Detection of neural activity

Abstract

An intervention device 110 for detecting neural activity is provided. The intervention device includes a magnetic sensor 120 coupled to an insertable portion of the intervention device. The magnetic sensor 120 is configured to generate a signal in response to a magnetic field generated by neural activity. A system 200 is also provided. The system includes the intervention device 110 and a controller 140 configured to receive the signal generated by the magnetic sensor 120 and output a detection result indicating neural activity in response to the received signal.

Description

Technical Field

[0001] The present disclosure relates to the detection of neural activity. An intervention device, system, computer-implemented method, and computer program product are disclosed.

Background Art

[0002] The assessment of neural activity is performed in various medical procedures to investigate neurological behavior. For example, brain function is monitored via electroencephalogram recording "EEG". Neural activity can also be monitored during renal denervation. Renal denervation is an interventional procedure for treating drug-resistant hypertension, i.e., elevated blood pressure. Renal denervation is typically performed by excising the (sympathetic) nerves between the central nervous system and the kidney, usually in the vicinity of the renal artery. This procedure is typically performed using an intervention device such as an ablation catheter. The effect of the ablation procedure is to remove the stimulant for hypertension. However, the relatively low clinical success rate of renal denervation, measured via a long-term decrease in blood pressure, presents an obstacle to its widespread adoption, combined with the high cost of the procedure. Quantification of neural activity may help increase the clinical success rate of renal denervation. The improvement of the procedure may involve more accurate localization of the nerves, better stratification of patients for denervation therapy, and more direct and comprehensive verification of the success of the procedure.

[0003] When a nerve is activated, it induces an electrical impulse often called an "action potential" that propagates in the forward direction along the associated nerve fibers, and thus seemingly transmits a pulse. It is difficult to quantify the action potential without piercing the tissue to bring the electrode very close to or into contact with the nerve fiber. Such drawbacks impede the electrical measurement of neural activity. However, the time-varying electrical impulse within the nerve fiber generates a magnetic field around the nerve fiber. This magnetic field is in the range of less than picotesla and enables the measurement of neural activity using magnetic sensors.

[0004] To measure the activity of nerve cells, i.e., neurons, various magnetic sensors have been used. For example, in magnetoencephalogram "MEG" systems, surface sensors are placed around the head. Magnetic sensors such as induction sensors, superconducting quantum interference device "SQUID" sensors, and optically pumped magnetometer "OPM" sensors have been used to sense the magnetic fields generated by the activity of neurons in the brain. The strength of this magnetic field rapidly decreases with the distance from the neuron or nerve. However, the cumulative magnetic field generated by a large number of neurons can be detected by magnetic sensors placed on the skin, i.e., at a few centimeters from the source. Similar sensors have been used in magnetocardiogram "MCG" systems to monitor the magnetic fields emitted by the pulsating heart from the surface position. In the MCG system, magnetic sensors are placed near the heart on the chest. In this setting, millions of nerves and muscle fibers are simultaneously activated, generating a cumulative signal strong enough to be detected by sensors placed on the skin several centimeters away from the nerves.

[0005] However, the magnetic fields emitted by some nerves can be much smaller. This is the case for renal nerves, which contain only a few hundred to a few thousand nerve fibers. The renal nerves are located in the adventitia (outer layer) of the renal artery wall and extend along the renal artery. The magnetic fields generated by the renal nerves rapidly decay with distance, and as a result, they are too small to be sensed by surface sensors placed on the skin. Therefore, to detect the magnetic fields generated by some types of nerves such as renal nerves, it is necessary to insert magnetic sensors into the body and position them close to the nerves of interest. This, in turn, imposes constraints on the size of the magnetic sensors that can be used to detect nerve activity in an invasive setting. Also, the magnitude of the magnetic field close to the nerve varies greatly depending on the sensing position. Furthermore, it may be difficult to obtain accurate measurements of the magnetic fields from the nerves in the presence of magnetic interference from other sources.

[0006] WO2013 / 096461A1 describes an apparatus for locally monitoring nerve activity that can be incorporated into a nerve ablation catheter. The catheter comprises magnetic sensing for identifying nerves and evaluating the success of ablation. The catheter also comprises an ablation instrument for stimulating and destroying nerve tissue. In the disclosed apparatus, a magnetic sensor is configured to sense a magnetic field generated in response to artificial activation of a nerve by the ablation instrument. Summary of the Invention Problems to be Solved by the Invention

[0007] However, there remains a need to improve the detection of induced and / or natural nerve activity in an intervention device. Means for Solving the Problems

[0008] According to one aspect of the present disclosure, an intervention device for detecting nerve activity is provided. The intervention device includes a magnetic sensor. The magnetic sensor is coupled to an insertable portion of the intervention device. The magnetic sensor is configured to generate a signal in response to a magnetic field generated by nerve activity.

[0009] According to another aspect of the present disclosure, a system is provided. The system includes an intervention device and a controller. The controller is configured to receive a signal generated by the magnetic sensor and output a detection result indicating nerve activity in response to the received signal.

[0010] Further aspects, features, and advantages of the present disclosure will become apparent from the following description of examples made with reference to the accompanying drawings. Brief Description of the Drawings

[0011]

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DETAILED DESCRIPTION OF THE INVENTION

[0012] Examples of the present disclosure are provided with reference to the following description and drawings. In this description, for purposes of explanation, numerous specific details of the specific examples are set forth. As used herein, references to "examples," "embodiments," or similar language mean that a feature, structure, or characteristic described in connection with the example is included in at least one example. Also, it should be understood that features described in connection with one example may be used in another example, and not all features are necessarily repeated in each example for the sake of brevity. For example, features described in connection with an intervention device may be implemented in a corresponding manner in a system, and also in a computer-implemented method and a computer program product.

[0013] In the following description, an intervention device including a magnetic sensor is referred to. The magnetic sensor is configured to generate a signal in response to a magnetic field generated by neural activity. In some examples, an intervention device in the form of an ablation device is referred to. In some examples, the ablation device is an ablation catheter. However, it should be understood that the intervention device may alternatively be a type of device different from a (RF / high-frequency ultrasound "HIFU" / microwave) ablation device. For example, the intervention device may alternatively be a (guide) catheter, a (RF / high-frequency ultrasound "HIFU" / microwave) ablation catheter, a guide wire, an intravascular ultrasound "IVUS" device, an optical coherence tomography "OCT" device, a blood pressure sensing device and / or a blood flow sensing device, or a TEE probe, etc. Thus, the intervention device can generally be any type of intervention device.

[0014] This specification also refers to an example in which an interventional device in the form of an ablation device is used in renal denervation procedures. An exemplary ablation device is provided in the form of an ablation catheter adapted for insertion into the renal artery. However, this functions only as an example, and it should be understood that the interventional device can generally be configured for insertion into the body. The interventional device may be configured for insertion into various tissues in the body or for insertion into various lumens in the body. In some examples, the interventional device is configured for intravascular insertion, i.e., insertion into a vein or artery. Alternatively, it is contemplated that the interventional device can be configured for insertion into other lumens of the body, including, for example, the gastrointestinal tract, colon, esophagus, lung, urinary tract, nasal cavity, etc. Also, in some applications, it is contemplated that the interventional device may be used in open surgery. Further, it should be understood that the interventional device can generally be used in clinical procedures and the device is not limited to use in the exemplary renal denervation procedures described herein. The interventional device may be, for example, a sensing device where a magnetic field is sensed and no treatment is performed at all.

[0015] Reference is also made to operations performed by a controller. As will be described in more detail below, the controller may include one or more processors for performing some of these operations. Note that the operations performed by the controller may be provided in the form of a computer-implemented method. A computer-implemented method may be provided as a non-transitory computer-readable storage medium storing computer-readable instructions that, when executed by at least one processor, cause the at least one processor to perform the method. In other words, a computer-implemented method may be implemented in a computer program product. A computer program product may be provided by dedicated hardware or by hardware capable of executing software in association with appropriate software. When provided by a processor or controller, the functionality of the method features may be provided by a single dedicated processor, or by a single shared processor, or by multiple individual processors some of which may be shared. One or more of the functions of the method features may be provided by processors shared within a networked processing architecture such as, for example, a client / server architecture, a peer-to-peer architecture, the Internet, or the cloud.

[0016] The explicit use of the terms "processor" or "controller" should not be construed as exclusively referring to hardware capable of executing software, but can implicitly include, but is not limited to, digital signal processor "DSP" hardware, read-only memory "ROM" for storing software, random access memory "RAM", non-volatile storage devices, etc. Further, examples of the present disclosure can take the form of a computer-usable storage medium, or a computer-readable storage medium accessible computer program product, which provides program code for use by or in connection with a computer or any instruction execution system. For the purposes of this description, a computer-usable storage medium or a computer-readable storage medium can be any device capable of having, storing, communicating, propagating, or transporting a program for use by or in connection with an instruction execution system, apparatus, or device. The medium can be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system or device or propagation medium. Examples of computer-readable media include semiconductor or solid state memory, magnetic tape, removable computer disk, random access memory "RAM", read-only memory "ROM", rigid magnetic disk, and optical disk. Current examples of optical disks include compact disk read-only memory "CD-ROM", compact disk read / write "CD-R / W", Blu-Ray (registered trademark), and DVD.

[0017] As described above, there remains a need to improve the detection of induced and / or natural neural activity in an intervention device.

[0018] FIG. 1 is a schematic diagram showing a cross-section of a blood vessel VES covered by a bundle of nerve fibers BNF 1..3 and an example of an intervention device ID, according to some aspects of the present disclosure. For example, the blood vessel VES shown in FIG. 1 may represent a renal artery of a subject, and the bundle of nerve fibers BNF 1..3 may represent renal nerves. The bundle of nerve fibers BNF 1..3It may be desirable to measure the activity of the renal nerves represented by during a clinical trial. For example, it may be desirable to measure the activity of the renal nerves in order to stratify patients for treatment with a given treatment. Patient stratification may have criteria by which the eligibility of a patient for successful renal denervation treatment can be predicted or calculated. The intervention device ID may be, for example, a sensing catheter inserted into the body from the inguinal region and navigated to the renal artery VES via the vasculature. The intervention device ID may be advanced through the vasculature via a guiding catheter to the renal artery. After reaching the renal artery VES, a portion of the intervention device ID may be placed near the wall of the blood vessel VES 1..3 to measure the magnetic field emitted by the renal nerves represented by one of the bundles of nerve fibers BNF 1..3 . As another example, it may be beneficial to measure the magnetic field emitted by the renal nerves represented by one of the bundles of nerve fibers BNF 1..3 during a therapeutic treatment for the renal nerves. In this example, the intervention device ID may be an ablation catheter. Continuing to refer to FIG. 1, treatment of the renal nerves may include applying energy from an ablation catheter to one of the bundles of nerve fibers BNF 1 to suppress their activation and thereby treat the subject's hypertension. The ablation catheter can apply heat, high-frequency ultrasound "HIFU", microwave, radio frequency "RF", or another form of ablation energy through the wall of the blood vessel VES to the bundle of nerve fibers BNF 1 to treat the bundle of nerve fibers BNF 1 . During an ablation treatment procedure, it may be beneficial to measure the activity of the treated bundle of nerve fibers BNF

[0019] to determine the effectiveness of the treatment. As described above, when a nerve is activated, the nerve transmits an electrical impulse, often called an "action potential", along the associated nerve fibers. FIG. 2 is a schematic diagram showing an example of a typical action potential signal on a nerve fiber according to some aspects of the present disclosure. The action potential shown in FIG. 2 may be, for example, the bundle of nerve fibers BNF shown in FIG. 1 1..3It can be generated by one of them. The action potential shown in FIG. 2 represents the potential at a point on a nerve fiber as an electrical impulse passes through. Before any activation, the potential on the nerve fiber is at a resting potential of about -70 mV. A stimulus is applied at time T 0 In addition. If the stimulus is large enough, i.e., it is greater than the threshold potential V of about -55 mV TH When greater, depolarization occurs during period I of FIG. 2, and then repolarization occurs during period II. After the refractory period III, the potential on the nerve fiber returns to the resting potential of about -70 mV during period IV.

[0020] The action potential signal shown in FIG. 2 can be seen as a wave generated by successive depolarization and repolarization across the nerve cell membrane (axon) and caused by the movement of those ions across its successive ion channels. The net current does not flow along the nerve fiber as would be expected in an electrical wire. The nature of the propagating wave of the action potential signal is due to a small delay between depolarization and repolarization and the fact that the previous channel cannot be reactivated immediately because it has not yet been repolarized. The movement (or toggling) of ions across one channel of the cell membrane triggers the next channel after a specific delay, and so on. From a fixed point on the nerve, the electrical impulse appears as a time-varying action potential.

[0021] The typical action potential signal shown in FIG. 2 was used to generate a model for simulating the magnetic field that can be measured in the vicinity of a nerve fiber. Various aspects of this model are shown in FIG. 3, which is, according to some aspects of the present disclosure, a) an example of a model of a nerve fiber extending along and adjacent to a blood vessel lumen, b) a schematic diagram showing a modeled electric dipole current representing depolarization and repolarization of a nerve fiber. Generally, the wave-like propagation of an action potential along a nerve fiber involves charge (ion) toggling in a plurality of channels arranged along the nerve at different times, making it difficult to capture in a biophysical model. This destabilizes the problem along a relatively large spatial distance along the nerve fiber. Thus, in the model shown in FIG. 3, the estimated magnetic field distribution around the renal nerve was modeled by approximating the action potential as a current flowing in opposing electric dipoles aligned with the direction of the nerve fiber, as shown in FIG. 3a). The electric dipoles shown in FIG. 3a) have a combined length L. The resulting currents I and I’ are shown in FIG. 3b). This approximation transforms the unstable problem into a steady-state model, and the opposing dipoles model depolarization and repolarization as if they were permanent.

[0022] The results of the simulation performed using the model in FIG. 3 are shown in FIG. 4, which is, according to some aspects of the present disclosure, a) a simulated magnetic flux density, and b) a schematic diagram showing an example of the corresponding streamlines around a nerve fiber. FIG. 4 represents a snapshot at a particular time at a fixed position next to the nerve. The simulated magnetic flux density shown in FIG. 4 has an axially symmetric magnetic field around the nerve fiber.

[0023] However, in reality, both the electrical impulses and magnetic fields generated by nerve activation propagate along the nerve fiber. Further, the magnetic field shown in FIG. 4 represents only the magnetic field generated by a single nerve fiber. These drawbacks of the model were captured in a more detailed model.

[0024] In a more detailed model, the propagation of the magnetic field was modeled by assigning a constant propagation speed v to pairs of opposing dipoles. An electromotive force was also defined inside the dipoles to generate local currents in the range of 50 to 100 nA. Further, in reality, a nerve bundle contains thousands of fibers. Although the activation of the nerves within the bundle is synchronized, the differences between the nerve fibers within the bundle are due to the propagation of the action potential, resulting in dynamic magnetic field signals with different arrival times for each fiber. In a more detailed model, the effect of a bundle of nerve fibers was modeled using a Gaussian distribution of the arrival times of the magnetic field signals of the fibers within the bundle.

[0025] The results of simulations performed using this more detailed model are shown in FIG. 5, which is a diagram showing, according to some aspects of the present disclosure, a) a model of the dipole current in a nerve fiber using a sensor arranged at a radial distance r, b) the predicted magnetic flux density resulting from the modeled dipole current, c) the predicted magnetic flux density at various radial distances r, and d) an example of the distribution of the arrival times of the magnetic flux density used to generate the predicted magnetic flux density in c). The magnetic flux density signal shown in FIG. 5c) has an amplitude of up to about 1.5 pT depending on the radial distance between the sensor and the nerve bundle. This is consistent with the typical radial decrease of the magnetic field around a dipole reported in the literature. Further, it should follow a power law with n in the range of about 1 to 3 depending on the distance, type of nerve, and number of fibers. The simulations show that measurements of the magnetic field generated by the renal nerves can be performed using a magnetic sensor with a sensitivity of a few picotesla when the sensor is located within a few millimeters of the nerve bundle. The results of this more detailed model were then used to design a magnetic sensor for detecting nerve activity.

[0026] Various examples of an intervention device including a magnetic sensor for detecting nerve activity are described below. The magnetic sensor can be used to measure a magnetic field generated by nerve activity, such as the activity of the renal nerves, as described above with reference to FIG. 1. In general, the magnetic sensor disposed on the intervention device may be used to measure a magnetic field generated in response to artificial activation of the nerve or may be used to measure a magnetic field generated by natural, i.e., spontaneous activation of the nerve.

[0027] FIG. 6 is a schematic diagram showing an example of an intervention device 110 for detecting nerve activity according to some aspects of the present disclosure. In the illustrated example, the intervention device includes a magnetic sensor 120. The magnetic sensor 120 is coupled to an insertable portion of the intervention device, i.e., is insertable into a body cavity such as, for example, the renal artery. The magnetic sensor 120 is configured to generate a signal in response to a magnetic field generated by nerve activity.

[0028] Referring to FIG. 6, in this example, the intervention device 110 is a catheter. The catheter includes an insertable portion that is inserted into the lumen LUM of the blood vessel VES shown in FIG. 6. Thus, in this example, the insertable portion of the intervention device is sized for insertion into a blood vessel. The magnetic sensor 120 can generally be coupled to any location on the insertable portion of the intervention device. For example, the magnetic sensor 120 may be coupled to the distal end of the insertable portion or at a position proximal to the distal end of the insertable portion. In the illustrated example, the magnetic sensor 120 is coupled to the intervention device at a position proximal to the distal end of the insertable portion of the catheter. In general, the magnetic sensor 120 can be coupled to any position on the insertable portion of the intervention device, and the intervention device can be insertable into any region of an anatomical structure.

[0029] Continuing to refer to FIG. 6, the magnetic sensor 120 generates a signal in response to a magnetic field generated by neural activity. The signal can be transmitted to a controller such as controller 140 shown in FIG. 6. Generally, the generated signal may be an optical signal or an electrical signal. For example, in the implementation described below where the magnetic sensor is provided by an optically pumped magnetometer "OPM", the generated signals are optical signals, and these are optically transmitted to the controller 140 via an optical fiber that delivers light illumination to the optical cell of the OPM. Optically transmitting the signal avoids the risk of generating a magnetic field that can interfere with the operation of the magnetic sensor 120. The signal can alternatively be transmitted wirelessly. The controller 140 may process the signal to output a detection result indicating neural activity, as will be described in more detail below.

[0030] The magnetic field sensed by the magnetic sensor 120 can be generated by nerves such as the bundle of nerve fibers BNF shown in FIG. 6 1 Generally, neural activity may be artificially triggered or may be triggered naturally, i.e., spontaneously. In the former case, neural activity may be triggered by applying a stimulus from within a blood vessel VES, i.e., an intravascular location, or more generally from an in-body location, or alternatively by applying a stimulus from a location outside the body, i.e., an extracorporeal location. Neural activity can be triggered using various techniques, including those involving the delivery of electrical energy, RF energy, thermal energy, and tactile stimuli. In one example, the intervention device is an intravascular RF ablation device, and neural activity is stimulated by means of RF energy from the intravascular RF ablation device to the nerve.

[0031] Continuing to refer to FIG. 6, the magnetic sensor can be disposed within the blood vessel VES such that the magnetic sensor is adjacent to or in contact with the wall of the blood vessel VES to detect a magnetic field generated by the bundle of nerve fibers BNF 1 This magnetic field rapidly attenuates with the separation between the nerve fiber and the magnetic sensor, and thus, when the magnetic sensor 120 is in the illustrated position, it is the bundle of nerve fibers BNF 1a bundle of nerve fibers BNF that is much weaker than the contribution from 2 can detect the contribution from.

[0032] The magnetic sensor 120 shown in FIG. 6 can be provided by various types of magnetic sensors. For example, the magnetic sensor 120 can be provided by an optically pumped magnetometer “OPM” as described above. FIG. 7 is a schematic diagram showing a first example of a magnetic sensor 120 including an optically pumped magnetometer according to some aspects of the present disclosure. Referring to FIG. 7, the OPM has an optical cell 130 containing an alkali metal in a liquid and / or gas phase. The alkali metal may be, for example, rubidium, cesium, or potassium. The OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the alkali metal. The magnetic field-dependent optical property may be, for example, the direction of the atomic spin of the alkali metal.

[0033] Referring to FIG. 7, an exemplary optical cell 130 includes a tubular member surrounded by optical windows at its axial ends and, in combination with the tubular member, serves to contain an alkali metal in its liquid and / or gas phase. As an example, the optical cell 130 shown in FIG. 7 can have a diameter of about 1 millimeter or less such that the optical cell 130 can be coupled to an intervening device and inserted into a subject. In some examples, the optical cell 130 has a diameter of about 0.5 millimeter or less, a length of about 3 millimeters, and a resulting volume of 1 cubic millimeter or less. A bundle of nerve fibers BNF 1 is also shown in FIG. 7. As described above with reference to FIG. 4, a bundle of nerve fibers BNF 1 neural activity in generates a magnetic field. A bundle of nerve fibers BNF 1To detect the magnetic field generated thereby, light irradiation is input into the optical cell 130 via the input optical fiber IPF and the input lens IPL. The light irradiation irradiates the liquid and / or the gas-phase alkali metal within the optical cell 130. The light irradiation may be provided by a laser (not shown in FIG. 7) having a wavelength corresponding to the resonance frequency of the atoms of the alkali metal. The laser may be controlled by the controller 140 shown in FIG. 6. The laser provides a polarized beam passing through the optical cell 130. In some examples, the beam may have circular polarization. At resonance, the atomic spins of the alkali metal atoms within the optical cell 130 are aligned with the propagation direction of the laser radiation. A change in the magnetic field in the vicinity of the optical cell deflects the atomic spin direction, which causes a change in the amount of radiation transmitted through the optical cell 130. In other words, the direction of the spin of the atoms of the alkali metal is susceptible to the influence of the magnetic field. In the example shown in FIG. 7, the radiation transmitted through the optical cell is collected by the output lens OPL and coupled via the output optical fiber OPF to a photodetector (not shown in FIG. 7). A polarizer may be included in the optical path to measure the transmittance of a specific polarization. In one example, the photodetector may be provided by a polarimeter. The photodetector measures the amount of radiation transmitted through the optical cell 130 with a specific polarization, thereby determining the intensity of the magnetic field in the vicinity of the optical cell in a specific plane.

[0034] Variations of the above-described embodiments of the OPM are also contemplated.

[0035] In one example, the optical cell 130 of the OPM further includes a background gas. In this example, the OPM is further configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the background gas. The background gas may include, for example, helium. In this example, the direction of the spin of the atoms of the background gas, such as helium, is also susceptible to changes in the magnetic field. The magnetic field generated by neural activity may be detected via a change in the spin of helium atoms in the optical cell 130 in a manner similar to that described above for alkali metal atoms. In other words, by irradiating the optical cell 130 containing helium gas and a liquid and / or gaseous alkali metal, a change in the transmission of the optical cell resulting from the deflection of the atomic spin directions of both the helium gas and the alkali metal can be measured to detect the magnetic field. Laser radiation at a wavelength different from the resonance of the alkali metal atoms may be used to induce the resonance of the helium atoms. This allows the transmittance measurements of helium and the alkali metal to be performed separately.

[0036] By using the model described above with reference to FIGS. 2 through 5, the inventors have determined that detection of the magnetic field generated by the renal nerves from a position within the renal artery can be achieved by placing a magnetic sensor having a sub-picoTesla sensitivity a few millimeters from the bundle of nerve fibers. The inventors have also determined that the magnetic field sensitivity of the OPM cell is determined by the density of atoms per unit volume in the gas phase within the cell. The magnetic field sensitivity of the OPM cell is given by the formula: Resolution (picoTesla) ∝ 1 / √(n·V) can be described by, where n represents the density of atoms per unit volume of the gas phase within the cell, and V represents the volume of the cell. In this equation, lower values of resolution correspond to more sensitive OPM cells. Furthermore, the atoms must be in the gas phase in order to allow for free spins in appropriate quantum states. In the case of alkali metals such as rubidium, the boiling point is higher than room temperature. Therefore, the optical cell must be heated to reach the gas phase. Above the boiling temperature, the atomic density n per unit volume of the gas phase within the cell is significantly dependent on temperature. Further increases in the temperature of the cell result in larger densities n and increased sensitivity of the OPM. In contrast, helium has a boiling point that is significantly lower than room temperature or body temperature, and as a result, substantially all helium atoms are in the gas phase at these temperatures. Consequently, the magnetic field can be detected via changes in the spins of helium atoms at room temperature or body temperature. Heating has little effect on the sensitivity of optical cells containing helium. The pressure can be increased in optical cells containing helium so as to increase the atomic density n per unit volume of the gas phase, assuming that the helium remains in the gas phase. However, n remains lower than in the case of heated alkali metals such as rubidium, cesium, or potassium, and as a result, the expected sensitivity of an OPM with helium is lower than that of an OPM containing an alkali metal.

[0037] Generally, higher atomic densities n increase the relaxation time of atomic transitions between quantum states. Therefore, the bandwidth of the OPM is inversely proportional to the atomic density n. As a result, there is an upper limit to the atomic density within the optical cell for sufficient bandwidth of the device.

[0038] An OPM can be provided that includes an optical cell containing both a background gas such as helium and a liquid and / or gas phase alkali metal, such that the optical cell can operate in a relatively low sensitivity mode in which the optical cell is not heated and the magnetic field generated by neural activity is detected via changes in the spins of atoms of the background gas, e.g., helium, and in a relatively high sensitivity mode in which the optical cell is heated and the magnetic field generated by neural activity is detected via changes in the spins of atoms of the alkali metal.

[0039] Thus, in some examples, the OPM described with reference to FIG. 7 also includes a heater configured to supply heat to the optical cell. In this regard, the use of various types of heaters is contemplated. The heater may include, for example, a resistive element thermally coupled to the housing of the optical cell 130. In this example, electrical energy can be delivered to the resistive element via an electrical wire that extends along the length of the intervention device to the controller 140. To avoid the risk of interference between the magnetic field generated by the current in the resistive heater and the magnetic sensor 120, the heater may be operated in a pulse mode, as described later with reference to FIG. 12, and the magnetic field is sensed by the magnetic sensor 120 during a period after the supply of electrical energy to the heater is switched off. Alternatively, the heater may be provided by a light absorber thermally coupled to the housing of the optical cell. In this example, for example, the same laser used to irradiate the optical cell, or a second laser emitting a light wavelength different from the wavelength of the laser irradiating the optical cell, may be coupled to the light absorber. The light absorber is configured to absorb the light wavelength emitted by the light source. When the same laser is used to irradiate and heat the optical cell, the input optical fiber IPF may deliver the light irradiation from the laser to a beam splitter, which directs a first portion of the irradiation from the laser to the light absorber and a second portion of the irradiation from the laser to the optical cell. When a second laser is used to heat the optical cell, a second optical fiber may be used to couple the irradiation from the second laser to the light absorber. The use of the second laser separates the operation of heating the optical cell from the operation of detecting the magnetic field through changes in the spin direction of the atoms in the optical cell. The use of a light absorber in combination with such a light source may provide a heater having a smaller geometry than a resistive heater and also reduce the risk of generating a magnetic field that can interfere with the magnetic sensor 120.

[0040] The inventors have also found that, as described above, by heating the optical cell, a significant improvement in the sensitivity of the above-described OPM can be achieved, but these improvements come at the expense of the need to insulate the OPM or remove the heat dissipated by the OPM to prevent damage to the tissue. For example, in one design, at a temperature of 50°C, the OPM cell can achieve a sensitivity of about 150 femtotesla, while by heating the OPM cell to a temperature of about 100°C, the OPM cell can achieve a five-fold improvement in sensitivity to about 30 femtotesla. To achieve such an optical cell temperature within the intervention device without damaging the tissue, in one approach, insulation may be provided to limit the rate of heat energy escaping from the OPM, thereby limiting the temperature rise on the outer surface of the OPM. In another approach that can be combined with the previous approach, the heat dissipated by the OPM can be removed from the OPM using a cooling configuration. In this regard, the use of various cooling configurations is contemplated. In some of these cooling configurations, the medium into which the intervention device is inserted is used to remove the dissipated heat. In one example, the OPM has a housing configured to provide thermal contact between the OPM and the medium into which the intervention device is inserted. In this example, heat is removed from the OPM by the medium. When the medium is blood, for example, the flowing blood can be used to remove a significant amount of heat. The thermal contact may be provided by forming the OPM housing from various thermally conductive materials such as metal, which can form a thermal path between the OPM housing and the medium. In a related example that can be used in combination with the previous example, the OPM is in thermal contact with the outer surface of the intervention device 110 to cool the OPM through the outer surface of the intervention device. By providing such thermal contact to the intervention device, heat is dissipated through the intervention device, which limits the temperature of the OPM and thereby reduces the risk of damage to the tissue in thermal contact with the OPM. In another example that can be used in combination with any of the previous examples, the intervention device includes a channel configured to supply a cooling fluid to the OPM. The channel may extend along the length of the intervention device such that the cooling fluid can be supplied to the OPM from a location external to the subject.The channel can be coupled to an open circuit source of cooling fluid, or a source of cooling fluid such as a closed circuit heat exchanger. The cooling fluid can include, for example, water or saline.

[0041] In these examples that include a heater, the intervention device can also include i) a temperature sensor in thermal contact with the outer surface of the intervention device, or ii) the optical cell 130. The temperature sensor can be used to monitor and control, as described below, the temperature of the outer surface of the intervention device or the optical cell 130, respectively.

[0042] The sensitivity of the OPM described with reference to FIG. 7 can also be improved by measuring the transmittance of the light beam that passes through the optical cell 130 multiple times. In this case, each pass of the light beam has an incremental effect on the measured transmittance. Thus, in one example, the OPM is configured to measure the transmittance of the light beam passing through the optical cell 130 to generate a signal in response to the magnetic field generated by neural activity, and the OPM has a plurality of optical elements configured to provide a plurality of paths for the light beam passing through the optical cell 130.

[0043] In this example, the optical element may be provided by a reflective element and / or a lens in combination with an optical fiber. Two embodiments of this example are described with reference to FIGS. 8 and 9. FIG. 8 is a schematic diagram showing a second example of the magnetic sensor 120 including an optically pumped magnetometer according to some aspects of the present disclosure. The example shown in FIG. 8 includes elements also represented in FIG. 7. Elements of FIG. 8 having the same labels as in FIG. 7 provide the same functions as described with reference to FIG. 7. Compared to FIG. 7, FIG. 8 further includes a plurality of reflective elements MIR configured to provide a plurality of paths for the light beam irradiating the optical cell through the optical cell 130 1..4 FIG. 9 is a schematic diagram showing a third example of the magnetic sensor 120 including an optically pumped magnetometer according to some aspects of the present disclosure. The example shown in FIG. 9 includes elements also represented in FIG. 7. Elements of FIG. 9 having the same labels as in FIG. 7 provide the same functions as described with reference to FIG. 7. Compared to FIG. 7, FIG. 9 includes a plurality of lenses LEN 1..4further includes an optical fiber LOF, which is configured to provide a plurality of paths of the light beam irradiating the optical cell via the optical cell 130.

[0044] The inventors have also observed that a drawback of some existing magnetic sensors is that they cannot provide information regarding the position of the nerves that contribute most to the detected magnetic field level. As can be understood from FIG. 1, the magnetic sensor disposed on the intervention device ID at the illustrated position can detect the magnetic field generated by the nerve fiber bundle BNF 1 However, the signal generated by such a sensor provides little information regarding the direction in which the nerve fiber bundle BNF 1 is disposed. The physician knows only the direction in which the nerve fiber bundle BNF 1 is disposed by moving the magnetic sensor towards the nerve fiber bundle and observing the associated increase in the detected magnetic field. If the direction of the nerve fiber bundle BNF 1 is known before moving the magnetic sensor, it helps the physician to place the magnetic sensor closer to the nerve fiber bundle.

[0045] In one example, the magnetic sensor 120 includes a plurality of magnetic sensor elements, and each magnetic sensor element is configured to detect a magnetic field across different volumes of the intervention device.

[0046] This example can be used to improve the placement of the sensor with respect to the nerve fiber bundle. This example is described with reference to FIG. 10, which is a schematic diagram showing a fourth example of a magnetic sensor 120 including an optical pumping magnetometer according to some aspects of the present disclosure. The example shown in FIG. 9 includes elements also represented in FIG. 7. Elements in FIG. 10 having the same labels as in FIG. 7 provide the same functions as described with reference to FIG. 7. In FIG. 10, there are four magnetic sensor elements. Each magnetic sensor element includes an input lens IPL 1..4 and an input optical fiber IPF 1..4 configured to couple light irradiation to a portion of the optical cell 130, and a corresponding output lens OPL configured to collect light irradiation from a portion of the optical cell and couple the collected light irradiation to a photodetector1..4 and an output optical fiber. Each part of the optical cell represents a sensing volume in which a magnetic field is sensed by the magnetic sensor element. The parts of the optical cell are defined by the cell wall CWL 1..4 The cell wall confines the gas within the optical cell to individual sensing volumes. The strength of the magnetic field across each sensing volume is determined by measuring the transmittance of light irradiation through each part of the optical cell in the manner described in connection with FIG. 7. The OPM120 shown in FIG. 10 is also coupled to the interventional device as described above. By doing so, each of the magnetic sensor elements can be used to detect a magnetic field across different volumes of the interventional device.

[0047] In the above example, the measurement of the magnetic field strength in each of the different volumes of the interventional device provides the user with information regarding how to reposition the interventional device so as to move it towards the nerve. For example, in the example shown in FIG. 10, since the uppermost optical path is closest to the bundle of nerve fibers BNF 1 the magnetic field measured in this optical path as a result of nerve activity in the bundle of nerve fibers BNF 1 will be higher than the magnetic field measured in the lower optical path of FIG. 10. Thus, the direction in which the nerve is located can be determined based on a comparison of the values of the magnetic field strengths measured in different volumes of the interventional device.

[0048] In another example, the interventional device described with reference to FIG. 6 also includes an expandable balloon or basket. The balloon or basket is coupled to the insertable portion of the interventional device to fix the insertable portion of the interventional device within the lumen when the expandable balloon or basket is in an expanded state. This example can be used, for example, to provide magnetic field measurement values at a fixed position within the lumen without being affected by the movement of the subject, the movement of the heart, blood flow, etc.

[0049] The exemplary interventional device described above may form part of a system 200 that includes a controller 140. The controller 140 receives the signals generated by the magnetic sensors and outputs a detection result indicating nerve activity in response to the received signals.

[0050] FIG. 11 is a schematic diagram showing an example of a system 200 including an intervention device 110 for detecting neural activity and a controller 140 according to some aspects of the present disclosure. The example shown in FIG. 11 includes the elements also represented in FIG. 6. In FIG. 11, the system 200 includes the intervention device 110 and the controller 140 described in connection with FIG. 6. Elements in FIG. 11 having the same labels as in FIG. 6, such as the intervention device 220, provide the same functions as described above with reference to FIG. 6. The controller 140 shown in FIG. 11 may include one or more processors and / or electronic circuits. The one or more processors and / or electronic circuits are configured to perform various operations described with respect to the controller. For example, the controller may include a photodetector and electronic circuits that each detect and amplify the received signals. The controller may also include an analog-to-digital converter “ADC” that digitizes the signals, and a processor that converts the digitized signals and / or performs further operations on the digitized signals, such that they may be displayed as detection results on a display device such as a monitor.

[0051] The various detection results can be output by the controller 140. In one example, the detection result includes a signal generated by the magnetic sensor 120, i.e., a time-dependent signal representing the time-dependent magnetic field generated by neural activity. In another example, the detection result includes the magnitude of the signal generated by the magnetic sensor 120, i.e., a signal representing the magnitude of the magnetic field generated by neural activity. In another example, the detection result includes an estimation of the separation between the magnetic sensor 120 and the nerve that generated the neural activity. The estimated value of the separation between the magnetic sensor 120 and the nerve can be determined based on the magnitude of the signal generated by the magnetic sensor. The model described above with reference to FIGS. 2 through 5 can be used in FIG. 5 to provide a look-up table that associates the magnitude of the signal with the separation r. In another example, the detection result includes an indicator of the state (e.g., healthy, unhealthy) of the nerve that generated the neural activity. In another example, the detection result includes a measurement of sympathetic overdrive in the nerve that generated the neural activity. In another example, the detection result includes the suitability for the nerve that generated the neural activity to be treated by renal denervation therapy. The suitability can be evaluated by determining the distance between the magnetic sensor 120 and the nerve that caused the detected neural activity based on the detected magnetic field strength. If the distance is too large, the cell wall may be damaged by operating the ablation device, and / or the nerve may not be sufficiently ablated. Alternatively or additionally, the suitability may be evaluated based on the signature of the detected signal as described later with reference to FIG. 14. For example, the magnitude of sympathetic overdrive can be determined from the signature, and this magnitude is used to determine the suitability of the nerve for treatment by renal denervation therapy. In another example, the detection result includes a measure of the effectiveness of the renal denervation procedure performed on the nerve that caused the neural activity. The measure of the effectiveness of the renal denervation procedure can be determined based on a comparison of the signals generated by the magnetic sensor before and after the renal denervation procedure. As the treatment progresses, the amplitude of the detected magnetic signal decreases until the treated nerve is destroyed.Furthermore, as will be described later with reference to FIG. 14, the signature of the magnetic field pulses generated by the nerves, i.e., the frequency of the pulses within the pulse train and the number of pulses within the pulse train, can also change during treatment. Thus, a measure of the effectiveness of the treatment can be determined by measuring the amplitude and / or signature of the pulses. The user of the system can also be informed that the treatment can be terminated when the desired level of treatment effectiveness is reached, i.e., when the amplitude and / or signature of the pulses reaches the desired state. Other detection results can also be output by the controller 140. The detection results can be output in various forms such as a computer-readable storage medium, a printer, or a display device such as a monitor.

[0052] In one example of the system 200 described with reference to FIG. 11, the intervention device can be translated along the axis of the lumen while generating detection results in order to provide a 2D or 3D map of the detection results. The intervention device can be translated using various manipulators. Changes in magnetic field strength and direction along the scanning path from the nerve are expected to be reproducible. As a result, by translating the intervention device multiple times along the axis of the lumen and generating corresponding maps, detected features that do not appear in multiple maps can be identified as noise or interference and discarded. The combined map can then be generated from the individual maps by selecting maps that do not contain the identified noise or interference and, for example, averaging them or combining maps from which the interference has been removed. The 2D or 3D map of the detection results may be output by the controller 140.

[0053] As described above with respect to the intervention device 110, in some examples, the magnetic sensor 120 has an OPM, and the OPM further has a heater configured to supply heat to the optical cell 130. In one example of the system 200 described with reference to FIG. 11, the controller 140 can be configured to selectively operate the OPM in a relatively low sensitivity mode, in which a relatively low power level is supplied to the optical cell 130 by the heater to generate a signal in response to a magnetic field generated by neural activity, and in a relatively high sensitivity mode, in which a relatively high power level is supplied to the optical cell 130 by the heater.

[0054] In this example, the optical cell 130 can contain one type of alkali metal in a liquid and / or gas phase. The alkali metal can be, for example, rubidium. The two sensitivity levels provided in this way can be used, for example, first to identify the position of a bundle of nerve fibers in a relatively low sensitivity mode and then, after identifying the bundle of nerve fibers, to switch the OPM to operation in a relatively high sensitivity mode to perform a quantified analysis of the identified bundle of nerve fibers. In this example, the relatively low power level can be, for example, negligible or zero power. In this example, changes in the magnetic field in the vicinity of the optical cell are detected via the magnetic field-dependent optical properties of the same alkali metal atoms, i.e., changes in the atomic spin direction, in both the relatively low sensitivity mode and the relatively high sensitivity mode. By operating the OPM in this way, the OPM can consume less power when a relatively low power is applied to the heater, so the temperature or power consumption of the OPM can be reduced. Limiting the temperature or power consumption in this way also limits the risk that the OPM will damage tissue. In this example, the controller can automatically switch between the relatively low sensitivity mode and the relatively high sensitivity mode in response to the detection of a magnetic field in the relatively low sensitivity mode that exceeds a predetermined threshold.

[0055] Alternatively, in this example, the optical cell 130 may instead contain two different types of alkali metals in the liquid and / or gas phase, such as rubidium and cesium, or the optical cell 130 may also contain one type of alkali metal in the liquid and / or gas phase, as well as a background gas such as helium. The two types of alkali metals, or one type of alkali metal and the background gas, can then be used in a similar manner to provide a relatively low-sensitivity mode and a relatively high-sensitivity mode. In this example, a change in the magnetic field in the vicinity of the optical cell is detected via the magnetic field-dependent optical properties of different materials, i.e., different alkali metals, or the background gas and the alkali metal atoms, i.e., changes in the atomic spin direction, in each of the relatively low-sensitivity mode and the relatively high-sensitivity mode.

[0056] In these examples, the optical cell 130 includes an alkali metal in the liquid and / or gas phase and a background gas, and the OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the alkali metal and the background gas. In the relatively low-sensitivity mode, the optical properties of the background gas are sensed, and in the relatively high-sensitivity mode, the optical properties of the alkali metal are sensed. Alternatively, the optical cell 130 includes a first alkali metal in the liquid and / or gas phase and a second alkali metal in the liquid and / or gas phase, and the OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the first alkali metal and the second alkali metal. In the relatively low-sensitivity mode, the optical properties of the first alkali metal are sensed, and in the relatively high-sensitivity mode, the optical properties of the second alkali metal are detected.

[0057] As described above, in some examples, the OPM includes a heater configured to supply heat to the optical cell 130. In these examples, the intervention device may also include a temperature sensor. The temperature sensor may be in thermal contact with either i) the outer surface of the intervention device or ii) the optical cell 130. In one example of the system 200 described with reference to FIG. 11, the controller 140 is configured to operate the heater in response to the temperature measured by the temperature sensor. For example, the heater may be switched on until the temperature detected by the sensor reaches a predetermined value. At this time, the heater may be switched off. The temperature of the heater then decreases as a result of heat dissipation and / or active cooling, after which the heating cycle is repeated. The controller 140 may alternatively or additionally be configured to control the cooling configuration described above in response to the temperature measured by the temperature sensor. For example, the cooling configuration may be activated when the temperature measured by the temperature sensor exceeds a predetermined threshold value.

[0058] By operating the heater in response to the temperature measured by the temperature sensor, the risk of tissue damage can be reduced. The controller may operate the heater in continuous mode or pulse mode. When operating in continuous mode, the controller may operate the heater in a digital manner such that the heater is switched on when the temperature measured by the temperature sensor falls below a desired temperature threshold and the heater is switched off when the temperature measured by the temperature sensor reaches the desired temperature threshold. Alternatively, the controller may operate the heater in continuous mode in an analog manner by using a proportional-integral-derivative controller "PID" feedback loop.

[0059] Alternatively, the controller may operate the heater in pulse mode and use the temperature measured by the temperature sensor to determine when to switch off the heater. An example of the operation of the heater in pulse mode is, according to some aspects of the present disclosure, a) the magnitude P of the power applied to the heater of the optical cell of the OPM HEATER , b) the resulting temperature T of the optical cellCELL 、c) The magnetic field B generated by the activated nerve NERVE 、and d) The signal B generated by the OPM in response to the detection of the magnetic field B NERVE is described with reference to FIG. 12, which is a schematic diagram showing an example thereof. DETECTED

[0060] FIG. 12 shows, in a), the magnitude P of the power applied to the heater of the optical cell of the OPM. HEATER The power P HEATER is applied in pulse mode to limit the amount of power dissipated in the medium into which the OPM is inserted and also to limit the power consumption of the OPM. A certain level of power is applied to the heater at intervals of t 0 - t 1 、t 2 - t 3 、t 4 - t 5 The resulting temperature T of the optical cell CELL is shown in FIG. 12b. This temperature can be measured by a temperature sensor in thermal contact with the optical cell 130. Alternatively, this temperature may be measured by a temperature sensor in thermal contact with the outer surface of the intervening device. In the example shown, the heater periodically applies heat to the optical cell. The heater power supply is switched on at times t 0 、t 2 、t 4 During the intervals when power is applied to the heater, i.e., t 0 -t 1 、t 2 -t 3 、and t 4 -t 5 the temperature of the cell rises until the threshold temperature T Th is reached. When the temperature T of the cell CELL reaches the threshold temperature T Th the power P HEATER applied to the heater is switched off. During the intervals when no power is applied to the heater, i.e., t 1 -t 2 and t 3 -t 4 the temperature T of the cell CELL ​As described above, it is reduced by heat loss to the medium into which the OPM is inserted, or heat loss to the cooling fluid. FIG. 12c shows the magnetic field B generated by the activated nerve NERVE In this example, the nerve is spontaneously activated, at t 0 and t 3 and includes a first set of pulses that overlap with the interval between t 4 and t 5 As seen in FIG. 12d, the magnitude of the signal B NERVE generated by the OPM in response to the detection of the magnetic field B DETECTED is higher in FIG. 12c during the time periods corresponding to the intervals t 0 -t 1 , t 2 -t 3 , and t 4 -t 5 than outside these intervals. This is due to the heating of the optical cell of the OPM and the resulting increase in the sensitivity of the OPM in these intervals. In practice, as shown in FIG. 12d, the signal B DETECTED generated by the OPM is delayed compared to the intervals t 0 -t 1 , t 2 -t 3 , and t 4 -t 5 when power is supplied to the heater. This delay is caused by the time difference between the time when heat is applied to the heater and the resulting cell temperature T CELL . As shown in FIG. 12d, in some cases, the increase in sensitivity may occur only when the cell temperature T CELL exceeds a specific temperature T T . Due to the time difference in the cell temperature after the application of power to the heater, the signal B DETECTED generated by the OPM can therefore be delayed compared to the signal P HEATER as shown in FIG. 12. Thus, in the illustrated example, at least a portion of the spontaneous activation of the nerve in c) is detected. As can be understood, the frequency at which power P HEATER is applied to the heater in FIG. 12a, and the threshold temperature T ThBy adjusting, desired power consumption, cell temperature, and duration of the sensing period can be achieved. Instead of operating in the pulse mode shown in FIG. 12, the OPM may alternatively be operated in the continuous mode as described above, and the applied power P HEATER is continuously adjusted over the entire period according to the measured temperature T CELL of the cell.

[0061] As described above in connection with the intervention device 110, in some examples, the magnetic sensor 120 includes an optically pumped magnetometer OPM, the OPM includes an optical cell 130 containing a liquid and / or gaseous alkali metal, and the OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the alkali metal. In one example of the system 200 described with reference to FIG. 11, the OPM includes a light source configured to provide an optical pump beam, the OPM is configured to measure the magnetic field-dependent optical properties of the alkali metal in response to excitation of the alkali metal in the optical cell 130 by the optical pump beam, and the controller 140 is further configured to modulate the intensity of the optical pump beam between a relatively low intensity and a relatively high intensity, and the OPM is configured to measure the magnetic field-dependent optical properties of the alkali metal by determining the transmittance of the optical pump beam through the optical cell 130 while the optical pump beam excites the alkali metal at a relatively higher intensity.

[0062] In this example, instead of operating the light source of the OPM in continuous mode, the light source is operated in pulsed mode. This has the effect of enabling the system 200 to operate at a reduced level of power. The relatively low intensity may be negligible or may even be zero intensity. This example may be implemented in combination with the previous example. Thus, the pulsed operation of the heater shown in FIG. 12a may be implemented in combination with the modulation of the optical pump beam. Thus, the pulsed operation of the heater may be synchronized with the modulation of the intensity of the optical pump beam such that the heater applies heat to the optical cell when the optical pump has a relatively high intensity.

[0063] As described in connection with the intervention device 110 above, in some examples, the magnetic sensor 120 includes a plurality of magnetic sensor elements. Each magnetic sensor element is configured to detect a magnetic field across a different volume of the intervention device 110. These examples are described with reference to FIG. 10. In one example of the system 200 described with reference to FIG. 11, the controller 140 further measures the signal-to-noise ratio of the signals generated by the magnetic sensor elements, and generates a detection result using the signal(s) from one or more magnetic sensor elements having the highest signal-to-noise ratio. It may be configured as follows.

[0064] Referring to FIG. 10, in this example, an example of a magnetic sensor element is provided by the uppermost optical path within the optical cell 130 closest to the bundle of nerve fibers BNF 1 , OPF 1 and the lens IPL 1 , OPL 1 together with its associated input and output optical fibers IPF 1 In this exemplary configuration, the bundle of nerve fibers BNF 1Activation is expected to generate a signal having a higher signal-to-noise ratio than the lowermost magnetic sensor element in FIG. 10. Thus, in this example, the detection result is generated using the signal from the uppermost magnetic sensor element having the highest signal-to-noise ratio. By using the sensor element or elements having the highest signal-to-noise ratio to generate the detection result, the overall signal-to-noise ratio of the detection result can be improved. This improves the accuracy of the detection result.

[0065] In this example, the signal-to-noise ratio of the signals generated by the magnetic sensor elements can be measured in various ways. For example, a scanning procedure in which each of the individual signals from the separate magnetic sensor elements is measured sequentially may be used. The scanning procedure may include, for example, measuring the signals generated by each of the magnetic sensor elements in a sequence that progresses around the axis of the intervention device. Alternatively, the individual signals from the separate magnetic sensor elements may all be measured simultaneously. By further determining and outputting a signal indicative of the magnetic sensor element having the signal with the highest signal-to-noise ratio, the direction in which the activated nerve is located can be determined. This information can be used by the physician to determine in which direction to maneuver the intervention device to perform a treatment on the activated nerve.

[0066] Thus, in one example, the sensor elements are distributed around the axis of the intervention device 110 such that the sensor elements generate signals in response to magnetic fields generated in different orientations around the axis, and the controller 140 is further configured to identify the orientation around the axis of the intervention device 110 in which the measured signal has the maximum signal-to-noise ratio.

[0067] In this example, the controller 140 can identify the orientation of the maximum signal-to-noise ratio in various ways. For example, the controller may output a graphic representation of the orientation having the maximum signal-to-noise ratio to a display device. The graphic representation may include, for example, an icon representing the intervention device and the relative orientation in which the measurement signal having the maximum signal-to-noise ratio was measured.

[0068] In this example, the intervention device 110 may also include one or more actuators for adjusting the position and / or orientation of the insertable portion of the intervention device. The one or more actuators may also be used with the single sensor example shown in FIG. 7. The one or more actuators are configured to automatically maneuver the insertable portion in a direction of an orientation having a maximum signal-to-noise ratio.

[0069] Accordingly, this example provides for an automatic repositioning of the intervention device toward a bundle of nerve fibers that generated a magnetic field. The actuator may be provided, for example, by an expandable balloon such as an angioplasty balloon or, alternatively, by an actuator of a steerable catheter or a guide wire manipulator. In the former case, one or more expandable balloons may be disposed around the axis of the intervention device 110 such that, when expanded, the expandable balloon presses the magnetic sensor element on the opposite side of the axis transversely to the axis in a direction of an orientation having a maximum signal-to-noise ratio. This example is described with reference to FIG. 13, which is a schematic diagram showing an example of a cross-section of a blood vessel VES covered by a bundle of nerve fibers BNF 1..3 and an intervention device ID including an expandable balloon. As shown in FIG. 13, the intervention device includes a plurality of magnetic sensors 120 1..4 In this example, the orientation having the maximum signal-to-noise ratio is identified as the direction of the bundle of nerve fibers BNF 2 In response to this identification, the expandable balloon BAL is automatically inflated to maneuver the insertable portion of the intervention device in the direction of the bundle of nerve fibers BNF 2 The intervention device ID may also include one or more additional expandable balloons (not shown in FIG. 13) for maneuvering the intervention device ID in different directions. In one example, one or more expandable balloons operating in a manner similar to the expandable balloon BAL are coupled to the intervention device at positions diametrically opposed to the respective magnetic sensors 120 1..4 Accordingly, when the expandable balloon BAL expands, the intervention device is in the magnetic sensor 120 1..4It is moved within the lumen so as to be moved closer to the blood vessel wall.

[0070] After the intervention device ID shown in FIG. 13 is moved closer to the blood vessel wall by the expandable balloon, a map of the magnetic field around the blood vessel can be generated by rotating the intervention device ID around the longitudinal axis of the intervention device. Similarly, a map of the magnetic field along the blood vessel can be generated by translating the intervention device ID along the axis of the blood vessel. The rotation and translation may be provided by the user in response to instructions provided by the controller 140. Alternatively, the controller may generate control signals for controlling a manipulator or robot to provide the desired rotation / translation. The balloon may be expanded, for example, so that the magnetic sensor 120 1..4 contacts the blood vessel wall. In this way, the magnetic sensor 120 1..4 By using an expandable balloon to bring it closer to the blood vessel wall, the separation between the magnetic sensor 120 1..4 and the nerve generating the magnetic field is reduced, resulting in an increase in the detected magnetic field strength. By expanding the balloon so that the magnetic sensor 120 1..4 contacts the blood vessel wall, the reliability of the magnetic field map is improved because the separation between the magnetic sensor 120 1..4 and the nerve generating the magnetic field is controlled.

[0071] A map of the magnetic field around or along the blood vessel can be generated in a similar manner using an intervention device that includes a single magnetic sensor 120 and one or more expandable balloons. Thus, a similar map can be generated by attaching one or more expandable balloons to the intervention device shown in FIG. 7 and rotating or translating the intervention device as described above.

[0072] As described above with reference to FIG. 6, the neural activity sensed by sensor 120 via the detected magnetic field may be artificially triggered or may be triggered naturally, i.e., spontaneously. The inventors have found that for spontaneously activated nerves, the signature of the signal generated by magnetic sensor 120 can be used as a measure of renal sympathetic nerve overdrive. As described above, renal sympathetic nerve overdrive is an indicator of hypertension, i.e., elevated blood pressure.

[0073] FIG. 14 is a graph showing, according to some aspects of the present disclosure, a) the signature of a pulse train representing the magnetic field detected from the renal nerves in a non-hypertensive subject, and b) the signature of a pulse train representing the magnetic field detected from the renal nerves in a hypertensive subject with increased renal nerve activity. In FIG. 14, for the non-hypertensive subject and for the hypertensive subject, the normalized magnetic field intensity is plotted on each of the vertical axes against the time in seconds on each of the horizontal axes. A large difference can be observed between the upper graph for the non-hypertensive subject and the lower graph for the hypertensive subject. These include differences in the period of the pulses, the duration of the pulse train, and the number of pulses within the pulse train. Thus, these differences can be used to distinguish between non-hypertensive and hypertensive subjects.

[0074] In an example of system 200 described with reference to FIG. 11, controller 140 may be further configured to output a detection result indicating neural activity in response to the received signal by identifying the signature in the received signal and outputting a measurement of renal sympathetic nerve overdrive based on the identified signature.

[0075] In this example, the signature of the received signal can include one or more of, for example, the period of one or more pulses in a pulse train in a signal generated in response to a magnetic field generated by spontaneous neural activity, the duration of the pulse train in a signal generated in response to a magnetic field generated by spontaneous neural activity, and the count of the number of pulses in a pulse train in a signal generated in response to a magnetic field generated by spontaneous neural activity. Also, for example, the number of pulses per second measured over a period of one minute is significantly different between two groups. A clear distinction between these groups of subjects is shown in FIG. 15, which shows a plot of the pulse repetition time Rt within the pulse train versus the number of pulses nP within the pulse train for simulated magnetic fields in groups of non-hypertensive subjects (circular symbols) and hypertensive subjects (stars) according to some aspects of the present disclosure.

[0076] The inventors have also found that the signals measured by the magnetic sensor 120 described above with reference to FIGS. 6 and 11 are susceptible to interference from various magnetic field sources not related to neural activity. Generally, magnetic fields are present everywhere, including the Earth's magnetic field and those from electronic devices. Magnetic fields may also be generated within the subject by physiological signals having causes different from the nerves of interest. Magnetic fields may also be generated by physiological signals in other subjects in the vicinity of the object of interest. The presence of a large background magnetic field presents a challenge for sensitive magnetic field sensors as these magnetic fields can saturate the magnetic sensor. In the examples described below, various embodiments in which magnetic field compensation is used to compensate for such magnetic field interference are described.

[0077] In one example, active compensation of the global magnetic field is used to reduce the effect of magnetic field interference on the magnetic sensor 120. In this example, the intervention device 110, and the subject in which neural activity is measured are also surrounded by a plurality of Helmholtz coils. For example, three pairs of Helmholtz coils may be used, with each pair separated along one of the orthogonal axes x, y, and z. The Helmholtz coils HH x, x’ , HH y,y’ and HHz,z’ An example of this configuration, which includes three pairs, is shown in FIG. 16, and each pair is separated along the corresponding orthogonal axes x, y, and z. Active compensation for magnetic field interference is achieved by adjusting the current in each of the coils in real time in response to the measurement of magnetic field interference. The current in the coil generates a magnetic field within the volume enclosed by the coil, which has the effect of reducing magnetic field interference. In this case, Helmholtz coils can be used to compensate for both, for example, the static magnetic field interference from the Earth's magnetic field and the deterministic magnetic field interference caused by, for example, electronic devices.

[0078] In another example, a passive magnetic shield is used to reduce the effect of magnetic field interference on the magnetic sensor 120. In this example, the intervening device 110, and the subject in which neural activity is measured are also surrounded by a magnetic shield material. The intervening device 110 and the subject may be surrounded by, for example, a magnetic shield material in the form of a cylinder. An effective magnetic shield material typically has a high magnetic permeability value. An example of such a material is Mu-metal, which is a nickel-iron alloy. Some nickel-iron Mu-metals that provide a high degree of magnetic shielding have more than 40% nickel.

[0079] In another example, active compensation of the local magnetic field is used to reduce the effect of magnetic field interference on the magnetic sensor 120. In this example, the intervening device 110, and a part of the subject in which neural activity is measured are also surrounded by a plurality of Helmholtz coils. This example is similar to the previous example of active compensation of the global magnetic field described above, with the difference that only a part of the subject, rather than the entire subject, is surrounded by a plurality of Helmholtz coils. This example operates in the same way as described above for active compensation of the global magnetic field. In this example, the local magnetic field to be compensated can include magnetic fields generated within the subject other than the nerve of interest. For example, this example can be used to reduce the effect of magnetic field interference from the beating heart of the subject.

[0080] All three of these examples of magnetic shields may be used together to improve the degree of shielding against magnetic field interference. An example of a configuration in which these three forms of magnetic shields are used together will be described with reference to FIG. 16, which shows an example of a system 200 that includes a nested magnetic field shield configuration according to some aspects of the present disclosure. In this example, the system 200 includes a first outermost layer FSL of a magnetic shield having a plurality of Helmholtz coils configured to provide active compensation for a global magnetic field generated outside the subject, a second innermost layer SSL of a magnetic shield having a plurality of Helmholtz coils configured to provide active compensation for a local magnetic field generated inside the subject, and a third layer CSL of a magnetic shield sandwiched between the first and second layers, the third layer of the magnetic shield having a passive magnetic shield material.

[0081] By doing so, the output of the magnetic field sensor 120 can remain sensitive to the weak magnetic field generated by neural activation and saturation as a result of magnetic field interference can also be avoided.

[0082] Despite the use of the above-described configuration to compensate for magnetic field interference, the inventors have also found that there can be some residual magnetic field interference within the volume enclosed by the second innermost layer SSL of the magnetic shield. The cause of this interference may be external to the second innermost layer SSL of the magnetic shield, or alternatively, the cause may be within the second innermost layer. For example, this interference can arise from the Earth's magnetic field or can be generated within the subject by another source other than the nerve of interest. For example, it may have its cause in the subject's beating heart. This interference can vary depending on the location within the volume enclosed by the second innermost layer SSL of the magnetic shield. For example, this can increase as the magnetic sensor 120 is moved towards the heart. To compensate for such spatial dependence of the interference, in one example, an intervention device including a motion sensor 160 is provided. This example is described with reference to FIG. 17, which shows an example of a system 200 including one or more coils 150 configured to generate a magnetic field to compensate for the background magnetic field detected by an intervention device 110, a motion sensor 160, and a magnetic sensor 120, according to some aspects of the present disclosure. In this example, the system 200 includes one or more coils 150, SSL configured to generate a magnetic field to compensate for, i.e., reduce the magnitude of, the background magnetic field detected by the magnetic sensor 120. The intervention device 110 further has a motion sensor 160. The motion sensor 160 is mechanically coupled to the intervention device 120 to detect the motion of the magnetic sensor 120. The controller 140 is also, measure the background magnetic field based on the signal generated by the magnetic sensor 120 in the absence of the magnetic field generated by nerve activity, apply a signal to one or more coils 150, SSL to compensate for the background magnetic field during measurement of the magnetic field generated by nerve activity, repeatedly measure the background magnetic field and the corresponding application of the signal to one or more coils in response to detection of the motion of the intervention device 110 by the motion sensor, configured as follows.

[0083] The effect of the operations performed by the controller in this example is to recalibrate the magnetic field compensation provided by one or more coils in the case of the movement of the interventional device. By doing so, when the interventional device is moved within the volume enclosed by the second innermost layer SSL of the magnetic shield, for example, fluctuations in magnetic field interference due to changes in the proximity between the magnetic sensor and the pulsating heart can be compensated for. In this example, one or more coils 150, SSL may include, for example, a plurality of Helmholtz coils and may be provided by the second innermost layer SSL of the magnetic shield described above with reference to FIG. 16. Alternatively, one or more coils 150, SSL may form part of the interventional device. For example, one or more coils 150, SSL may be coupled to a guide catheter through which the interventional device 110 is inserted into the subject.

[0084] In this example, the motion sensor can be provided by various devices including, for example, one or more of an accelerometer, a gyroscope, and an optical fiber-based position tracking system. An example of an optical fiber-based position tracking system is described in WO 2013 / 136247. This system determines the position and shape of the subject based on the amount of strain induced in one or more fiber Bragg gratings.

[0085] In a related example, the system described with reference to FIG. 17 provides compensation for magnetic field interference generated by cardiac activity in a subject where neural activity is measured using an electrocardiogram, ECG, signal. In this example, the signal generated by the magnetic sensor 120 is generated in response to the magnetic field generated by the neural activity of the subject, and the background magnetic field is at least partially generated by the cardiac activity of the subject. In this example, the controller 140 is further configured to receive the electrocardiogram, ECG, signal of the subject, and the controller 140 is configured to apply a signal to one or more coils in synchronization with the received ECG signal to apply a time-dependent signal to one or more coils in order to compensate for the background magnetic field during the measurement of the magnetic field generated by neural activity.

[0086] In this example, an electrocardiogram (ECG) signal for a subject can be generated using various devices, including using ECG electrodes attached to the subject. The heart can be considered the strongest common source of magnetic interference in the vicinity of the kidneys. The magnetic field generated by the heart has a peak during depolarization of the ventricles. This magnetic field can exceed the dynamic range of some magnetic sensors and thus risk saturating the output of such sensors. The implementation described in this example reduces the risk of saturation by reducing the effect of the heart's magnetic field on the magnetic sensors. In this example, a compensating magnetic field can be applied in synchronization with a position on the received ECG signal, such as the R peak of the ECG signal.

[0087] In another related example, the system described with reference to FIG. 17 provides compensation for magnetic field interference using a 3D background magnetic field map. In this example, the controller 140 is further configured to receive tracking data representing the position of the magnetic sensor 120 within the sensing area, receive a 3D background magnetic field map representing the background magnetic field distribution within the sensing area, estimate the magnitude of the background magnetic field distribution at the position of the magnetic sensor 120 within the sensing area based on the received tracking data and the received 3D background magnetic field map, and is configured to apply a signal to one or more coils to compensate for the background magnetic field during measurement of the magnetic field generated by neural activity, at least in part based on the estimated magnitude of the background magnetic field distribution at the position of the magnetic sensor 120.

[0088] ​In this example, the tracking data can be provided by various tracking systems including the above-described optical fiber-based position tracking system described in WO 2013 / 136247 pamphlet, or by tracking the position of the magnetic sensor 120 using an imaging system. The imaging system may be, for example, a projection X-ray imaging system, or a CT imaging system, or an ultrasonic imaging system. For example, the shape of the magnetic sensor or the shape of the fiducial marker that identifies its position can be tracked within the image data generated by such an imaging system in order to determine the position of the magnetic sensor. The 3D background magnetic field map can be measured using the magnetic sensor 120 by placing the magnetic sensor at one or more positions within the volume where the magnetic field is compensated by one or more coils 150, SSL when there is no patient within the volume. After placing the subject within this volume, the position of the magnetic sensor 120 determined by the tracking data is used to estimate the value of the background magnetic field at the current position of the magnetic sensor by interrogating the 3D background magnetic field map. The controller 140 then applies a signal to one or more coils to compensate for the background magnetic field by providing a field that compensates for the estimated value of the background magnetic field at the current position of the magnetic sensor determined by interrogating the 3D background magnetic field map.

[0089] The above-described operations performed by the controller 140 can be provided in the form of a computer-implemented method for use with the above-described system 200. Thus, in one example, a computer-implemented method for use with the system 200 is instructions for receiving a signal generated by the magnetic sensor 120, and instructions for outputting a detection result indicating neural activity in response to the received signal, and includes.

[0090] The other operations described above as being performed by the controller 140 may be provided similarly as instructions of a computer-implemented method.

[0091] The above-described operations performed by the controller 140 may be provided in the form of a computer program product for use with the above-described system 200. Thus, in one example, when a computer program product for use with the system 200 is executed by one or more processors, the one or more processors are caused to receive a signal generated by the magnetic sensor 120 and output a detection result indicating neural activity in response to the received signal, have an instruction.

[0092] The other operations described above as being performed by the controller 140 may be provided similarly as instructions of a computer program product.

[0093] The above examples are to be understood as illustrative of the present disclosure and not limiting. Further examples are contemplated. For example, the examples described in connection with the intervention device 110 may also be included within the system 200. Additionally, note that the examples described with respect to the system 200 include operations performed by a controller. These operations may be provided in the form of instructions on a computer program product and, when executed by one or more processors, cause the one or more processors to execute the instructions. Similarly, these operations may be instructions stored on a non-transitory computer-readable storage medium and provided in the form of instructions that, when executed by at least one processor, cause the at least one processor to execute the instructions. It should be understood that the features described with respect to any one example may be used alone or in combination with other described features, and may be combined with one or more other features of another of the examples, or with combinations of other examples. Further, equivalents and modifications not described above may also be used without departing from the scope of the invention as defined in the appended claims. In the claims, the word "comprising" does not exclude other elements or acts, and the indefinite articles "a" or "an" do not exclude a plurality. The mere fact that certain features are recited in mutually different dependent claims does not indicate that a combination of these features cannot be advantageously used. Any reference signs in the claims should not be construed as limiting their scope.

Claims

1. An intervention device for detecting neural activity, comprising a magnetic sensor coupled to an insertable portion of the intervention device, wherein the magnetic sensor is configured to generate a signal in response to a magnetic field generated by neural activity, Controller and In a system having, The controller is configured to receive the signal generated by the magnetic sensor and to output a detection result indicating neural activity in response to the received signal. The aforementioned magnetic sensor is An optical pumping magnetometer (OPM) comprising an optical cell containing an alkali metal in liquid and / or gas phase, wherein the OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the alkali metal, A heater configured to supply heat to the optical cell, It has, The controller is configured to selectively operate the OPM in a relatively low-sensitivity mode, where a relatively low power level is supplied to the optical cell by the heater, and in a relatively high-sensitivity mode, where a relatively high power level is supplied to the optical cell by the heater, in order to generate a signal in response to a magnetic field generated by neural activity. system.

2. The optical cell comprises an alkali metal in liquid and / or gas phase and a background gas, and the OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the alkali metal and the background gas, wherein in the relatively low-sensitivity mode, the optical properties of the background gas are sensed, and in the relatively high-sensitivity mode, the optical properties of the alkali metal are sensed, or The optical cell comprises a first alkali metal in liquid and / or gas phase and a second alkali metal in liquid and / or gas phase, and the OPM is configured to generate a signal in response to a magnetic field generated by neural activity by measuring the magnetic field-dependent optical properties of the first alkali metal and the second alkali metal, wherein in the relatively low-sensitivity mode, the optical properties of the first alkali metal are sensed, and in the relatively high-sensitivity mode, the optical properties of the second alkali metal are sensed. The system according to claim 1.

3. The intervention device further includes a temperature sensor, The temperature sensor is in thermal contact with i) the outer surface of the intervention device, or ii) the optical cell. The controller is configured to operate the heater in response to the temperature measured by the temperature sensor. The system according to claim 1.

4. The OPM has a light source configured to provide an optical pump beam, and the OPM is configured to measure the magnetic field-dependent optical properties of the alkali metal in response to the excitation of the alkali metal in the optical cell by the optical pump beam. The controller is configured to modulate the intensity of the optical pump beam between a relatively low intensity and a relatively high intensity. The OPM is configured to measure the magnetic field-dependent optical properties of the alkali metal by determining the transmittance of the optical pump beam passing through the optical cell while the optical pump beam excites the alkali metal with the relatively high intensity. The system according to claim 1.

5. The aforementioned controller further, Identify the signature in the received signal, By outputting a measurement of renal nerve sympathetic overdrive based on the identified signature, the detection result showing neural activity in response to the received signal is output. It is configured in such a way. The system according to claim 1.

6. The system further comprises one or more coils configured to generate a magnetic field for compensating for the background magnetic field detected by the magnetic sensor, The intervention device further includes a motion sensor, The motion sensor is mechanically coupled to the intervention device to detect the movement of the magnetic sensor. The aforementioned controller further, The background magnetic field is measured based on the signal generated by the magnetic sensor in the absence of a magnetic field generated by neural activity. To compensate for the background magnetic field during measurement of the magnetic field generated by neural activity, a signal is applied to one or more coils. In response to the detection of movement of the intervention device by the motion sensor, the measurement of the background magnetic field and the application of corresponding signals to one or more coils are repeated. It is configured in such a way. The system according to claim 1.

7. The signal is generated in response to a magnetic field generated by the neural activity of the target, and the background magnetic field is at least partially generated by the cardiac activity of the target. The controller is further configured to receive electrocardiogram (ECG) signals for the subject, The controller is configured to apply a time-dependent signal to one or more coils in synchronization with the received ECG signal in order to compensate for the cardiac activity, and to apply a signal to one or more coils in order to compensate for the background magnetic field during measurement of the magnetic field generated by neural activity. The system according to claim 6.

8. The aforementioned controller further, Tracking data representing the position of the magnetic sensor within the sensing area is received. A 3D background magnetic field map representing the background magnetic field distribution within the sensing area is received. Based on the received tracking data and the received 3D background magnetic field map, the magnitude of the background magnetic field distribution at the location of the magnetic sensor within the sensing area is estimated. It is configured in such a way, The controller is configured to apply a signal to one or more coils to compensate for the background magnetic field during measurement of a magnetic field generated by neural activity, based at least in part on the estimated magnitude of the background magnetic field distribution at the location of the magnetic sensor. The system according to claim 6 or claim 7.

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