Device for the localization, characterization and / or stimulation of a particular nerve of a patient

Abstract

Device (1) for the stimulation of a particular nerve, preferably a vagus nerve, of a patient comprising a microelectrode array (2) comprising multiple microelectrodes (3), and a control unit (4) connected to the microelectrode array (2), wherein the microelectrode array (2) is connectable to the patient, preferably to an ear (5) of the patient, and the control unit (4) is adapted to detect at least one physiological and / or at least one anatomical parameter of the patient via the microelectrode array (2), and wherein the control unit (4) is adapted to select specific microelectrodes (3) of the microelectrode array (2), optionally as stimulation microelectrodes, when the microelectrode array (2) is connected to the patient, preferably to the ear (5) of the patient, based on the detected physiological parameter and / or anatomical parameter, and wherein the control unit (4) is optionally adapted to stimulate the particular nerve, preferably the vagus nerve, of the patient via the selected stimulation microelectrodes (3).

Description

[0001] Device for the localization, characterization and / or stimulation of a particular nerve of a patient

[0002] The present invention concerns a device for the stimulation of a particular nerve, preferably a vagus nerve, of a patient and a method for operating a device for the stimulation of a particular nerve, preferably a vagus nerve, of a patient. In another aspect, the invention relates to a device for the localization of a particular nerve, preferably a vagus nerve.

[0003] The field of the invention relates to systems and methods for providing stimulation of central nervous system tissue, muscles, or nerves, or combinations thereof. More particularly, the invention relates to providing neurostimulation to the particular nerve, preferably the vagus nerve, and / or its branches to provide therapeutic outcomes, such as the treatment of pain.

[0004] The electrical stimulation of a biological tissue, e.g., a muscle or a nerve, often afferent nerves, to indirectly affect the stability or performance of a physiological system, such as the autonomic nervous system, can provide functional and / or therapeutic outcomes, and has been used for activating target muscles or nerves to provide relief for a variety of disorders. Many systems use stimulators like for example pulse generators and electrodes to deliver electrical charge to the target site of the muscle or nerve. The electrical stimulation of the vagus nerve, for instance, abbreviated VNS, is a therapy that can be used in the treatment of chronic pain and other ailments like depression, stroke, migraine, peripheral arterial disease, chronic immunological diseases and / or sleep disorders. Neuromodulation, particularly the electrical stimulation of the autonomic nervous system, has emerged as a promising non- pharmacological therapeutic approach for various chronic ailments. The electrical vagus nerve stimulation presents an appealing target for neuromodulation since the vagus nerve connects mutually the brain and the body, not only governing but also sensing vital physiological processes within the heart, lungs, and gastrointestinal tract.

[0005] In order to apply stimuli to the vagus nerve, devices for the stimulation of the vagus nerve are available on the market, which introduce electrical stimuli to at least a first afferent nerve fiber in a first auricular branch of a vagus nerve of a patient. The stimuli are hereby controlled via a control circuit.

[0006] US 20230302273 Al discloses a device comprising electrodes for the stimulation of the vagus nerve of a patient, wherein the device has to be placed on the patient at a position corresponding to an auricular branch of the vagus nerve. This placement has to be performed by a trained physician. WO 2021187877 Al, filed by the same applicant, discloses a similar device. US 20230241375 Al discloses a device for the stimulation of auricular nerves such as the vagus nerve. Electrodes of the device have to be placed on a patient at very specific positions, which get verified by transillumination and impedance measurements.

[0007] US 2015112405 Al discloses a device comprising electrodes for the stimulation of the vagus nerve of a patient. This device has to be placed on the patient by a professional, as the placement of the electrodes is based on tradition and theory of acupuncture. Also, the positioning of the electrodes must be within 2mm of the vagus nerve.

[0008] However, it has been found, that if the stimulation of the vagus nerve is controlled by vital parameters or bodily functions of the patient, rather than a predetermined non-personalized sequence, an increase in effectiveness of the vagus nerve stimulation itself, a reduction in side-effects of the stimulation, such as pain perception during stimulation, and a reduction in non-responders, and therefore an increase in the resulting therapeutic effectiveness can be achieved.

[0009] The object of the present invention is to provide a device for the stimulation of a particular nerve of a patient, including but not limited to the vagus nerve, and a method for operating a device for the stimulation of the particular nerve of a patient with an increased effectiveness compared to the prior art.

[0010] Therefore, the subject of the present invention is a device for the stimulation of the particular nerve, preferably the vagus nerve, in form of a non-invasive medical device applied on the patient, preferably on the ear, that treats chronic pain, preferably back pain, depression, stroke, migraine, peripheral arterial disease, chronic immunological diseases and / or sleep disorders by stimulating the particular nerve. The radically-new treatment concept is based on intrinsic personalization of stimulation parameters at any time, guided by both the individual micro-anatomy of the patient’s body, preferably the ear, and phenotypic time-varying physiology of the body. Specifically, a novel single-unit plug-and-treat device with embedded sensing capabilities for a unique closed-loop control in selecting appropriate 3D stimulation microelectrodes close to the particular nerve of a patient, tuned with optimal stimulation patterns to achieve easily accessible, truly individualized, and efficient treatment for chronic pain patients with no or minor side-effects is disclosed.

[0011] The vision of the present invention is to fight sustainably chronic pain, a major healthcare problem today, with insufficient pharmacological treatment associated with devastating sideeffects. Neuromodulation, e.g., of the vagus nerve, abbreviated VN projecting bodily signals directly to the brain, offers a powerful strategy for the systemic brain-controlled treatment of chronic pain. The auricular vagus nerve stimulation, or aVNS, has already shown promising results. The device for the stimulation of a particular nerve, preferably a vagus nerve, of a patient according to the invention comprises a microelectrode array comprising multiple individual microelectrodes, and a control unit connected to the microelectrode array. The microelectrode array is connectable to the patient, preferably to an ear of the patient, in particular to the auricle of an ear, of the patient, and the control unit is adapted to detect at least one physiological parameter and / or at least one anatomical parameter of the patient via the microelectrode array, when the microelectrode array is connected to the patient, preferably to the ear of the patient. The physiological parameter may for example be a compound action potential of one or more nerves, preferably auricular nerves, more preferably the vagus nerve. The anatomical parameter may for example be a spatial localization of vessels, a spatial localization of nerves and / or a type of the nerve in the area of the microelectrode array. The physiological parameter and / or the anatomical parameter may also be determined via impedance tomography. Furthermore, the physiological parameter and / or the anatomical parameter may also be an instantaneous cardiac activity, e.g. systole or diastole and / or a respiratory activity, e.g. inspiration or expiration phase and / or an auricular smooth muscle activity of the patient.

[0012] The control unit of the device according to the invention is furthermore adapted to select specific microelectrodes of the microelectrode array which are located in proximity to the particular nerve, preferably to the vagus nerve, of the patient as stimulation microelectrodes, when the microelectrode array is connected to the patient, preferably to the ear of the patient, based on the at least one physiological and / or the at least one anatomical parameter.

[0013] According to the invention, the control unit is adapted to stimulate the particular nerve, preferably the vagus nerve, of the patient via the selected stimulation microelectrodes. Preferably, the selected stimulation microelectrodes are those microelectrodes of the microelectrode array, which are located closer to the particular nerve, preferably to the vagus nerve, of the patient compared to a predefined maximum distance from the particular nerve.

[0014] Compared to the prior art disclosed e.g. in US 20230302273 Al, US 20230241375 Al, WO 2021187877 Al and US 2015112405 Al, which use regular electrodes, the device according to the invention features microelectrodes that enable a precise stimulation of the vagus nerve, without the need for an exact placement of the device and the knowledge of the location of the auricular vagus nerve. As such, the device can be used by the patient themself, without the need for a trained professional.

[0015] Preferably, the device according to the invention is a device for the stimulation of a vagus nerve, of a patient comprising a microelectrode array comprising multiple individual microelectrodes, and a control unit connected to the microelectrode array, wherein the microelectrode array is connectable to an ear of the patient, and the control unit is adapted to detect at least one physiological and / or at least one anatomical parameter of the patient via the microelectrode array, when the microelectrode array is connected to the ear of the patient, and wherein the control unit is adapted to select specific microelectrodes of the microelectrode array as stimulation microelectrodes which are located in proximity to the vagus nerve of the patient, when the microelectrode array is connected to the ear of the patient, based on the detected physiological parameter and / or anatomical parameter, and wherein the control unit is adapted to stimulate the vagus nerve of the patient via the selected stimulation microelectrodes.

[0016] In another preferred embodiment, the particular nerve is a trigeminal nerve, and the microelectrode array is connectable to a face and / or forehead of the patient.

[0017] In another preferred embodiment, the particular nerve is a phrenic nerve, and the microelectrode array is connectable to a neck of the patient.

[0018] In another preferred embodiment, the particular nerve is a sacral nerve, and the microelectrode array is connectable to a pelvis of the patient.

[0019] In another preferred embodiment, the particular nerve is a tibial nerve, and the microelectrode array is connectable to an ankle and / or leg of the patient.

[0020] In another preferred embodiment, the particular nerve is an occipital nerve, and the microelectrode array is connectable to the back of the head of the patient.

[0021] In another preferred embodiment, the particular nerve is a median nerve and / or an ulnar nerve and / or radial nerve, and the microelectrode array is connectable to an arm of the patient.

[0022] In another preferred embodiment, the particular nerve is a carotid sinus nerve, and the microelectrode array is connectable to a neck of the patient.

[0023] In another preferred embodiment, the particular nerve is a sciatic nerve, and the microelectrode array is connectable to a pelvis of the patient.

[0024] The control unit may also be adapted to determine a spatial localization of vessels, nerves and / or a type of nerve in the area of the microelectrode array, and / or determine a cardiac activity and / or a respiratory activity and / or a smooth muscle activity and / or an auricular smooth muscle activity of the patient from the at least one physiological and / or anatomical parameter of the patient. The control unit may also preferably stimulate the particular nerve of the patient dependent on the determined spatial localization of vessels, spatial localization of nerves and / or the identified type of the nerve in the area of the microelectrode array, and / or dependent on the momentary cardiac activity and / or respiratory activity and / or smooth muscle activity and / or auricular smooth muscle activity. Preferably the control unit is adapted to stimulate the afferent vagus nerve of the patient via the selected microelectrodes.

[0025] Furthermore, each of the microelectrodes of the device according to the invention may comprise at least one needle adapted to at least partially pierce the skin of the patient. Preferably the needle is a microneedle and adapted to at least partially pierce the outer isolating layer of the skin of the patient.

[0026] Furthermore, the microelectrode array may be at least partially flexible in order to optimally adapt to the individual anatomy, preferably the individual ear curvature of different patients.

[0027] The control unit is preferably adapted to determine cardiac activity of the patient from the at least one physiological parameter of the patient, and to predict a systolic and / or a diastolic activity of the heart of the patient based on the cardiac activity. The control unit may be adapted to stimulate the particular nerve of the patient dependent on the predicted systolic and / or a diastolic activity, or the predicted systolic and / or diastolic phases, of the heart of the patient. Preferably, the control unit may be adapted to stimulate the vagus nerve of the patient dependent on the predicted systolic and / or a diastolic activity, or the predicted systolic and / or diastolic phases, of the heart of the patient. Hereby the therapeutic effectiveness of the device according to the invention may be improved.

[0028] According to a preferred embodiment of the device according to the invention, the control unit may be adapted to detect the at least one physiological and / or the at least one anatomical parameter of the patient via impedance tomography. The physiological parameter may for example be a compound action potential. Hereby different types of nerves, especially recruited auricular nerves, may be distinguished from another. Hence, the device according to the invention can be used also as a device for the characterization of a particular nerve. According to a preferred embodiment of the device according to the invention, the control unit is adapted to stimulate the particular nerve of the patient via the selected microelectrodes depending on the detected physiological and / or anatomical parameter. According to a further preferred embodiment of the device according to the invention, the control unit is adapted to stimulate the vagus nerve of the patient via the selected microelectrodes depending on the detected physiological and / or anatomical parameter. This can improve the therapeutic effectiveness of the device, reduce side-effects, and avoid non-responders.

[0029] In another aspect of the invention, a device for the localization of a nerve, preferably an auricular nerve, of a patient is hereby provided, comprising a microelectrode array comprising multiple individual microelectrodes, and a control unit connected to the microelectrode array, wherein the microelectrode array is connectable to the patient, preferably to an ear of the patient, and the control unit is adapted to detect at least one physiological and / or at least one anatomical parameter of the patient via the microelectrode array, when the microelectrode array is connected to the patient, preferably to the ear of the patient, and wherein the control unit is adapted to select specific microelectrodes of the microelectrode array which are located in proximity to the nerve of the patient, when the microelectrode array is connected to the patient, based on the detected physiological parameter and / or anatomical parameter.

[0030] Compared to the device for stimulation disclosed hereinabove, this device for the localization of a nerve is not configured to stimulate the nerve. In other words, the control unit of the device for the localization of a nerve is adapted to only generate an electrical current (or stimulus) whose amplitude, frequency, and / or duration is insufficient to elicit an action potential in a targeted nerve fiber. Such an electric current below a stimulation threshold can be based on theoretical principles. For instance, specific examples of threshold electrical currents below a stimulation threshold can be illustrated by e.g. a short pulse duration below 100 ps, which is generally recognized as an approximate threshold under which no excitation of a nerve fiber takes place. For example, a pulse duration of 100 ps or below, preferably 50 ps or below, more preferably 20 ps or below, more preferably 10 ps or below, more preferably 1 ps or below, will most likely not lead to an excitation of a nerve fiber given typical and safe current values used in neurostimulation stimulation (typically in the range of 1mA and below). Another example can be given by using a frequence of 5 kHz or above, preferably 10 kHz or above, more preferably 50 kHz or above, more preferably 100 kHz or above, more preferably 150 kHz or above, more preferably 200 kHz or above. Such a high frequency is also generally recognized as an approximate threshold over which no excitation of a nerve fiber takes place given typical and safe current values used in neurostimulation stimulation (typically in the range of 1mA and below). This is due to the fact that nerves and their axons are simply too inert to follow the fast consecutive changes of the depolarizing and hyperpolarizing half-periods of stimulation.

[0031] The physiological parameter may for example be a compound action potential of one or more nerves, preferably auricular nerves, more preferably the vagus nerve. The anatomical parameter may for example be a spatial localization of vessels, a spatial localization of nerves and / or a type of the nerve in the area of the microelectrode array. The physiological parameter and / or the anatomical parameter may also be determined via impedance tomography. Furthermore, the physiological parameter and / or the anatomical parameter may also be an instantaneous cardiac activity, e.g. systole or diastole and / or a respiratory activity, e.g. inspiration or expiration phase and / or an auricular smooth muscle activity of the patient. In a preferred embodiment, each of the microelectrodes comprises at least one needle adapted to at least partially pierce the skin of the patient. Preferably the needle is a microneedle and adapted to at least partially pierce the outer isolating layer of the skin of the patient.

[0032] In a preferred embodiment, the microelectrode array is at least partially flexible. This helps to optimally adapt the microelectrode array to the individual anatomy, preferably the individual ear curvature, of different patients.

[0033] In a preferred embodiment, the control unit is adapted to detect the at least one physiological parameter and / or the at least one anatomical parameter of the patient via impedance tomography. Further preferred, the physiological parameter is a compound action potential. Hereby different types of nerves, especially recruited auricular nerves, may be distinguished from another.

[0034] The method for operating the devices according the invention comprises the steps of

[0035] - Connecting the microelectrode array to the patient, preferably to an ear of the patient; and

[0036] - Applying an electrical current below a stimulation threshold (in terms of stimulation strength and / or pulse duration and / or frequency) between two microelectrodes of the microelectrode array, detecting a voltage distribution throughout the microelectrode array via the control unit and assigning a respective individual voltage value to the respective individual microelectrodes of the microelectrode array via the control unit.

[0037] This method according to the invention can be used to operate either the device for the stimulation of a particular nerve, or to operate the device for the localization of a nerve.

[0038] In the first case, the device for stimulation is adapted to generate an electrical current that may or may not stimulate a nerve. Hence, according to this method, the electrical current is limited to an electrical current below a stimulation threshold. As will be described further below, this device can later be used to stimulate the nerve in order to get a nerve response. Based on the nerve response, it is possible to discern whether the nerve is a particular nerve. In other words, the device for stimulation can be used as a device for the characterization of a particular nerve.

[0039] In the second case, the device for localization is adapted to only generate an electrical current that cannot stimulate a nerve. In this case, device cannot be used to stimulate the nerve, hence it is not possible to discern (characterize) whether the nerve is a particular nerve. By detecting the voltage distribution, the spatial conductivity distribution of the tissue of the patient, preferably of the auricular tissue of the patient’s ear, can be determined, which enables the control unit to determine if the microelectrode array is working correctly.

[0040] The term “below a stimulation threshold” as used herein is to be understood as referring to an electrical current (or stimulus) whose amplitude, frequency, and / or duration is insufficient to elicit an action potential in a targeted nerve fiber. This can also be referred to as a subthreshold electrical current. A current below a stimulation threshold therefore does not stimulate (excite / recruit) the nerve and does not lead to propagation of neural activity. More specifically, a pulsatile current below a stimulation threshold is one that falls below the rheobase (the minimum current amplitude that, when applied for a very long duration, is capable of triggering an action potential) and / or that does not meet the combination of amplitude and pulse duration defined by chronaxie (the minimum stimulus duration needed to excite the nerve when the current is set to twice the rheobase). For harmonic currents as stimulus, increasing frequency (above about 100Hz) of oscillation necessarily raises the amplitude threshold for stimulation, so that applicable currents in the auricle (typically in the range of 1mA and below) become necessarily subthreshold at higher frequencies (e.g., 100kHz).

[0041] In practice, an electrical current below a stimulation threshold depends on several factors, like the distance between the electrode and the targeted nerve fiber, what kind of tissue is surrounding the nerve fiber, the cross-sectional area and the local shape of the nerve fiber, the shape of electrode, the location of the reference electrode, the used frequency of the electrical current, etc.

[0042] A person skilled in the art can easily choose an electric current below a stimulation threshold based on the concrete details, or based on theoretical principles. For instance, specific examples of threshold electrical currents below a stimulation threshold can be illustrated by e.g. a short pulse duration below 100 ps, which is generally recognized as an approximate threshold under which no excitation of a nerve fiber takes place. For example, a pulse duration of 100 ps or below, preferably 50 ps or below, more preferably 20 ps or below, more preferably 10 ps or below, more preferably 1 ps or below, will most likely not lead to an excitation of a nerve fiber given typical and safe current values used in neurostimulation stimulation (typically in the range of 1mA and below). Another example can be given by using a frequence of 5 kHz or above, preferably 10 kHz or above, more preferably 50 kHz or above, more preferably 100 kHz or above, more preferably 150 kHz or above, more preferably 200 kHz or above. Such a high frequency is also generally recognized as an approximate threshold over which no excitation of a nerve fiber takes place given typical and safe current values used in neurostimulation stimulation (typically in the range of 1mA and below). This is due to the fact that nerves and their axons are simply too inert to follow the fast consecutive changes of the depolarizing and hyperpolarizing half-periods of stimulation.

[0043] Preferably the method also includes the step of calculating an impedance distribution using the applied electrical current and the detected voltage distribution and assigning a respective individual impedance value to the respective individual microelectrodes of the microelectrode array via the control unit. Hereby an impedance tomography of the patient’s ear is performed, which enables spatial localization of nerves and vessels under the microelectrode array in the ear of the patient.

[0044] According to a preferred embodiment of the method according to the invention, the method comprises the step of identifying at least one nerve of the patient, preferably one auricular nerve in the ear of the patient, by assigning neighboring microelectrodes of the microelectrode array, which exhibit essentially the same impedance value and / or voltage value to a nerve of the patient, preferably an auricular nerve of the patient, via the control unit. The determination if essentially the same impedance value and / or voltage value is exhibited between neighboring microelectrodes may preferably be made if the difference in voltage value and / or impedance value between the neighboring microelectrodes or a string, a series or a row of neighboring microelectrodes lies below a predetermined threshold. Preferably the method may also include identifying at least one nerve of the patient, preferably one auricular nerve in the ear of the patient, by assigning neighboring pairs of microelectrodes, which exhibit a difference in impedance value and / or voltage value above a predetermined threshold, to a nerve of the patient, preferably an auricular nerve of the patient, via the control unit.

[0045] Hereby an individual nerve can be identified in the ear of the patient, and specific microelectrodes can be assigned to the nerve, which are located in proximity to the course of the nerve, preferably in the patient’s ear, under the microelectrode array.

[0046] In the case of the device for stimulation, the method may also comprise selecting one pair of microelectrodes which have been assigned to the nerve, preferably to the auricular nerve, as excitation microelectrodes and selecting one pair of microelectrodes which have been assigned to the nerve, preferably to the auricular nerve, as detection microelectrodes. Furthermore, the method according to the preferred embodiment may include stimulating the nerve, preferably the auricular nerve, using the excitation microelectrodes, detecting a nerve response of the nerve, preferably the auricular nerve, using the detection microelectrodes; and determining a compound action potential of the nerve, preferably the auricular nerve, based on the detected nerve response via the control unit. Hereby it is possible to determine the specific compound action potential of the nerve in an easy and expedient manner. According to the preferred embodiment of the method according to the invention, and in the case of the device for stimulation, the method also includes comparing the determined compound action potential with a reference compound action potential of the particular nerve, preferably the vagus nerve, via the control unit. If the determined compound action potential corresponds, or at least essentially corresponds to the reference compound action potential of the particular nerve, preferably the vagus nerve, one pair of microelectrodes, which have been assigned to the nerve, preferably to the auricular nerve, is selected as stimulation microelectrodes and the particular nerve, preferably the vagus nerve, of the patient is stimulated using the selected stimulation microelectrodes via the control unit.

[0047] The invention also concerns a method for determining the position of a particular nerve, preferably a vagus nerve, of a patient comprising the steps of

[0048] - connecting a microelectrode array comprising microelectrodes to the patient, preferably to the auricle of an ear of the patient,

[0049] - applying an electrical current between two microelectrodes of the microelectrode array and detecting a voltage distribution throughout the microelectrode array and assigning a respective individual voltage value to the respective individual microelectrodes of the microelectrode array,

[0050] - calculating an impedance distribution using the applied electrical current and the detected voltage distribution and assigning a respective individual impedance value to the respective individual microelectrodes of the microelectrode array,

[0051] - identifying at least one nerve of the patient, preferably one auricular nerve in the ear of the patient, by assigning (a) neighboring microelectrodes of the microelectrode array, which exhibit essentially the same impedance value and / or voltage value to a nerve, preferably to an auricular nerve, of the patient and / or by assigning (b) neighboring pairs of microelectrodes, which exhibit a difference in impedance value and / or voltage value above a predetermined threshold to a nerve, preferably to an auricular nerve, of the patient,

[0052] - selecting one pair of microelectrodes which have been assigned to the nerve, preferably to the auricular nerve, as excitation microelectrodes and selecting one pair of microelectrodes which have been assigned to the nerve, preferably to the auricular nerve, as detection microelectrodes,

[0053] - stimulating the nerve, preferably the auricular nerve, using the excitation microelectrodes,

[0054] - detecting a nerve response of the nerve, preferably the auricular nerve, using the detection microelectrodes,

[0055] - determining a compound action potential of the nerve, preferably the auricular nerve, based on the detected nerve response,

[0056] - comparing the determined compound action potential with a reference compound action potential of the particular nerve, preferably of the vagus nerve, and - determining the position of the particular nerve, preferably of the vagus nerve, if the determined compound action potential corresponds essentially to the reference compound action potential of the particular nerve, preferably of the vagus nerve.

[0057] The invention furthermore concerns a method for stimulating a particular nerve, preferably a vagus nerve, of a patient comprising the steps of

[0058] - determining the position of the particular nerve on the patient, preferably the vagus nerve on an ear of the patient, and

[0059] - stimulating the particular nerve, preferably the vagus nerve, by applying electrical current thereto.

[0060] Within this method for stimulating the particular nerve, preferably the vagus nerve, of the patient, the position of the particular nerve, preferably the vagus nerve, is determined by using the device according to the invention and / or the method for determining the position of a particular nerve, preferably a vagus nerve, according to the invention.

[0061] Preferably, the particular nerve, preferably the vagus nerve, is furthermore stimulated within the systolic phase of the cardiac cycle, i.e., within the QT interval of the electrocardiogram of the patient, or within the diastolic phase, i.e., within the TP interval of the electrocardiogram.

[0062] Preferably, a stimulation angle a within the cardiac cycle of the patient is furthermore defined as where ti+i is a measured time point of an R peak after a stimulation of the particular nerve, preferably the vagus nerve, by applying electrical current, ti a measured time of the R peak before the stimulation, and ts a measured time of the onset of the stimulation, and wherein the stimulation angle a is chosen between -20° and 20° when the particular nerve, preferably the vagus nerve, is stimulated within the QT interval, and the stimulation angle a is chosen between 160° and 200° when the particular nerve, preferably the vagus nerve, is stimulated within the TP interval.

[0063] According to the preferred embodiment, the stimulation angle a is approximately 0° when the particular nerve, preferably the vagus nerve, is stimulated within a QT interval, and the stimulation angle a is approximately 180° when the particular nerve, preferably the vagus nerve, is stimulated within a TP interval.

[0064] Preferably the patient is a human patient or a mammalian patient. The method for stimulating a particular nerve, preferably a vagus nerve, of a patient according to the invention may furthermore be used for treating pain, preferably chronic pain or back pain, in a patient. The method may furthermore be used for treating depression, stroke, migraine, peripheral arterial disease, chronic immunological diseases and / or sleep disorders in a patient.

[0065] The device for the stimulation of the particular nerve, preferably the vagus nerve, according to the invention, as well as the method for operating the device and the employed stimulation regime is explained below with reference to the figures.

[0066] Figure la shows a microelectrode array of a device according to the invention in a preferred embodiment and a process to detect bundles of vessels and nerves under the microelectrode array.

[0067] Figure lb shows the microelectrode array of the device according to the invention in a preferred embodiment to record a compound action potential using excitation and detection microelectrodes, and thus to achieve fibre selectivity.

[0068] Figure 1c shows the temporal course of the compound action potential for the auricular vagus nerve (Ap fibre) in contrast to the course of the compound action potential for the auricular pain nerves (AS fibre).

[0069] Figure 2 shows the device according to the invention in a preferred embodiment before placing it on the ear of a patient, as a single unit without extra cables and stimulation needles.

[0070] Figure 3a shows three microelectrodes of a microelectrode array of the device according to the invention in a preferred embodiment.

[0071] Figure 3b shows the microelectrode array of the device according to the invention in a preferred embodiment, which is at least partially flexible.

[0072] Figure 4 and Figure 5 show systole-gated and diastole-gated auricular vagus nerve stimulation (aVNS). Chart (a) of Figure 4 shows an electric biosignal electrocardiogram SE (lead I Einthoven) with indicated peaks and the associated intervals during systole-gated aVNS, and chart (b) shows systole-gated aVNS with the stimulation signal S triggered by the onset of the systole of the heart at the time point ts where stimulation occurs within a QT interval of the electric biosignal SE. Figure 5 chart (c) shows SE during diastole-gated aVNS. The timing of aVNS in respect to the R peaks is delineated by the stimulation angle a. Figure 5 chart (d) shows diastole-gated aVNS with a stimulation signal ss triggered by the onset of the diastole of the heart, where stimulation occurs within a TP interval of the electric biosignal SE. Figure 6 shows non-gated aVNS. (a) The time series of RR intervals with its filtered respiration-free version (thick solid line). Figure 6 chart (b) shows the associated respiration signal SR with the onset of the inspiration (valleys) and expiration (peaks) phases. Figure 6 chart (c): the zoomed version of SR with the indicated respiration period. Figure 6 chart (d) Electrocardiogram SE with denoted RR intervals at time points , ti, ti+i, .. ., ti+5 and the onset of the stimulation with the angle a at the time point ts. The duration of the respiration cycle is indicated by the gray background. Figure 6 chart (e) shows the associated bursts of aVNS.

[0073] Figure 7 shows the slope k of the linear regression fit for the percentual change of RRi+i+n(n = 0,1,. . .6) in relation to RRi where the onset of aVNS occurred, visualized for systole- gated (solid black connecting means for all subjects), diastole-gated (solid black), and non-gated aVNS for all subjects, including k values for the filtered respiration-free version of RR (dashed lines). Figure 7 chart (a) shows the whole respiration cycle. Boxplots are included with k values of individual subjects for n = 0, 3 and 6. Figure 7 chart (b) shows inspiration (♦) versus expiration (A).

[0074] The huge societal pressure due to large number of desperate pain patients and vacant market of accessible / effective aVNS underline the urgent need to leverage now the full potential of aVNS, which can only be reached by fundamentally eased aVNS operation, precision-guided stimulation, and intrinsic personalization to enable its therapeutic efficiency.

[0075] Thus according to the invention, the device 1 for the stimulation of the particular nerve, preferably the vagus nerve, also named RELIEVE herein, comprises a microelectrode array 2, also named 3D MEA, which is connected to a control unit 4, and is adapted to sense a physiological parameter and / or an anatomical parameter of the patient, like for example an activity of the particular nerve, preferably the vagus nerve, and stimulate the particular nerve, preferably the vagus nerve, of the patient, for ground-breaking plug-and-treat and physio- anatomically personalized aVNS to treat chronic pain, with non-incremental technologies: The Plug-and-treat 3D MEA shows a decisively eased application as a single-module device to favour acceptance by clinicians who would virtually administer a simple electrical pill within a minute and be even able to monitor the efficiency of therapy with embedded sensing of physiological data without any external sensors.

[0076] The device 1 according to the invention may comprise 3D printed micro-needles for superficial trans-epidermal penetration only but still with focused stimulation of targeted VN fibres in the ear with unprecedented and personalized spatial resolution, leading to a tenth of invasiveness compared to existing aVNS (for example from 2mm needles down to 0.2mm). Thus, 3D MEA is designed to reduce patient stress in applying / operating aVNS in terms of a plug-and-treat device and to increase its wearing comfort through its non-stigmatizing all-in- one design to favour acceptance by patients. The device 1 for the stimulation of a particular nerve, preferably a vagus nerve, of a patient is shown in Figure 2, wherein the particular nerve is a vagus nerve, and comprises a microelectrode array 2, which is shown in detail in Figure la and Figure lb, comprising multiple microelectrodes 3 and a control unit 4 connected to the microelectrode array 2. The microelectrode array 2 is connectable to an ear 5 of the patient, and the control unit 4 is adapted to detect at least one physiological parameter and / or anatomical parameter of the patient via the microelectrode array 2, when the microelectrode array 2 is connected to the ear 5 of the patient. The control unit 4 is furthermore adapted to select specific microelectrodes 3 of the microelectrode array 2, which are located in proximity to the vagus nerve of the patient as stimulation microelectrodes, when the microelectrode array 2 is connected to the ear 5 of the patient, based on the detected physiological parameter and / or anatomical parameter. In addition, the control unit 4 is adapted to stimulate the vagus nerve of the patient via the selected stimulation microelectrodes 3. Hereby it is not necessary to manually specifically adapt the device 1 according to the invention to the individual anatomy, e.g. to the individual auricular anatomy, like vascularization and innervation of the patient in order to achieve specific and targeted nerve stimulation, preferably vagus nerve stimulation. Preferably, the control unit 4 is adapted to select the specific microelectrodes 3 of the microelectrode array 2 based on impedance tomography. The control unit 4 may also be adapted to derive compound action potentials preferably to attain fibre selectivity and thus to stimulate specifically the auricular vagus nerve. In other words, this device can also be used as a device for the characterization of a particular nerve. By stimulating a nerve, a nerve response can be measured and compared with a reference response of a particular nerve. If the measured nerve response matches the reference response of a particular nerve, the particular nerve has been successfully characterized.

[0077] The device 1 shown in Figure la and Figure lb is however not limited to locating a vagus nerve. The device 1 can also be used to locate a trigeminal nerve on a face and / or forehead of the patient, a phrenic nerve on a neck of the patient, a sacral nerve on a pelvis of the patient, a tibial nerve on an ankle and / or leg of the patient, an occipital nerve on the back of the head of the patient, a median nerve and / or an ulnar nerve and / or radial nerve on an arm of the patient, a carotid sinus nerve on a neck of the patient, and / or a sciatic nerve on a pelvis of the patient.

[0078] Furthermore, the device shown in Figure la and Figure lb may be a device for the localization of a particular nerve, preferably a vagus nerve, of a patient, comprising a microelectrode array 2 comprising multiple individual microelectrodes 3, and a control unit 4 connected to the microelectrode array 2, wherein the microelectrode array 2 is connectable to the patient, preferably to an ear of the patient, and the control unit 4 is adapted to detect at least one physiological and / or at least one anatomical parameter of the patient via the microelectrode array 2, when the microelectrode array 2 is connected to the patient, preferably to the ear of the patient, and wherein the control unit 4 is adapted to localize the particular nerve based on the detected physiological parameter and / or anatomical parameter.

[0079] The physiological parameter and / or the anatomical parameter may be determined via impedance tomography and may be a spatial localization of vessels, a spatial localization of nerves and / or a type of the nerve in the area of the microelectrode array 2, when the microelectrode array 2 is connected to the patient, e.g. to the ear 5 of the patient. The physiological parameter and / or the anatomical parameter may also be a cardiac activity and / or a respiratory activity and / or an auricular smooth muscle activity of the patient. The spatial localization of vessels, the spatial localization of nerves and / or the type of the nerve in the area of the microelectrode array 2, when the microelectrode array is connected to the patient, e.g. to the ear 5 of the patient, may also be derived from the at least one detected physiological parameter and / or the at least one detected anatomical parameter by the control unit 4. Also, the cardiac activity and / or the respiratory activity and / or the auricular smooth muscle activity of the patient may be derived from the detected at least one physiological parameter and / or the detected at least one anatomical parameter by the control unit 4.

[0080] The physiological parameter and / or the anatomical parameter may also be a compound action potential, which is shown in detail in Figure 1c. According to a preferred embodiment of the device according to the invention, the control unit 4 is adapted to stimulate the vagus nerve of the patient - but preferably not its auricular pain nerves - via the selected stimulation microelectrodes 3 depending on the detected physiological parameter and / or anatomical parameter. This can improve the therapeutic effectiveness of the device according to the invention, reduce side-effects, and avoid non-responders.

[0081] The device 1 according the invention is preferably operated by employing a method comprising the steps of connecting the microelectrode array 2 to the ear 5 of the patient, preferably to an auricle of the ear 5 of the patient, as seen in Figure 2, and applying an electrical current between two microelectrodes 3 of the microelectrode array 2 and detecting a voltage distribution throughout the microelectrode array 2 via the control unit 4 and assigning a respective individual voltage value to the respective individual microelectrodes 3 of the microelectrode array 2. The respective individual voltage values are therefore dependent on a given current application. Preferably an individual voltage value is assigned to each of the individual microelectrodes 3 of the microelectrode array 2. The individual voltage value can be understood as the voltage value present at the respective microelectrode 3 of the microelectrode array 2. The electrical current used preferably exhibits an amperage which lies below the threshold of nerve excitation. By detecting the voltage distribution, the conductivity of the tissue of the patient’s ear 5 can be determined, which enables the control 4 unit to determine if the microelectrode array 2 has been placed correctly on the patient’s ear 5, and if the microelectrodes 3 of the microelectrode array 2 are in contact with the tissue of the patient. In course of the present disclosure the terms individual voltage value and voltage value can be used interchangeably. This also applies to the expression individual microelectrodes 3, 3a, 3b, 3c and microelectrodes 3, 3a, 3b, 3c.

[0082] The method preferably also includes the step of calculating an impedance distribution using the applied electrical current and the detected voltage distribution and assigning a respective individual impedance value to the respective individual microelectrodes 3 of the microelectrode array 2 via the control unit 4. Preferably an individual impedance value is assigned to each of the individual microelectrodes 3 of the microelectrode array 2. The individual impedance value can be understood as the impedance value present at the respective microelectrode 3 of the microelectrode array 2. Hereby an impedance tomography of the patient’s ear 5 is performed, which enables the identification of nerves and vessels in the ear 5 of the patient, as seen in Figure la. Hereby the device 1 according to the invention automatically detects nerves and vessels, without the need for trained medical personnel and also in an expedient manner. In course of the present disclosure the terms individual impedance value and impedance value can be used interchangeably.

[0083] The method according to the invention may also comprise the step of identifying at least one nerve of the patient, preferably one auricular nerve in the ear 5 of the patient, by assigning neighboring microelectrodes 3 a of the microelectrode array 2 or preferably a string, a row or a series of neighboring microelectrodes 3a of the microelectrode array 2, which exhibit essentially the same impedance value and / or essentially the same voltage value to a nerve, preferably to an auricular nerve, of the patient via the control unit 4. This process is illustrated in Figure la, where neighboring microelectrodes 3a which exhibit essentially the same impedance value and / or essentially the same voltage value, and are therefore located on an equipotential line, are assigned to the nerve. The determination if essentially the same impedance value and / or essentially the same voltage value is exhibited between neighboring microelectrodes 3 a or a string of neighboring microelectrodes 3 a may preferably be made if the difference in voltage value and / or impedance value between the neighboring microelectrodes 3 a or the string of neighboring microelectrodes 3 a lies below a predetermined threshold.

[0084] Preferably the method may also include identifying at least one nerve of the patient, preferably one auricular nerve in the ear 5 of the patient, by assigning neighboring pairs of microelectrodes 3b, which exhibit a difference in impedance value and / or a difference in voltage value above a predetermined threshold to a nerve, preferably to an auricular nerve, of the patient via the control unit 4. Hereby an individual nerve can be identified e.g. in the ear 5 of the patient, and specific microelectrodes 3b can be assigned to the nerve, which are located in proximity to the course of the nerve in the patient’s ear 5. This is also illustrated in Figure la, wherein the pair of microelectrodes 3b, which lie in proximity to the nerve fulfills the beforementioned condition. According to a preferred embodiment, when multiple neighboring pairs of microelectrodes 3b fulfill this condition, these pairs are assigned to the nerve. This configuration is illustrated in detail in Figure lb, wherein multiple pairs of neighboring microelectrodes 3b are assigned to the nerve. All these microelectrodes 3b therefore are located in close proximity to the nerve. In Figure lb also microelectrodes 3c of the microelectrode array 2 are visible, which are neither neighboring microelectrodes 3a of the microelectrode array 2, which exhibit essentially the same impedance value and / or essentially the same voltage, nor neighboring pairs of microelectrodes 3b, which exhibit a difference in impedance value and / or a difference in voltage value above a predetermined threshold.

[0085] The method may also comprise selecting one pair of microelectrodes 3 which have been assigned to the nerve, preferably to the auricular nerve, as excitation microelectrodes 3 and selecting one pair of microelectrodes 3 which have been assigned to the nerve, preferably to the auricular nerve, as detection microelectrodes 3. This process is illustrated in Figure lb. Furthermore, the method according to the preferred embodiment may include stimulating the nerve, preferably the auricular nerve, using the excitation microelectrodes 3, detecting a nerve response of the nerve, preferably the auricular nerve, using the detection electrodes 3, and determining a compound action potential of the nerve, preferably the auricular nerve, based on the detected nerve response via the control unit 4, as can be seen in figure 1c. Hereby it is possible to determine the specific compound action potential of the nerve in an easy and expedient manner, without any dedicated and external sensors.

[0086] According to the preferred embodiment of the method according to the invention, the method also includes comparing the determined compound action potential with a reference compound action potential of the particular nerve, preferably the vagus nerve, via the control unit. If the determined compound action potential corresponds, or at least essentially corresponds to the reference compound action potential of the particular nerve, preferably the vagus nerve, one pair of microelectrodes 3, which have been assigned to the nerve, preferably to the auricular nerve, is selected as stimulation microelectrodes and the particular nerve, preferably the vagus nerve, of the patient is stimulated using the selected stimulation microelectrodes via the control unit 4. If the determined compound action potential corresponds, or at least essentially corresponds to the reference compound action potential of the particular nerve, preferably the vagus nerve, the respective nerve is identified as the particular nerve, preferably the vagus nerve, of the patient. Hereby it is also possible to differentiate different nerves and / or nerve types like Abeta or Adelta fibres of the patient from each other or differentiate nerves from vessels. Hereby fiber selectivity is achieved. This is also illustrated in Figure 1c.

[0087] According to a preferred embodiment of the method according to the invention, the microelectrode array 2 is applied to the patient, preferably to the ear 5 of the patient, after disinfection of the tissue surface, preferably of the auricular surface in the concha area. The microelectrodes 3 penetrate the outermost skin layer, the epidermis, which has an insulating and therefore current-limiting effect. This is achieved by the needles 6 of the microelectrodes 3 during application of the microelectrode array 2 to the patient, preferably the ear 5. The vascular and nerve bundles to be localized are more conductive than the surrounding tissue, e.g. the surrounding auricular tissue, and are located in the dermis layer, immediately below the epidermis. An electrical current is then applied, with an amperage which lies below the threshold of nerve excitation. This electrical current is applied either between two microelectrodes 3 here called excitation electrodes or one microelectrode 3, also called the measuring electrode and one or more connected microelectrodes 3 which serve as reference electrodes. The resulting voltage distribution or potential distribution is then measured and a respective individual voltage value is assigned to the respective individual microelectrodes 3 of the microelectrode array 2. This step can also be carried out several times with alternating excitation microelectrodes and / or measuring microelectrodes and / or reference microelectrodes.

[0088] According to the preferred embodiment of the method, an impedance tomography is then conducted, wherein the local impedance distribution of the tissue is then measured and / or approximated by the control unit 4, based on the applied amperage and the measured voltage distribution, or the voltage measured at the individual microelectrodes 3 of the microelectrode array 2, and the resulting respective individual impedance values are assigned to the respective individual microelectrodes 3 by the control unit 4. This allows for the identification of equipotential areas within the microelectrode array 2, of microelectrodes 3 which exhibit identical or approximately identical impedance values and / or voltage values. Since bundles of vessels and nerve fibers will run along these equipotential areas, it is therefore possible to identify the location of the individual nerve strands or nerves, preferably auricular nerves, in proximity to the microelectrodes 3 of the microelectrode array 2, and to assign neighboring microelectrodes 3 of the microelectrode array 2, which exhibit essentially the same impedance value and / or voltage value to a nerve, preferably an auricular nerve, of the patient via the control unit 4. It is also possible to approximate the location of the nerve strands or nerves, preferably auricular nerves, in proximity to the microelectrodes 3 by analyzing lines within the microelectrode array 2, which exhibit the largest local impedance variations between neighboring microelectrodes 3. Nerve strands run essentially perpendicular to these lines. Therefore, it is also possible to assign neighboring pairs of microelectrodes 3, which exhibit a difference in impedance value and / or voltage value above a predetermined threshold to a nerve, preferably an auricular nerve, of the patient via the control unit 4. Hereby microelectrodes 3 of the microelectrode array 2 can be identified, which are in close proximity to nerves, preferably auricular nerves, and vessels and / or are located farther away from nerves, preferably auricular nerves, and vessels of the patient. A further aim of the method according to the invention is to identify and select microelectrodes 3 in the microelectrode array 2, as stimulation microelectrodes which are closest to Abeta nerve fibers of the particular nerve, preferably the vagus nerve, originating from the vascular and neural bundle are selected for subsequent therapeutic stimulation of the particular nerve, preferably the vagus nerve, for a therapeutically effective treatment and therefore avoiding the activation of Adelta nerve fibers, which trigger pain and are therapeutically counterproductive. Therefore preferably a stimulation of the nerve, preferably the auricular nerve, using the excitation microelectrodes is conducted via the control unit 4, and a nerve response of the nerve, preferably the auricular nerve, is detected by the control unit 4 using the detection microelectrodes. In order to achieve this, preferably at least one pair of microelectrodes 3 which have been assigned to the nerve, preferably the auricular nerve, are selected as excitation microelectrodes and at least one pair of microelectrodes 3 which have been assigned to the nerve, preferably the auricular nerve, are selected as detection microelectrodes, as seen in Figure lb. According to a preferred embodiment of the method according to the invention, the transit times of the excitation signal until it reaches the pair of detection microelectrodes are recorded by the control unit 4. If optionally two pairs of excitation microelectrodes are used, the transit times between the excitation by the first excitation microelectrode pair and the second excitation microelectrode pair until the excitation signal reaches the single pair of detection microelectrodes are recorded and compared by the control unit 4. The fast Abeta nerve fibers can then be identified as those that exhibit a relatively short transit time, and the slow Adelta nerve fibers can be identified as those that exhibit a relatively long transit time.

[0089] The method according to the invention may then also comprise the step of determining a compound action potential of the nerve, preferably the auricular nerve, based on the detected nerve response via the control unit 4. The compound potential, preferably the auricular compound potential, to which both Abeta and Adelta nerve fibers contribute may be derived from the signal of the detection microelectrode pair for each vascular and nerve bundle. A comparison of the temporal course of the recorded compound potential with a reference course for the compound potential with a dominant contribution from Abeta, i.e. a reference course for the compound potential of the particular nerve, preferably the vagus nerve, may then be conducted.

[0090] This may be followed by a selection of at least one stimulation microelectrode or a stimulation microelectrode pair along that vascular and neural bundle along which the fast Abeta nerve fibers were identified and / or a compound action potential was recorded that shows the smallest deviation from the reference curve. Also reference electrodes may be are varied to better fulfill this condition. Hereby the stimulation parameters of the stimulation microelectrodes in the microelectrode array 2 may be selected in order to avoid over- or understimulation in therapy. Furthermore, the amplitude, pulse width, and frequency of the stimulus may be selected or increased so that the nerve’s compound potential, preferably the auricular compound potential, at the detection microelectrode pair is clearly and continuously apparent over time. This ensures a continuous input into the brain and thus avoids understimulation of the patient in therapy. Various machine learning methods may be used in the method according to the invention like iterative learning, Al, etc. The amplitude, pulse width and frequency of the stimulus may then be selected or increased so that the current temporal course of the compound potential approaches that of the comparison course with a dominant contribution from Abeta and a minimal contribution from Adelta, thus avoiding overstimulation of the patient in therapy which would occur if there were a dominant contribution from Adelta.

[0091] The invention also concerns a method for determining the position of a particular nerve, preferably a vagus nerve, of a patient comprising the steps of

[0092] - connecting a microelectrode array 2 comprising microelectrodes 3 to the patient, preferably to the auricle of an ear 5 of the patient,

[0093] - applying an electrical current between two microelectrodes 3 of the microelectrode array 2, detecting a voltage distribution throughout the microelectrode array 2 and assigning a respective individual voltage value to the respective individual microelectrodes 3 of the microelectrode array 2,

[0094] - calculating an impedance distribution using the applied electrical current and the detected voltage distribution and assigning a respective individual impedance value to the respective individual microelectrodes 3 of the microelectrode array 2,

[0095] - identifying at least one nerve, preferably one auricular nerve, in the ear 5 of the patient by assigning (a) neighboring microelectrodes 3 of the microelectrode array 2, which exhibit essentially the same impedance value and / or voltage value to a nerve, preferably an auricular nerve, of the patient and / or by assigning (b) neighboring pairs of microelectrodes 3, which exhibit a difference in impedance value and / or voltage value above a predetermined threshold to a nerve, preferably an auricular nerve, of the patient,

[0096] - selecting one pair of microelectrodes 3 which have been assigned to the nerve, preferably to the auricular nerve, as excitation microelectrodes and selecting one pair of microelectrodes 3 which have been assigned to the nerve, preferably to the auricular nerve, as detection microelectrodes,

[0097] - stimulating the nerve, preferably the auricular nerve, using the excitation microelectrodes,

[0098] - detecting a nerve response of the nerve, preferably the auricular nerve, using the detection microelectrodes,

[0099] - determining a compound action potential of the nerve, preferably the auricular nerve, based on the detected nerve response, - comparing the determined compound action potential with a reference compound action potential of the particular nerve, preferably the vagus nerve, and

[0100] - determining the position of the particular nerve, preferably the vagus nerve, if the determined compound action potential corresponds essentially to the reference compound action potential of the particular nerve, preferably the vagus nerve.

[0101] The invention furthermore concerns a method for stimulating a particular nerve, preferably a vagus nerve, of a patient comprising the steps of

[0102] - determining the position of the particular nerve on the patient, preferably the vagus nerve on an ear 5 of the patient, and

[0103] - stimulating the particular nerve by applying electrical current thereto.

[0104] Within this method for stimulating the particular nerve, preferably the vagus nerve, of the patient, the position of the particular nerve is determined by using the device 1 according to the invention and / or the method for determining the position of a particular nerve, preferably a vagus nerve, according to the invention.

[0105] Preferably, the particular nerve, more preferably the vagus nerve, is furthermore stimulated within a QT interval or a TP interval of an electrocardiogram of the patient.

[0106] Preferably the patient is a human patient or a mammalian patient. The method for stimulating a particular nerve, preferably a vagus nerve, of a patient according to the invention may furthermore be used for treating chronic pain, preferably back pain, in a patient.

[0107] The fabrication of the microelectrode array 2 is preferably conducted as follows:

[0108] (i) 3D structuring of non-conducive 3D flexible substrate (with the porosity generated by holes, perforated with laser structuring) to imitate spikes of micro-needles for epidermal penetration. The supporting cone-shaped posts are defined (at positions of micro-needles) needed to overcome the local stretch of epidermis / skin to be penetrated by micro-needles located on top of these posts.

[0109] (ii) Conductive material (e.g., Ag / AgCl at the regions of micro-needles) is printed with ink-jet printer, defining positions of conductive leads / micro-needles.

[0110] (iii) Ink-jet printed dielectric layer insulates conductive leads, leaving 3D electrode tips / micro-needles exposed.

[0111] (iv) Additional thin medical adhesive layer (cut with laser structuring) is applied on top to ensure a tight contact of 3D MEA or the microelectrode array 2 with the tissue surface, preferably the auricular surface.

[0112] (v) Substrate / dielectric / adhesive layers are perforated with laser-structured holes to ensure breathability of the microelectrode array 2 or the 3D MEA and reduced skin stress for application durations of up to 1 week (typical for aVNS), and high wearability. Physio-anatomical personalization of 3D MEA allows exploitation of the full therapeutic potential of aVNS, based on a closed-loop measure-stimulate architecture and physio- anatomical feedback, employing embedded sensing.

[0113] The system integration is preferably conducted as follows, wherein the particular nerve is the vagus nerve:

[0114] Connector to the microelectrode array 2, proprietary (de)multiplexing firmware / hardware / software, measuring / stimulating set-ups (using off-the-shelf array amplifier / impedance analyser) are established to operate the microelectrode array 2 and are preferably integrated in the control unit 4, 3D MEA in (i) voltage measurement, (ii) impedance measurement, and (iii) voltage / current stimulation modes. The modes use flexible selection of employed active / reference electrodes to personalize space / time locked stimulation.

[0115] System integration allows establishment of local / global closed-loops for aVNS. The temporal course of the auricular conductivity, that of the auricular compound potentials and the auricular smooth muscle activity can be used as biofeedback for the local / global closed-loop to govern the highly-individual space / time locked stimulation patterns.

[0116] The integrated system is preferably miniaturized / encapsulated for testing as a fully-integrated one-part device including 3D MEA / all electronics / rechargeable battery for operation / stimulation / sensing.

[0117] Local closed-loop is preferably established in firmware / software of the control unit 4:

[0118] (i) The auricular conductivity distribution determines the optimal stimulation electrodes (space locked stimulation) and is a performance measure for optimal actuator selection.

[0119] (ii) The timing / shape of compound action potentials determines the optimal time evolution of stimulation patterns (time locked stimulation) and is as biofeedback signal to controller (e.g., iterative learning control, extremum seeking control) to calculate optimal stimulus (e.g., magnitude, pulse width), (i) and (ii) serve as local / regional individual biofeedback. The system integration is validated with in-silico modelling.

[0120] Global closed-loop is preferably established in firmware / software, which is preferably run on the control unit 4.

[0121] (a) The temporal course of the auricular conductivity is used to derive cardiac and respiratory activity (incl. heart rate / heart rate variability) using principles of impedance plethysmography / respiratory sinus arrhythmia.

[0122] (b) The temporal course of the auricular sympathetically-innervated smooth muscle activity is used to estimate the sympathetic activity of the autonomic nervous system. The derived cardiac signal, respiratory signal, or the sympathetic activity serves as global / systemic individual biofeedback for systole-gated, expiration-gated, or even pain-gated aVNS (time locked stimulation), respectively, to end up with personalized stimulation patterns. In terms of control, the control plant from its input (actuator / stimulation by 3D MEA) to its output (sensing / individual biofeedback by 3D MEA) depends strongly on the individual / external conditions, and is subject to parameter variations. Thus, we strive to identify the control plant below the perception threshold of stimulation with controllers adapting to changing conditions (e.g., iterative learning control).

[0123] In order to individualize the aVNS preferably a cardiac activity (heart rate, local systolic / diastolic phases, heart rate variability), respiratory activity (respiration rate, insp. / exp. phases), and / or sympathetic activity are derived with the 3D MEA may be used as global / systemic individual biofeedback.

[0124] According to the invention, a systole-gated closed-loop may be used: 3D MEA may be activated during systole to interfere constructively with the natural timing of baroreflex.

[0125] Also an expiration-gated closed-loop may be used: 3D MEA is activated during expiration to interfere with parasympathetic activity.

[0126] According to a preferred embodiment of the device 1 according to the invention each of the microelectrodes 3 comprises at least one needle 6 adapted to at least partially pierce the skin of the patient. This can be seen in Figure 3a which shows a segment of the microelectrode array 2 with three individual microelectrodes 3, which include needles 6. Furthermore, the microelectrode array 2 may be at least partially flexible as depicted in Figure 3b, in order to maximize the contact area and ease the contact of the microelectrode array 2 with the tissue surface, preferably the ear surface 5 of the patient.

[0127] Novel continuous personalization locates automatically targeted micro-anatomical points in the ear to be stimulated by means of phenotypic / local patient-specific signatures, e.g., auricular conductivity, monitored with unmatched sub-millisecond latency in the loop. Optimal stimulation sequences for each patient under treatment are automatically determined via iterative learning from biofeedback formed by local / global patient-specific signatures, e.g., autonomic physiology. These signatures consider pain-affected physiology, allow for targeted fibre-selective stimulation and constructive synchronization of stimulation with personal physiological body rhythms to orchestrate effects on pain relief, prevent under and over stimulation, and save stimulation energy.

[0128] In-depth personalisation through sensing avoids non-responders and dispenses with common manual adjustments and readjustments of aVNS settings - all in favour of pain treatment outcome. The present invention boosts pain treatment success of aVNS by:

[0129] (a) miniaturized plug-and-treat architecture with finally clinician-friendly operation and patient-friendly application, without any extra wires / electrodes and avoiding random electrode placement, instead considering individual micro-anatomy of the ear, and with reduced side-effects;

[0130] (b) preferably on-site self-adaptive closed-loop architecture allowing not only to locate individual anatomically-distinct and functionally-distinct VN fibres but also stimulate them with individualized optimal intensities in a harmonious interaction with autonomic physiology, and providing feedback on therapeutic efficiency by embedded sensing. These novel technologies will not only improve reduction levels of individual pain but also establish an easily accessible / first-line treatment for not yet addressed patients.

[0131] The environmental footprint of aVNS is reduced by 3D MEA rechargeability and multiphasic stimulation saving energy. The device according to the invention therefore presents a major shift to radically simplified and intrinsically personalized aVNS, with 3D MEA constituting a plug-and-treat “electrical pill” for the medical community, addressing a significant societal health burden.

[0132] The device according to the invention therefore according to a preferred embodiment, wherein the particular nerve is a vagus nerve, constitutes a

[0133] (i) plug-and-treat concept of aVNS as a single-module device without any accessories with

[0134] (ii) decisively reduced invasiveness of focused aVNS through multiple / independent 3D MEA microelectrodes for epidermal penetration only, with the benefit of

[0135] (iii) focalized neurostimulation of auricular VNs only, using their distinct anatomical and functional properties. Multiple high-density electrodes of 3D MEA allow for contrasted recruitment of VN endings, in contrast to existing diffuse stimulation of nonspecific auricular nerve fibres. Rotating currents may be used to optimize fibre recruitment, with multiphasic stimulation increasing afferent inflow into the brain and thus reducing stimulation energy applied.

[0136] (iv) Embedded sensing of physiological and therapeutic data without any external sensors. The fundamental novelty is the embedded biofeedback that follows directly from ear sensors, not requiring anymore manual and cumbersome adjustments and readjustments based on external sources.

[0137] (v) Truly personalized therapeutic aVNS through the biofeedback reflecting not only individual micro-anatomy of the ear but also time-varying physiology of the patient’s body. The unique personalization is realized in space and time (space / time locked stimulation) through embedded closed-loops and stimulation / sensing properties of 3DMEA:

[0138] (v. l) micro-anatomical stimulation points are preferably individually selected in the ear,

[0139] (v.2) stimulation patterns are preferably individually shaped to allow fibre-selective and hence functional stimulation of VNs only (and to avoid stimulation of pain fibres in the ear), to prevent under / over stimulation of VNs, and thus to reduce non-responders,

[0140] (v.3) stimulation patterns are preferably synchronized with individual physiological parameters of the body, e.g., tuned to cardiac and respiration rhythms, in continuous synergy with the pain-affected physiology to strengthen systemic aVNS effects in pain therapy.

[0141] The body -brain interaction revolutionises understanding of links between health and the brain. The autonomic vagus nerve or VN plays a pivotal role in sensing and transmitting body- derived signals to the brain in order to adapt the efferent brain’s responses to autonomic physiology of the body. Thus, neuromodulation of the VN afferent projections is currently explored as treatment option in clinical disorders, incl. chronic pain e.g., cervical / low-back pain with its chronically unbalanced autonomic state and over-inflammation.

[0142] The invasive / non-invasive variants of VN stimulation such as aVNS are implicated in sustainable antinociceptive effects by modulating afferent VN target areas in the brain.

[0143] In its current form, market-ready aVNS according to the prior art requires a laborious set-up and highly experienced manual setting of numerous needles / electrodes in approximate auricular areas populated by VN, as based on averaged / non-personalized innervations of the ear. There is a need of multiple accessories e.g., electrode application pen, magnetic pen for adjustments and readjustments, incl. spreading long wires to external stimulator prone to misplacement when being worn for days / weeks by the patient. The so-called transcutaneous aVNS with surface electrodes implies diffuse stimulation of nonspecific nerves in the ear with the lack of spatial resolution / focus in stimulation points. The so-called percutaneous aVNS with needle electrodes has more focused stimulation but yet of nonspecific nerves, accompanied by prominent side-effects such as painful application and local bleeding due to relatively large and long stimulation needles (for example 2mm). The existing aVNS according to the prior art is one-time personalized in intensity at the time of its application and later triggered by the patient, requiring always subjective feedback on perception from the suffering patient and external help in the intensity readjustment in frail older patients. This punctual personalization is neither governed by the very individual micro-anatomy of the ear nor triggered by objective continuously time-varying physiology, both determining the therapeutic efficiency of aVNS. aVNS has no embedded sensing and thus no embedded feedback-related stimulation to personalize. Existing aVNS is not personalized continuously in time and uses only empirical / non-synchronized stimulation patterns, yielding divergent therapeutic results biased by individual and disease-specific trajectories, ending up in non- responders. Moreover, available aVNS devices lack implementation of a sham condition necessary for their reliable validation in clinical studies to enter routine use in clinics. All this prevent establishment and validation of aVNS and call for its radical simplification / personalization.

[0144] Thus, the ambition of the device according to the invention with respect to the state-of-the-art in a preferred embodiment, wherein the particular nerve is a vagus nerve, is that:

[0145] (i) The device according to the invention, also offers a plug-and-treat aVNS in easy / self- application without extra wires, needles, or accessories for patient-friendly and clinician- friendly treatment of chronic pain.

[0146] (ii) The continuous individualization of the device according to the invention is due to own objective physio-anatomical feedback directly from the ear - without any additional external sensors or any subjective feedback required to adapt stimulation - shaped as an embedded measure-stimulate architecture. The personalizing closed-loop control may be achieved on two levels:

[0147] (1) the local closed-loop accounts for individual micro-anatomical innervation of the ear in that individual anatomically / functionally distinct VN nerves are automatically located / recruited via a novel spatial resolution of aVNS with the high-density 3D MEA microelectrode area. Even fibre selectivity is realized in stimulation, avoiding non-VN coexcitation. Local side-effects of focused stimulation are significantly reduced by the device according to the invention, also called 3D MEA, using much smaller trans-epidermal microneedles (preferably <0.2mm).

[0148] (2) The global closed-loop aligns and synchronizes aVNS with the individual autonomic systemic physiology of the body at any time, such as time-varying cardiac and respiratory activity, to raise therapeutic efficiency of aVNS and avoid side-effects. This makes manual selection of stimulation points by experts obsolete, as well as manual adjustment and / or readjustment of stimulation strength.

[0149] Contributions breakthroughs related to the present invention to envisioned plug-and-treat and truly personalized aVNS neuromodulation in chronic pain treatment are the minimal invasiveness and single-module device for drastically improved acceptance by patient / clinician; multi-level closed-loops for genuine personalization on anatomical / physiological levels to increase therapeutic efficiency in pain therapy; and the use of the present device according to the invention per design not only for stimulation but also for monitoring of neuronal activity and physiology - a true innovation for personalized pain therapy management.

[0150] OBJECTIVES

[0151] Four specific objectives are set for a preferred embodiment of the device according to the invention, wherein the particular nerve is a vagus nerve: Objective#! : Establishment of micro-anatomical 3D auricular model - We perform micro- anatomical 3D imaging of the vagally innervated central region of the ear (cymba concha) of human body with the goal to establish individual in-silico 3D auricular models with annotated micro- structure incl. vascularization and innervation.

[0152] Objective#2: In-silico modelling of personalized stimulation - We use in-silico 3D auricular models for numerical aVNS optimisation with micro-needles applied to the modelled cymba concha with the goal to model sensing and stimulation properties of 3D MEA and to estimate the influence of its technological characteristics before expensive / laborious realization of 3D MEA. A personalized closed-loop operation of 3D MEA is modelled and optimized in-silico, incl. selective recruitment of individual auricular VN fibres.

[0153] Objective#3: Realization of integrated 3D MEA for personalized stimulation - We design, fabricate, characterize, and integrate 3D MEA for sensing, stimulation, and impedance measurements with closed-loop architecture. The goal is to prototype 3D MEA capable of individualized stimulation points and patterns for every ear micro-anatomy, every patient’s physiology, and at any time. Local closed-loop is established for targeted and selected recruitment of auricular VN while global closed-loop for constructive interference of stimulation with autonomic processes as cardiac, respiratory, or sympathetic activity to unleash systemic therapeutic effects.

[0154] Objective#4: Demonstration of data on safety, efficacy, and clinical therapeutic action - We perform in-lab testing for safety and efficacy of 3D MEA, for sensing of biofeedback signals, and for convergent and individualized operation of local and global closed-loops. Pre-clinical testing addresses protocol safety of 3D MEA and its action on autonomic physiology. Clinical testing evaluates therapeutic action / potency in chronic pain patients. Complementing this, physiological mechanisms of action are assessed via functional magnetic resonance imaging (fMRI) disclosing in-vivo modulations of VN projections in the brain in response to 3D MEA. This acts as an objective physiological proof complemented by the clinical therapeutic action, both anchoring working our research approach, according to objectives, starts with fundamental 3D micro-anatomical investigations of neuronal tissue (neuromodulation input from Objective#!). This serves as a basis for 3D in-silico and 3D mock-up modelling of this neuronal tissue which allows a pre-modelled development of a radically new 3D MEA technology for individualized / simplified aVNS (neuromodulation interface between physics and living matter from Objectives#2 and #3). Then 3D MEA experimental testing follows to prove safety, efficacy, and lastly therapeutic and physiological action in humans on the clinical and functional / anatomical levels of the brain (neuromodulation output from Objective#4). In a preferred embodiment, wherein the particular nerve is a vagus nerve, the methodology preferably starts with 3D micro-anatomical investigation of auricular spatial vascularization / innervation of a VN-innervated region (cymba concha). The quantified fibres in 3D to be recruited by trans-epidermal micro-needles of 3D MEA as proposed, enable generation of numerical - novel and individual - 3D auricular models (not averaged) subjected later to individualized in-silico stimulations to design / optimise space / time locked sensing / stimulator characteristics of 3D MEA. To account for a highly individual ear micro-anatomy, a novel local closed-loop is preferably established first in-silico, providing highly individualized 3D MEA stimulation. To account for highly individual time-varying autonomic processes in the body, another novel global closed-loop is established to raise therapeutic efficiency of 3D MEA at the individual level. Multidimensional space of parameters governing the closed-loop stimulation is searched for individual optima using iterative learning. 3D auricular models are also used to form physical 3D mock-up models (by 3D printers) for experimental testing of mechanical / electrical features of 3D MEA before its inlab testing. Modelling is essential for technological optimization of 3D MEA and its development, incl. its characterization, system integration, and closed-loop operation (without any external sensors). After mock-up-based testing, experimental testing continues with in-lab testing of the integrated 3D MEA to proof in-lab safety and (basic) efficacy on the human ear, with the focus on the individualized closed-loop aVNS. Pre-clinical testing follows in hospital to assess modulatory capacity of 3D MEA on the autonomic nervous system and to protocol its clinical safety. Clinical testing aims to show therapeutic potency of 3D MEA in chronic pain patients, incl. high-resolution autonomic monitoring of patients - the proper approach to assess individual effects of the highly personalised 3D MEA. Physiological action is finally assessed through fMRI validation in healthy persons / chronic pain patients directly at the brain level to distance the proposed 3D MEA from empirically-designed aVNS. Here we aim at a physiological proof of neuromodulation by 3D MEA in that its potential is uncovered to modulate afferent VN projections objectively / in-vivo in the brainstem, the nucleus of the solitary tract (NTS). NTS modulation, as reviewed by us, underlies antinociceptive aVNS effects and acts as relay to higher brain regions processing pain.

[0155] The fabrication part of the device according to the invention prefers according to a preferred embodiment sustainable and green technologies and does not harm any of the six environmental objectives of the EU Taxonomy Regulation. Gender dimension: female / male ears of different age are considered in the anatomical study, with females / males participating for in-lab, pre-clinical, clinical, and fMRI testing, accounting for gender-related differences in the anatomy / size / shape of ears and for potential differences in autonomic physiology in response to 3D MEA stimulation.

[0156] Clinical translation of 3D MEA is feasible through improved patient acceptance (plug-and- treat concept, no self-adaptation), reduced clinical load (no laborious set-up, therapeutic efficiency through intrinsic personalization), and cost savings (of regulatory 3D MEA approval and per patient due to proper pain management).

[0157] LONG TERM IMPACT

[0158] Chronic pain is one of the most underestimated healthcare problems in the word today, devastating quality of life of sufferers with serious physical / psychological comorbidities (50% worry and 27% feel socially isolated, with doubled suicide risk) and causing a major economic burden on the healthcare systems and society (about €440 billion annually in EU, 1.5-3% GDP). Chronic pain affects 150million Europeans, one of five people in adults, leading to addiction to opioid analgesics intake with most severe side-effects (respiratory depression), and loss of household income and productivity (1 / 3 of patients claim impacted income by 31%, 1 / 5 of patients lose their jobs). Patients with chronic pain must wait 2 years before their pain / symptoms are adequately managed - still the majority of 68% are in pain for more than 12 hours despite standard pharmacological treatment. These major shortcomings call emergently for new modalities to treat chronic pain as a brain disease.

[0159] Neuromodulation - affecting the electrical activity of the brain - turns out to be a promising for pain management (dominates today’s neurostimulation market), with aVNS as a neurostimulation modality with promising effects on chronic pain. However, existing neurostimulation still shows major drawbacks in (i) limited accessibility for medical centres / clinicians / patients due to its still major invasiveness, (ii) complexity (separate electrodes and long wires to handle), (iii) limited patient compliance (manual readjustment of stimulation strength), (iv) laborious application / operation in daily life (manual search for aVNS application points by experts), and (v) high costs (existing transcutaneous aVNS €2.5k per patient, invasive VN stimulation €20-30k per patient).

[0160] The present invention sets out to make treatment of chronic pain accessible, affordable, and effective with the proposed self-applicable plug-and-treat 3D MEA addressing the significant drawbacks (i)-(v) of existing neuromodulation therapies:

[0161] The impact / outcome in economy / technology is that we establish accessible / first-line treatment of chronic pain through neuromodulation. Ultimately, we bring anguished employees back to their work in favor of their income and company productivity. 3D MEA favors aVNS acceptance by overloaded clinicians - the technology facilitators - and patients due to its simple plug-and-treat concept in application / use and thus robustness towards handling errors. The reduced invasiveness of 3D MEA and diminished stress during its application on the ear favor this acceptance, as well as reduced labor costs for clinician. Patients’ physio-anatomical signatures are considered by the measure-stimulate 3D MEA, thus making the therapy very personal, efficient, and even more comfortable for patient (no additional pain during aVNS), and thus more attractive for the market. Direct cost savings of €lk per chronic low back pain (LBP) patient (=€20k-0.75-0.2-0.35) every year may be produced by 3D MEA for healthcare system / medical centers, with the potential of total treatment costs saving on EU level in the range of €6 billion

[0162] (=€440b-0.55-0.75-0.35-0.1) every year while addressing only 10% of LBP patients. This costs scaling assumes that (i) LBP patients account for 55% cases of chronic pain and whose pain was reduced by 50-75% by percutaneous needle-based aVNS (existing neurostimulation treatment), with annual total costs per LBP patient of €20k using standard pain care (20% direct healthcare costs, 80% indirect societal costs such as productivity loss); (ii) proper pain management reduced direct costs by 35% after service redesign or 40% after peripheral nerve field neurostimulation in LBP.

[0163] For industry, production costs are reduced by rechargeable set-up. Approval costs, regulatory costs, and application costs are reduced by low risk profile of 3D MEA (reduced invasiveness, afferent / sensori al stimulation, no overstimulation due to local closed-loop) and by simple patient application of our plug-and-treat aVNS (lowers required expertise within company). This attracts (new) manufacturing / marketing companies for exploitation and rises their profits, increasing EU competitiveness e.g., through cross-discipline innovations in aVNS / 3D printing.

[0164] New markets are opened by the personalization / lowered risk / eased application to address global challenges in health / inequalities in terms of sustainable development goals (SDG) like SDG3,10,12,17. Namely, more geriatrics are included by 3D MEA (avoid manually-to-adjust complex technologies, high costs), minorities (e.g., for stroke rehabilitation with easy-to-use aVNS to accelerate brain plasticity), and children (appreciate robust / easy-to-use / noninvasive high-tech). In addition to chronic pain (e.g., cervical / low-back pain), 3D MEA addresses systemic disorders as new markets, incl. arrythmias, stroke, depression, metabolic syndrome, Covid- 19 comorbidities.

[0165] Target groups that benefit are medical centers that purchase 3D MEA for pain patients, pain specialists (neurologists or orthopedics) who prescribe the therapy to patients, and chronic pain patients who wear 3D MEA. The simplicity in handling, therapy and cost efficiency, and true personalization attract medical centers and their willingness to pay for 3D MEA, as well as attract insurances for public reimbursement of this therapy in future.

[0166] The outcome in environment is that the 3D MEA fabrication outcome uses sustainable and green technologies, the integrated and miniaturised system is rechargeable to reduce its environmental footprint (SDG12). The outcome in society is happiness and improved life quality of chronic pain patients, with finally a restful overnight sleep, relieved from debilitating pain without depression, addiction to opioids. Patients become self-driven but not more pain-driven, socially (re)integrated, which facilitates their caregivers and favor families. This outcome yields healthy people being able to deal efficiently with their chronic pain.

[0167] New policies are issued on faster market entries of noninvasive and personalized neuromodulation devices (with afferent / sensorial stimulation not affecting directly the target organ and physio-anatomically personalized stimulation, both extending safety margins), new policies on eased regulatory approval for easy-to-use one-part neuromodulation systems (less prone to errors in use), and new policies on ethics (intrinsically greater safety margins ease ethic requirements).

[0168] The outcome in science is that we establish high-density multi-site sensor / stimulator array with high spatial / temporal resolution, meant but not limited to impactful aVNS, and realize a non-invasive but still anatomically focalized aVNS, even with fibre selectivity. We realize a true personalized / miniaturized aVNS - basis for the first ASIC on aVNS in future - using patient-specific signatures on the local / systemic physiology, to arrive at optimal stimulation for every patient at any point of time.

[0169] PREFERRED STIMULATION REGIME OF THE VAGUS NERVE

[0170] According to a preferred embodiment of the device 1 according to the invention, the control unit 4 is adapted to determine a cardiac activity of the patient from the at least one physiological parameter and / or the at least one anatomical parameter of the patient, and to predict a systolic and / or a diastolic activity, preferably in the following heartbeats of the patient, based on the determined cardiac activity.

[0171] Furthermore, the control unit 4 may be adapted to stimulate the particular nerve, preferably the vagus nerve, of the patient dependent on the predicted systolic and / or a diastolic activity of the heart of the patient.

[0172] The stimulation regime described in the following may be implemented with the device 1 according to the invention described hereinabove, or other devices which are suitable for the stimulation of the particular nerve, preferably the vagus nerve, of a patient. With respect to preferred embodiments where the particular nerve is a vagus nerve, these devices are commonly described as auricular vagus nerve stimulation (aVNS) systems and usually comprise individual electrodes, or may comprise electrode arrays, which are placed on the ear of a patient in the vicinity of the vagus nerve. These electrodes are used for the stimulation of the vagus nerve. The stimulation is controlled by a control unit connected to the electrodes or the electrode array.

[0173] In a preferred embodiment where the particular nerve is a vagus nerve, neuromodulation comes into focus as a non-pharmacological therapy with the vagus nerve as modulation target. aVNS has emerged to treat chronic diseases while re-establishing the sympathovagal balance and activating parasympathetic anti-inflammatory pathways. aVNS leads still to over and under-stimulation and is limited in therapeutic efficiency. A potential avenue is personalization of aVNS based on time-varying cardiorespiratory rhythms of the human body.

[0174] In a preferred embodiment of the present disclosure where the particular nerve is a vagus nerve, a personalized cardiac-gated aVNS is disclosed and its effects on the instantaneous beat-to-beat intervals of the human heart of a patient (RR intervals) are evaluated. Modulation of RR is expected to reveal the aVNS efficiency since the efferent cardiac branch of the stimulated afferent vagus nerve governs the instantaneous RR.

[0175] In course of the development five healthy subjects were subjected to aVNS. Each subject underwent two 25-minute sessions. The first session started with the non-gated open-loop aVNS, followed by the systole-gated closed-loop aVNS, then the non-gated, diastole-gated, and non-gated aVNS, each for 5min. In the second session, systole and diastole gated aVNS were interchanged. Changes in RR were analysed by comparing the prolongation of RR intervals with respect to the proceeding RR interval where aVNS took place. These RR changes are considered as a function of the personalized stimulation onset, the stimulation angle starting with R peak. The influence of the respiration phases is considered on the cardiovagal modulation. The results show that the systole-gated aVNS, where stimulation occurs within a QT interval of the electric biosignal electrocardiogram, tends to prolong and shorten RR when stimulated after and before the R peak, respectively. The later in time is the stimulation onset within the diastole-gated aVNS, where stimulation occurs within a TP interval of the electric biosignal electrocardiogram, the longer tends to be the subsequent RR interval. The tendency of the RR prolongation raises with increasing stimulation angle and then gradually levels off with increasing delay of the considered RR interval from the one where aVNS took place. The slope of this rise is larger for the systole-gated than diastolegated aVNS. When considering individual respiration phases, the inspiratory systole- gated aVNS seems to show the largest slope values and thus the largest cardiovagal modulatory capacity of the personalized time-gated aVNS.

[0176] It has been indicated during development of the present device according to the invention, aVNS capacity to modulate the heartbeat and thus the parasympathetic activity which is attenuated in chronic diseases. The modulation has been found highest for the systole-gated aVNS during inspiration. aVNS alters signal processing and activates reflex circuitries in the brain, exploits brain plasticity and neural adaptation, affects nociceptive processing and parasympathetic antiinflammatory pathways, with the modulation of the brain chemistry and autonomic function leading to re-established sympatho-vagal balance with reduced sympathetic dominance, especially, in chronic diseases.

[0177] Despite promising results of aVNS according to the state of the art, the reported therapeutic outcomes lack consistency and are difficult to predict; the required therapeutic dose is unknown, with potential side effects due to over and under- stimulation that generate nonresponders. The stimulation parameters are empirically selected while the stimulation strength is usually titrated based on one-time individual perception of the patient. This open-loop aVNS disregards momentary and time-varying therapeutic needs in view of the individual and time-varying physiological state of the patient, which, in fact, is the very target of aVNS treatment.

[0178] A closed-loop aVNS, i.e., a continuously personalized aVNS, with an instantaneous and continuous biofeedback is required to account for the individual physiology. aVNS settings may be continuously adapted based on the biofeedback and subsequently avoid, for instance, over and under- stimulation. The biofeedback is given by various autonomic biomarkers such as cardiac cycle and heart rate variability, respiration cycle, saliva composition, pupil diameter and reflex, and electroencephalography. Not only magnitude- related settings of aVNS can be customized (e.g., stimulation magnitude) but also time-gated aVNS settings (e.g., onset and offset of aVNS) (Kaniusas et al., 2019b; Thompson et al. ,2021; Mylavarapu et al., 2023). Therefore, the temporal stimulation sequences of aVNS are synchronized with inner biological rhythms of the body to interfere with residual activities of the autonomic nervous system in favour of therapy.

[0179] In course of the invention, cardiac-gated aVNS and its instantaneous non-averaged modulatory effects have been evaluated on the cardiovagal branch of the heart, governed by the autonomic nervous system. In particular, these modulatory effects of the systole-gated aVNS (i.e., with aVNS onset at the start of the cardiac systole, where stimulation occurs within a QT interval of the electric biosignal electrocardiogram) and the diastole-gated aVNS (i.e., with aVNS onset at the start of cardiac diastole, where stimulation occurs within a TP interval of the electric biosignal electrocardiogram) on beat-to-beat intervals have been investigated. These intervals are triggered by the cardiovagal branch projecting from the brain to the sinoatrial node, the pacemaker of the heart. Moreover, we consider explicitly the respiration phase of the applied aVNS and thus the respiration influence on heartbeats. This is the first report on cardiac-gated aVNS, namely, systole-gated or diastole-gated aVNS, compared with non-personalized aVNS, with considered respiration phases.

[0180] According to a preferred embodiment, three different triphasic stimulation patterns were applied on the three needle electrodes, each composed out of six consecutive pulses of different magnitudes of 500ps duration each, with the total duration of 3ms of a single triphasic symbol. The sum over all three stimulation patterns equals to zero voltage at any time, making obsolete any reference electrode and increasing robustness of aVNS. A fixed burst length of 100 triphasic symbols per stimulation event was implemented, with the resulting burst duration of 300ms per stimulation event; see Figure 4 for demonstrated successive bursts with the magnitude of 50m V.

[0181] Each subject underwent two sessions on different days but at the same time of the day (to minimize circadian influence) in a quiet room and sitting position. The session started after a setup phase, ensuring resting pulse, resting respiratory rate, and at least 2min accommodation to aVNS after placement of needle electrodes.

[0182] The stimulation magnitude was increased from OmV in steps of lOOmV to reach a clear tingling perception - as reported by the subject - but not pain, and then was fixed for the whole session. After each session, needles were removed. The electrode position was slightly altered from the first to second session in order to avoid both formation of scar tissue and increase in the electrode impedance.

[0183] Each session lasted for 25min. The first session consisted of a subsequent application of the non-gated open-loop aVNS (stimulation bursts applied every second) for 5min, the systolegated closed-loop aVNS (stimulation burst onsets within the systolic phase, starting with the R peak in ECG) for another 5min, then again the non-gated open -loop aVNS for 5min, followed by the diastole-gated closed-loop aVNS (stimulation burst onsets within the diastolic phase derived from ECG) for 5min, and finally the non-gated aVNS for the last 5min. In the second session, the systole-gated and diastole-gated intervals were interchanged.

[0184] Closed-loop aVNS:

[0185] The R peak derived from ECG - used as biofeedback for the closed-loop aVNS - served as a reference point within the cardiac cycle for the time-gated aVNS. Since the real-time closed- loop aVNS stimulator has intrinsic delays in the range of 100ms for the processing of ECG and formation of stimulation patterns for the output of the closed-loop aVNS, an instantaneous cardiac- gated aVNS is not possible at an arbitrary time point within the cardiac cycle of the just detected R peak. Thus, a simple predictive stimulation was realized for the next heart cycle in which the stimulation took place. Namely, the associated five consecutive beat-to-beat intervals were monitored, covering approximately the last full respiration cycle. The average of these intervals, assuming that the subjects were in their resting stationary state, allowed to estimate the duration of the following heartbeat interval and thus the approximate position of the next predicted R peak. In this interval, the cardiac-gated stimulation could be triggered at any time point within the cardiac cycle, in spite of the aforementioned delays.

[0186] The resulting uncertainty in this simple prediction was quantitatively monitored and evaluated via histograms. Thus, the systole-gated aVNS was realized at the predicted R peak following the detected R peak. Figure 4 charts a and b illustrate the onset of the systole-gated aVNS with the R peak at the time point ts . For the diastole- gated aVNS, aVNS starts 500ms after the predicted R peak to match approximately the end of the T- wave of ECG (i.e., the start of diastole), as illustrated in Figure 5, charts c and d. The choice of 500ms delay lies in the assumption that the diastole begins at rest after about 40% of the cardiac cycle duration (the cycle starting with the R peak), so that for the expected cycle duration of about Is at rest (and shorter cycles), the proposed delay of 500ms should guarantee the onset of the diastole-gated aVNS within the initial section of diastole. In contrast, the non-gated aVNS, as shown in Figure 6, charts d and e, shows no synchrony with the ECG waveform, with ts periodically occurring with 1Hz in both systole and diastole.

[0187] Data processing:

[0188] According to a preferred embodiment, the recorded beat-to-beat intervals (RR intervals, the distance between two consecutive R peaks) were detected from ECG using proprietary algorithms (based on peak detection tools) and visually controlled for absent ectopic beats and strong movement artefacts. In total, 8811 heartbeats were included finally in the beat-to-beat analysis. The data processing was conducted with MATLAB R2023b (The Math Works Inc., MA). In order to quantify the prediction with the monitored aVNS patterns and ECG, an accurate stimulation location is reconstructed within each individual cardiac cycle. All cycles are normalized to 360° and start at the R peak (i.e., located at 0° or 360°), which allows a joint consideration of heartbeats of different individual durations. This normalization maps the duration of the cardiac cycle onto a scale from 0 to 360°, with values exceeding 360° corresponding seamlessly to values greater than 0°, that captures the repetitive nature of the cardiac cycle.

[0189] The respective stimulation angle within the cardiac cycle - as demonstrated in Fig. 6, chart d - may be defined as where ti+i is the measured time point of the R peak after aVNS, ti the measured time of the R peak before the stimulation, and ts the measured time of the onset of the burst of aVNS (considering variable delays of the stimulator). Consequently, the systole-gated aVNS is theoretically described by a~0°, as seen in Figure 4 chart a while the diastole-gated aVNS by a theoretical a -180° see Figure 5 chart c.

[0190] In general, the stimulation angle a may be chosen between -20° and 20° when the particular nerve, preferably the vagus nerve, is stimulated according using a systole-gated aVNS and therefore within a QT interval, and the stimulation angle a may be chosen between 160° and 200° when the particular nerve, preferably the vagus nerve, is stimulated according using a diastole-gated aVNS, and therefore within a TP interval. Preferably the stimulation angle a is approximately 0° when the particular nerve, preferably the vagus nerve, is stimulated within a QT interval, and the stimulation angle a is preferably approximately 180° when the vagus nerve is stimulated within a TP interval.

[0191] The physiological impact of the cardiac-gated aVNS may be beat-to-beat evaluated considering for each RR interval in which aVNS takes place, the duration modification in up to seven subsequent cardiac cycles. Specifically, considering the i-th heartbeat with aVNS onset, i.e., RRi , the percentual change ARRi+i+n of a subsequent RRi+i+nmay be calculated as where i = 1,2,. . .N-7, n = 0,1,. . .6, and N is the number of heartbeats analysed see Figure 6 chart d.

[0192] Then, the change ARRi+i+nmay be evaluated as a function of a (based on the measured times from Equation 1) in scatterplots, for each considered heartbeat in the non-gated and gated aVNS. A linear regression is calculated in scatterplots using equal a ranges for the systolegated aVNS (a = 0° ± 60°), the diastole- gated aVNS (a = 180° ± 60°), and for the non-gated aVNS (a = 0-360°). The slope of the linear regression line is then determined for each subject, yielding five slopes per stimulation protocol and per ARRi+i+n.

[0193] For RSA-based investigations, it is possible to pre-filter RR intervals with a FIR band-stop filter (Kaiser-Bessel window, filter order 52) with the cut-off frequency situated at the respiration rate fR. This diminishes the respiration-related changes in RR intervals and thus attenuated RSA effects see Figure 6 chart a. Before the application of this filter, RR intervals were linearly interpolated with 3Hz to arrive at equidistant time points. The instantaneous fR is derived from the respiration belt signal, subjected first to moving average filter to smooth it Figure 6 chart b. Then onsets of inspiration and expiration phases are acquired as minima and maxima, respectively, of the smoothed respiration signal for each individual respiration cycle while using proprietary algorithms (based on the first derivatives). These onsets enable finally the calculation of fR see Figure 6 chart c. The pre-filtered version of RR is referred to as respiration-free RR. The calculus of ARRi+i+nis performed on both, the raw RR and respiration-free RR sequences. The detected onsets of inspiration and expiration phases were also used to allocate the onsets of the applied individual aVNS bursts either to inspiration or expiration. This allows to conduct the linear regression analysis (from above) separately for inspiration and expiration phases of individual respiratory cycles.

[0194] The systole-gated and diastole-gated aVNS in a preferred embodiment where the particular nerve is the vagus nerve, are illustrated in Figures 4 and 5. The stimulation bursts onset with the measured stimulation angle that a is preferably close to 0° for the systole-gated aVNS; i.e., aVNS starts with the R peak, with the start of systole, see Figure 4 chart a. For the diastole-gated aVNS, the angle a is preferably close to 180°; i.e., aVNS starts after the T wave in ECG see Figure 5 chart c. By contrast, the non- personalized non-gated aVNS - as shown in Fig. 6 charts d and e - shows dispersed values of a between 0° and 360°, with stimulation bursts being out of synchrony with R peaks of ECG. The raw and respiration-free RR sequences, Figure 6 chart a, are illustrated along the respiration signal and its smoothed version see Figure 6 chart b.

[0195] The dispersions of the measured a at the targeted a =0° for the systole-gated aVNS and at the targeted a =180° for the diastole-gated aVNS may be quantitatively assessed via histograms to evaluate if the measured a coincides with the theoretical 0° and 180° for the two aVNS settings. In contrast to the non-gated aVNS with equally distributed in the range from 0° to 360°, the systole- gated aVNS exhibits a maximum probability around at 0° while the diastole-gated aVNS peaks near 160°. For the systole-gated aVNS, the targeted and mean actual values of a overlap (a = 0°) with a dispersion of about ±20% at 50% height of the histogram. For the diastole-gated aVNS, the targeted and mean actual values of a do not overlap (a = 180° versus 160°), with even a larger dispersion of about ±35% at 50% height.

[0196] Figure 7 illustrates the slopes of the linear regression lines for n = (0, 1,. . .6) as the mean value for all subjects, see connecting lines in Figure 7 charts a and b, and individual values for n = 0, 3, and 6, see boxplots in Figure 7 chart a. That is, seven consecutive RR intervals are considered, including gated and non-gated aVNS. With increasing n, the mean values of the gated aVNS increase and then the level off at about the fourth heartbeat (n = 3) following the one with the active aVNS. The mean slopes for the systole-gated aVNS start at 0.047 % / ° (n = 0) and end up at 0.134 % / ° (n = 6), while those for the diastole-gated aVNS start at 0.054 % / ° (n = 0) and end up at 0.106 % / ° (n = 6), see Figure 7, chart (a). By contrast, the non-gated aVNS shows the mean slope of zero (1.3e-5 % / ° for n = 0 and 3.7e-4 % / ° for n = 6). When the respiration-free RR sequence is used as a basis for the slope calculus, the mean slope values decrease by an offset of about 0.025 % / ° for all n values, as compared with the unfiltered raw RR, see Figure 7 chart a. The mean slope values for the respiration-free RR reach 0.105 % / ° (n = 6) for the systole-gated and 0.08 % / ° (n = 6) for the diastole-gated aVNS.

[0197] Figure 7, chart b considers separately inspiration and expiration phases for all subjects. The maximum mean values of the regression slope for all n are observed for the systole-gated aVNS during inspiration, with the peak value of about 0.18 % / ° at n = 4. In relative terms, for the systole-gated aVNS, inspiration increases the mean slope by >0.05 % / ° for n > 0 and the observed ARR by even about 50% in relation to expiration. In contrast, the diastole-gated aVNS shows similar mean values of the slope for all n regardless of the respiration phase. The respiration-free RR decreases the respective slopes for the systole-gated and diastole-gated aVNS during both inspiration and expiration.

[0198] The time-gated aVNS, namely, the systole-gated and diastole-gated aVNS, is realized to evaluate its effects on the efferent cardiovagal branch of the autonomic nervous system that governs heartbeats. The resulting beat-to-beat RR intervals are assessed to derive their individual duration changes. These beat-to-beat modulatory effects are expected to disclose efferent vagus nerve modulation by aVNS that stimulates the afferent vagus nerve in the ear.

[0199] The systole-gated aVNS is superior to the diastole-gated aVNS. Since most of the afferent vagal inflow from arterial baroreceptors into the nucleus of the solitary tract is present in systole, this may indicate that the brainstem could be more receptive in systole for the artificially-induced afferent vagal inflow from aVNS. Consequently, the resulting modulation efficiency of the personalized time-gated aVNS, see Figures 4 and 5, is quantified and also compared with that of the non-personalized non-gated aVNS; see Figure 6.

[0200] The realized systole-gated and diastole-gated aVNS show the onset of the periodic stimulus aligned distinctly with the onset of systole and diastole, respectively, see Figure 4 and 5. This alignment is completely random in the non-gated aVNS, see Figure 6. The stimulation angle a - introduced in this work - quantifies jointly the systole-gated, diastole-gated, and non-gated aVNS. For the time-gated aVNS, the R peak in ECG served as the reference point of the current cardiac cycle. Given a non-zero processing time of ECG and intrinsic delays in the output formation of aVNS, a flexible time-gated stimulation can only be performed within the next cardiac cycle. This requires prediction of the next R peak to target the associated systole or diastole, the start of which initiates the systole-gated and diastole-gated aVNS, respectively.

[0201] The attained prediction accuracy is reflected by the position and dispersion of histograms. The limited accuracy is mainly due to (i) a predictive nature of the R peak detection, (ii) the ongoing RSA, periodically accelerating and decelerating RR intervals, with this respiration influence not considered explicitly by the prediction, and (iii) the natural and non-paced respiration of subjects during the study, rendering the respiratory modulation of RR intervals even more unpredictable. The accuracy is lower for the prediction of diastole than systole, which could be attributed to the fact that RSA mainly affects the duration of diastole but not that of systole. The limited accuracy of the systole-gated aVNS may also cause the stimulation onset before the R peak which would imply the end of diastole but not the start of systole. Similarly, the limited accuracy of the diastole-gated aVNS may result in stimulation at the end of systole. This may have compromised targeted modulation effects and indicates the need for an improved prediction algorithm with a narrower dispersion width of histograms.

[0202] The results show that the systole-gated aVNS tends to prolong and shorten the following RR intervals when stimulation started after and before the R peak, respectively. This can be derived from positive values of the slope and the crossing point, located close to the R peak, the physiological onset of systole. This observation is especially dominant for later heartbeats starting approximately with the fourth heartbeat, after the considered heartbeat with the active aVNS (Figure 7). This delayed accumulation of deceleration and acceleration of heartbeats (in response to aVNS) may be attributed to processing in the brain, for the brain separates the afferent vagus nerve (subject to electrical stimulation) and the efferent cardiovagal nerve (connecting to the sinoatrial node and thus governing RR intervals, subject to monitoring). From experimental physiology, cardiovagal responses are reported to have a relatively short delay of a few heartbeats only supporting the hypothesis of the processing delays.

[0203] In the diastole-gated aVNS, the later in time is the stimulation onset within diastole, the longer tends to be the subsequent RR intervals. This observation is based on the positive regression slope and the crossing point near a =145°, the angle which corresponds roughly to the physiological onset of diastole. The tendency of the RR prolongation (i.e., the regression slope) raises with increasing time distance (or delay) from the considered heartbeat where aVNS took place. Then, as in the case of the systole-gated aVNS, the increases in the slope gradually levels off at about the fourth heartbeat, see Figure 7.

[0204] The regression slope is larger for the systole-gated than diastole-gated aVNS, especially for later heartbeats by about 25%, and is zero for the non-gated aVNS, see Figure 7 chart a. This would imply that the systole-gated aVNS modulates the duration of heartbeats stronger than the diastole-gated aVNS. From a physiological perspective, the systole-gated afferent stimulation of the vagus nerve in the ear coincides in time with afferent responses of baroreceptors in systole, which project also via the vagus nerve into the brainstem, the nucleus of the solitary tract. Thus, we hypothesise that this temporal coincidence raises the brain alertness to all vagal inflows during systole, incl. aVNS during systole, to minimize average metabolic needs of the brain. aVNS may also influence RR intervals through the mechanism of RS A, in that the vagally- mediated aVNS may modulate the dominance of the vagally-mediated RS A. When the respiration influence is filtered out of RR sequence, lower regression slopes result for the time-gated aVNS see Figure 7. Therefore, it may be hypothesised that modulatory effects of the time-gated aVNS are partly hidden within the respiration-related changes in RR and these modulatory effects could be related to RSA mechanisms in the brain, with the involved respiration centre in the medulla. When considering individual respiration phases, the systolegated aVNS with the onset in inspiration shows largest regression slopes for all heartbeats see Figure 7 chart b, e.g., larger by about 50% than in expiration. Thus, the inspiratory systolegated aVNS seems to have the largest cardiovagal modulatory capacity.

[0205] Cardiovagal effects of the systole-gated aVNS appear to be dependent on the respiration cycle.

[0206] It is therefore indicated herein, that a specific timing of a stimulation of the particular nerve, especially the vagus nerve aVNS, within the cardiac cycle tends to influence the response of the autonomic nervous system, especially of the efferent cardiovagal branch of the system. The resulting modulation of the heartbeat duration indicates a favourable aVNS influence on the parasympathetic activity that is pathologically attenuated in chronic diseases. The modulatory capacity of aVNS to influence the parasympathetic activity seems to be the highest for the personalized systole-gated aVNS during inspiration. The personalised aVNS may favor consistency of therapeutic effects avoiding non-responders, may reduce side effects of aVNS, and minimize energetic footprints of stimulation patterns. Preferably, the device and methods according to the invention disclosed herein may be applied to a patient, which is a human patient or a mammalian patient. Furthermore, they may be used for treating chronic pain, preferably back pain, in the patient.

Claims

Claims1. Device (1) for the stimulation of a particular nerve, preferably a vagus nerve, of a patient comprising a microelectrode array (2) comprising multiple individual microelectrodes (3, 3a, 3b, 3c), and a control unit (4) connected to the microelectrode array (2), wherein the microelectrode array (2) is connectable to the patient, preferably to an ear (5) of the patient, and the control unit (4) is adapted to detect at least one physiological and / or at least one anatomical parameter of the patient via the microelectrode array (2), when the microelectrode array (2) is connected to the patient, preferably to the ear (5) of the patient, and wherein the control unit (4) is adapted to select specific microelectrodes (3, 3a, 3b) of the microelectrode array (2) as stimulation microelectrodes which are located in proximity to the particular nerve, preferably to the vagus nerve, of the patient, when the microelectrode array (2) is connected to the patient, preferably to the ear (5) of the patient, based on the detected physiological parameter and / or anatomical parameter, and wherein the control unit (4) is adapted to stimulate the particular nerve, preferably the vagus nerve, of the patient via the selected stimulation microelectrodes (3, 3a, 3b).

2. Device (1) according to claim 1, characterized in that the control unit (4) is adapted to determine a cardiac activity and / or a respiratory activity and / or a smooth muscle activity and / or an auricular smooth muscle activity of the patient from the at least one physiological parameter and / or the at least one anatomical parameter of the patient and to stimulate the particular nerve of the patient dependent on the determined cardiac activity and / or respiratory activity and / or smooth muscle activity and / or auricular smooth muscle activity.

3. Device (1) according to any of claims 1 or 2, characterized in that each of the microelectrodes (3, 3a, 3b, 3c) comprises at least one needle (6) adapted to at least partially pierce the skin of the patient.

4. Device (1) according to any of claims 1 to 3, characterized in that the microelectrode array (2) is at least partially flexible.

5. Device (1) according to claim 1, characterized in that the control unit (4) is adapted to determine a cardiac activity of the patient from the at least one physiological parameter of the patient, and to predict a systolic and / or a diastolic activity of the heart of the patient based on the cardiac activity.

6. Device (1) according to claim 5, characterized in that the control unit (4) is adapted to stimulate the particular nerve of the patient via the selected stimulation microelectrodes (3, 3a, 3b) dependent on the predicted systolic and / or diastolic activity of the heart of the patient.

7. Device (1) according to claim 1, characterized in that the control unit (4) is adapted to detect the at least one physiological parameter and / or the at least one anatomical parameter of the patient via impedance tomography.

8. Device (1) according to claim 1, characterized in that the physiological parameter is a compound action potential.

9. Device (1) according to claim 1, characterized in that the control unit (4) is adapted to stimulate the particular nerve of the patient via the selected stimulation microelectrodes (3, 3a, 3b) depending on the at least one physiological parameter and / or the at least one anatomical parameter.

10. Device (1) for the localization of a nerve, preferably an auricular nerve, of a patient comprising a microelectrode array (2) comprising multiple individual microelectrodes (3, 3a, 3b, 3c), and a control unit (4) connected to the microelectrode array (2), wherein the microelectrode array (2) is connectable to the patient, preferably to an ear (5) of the patient, and the control unit (4) is adapted to detect at least one physiological and / or at least one anatomical parameter of the patient via the microelectrode array (2), when the microelectrode array (2) is connected to the patient, preferably to the ear (5) of the patient, and wherein the control unit (4) is adapted to select specific microelectrodes (3, 3a, 3b) of the microelectrode array (2) which are located in proximity to the nerve of the patient, when the microelectrode array (2) is connected to the patient, based on the detected physiological parameter and / or anatomical parameter.

11. Device (1) according to claim 10, characterized in that each of the microelectrodes (3, 3a, 3b, 3c) comprises at least one needle (6) adapted to at least partially pierce the skin of the patient.

12. Device (1) according to any of claims 10 to 11, characterized in that the microelectrode array (2) is at least partially flexible.

13. Device (1) according to any of claims 10 to 12, characterized in that the and the control unit (4) is adapted to detect the at least one physiological parameter and / or the at least one anatomical parameter of the patient via impedance tomography.

14. Method for operating a device according to any of claims 1 to 9 or for operating a device according to any of claims 10 to 13, characterized by the steps- Connecting the microelectrode array (2) to the patient, preferably to an ear of the patient;- applying an electrical current below a stimulation threshold between two microelectrodes (3, 3a, 3b, 3c) of the microelectrode array (2), detecting a voltage distribution throughout the microelectrode array (2) and assigning a respective individual voltage value to the respective individual microelectrodes (3, 3a, 3b, 3c) of the microelectrode array (2) via the control unit (4).

15. Method according to claim 14, characterized byCalculating an impedance distribution using the applied electrical current and the detected voltage distribution and assigning a respective individual impedance value to the respective individual microelectrodes (3, 3a, 3b, 3c) of the microelectrode array (2) via the control unit (4).

16. Method according to claim 15, characterized by identifying at least one nerve of the patient, preferably one auricular nerve in the ear of the patient, by assigning neighboring microelectrodes (3 a) of the microelectrode array (2), which exhibit essentially the same impedance value and / or voltage value to a nerve of the patient, preferably an auricular nerve of the patient, via the control unit (4).

17. Method according to claim 15 or 16, characterized by identifying at least one auricular nerve in the ear of the patient by assigning neighboring pairs of microelectrodes (3b), which exhibit a difference in impedance value and / or voltage value above a predetermined threshold to an auricular nerve of the patient via the control unit (4).

18. Method for determining the position of a particular nerve, preferably a vagus nerve, of a patient comprising the steps of- connecting a microelectrode array (2) comprising individual microelectrodes (3, 3 a, 3b, 3 c) to the patient, preferably on the auricle of an ear (5) of the patient,- applying an electrical current between two microelectrodes (3, 3a, 3b, 3c) of the microelectrode array (2), detecting a voltage distribution throughout the microelectrode array (2), and assigning a respective individual voltage value to the respective individual microelectrodes (3, 3a, 3b, 3c) of the microelectrode array (2),- calculating an impedance distribution using the applied electrical current and the detected voltage distribution and assigning a respective individual impedance value to the respective individual microelectrodes (3, 3a, 3b, 3c) of the microelectrode array (2),- identifying at least one nerve of the patient, preferably one auricular nerve, in the ear of the patient, by assigning (a) neighboring microelectrodes (3 a) of the microelectrode array (2), which exhibit essentially the same impedance value and / or voltage value to a nerve, preferably to an auricular nerve, of the patientand / or by assigning (b) neighboring pairs of microelectrodes (3b), which exhibit a difference in impedance value and / or voltage value above a predetermined threshold to a nerve, preferably to an auricular nerve, of the patient,- selecting one pair of microelectrodes (3, 3a, 3b) which have been assigned to the nerve, preferably to the auricular nerve, as excitation microelectrodes and selecting one pair of microelectrodes (3, 3a, 3b) which have been assigned to the nerve, preferably to the auricular nerve, as detection microelectrodes,- stimulating the nerve, preferably the auricular nerve, using the excitation microelectrodes,- detecting a nerve response of the nerve, preferably the auricular nerve, using the detection microelectrodes,- determining a compound action potential of the nerve, preferably the auricular nerve, based on the detected nerve response,- comparing the determined compound action potential with a reference compound action potential of the particular nerve, preferably of the vagus nerve, and- determining the position of the particular nerve, preferably of the vagus nerve, if the determined compound action potential corresponds essentially to the reference compound action potential of the particular nerve, preferably of the vagus nerve.

19. Method for stimulating a vagus nerve of a patient comprising the steps of- determining the position of the particular nerve on the patient, preferably the vagus nerve on an ear (5) of the patient, and- stimulating the particular nerve by applying electrical current thereto.

20. Method according to claim 19, wherein the position of the particular nerve, preferably the vagus nerve, is determined by using a device (1) according to any one of claims 1 to 9 or a method according to claim 18.

21. Method according to claim 19 or 20, wherein the particular nerve, preferably the vagus nerve, is stimulated within a QT interval or a TP interval of an electrocardiogram of the patient.

22. Method according to claim 21, wherein a stimulation angle a within the cardiac cycle of the patient is defined aswhere ti+i is a measured time point of an R peak after a stimulation of the particular nerve, preferably the vagus nerve, by applying electrical current, ti a measured time of the R peak before the stimulation, and ts a measured time of the onset of the stimulation,and wherein the stimulation angle a is chosen between -20° and 20° when the particular nerve, preferably the vagus nerve, is stimulated within a QT interval, and the stimulation angle a is chosen between 160° and 200° when the particular nerve, preferably the vagus nerve, is stimulated within a TP interval.

23. Method according to claim 22, wherein the stimulation angle a is approximately 0° when the particular nerve, preferably the vagus nerve, is stimulated within a QT interval, and the stimulation angle a is approximately 180° when the particular nerve, preferably the vagus nerve, is stimulated within a TP interval.

24. Method according to any one of claims 18 to 23, wherein the patient is a human patient or a mammalian patient.

25. Method according to any one of claims 18 to 24 for treating pain, preferably back pain, depression, stroke, migraine, peripheral arterial disease, chronic immunological diseases and / or sleep disorders in a patient.

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