System and method for selective nerve modulation

Abstract

The invention provides a system (100) for determining an operational scheme of an implantable device (2000) for modulating an action potential in a nerve (10) of a subject (50), wherein the system (100) comprises the implantable device (2000) and a control system (300), and wherein the system (100) comprises or is functionally couplable to a physiological sensor (130), wherein the implantable device (2000) comprises an electrode arrangement (200) and a pulse generator (140), wherein the electrode arrangement (200) comprises n electrodes (220), wherein n ≥ 4, wherein the control system (300) is configured to execute a commissioning mode wherein: the electrode arrangement (200) is configured to engage the nerve (10) such that the electrodes (220) are arranged around the nerve (10) in an electrode array (230); the pulse generator (140) is configured to successively provide electrical signals (40) to the nerve (10) with different electrode sets (20) of the electrodes (220); the physiological sensor (130) is configured to monitor one or more physiological parameters of the subject (50) and to provide related sensor signals to the control system (300); and the control system (300) is configured to define an operational scheme based on the related sensor signals and a target physiological response, wherein the operational scheme designates an operational electrode set (25) and electrical signal parameters, wherein the operational electrode set (25) comprises at least two of the electrode sets (20); wherein in an operational mode of the implantable device (2000) the implantable device (2000) is configured to operate based on the operational scheme.

Description

[0001] SYSTEM AND METHOD FOR SELECTIVE NERVE MODULATION

[0002] FIELD OF THE INVENTION

[0003] The invention relates to a system for determining an operational scheme of an implantable device. The invention further relates to a method for determining an operational scheme of an implantable device. The invention further relates to a computer program product. The invention further relates to a data carrier.

[0004] BACKGROUND OF THE INVENTION

[0005] Methods for determining an operational scheme of an implantable device are known in the art. For instance, US6052624A describes a programming system and method for use with an implantable tissue stimulator to allow a clinician or patient to determine an electrode stimulation pattern, including which electrodes of a multiplicity of electrodes in an electrode array should receive a stimulation current, including the amplitude, width and pulse repetition rate of such current. The system and method allow the clinician or user to select and visualize a particular group of electrodes of the electrode array by displaying a visual image of the array, and then allows selection of a group of electrodes in the array, as well as to move the selected group or change the size of the selected group, while applying a stimulation pulse current having a selected amplitude, width and pulse repetition rate, to the group of electrodes. Movement of the selected group of electrodes is facilitated through the use of a directional pointing device, such as a joystick.

[0006] SUMMARY OF THE INVENTION

[0007] Electrical stimulators can be used to elicit or inhibit (or “block”) the propagation of action potentials along axons in a nerve. In particular, devices that elicit action potentials may be in clinical use for a number of peripheral and cranial nerves for the treatment of various conditions (e.g., Vagus nerve stimulator for the treatment of epilepsy, depression, or to foster stroke rehabilitation, Hypoglossal nerve stimulators for the treatment of sleep apnea, Occipital nerve stimulators for the treatment of headaches).

[0008] Current medical devices designed for nerve modulation may lack selectivity, particularly for nerves that (a) innervate multiple end-organs, (b) contain both afferent and efferent fibers, and / or (c) contain different fiber types. A lack of such stimulation selectivity may lead to unwanted side effects that may, in turn, compromise therapeutic efficacy. For instance, established Vagus Nerve Stimulation (VNS) devices may have been reported toinadvertently stimulate efferent fibers. This unintended activation can lead to interference with essential functions, such as speech and swallowing in the case of exciting A alpha fibers, but may also lead to cardiac arrhythmias and syncopes when exciting B fibers, as has been reported in a number of patients.

[0009] The nonselective nature of nerve stimulation devices may pose substantial doselimiting challenges, as the degree of unwanted effects restricts the amount of electrical charge that can be applied to achieve optimal desired physiological responses. The clinical implications of this limitation are profound, as patients may not receive adequate stimulation to achieve therapeutic benefits while simultaneously experiencing adverse effects.

[0010] Recent advancements in electrode material technology, particularly the development of high-charge injection materials and multi-contact cuff electrodes, present potential avenues for targeted stimulation. These innovations allow for the selective activation of specific electrode pairs (in the case of bipolar stimulation), thereby attempting to mitigate unwanted side effects. However, these methods may typically result in a loss of efficacy because they may not engage all relevant nerve fibers necessary for achieving the desired physiological outcomes. In addition, the charges and charge densities at a selected electrode pair may be especially high to try to recruit a maximum of fibers in reach of this contact, thereby also increasing the likelihood of unwanted side effects.

[0011] Moreover, high-frequency (HF) blocking techniques may introduce additional complications, as the stimulation intensity levels required to achieve nerve conduction blocking can lead to significant increases in local tissue temperature. This thermal buildup poses potential safety risks, potentially damaging both the nerve and surrounding tissue structures. In particular, HF Block may require relatively high amounts of energy to establish nerve conduction effects, since blocking thresholds are often a multiple of the stimulation thresholds.

[0012] The prior art may describe spatially selective electrode designs. For instance, the prior art may describe mapping physiological signals elicited by individual contact pairs on a cuff electrode, and choosing one electrode with the maximum response (the main vector) for the modulation of nerve activity. However, these designs may typically be limited in finetuning of the charge injection and energy distribution, which can lead to inadequate modulation of nerve conduction and excess thermal build up.

[0013] The prior art may describe methods involving (brute force) testing of different electrode combinations and operational parameters to arrive at a single suitable electrode set and operational parameters for a particular desired physiological effect. However, especially in cases where more than one electrode pair (incl. one cathode and one anode contact) are to beselected, such approaches may be extremely time-intensive to implement due to the large number of possible electrode combinations and the associated operational parameters. Such procedures may be undesirable in a clinical setting, as time to select appropriate stimulation settings and electrode selection, e.g. during patient visits, is limited and costly, and as extended testing periods may put an undue burden on the patient. In practice, such methods may thus be limited to testing only a relatively small number of combinations and selecting the tested combination with the most positive results.

[0014] The prior art may further describe methods involving a patient or a clinician dynamically changing the selected electrodes and / or the operational parameters, e.g. by moving a joystick to ‘steer’ towards specific electrodes and / or operational parameters, until a suitable set of electrodes and associated parameters is identified. Although such an approach may facilitate converging on selected electrodes and operational parameters relatively quickly, substantially better options may be missed, i.e., a local optimum may, depending on the circumstances, be found relatively quickly, but better options may be available in terms of efficacy, physiological effect, and / or side effect avoidance.

[0015] There may thus be a need for a method that achieves selective nerve modulation for maximizing physiological efficacy while minimizing adverse impacts, including adverse thermal impacts in the case of nerve conduction blocking. There may further be a need for a method for determining the operational scheme of electrodes and operational parameters relatively quickly.

[0016] Hence, it is an aspect of the invention to provide an alternative system and method for determining an operational scheme of an implantable device, which preferably further at least partly obviates one or more of above-described drawbacks. The present invention may have as object to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0017] In a first aspect, the invention may provide a system for determining an operational scheme of an implantable device, especially of an implantable device for modulating an action potential in a nerve of a subject. The system may comprise the implantable device and a control system and may especially comprise or be functionally couplable to a physiological sensor. In embodiments, the implantable device may comprise an electrode arrangement and a pulse generator. In particular, the electrode arrangement may comprise n electrodes, especially wherein n > 4. In further embodiments, the pulse generator may be configured to provide an electrical signal to the electrodes, especially via the electrodes. In embodiments, the control system may be configured to execute a commissioning mode.Further, in embodiments, the implantable device may be configured for operating in an operational mode. In the commissioning mode, the electrode arrangement may be configured to engage the nerve such that the electrodes are arranged (circumferentially) around the nerve in an electrode array. Further, in the commissioning mode, the pulse generator may be configured to successively provide electrical signals to the nerve with different (commission) electrode sets of the electrodes. Yet further, in the commissioning mode, the physiological sensor may be configured to (continuously) monitor one or more physiological parameters of the subject and to provide related sensor signals to the control system. Especially, in the commissioning mode, the control system may be configured to define an operational scheme based on the related sensor signals and a target physiological response. The operational scheme may especially designate an operational electrode set and (corresponding) electrical signal parameters (or “signal parameters”), especially wherein the operational electrode set comprises at least two of the (commission) electrode sets. In embodiments, in the operational mode of the implantable device, the implantable device may be configured to operate (the pulse generator) based on the operational scheme.

[0018] In specific embodiments, the invention may provide a system for determining an operational scheme of an implantable device for modulating an action potential in a nerve of a subject, wherein the system comprises the implantable device and a control system, and wherein the system comprises or is functionally couplable to a physiological sensor, wherein the implantable device comprises an electrode arrangement and a pulse generator, wherein the electrode arrangement comprises n electrodes, wherein n > 4, wherein the control system is configured to execute a commissioning mode wherein: the electrode arrangement is configured to engage the nerve such that the electrodes are arranged around the nerve in an electrode array; the pulse generator is configured to successively provide electrical signals to the nerve with different electrode sets of the electrodes; the physiological sensor is configured to monitor one or more physiological parameters of the subject and to provide related sensor signals to the control system; and the control system is configured to define an operational scheme based on the related sensor signals and a target physiological response, wherein the operational scheme designates an operational electrode set and electrical signal parameters, wherein the operational electrode set comprises at least two of the electrode sets; wherein in an operational mode of the implantable device the implantable device is configured to operate based on the operational scheme.

[0019] In particular, the approach of the invention may facilitate selecting a suitable operational electrode set by screening with a small number of (commission) electrode sets. Inparticular, the individual effects of the electrode sets can be determined and subsequently a combination of these electrode sets can be selected to act as an operational electrode set. The operational electrode set may - compared to the tested (commission) electrode sets - comprise a larger number of electrodes, which may facilitate distributing energy over a larger nerve interface, thereby recruiting more target axons at lower intensity levels, limiting undesired side and thermal effects. Hence, the approach of the invention may facilitate testing a substantially smaller number of electrode sets compared to a brute force method, while facilitating the selection of a suitable operational electrode set via inference based on the tested electrode sets. The invention may thereby provide a time-efficient method for determining parameters for effective nerve stimulation and / or blocking while complying with safety criteria, minimizing adverse effects, and saving energy.

[0020] In particular, the invention may provide a novel approach for stimulating or blocking action potential conduction in a nerve using multiple electrode pairs (simultaneously), with charges and charge densities distributed according to the physiological responses of target nerve fibers. The approach may leverage a calibration process (also termed "titration") to map the physiological responses in dependence of electrode locations. The titration process may include a series of systematic stimulation (or blocking) trials, wherein varying intensities and pulse widths are applied to identify both superficial and deeper target fibers. By mapping the physiological responses elicited by these stimulations (or blocks), the operational parameters may be tuned to deliver effective signals to the relevant nerve fibers while reducing thermal buildup and energy expenditure relative to prior art solutions.

[0021] In further embodiments, the control system may be configured to test the operational scheme. In particular, in an evaluation mode, the control system may be configured to operate the implantable device according to the operational scheme to determine and evaluate scheme performance, and, if needed, to revise or discard the operational scheme. For instance, in the evaluation mode, similar to in the commissioning mode, the physiological sensor may (be configured to) monitor the one or more physiological parameters of the subject and to provide related sensor signals to the control system. Further, in the evaluation mode, the control system may be configured to receive user input, such as from the subject or from a physician. If the operational scheme is to be discarded, the control system may proceed with a different operational scheme (also see below) or, if needed, may continue or re-initiate the commissioning mode.

[0022] The use of operational electrode sets comprising multiple electrode sets, e.g., 4-6 electrodes in total, may facilitate substantially reducing undesired local heating whilesubstantially extending battery life of the implantable device. Further, the use of such operational electrode sets may facilitate an improved desired physiological response while reducing thermal build-up and reducing battery usage (see further below). The extended battery life resulting from a reduced battery usage may reduce the need for the subject to monitor the battery life and to recharge the battery, which may reduce a psychological burden on the subject and improve therapy adherence. Further, if batteries are less frequently charged, the overall battery longevity may increase, which may result in fewer clinical procedures for battery replacements.

[0023] Further, the invention may facilitate exploring the effects of different operational parameters while testing the electrode sets (also see further below). In the commissioning stage, a stimulation amplitude or pulse width ramp may be applied to determine relevant response trigger thresholds, both for desired and undesired physiological responses. For instance, the amplitude (or “intensity”) of an applied electrical signal may determine the penetration depth into the nerve fiber, which may affect the physiological effects of the electrical signal.

[0024] The invention may thus provide a system for determining an operational scheme of an implantable device for modulating an action potential in a nerve of a subject, such as in a nerve of a human patient.

[0025] The term “operational scheme” may herein refer to a combination of electrodes and associated electrical signal parameters suitable for operation of an implantable device, specifically in the context of modulating action potential conduction in a nerve. In particular, while multiple distinct operational schemes may be identified for an implantable device, the implantable device may, during operation, especially operate according to a single operational scheme (at a time).

[0026] The implantable device may be configured to be at least partially implanted in the subject. Hence, (external) components of the device may be biocompatible. In embodiments, the implantable device may further comprise the control system (see below), especially wherein the control system comprises or is functionally coupled to the pulse generator.

[0027] In embodiments, the implantable device may be configured to be implanted at the neck of the subject. Such embodiments may be particularly convenient for stimulation of a cranial nerve, especially for stimulation of the vagus nerve (also see below).

[0028] The implantable device may be configured for modulating action potential conduction in a nerve, especially in an axon (or: “nerve fiber”) thereof.The term “nerve” may herein refer to a bundle of axons providing communication pathways from the central nervous system to peripheral organs or vice versa. In particular, the communication between the central nervous system and peripheral organs may occur through the conduction of action potential(s) along axons, which may be elongated components of neurons. In particular, the conduction of action potential along axons may lead to the activation of (downstream) biological processes, such as to muscle contraction.

[0029] In embodiments, the system may especially comprise an arrangement, especially wherein the arrangement is configured for implantation in a subject, such as in a human subject. Hence, the arrangement may especially comprise an implantable arrangement. In particular, (external) components of the arrangement may be biocompatible.

[0030] The system may, in embodiments, further comprise a control system. The control system may be configured to control the implantable device and / or the physiological sensor (see below), especially at least the pulse generator (of the implantable device), during the commissioning mode.

[0031] The term “controlling” and similar terms herein may especially refer at least to determining the behavior or supervising the running of an element. Hence, herein “controlling” and similar terms may e.g. refer to imposing behavior to the element (determining the behavior or supervising the running of an element), etc., such as e.g. measuring, displaying, actuating, opening, shifting, changing temperature, etc.. Beyond that, the term “controlling” and similar terms may additionally include monitoring. Hence, the term “controlling” and similar terms may include imposing behavior on an element and also imposing behavior on an element and monitoring the element. The controlling of the element can be done with a control system. The control system and the element may thus at least temporarily, or permanently, functionally be coupled. The element may comprise the control system. In embodiments, the control system and the element may not be physically coupled. Control can be done via wired and / or wireless control. The term “control system” may also refer to a plurality of different control systems, which especially are functionally coupled, and of which e.g. one master control system may be a control system and one or more others may be slave control systems.

[0032] The system may further comprise or be functionally coupled to a physiological sensor. Hence, in embodiments, the system may comprise the physiological sensor. In further embodiments, the system, especially the control system, may be functionally coupled to the physiological sensor. The system, especially the control system, may, for instance, be configured to receive and / or acquire data from the physiological sensor.In particular, in embodiments, the system, especially the control system, may be configured to receive (related) sensor signals comprising (measurements of) one or more physiological parameters of the subject.

[0033] The term “physiological sensor” may herein refer to any sensor suitable for collecting physiological data concerning a subject. The physiological sensor may, for instance, be selected from the group comprising a heart rate monitor, a blood pressure sensor, a pulse oximeter, a thermometer, a blood glucose monitor, electromyography (EMG) sensor, a spirometer, an electroencephalography (EEG) headset, a skin conductance sensor, an accelerometer, a hydration sensor, etc.. The term “physiological sensor” may herein also refer to a plurality of (different) physiological sensors configured to sense different physiological parameters. It will be clear to the person skilled in the art that a large variety of potentially relevant physiological parameters may be sensed (or “monitored”) using physiological sensors.

[0034] For instance, in embodiments, the one or more physiological parameters may be selected from the group comprising a respiratory rate, a respiratory volume, e.g., tidal volume or minute volume, coughing, airway resistance, lung compliance, lung elastance, inspiration / expiration ratio, a pulmonary oscillometry parameter, e.g., R5, R5-20, R5-19, AX, or X5, a spirometry parameter, e.g., FEV1, FVC, FEV1 / FVC, FEF 25-75, MW, or VC, a lung plethysmography parameter, respiratory and cardiac parameters derived from transthoracic impedance measurements, tracheal pressure, e.g., by pressure sensor, heart rate, e.g., by electrocardiogram (ECG) or pulse oximetry, heart rate variability, e.g., pNN50, HF / LF, SDNN, RMSSD, SI, or NN50, a heart rhythm abnormality, such as an abnormality detectable by ECG (e.g., bradyarrhythmias, tachyarrhythmias, atrioventricular (AV) blocks, sinoatrial (SA) blocks, bundle branch blocks, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, QT prolongation), a stroke volume change, especially changes in ejection fraction, a heart contractility parameter, a heart movement abnormality, e.g., detectable by echocardiography, magnetic resonance imaging (MRI), or transthoracic impedance tomography, a systemic blood pressure, a pulmonary blood pressure, a glucose plasma level, a plasma level of a biomarker, e.g., a plasma level of one or more of insulin, glucagon, glucagon-like peptide-1 (GLP1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), leptin, ghrelin, amylin, neurofilament light chain, C-reactive protein (CRP), calprotectin, procalcitonin, fibrinogen, white blood cell count (WBC), tumor necrosis factor (TNF) alpha, interleukin-6 (IL6), interleukin- 1 (IL1) alpha and beta, interleukin- 12 (IL 12), and other inflammatory biomarkers, body temperature, blood oxygen level, e.g., paO2 and SatO2, blood CO2 level, e.g., paCO2, brain activity, e.g., a brain activity change detected by EEG,magnetoencephalography or functional MRI (fMRI), a nerve activity, e.g., a spontaneous or evoked activity change, such as detectable by recording electrodes, stomach motility, intestinal motility, e.g., detected by abdominal surface EMG, a laryngeal activity, e.g., detectable by needle or surface or endotracheal surface EMG, such as relating to the activity of cricopharyngeal, cricothyroideal or other laryngeal muscles, and a pain level, e.g., based on subject or physician input.

[0035] Herein, the term “R5” refers to a resistance at 5 Hz. Further, the term “R5-20” refers to a difference in resistance at 5 Hz and 20 Hz, while the term “R5-19” refers to a difference in resistance at 5 Hz and 19 Hz. The term “AX” refers to an area under the reactance curve, and the term “X5” refers to a reactance at 5 Hz.

[0036] The term “FEV1” refers to a forced expiratory volume in 1 second (of forced expiration), the term “FVC” refers to a forced vital capacity, and the term “FEV1 / FVC” refers to a ratio between FEV1 and FVC. The term “FEF 25-75” refers to a forced expiratory flow between 25% and 75% of the FVC. Further, the term “MW” refers to a maximum voluntary ventilation, and the term “VC” refers to a vital capacity.

[0037] The term “heart rate variability”, or “HRV”, refers to a variability in the time interval between heartbeats. The term “pNN50” refers to a percentage of successive NN intervals differing by > 50 ms, wherein the NN interval is the interval between (two) normal R-peaks in an ECG. The term “HF / LF” refers to a ratio between high frequency (power) and low frequency (power). The term “SDNN” refers to a standard deviation of NN intervals. Further, the term “RMSSD” refers to a root mean square of successive differences. The term “SI” refers to a stress index, and the term “NN50” refers to a number of (pairs of) successive NN intervals differing by > 50 ms.

[0038] The term “paO2” refers to a partial pressure of oxygen (O2) in arterial blood. Further, the term “SatO2” refers to an oxygen saturation. The term “paCO2” refers to a partial pressure of carbon dioxide (CO2) in arterial blood.

[0039] In embodiments, the one or more physiological parameters may comprise (at least) a respiratory rate. In further embodiments, the one or more physiological parameters may comprise (at least) a respiratory volume, e.g., a tidal volume or a minute volume. In further embodiments, the one or more physiological parameters may comprise (at least) coughing. In further embodiments, the one or more physiological parameters may comprise (at least) airway resistance. In further embodiments, the one or more physiological parameters may comprise (at least) lung compliance. In further embodiments, the one or more physiological parameters may comprise (at least) lung elastance. In further embodiments, the one or more physiologicalparameters may comprise (at least) inspiration / expiration ratio. In further embodiments, the one or more physiological parameters may comprise (at least) a pulmonary oscillometry parameter, especially one or more of R5, R5-20, R5-19, AX, or X5, a spirometry parameter, e.g., FEV1, FVC, FEV1 / FVC, FEF 25-75, MW, or VC. In further embodiments, the one or more physiological parameters may comprise (at least) a lung plethysmography parameter. In further embodiments, the one or more physiological parameters may comprise (at least) a respiratory and / or cardiac parameter derived from transthoracic impedance measurements. In further embodiments, the one or more physiological parameters may comprise (at least) tracheal pressure, especially determined by pressure sensor. In further embodiments, the one or more physiological parameters may comprise (at least) heart rate, especially determined using ECG or pulse oximetry. In further embodiments, the one or more physiological parameters may comprise (at least) heart rate variability, especially one or more of pNN50, HF / LF, SDNN, RMSSD, SI, or NN50. In further embodiments, the one or more physiological parameters may comprise (at least) a heart rhythm abnormality, such as an abnormality detectable by ECG (e.g., bradyarrhythmias, tachyarrhythmias, AV blocks, SA blocks, bundle branch blocks, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, QT prolongation). In further embodiments, the one or more physiological parameters may comprise (at least) a stroke volume change, especially a change in ejection fraction. In further embodiments, the one or more physiological parameters may comprise (at least) a heart contractility parameter. In further embodiments, the one or more physiological parameters may comprise (at least) a heart movement abnormality, e.g., a heart movement abnormality detectable by echocardiography, MRI, or transthoracic impedance tomography. In further embodiments, the one or more physiological parameters may comprise (at least) a systemic blood pressure. In further embodiments, the one or more physiological parameters may comprise (at least) a pulmonary blood pressure. In further embodiments, the one or more physiological parameters may comprise (at least) a glucose plasma level. In further embodiments, the one or more physiological parameters may comprise (at least) a plasma level of a biomarker, especially a plasma level of one or more of insulin, glucagon, GLP1, GIP, CCK, PYY, leptin, ghrelin, amylin, neurofilament light chain, CRP, calprotectin, procalcitonin, fibrinogen, WBC, TNF alpha, IL6, IL1 alpha and beta, IL 12, and other inflammatory biomarkers. In further embodiments, the one or more physiological parameters may comprise (at least) body temperature. In further embodiments, the one or more physiological parameters may comprise (at least) blood oxygen level, especially paO2, or especially SatO2. In further embodiments, the one or more physiological parameters may comprise (at least) blood CO2level, especially paCO2. In further embodiments, the one or more physiological parameters may comprise (at least) brain activity, such as a brain activity changes detectable by EEG, magnetoencephalography and / or fMRI. In further embodiments, the one or more physiological parameters may comprise (at least) a nerve activity, especially a spontaneous activity change, or especially an evoked activity change, such as detectable by recording electrodes. In further embodiments, the one or more physiological parameters may comprise (at least) stomach motility. In further embodiments, the one or more physiological parameters may comprise (at least) intestinal motility, such as detectable by abdominal surface EMG. In further embodiments, the one or more physiological parameters may comprise (at least) a laryngeal activity, such as detectable by needle or surface or endotracheal surface EMG, such as relating to the activity of cricopharyngeal, cricothyroideal or other laryngeal muscles. In further embodiments, the one or more physiological parameters may comprise (at least) a pain level, e.g., based on subject or physician input.

[0040] It will be clear to the person skilled in the art that the type of relevant physiological data, and thus the relevant type of physiological sensor, may depend on target and undesired physiological responses for a specific indication, or even for a specific subject. The person skilled in the art will be capable of selecting appropriate sensor modalities for a given subject and / or indication.

[0041] The implantable device may comprise an electrode arrangement. The electrode arrangement may comprise n electrodes, wherein n > 3, such as > 4, especially > 6. In further embodiments, n > 8, such as > 12, especially > 16. In further embodiments, n < 200, such as < 150, especially < 100, such as < 60. The electrode arrangement may especially be configured to engage a nerve such that (at least part of) the electrodes are arranged around the nerve in an electrode array. In particular, when the electrode arrangement engages the nerve, the electrodes may be arranged in (electrical) contact with the nerve.

[0042] The term “electrode array” may herein also refer to a plurality of electrode arrays. In particular, the electrode arrangement may be configured to engage a nerve such that the electrodes are arranged around the nerve in a plurality of electrode arrays, wherein the electrode arrays are separated along a longitudinal dimension of the nerve.

[0043] In embodiments, the electrode arrangement, especially the electrode array, may comprise a first electrode array (or “first array”) and a second electrode array (or “second array”). Especially, the first electrode array and the second electrode array may be configured (to be) spatially separated along a longitudinal dimension of the nerve.In embodiments, at least part of the electrode sets may comprise a first (commission) electrode from the first array and a second (commission) electrode from the second array.

[0044] In further embodiments, at least one electrode set of the operational electrode set comprises a first electrode from the first electrode array and a second electrode from the second electrode array.

[0045] In further embodiments, the first electrode array may comprise m first electrodes. In embodiments, m may be selected from the range of 3 - 40, such as from the range of 4 - 16, especially from the range of 4 - 10, such as from the range of 6 - 8. In further embodiments, m > 3, such as > 4, especially > 6. In further embodiments, < 16, especially < 12, such as < 10, especially < 8. In further embodiments, m may be selected from the range of 4 - 10. The number of electrodes may be selected in view of the ability for spatial targeting (or “spatial resolution”) and in view of desired electrode contact areas for stimulation. For typical nerve sizes, electrode arrays comprising 4-10 electrodes may offer both a suitable spatial resolution as well as suitable electrode surface areas for contacting the nerve.

[0046] Similarly, in embodiments, the second electrode array may comprise n2 second electrodes. In embodiments, n2 may be selected from the range of 3 - 40, such as from the range of 4 - 16, especially from the range of 4 - 10, such as from the range of 6 - 8. In further embodiments, n2 > 3, such as > 4, especially > 6. In further embodiments, m < 16, especially < 12, such as < 10, especially < 8. In further embodiments, n2 may be selected from the range of 4 - 10.

[0047] In embodiments, the first array may comprise m electrodes, the second array may comprise n2 electrodes, and = n2, especially wherein m is selected from the range of 4-10.

[0048] The electrodes of the first array and of the second array may especially be longitudinally aligned (along the nerve). In further embodiments, at least part of the first electrodes may be aligned with (respective) second electrodes. In particular, in embodiments, for each first electrode may apply that the first electrode is longitudinally aligned with a (respective) second electrode. In such embodiments, it may be particularly beneficial when surface areas, especially contact surface areas, of the (aligned) electrodes are (essentially) the same, forming a symmetric pair of contact sites along the nerve fibers. Hence, in further embodiments, for each first electrode may apply that the (contact) surface areas of the first electrode and of the (therewith aligned) second electrode differ by less than 10 %, especiallyby less than 5%, such as by less than 3 %, especially by less than 1 %, including (essentially) by 0 %.

[0049] The difference in (contact) surface area may be determined relative to the largest (contact) surface area of the respective electrodes.

[0050] The term ‘contact surface area’ may herein refer to the area of the electrode that, during use, will be in (physical) contact with the nerve. For instance, in embodiments, part of a surface area of the electrode may be a contact surface area in (physical) contact with the nerve, whereas a (non-conductive) material may be arranged between the nerve and another part of the surface area of the electrode.

[0051] In further embodiments, longitudinally aligned electrodes, such as first electrodes and second electrodes, and / or such as second electrodes and third electrodes (see below), may have (essentially) equal lengths (L) and widths (W). In particular, in embodiments, longitudinally aligned electrodes may have (essentially) the same aspect ratio. In embodiments, the aspect ratio of longitudinally aligned electrodes differs less than 10 %, especially less than 5 %, such as less than 3%, including (essentially) 0%.

[0052] In further embodiments, electrodes of the first electrode array and the second electrode array may be arranged in a staggered configuration. In such embodiments, the first electrodes and the second electrodes may be positioned at an offset or an alternating pattern rather than being longitudinally aligned.

[0053] In further embodiments, the electrode arrangement, especially the electrode array, may further comprises a third electrode array (or “third array”), wherein the third electrode array is spatially separated from the first electrode array and from the second electrode array along the longitudinal dimension of the nerve. In such embodiments, at least part of the electrode sets may (further) comprise a third (commission) electrode from the third electrode array. Especially, at least part of the electrode sets may comprise a first (commission) electrode from the first array, a second (commission) electrode from the second array, and a third (commission) electrode from the third array. In further embodiments, at least one electrode set of the operational electrode set may comprise a third electrode from the third electrode array.

[0054] In embodiments, for each second electrode may apply that the second electrode is longitudinally aligned with a (respective) third electrode, especially wherein (contact) surface areas of the second electrode and of the third electrode differ by less than 10 %, especially by less than 5 %, such as by less than 3 %, especially by less than 1 %, including by (essentially) 0 %.The third electrode array may comprises m third electrodes. In embodiments, ns may be selected from the range of 3 - 40, such as from the range of 4 - 16, especially from the range of 4 - 10, such as from the range of 6 - 8. In further embodiments, ns > 3, such as > 4, especially > 6. In further embodiments, ns < 16, especially < 12, such as < 10, especially < 8. In further embodiments, ns may be selected from the range of 4 - 10. In further embodiments, the second array may comprise n2 electrodes, the third array may comprise ns electrodes, and n2 = ns. In further embodiments, m = n2 = ns.

[0055] The electrodes may comprise essentially any biocompatible electrode material. In embodiments, the electrodes may especially comprise a high charge-injection material selected from the group comprising platinum iridium oxide and reduced graphene oxide. High charge-injection materials may be relatively robust to direct current (DC) bias, and may thus be relatively tolerant to accumulating charge, and may therefore also be safer for the surrounding biological tissue (as electrode damage may lead to tissue damage).

[0056] The electrode arrangement may especially comprise a hosting element configured for at least partially surrounding the (target) nerve. As a nerve may typically have a tubular shape, the hosting element may be configured to define a tubular space for hosting the nerve. In particular, in embodiments, the hosting element may comprise a tubular hosting element, wherein the tubular hosting element is configured to define a tubular space for hosting the nerve. Especially, during use, such as during one or more of the commissioning mode and the operational mode, the (tubular) hosting element may (partially) surround the nerve and be in physical contact with the nerve.

[0057] The implantable device may further comprise a pulse generator. The pulse generator may be configured to provide an electrical signal (or “electrical pulse”) via the electrode arrangement, especially via a commission electrode set or an operational electrode set (see below). In particular, when the electrode arrangement is configured engaged with a nerve, the pulse generator may be configured to apply an electrical signal to the nerve via the electrode arrangement.

[0058] As described above, the system may further comprise a control system. The control system may be configured to (have the system) execute a commissioning mode. The commissioning mode may be directed to identifying an operational scheme of the implantable device for eliciting a desired physiological response in a subject.

[0059] The commissioning mode may be executed when the electrode arrangement engages a nerve, such as (directly) after implantation of the implantable device, or such as when a desired physiological response is no longer achieved and a new operational scheme is to beidentified, e.g., in view of an issue with an electrode in a (former) operational electrode set. In either case, in the commissioning mode the electrode arrangement may (be configured to) engage the nerve.

[0060] It may be undesirable that the commissioning mode needs to be repeated when a desired physiological response is no longer achieved as any delay may be uncomfortable for the subject. Accordingly, the control system may (be configured to) designate a plurality of operational schemes based on the related sensor signals and the target physiological response. In such embodiments, the implantable device may be configured switchable between the defined operational schemes, such as based on user input. For instance, the system, especially the control system, may comprise a user interface allowing a user to switch between operational schemes.

[0061] If multiple operational schemes are defined, the implantable device may further be configured to alternate between (operating according to) the different operational schemes (of the plurality of operational schemes), e.g., according to user input or according to a time schedule. Such switching may be beneficial in view of local thermal heat build-up (switch to other contact areas) and / or in view of conditioning or habituation.

[0062] Further, switching between electrode sets may, in embodiments, also occur within an operational scheme. In particular, an operational scheme may define (regular) switching between different electrode sets and / or electrical signal parameters. The switching may facilitate avoiding excess local thermal heat generation and desensitization.

[0063] In general, however, the operational scheme may prescribe simultaneous operation of the electrode sets in the operational electrode set (during at least part of an operational time period). By distributing the provided current over multiple electrode sets, overall thermal heat generation and battery usage may be reduced.

[0064] In the commissioning mode, the pulse generator may (be configured to) successively provide electrical signals to the nerve with different (commission) electrode sets of the electrodes.

[0065] The electrical signals may have signal parameters selected for modulating nerve activity. For instance, the electrical signals may have signal parameters selected for stimulating, such as initiating or enhancing, action potential conduction in the nerve. Alternatively, the electrical signals may have signal parameters selected for blocking, such as preventing or reducing, action potential conduction in the nerve, such as by preventing the action potential to propagate beyond an area of the nerve covered by an electrode. The signal parameters may, forinstance, comprise a frequency, an intensity (current amplitude), a duration, a pulse width, a duty cycle, a pulse shape, a net charge accumulation (over time), and a charge per time (CPT).

[0066] The term “amplitude” may herein especially refer to a maximum absolute value of a difference between a peak amplitude and a reference amplitude.

[0067] The term “charge per time” (CPT) of an electrical signal may herein refer to the product of the frequency FE, the (absolute) amplitude AE, and the pulse width Tp(of each phase) of the electrical signal during a timeframe, such as during a therapeutic period, i.e. CPT = FE*AE*TP. In particular, the frequency FE, the (absolute) amplitude AE, and the pulse width Tp (of each phase) may be constant during the timeframe.

[0068] For a given electrode geometry, the spread of the electric field within a nerve depends on the applied extracellular potential (via the electrode set). Higher current amplitudes / pulse widths may result in a larger penetration depth, which may in turn result in modulation of deeper fibers. Depending on the nerve topology of a subject, the relevant fibers for the target physiological effect could be located superficially or deep in the nerve. Similarly, fibers with different diameters may be addressable with different signal parameters. Accordingly, in order to effectively map the respective contribution of individual electrode sets and their location on the nerve, different signal parameters may be explored. In particular, during the commissioning mode, the pulse generator may be configured to provide each electrical signal with a temporal variation in one or more signal parameters. Thereby, different values of one or more signal parameters may be evaluated for a (commission) electrode set in a single electrical signal, which may substantially reduce the duration of the commissioning mode. Accordingly, in embodiments, the pulse generator may (be configured to) provide the electrical signals (for each electrode set) with a temporal variation in one or more of intensity (current amplitude), charge per time, duration, frequency, pulse width, duty cycle, and pulse shape (e.g., rectangular, or sinusoidal), a gap duration (of gap phases; see below), and a cathodic / anodic amplitude ratio, especially in one or more of intensity, charge per time, gap duration, and pulse width, such as in one or more of intensity, charge per time, and pulse width.

[0069] The commissioning mode may thus involve the application of a ramped stimulation protocol. For instance, the control system may initiate a series of stimulation trials, gradually increasing the amplitude and / or pulse width in a controlled manner. In contrast to currently used strategies of using bursts of pulses to determine strengths of physiological responses in a point-by-point manner, using continuous amplitude (and / or pulse-width) ramps may provide a much faster and more exact quantification of electrode contact site contributions and corresponding signal parameters to a physiological response. Speed and precision may bekey factors in the context of clinical feasibility, and may facilitate exploring more available options (in terms of electrodes and signal parameters), which may in turn lead to improved operational schemes.

[0070] Accordingly, in embodiments, in the commissioning mode, the pulse generator may (be configured to) provide the electrical signals with an intensity ramp and / or with a pulse width ramp. The ramp(s) may especially be monotonically increasing or decreasing. In embodiments, the ramps may be continuously increasing or decreasing. In further embodiments, the ramps may comprise stepwise increases or stepwise decreases. In view of safety considerations, an increasing ramp may be preferred such that an electrical signal can be ceased, e.g., automatically in view of detected physiological signals or by the subject, when adverse effects are detected to avoid higher signal parameters.

[0071] Especially, in embodiments, the pulse generator may (be configured to) provide the electrical signals with a monotonically increasing intensity ramp, especially a continuously monotonically increasing intensity ramp, or especially a stepwise monotonically increasing intensity ramp.

[0072] In further embodiments, the pulse generator may (be configured to) provide the electrical signals with a monotonically increasing pulse width ramp, especially a continuously monotonically increasing pulse width ramp, or especially a stepwise monotonically increasing pulse width ramp.

[0073] In embodiments, the electrical signal may comprise cathodic phases and anodic phases. In embodiments, the cathodic and anodic phases may be successively arranged (without intervening gaps). For instance, the phases may be arranged as follows: Cathodic-Anodic-Cathodic- Anodic-C-A-C-A-.... The absence of gaps (or gaps with short durations) may provide the benefit that the amplitude may be kept (relatively) low (depending on pulse width), which may lower energy consumption.

[0074] The terms “cathodic phase” and “anodic phase” herein refer to phases wherein the electrical signal has opposite sign, i.e., the sign of the electrical signal in the cathodic phase is the opposite of the sign of the electrical signal in the anodic phase, wherein the sign of the cathodic phase may be negative.

[0075] In further embodiments, the electrical signal may further comprise gap phases, especially wherein the gap phases are interspersed between successive cathodic phases and anodic phases. For instance, the phases may be arranged as follows: Cathodic-Gap-Anodic-G-C-G-A-G-..., or as follows: Cathodic-Gap-Anodic-G-A-G-C-G-C-G-A-.... Hence, in embodiments, the electrical signal further comprises gap phases, wherein the gap phases areinterspersed between successive cathodic phases and anodic phases (including between successive anodic phases and thereupon following cathodic phases), and, in embodiments where cathodic phases (and anodic phases) may be grouped together in sets of two, in between (each set of) two successive anodic phases and in between (each set of) two successive cathodic phases. The gap phases may facilitate charge balancing and / or recovery of the nerve fibers in between successive cathodic and anodic phases. However, other arrangements of gap phases are also possible.

[0076] The term “electrode set” (also “commission electrode set”) may herein refer to a group of one or more electrodes tested (as a group) during the commissioning stage. For instance, in the context of bipolar stimulation, the electrode set may comprise two electrodes. Alternatively, in the context of tripolar stimulation, the electrode set may comprise three electrodes. Within the commissioning stage, electrode sets with different numbers of electrodes may be evaluated.

[0077] The electrode sets may especially be proper subsets of the (total set of) electrodes. These electrode sets can cover single electrodes (monopolar), electrode pairs (bipolar), three electrodes (tripolar), and in principle also larger numbers of electrodes. In embodiments, each electrode set may comprise at least one electrode, such as at least 2 electrodes, especially at least 3 electrodes, such as at least 4 electrodes. In further embodiments, each electrode set may comprise at most 8 electrodes, such as at most 6 electrodes, especially at most 4 electrodes, such as at most 3 electrodes. For instance, in embodiments, each electrode set may comprise 2-4 electrodes, such as 2-3 electrodes, especially 2 electrodes.

[0078] The electrode sets may comprise multiple electrodes from the same electrode array. In principle, an electrode set may comprise electrodes from a single electrode array, such as only first electrodes or only second electrodes. Generally, however, the electrode sets may comprise electrodes from multiple electrode arrays. For instance, in embodiments, (at least part of) the electrode sets may comprise one or more electrodes from two (different) electrode arrays, such as one or more first electrodes and one or more second electrodes. Especially, (at least part of) the electrode sets may comprise one or more electrodes from each electrode array. In further embodiments, (at least part of) the electrode sets may comprise at most half of the electrodes of each electrode array, such as at most a quarter of the electrodes, e.g., at most half of the first electrodes and at most half of the second electrodes. In yet further embodiments, (at least part of) the electrode sets may comprise 5-50% of the electrodes of each electrode array.

[0079] Hence, the pulse generator, optionally controlled by the control system, may (successively) provide electrical signals, especially time-varying electrical signals, to the nervevia multiple electrode sets (one at a time) during the commissioning stage. Thereby, different sets of electrodes and different signal parameters can be evaluated for defining a suitable operational scheme (see below). The control system may thus be configured to access stimulation information, i.e., information on the used electrode sets and on the electrical signals. For instance, the control system may be configured to obtain the stimulation information from the pulse generator, such as by the pulse generator being configured to provide the stimulation information to the control system. Alternatively, the control system may define the stimulation information and may control the pulse generator to act accordingly.

[0080] Further, in order to determine the physiological effects of the different electrode sets and signal parameters, the physiological sensor may monitor the subject. Accordingly, during the commissioning mode, the physiological sensor may (be configured to) monitor, such as to intermittently sense, or such as to continuously monitor, one or more physiological parameters (see above) of the subject, and especially to provide related sensor signals to the control system. As will be clear to the skilled person, the physiological parameters may especially be selected in view of a target physiological response and an undesired physiological response. The terms “target physiological response” and “undesired physiological response” may herein also refer to a plurality of such responses.

[0081] The term related sensor signal may herein refer to a signal that is related to the detected physiological parameter(s). In particular, the related sensor signal may comprise raw and / or processed data related to the one or more physiological parameters.

[0082] Based on the stimulation information and the related sensor signal, the control system may determine the suitability of different electrode sets and corresponding operational parameters for achieving a target physiological response, while not achieving an undesired physiological response. Accordingly, in the commissioning mode, the control system may (be configured to) define an operational scheme based on the stimulation information, the related sensor signals, a target physiological response, and an undesired physiological response. The operational scheme may designate an operational electrode set and (corresponding) electrical signal parameters.

[0083] In embodiments, the control system may (be configured to) define the operational scheme essentially automatically, i.e., without the intervention of a user, such as the subject, or such as a physician.

[0084] In further embodiments, the control system may (be configured to) define the operational scheme in interaction with an (expert) user, such as in interaction with a physician. The control system may, for instance, be configured to provide one or more options for theoperational scheme in view of predefined criteria, and the user may provide user input to tailor the operational scheme. Thereby, the user may tune the operational scheme in view of any (secondary) factors relevant for the subject.

[0085] In the definition of the operational electrode set, the control system may consider the effects on the target physiological response for different electrode sets in view of (a) the tested signal parameters, (b) predefined limits to stimulation conditions, such as limits to amplitude or thermal heat generation, and (c) adverse effects. For instance, if (onset of) the desired physiological response is only observed above a first intensity threshold for a first electrode set, the control system may set the first intensity threshold as a minimal value (or “lower boundary”) for the first electrode set. Similarly, if (onset of) an undesired adverse effect is observed above a second intensity threshold for a second electrode set, the control system may set the second intensity threshold as a maximal value (or “upper boundary”) for the second electrode set. Similarly, a desired response may only be observed above a threshold, or an undesired effect may only be observed below a threshold.

[0086] Accordingly, in embodiments, the control system may be configured to determine threshold values for the electrode sets based on the related sensor signals and the target physiological response. In such embodiments, the control system may (be configured to) define the operational scheme in view of the threshold values. For instance, in further embodiments, the electrical signal parameters comprise intensity parameters, wherein the control system is configured to define the intensity parameters for each electrode set in the operational electrode set in view of the intensity threshold values. In particular, in such embodiments, the selected electrical signal parameters may satisfy the threshold value(s) for each electrode set in the operational electrode set. Further, in such embodiments, if the threshold values for a given electrode set cannot be satisfied, the electrode set may be omitted from the operational electrode set, i.e., other electrode sets may be selected. In further embodiments, the threshold values may comprise one or more of intensity threshold values, charge per time (CPT) threshold values, and charge density threshold values.

[0087] In further embodiments, the (intensity) threshold values comprise minima, and the control system is configured to define the signal parameters above the minima, such as to define intensity parameters above intensity minima. Similarly, in embodiments, the (intensity) threshold values comprise maxima, and the control system is configured to define the signal parameters below the maxima, such as to define intensity parameters below intensity limits.

[0088] Accordingly, in the operational mode of the implantable device, the pulse generator may be configured to operate in view of the threshold values.The control system may further be configured to define the operational scheme in view of predefined operational limit, such as predefined safety limits.

[0089] For instance, in embodiments, the control system may have access to a predefined total electrical current limit Emax. In such embodiments, the electrical signal parameters (of the operational scheme) may comprise an electrical current value E20 for each electrode set. In particular, the control system may be configured to define the operational scheme such that the (combined) electrical current values E20 (of all electrode sets in the operational scheme) are below or equal to the total electrical current limit Emax, i.e., SF=i E20 (0 Emax, where n is the number of electrode sets in the operational scheme, and wherein E2o(i) corresponds to the electrical current value E20 for the ithelectrode set in the operational scheme. In further embodiments, Emaxmay be selected from the range of 50 pA -20 mA, especially from the range of 1 - 12 mA , or especially from the range of 100 pA - 10 mA, such as from the range of 500 pA - 6 mA.

[0090] Similarly, in embodiments, the electrical signal parameters for each electrode set in the operational electrode set include a charge density D20. That is, the electrical signal parameters (of the operational scheme) may comprise a charge density D20 for each electrode set. In embodiments, the charge density D20 may be selected from the range of 0.002 mC / cm2- 1.2 mC / cm2, such as from the range of 0.005 mC / cm2- 0.6 mC / cm2, especially from the range of 0.01 mC / cm2- 0.3 mC / cm2, such as from the range of 0.02 mC / cm2- 0.2 mC / cm2The charge density D20 may be the same for each electrode set, i.e., each electrode set may have the same charge density D20. Alternatively, the charge density D20 may be individually selected for each electrode set, such as individually selected from the range of 0.002 - 1.2 mC / cm2, such as from the range of 0.005 - 0.6 mC / cm2, especially from the range of 0.01 - 0.3 mC / cm2, such as from the range of 0.02 - 0.2 mC / cm2In such embodiments, the electrical signal parameters may further include a mean charge density Dm, wherein the mean charge density Dmmay be (the mean) determined from the charge densities D20 of all electrode sets in the operational electrode set. In embodiments, the mean charge density Dmmay be selected from the range of 0.002 - 1.2 mC / cm2, such as from the range of 0.005 - 0.6 mC / cm2, especially from the range of 0.01 - 0.3 mC / cm2, such as from the range of 0.02 - 0.2 mC / cm2

[0091] In further embodiments, the electrical signal parameters for the operational electrode set include a total charge per time CPTtot. In such embodiments, the electrical signal parameters (of the operational scheme) may comprise a CPT for each electrode set. In particular, the control system may be configured to define the operational scheme such that the (combined) charge per time CPT20 (of all electrode sets in the operational scheme) are equal tothe total charge per time CPTtot, i.e., ^F=i CPT2Q(i) = CPTtot, where n is the number of electrode sets in the operational scheme, and wherein CPT2o(i) corresponds to the charge per time CPT20 for the ithelectrode set in the operational scheme. In further embodiments, the total charge per time CPTtot may be selected from the range of 0.25 - 7.0 mC / s, such as from the range of 1.0 - 7.0 mC / s, or such as from the range of 0.75 - 6.5 mC / s, especially from the range of 1.0 - 6.0 mC / s. In further embodiments, the total charge per time CPTtot may be selected from the range of 0.4 - 5.0 mC / s, especially from the range of 0.5 - 4.0 mC / s, such as from the range of 0.7 - 3.0 mC / s, especially from the range of 0.8 - 2.0 mC / s, such as from the range of 0.9 - 1.5 mC / s. In particular, a charge per time (CPT) in such range may provide an effective blocking effect while having limited to no undesired transiently initiating action potentials before the nerve block is established (“onset effect”) or after the block is relieved (“offset effect”).

[0092] In embodiments, the operational electrode set may comprise at least two of the electrode sets. In particular, the operational electrode set may be a superset of two or more electrode sets, especially without any single electrode set of the two or more electrode sets comprising the operational electrode set. In other words, the operational electrode set may not necessarily be tested as an (commission) electrode set during the commissioning mode, but the suitability of the operational electrode set may be derived from the tests performed using the electrode sets (comprised by the operational electrode set). For instance, if two non-overlapping electrode sets of two electrodes each are identified that are both suitable for achieving the target physiological response, the operational electrode set may comprise all four electrodes of the two electrode sets, and the operational parameters may be selected in view of the performance of the individual electrode sets (see examples below). By operating using multiple electrode sets, the total charge applied to the nerve may remain the same as when using a single electrode set, while the (combined) thermal energy deployed during stimulation or the (required) energetic demand to apply the electrical signal(s) may be substantially lower (as these factors may scale supralinearly, such as according to a power law). The lower intensity may result in decreased thermal heat generation and in a lower energy consumption.

[0093] In further embodiments, the operational electrode set may comprise at least two electrode sets, such as at least three electrode sets, especially at least four electrode sets.

[0094] In further embodiments, the operational electrode set may comprise at least four electrodes, such as at least five electrodes, especially at least six electrodes.

[0095] In specific embodiments, each electrode set may comprise two electrodes, and the operational electrode set comprises 2-4 electrode sets, such as 2-3 electrode sets, especially2 electrode sets. An operational electrode set comprising 2 electrode sets may be provide a suitable balance between the complexity, size, energy demand, and / or cost of the electronics on one side, and the performance of the implantable device on the other side. However, an operation electrode set comprising more than 2 electrode sets is herein not excluded.

[0096] As described above, the use of multiple electrode sets may facilitate reducing energy consumption and thermal heat generation by splitting the applied charge, thereby resulting in a lower overall intensity. For reducing the overall intensity with two electrode sets, a 50 / 50 split may be preferred. Further, in view of the strength of the desired response, it may be preferred to allocate a larger proportion of the current to the best-performing electrode set. Similarly, as describe above, the electrical signal parameters for different electrode sets may be selected in view of the respective threshold values, which may differ for different electrode sets. In view of the response strength and the threshold values an unequal charge distribution may be preferred, e.g. a 40 / 60 split or a 30 / 70 split.

[0097] For instance, in specific embodiments, the operational electrode set comprises 2 electrode sets, wherein the electrical current values E20 for the 2 electrode sets (in the operational electrode set) differ by less than 40% (relative to a largest electrical current value for the 2 electrode sets), such as by less than 35%, especially by less than 30%, such as by less than 25%.

[0098] It will be clear to the person skilled in the art that various approaches may be taken for determining a (final) distribution of the electrical parameters over the different electrode sets. For instance, when the operational electrode set comprises two electrode sets, as a rule of thumb, a 50 / 50 current distribution may be selected. More generally, if n electrode sets are selected, each electrode set may be assigned l / nthof a total current. Such an approach may be attractive due to its simplicity. Another approach may be to distribute the current according to the effect strength of each electrode set on the desired physiological response, assigning a higher proportion of the current to electrode sets with a higher effect strength. Such an unequal current distribution may, for instance, be selected to be proportional to the effect strength (or “a linear division”), but may also be non-linear (squared, sqrt, polynomial, etc.). Relative to an equal split, an unequal split may facilitate eliciting a stronger physiological response for a given total current.

[0099] In further embodiments, the operational electrode set comprises n electrode sets, wherein the electrical signal parameters include an electrical current value E20 for each of the n electrode sets, wherein the electrical current values E20 comprise a lowest electrical current value E2o,min and a highest electrical current value E2o.max, and wherein E?o max E?o min < 5, suchas < 4, especially < 3, such as < 2. Further, in embodiments, E2o,max / E2o,min < 1.40, such as < 1.35, especially < 1.30, such as < 1.25. In further embodiments, n may be selected from the range of 2-4.

[0100] In further embodiments, the operational electrode set comprises n electrode sets, wherein the electrical signal parameters include a CPT value CPT20 for each of the n electrode sets, wherein the CPT values CPT20 comprise a lowest CPT value CPT2o,min and a highest CPT value CPT2o.max, and wherein CPT2o,max / CPT2o,min < 5, such as < 4, especially < 3, such as < 2. Further, in embodiments, CPT2o,max / CPT2o,min < 1.40, such as < 1.35, especially < 1.30, such as < 1.25. In further embodiments, n may be selected from the range of 2-4.

[0101] In further embodiments, the operational electrode set comprises n electrode sets, wherein the electrical signal parameters include a charge density value D20 for each of the n electrode sets, wherein the charge density values D20 comprise a lowest charge density value D2o,min and a highest charge density value D2o.max, and wherein D?omax / D?omin < 5, such as < 4, especially < 3, such as < 2. Further, in embodiments, D?omax / D?omin < 1.40, such as < 1.35,

[0102]

[0103] especially < 1.30, such as < 1.25. In further embodiments, n may be selected from the range of 2-4.

[0104] The operational scheme may be defined in view of suitability for eliciting the target physiological response. Accordingly, the implantable device may subsequently operate in line with the operational scheme to provide the target physiological response. Hence, in embodiments, in an operational mode of the implantable device, the implantable device is configured to operate (the pulse generator) based on the operational scheme.

[0105] In embodiments, the operational scheme may indicate (precise) electrical signal parameters for the operational electrode set.

[0106] However, in further embodiments, the operational scheme may comprise electrical signal parameter ranges for the operational electrode set. In such embodiments, the implantable device may be configured to vary the operational electrical signals within the electrical signal parameter ranges, such as in view of real-time physiological responses to the electrical signal. For instance, in the operational mode, the physiological sensor may be configured to monitor one or more physiological parameters of the subject and to provide related operational sensor signals to an implantable device control system (of the implantable device), or especially to the control system, especially wherein the (implantable device) control system is configured to select signal parameters within the electrical signal parameter ranges based on the related operational sensor signals.In further embodiments, in the operational mode, the control system may be configured to update the operational scheme based on the related operational sensor signals and the target physiological response to provide an updated operational scheme comprising updated electrical signal parameter ranges for the operational electrode set, especially wherein the updated electrical signal parameter ranges fall within the (original) electrical signal parameter ranges. Thereby, a suitable parameter space may be initially identified, e.g., together with a physician, and the parameter space may be narrowed over time based on detected physiological responses and / or user input corresponding to different signal parameters, i.e., the control system may be configured to further tune the operational scheme during use (within predefined signal parameter ranges). Subsequently, in such embodiments, the implantable device may (be configured to) operate (the pulse generator) based on the updated operational scheme.

[0107] Besides objective data obtained by the physiological sensor, also effects self-reported by the subject or observed by a physician may facilitate identifying a suitable operational electrode set. Accordingly, in embodiments, the control system may be configured to receive user input, such as input from the subject, or such as input from a physician. For instance, the control system may comprise a user interface configured to receive user input. In such embodiments, the control system may be configured to define the operational scheme in dependence of the user input.

[0108] It will be clear to the person skilled in the art that the nerves to be engaged should be selected in view of the target physiological response, i.e., not all physiological responses can be achieved with any nerve.

[0109] In embodiments, the nerve may, for instance, comprise a cranial nerve, especially a vagus nerve. The vagus nerve may play a key role in the regulation of various physiological functions, including functions related to respiration, heart rate, digestion, and immune response. Further, stimulation of the vagus nerve can (directly) influence brain activity, e.g., in the context of treating epilepsy. By applying electrical signals to the vagus nerve, a wide range of target physiological responses may thus be achievable but, by extent, also various undesired physiological responses may be elicited. The system of the invention may be particularly suitable in identifying an operational scheme to selectively achieve the target physiological responses while limiting, or even avoiding, any undesired physiological responses, which may be particularly useful when addressing the vagus nerve.

[0110] For instance, in embodiments, the nerve may comprise the vagus nerve, the target physiological response may comprise a pulmonary response, and the undesired physiological response comprises a cardiac arrhythmia, such as an arrhythmia selected fromthe group comprising severe sinus bradycardia, AV blocks, SA blocks, bundle branch blocks, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation.

[0111] The target physiological response may be achievable by modulation of action potential conduction in the nerve, such as in the vagus nerve. Depending on the target physiological response, the modulation may be an increase in action potential conduction or a decrease in action potential conduction. Hence, in embodiments, the operational mode may comprise blocking of the action potential in the nerve (to achieve the target physiological response). In further embodiments, the operational mode may comprise stimulating, such as eliciting or increasing, the action potential in the nerve (to achieve the target physiological response).

[0112] In embodiments, the control system may be configured to determine a (relative) magnitude of the target physiological response, and optionally of the undesired physiological response, for each of the electrode sets in the commissioning mode. In such embodiments, the control system may be configured to define the operational scheme in view of the (relative) magnitude of the target physiological response and, if applicable, (the (relative) magnitude of) the undesired physiological response. For instance, the best performing electrode set may be assigned a larger proportion of the current than the other electrode set(s) in the operational electrode set, i.e., the electrical current values E20 may be assigned in proportion to the performance of the electrode sets in achieving the target physiological response. Accordingly, in embodiments, the control system may (be configured to) define the electrical current values E20 for each electrode set in the operational scheme in view of the (relative) magnitude of the target physiological response, and optionally in view of the (relative) magnitude of the undesired physiological response.

[0113] Similarly, in embodiments, the best performing electrode set may be assigned a larger proportion of the total charge per time CPTtot than the other electrode set(s) in the operational electrode set, i.e., the CPT20 may be assigned in proportion to the performance of the electrode sets in achieving the target physiological response. Accordingly, in embodiments, the control system may (be configured to) define the CPT20 for each electrode set in the operational scheme in view of the (relative) magnitude of the target physiological response, and optionally in view of the (relative) magnitude of the undesired physiological response.

[0114] In further embodiments, the best performing electrode set may be assigned a larger charge density D20 than the other electrode set(s) in the operational electrode set, i.e., the D20 may be assigned in proportion to the performance of the electrode sets in achieving the target physiological response. Accordingly, in embodiments, the control system may (beconfigured to) define the D20 for each electrode set in the operational scheme in view of the (relative) magnitude of the target physiological response, and optionally in view of the (relative) magnitude of the undesired physiological response.

[0115] In specific embodiments, the control system may be configured to define the operational scheme in view of a ratio between the magnitude of the target physiological response for (or “elicited by”) different electrode sets. For instance, if two electrode sets are selected for the operational electrode set, and the performance of a first electrode set is double that of the second electrode set, the control system may be configured to prioritize applying current via the first electrode set. For instance, the control system may be configured to define the electrical current values for the electrode sets in line with the ratio between their target physiological response magnitudes, e.g., £20,1 / 1120,2 = 2 for the above example, where £20,1 and E20.2 are the electrical current values for the first and second electrode set, respectively. Accordingly, in embodiments, a ratio between the electrical current values E20 assigned to the electrode sets may be (essentially) equal to a ratio between the (relative) magnitudes of the target physiological response for the (respective) electrode sets. The current values may, as described above, further be selected in view of threshold values and in view of maximal differences between the electrode sets. Accordingly, the control system may be configured to define the electrical current values to be close to the ratio (insofar possible), while satisfying the threshold values and the maximal differences between the electrical current values for different electrode sets.

[0116] Similarly, in embodiments, a ratio between the CPT values CPT20 assigned to the electrode sets may be (essentially) equal to a ratio between the (relative) magnitudes of the target physiological response for the (respective) electrode sets. The CPT values may further be selected in view of threshold values and in view of maximal differences between the electrode sets.

[0117] In further embodiments, a ratio between the charge density values D20 assigned to the electrode sets may be (essentially) equal to a ratio between the (relative) magnitudes of the target physiological response for the (respective) electrode sets. The charge density values may further be selected in view of threshold values and in view of maximal differences between the electrode sets.

[0118] In a second aspect, the invention further provides a method for determining an operational scheme of an implantable device for modulating an action potential in a nerve of a subject. In particular, the implantable device may comprise an electrode arrangement, wherein the electrode arrangement comprises n electrodes, especially wherein n > 4. The electrodearrangement may be configured engaged with the nerve such that the electrodes are arranged (circumferentially) around the nerve in an electrode array. The method may comprise successively providing electrical signals to the nerve with different (commission) electrode sets of the electrodes, especially using a pulse generator. The method may further comprise monitoring one or more physiological parameters of the subject and providing related (sensor) signals, especially using one or more physiological sensors. In embodiments, the method may comprise defining an operational scheme based on the related (sensor) signals and a target physiological response. The operational scheme may especially designate an operational electrode set and (corresponding) electrical signal parameters. In embodiments, the operational electrode set may comprise at least two of the (commission) electrode sets. The method may further comprise configuring (or ‘setting up’) an operational mode of the implantable device, wherein, in the operational mode, the implantable device operates based on the operational scheme.

[0119] Hence, the invention provides, in specific embodiments, a method for determining an operational scheme of an implantable device for modulating an action potential in a nerve of a subject, wherein the implantable device comprises an electrode arrangement, wherein the electrode arrangement comprises n electrodes, wherein n > 4, wherein the electrode arrangement is configured engaged with the nerve such that the electrodes are arranged around the nerve in an electrode array, and wherein the method comprises: successively providing electrical signals to the nerve with different electrode sets of the electrodes; monitoring one or more physiological parameters of the subject and providing related sensor signals; defining an operational scheme based on the related sensor signals and a target physiological response, wherein the operational scheme designates an operational electrode set and electrical signal parameters, wherein the operational electrode set comprises at least two of the electrode sets; and configuring an operational mode of the implantable device, wherein, in the operational mode, the implantable device operates based on the operational scheme.

[0120] The implantable device may especially be implanted in the subject prior to the execution of the method. In particular, the electrode arrangement may be configured engaged with the nerve, such as with the vagus nerve, prior to the execution of the method.

[0121] In specific embodiments, however, the method may comprise implanting the implantable device in the subject. Especially, the method may comprise arranging the electrode arrangement to engage with the nerve.

[0122] In embodiments, the method may comprise providing the electrical signals with each electrode set with a temporal variation in one or more of intensity, charge per time,duration, frequency, pulse width, duty cycle, and pulse shape, especially in one or more of intensity and pulse width.

[0123] In further embodiments, the method may comprise determining threshold values, such as intensity threshold values, for the electrode sets based on the related sensor signals and the target physiological response. In such embodiments, the method may further comprise defining the electrical signal parameters (of the operational scheme) in view of the threshold values. For instance, the method may comprise defining intensity parameters (of the electrical signal parameters) for each electrode set in the operational electrode set in view of the intensity threshold values.

[0124] As described above, the electrode arrangement, especially the electrode array, may comprise a plurality of electrode arrays, such as (at least) a first electrode array and a second electrode array. In such embodiments, the electrode arrays, such as the first electrode array and the second electrode array, may be configured spatially separated along a longitudinal dimension of the nerve. In further embodiments, at least part of the electrode sets may comprise electrodes from multiple electrode arrays, such as a first electrode from the first electrode array and a second electrode from the second electrode array. In further embodiments, at least one electrode set of the operational electrode set may comprise electrodes from multiple electrode arrays, such as a first electrode from the first electrode array and a second electrode from the second electrode array.

[0125] In further embodiments, the electrode arrangement, especially the electrode array, may further comprise a third electrode array. The third electrode array may be spatially separated from the first electrode array and from the second electrode array along the longitudinal dimension of the nerve. In further embodiments, at least part of the electrode sets comprise electrodes from three or more electrode arrays, such as a first electrode from the first electrode array, a second electrode from the second electrode array, and a third electrode from the third electrode array. In further embodiments, the operational electrode set comprises at least one electrode set comprising a third electrode from the third electrode array.

[0126] The method may comprise monitoring one or more physiological parameters, optionally using one or more physiological sensors (see above). In embodiments, the physiological parameters may be selected from the group comprising a respiratory rate, a respiratory volume, e.g., tidal volume or minute volume, coughing, airway resistance, lung compliance, lung elastance, inspiration / expiration ratio, a pulmonary oscillometry parameter, e.g., R5, R5-20, R5-19, AX, or X5, a spirometry parameter, e.g., FEV1, FVC, FEV1 / FVC, FEF 25-75, MW, or VC, a lung plethysmography parameter, respiratory and cardiac parametersderived from transthoracic impedance measurements, tracheal pressure, e.g., by pressure sensor, heart rate, e.g., by ECG or pulse oximetry, heart rate variability, e.g., pNN50, HF / LF, SDNN, RMSSD, SI, or NN50, a heart rhythm abnormality, such as an abnormality detectable by ECG (e.g., bradyarrhythmias, tachyarrhythmias, AV blocks, SA blocks, bundle branch blocks, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, QT prolongation), a stroke volume change, especially changes in ejection fraction, a heart contractility parameter, a heart movement abnormality, e.g., detectable by echocardiography, MRI, or transthoracic impedance tomography, a systemic blood pressure, a pulmonary blood pressure, a glucose plasma level, a plasma level of a biomarker, e.g., a plasma level of one or more of insulin, glucagon, GLP1, GIP, CCK, PYY, leptin, ghrelin, amylin, neurofilament light chain, CRP, calprotectin, procalcitonin, fibrinogen, WBC, TNF alpha, IL6, IL1 alpha and beta, IL 12, and other inflammatory biomarkers, body temperature, blood oxygen level, e.g., paO2 and SatO2, blood CO2 level, e.g., paCO2, brain activity, e.g., a brain activity change detected by EEG, magnetoencephalography or fMRI, a nerve activity, e.g., a spontaneous or evoked activity change, such as detectable by recording electrodes, stomach motility, intestinal motility, e.g., detected by abdominal surface EMG, a laryngeal activity, e.g., detectable by needle or surface or endotracheal surface EMG, such as relating to the activity of cricopharyngeal, cricothyroideal or other laryngeal muscles, and a pain level, e.g., based on subject input or physician input.

[0127] As described above, the method may comprise defining an operational scheme based on the related (sensor) signals and a target physiological response. Optionally, the method may further comprise considering one or more undesired physiological responses. Accordingly, in embodiments, the method comprises defining the operational scheme based on the related sensor signals, the target physiological response, and an undesired physiological response.

[0128] For instance, in embodiments, the nerve comprises the vagus nerve, and the method comprises defining the operational scheme based on the related (sensor) signals, the target physiological response and an undesired physiological response, especially wherein the target physiological response comprises a pulmonary response, and especially wherein the undesired physiological response comprises a cardiac arrhythmia.

[0129] In embodiments, the operational electrode set may comprise at least two of the electrode sets. In particular, the operational electrode set may be a superset of two or more electrode sets, especially without any single electrode set of the two or more electrode sets comprising the operational electrode set. In further embodiments, the operational electrode setmay comprise at least two electrode sets, such as at least three electrode sets, especially at least four electrode sets. In further embodiments, the operational electrode set may comprise at least four electrodes, such as at least five electrodes, especially at least six electrodes. In specific embodiments, each electrode set may comprise two electrodes, and the operational electrode set comprises 2-4 electrode sets, such as 2-3 electrode sets, especially 2 electrode sets.

[0130] The method may comprise defining the electrical signal parameters in view of one or more of predefined limit values, predefined target values, and predefined current distribution considerations (also see above).

[0131] For instance, in embodiments, the electrical signal parameters (in the operational scheme) may comprise an electrical current value E20 for each electrode set. In such embodiments, the method may comprise defining the operational scheme in view of a predefined total electrical current limit Emax such that the (combined) electrical current values E20 are below or equal to the total electrical current limit Emax. In further embodiments, the total electrical current limit Emaxis selected from the range of 50 pA - 20 mA, especially from the range of 1 - 12 mA , or especially from the range of 100 pA - 10 mA, such as from the range of 500 pA - 6 mA.

[0132] In further embodiments, the operational electrode set comprises 2 electrode sets, and the method comprises selecting the electrical current values E20 for the 2 electrode sets to differ by at most 40% (relative to a largest electrical current value for the 2 electrode sets), such as by at most 35%, especially by at most 30%, such as by at most 25%.

[0133] In further embodiments, the electrical signal parameters for each electrode set in the operational electrode set include a charge density D20. That is, the electrical signal parameters (of the operational scheme) may comprise a charge density D20 for each electrode set. In particular, the method may comprise defining the operational scheme such that each electrode set in the operational scheme has a charge density D2o.In embodiments, the charge density D20 for each electrode set may be (individually) selected from the range of 0.002 mC / cm2- 1.2 mC / cm2, such as from the range of 0.005 mC / cm2- 0.6 mC / cm2, especially from the range of 0.01 mC / cm2- 0.3 mC / cm2, such as from the range of 0.02 mC / cm2- 0.2 mC / cm2As indicated above, the charge density D20 may be the same for each electrode set in the operational electrode set, yet may also be selected individually for each electrode set.

[0134] Yet further, in embodiments, the electrical signal parameters for the operational electrode set include a (predefined) total charge per time CPTtot. In such embodiments, the method may comprise defining the operational scheme such that the (combined) charge per time CPT20 (of all electrode sets in the operational scheme) are equal to the total charge pertime CPTtot, i.e., ^

[0135]

[0136] F=i CPT2Q(i) = CPTtot, where n is the number of electrode sets in the operational scheme, and wherein CPT2o(i) corresponds to the charge per time CPT20 for the ithelectrode set in the operational scheme. In further embodiments, the total charge per time CPTtot may be selected from the range of 0.25 - 7.0 mC / s, such as from the range of 1.0 - 7.0 mC / s, or such as from the range of 0.75 - 6.5 mC / s, especially from the range of 1.0 - 6.0 mC / s. In further embodiments, the total charge per time CPTtot may be selected from the range of 0.4 -5.0 mC / s, especially from the range of 0.5 - 4.0 mC / s, such as from the range of 0.7 - 3.0 mC / s, especially from the range of 0.8 - 2.0 mC / s, such as from the range of 0.9 - 1.5 mC / s.

[0137] The method may further comprise defining a plurality of operational schemes based on the related (sensor) signals and the target physiological response, and optionally further based on the undesired physiological response. In such embodiments, the method may comprise configuring the implantable device to alternate between (operating according to) different operational schemes (of the plurality of operational schemes).

[0138] In a further aspect, the invention may provide a computer program product comprising instructions for execution on a control system functionally coupled to a system, wherein the instructions, when executed by the control system, cause the system to carry out the method of the invention.

[0139] In a further aspect, the invention may provide a data carrier, carrying thereupon program instructions which, when executed by a control system functionally coupled to a system, cause the system to carry out the method of the invention.

[0140] The embodiments described herein are not limited to a single aspect of the invention. For example, an embodiment describing the method may, for example, further relate to the system, especially to a mode of the system, such as to the commissioning mode or the operational mode, or especially to the control system. Similarly, an embodiment of the system describing an operation of the system may further relate to embodiments of the method. In particular, an embodiment of the method describing an operation (of the system) may indicate that the system may, in embodiments, be configured for and / or be suitable for the operation. Similarly, an embodiment of the system describing actions of (a stage in) a mode, such as of a commissioning mode or operational mode, may indicate that the method may, in embodiments, comprise those actions.

[0141] BRIEF DESCRIPTION OF THE DRAWINGS

[0142] Embodiments of the invention will now be described, by way of example only, with reference to the accompanying schematic drawings in which corresponding referencesymbols indicate corresponding parts, and in which: Fig. 1 schematically depicts an embodiment of the system and the method of the invention. Fig. 2A-C schematically depict further features of the system of the invention. Fig. 3 A-C depict experimental results obtained with the system and method of the invention. The schematic drawings are not necessarily on scale.

[0143] DETAILED DESCRIPTION OF THE EMBODIMENTS

[0144] Fig. 1 schematically depicts multiple electrode arrays 230 of a system 100 comprising electrodes 220 circumferentially arranged around a nerve 10. Specifically, in Fig.

[0145] 1, the electrode arrangement 200 is configured to engage the nerve 10 such that the electrodes 220 are arranged circumferentially around the nerve 10 in at least two electrode arrays 230. The left side of Fig. 1 depicts successive testing of electrode sets 20, while the right side of Fig.

[0146] 1 depicts an operational electrode set 25 comprising multiple electrode sets 20.

[0147] Specifically, Fig. 1 schematically depicts an embodiment of a system 100 for determining an operational scheme of an implantable device 2000 for modulating an action potential in a nerve 10 of a subject 50 (see Fig. 2C). The system 100 comprises the implantable device 2000 and a control system 300. The system 100, especially the control system 300, comprises or is functionally couplable to a physiological sensor 130. Further, the implantable device 2000 comprises an electrode arrangement 200 and a pulse generator 140, wherein the electrode arrangement 200 comprises n electrodes 220, wherein n > 4. The control system 300 may especially be configured to execute a commissioning mode. In the commissioning mode, the electrode arrangement 200 is configured to engage the nerve 10 such that the electrodes 220 are arranged around the nerve 10 in an electrode array 230. Further, in the commissioning mode, the pulse generator 140 is configured to successively provide electrical signals 40 to the nerve 10 with different (commission) electrode sets 20 of the electrodes 220 (see also Fig. 3B). This is schematically depicted on the left side of Fig. 1, where each sub-figure corresponds to the testing of a different electrode set 20 of 2 electrodes 220, and wherein the dots between the second and third sub-figures represent the testing of additional electrode sets 20 in between. While the pulse generator 140 successively provides electrical signals 40 with different electrode sets 20, the physiological sensor 130 is configured to (continuously) monitor one or more physiological parameters of the subject 50 and to provide related sensor signals to the control system 300. Further, in the commissioning mode, the control system 300 is configured to define an operational scheme based on the related sensor signals and a target physiological response, especially wherein the operational scheme designates an operational electrode set 25and (corresponding) electrical signal parameters, wherein the operational electrode set 25 comprises at least two of the electrode sets 20. In Fig. 1, the operational electrode set 25 is schematically indicated on the right side, where one of the electrode sets 20 corresponds to the top electrode set 20 depicted on the left, and the other electrode set 20 is not separately depicted on the left. In embodiments, in an operational mode of the implantable device 2000, the implantable device 2000 is configured to operate (the pulse generator 140) based on the operational scheme. For instance, in embodiments, the control system 300 may be configured to configure the implantable device 2000, especially the pulse generator 140, to operate according to the operational scheme.

[0148] In the depicted embodiment, the electrode arrangement 200, especially the electrode array 230, comprises a first electrode array 231 and a second electrode array 232, wherein the first electrode array 231 and the second electrode array 232 are configured spatially separated along a longitudinal dimension of the nerve 10. Further, in the depicted embodiment, at least one electrode set 20 of the operational electrode set 25 comprises a first electrode 221 from the first electrode array 231 and a second electrode 222 from the second electrode array 232. In particular, the electrode sets 20 depicted on the left side of Fig. 1 all include a first electrode 221 from the first electrode array 231 and a second electrode 222 from the second electrode array 232.

[0149] In embodiments, the first electrode array 231 may comprise m first electrodes 221, wherein nl is selected from the range of 3-40, such as from the range of 4-10. Similarly, in embodiments, the second electrode array 232 may comprise n2 second electrodes 222, especially wherein n2 is selected from the range of 3-40, such as from the range of 4-10. In Fig.

[0150] 1, each electrode array 230 comprises 6 electrodes 220, i.e., ni=n2=6. Further, in the depicted embodiment, the first electrodes 221 are configured longitudinally aligned with the second electrodes 222 along the nerve 10.

[0151] In the depicted embodiment, each electrode set 20 comprises 2 - 4 electrodes 220. Specifically, each depicted electrode set 20 comprises two electrodes 220. Further, in the depicted embodiment, the operational electrode set 25 comprises 2-4 electrode sets 20, particularly two electrode sets 20. Hence, in the depicted embodiment, the operational electrode set 25 comprises four electrodes 220.

[0152] Fig. 1 further schematically depicts an embodiment of the method for determining an operational scheme of an implantable device 2000 for modulating an action potential in a nerve 10 of a subject 50. In particular, Fig. 1 depicts an implantable device 2000 comprising an electrode arrangement 200, wherein the electrode arrangement 200 comprises nelectrodes 220, wherein n > 4, and wherein the electrode arrangement 200 is configured engaged with the nerve 10 such that the electrodes 220 are arranged around the nerve 10 in an electrode array 230. In the depicted embodiment, the method comprises successively providing electrical signals 40 to the nerve 10 with different (commission) electrode sets 20 of the electrodes 220, especially using a pulse generator 140. The method further comprises monitoring one or more physiological parameters of the subject 50, such as using one or more physiological sensors 130, and providing related sensor signals. The method further comprises defining an operational scheme based on the related sensor signals and a target physiological response, wherein the operational scheme designates an operational electrode set 25 and (corresponding) electrical signal parameters, wherein the operational electrode set 25 comprises at least two of the electrode sets 20. After the operational scheme is defined, the method comprises configuring an operational mode of the implantable device 2000, wherein, in the operational mode, the implantable device 2000 operates based on the operational scheme.

[0153] Fig. 1 further schematically depicts a data carrier 310, carrying thereupon program instructions which, when executed by a control system 300 functionally coupled to a system 100, cause the system 100 to carry out the method of the invention.

[0154] Fig. 2A schematically depicts a cross-sectional view of the system 100 depicted in Fig. 1. In particular, Fig. 2A schematically depicts an electrode array 230 comprising six electrodes 220, wherein the electrodes 220 are circumferentially arranged around the nerve 10, especially around the vagus nerve 11. Reference W represent the electrode width.

[0155] Fig. 2A further schematically depicts nerve fibers 15 in the nerve 10. As depicted, nerve fibers 15 may be centrally or peripherally located in the nerve 10. For providing a signal to a peripherally arranged nerve fiber 15, electrodes 220 in close proximity to the nerve fiber 15 may be most suitable to selectively target the corresponding nerve fiber 15. Hence, it may be beneficial to have electrodes 220 circumferentially arranged around the nerve 10 for selective targeting.

[0156] Further, when two electrodes 220 that are spaced relatively close together (along the longitudinal axis A) are used for stimulation, the electrical signal 40 may pass through the nerve 10 relatively close to a surface of the nerve 10, and may thus be most suitable for targeting laterally arranged (or “superficial”) nerve fibers 15. In contrast, when two electrodes 220 that are spaced relatively far apart (along the longitudinal axis A) are used for stimulation, the electrical signal 40 may pass through the nerve 10 close to the center of the nerve 10, and may thus be most suitable for targeting medially arranged (or “ deeper”) nerve fibers 15. Further, also electrode length (along the longitudinal axis A) may influence the ability to target laterallyvs. medially arranged nerve fibers 15. In particular, smaller electrodes 220 may be more suitable for targeting peripherally arranged nerve fibers 15, whereas longer electrodes 220 may be more suitable for targeting centrally arranged nerve fibers 15.

[0157] Hence, it may be beneficial to provide an arrangement 200 with three or more electrode arrays 230 to provide additional flexibility in selecting the distances between the electrodes 220 used for providing the electrical signal 40.

[0158] Fig. 2B schematically depicts an embodiment of the system 100, especially of the implantable device 2000, wherein the implantable device 2000 comprises a hosting element 2100. Specifically, the implantable device 2000 comprises a tubular hosting element 2100, wherein, in one or more of the commissioning mode and the operational mode, the electrodes 220 are arranged within the tubular hosting element 2100, and wherein the tubular hosting element 2100 is configured for at least partially surrounding the nerve 10 such that the electrodes 220 are brought in contact with the nerve 10. In particular, the hosting element 2100 comprises a first electrode array 231, a second electrode array 232 and a third electrode array 233. In the depicted embodiment, the hosting element 2100 is, for visualization purposes, depicted flat (or “unrolled”).

[0159] In particular, in the depicted embodiment, the first electrode array 231 comprises first electrodes 221, the second electrode array 232 comprises second electrodes 222, and the third electrode array 233 comprises third electrodes 223. In the depicted embodiment, the electrodes 220 of the three arrays 230 are aligned along the longitudinal axis A. Accordingly, the hosting element 2100 comprises aligned sets 224 of longitudinally aligned electrodes 220, wherein each aligned set 224 comprises a first electrode 221, a second electrode 222 and a third electrode 223. In further embodiments, the (commission) electrode sets 20 may comprise one or more of the aligned sets 224 or proper subsets thereof, e.g., an electrode set 20 may comprise two of the electrodes 220 of an aligned set 224.

[0160] In the depicted embodiment, the (first electrodes 221 of the) first electrode array 231 and (second electrodes 222 of) the second electrode array 232 are separated by a first edge-to-edge distance di along the longitudinal axis A. In embodiments, the first edge-to-edge distance di may be selected from the range of 0.2 - 5 mm, especially from the range of 0.5 - 3 mm, such as from the range of 0.5 - 2 mm. Similarly, the (second electrodes 222 of the) second electrode array 232 and the (third electrodes 223 of the) second electrode array 233 are separated by a second edge-to-edge distance d? along the longitudinal axis A. In embodiments, the second edge-to-edge distance d? may be selected from the range of 0.2 - 5 mm, especially from the range of 0.5 - 3 mm. As depicted in Fig. 2B, the first distance di and the seconddistance d? may especially differ. Further, as depicted in Fig. 2B, the (first electrodes 221 of the) first electrode array 231 and the (third electrodes 223 of the) third electrode array 233 may be separated by a third edge-to-edge distance ds along the longitudinal axis A, wherein ds = di + d? + L2, wherein L2 is the length of a second electrode 222 (along the longitudinal axis A).

[0161] Further, in the depicted embodiment, for each first electrode 221 (of a first subset of the first electrodes 221) applies that the first electrode is longitudinally aligned with a (respective) third electrode 223 (of a third subset of the third electrodes 223), wherein (contact) surface areas of the first electrode 221 and of the third electrode 223 differ by less than 5%, such as by less than 3%, especially by less than 1%. In particular, in the depicted embodiment, the (contact) surface areas of the first, second and third electrodes 221,222,223 may be essentially the same.

[0162] Fig. 2B further schematically depicts a first electrode array 231 comprising m first electrodes 221, a second electrode array 232 comprising m second electrodes, and a third electrode array 233 comprising ns third electrodes, wherein each of m, m and ns are selected from the range of 3 - 12, especially from the range of 4 - 10. In particular, in the depicted embodiment, ni=n2=ns=6.

[0163] Fig. 2C schematically depicts an embodiment of the system 100, wherein the system 100 comprises an (implantable) device 2000, wherein the implantable device 2000 is implanted in a subject 50, especially at the neck of the subject 50. In particular, in the depicted embodiment, the implantable device 2000 comprises the electrode arrangement 200, wherein the electrode arrangement 200 comprises the hosting element 2100, and wherein the hosting element 2100 hosts the nerve 10, here especially the vagus nerve 11, of the subject 50.

[0164] In such embodiments, the implantable device 2000, especially the electrode arrangement 200, may comprise a biocompatible material, especially at least at external surfaces of the implantable device 2000. Further, in embodiments, the electrode arrangement 200 may comprise a biocompatible carrier substrate, wherein the biocompatible carrier substrate comprises openings, wherein the electrodes 220 are configured to contact the nerve 10 through the openings.

[0165] In the depicted embodiment, the implantable device 2000 further comprises an (implantable) pulse generator 140. The pulse generator 140 may especially be configured to provide the electrical pulse 40 to the nerve 10 via (at least part of) the electrodes 220 of the electrode arrangement 200.In the depicted embodiment, the implantable device 2000 further comprises a control system 300. The control system 300 may especially be configured to control one or more of the pulse generator 140 and the electrodes 220.

[0166] In the depicted embodiment, the control system 300 is depicted as a part of the implantable device 2000, and a separate user interface 320 is depicted for interacting with the control system 300. In embodiments, the control system 300 may be configured to receive user input (e.g., input from a physician), optionally via a user interface 320, wherein the control system 300 is configured to define the operational scheme in dependence of the user input. In further embodiments, the control system 300 may be physically separate from the implantable device 2000.

[0167] Experiments

[0168] Unless specified otherwise, all experiments described herein were performed using the following materials and methods.

[0169] Experiments involving sheep were performed by DVMs (Doctor of Veterinary Medicine) after obtaining regulatory and ethical clearance. Studies were conducted in compliance with ISO 10993-2 and applicable standards of the Clinical Research Organization (CRO). Studies were performed between 2024 and 2025. Female sheep from the Ile-de-France breed with a weight between 45 and 65 kg were obtained from local breeders. The health status of the sheep was monitored by the CRO. After acclimation, sheep were premedicated with morphine (0.2 mg / kg intramuscularly) and midazolam (0.5 mg / kg intramuscularly). Anesthesia was induced with propofol 2-4 mg / kg intravenously (IV). Study animals were then intubated with an appropriately sized endotracheal tube (between 7-9 mm diameter) and maintained with a constant rate infusion of propofol 5-30 mg / kg / h intravenously and repeated boli of midazolam 0.5 mg / kg intravenously. Respiratory rates were set at 10-20 cycles / min, and a tidal volume of 10 ml / kg with 100% fractional pO2. Respiratory rates were adapted to end-tidal CO2 with a target of approximately 40 cm H2O. Fluid replacement was done with lactated Ringer (5 to 20 mL / kg / h). The following physiological parameters were obtained: ECG (1 or 3-lead), local temperature at the left implantation site underneath the cuff electrode (just beneath the contact surface of an (active) electrode set 20), systemic and pulmonary artery pressure, end-tidal pCO2, airway resistance, compliance, EMGs of the cricothyroideal and cricopoharyngeal muscles. Parameters were acquired by anesthesia monitors and / or the ADI powerlab system (ADInstruments Limited, Oxford, UK).

[0170] The left vagus nerve was exposed to a maximum length and freed from any adhering tissue. Surgical access to the right vagus nerve was also prepared, and the right vagusnerve was entwined by a ligature (soft latex cord) for later recovery. EMG electrodes were placed, and 1 to 2 cuff electrodes were placed around the vagus nerve 11. Electrodes were connected to a Model 3820 stimulator unit (Controlled by a Model 3800 Multichannel Stimulator, A-M systems, Sequim, Washington, USA). Stimulation protocols were steered by proprietary software written in Matlab R2021b (The MathWorks Inc., Natick, USA). A multichannel electrode cuff was placed around the left cervical vagus nerve in anesthetized and ventilated adult female sheep. An electrocardiogram was recorded via two to six needle electrodes on the thorax of the animal in an Einthoven configuration against one ground electrode placed on the right leg of the animal. Systemic blood pressure was collected via a pressure catheter (SPR-350S Mikro-Tip®, Millar Houston, Texas, USA) placed in the abdominal aorta via the femoral artery. Pulmonary arterial pressure was monitored by a pressure catheter placed in the proximal pulmonary artery. Heart rate was calculated from the systemic blood pressure and averaged for 3 cycles. Application of active stimulation and blocking traces was simultaneously collected from the signal generator 140. Generally, bipolar stimulation pulses were current controlled.

[0171] Identification of the effective electrode sets 20 in the commissioning mode was performed by stimulation with each electrode contact pair (successively) with 60s-long equal test pulses (asymmetric biphasic rectangular pulses of 200ps, 60 Hz, Ratio 1 :4) in randomized order.

[0172] The Total Electrical Energy Delivered (TEED) was used as a proxy for the energy demand, i.e., the energy demand of the stimulation is estimated based on the TEED.

[0173] Fig. 3 A depicts physiological responses observed when stimulating a nerve 10 of a subject 50, specifically of a sheep, with six different electrode sets 20,20a,20b,20c,20d,20e,20f each comprising two electrodes 220. Specifically, Fig. 3A indicates the observed change AP (in percentage) of four different physiological parameters: Pl: heart rate; P2: mean arterial pressure (MAP); P3: airway resistance; and P4: airway dynamic compliance.

[0174] For instance, if the target physiological response relates to a reduction of the heart rate (Pl), electrode sets 20a and 20b may substantially outperform electrode sets 20c, 20d, 20e, and 20f in terms of magnitude of the physiological response. Electrode sets 20a and 20b may thus be considered for the operational electrode set 25.

[0175] With the tested parameters, electrode set 20a was observed to reduce Pl with 38%, while electrode set 20b was observed to reduce Pl with 16%. The magnitude of the effect may be considered when assigning the electrical signal parameters in the operational schemefor the different electrode sets 20. As electrode set 20a leads to a larger reduction in Pl, the current may be preferentially applied via electrode set 20a. For instance, if the current distribution is selected proportional to the effect magnitude, electrode set 20a would be assigned 70% of the current (38 / (38+16)), whereas electrode set 20b would be assigned 30% of the current (16 / (38+16)).

[0176] Alternatively, if P4 would correspond to the target physiological response while Pl would be a strongly undesired physiological response, electrode sets 20c and 20d may be particularly suitable electrode sets 20.

[0177] Fig. 3B schematically depicts experimental results obtained with a different sheep, for which an operational electrode set 25 comprising two electrode sets 20 of two electrodes 220 each was defined. In particular, with a predefined total electrical current limit Emax of 6 mA, an operational scheme with a 50 / 50 split of the electrical current values for the two different electrode sets 20 was defined.

[0178] Specifically, bronchoconstriction was induced by exposing the sheep to inhalational CO2 (fraction of inhaled air: 8%). A High Frequency (HF) block was applied for a period of 60 s with charge-balanced biphasic symmetric pulses at 6000 pA current amplitude, 25ps pulse width and 20000 Hz frequency. To evaluate the efficacy of the applied HF block, the overall minimum of the airway resistance R (in mbar / L / s) during the block was compared to the airway resistance R at the start of the block (hereafter: “block effect min”). Further, the airway resistance R at the end of the block was compared to the airway resistance R at the start of the block as a measure of the block effect (hereafter: “block effect end”). Besides this, the temperature T (measured beneath the contact surface of the active electrodes 220), heart rate HR, and mean arterial pressure MAP were recorded to determine further physical effects of the applied block.

[0179] Fig. 3B depicts (from left to right) three time periods n, 12, 13 during which an electrical signal 40, 40a, 40b is applied (wherein the time axis is labeled according to hh:mm:ss). During n, a first electrical signal 40a is applied via a first electrode set 20a, while simultaneously a second electrical signal 40b is applied via a second electrode set 20b, wherein the first and second electrical signals 40a, 40b each have a current amplitude of 3000 pA (for a total current amplitude of 6000 pA with a 50 / 50 split over the electrode sets 20). The first and second electrode sets 20a, 20b especially form the operational electrode set 25. During 12, a second electrical signal 40b with a current amplitude of 6000 pA is applied via the second electrode set 20b (only), while during 13, a first electrical signal 40a with a current amplitude of 6000 pA is applied via the first electrode set 20a (only). Below each electrical signal40, 40a, 40b, the corresponding observed airway resistance R (in mbar / L / s), local temperature T (in °C), heart rate HR (in beats per minute), and mean arterial pressure MAP (in mmHg) is depicted. The dashed box indicates the time period in which the block is applied.

[0180] A reduction in airway resistance R (the target physiological response) is observed during the time periods n and 13 (with a larger reduction observed during n), while the airway resistance R appears to remain relatively unaffected during the electrical signal 40b of i2. Further, a relatively large increase in the local temperature T is observed during the electrical signals 40a, 40b of 12 and 13, while during n (i.e., with the operational electrode set 25,) the local temperature T increases significantly less. Meanwhile, the effects of each blocking signal on the heart rate HR and the mean arterial pressure MAP appears similar.

[0181] The signal conditions and experimental observations are summarized in the following table:

[0182] Time period T1 T2 T3

[0183] T increase (°C) 0.5 1.0 1.1 TEED (%) 50 100 100 Active electrode set 20a & 20b 20b 20a Current (mA) 3 & 3 6 6 Block effect min (%) 40.1 13.8 19.4 Block effect end (%) 20.7 0 7.7

[0184]

[0185] Hence, in each of the time periods ti, t2, and t3, a total current of 6 mA is applied and a target physiological effect, specifically a blocking effect on pulmonary B fibers, was observed. Successful block of the efferent pulmonary B fibers was demonstrated with the operational electrode set 25 comprising both electrode sets 20a, 20b (distributed), with single electrode set 20b (non-distributed), and with single electrode set 20a (non-distributed). Here, the distributed high frequency block, compared to both single electrode applications (with matched total amplitude and total charge per time levels), showed superior block effect (40.1% vs 13.8% and 19.4% for block effect min, and 20.7% vs 0% and 7.7% for block effect end) while generating less heat (0.5 °C vs. 1.0 °C and 1.1 °C).

[0186] A similar performance as described above has been observed with 50 / 50 current splits in a different animal:

[0187] Time period ti t2 t3

[0188] T increase (°C) 0.3 0.1 0.3

[0189]

[0190] Estimated energy 100 50 100 demand (%)

[0191] Active electrode set 20a 20a & 20b 20b Current (mA) 6 3 & 3 6 Block effect min (%) 18.2 14.4 20.9 Block effect end (%) 0 9 11

[0192]

[0193] It shoulc be noted that the lack of a block effect end for the first electrode set 20a could be an artifact of a stimulation signal applied previously (with the same first electrode set 20a) to identify suitable electrode sets 20. In particular, with the distributed high frequency block, similar magnitudes of the target physiological effect were observed with substantially reduced thermal heat generation and battery usage.

[0194] Fig. 3C schematically depicts the use of an amplitude ramp to determine a (minimum amplitude) threshold for stimulation and / or an effective electrode set 20 during the commissioning mode. Here, TSindicates a starting time of the ramp, and reindicates an end time of the ramp (wherein the time is provided as hh:mm:ss). The ramp depicted in Fig. 3C may especially be a stepwise monotonically increasing intensity ramp, wherein the amplitude increases from 0 pA to 2400 pA over a period of 60 seconds, with each step increasing the amplitude by 24 pA (i.e., 100 steps are used, with a step duration of 60 / 100 = 0.6 s for each step). It will be clear to the person skilled in the art that a different step size (i.e., a different number of steps) may be used for the ramp, and that the invention is not limited to the step size mentioned here. The ramp is applied using the first electrode set 20a from Fig. 3B, wherein the charge-balanced biphasic symmetric pulses of the (first) electrical signal 40,40a have a (constant) pulse width of 200 ps, and a frequency of 30 Hz. As a stimulation signal is used for the present ramp, the frequency used for the electrical signal 40,40a is lower than that reported for the blocking signal of Fig. 3B. Reference EMG1 indicates a first EMG trace (with units mV) from the cricothyroideal muscle, and reference EMG2 indicates a second EMG trace (with units mV) from the cricopoharyngeal muscle.

[0195] As can be seen from Fig. 3C, at lower amplitudes, no effect on the heart rate HR, mean arterial pressure MAP, airway resistance R, and first and second EMG traces EMG1,EMG2 is observed. However, at an amplitude of -540 pA (i.e., after -13.5 s), a decrease in heart rate HR occurs. Further, at an amplitude of -990 pA (i.e., after -24.8 s), an increase in the activity of the cricothyroideal and cricopoharyngeal muscles is observed. Finally, at an amplitude of -1450 pA (i.e., after -36.2 s), an increase in airway resistance R is observed. Hence, depending on the amplitude of the electrical signal 40,40a, one or more physiologicalresponses may be elicited. Across multiple test electrode sets 20, one can identify more or less suitable electrodes 220 based on the relative delay of the target fiber responses, and subsequently higher amplitude may be induced to achieve a certain target response. That is, a (low frequency and / or low intensity) stimulation signal may be used to identify suitable electrode sets 20 in the commissioning mode based on the relative delay in and / or magnitude of the response of the target fiber(s), after which a (high frequency and / or high intensity) blocking signal may be applied in the operational mode. Of course, also a stimulation signal may be applied in the operational mode, see also above.

[0196] The term “plurality” refers to two or more. Furthermore, the terms “a plurality of’ and “a number of’ may be used interchangeably.

[0197] The terms “substantially” or “essentially” herein, and similar terms, will be understood by the person skilled in the art. The terms “substantially” or “essentially” may also include embodiments with “entirely”, “completely”, “all”, etc. Hence, in embodiments the adjective substantially or essentially may also be removed. Where applicable, the term “substantially” or the term “essentially” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. Moreover, the terms ’’about” and “approximately” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. For numerical values it is to be understood that the terms “substantially”, “essentially”, “about”, and “approximately” may also relate to the range of 90% - 110%, such as 95%-105%, especially 99%-101% of the values(s) it refers to.

[0198] The term “comprise” also includes embodiments wherein the term “comprises” means “consists of’.

[0199] The term “and / or” especially relates to one or more of the items mentioned before and after “and / or”. For instance, a phrase “item 1 and / or item 2” and similar phrases may relate to one or more of item 1 and item 2. The term "comprising" may in an embodiment refer to "consisting of' but may in another embodiment also refer to "containing at least the defined species and optionally one or more other species".

[0200] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.The devices, apparatus, or systems may herein amongst others be described during operation. As will be clear to the person skilled in the art, the invention is not limited to methods of operation, or devices, apparatus, or systems in operation.

[0201] The term “further embodiment” and similar terms may refer to an embodiment comprising the features of the previously discussed embodiment, but may also refer to an alternative embodiment.

[0202] It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims.

[0203] In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim.

[0204] Use of the verb "to comprise" and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, “include”, “including”, “contain”, “containing” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0205] The article "a" or "an" preceding an element does not exclude the presence of a plurality of such elements.

[0206] The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In a device claim, or an apparatus claim, or a system claim, enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0207] The invention also provides a control system that may control the device, apparatus, or system, or that may execute the herein described method or process. Yet further, the invention also provides a computer program product, when running on a computer which is functionally coupled to or comprised by the device, apparatus, or system, controls one or more controllable elements of such device, apparatus, or system.

[0208] The invention further applies to a device, apparatus, or system comprising one or more of the characterizing features described in the description and / or shown in the attached drawings. The invention further pertains to a method or process comprising one or more of the characterizing features described in the description and / or shown in the attached drawings.Moreover, if a method or an embodiment of the method is described being executed in a device, apparatus, or system, it will be understood that the device, apparatus, or system is suitable for or configured for (executing) the method or the embodiment of the method, respectively.

[0209] The various aspects discussed in this patent can be combined in order to provide additional advantages. Further, the person skilled in the art will understand that embodiments can be combined, and that also more than two embodiments can be combined. Furthermore, some of the features can form the basis for one or more divisional applications.

Claims

46CLAIMS1. A system (100) for determining an operational scheme of an implantable device (2000) for modulating an action potential in a nerve (10) of a subject (50), wherein the system (100) comprises the implantable device (2000) and a control system (300), and wherein the system (100) comprises or is functionally couplable to a physiological sensor (130), wherein the implantable device (2000) comprises an electrode arrangement (200) and a pulse generator (140), wherein the electrode arrangement (200) comprises n electrodes (220), wherein n > 4, wherein the control system (300) is configured to execute a commissioning mode wherein:the electrode arrangement (200) is configured to engage the nerve (10) such that the electrodes (220) are arranged around the nerve (10) in an electrode array (230);the pulse generator (140) is configured to successively provide electrical signals (40) to the nerve (10) with different electrode sets (20) of the electrodes (220);the physiological sensor (130) is configured to monitor one or more physiological parameters of the subject (50) and to provide related sensor signals to the control system (300); andthe control system (300) is configured to define an operational scheme based on the related sensor signals and a target physiological response, wherein the operational scheme designates an operational electrode set (25) and electrical signal parameters, wherein the operational electrode set (25) comprises at least two of the electrode sets (20);wherein in an operational mode of the implantable device (2000) the implantable device (2000) is configured to operate based on the operational scheme.

2. The system (100) according to claim 1, wherein in the commissioning mode the pulse generator (140) is configured to provide the electrical signals (40) with each electrode set (20) with a temporal variation in one or more of intensity, charge per time, duration, frequency, pulse width, duty cycle, and pulse shape, and wherein each electrode set (20) comprises at least 2 electrodes (220).

3. The system (100) according to claim 2, wherein the control system (300) is configured to determine intensity threshold values for the electrode sets (20) based on the related sensor signals and the target physiological response, wherein the electrical signal parameters comprise intensity parameters, and wherein for each electrode set (20) in the47operational electrode set (25) the control system (300) is configured to designate the intensity parameters in view of the intensity threshold values.

4. The system (100) according to any one of the preceding claims, wherein the electrode array (230) comprises a first electrode array (231) and a second electrode array (232), wherein the first electrode array (231) and the second electrode array (232) are configured spatially separated along a longitudinal dimension of the nerve (10), and wherein at least one electrode set (20) of the operational electrode set (25) comprises a first electrode (221) from the first electrode array (231) and a second electrode (222) from the second electrode array (232).

5. The system (100) according to claim 4, wherein the first electrode array (231) comprises nl first electrodes (221), wherein nl is selected from the range of 4-10, and wherein the second electrode array (232) comprises n2 second electrodes (222), wherein n2 is selected from the range of 4-10.

6. The system (100) according to claim 5, wherein nl=n2, and wherein the first electrodes (221) are configured longitudinally aligned with the second electrodes (222) along the nerve (10).

7. The system (100) according to any one of the preceding claims, wherein one or more applies ofthe control system (300) is configured to define the operational scheme based on the related sensor signals, the target physiological response and an undesired physiological response; andthe physiological parameters are selected from the group consisting of respiratory rate, respiratory volume, coughing, airway resistance, lung compliance, lung elastance, inspiration / expiration ratio, a pulmonary oscillometry parameter, a spirometry parameter, a lung plethysmography parameter, respiratory and cardiac parameters derived from transthoracic impedance measurements, tracheal pressure, heart rate, heart rate variability, a heart rhythm abnormality, a stroke volume, a heart contractility parameter, a heart movement abnormality, systemic blood pressure, pulmonary blood pressure, glucose plasma level, a plasma level of a biomarker, body temperature, blood oxygen level, blood CO2 level, brain activity, nerve activity, stomach motility, intestinal motility, laryngeal activity, and a pain level.

488. The system (100) according to claim 7, wherein the nerve (10) comprises the vagus nerve (11), wherein the target physiological response comprises a pulmonary response, and wherein the undesired physiological response comprises a cardiac arrhythmia.

9. The system (100) according to any one of the preceding claims, wherein one or more applies of:the implantable device (2000) comprises a tubular hosting element (2100), wherein, in one or more of the commissioning mode and the operational mode, the electrodes (220) are arranged within the tubular hosting element (2100), wherein the tubular hosting element (2100) is configured for at least partially surrounding the nerve (10) such that the electrodes (220) are brought in contact with the nerve (10);the operational electrode set (25) comprises at least four electrodes (220); and each electrode set (20) comprises 2 - 4 electrodes (220).

10. The system (100) according to claim 9, wherein each electrode set (20) comprises two electrodes (220), and wherein the operational electrode set (25) comprises 2-4 electrode sets (20).

11. The system (100) according to any one of the preceding claims, wherein the control system (300) has access to a predefined total electrical current limit (Emax), wherein the electrical signal parameters comprise an electrical current value (E20) for each electrode set (20), wherein the control system (300) is configured to define the operational scheme such that the electrical current values (E20) are below or equal to the total electrical current limit (Emax), wherein Emax is selected from the range of 100 pA - 10 mA.

12. The system (100) according to claim 10 and claim 11, wherein the operational electrode set (25) comprises 2 electrode sets (20), and wherein the electrical current values (E20) for the 2 electrode sets (20) differ by less than 35%.

13. The system (100) according to any one of the preceding claims, wherein one or more applies of:the electrical signal parameters for each electrode set (20) in the operational electrode set (25) include a charge density D20, wherein the charge density is selected from the range of 0.002 mC / cm2- 1.2 mC / cm2;the operational mode comprises: (i) blocking of the action potential in the nerve (10), or (ii) eliciting of the action potential in the nerve (10); andthe control system (300) is configured to designate a plurality of operational schemes based on the related sensor signals and the target physiological response, wherein in the operational mode the implantable device (2000) is configured to alternate between different operational schemes.

14. A method for determining an operational scheme of an implantable device (2000) for modulating an action potential in a nerve (10) of a subject (50), wherein the implantable device (2000) comprises an electrode arrangement (200), wherein the electrode arrangement (200) comprises n electrodes (220), wherein n > 4, wherein the electrode arrangement (200) is configured engaged with the nerve (10) such that the electrodes (220) are arranged around the nerve (10) in an electrode array (230), and wherein the method comprises:successively providing electrical signals (40) to the nerve (10) with different electrode sets (20) of the electrodes (220);monitoring one or more physiological parameters of the subject (50) and providing related sensor signals;defining an operational scheme based on the related sensor signals and a target physiological response, wherein the operational scheme designates an operational electrode set (25) and electrical signal parameters, wherein the operational electrode set (25) comprises at least two of the electrode sets (20); andconfiguring an operational mode of the implantable device (2000), wherein, in the operational mode, the implantable device (2000) operates based on the operational scheme.

15. The method according to claim 14, wherein the method comprises providing the electrical signals (40) with each electrode set (20) with a temporal variation in one or more of intensity, charge per time, duration, frequency, pulse width, duty cycle, and pulse shape.

16. The method according to claim 15, wherein the electrical signal parameters comprise intensity parameters, and wherein the method comprises:determining intensity threshold values for the electrode sets (20) based on the related sensor signals and the target physiological response; andselecting the intensity parameters for each electrode set (20) in the operational electrode set (25) in view of the intensity threshold values.

17. The method according to any one of the preceding claims 14-16, wherein one or more applies of:the electrode array (230) comprises a first electrode array (231) and a second electrode array (232), wherein the first electrode array (231) and the second electrode array (232) are configured spatially separated along a longitudinal dimension of the nerve (10), and wherein at least one electrode set (20) of the operational electrode set (25) comprises a first electrode (221) from the first electrode array (231) and a second electrode (222) from the second electrode array (232);the nerve (10) comprises the vagus nerve (11), wherein the method comprises defining the operational scheme based on the related sensor signals, the target physiological response and an undesired physiological response, and wherein the target physiological response comprises a pulmonary response, wherein the undesired physiological response comprises a cardiac arrhythmia;each electrode set (20) comprises 2 - 4 electrodes (220), and wherein the operational electrode set (25) comprises 2-4 electrode sets (20); andthe electrical signal parameters comprise an electrical current value (E20) for each electrode set (20), wherein the method comprises defining the operational scheme in view of a predefined total electrical current limit (Emax) such that the electrical current values (E20) are below or equal to the total electrical current limit (Emax), wherein Emax is selected from the range of 100 pA - 10 mA.

18. The method according to claim 17, wherein each electrode set (20) comprises 2- 4 electrodes (220), wherein the operational electrode set (25) comprises 2-4 electrode sets (20); wherein the electrical signal parameters comprise the electrical current value (E20) for each electrode set (20); wherein the operational electrode set (25) comprises 2 electrode sets (20), and wherein the method comprises:selecting the electrical current values (E20) for the 2 electrode sets (20) to differ by less than 35%.

19. The method according to any one of the preceding claims 14-18, wherein one or more applies of:the electrical signal parameters for the operational electrode set (25) include a charge density, wherein the method comprises selecting the charge density for each electrode set (20) in the operational electrode set (25) from the range of 0.002 mC / cm2- 1.2 mC / cm2; and the method comprises: (i) defining a plurality of operational schemes based on the related sensor signals and the target physiological response; and (ii) configuring the implantable device (2000) to alternate between different operational schemes.

20. A computer program product comprising instructions for execution on a control system (300) functionally coupled to a system (100), wherein the instructions, when executed by the control system (300), cause the system (100) to carry out the method according to any one of the preceding claims 14-19.

21. A data carrier (310), carrying thereupon program instructions which, when executed by a control system (300) functionally coupled to a system (100), cause the system (100) to carry out the method according to any one of the claims 14-19.

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