System for the transcutaneous auricular vagus nerve stimulation

Abstract

The present invention relates to a system for the transcutaneous auricular vagus nerve stimulation of a patient. The system comprises an abdominal sensor, a control unit and an auricular device, connected to each other. The abdominal sensor detects diaphragmatic activity and provides the control unit with a signal representative of the patient's diaphragmatic activity. The control unit processes the signal received from the abdominal sensor and controls the auricular device on the basis of the diaphragmatic activity. The auricular device emits pulses on command of the control unit; it comprises two stimulating electrodes that, in use, maintain contact with the upper and lower concha of the patient's auricle. The control unit controls the auricular device in such a way that it emits a series of bi-phase pulses during the diaphragm relaxation phase, wherein the series has a frequency comprised between 1 Hz and 200 Hz, the bi-phase pulses have a duration between 100 μs and 1000 μs and a current intensity between 0.1 mA and 5.0 mA.

Description

[0001] SYSTEM FOR TRANSCUTANEOUS AURICULAR VAGUS NERVE STIMULATION

[0002] DESCRIPTION

[0003] TECHNICAL FIELD

[0004] The present invention relates to systems and devices for vagus nerve stimulation.

[0005] STATE OF THE ART

[0006] Vagus Nerve Stimulation (VNS) is a very important technique for the treatment of chronic diseases, such as drug-resistant depression and epilepsy, in drugresistant patients.

[0007] For stimulation, stimulators are used, i.e. devices capable of stimulating the vagus nerve with electrical signals. Besides invasive implantable stimulators, there are minimally invasive and non-invasive alternatives. Minimally invasive stimulators are represented by percutaneous stimulators and non-invasive stimulators by transcutaneous stimulators.

[0008] Percutaneous stimulators (e.g. VIVO marketed by AURIMOD GMBH, Vienna, Austria) are equipped with percutaneous needles that pass through the skin and reach the nerve to stimulate it electrically. The use of these stimulators requires the direct supervision of a physician for both positioning the needle and monitoring treatment. Percutaneous stimulators only allow short-term treatments (maximum 7 days) and have side effects specifically related to needle insertion, such as local skin irritation (dermatitis), local bleeding, pain at the side of stimulation and vertigo (Kaniusas et al., 2019, DOI: 10.3389 / fnins.2019.00854). Consequently, their actual application is limited and, in general, not suitable for paediatric subjects.

[0009] Transcutaneous stimulators, on the other hand, are equipped with electrodes that are applied to the skin without perforating it; therefore, they can be applied by the actual patient, without the supervision of a physician.

[0010] In the case of transcutaneous auricular vagus nerve stimulation (taVNS), the stimulating electrodes must be positioned stably on the skin of the ear for the entire duration of the treatment. However, in current transcutaneous stimulators, electrode positioning is not stable, so that stimulation is often interrupted and the possibilities of using the stimulator are limited to resting conditions or at least to static or low-dynamic activities.

[0011] In addition, most stimulators do not allow effective stimulation of the vagus nerve. It is, in fact, well known that efficient stimulation of the vagus nerve must occur while the nerve is active, i.e. in correspondence with the presence of electrical stimuli on the nerve itself. Most commercially available stimulators, however, transmit electrical stimuli to the nerve regardless of the condition, active or not, of the nerve itself. This leads, on the one hand, to excessive use of the batteries and, on the other hand, to risks of skin irritation due to prolonged duration of the treatment.

[0012] To make treatment more efficient, and reduce the risk of skin irritation, international patent application WO 2010 / 114836 A2 proposes a stimulator in which neurostimulation is delivered to the afferent nerve fibres of a patient's vagal auricular nerve. Neurostimulation is harmonised with the patient's pulmonary activity, which is detected indirectly, either via a mechanical sensor that detects thoracic expansion or via a sensor that detects airflow in the nose. In an embodiment, neurostimulation is regulated on a part of the respiratory cycle. For example, the auricular branch of the vagus nerve can be stimulated at the end of exhalation. In another embodiment, a multi-electrode stimulation regime is harmonised with pre-selected triggers within the respiratory cycle to achieve selective and / or bilateral stimulation.

[0013] Similarly, US 2024 / 001120 Al describes a solution for achieving therapeutic results, whereby neurostimulation is administered to the spinal cord, vagus nerve or branches of the vagus nerve. Neurostimulation is timed in relation to lung activity and lung activity is detected by means of a respiratory belt with a strain gauge or a nasal airflow sensor.

[0014] OBJECTS AND SUMMARY OF THE INVENTION

[0015] The aim of the present invention is to at least partially overcome the drawbacks of the prior art.

[0016] In particular, it is a task of the present invention to allow more efficient stimulation of the vagus nerve, particularly near the nerve endings in the auricle.

[0017] A further task of the present invention is to provide a stimulator that can be easily and stably positioned to allow efficient stimulation of the vagus nerve even under dynamic conditions of use.

[0018] These and other objects and tasks of the present invention are achieved by means of a system incorporating the features of the appended claims, which form an integral part of the present description.

[0019] In accordance with one aspect, the invention concerns a system for transcutaneous auricular vagus nerve stimulation of a patient. The system of the invention comprises an abdominal sensor, a control unit and an auricular device, connected to each other. The abdominal sensor is configured to detect diaphragmatic activity and to provide the control unit with a signal representative of the patient's diaphragmatic activity.

[0020] The control unit is configured for processing the signal representative of the diaphragmatic activity received from the abdominal sensor and for controlling the auricular device on the basis of the diaphragmatic activity, according to a pre- loaded logic.

[0021] The auricular device is configured for emitting electrical pulses on command of the control unit.

[0022] The auricular device comprises at least two stimulating electrodes and is configured for maintaining, in use, a first stimulating electrode in contact with the upper concha and a second stimulating electrode in contact with the lower concha of the auricle of the patient.

[0023] Finally, the logic preloaded in the control unit involves controlling the auricular device in such a way that it emits a series of bi-phase pulses during the diaphragm relaxation phase, wherein the series has a frequency comprised between 1 Hz and 200 Hz, the bi-phase pulses have a duration comprised between 100 ps and 1000 ps and a current intensity comprised between 0.1 mA and 5.0 mA.

[0024] This system allows stimulation to be applied in a targeted manner (gated stimulation) during the effective relaxation of the diaphragm, thus maximising treatment efficiency.

[0025] Preferably, each bi-phase pulse comprises a first cathodic half -pulse and a second anodic half-pulse.

[0026] It was found that cathodic stimulation achieves faster depolarisation of nerve endings than anodic stimulation. Therefore, starting the stimulation with a cathodic half-pulse allows lower current intensities to be used overall than the opposite solution, in which stimulation starts with an anodic half-pulse.

[0027] In accordance with some embodiments, the bi-phase pulse comprises a delay between the two half -pulses. Preferably the delay has a duration Pa comprised between 0 jis and 150 jas, even more preferably around 50 jis.

[0028] The delay contributes to reducing the threshold to reach the nerve endings' action potential and also has the function of preventing the secondary pulse from destructively interfering with the transient that precedes the nerve action potential. Preferably the first cathodic half -pulse has duration Pi, current intensity Ii, and delivers a charge Qi = Pi * Ii and the second anodic half-pulse has duration P2, current intensity I2, and delivers a charge Q2 = P2 * I2; thus, advantageously Qi = - 02.

[0029] The fact that the two half-pulses are balanced in terms of charge, i.e. that the relationship Qi = - Q2 applies, prevents a build-up of charges, potentially damaging to the nerve endings, from occurring in the tissues subjected to stimulation.

[0030] Preferably, the control unit is further configured for:

[0031] - identifying, within the signal received from the abdominal sensor, the individual diaphragmatic cycles Tt;

[0032] - identifying, within each diaphragmatic cycle Tt, the beginning of the contraction phase Tc of the diaphragm and the beginning of the relaxation phase Tr of the diaphragm;

[0033] - commanding the ear device to begin vagus nerve stimulation at the beginning of the relaxation phase of the diaphragm Tr.

[0034] This operating configuration of the control unit allows for the best possible implementation of the invention.

[0035] Preferably the control unit is also configured to control the auricular device to terminate vagus nerve stimulation at the beginning of the contraction phase Tc of the diaphragm.

[0036] This solution makes the best use of the diaphragm relaxation phase alone, avoiding the application of unnecessary stimulation pulses while the vagus nerve is not active.

[0037] Preferably, the abdominal sensor comprises sensing electrodes configured to acquire transcutaneous diaphragm electromyography (tcEMGd).

[0038] Transcutaneous diaphragm electromyography and widely known technique per se that is a safe, non-invasive and allows particularly precise detection of diaphragm activity.

[0039] In accordance with other embodiments, the abdominal sensor may comprise surface microphones configured to detect the vibration of diaphragmatic muscle fibres by phonomiography, or accelerometers configured to detect the vibration of diaphragmatic muscle fibres by mechanomyography.

[0040] Phonomiography and mechanomyography are other techniques for detecting diaphragm activity that, in certain specific situations, can be used as an alternative to electromyography.

[0041] Preferably, the stimulating electrodes comprise a convex surface.

[0042] The convex shape of the stimulating electrodes, as opposed to the flat shape, allows for more precise stimulation of the target areas and limits local side effects.

[0043] In accordance with a second aspect, the invention concerns a method for transcutaneous auricular vagus nerve stimulation (taVNS) of a patient. The method of the invention comprises the steps of:

[0044] - providing an abdominal sensor, a control unit, and an auricular device, connected together, wherein the auricular device comprises at least two stimulating electrodes;

[0045] - applying a first stimulating electrode in contact with the upper concha of the patient's auricle;

[0046] - applying a second stimulating electrode in contact with the lower concha of the patient's auricle;

[0047] - detecting the patient's diaphragmatic activity;

[0048] - providing the control unit with a signal representative of the patient's diaphragmatic activity;

[0049] - processing the signal representative of diaphragmatic activity to identify individual diaphragmatic cycles Tt;

[0050] - identifying, within each diaphragmatic cycle Tt, the beginning of the contraction phase Tc of the diaphragm and the beginning of the relaxation phase Tr of the diaphragm;

[0051] - controlling the auricular device in such a way that it emits a series of bi-phase pulses during the diaphragm relaxation phase, wherein the series has a frequency comprised between 1 Hz and 200 Hz, the bi-phase pulses have a duration comprised between 100 ps and 1000 ps and a current intensity comprised between 0.1 mA and 5.0 mA.

[0052] The method of the invention allows for targeted vagus nerve stimulation (gated stimulation) during the actual relaxation phase of the diaphragm, thereby maximising the efficiency of the treatment.

[0053] Preferably, in the step of controlling the auricular device, each bi-phase pulse comprises a first cathodic half -pulse and a second anodic half-pulse. It was found that cathodic stimulation achieves faster depolarisation of nerve endings than anodic stimulation. Therefore, starting the stimulation with a cathodic half-pulse allows lower current intensities to be used overall than the opposite solution, in which stimulation starts with an anodic half-pulse.

[0054] Preferably, the step of detecting the patient's diaphragmatic activity comprises the step of acquiring transcutaneous diaphragm electromyography (tcEMGd).

[0055] Transcutaneous diaphragm electromyography and widely known technique per se that is a safe, non-invasive and allows particularly precise detection of diaphragm activity.

[0056] Further features and advantages of the present invention will be more evident from the description of the accompanying drawings.

[0057] BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The invention is described hereinbelow with reference to certain examples provided by way of non-limiting example and illustrated in the accompanying drawings. These drawings illustrate different aspects and embodiments of the present invention and reference numerals illustrating structures, components, materials and / or similar elements in different drawings are indicated by similar reference numerals, where appropriate.

[0059] Figure l.a represents a schematic view of the system of the invention applied to a patient;

[0060] Figure l.b represents a partial view of a possible variant of the system in Figure l.a;

[0061] Figure 2 schematically represents the patient's left ear;

[0062] Figures 3 represent an auricular device in accordance with the invention, applied to the left ear of a patient;

[0063] Figure 4 schematically represents the acquired signal, the processed signal and the signal generated by the system of the invention;

[0064] Figure 5 represents an enlarged view of the detail indicated by V in Figure 4 and shows in detail a single bi-phase pulse generated by the system of the invention; and

[0065] Figure 6 represents a block diagram of a method for EMGd signal processing.

[0066] DETAILED DESCRIPTION OF THE INVENTION

[0067] Some preferred embodiments will be described in detail below, although the invention is susceptible to various alternative modifications. It must in any case be understood that there is no intention to limit the invention to the specific embodiment illustrated, but, on the contrary, the invention intends to cover all the modifications and / or use of elements or equivalent steps that fall within the scope of the invention as defined in the claims.

[0068] Unless otherwise defined, all the terms of the art, notations and other scientific terms used herein are intended to have the meanings commonly understood by those skilled in the art to which this description belongs. In some cases, terms with commonly understood meanings are defined herein for clarity's sake and / or ready reference; the insertion of such definitions in the present description must therefore not be interpreted as representative of a substantial difference with respect to what is generally understood in the art.

[0069] The terms "comprising", "having", "including" and "containing" are to be understood as open terms (i.e. with the meaning "comprising, but not limited to") and are to be considered as a support also for terms such as "essentially consist of", "essentially consisting of", "to consist of" or "consisting of".

[0070] The use of "for example", "etc.", "or" indicates non-exclusive alternatives without limitation, unless otherwise indicated. The use of "includes" means "includes, but not limited to" unless otherwise indicated.

[0071] Numerous studies and scientific articles are cited within the scope of this discussion. They are first identified by the name of the main author and the year of publication, data that may give a more immediate indication to the expert; however, in order to provide an unambiguous indication, each study is also identified by its DOI (Digital Object Identifier).

[0072] In accordance with a first aspect, the invention relates to a system 10 for transcutaneous auricular vagus nerve stimulation (taVNS) of a patient 12. The system 10 comprises an abdominal sensor 14, a control unit 16 and an auricular device 18, connected to each other, wherein:

[0073] - the abdominal sensor 14 is configured to detect diaphragmatic activity and to provide the control unit 16 with a signal representative of the patient's 12 diaphragmatic activity;

[0074] - the control unit 16 is configured for processing the signal representative of the diaphragmatic activity received from the abdominal sensor 14 and for controlling the auricular device 18 on the basis of the diaphragmatic activity, according to a pre-loaded logic;

[0075] - the auricular device 18 is configured for emitting electrical pulses 19 on command of the control unit 16, - the auricular device 18 comprises at least two stimulating electrodes 20 and is configured for maintaining, in use, a first stimulating electrode 20i in contact with the upper concha 22 and a second stimulating electrode 202 in contact with the lower concha 24 of the auricle 26 of the patient 12; wherein the logic preloaded in the control unit 16 involves controlling the auricular device 18 in such a way that it emits a series of bi-phase pulses 19 during the diaphragm relaxation phase, wherein the series has a frequency comprised between 1 Hz and 200 Hz, the bi-phase pulses 19 have a duration comprised between 100 ps and 1000 ps and a current intensity comprised between 0.1 mA and 5.0 mA.

[0076] In accordance with certain embodiments of the invention, each bi-phase pulse 19 comprises a first cathodic half-pulse 19i and a second anodic half-pulse 192. In accordance with other embodiments, conversely, each bi-phase pulse 19 comprises a first anodic half-pulse 192 and a second cathodic half-pulse 19i.

[0077] In some embodiments of the system 10, the abdominal sensor 14 comprises sensing electrodes 28 configured to acquire transcutaneous diaphragm electromyography (tcEMGd). These sensing electrodes 28, known per se, are preferably adhesive and can be wet, dry or made of a viscous conducting material, such as hydrogel. Preferably, the sensing electrodes 28 are pre-gelled Silver / Silver Chloride (Ag / AgCl) adhesives with stainless steel clips; alternatively, other types of sensors can be used, such as sensing electrodes 28 made of conductive polymers.

[0078] Preferably, the abdominal sensor 14 can adopt different configurations. For example, the sensing electrodes 28 can be placed on the chest wall bilaterally, on the haemiclavicular line at the level of the inferior costal margin, proximal to the diaphragm apposition zone (see Figure l.a). Alternatively, the sensing electrodes 28 can be placed on the chest wall monolaterally, on the anterior axillary line at the level of the sixth and eighth intercostal spaces (see Figure l.b). In addition, the two sensing electrodes 28 can be independent and separated from each other (Figure l.a) or connected and incorporated into a single adhesive patch (Figure l.b).

[0079] The abdominal sensor 14 can be connected to the sensing electrodes directly with a stainless steel clip system or via cables. Alternatively, the abdominal sensor 14 can adopt other configurations, all of which are known to a person skilled in the art.

[0080] In accordance with other embodiments, the abdominal sensor 14 may comprise surface microphones (not shown), configured to detect the vibration of diaphragmatic muscle fibres by phonomiography. In other embodiments, the abdominal sensor 14 may comprise accelerometers (not shown) configured to detect the same vibration of the diaphragmatic muscle fibres by mechanomyography.

[0081] As is clear to a person skilled in the art, the control unit 16 may be any electronic device configured to execute pre-loaded logic in the form of an executable programme. By way of example, the control unit 16 may be a dedicated chip, internal to the system 10, or any external device, such as a computer, smartphone, tablet, or the like.

[0082] In more detail, the control unit 16 is configured to analyse the waveforms of the signal provided by the abdominal sensor 14 and, based on them, generate an activation command for the auricular device 18. The preferred logic for controlling stimulation is described below.

[0083] The auricular device 18 preferably comprises at least two stimulating electrodes 20, a stimulator circuit 30 and a power supply, e.g. a battery 32. If the auricular device 18 is of the wireless type, it must also comprise a receiving antenna configured to receive commands emitted by the control unit 16.

[0084] In accordance with an embodiment of the auricular device 18, there are two stimulating electrodes 20: a first stimulating electrode 20i is intended to be placed within the upper concha 22 (cymba conchae) and a second stimulating electrode 202 is intended to be placed within the lower concha 24 (cavum conchae) of the auricle 26 of the patient 12. Preferably, the stimulating electrodes 20 are adhesive and are configured to firmly maintain contact with the skin of the patient to which they are applied.

[0085] In accordance with other embodiments, the stimulating electrodes 20 may take different forms, e.g. they may constitute a single unit or several units, intended to be placed on the inner surface of the auricle 26. Preferably, the stimulating electrodes 20 have convex shapes, such as spheres or hemispheres, but they can also be small discs. The stimulating electrodes 20 are made of conductive materials suitable for contact with the patient's skin 12. These materials, known in the industry, are for example copper, steel, silver and / or silver chloride. The stimulating electrodes 20 can be around 2-5 mm in diameter, depending on the application.

[0086] To improve the interface between the patient's 12 skin and the stimulating electrodes 20, an adhesive and / or conductive solution, e.g. a hydrogel solution, can be provided.

[0087] Since it has been demonstrated by several studies (de Gurtubay et al., 2021, DOI: 10.1002 / brb3.2343) that the upper concha 22 and the lower concha 24 are innervated by the afferent branch of the vagus nerve, it is possible to evaluate different positioning of the stimulating electrodes 20 in these two areas of the auricle 26. Stimulation of the left auricle 26 is preferable to avoid the adverse cardiac effects that may arise from stimulation of the right auricle 26 (Kim et al., 2022, DOI: 10.1038 / s41598-022-25864-l).

[0088] As is clear to a person skilled in the art, depending on the specific requirements, the control unit 16 can be housed in the abdominal sensor 14 or in the auricular device 18, but it can also be an external unit. Similarly, the connection between the abdominal sensor 14, the control unit 16 and the auricular device 18 can be a wireless connection (e.g. by exploiting Bluetooth® technology) but, additionally or alternatively, it can also exploit a wired connection. Finally, depending on the type of connection, it may also be necessary to provide one or more batteries 32, configured to make the individual components autonomous in terms of power supply. Each battery 32 can be of the fixed and rechargeable type, or removable for charging and / or replacement.

[0089] The stimulator circuit 30 receives commands from the control unit 16 and, on the basis of these commands, delivers various electrical signals to the stimulating electrodes 20. In particular, the auricular device 18 can deliver cathodic stimulation or, alternatively, anodic stimulation. The generated stimulation comprises a constant current discharge of square-wave pulses 19, preferably biphase, at a frequency comprised between 1 Hz and 200 Hz, preferably between 1 Hz and 100 Hz, depending on the specific clinical application. For example, it is known in the literature that a frequency of around 1 Hz is particularly effective for the treatment of epilepsy, while the Applicant's studies have shown that frequencies comprised between 10 Hz and 30 Hz are particularly effective for the treatment of pain and inflammatory states. The current intensity I of the bi-phase pulses 19 can be set by the user, e.g. by the patient 12 himself, and can vary between 0.1 mA and 5.0 mA. Each bi-phase pulse 19 can vary in duration between 100 ps and 1000 ps. In addition, a pause of up to 60 seconds between two successive stimulation cycles can be introduced during stimulation.

[0090] In the embodiment depicted by way of example in Figures 3.a and 3.b, the auricular device 18 takes the form of a miniaturised stand-alone wireless device configured to adapt to the shape of the user's auricle 26, in particular the left auricle 26. The auricular device 18 comprises flexible and rigid parts and is made of polymer material suitable for prolonged contact with the patient's 12 skin. Preferably, the auricular device 18 comprises a behind-the-ear case 34, configured to be positioned behind the auricle 26 to hold the entire auricular device 18. In the embodiment of the auricular device 18 and in particular of the behind-the-ear case 34, experience derived from the widely known hearing aid sector can be particularly useful. In this embodiment, the stimulating electrodes 20 are made of hydrogel and have an adhesive hemispherical surface. In this way, the auricular device 18 avoids risks of electrode displacement and / or poor skin contact, while allowing good freedom of movement for patient 12 during therapy.

[0091] In planar electrodes, e.g. disc-shaped, the current density is not uniform for geometric reasons, but is significantly higher near the outer edge of the electrode than in the centre. This increases the risk of skin irritation in the peripheral areas of the electrode (Merrill et al., 2005, DOI: 10.1016 / j.jneumeth.2004.10.020). In addition, the electric field generated is not uniform and therefore stimulation of the target tissue is not homogeneous, with the risk of failing to achieve adequate activation of the vagus nerve. Thanks to the use of stimulating electrodes 20 with a hemispherical rather than planar shape, more precise stimulation of target areas is achieved, and local side effects are limited.

[0092] In the present invention, the transcutaneous auricular vagus nerve stimulation session is performed according to diaphragmatic control (known in the field as "gated stimulation"), i.e., based on actual diaphragmatic activity and not on a probabilistic basis, as is the case with devices that use uncontrolled stimulation (non-gated stimulation) and alternate between fixed, pre-set periods of stimulation and pause. In preferred embodiments, diaphragmatic activity can be accurately detected through the acquisition of transcutaneous electromyography, a technique widely known per se, that is safe and non- invasive. One or more sensing electrodes 28 are placed near the diaphragm, e.g. on the chest wall proximal to the diaphragm apposition zone, to measure the electrical muscle activity detected through the skin of the patient 12. This acquisition of transcutaneous electromyography can, for instance, be performed via FANTM DEVLPR, which is a plug-in application board (or "shield") available in open-source form for the Arduino® platform.

[0093] The signal acquired, shown schematically at the top of Figure 4, is transcutaneous diaphragm electromyography (electromyography of the diaphragmatic muscle or EMGd). The control unit 16 of the invention is configured to process this signal so as to identify, within each diaphragmatic cycle Tt, the onset of the contraction phase Tc of the diaphragm and the onset of the relaxation phase Tr of the diaphragm. In particular, the onset of the diaphragm relaxation phase Tr is the moment when control unit 16 commands the auricular device 18 to begin vagus nerve stimulation.

[0094] A method for processing the EMGd signal by the control unit 16 is depicted in broad terms in the block diagram in Figure 6.

[0095] Prior to digitisation and collection, the signal acquired by the abdominal sensor 14 can be processed according to techniques known in signal theory. For example, the acquired signal can be amplified to improve the signal-to-noise ratio (SNR) and / or it can be filtered to remove noise outside the frequency band of the EMG signal (e.g. noise outside the range between 5 Hz and 400Hz) or the mains frequency 50 / 60Hz.

[0096] According to current scientific literature, there are several methods for extracting muscle activity, such as the rectification and application of the root mean square (RMS) or the fixed sample entropy (fSampEn). In addition, linear regression or adaptive threshold can be used to identify the relaxation and / or contraction phase of the diaphragmatic muscle.

[0097] For example, following the calculation of the diaphragm signal using fSampEn or RMS, it is possible to calculate the linear correlation coefficient for a moving window of n samples. Subsequently, by determining the rate of change from the previously obtained value, it is possible to choose a threshold for the recognition of fiducial points (e.g. maximum contraction and maximum relaxation of the diaphragm). This threshold can also be made adaptive over time to adjust to various situations independently.

[0098] Once the start of the relaxation phase Tr has been identified, the control unit 16 can activate the stimulator circuit 30 of the auricular device 18 to start emitting stimuli.

[0099] By way of example, the components of the system 10 can adopt Bluetooth technology® for real-time data sharing, in particular between the abdominal sensor 14, the control unit 16 and the auricular device 18, in order to provide stimulation at the exact moment when the onset of diaphragmatic muscle relaxation is recognised. The stimulator circuit 30 of the auricular device 18 receives a trigger signal from the control unit 16. Therefore, stimulation is regulated directly on the basis of diaphragmatic activity, and in particular on the onset of diaphragmatic relaxation, as schematically illustrated in Figure 4. This type of stimulation is therefore called "gated stimulation". Preferably, the stimulator circuit 30, by means of the stimulating electrodes 20 positioned in the auricle 26, can deliver trains of discharges with a stimulation frequency comprised between 1 Hz and 200 Hz, e.g. of 25 Hz, with a duration comprised between approximately 0.5 s and 2.0 s.

[0100] Figure 4 at its bottom shows three successive trains 21 of bi-phase pulses 19, corresponding to three successive phases of diaphragm relaxation.

[0101] A preferred form for the individual bi-phase pulse 19 is schematically depicted in Figure 5. It advantageously comprises a rectangular bi-phase wave consisting of a first cathodic half-pulse 19i, a second anodic half-pulse 192 and a possible delay 19a between the two half-pulses. The first half-pulse 19i of the waveform, or stimulating half-pulse, serves to elicit the desired physiological effect, like the triggering of an action potential in nerve endings. The first half-pulse 19i has duration Pi and current intensity Ii, so it delivers a total charge Qi = Pi * Ii. The second half-pulse 192, or reversal half-pulse, serves to reverse the electrochemical processes occurring during the first stimulating half-pulse 19i. The second halfpulse 192 has duration P2 and current intensity I2, so it delivers a total charge Q2= p2* i2. The two half-pulses 19i and 192 are balanced in terms of charge, i.e. Qi = - Q2 (Figure 5); this prevents a build-up of charges, potentially damaging to the tissue and nerve endings, from occurring in the tissues subjected to stimulation. Cathodic stimulation (negative half -pulse 19i) achieves a faster depolarisation of the nerve endings than anodic stimulation; the latter has efficacy in depolarising a nerve ending comprised between 1 / 7 to 1 / 3 of that of cathodic stimulation. Therefore, in the embodiments in which the bi-phase pulse 19 comprises first an anodic half-pulse 192 and second a cathodic half-pulse 19i , possibly separated by a delay 193, the initial anodic stimulation requires a higher current intensity than in the case described above in which the initial stimulation is cathodic, in order to induce the same depolarisation (Daniel R. Merrill et al. 2004, DOI: 10.1016 / j.jneumeth.2004.10.020).

[0102] The addition of a delay 19s, between the first half-pulse 19i of stimulation and the second half-pulse 192 of reversal, also contributes to reducing the threshold for reaching the nerve endings' action potential. The delay 193 also has the function of preventing the secondary pulse from destructively interfering with the transient preceding the nerve action potential. However, the delay 19s should not be too long to prevent the products of the Faradic reactions caused by the first half-pulse 19i of stimulation from accumulating to levels that could cause tissue damage. The delay 19s can have a duration Pd comprised between 0 | s and 150 | s, preferably around 50 (is. By way of example, the amplitude of the cathodic half-pulse 19i can be approximately 250 gs (Pi), while the current intensity can be set by the user in a range comprised between 0.1 mA and 5.0 mA depending on daily sensitivity, so that the stimulus is perceptible but remains below the pain threshold. The amplitude of the anodic half-pulse 192 may be approximately 500 gs (P2) while the current intensity will be half the current set by the user for the first cathodic half-pulse 19i in order to have a zero overall charge (e.g, if for the cathodic pulse 19i Ii = 1.0 mA then for the anodic pulse 192 I2 = 0.5 mA). The total duration of the pulse 19 can therefore be approximately 800 gs or 0.8 ms: in the example Pi + Pd + P2 = 250 gs + 50 gs + 500 gs.

[0103] Within the scope of treatment of a pain and / or inflammation condition, the stimulation frequency is preferably comprised between 10 Hz and 30 Hz. If the frequency is set to 25 Hz, the total period Ppof the bi-phase pulse 19 is 40 ms. During each diaphragmatic cycle Tt, a single train 21 consisting of a total of 50 bi-phase pulses 19 is delivered, assuming a diaphragmatic relaxation phase Tr of about 2 seconds.

[0104] According to the invention, the onset of the contraction phase Tc of the diaphragm corresponds to interruption of stimulation. With each subsequent diaphragm relaxation cycle Tr, stimulation will resume with the characteristics described above.

[0105] In contrast to the uncontrolled stimulation of the prior art (i.e. non-gated stimulation), the approach of the invention significantly increases therapeutic efficacy, as it only stimulates during the state of effective responsiveness of the vagus nerve, and reduces the treatment time, both within a single day and over the entire course of therapy.

[0106] The system 10 of the invention is compact and, particularly in its wireless design, offers a safe and comfortable option for non-invasive vagus nerve stimulation. The solution of the invention is suitable for paediatric patients 12 and allows patients 12 freedom of movement and activity, even during treatment. In this way, the system 10 of the invention makes vagus nerve stimulation accessible to all patients 12.

[0107] The main features of the invention are derived from a real-life study on the use by patients 12 of known types of vagus nerve stimulators, a use which is the ultimate aim of the system 10 of the invention. In particular, it should be noted that the system 10 of the invention, unlike other systems of the known type used in the study, does not rely on a probabilistic technique (as is the case with devices using uncontrolled stimulation, or non-gated stimulation, and alternating fixed, pre-set periods of stimulation and pause). The system 10 of the invention bases the stimulation on the direct detection of actual diaphragmatic activity by means of transcutaneous electromyography (or possibly by means of phonomiography or mechanomyography).

[0108] The advantage of directly using diaphragmatic activity as a reference to pace vagus nerve stimulation is related to the fact that vagal afferents innervate the diaphragm to promote cardio-respiratory coupling. In particular, vagus nerve afferents signal to the heart the diaphragm relaxation, thus inducing a bradycardia phase during exhalation in order to optimise gas exchange at the alveolar level. Experimental studies of cardio-respiratory physiology have highlighted the close relationship and synchronisation between diaphragmatic activity and vagus nerve activity. Indeed, it has been seen that abolishing diaphragmatic activity through paralysis also abolishes the vagus-mediated cardiorespiratory coupling and respiratory sinus arrhythmia disappears (Parkes M. J. 2005, DOI: 10.1113 / expphysiol.2005.031625; Julien C et al. 2009, DOI: 10.1152 / japplphysiol.00196.2009). This relationship was also highlighted by a study of the group presenting this inventive proposal. Indeed, it has been seen that in patients undergoing bilateral lung transplantation, in which lung afferents are interrupted but diaphragmatic afferents are preserved, cardio-respiratory coupling is preserved (Tobaldini et al. 2021, DOI: 10.1186 / sl2931-021 -01752-6). It should be noted in this regard that the pulmonary activity of the patient 12, which is used to command neurostimulation in the solution proposed by WO 2010 / 114836, is a partial measure of the activity and effective responsiveness of the vagus nerve since, as can be seen from the above-mentioned literature, it is better represented by diaphragmatic activity than by pulmonary activity. Therefore, by synchronising the stimulation with the relaxation phases of the diaphragm in accordance with the invention, it is possible to precisely direct the pulses 19 through the windows of vagus nerve activity and avoid refractory phases of the nerve. In this way, all electrical input from the system 10 to the afferent branch of the vagus nerve is effective. In other words, instead of considering indirect measures of diaphragm activity, such as chest expansion or airflow, the system 10 of the invention bases the control of stimulation (gated stimulation) directly on the origin of the cardiorespiratory coupling itself. This system 10 allows much more accurate identification of the vagus nerve activity windows and, consequently, more precise and efficient vagus nerve stimulation.

[0109] The Applicant conducted a clinical study on the effectiveness of the basic characteristics that stimulation must have to achieve a clinically significant effect on chronic pain (Bellocchi et al., 2023, DOI: 10.1136 / rmdopen-2023-003265). In particular, the Applicant used commercially available devices to assess the optimal stimulation parameters. The Applicant treated with transcutaneous auricular vagus nerve stimulation a group of patients 12 suffering from an autoimmune disease, with a history of chronic pain of at least 10 years and pain severity of at least 6 points (on a scale of 0 to 10, where 0 is absence of pain) and therefore moderate to severe. This campaign of studies has shown that the main stimulation parameters described above (frequency of 25 Hz, bi-phase square waveform and pulse width 19 of 250 ps) are statistically and clinically effective in reducing chronic pain.

[0110] To analyse the degree of satisfaction and problems associated with treatment with transcutaneous auricular vagus nerve stimulation, a survey was conducted by interviewing the patients 12 involved in the clinical trials. The age of the patients 12 ranged from 21 to 79 years and the patients 12 belonged to 3 main groups: an immunological group with chronic pain, a cardiovascular group and a psychiatric group. A structured interview was conducted, organised around five aspects: ease of use, learnability, satisfaction, portability and future use.

[0111] Overall, the patients 12 were satisfied with the effectiveness of the treatment, with an average rating of 3.5 out of 5. However, a relative majority of respondents (40%) complained about the unstable contact of the stimulating electrodes 20 with the skin and poor portability (34%). It is worth mentioning that the campaign of studies, aimed at defining the optimal parameters of the pulses 19 for stimulation, was conducted with known, commercially available devices; in particular, the studies were conducted with a device comprising a pulse generator and a wired auricular electrode; moreover, the type of stimulation was uncontrolled, or non-gated stimulation. According to the patients 12, the contact of the known stimulating electrode 20 was very unstable and easily detached, resulting in frequent interruptions of stimulation. Moreover, due to these aspects, the possibilities of using the stimulator were limited to low-dynamic activities (e.g. while watching TV or reading), thus introducing considerable limitations for the patient 12 and reducing treatment compliance and increasing the risk of treatment abandonment.

[0112] It is clear that the above examples must not be interpreted in a limiting sense and the invention thus conceived is susceptible of numerous modifications and variations.

[0113] In accordance with a second aspect, the invention concerns a method for transcutaneous auricular vagus nerve stimulation of a patient 12 (taVNS). The method of the invention comprises the steps of: - providing an abdominal sensor 14, a control unit 16, and an auricular device 18, connected together, wherein the auricular device 18 comprises at least two stimulating electrodes 20;

[0114] - applying a first stimulating electrode 20i in contact with the upper concha 22 of the patient's 12 auricle 26;

[0115] - applying a second stimulating electrode 202 in contact with the lower concha 24 of the patient's 12 auricle 26;

[0116] - detect the patient's 12 diaphragmatic activity;

[0117] - providing the control unit 16 with a signal representative of the patient's 12 diaphragmatic activity;

[0118] - processing the representative signal of diaphragmatic activity to identify individual diaphragmatic cycles Tt;

[0119] - identifying, within each diaphragmatic cycle Tt, the onset of the contraction phase Tc of the diaphragm and the onset of the relaxation phase Tr of the diaphragm;

[0120] - controlling the auricular device 18 in such a way that it emits a series of bi-phase pulses 19 during the diaphragm relaxation phase, wherein the series has a frequency comprised between 1 Hz and 200 Hz, the bi-phase pulses 19 have a duration comprised between 100 ps and 1000 ps and a current intensity comprised between 0.1 mA and 5.0 mA.

[0121] Preferably, in the step of controlling the auricular device 18, each bi-phase pulse 19 comprises a first cathodic half -pulse 19i and a second anodic half-pulse 192.

[0122] Preferably, the step of detecting the patient's 12 diaphragmatic activity comprises the step of acquiring transcutaneous diaphragm electromyography (tcEMGd).

[0123] Many possible options for advantageously performing the method of the invention can be clearly deduced by a person skilled in the art from the description provided above in relation to the system 10 and its optional and preferred features.

[0124] As a person skilled in the art can clearly understand from the present description, the invention at least partially overcomes the drawbacks of the prior art.

[0125] In particular, the system of the present invention allows more efficient stimulation of the vagus nerve, particularly near the nerve endings of the auricle.

[0126] In addition, the system of the present invention features an easily and stably positionable stimulator that allows efficient stimulation of the vagus nerve even under dynamic conditions of use.

[0127] In conclusion, the materials used, as well as the contingent shapes and dimensions of the aforementioned devices, apparatuses and terminals, may be any according to the specific implementation requirements without thereby abandoning the scope of protection of the following claims.

Claims

CLAIMS1. System (10) for the transcutaneous auricular vagus nerve stimulation of a patient (12), comprising an abdominal sensor (14), a control unit (16) and an auricular device (18), connected to each other, wherein:- the abdominal sensor (14) is configured for detecting the diaphragmatic activity and for providing the control unit (16) with a signal representative of the diaphragmatic activity of the patient (12);- the control unit (16) is configured for processing the signal representative of the diaphragmatic activity received from the abdominal sensor (14) and for controlling the auricular device (18) on the basis of the diaphragmatic activity, according to a pre-loaded logic;- the auricular device (18) is configured for emitting electrical pulses (19) on command of the control unit (16);- the auricular device (18) comprises at least two stimulating electrodes (20) and is configured for maintaining, in use, a first stimulating electrode (20i) in contact with the upper concha (22) and a second stimulating electrode (20?) in contact with the lower concha (24) of the auricle (26) of the patient (12); wherein the logic pre-loaded in the control unit (16) involves controlling the auricular device (18) in such a manner that it emits a series of bi-phase pulses (19) during the relaxation phase of the diaphragm, wherein the series has a frequency comprised between 1 Hz and 200 Hz, the bi-phase pulses (19) have duration comprised between 100 ps and 1000 ps and current intensity comprised between 0,1 mA and 5,0 mA.

2. System (10) according to claim 1, wherein each bi-phase pulse (19) comprises a first cathodic half-pulse (19i) and a second anodic half-pulse (192).

3. System (10) according to claim 2, wherein the bi-phase pulse (19) comprises a delay (19a) between the two half-pulses (19i, 192).

4. System (10) according to claim 3, wherein the delay (19a) has duration Pa comprised between 0 ps and 150 ps, preferably of about 50 ps.

5. System (10) according to one or more of claims 2 to 4, wherein the first cathodic half-pulse (19i) has duration Pi, current intensity Ii, and delivers a charge Qi = Pi * h; the second anodic half-pulse (192) has duration P2, current intensity I2, and delivers a charge Q2 = P2 * I2; and wherein Qi = - Q2.

6. System (10) according to one or more of the preceding claims, wherein the control unit (16) is configured for:- identifying, within the signal received from the abdominal sensor (14), the individual diaphragmatic cycles Tt;- identifying, within each diaphragmatic cycle Tt, the onset of the contraction phase Tc of the diaphragm and the onset of the relaxation phase Tr of the diaphragm;- controlling the auricular device (18) for starting the stimulation of the vagus nerve at the onset of the relaxation phase Tr of the diaphragm.

7. System (10) according to claim 6, wherein the control unit (16) is further configured for controlling the auricular device (18) for ending the stimulation of the vagus nerve at the onset of the contraction phase Tc of the diaphragm.

8. System (10) according to one or more of the preceding claims, wherein the abdominal sensor (14) comprises sensing electrodes (28) configured for acquiring transcutaneous diaphragm electromyography (tcEMGd).

9. System (10) according to one or more of claims 1 to 7, wherein the abdominal sensor (14) comprises surface microphones, configured for detecting the vibration of the diaphragmatic muscle fibers by means of phonomyography.

10. System (10) according to one or more of claims 1 to 7, wherein the abdominal sensor (14) comprises accelerometers configured for detecting the vibration of the diaphragmatic muscle fibers by means of mechanomyography.

11. System (10) according to one or more of the preceding claims, wherein the stimulating electrodes (20) comprise a convex surface.

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