerometers which signals are processed and/or filtered to obtain estimates of distance, motion or speeds, when the instrument is mounted on a robot, a motion platform or a passive manipulator with measurement functionality or any other type of sensory system.

Furthermore, in practical use, the stationary point detection algorithm may be developed without knowing the actual distance to the substrate but by simply steering the instrument towards the surface, recording the change in impedance and by marking the location in the vicinity of the surface (which could be performed blindly or confirmed visually by using magnifying lenses, a microscope or similar) where the impedance shows a transition pattern. In any of such embodiments, aside from the impedance, an indication of the direction of motion whether it is towards the surface of interest or away from the surface of interest would suffice for the method of the invention to work. The motion direction could be obtained from any type of sensor that captures the relative displacement between the instrument and the surface or it could also be indicated approximately by the operator that could convey the intention to move towards or away from the surface e.g. by pushing on any kind of button or foot pedal to communicate his/her intention to the system. In some embodiments one may opt for sake of simplicity not to take into account whether or not the instrument is approaching or retracting from the surface. In this scenario disregarding the motion direction a signal will be generated each time the transition in the impedance signal is passed, independent of whether it is during the approaching or the retraction phase. The interpretation of which phase it concerns could be left to the user.

In an embodiment of the invention the information whether or not the instrument is moving towards the surface or moving away from the surface is not obtained from an additional sensor or from human input, but is obtained directly from the variations of the phase that is measured, whereby in line with equation 2 the instrument is estimated to be moving towards the surface upon a decrease of the phase (the phase becomes more negative) and is estimated to be moving away from the surface upon an increase in impedance phase (the phase becomes less negative). In an embodiment of the invention the transition could be communicated both during the approaching and the retracting phase whereby the way of communicating upon approach or retraction may be different. E.g. in case of auditory cues a high or low pitch may be generated during approach phase and a low or high pitch during retraction. The operator may be informed in such case to be extra careful upon approach and to be able to relax his/her attention upon retraction.

Where the present invention describes an instrument containing a probe electrode that is exposed at the tip 38 of the probe 21 allowing measuring the distance between the tip 38 and the target point, e.g. the collection of neurons, in other embodiments the electrode 22 may be exposed at a predetermined distance (larger than 0 mm) from the tip 38 of the probe 21, whereby the remaining part distal to the probe electrode 22 until the tip 38 of the instrument is produced from non-conductive material. The distance from the probe electrode 22 to the tip 38 of the probe 21 may be chosen advantageously such that upon detection of the transition point the tip 38 is at a preferred distance to the target point which may be larger or smaller than the typical distance where a transition in impedance takes place. The distance may be chosen such that upon detection of the transition in impedance, the tip 38 makes contact with the target point or penetrates a surface containing the target point over a particular desired distance. Such configuration could be advantageous e.g. in the case where one wants to implement a motion- compensation scheme based on the said invention and where one wants to update the estimate of the period, the phase or the distance between the moving organ and the instrument, while controlling the instrument tip at a certain distance, in contact with or inserted over a predetermined amount relative to the surface. The probe electrode 22 may be configured in such a way that it reaches the tip 38 of the probe 21 or that it reaches up to a predetermined distance away from the tip 38 of the probe 21, whereby the configuration is established such that it preferentially occupies one side or a portion of a side of the tip 38 of the probe 21 or of a portion close to but at a distance of the tip 21, whereas the other side or the remainder of the portion of the probe 21 is non-conductive. Such embodiment would be advantageous to determine the relative orientation or inclination of the probe 21 with respect to the target point, e.g. the collection of neurons, as when executed in sufficient close proximity to the collection of neurons the orientation or inclination of the probe could be derived by detecting a stationary point in the impedance amplitude. For instance, when rotating the probe 21 about an axis that is e.g. parallel to the longitudinal axis thereof, the electrode 22 would subsequently come closer to and go further away from the target point, e.g. the collection of neurons, in a similar way that the non-conductive material would come closer to and go further away from the target point, e.g. the collection of neurons. The probe 21 could be rotated in such a manner that one or more stationary points would arise in the impedance signal. Based on this stationary point or set of stationary points, the orientation where e.g. the electrode 22 is the closest to the target point, e.g. the collection of neurons, or the electrode 22 is the farthest away from the target point, e.g. the collection of neurons, or any intermediate appropriate orientation of the electrode 22 with respect to the target point, e.g. the collection of neurons, could be obtained. A similar approach could be followed to determine the inclination of the probe 21 with respect to the target point, e.g. the collection of neurons, whereby one could re-orient the probe 21 in such a manner with respect to the tissue such that the distance of the tip 38 of the probe 21 with respect to the target point, e.g. the collection of neurons, would stay constant, but where the distance of the electrode 22 itself, when put at an offset from the tip 38 of the probe 21, to the target point, e.g. the collection of neurons, would vary when yawing or pitching the probe 21 relative to the target point, e.g. the collection of neurons. Through detection of stationary points in the impedance amplitude one could determine an advantageous inclination of the probe 21 relative to the target point, e.g. the collection of neurons.

An example of an application whereby the above embodiment would be of interest is in CTO (Coronary Total Occlusion) where one or more catheters are introduced in the coronaries in order to remove the occlusion of the coronary by crossing the occlusion and placing a stent to keep the formerly occluded vessel open. In some treatments the catheter or a guidewire is maneuvered through the vessel wall and more particularly through the media of the vessel and passed aside the occlusion. After having passed the occlusion it is a challenge to steer the catheter or guidewire back into the true lumen beyond the occlusion. More in particular it is difficult to determine in which direction to steer the tip of the catheter or guidewire. In accordance with embodiments of the present invention, the catheter or guidewire can be provided with a probe electrode 22 at one of its sides. Such catheter could then be employed, whereby the catheter or guidewire is rotated about its axis (or any other maneuver is conducted) to determine when the distance to the true lumen becomes minimal. A receiving electrode may be mounted on a second catheter or guidewire that is introduced in the true lumen at the side where the crossing catheter or guidewire is to come out of the media into the true lumen. At present such second catheter or guidewire is often used for visual guidance. As under fluoroscopic vision the lumen is hardly visible, but catheters and guidewires are visible, the second catheter or guidewire forms a visual landmark indicating where the lumen is and hence towards which direction to steer the first catheter or guidewire. This technique is known in general, and is referred to as the kissing technique. While one can visually confirm that the guidewires are moving towards or away from each other, it is currently not possible to know in which direction to steer the first guidewire or catheter such that it would move towards the second catheter. This technique could be made more reliable, in accordance with embodiments of the present invention, if based on detecting the stationary points in the impedance measurements the relative orientation of both catheters could be determined. The first catheter could namely be moved about its longitudinal axis, impedances could be measured and when a stationary point is reached the first guidewire or catheter could be moved in a direction determined by the location of this stationary point.

For example, assume a steerable guidewire or catheter with a distal section that can bend in a certain direction e.g. by pulling on a pull wire as depicted in Fig. 9 where upon pulling the wire the distal bendable section of length L bends and takes on a circular shape which, without loss of generality is located in the XY plane of a coordinate frame that is attached at the base of the distal bendable section. By pulling the cable the bending angle grows to angle b, whereby for example b, the radius R of the circle and the length of the distal section relate as L = R* b. Now, assume that without loss of generality, the electrode is located in the XY-plane at one side of the guidewire or catheter body and that the guidewire or catheter is rotated about its longitudinal axis until a stationary point is found, this would indicate that the second catheter is located also in the XY plane and that at this point pulling on the wire will make the first catheter bend towards the second catheter. Such or similar strategies can be implemented to steer the guidewire or catheter more reliably in a desired direction.

In another embodiment the second catheter or guidewire could be controlled to rotate about its axis or both the first and the second catheters or guidewires could be controlled jointly such as to rotate relative to each other based on the impedance values until reaching a stationary point or reaching a relative orientation defined relative to a stationary point.

Although embodiments of the method are described in the context of retinal vein occlusion treatment, the method is not limited to use in such situations and may be used in any situation which requires monitoring of the distance between a probe electrode and a retina. For example, subretinal surgery involves subretinal injection in cases such as gene or cell therapy. When retinal cells or genes are faulty and/or damaged, they cause partial blindness. Degenerations due to these pathologies are tackled by injecting functional copies of the faulty genes (for gene therapy) or healthy retinal pigment epithelium (RPE) cells (for cell therapy) at the back of the eye. Embodiments of the present invention allow to control the position of the injection instrument, which acts as a probe electrode, relative to the retina by outputting a signal depending on whether a stationary point is detected. The output signal could be provided to a device for controlling the position of the injection instrument, thus allowing the position to be corrected depending on whether a stationary point is detected. For example, if the injection tool-retina distance is decreased and a stationary point is detected, the tool could be moved further from the retina in order to maintain a preset tool-retina distance.

Although embodiments of the method are described in the context of target points being neurons of the retina, the present invention is not limited to use in such situations and may be used in any situation which requires monitoring of the distance between an electrode and a target point in a collection of neurons. For example, the study of neuronal responses in the brain requires position control to stabilize an electrode and measure the action potential. A specific example is the investigation on how sound signals are processed by different auditory nuclei as the signals propagate through the brain. The relative motion between neuron and micro electrode for measuring the action potential due to physiological motion e.g. induced by heart beat and breathing makes this measurement complicated. Embodiments of the present invention allow to control the position of the electrode relative to the neuron by outputting a signal depending on whether a stationary point is detected. The output signal could be provided to a device for controlling the position of the electrode, thus allowing the position to be corrected depending on whether a stationary point is detected. For example, if the electrode- neuron distance is decreased and a stationary point is detected, the electrode could be moved further from the neuron in order to maintain a preset electrode-neuron distance.

An alternative use could be e.g. to measure the amplitude and the phase of the physiological motion from a safe distance. For example, at close vicinity, but without making contact, the interval of (local) physiological motion could be estimated by measuring the time interval between subsequent occurrences of stationary points in the impedance. The phase could be characterized as the time within a cycle where the stationary point arrives. This information could then be used to establish a motion compensation system that regulates the position at a constant distance from a collection of neurons. In order to make gentle contact with the neuron (for measurement of the neuronal response), an increasing reference offset displacement could be added on top of the above motion-compensation control commands to incrementally approach the targeted (and moving) neuron. In an alternative embodiment the electrode could be positioned statically at a safe but nearby distance and the estimated physiological motion could be used to adjust the control of one or other secondary instruments for which physiological motion compensation would be advantageous.

Another example is motion control in heart surgery. The heart has its own collection of neurons meant to ensure its functioning. A specific example is the treatment of Atrial Fibrillation (AFib), affecting over 33.5 million patients worldwide. RadioFrequency Ablation is a common treatment for this disease where a catheter is inserted through the radial artery or femoral artery to reach the left atrium of the heart. Once the targeted area is reached, the anatomical structures responsible for AFib are ablated. Embodiments of the present invention allow to control the position of the catheter relative to a target point in the collection of neurons of the heart by outputting a signal whether a stationary point is detected, thus allowing compensation for physiological motion such as that caused by the beating of the heart. The output signal could be provided to a device for controlling the position of the catheter, thus allowing the position to be corrected depending on whether a stationary point is detected. For example, if the catheter-target distance is decreased and a stationary point is detected, the catheter could be moved further from the target in order to maintain a preset electrode-target distance. An alternative use according to embodiments of the present invention is to measure the amplitude and the phase of the heartbeat from a safe distance. E.g. at close vicinity, but without making contact to the beating heart-wall, the interval of (local) heartbeat can be estimated by measuring the time interval between subsequent occurrences of stationary points in the impedance. The phase can be characterized as the time within a cycle where the stationary point arrives. This information can then be used to establish a motion compensation system that regulates the position at a constant distance from the heart wall. This approach can also be used to follow the heart-wall in contact. E.g. in RFA of AFib one ideally ablates the heart wall with a constant force between 10 and 40 gram force. By combining the abovementioned motion-compensation scheme (e.g. in feedforward) with a force control scheme e.g. after having established contact with the heart wall it is possible to simplify the work by a force controller aiming to establish a constant force contact with the beating heart wall. A further application concerns the use during administration of regional anesthesia. E.g. for peripheral nerve blocks nerves need to be localized prior to injecting the anesthetic. When an injection needle is introduced, the needle needs to be moved in the close vicinity of the targeted nerves. Care should be taken that the needle is progressed sufficiently. At the same time the needle should not be placed too close or into the nerve as this could cause a nerve injury. Electrical nerve stimulation is one manner to estimate the distance to the nerve, whereby in the vicinity of the nerve an electrical stimulus is generated which, when close enough, causes the nerve to depolarize and induce a muscular contraction. Clinicians estimate the distance to the nerve by observing muscular contraction. This method requires careful observation, is subjective and occupies the attention of the surgeon. A method whereby a stationary point is detected in the impedance spectrum could offer a more objective approach that requires less attention as the presence of the stationary point could be signal with auditory, visual or other cues. Ultimately, it could form the base of an automatic injection system that allows clinicians to focus on other parts of the procedure.

Claims

1. Apparatus (20) for monitoring a distance between a probe electrode (22) and a target point, comprising:

the probe electrode (22) and a receiving electrode (30) suitable for being positioned relative to the target point such that, in use, current is driven between the probe electrode (22) and the receiving electrode (30) via the target point; an impedance measuring device (27) coupled to the probe electrode (22) and to the receiving electrode (30); and

a processor (40) coupled to the impedance measuring device (27);

wherein the processor (40) is configured for receiving at least three probe electrode - receiving electrode impedance measurements for at least three different probe electrode - target point distances, and for determining from the at least three measurements whether a stationary point exists in the impedance.

2. The apparatus of claim 1, wherein the processor (40) is further configured for outputting an output signal in dependence upon the presence or absence of a stationary point.

3. The apparatus of claim 2, wherein the processor (40) is configured for outputting any of an audio signal, a visual signal, a tactile or a kinaesthetic signal.

4. The apparatus of any of claims 2 or 3, further comprising a control system configured for receiving the output signal and for, based on the received output signal, dynamically controlling one or more of the position, velocity or acceleration of one or more devices.

5. The apparatus of claim 4, wherein the control system is configured for, based on the received output signal, dynamically controlling one or more of the position, velocity or acceleration of the probe electrode.

6. The apparatus of any of the previous claims, wherein the probe electrode is comprised in a cannulation needle.

7. The apparatus according to any of the previous claims, wherein the impedance measuring device (27) is adapted for measuring the impedance at a frequency such that the magnitude of the phase of the impedance measurements is greater than -25°

8. A method of monitoring a distance between a pre-implanted probe electrode and a target point, in a system wherein the pre-implanted probe electrode and a pre implanted receiving electrode have been positioned relative to the target point such that, in use, current is driven between the pre-implanted probe electrode and the pre-implanted receiving electrode via the target point, the method comprising the steps of:

receiving at least three probe electrode-receiving electrode impedance measurements for at least three different probe electrode-target point distances; and

determining whether a stationary point exists in the impedance.

9. The method of claim 8, further comprising outputting an output signal in dependence upon the presence or absence of a stationary point.

10. The method of claim 9, wherein outputting an output signal comprises outputting any of an audio signal, a visual signal, a tactile or kinaesthetic signal.

11. The method of any of claims 9 or 10, further comprising using the output signal for dynamically controlling the position, velocity and/or acceleration of one or more other devices.

12. The method of any of claims 8 to 11, wherein receiving at least three probe electrode-receiving electrode impedance measurements comprises performing at least three probe electrode-receiving electrode impedance measurements.

13. The method of claim 12, wherein performing the at least three probe electrode receiving electrode impedance measurements comprises performing impedance measurements at a frequency selected such that the magnitude of the phase of the impedance measurements is greater than -25°.

14. A computer program product comprising instructions which, when the program is executed by a computer operatively linked to an apparatus (20) for monitoring a distance between a probe electrode (22) and a target point as in any of claims 1 to 7, cause the apparatus to carry out the steps of the method of any of claims 8 to 13.