Method for alleviating dyspnea with neuromodulation

Abstract

It is provided a method of treating dyspnea in a subject comprising contacting an electrode or transducer invasively or non-invasively and generating an electrical or magnetic field to a neurological structure of the subject; delivering an electrostimulation to the neurological structure stimulating an ascending pathway of the nervous system of the subject, thereby treating dyspnea.

Description

METHOD FOR ALLEVIATING DYSPNEA WITH NEUROMODULATIONCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application is claiming priority from U.S. Provisional Application No. 63 / 779,379 filed March 28, 2025, the content of which is hereby incorporated by reference in their entiretyTECHNICAL FIELD

[0002] It is provided a method for treating dyspnea by electrically stimulating an ascending pathway of the nervous system of a subject.BACKGROUND

[0003] Dyspnea, also known as “breathlessness”, “air hunger”, “chest tightness” or “shortness of breath”, is one of the most unpleasant and common symptoms characterized by the feeling of running out of air and a sense of powerlessness in trying to physiologically manage this perception. It affects about 10% of the general population, and it appears to be more prevalent in the elderly population. In individuals older than 70 years old, 32% are affected by dyspnea. Management of dyspnea is difficult and expensive as it often coexists with other chronic respiratory illnesses such as chronic obstructive pulmonary disease (COPD) or congestive heart failure. Considering that as many as 12% of hospitalized patients suffer from dyspnea at rest, its economic burden is substantial. While the treatment of dyspnea should target the underlying cause, there are many cases of severe cardiopulmonary diseases that remain insufficiently relieved (e.g. COPD and pulmonary fibrosis). Symptomatic management options for dyspnea are limited, and include opioids, ventilator propelling air across face, and pulmonary rehabilitation. The results of these approaches are often underwhelming, and many patients are left living with this unpleasant sensation. More precisely, 90% of COPD patients suffer from severe dyspnea in their last year of life. Around 50% of these are not relieved by optimal treatments. As a stark reminder of the distress caused by chronic breathlessness in respiratory disease, 7% of people who request medically assisted death do so for terminal lung disease.

[0004] It is thus highly desired to be provided with new means to alleviate and treat dyspnea.SUMMARY

[0005] It is provided a method of treating dyspnea in a subject comprising generating an electrical or magnetic field on a neurological structure of the subject, wherein the electrical or magnetic field delivering an electrostimulation on the neurological structure stimulating or modulating an ascending pathway of the nervous system of the subject, thereby treating dyspnea.

[0006] In an embodiment, an electrode or a transducer is used to generate the electrical or magnetic field.

[0007] Accordingly, it is provided a method of treating dyspnea in a subject comprising contacting an electrode or transducer to a region of the subject proximate to a neurological structure of the subject; and delivering an electrostimulation via the electrode or transducer to generate an electrical or magnetic field on the neurological structure, thereby stimulating or modulating an ascending pathway of the nervous system of the subject and treating dyspnea

[0008] In another embodiment, the electrode or transducer being connected to a pulse generator.

[0009] In a further embodiment, the electrode or transducer is contacting invasively or non-invasively to the neurological structure.

[0010] In an embodiment, the neurological structure is vagal nerve, a spinal afferent nerve, a trigeminal nerve, a trigeminal tract, nucleus tractus solitarius, a spinal trigeminal nucleus, a trigeminothalamic tract, anterolateral spinothalamic pathway, posterior column / medial lemniscal pathway, a ventral posterior nucleus, or a combination thereof.

[0011] In a further embodiment, the ascending pathway is stimulated by a vagal nerve stimulation (VNS), transcutaneous VNS (tVNS), trigeminal transcutaneous electric nerve stimulation (TENS), spinal cord stimulation (SCS), deep brain stimulation (DBS), or by a combination thereof.

[0012] In an embodiment, the vagal nerve is stimulated at an auricular branch, a cervical branch, or a peripheral field thereof.

[0013] In an embodiment, the electrode is contacted transcutaneously or surgically connected to the neurological structure.

[0014] In a further embodiment, the electrostimulation is delivered non-invasively.

[0015] In another embodiment, the electrostimulation is of a pulse duration of between 50-500 ps at a frequency of between 10 to 5000 Hz at 0.1-80 mA.

[0016] In an embodiment, dyspnea is due to a respiratory disorder, to a cardiac disorder, a neurological disorder, a psychiatric disorder, an external stimulus, a metabolic disorder, an infectious disease, deconditioning, obesity, intense exercise or pregnancy.

[0017] In a further embodiment, the respiratory disorder is an obstructive lung disease, a restrictive lung disease, a parenchymal lung disease, a pleural lung disease, a tracheobronchial disease, an oro-nasal disease, a pulmonary vascular disease, or a breathing pattern disorder.

[0018] In an embodiment, the cardiac disorder is a cardiomyopathy, an arrythmia, a valvular dysfunction, a congenital heart disease, a pulmonary arterial hypertension, a pericardial disease a pulmonary embolism or shunting.

[0019] In an embodiment, the neurological disorder is a motoneuron disease, a spinal cord dysfunction or injury, a paralysis, a polyneuropathy, an Ondine syndrome, a post brain trauma, a stroke, an epilepsy, a brain tumour, an encephalitis, a recurrent laryngeal nerve palsy, multiple sclerosis or myasthenia gravis.

[0020] In another embodiment, the psychiatric disorder is a panic attack or disorder, an anxiety, posttraumatic disorder, a conversion disorder, or depression.

[0021] In a further embodiment, the external stimuli is an endotracheal intubation, a mechanical ventilation, ECMO, ora mechanical heart.

[0022] In an embodiment, the metabolic disorder is a mitochondrial disease, a glycogen storage disease, an hypophosphatemia, a sickle cell disease, anemia, a lactic acidosis, an acidosis, a poisoning, an hyperthyroidism, or cachexia.

[0023] In another embodiment, the infectious disease is a respiratory viral disease, an acute poliomyelitis, a bacterial pneumonia, a tuberculosis, or as consequence of a previous infection.

[0024] It is also provided a system for treating dyspnea in a subject comprising an electrode or transducer configured to be positioned on a region of the subject proximate to a neurological structure associated with an ascending pathway of the nervous system of the subject, and a pulse generator connected to the electrode or transducer, the pulse generator being configured to deliver an electrostimulation to the neurological structure to stimulate or modulate the ascending pathway, thereby treating dyspnea.

[0025] In an embodiment, the electrode or transducer is a transcutaneous electrode configured for non-invasive stimulation of the trigeminal nerve or the vagal nerve.

[0026] In another embodiment, the electrode is a surgically implantable electrode configured for invasive stimulation of the trigeminal nerve, the vagal nerve, a brainstem structure, a thalamic structure, a cortical structure, or the spinal cord.

[0027] It is further provided a kit for treating dyspnea in a subject comprising the system as described herein and instruction for generating the electrical or magnetic field to the neurological structure of the subject.

[0028] As encompassed, the system or the kit described herein are for treating dyspnea following the method as provided herewith.

[0029] It is further provide the use of an electrostimulation of a neurological structure for treating dyspnea in a subject, wherein the electrostimulation stimulates or modulates an ascending pathway of the nervous system of the subject, and wherein the neurological structure is selected from the group consisting of a trigeminal nerve, a vagal nerve, a sensory nucleus of the brainstem, a thalamic structure, a cortical structure, and a spinal cord structureDETAILED DESCRIPTION

[0030] In accordance with the present description, there is provided a method for treating dyspnea in a subject comprising generating an electrical or magnetic field on a region of the subject and delivering an electrostimulation on a neurological structure stimulating or modulating an ascending pathway of the nervous system of the subject.

[0031] As with any other sensory perception, the impression of dyspnea arises from neurological pathways. Neuromodulation is a field of medicine where neuralpathways are modulated for therapeutic purposes using electrical interfaces. Clinically approved systems typically consist of an electrode or transducer generating an electrical or magnetic field in the vicinity of a target structure (e.g. peripheral nerve, spinal cord, brain) and connected to an implanted pulse generator which is programmed to deliver the therapy. This approach is routinely used in many disorders, including epilepsy (vagal nerve stimulation), pain or angina (spinal cord stimulation), Parkinson’s disease (deep brain stimulation), and depression (transcranial magnetic stimulation).

[0032] Dyspnea can arise from any cause, including but not limited to respiratory disorders, such as for example obstructive lung diseases (e.g. emphysema, asthma), restrictive lung diseases (e.g. interstitial lung disease, kyphoscoliosis, myopathy affecting breathing muscles), parenchymal lung diseases (e.g. pneumonia, neoplasm, pneumonitis, cystic fibrosis, sarcoidosis, histiocytosis, pneumothorax, pulmonary oedema), pleural lung disease (e.g. pleural effusion, fibrothorax), tracheobronchial disease (e.g. stenosis, papilloma, vocal cord dysfunction), oro-nasal disease (e.g. chronic sinusitis, macroglossia), pulmonary vascular disease (e.g. hepatopulmonary syndrome, arterio-venous malformation), or breathing pattern disorder (e.g. dysfunctional breathing pattern).

[0033] Dyspnea can also arise from cardiac disorders, such as for example but not limited to, cardiomyopathy, arrythmia, valvular dysfunction, congenital heart disease, pulmonary arterial hypertension, pericardial disease (e.g. effusion, acute pericarditis, constrictive pericarditis), pulmonary embolism or shunting.

[0034] Also encompassed, dyspnea treated by the method described herein can also arise from neurological disorders such as, for example but not limited to, motor neuron disease, spinal cord dysfunction / injury, paralysis, polyneuropathy, Ondine syndrome, post brain trauma, stroke, epilepsy, brain tumour, encephalitis, recurrent laryngeal nerve palsy, multiple sclerosis or myasthenia gravis.

[0035] Also encompassed, dyspnea treated by the method described herein can also arise from psychiatric disorders, such as for example but not limited to, panic attacks I disorder, anxiety, posttraumatic disorder, conversion disorder, or depression.

[0036] Furthermore, dyspnea treated by the method described herein can also arise from external stimuli, such as for example but not limited to, endotrachealintubation, mechanical ventilation (invasive or non-invasive), extracorporeal membrane oxygenation (ECMO), or mechanical heart.

[0037] Also encompassed, dyspnea treated by the method described herein can also arise from metabolic disorders, such as for example but not limited to, mitochondrial disease, glycogen storage disease, hypophosphatemia, sickle cell disease, anemia, lactic acidosis, acidosis, poisoning, hyperthyroidism, or cachexia.

[0038] Also encompassed, dyspnea treated by the method described herein can also arise from infectious disease, such as for example but not limited to, respiratory viral disease (e.g. flu), acute poliomyelitis, bacterial pneumonia, tuberculosis, or as consequence of previous infection (e.g. long covid19, post-polio syndrome or potts syndrome).

[0039] Also encompassed, dyspnea treated by the method described herein can also arise from deconditioning or obesity, intense exercise or pregnancy.

[0040] In an embodiment, it is provided a method of electrical or magnetic stimulation of an ascending pathway of the nervous system of a patient to treat dyspnea in an invasive or non-invasive matter.

[0041] It is known that the central nervous system uses ascending and descending pathways to communicate with the external environment. Ascending pathways transport sensory information in afferent pathways from the body to the brain.

[0042] Mechanical, proprioceptive and inflammatory stimuli from the lungs are transported through the vagal nerve to the CNS. Other nociceptive stimuli from the lungs travel through spinal afferent nerves (to T1-T6). Travelling through trigeminal nerve are other sensitive stimuli from the face (mechanical, thermal, nociceptive, etc.) including the sensation of air flowing over the face.

[0043] The ascending pathways related to dyspnea project to sensory nuclei of the brainstem, including trigeminal tract, the principal sensory nucleus of cranial nerve V, the nucleus tractus solitarius, the spinal trigeminal nucleus, the trigeminothalamic tract, the spinothalamic anterolateral pathway, and the posterior columns / medial lemniscal pathway.

[0044] Also included in ascending pathway of the CNS is the ventral posterior nucleus which is a sensory relay nucleus in the thalamus of the brain. All thesestructure regions or nerve circuits of a patient body are accessible non-invasively or invasively in order to stimulate or modulate the ascending pathways allowing the brain to receive information about internal and external stimuli.

[0045] Vagal nerve stimulation (VNS) and trigeminal nerve field stimulation have shown promise in modulating respiratory pathways. As provided herewith, transcutaneous VNS (tVNS) and trigeminal transcutaneous electric nerve stimulation (TENS) are non-invasive techniques that improve dyspnea management by targeting these neural circuits.

[0046] Considering that tVNS and trigeminal TENS are well-explored techniques with established efficacy in pain modulation and given the connection to the gate control theory and chronic pain neuromodulation, it was investigated and demonstrated that dyspnea could be relieved by targeting specific neurological structures, such as trigeminal and vagal nerves, using these transcutaneous neuromodulation methods.

[0047] Stretch receptors of the lungs sense the inspiratory depth and send signals travelling in the sensory vagal nerve to increasingly stimulate the pneumotaxic center located in the pons to off-switch the inspiration and to begin the expiration process. These signals inhibit the dorsal respiratory group and stimulate the ventral respiratory group, which plays a role in the modulation of both inspiration and expiration. Vagal afferences pass by the amygdala, medial dorsal regions of the thalamus, and the posterior insula and cingulate cortices. Its projections might convey to hippocampus, operculum, putamen, and other prefrontal areas.

[0048] Vagal nerve stimulation (VNS) is currently employed clinically for some refractory cases of epilepsy and depression. It has been proposed that the vagal nerve impacts the physiologic onset of dyspnea. Nonetheless, Ohemeng et al. (2020, Otolaryngol Clin North Am., 53(1): 127-143) showed that VNS can also induce dyspnea as a side effect. In asthma, Miner et al. (2012, Acad. Emerg. Med., 19(4): 421-429) demonstrated that VNS can increase the forced expiratory volume in one second (FEV1), which could influence dyspnea in this illness.

[0049] Invasive vagus nerve stimulation (VNS) is approved for treating epilepsy, depression, obesity, and stroke rehabilitation. However, transcutaneous VNS (tVNS) offers a more convenient method to achieve some of the benefits of vagal nerve neurostimulation. TVNS can be applied to different regions, such as the tragus of the ear, stimulating the afferent auricular branch of the VN, or the anterolateral neck, alongthe path of the VN, stimulating the cervical branch of the VN. This non-invasive technique has shown to be reasonably effective and demonstrates positive results for conditions such as refractory epilepsy, depression, migraines, certain pain disorders, heart failure, and gastrointestinal inflammatory diseases.

[0050] Nasal cold receptors arising from the V2 and V3 distributions of the trigeminal nerve (CN V) can affect respiration and decrease breathlessness if stimulated by propelling cool air on the face. Also, peripheral trigeminal nerve field stimulation is sometimes used in refractory chronic facial pain syndromes. These treatments might be linked to the gate control theory studied in chronic pain, explaining that stimulation of certain afferences could inhibit the intensity of other unpleasant afferences.

[0051] Transcutaneous electric nerve stimulation (TENS) is used in physiotherapy to treat various types of pain, among its other uses. Trigeminal TENS theoretically and technically modulates nerve transmission, and it has shown some efficacy in reducing trigeminal neuralgia by targeting the trigeminal nerve. This suggests that the trigeminal nerve can be effectively targeted by TENS and could potentially be stimulated for other purposes, similar to the way air blown (e.g. by facial ventilator) on the face can have an effect on dyspnea. One caveat to using trigeminal TENS is that this technique activates A-beta fibres, which are not those that are involved in the perception of heat / cold. No evidence documented the effectiveness and the appropriate application of this approach for dyspneic patients.

[0052] Accordingly, it is provided a method of treating dyspnea in a subject comprising contacting an electrode or transducer generating an electrical field on a neurological structure of the subject, the electrode being connected to a pulse generator, delivering an electrostimulation on the neurological structure stimulating or modulating an ascending pathway of the nervous system of the subject, thereby treating dyspnea. The electric field can be provided in a non-invasive or invasive matter.

[0053] Encompassed herein is a non-invasive transcutaneous electrical nerve stimulation (TENS) of the trigeminal nerve, by for example, a 60-microsecond pulse duration at a frequency of 100 Hz with a constant stimulation mode. Similarly, it is encompassed a non-invasive transcutaneous vagal nerve stimulation (tVNS) of the auricular branch or peripheral field (between the tragus and the cymba conchae) or thecervical branch or peripheral field (anteriorly, next to the trachea). The stimulation can be, e.g. but not limited to, applied directly on the neck area of the cervical branch of the vagal nerve, at 5000-Hz pulse, 25Hz and 30-40 mA (20-25 on the gammaCore intensity scale). It is reported that a female patient following a non-invasive stimulation of the cervical branch on the neck area felt little dyspnea compared to usual during an exercise testing.

[0054] In an embodiment, tVNS parameters encompassed herein are pulse width of 100-500 ps at a frequency of 10 to 200 Hz (usually below 25 Hz), 30V (peak), 60mA (peak). Facial TENS parameters encompassed herein are (but not limited to) a (50-60)-microsecond pulse duration at a frequency of 80-120 Hz with constant, modulation, burst stimulation modes; 1-60 mA

[0055] Also encompassed is an invasive stimulation a subcutaneous trigeminal nerve field stimulation. As encompassed herein, “invasive” stimulation is intended to mean a surgically implanted electrode generating an electrical field in the vicinity of the neurological structure or nerve field in order to stimulate or modulate the targeted ascending pathway (dyspnea-related afferences or central ascending pathways).

[0056] Also encompassed is complete vagal nerve stimulation wherein electrodes are surgically implanted on the vagal nerve, or a deep brain stimulation on sensory brainstem, thalamic or cortical structures, as well as a spinal cord stimulation (SCS).

[0057] In an embodiment, the trigeminal tract structures in the brainstem, are stimulated at a pulse width of 60 ps, frequency of 2-1200 Hz and amplitude of 0.1-8 mA. At such stimulation, it is reported that a patient felt he is breathing more easily with the stimulation ongoing.

[0058] In an embodiment, deep brain stimulation (DBS) on the trigeminal tract parameters encompassed herein are pulse width between 30- 200 ps, frequency between 10-200 Hz, and amplitude of 1-3 V.EXAMPLE ITesting protocol

[0059] A cross-over trial in people with severe COPD (FEV1 20-50% predicted, COPD Assessment test (CAT) >10) and significant exertional dyspnea referred for pulmonary rehabilitation is conducted. At the time of rehabilitation pre-assessment, participants routinely undergo a baseline maximal Cardiopulmonary Exercise Testing(CPET) on ergocycle to measure VO2max with repetitive assessments of the Borg scale and continuous monitoring of vital signs (oxygen saturation, heart rate, blood pressure, respiratory rate) throughout the test. Spirometry and symptom questionnaires (CAT score) are also routinely measured. In two dedicated study visits conducted 2 weeks apart from each other, n=8 participants will perform a submaximal constant workrate (CWR) at 80% workload of the VO2 max, either with cervical tVNS (n=4) or trigeminal TENS (n=4). In a cross-over design, both patient groups undergo sham and active treatment of the neuromodulation technique in a randomly assigned number. The main outcome will be feasibility, assessed by the percentage of patients recruited, the percentage of recruited patients who attend all visits and complete all tests, the acceptability and suitability of the interventions (including an evaluation of sham as an exploratory outcome), and the incidence of adverse or undesirable events related to the procedures. Exploratory outcomes involve changes in dyspnea symptoms, measured using the Borg scale and the Visual Analogue Scale (VAS).

[0060] While the present disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations and including such departures from the present disclosure as come within known or customary practice within the art and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating dyspnea in a subject comprising:a) contacting an electrode or transducer to a region of the subject proximate to a neurological structure of the subject; andb) delivering an electrostimulation via the electrode or transducer to generate an electrical or magnetic field on the neurological structure, thereby stimulating or modulating an ascending pathway of the nervous system of the subject and treating dyspnea.

2. The method of claim 1, wherein the electrode or transducer being connected to a pulse generator.

3. The method of claim 1 or 2, wherein the electrode or transducer is contacting invasively or non-invasively to the neurological structure.

4. The method of any one of claims 1-3, wherein the neurological structure is a vagal nerve, a spinal afferent nerve, a trigeminal nerve, a trigeminal tract, a nucleus tractus solitarius, a spinal trigeminal nucleus, a trigeminothalamic tract, anterolateral spinothalamic pathway, posterior column / medial lemniscal pathway, a ventral posterior nucleus, or a combination thereof.

5. The method of any one of claims 1-4, wherein the ascending pathway is stimulated by a vagal nerve stimulation (VNS), transcutaneous VNS (tVNS), trigeminal transcutaneous electric nerve stimulation (TENS), spinal cord stimulation (SCS), deep brain stimulation (DBS), or by a combination thereof.

6. The method of claim 5, wherein the vagal nerve is stimulated at an auricular branch, a cervical branch, or a peripheral field thereof.

7. The method of any one of claims 1-6, wherein the electrode is contacted transcutaneously or surgically connected to the neurological structure.

8. The method of any one of claims 1-7, wherein the electrostimulation is delivered non-invasively.

9. The method of any one of claims 1-8, wherein the electrostimulation is of a pulse duration between 50-500 ps at a frequency of between 10 to 5000 Hz at 0.1-80 mA.

10. The method of any one of claims 1-9, wherein dyspnea is due to a respiratory disorder, a cardiac disorder, a neurological disorder, a psychiatric disorder, an external stimulus, a metabolic disorder, an infectious disease, deconditioning, obesity, intense exercise or pregnancy.

11. The method of claim 10, wherein the respiratory disorder is an obstructive lung disease, a restrictive lung disease, a parenchymal lung disease, a pleural lung disease, a tracheobronchial disease, an oro-nasal disease, a pulmonary vascular disease, or a breathing pattern disorder.

12. The method of claim 10, wherein the cardiac disorder is a cardiomyopathy, an arrythmia, a valvular dysfunction, a congenital heart disease, a pulmonary arterial hypertension, a pericardial disease a pulmonary embolism or shunting.

13. The method of claim 10, wherein the neurological disorder is a motoneuron disease, a spinal cord dysfunction or injury, a paralysis, a polyneuropathy, an Ondine syndrome, a post brain trauma, a stroke, an epilepsy, a brain tumour, an encephalitis, a recurrent laryngeal nerve palsy, multiple sclerosis or myasthenia gravis.

14. The method of claim 10, wherein the psychiatric disorder is a panic attack or disorder, an anxiety, posttraumatic disorder, a conversion disorder, or depression.

15. The method of claim 10, wherein the external stimuli is an endotracheal intubation, a mechanical ventilation, extracorporeal membrane oxygenation (ECMO), or a mechanical heart.

16. The method of claim 10, wherein the metabolic disorder is a mitochondrial disease, a glycogen storage disease, an hypophosphatemia, a sickle cell disease, anemia, a lactic acidosis, an acidosis, a poisoning, an hyperthyroidism, or cachexia.

17. The method of claim 10, wherein the infectious disease is a respiratory viral disease, an acute poliomyelitis, a bacterial pneumonia, a tuberculosis, or as consequence of a previous infection.

18. A system for treating dyspnea in a subject comprising:(a) an electrode or transducer configured to be positioned on a region of the subject proximate to a neurological structure associated with an ascending pathway of the nervous system of the subject; and(b) a pulse generator connected to the electrode or transducer, the pulse generator being configured to deliver an electrostimulation to the neurological structure to stimulate or modulate the ascending pathway, thereby treating dyspnea.

19. The system of claim 18, wherein the electrode or transducer is a transcutaneous electrode configured for non-invasive stimulation of the trigeminal nerve or the vagal nerve.

20. The system of claim 18, wherein the electrode is a surgically implantable electrode configured for invasive stimulation of the trigeminal nerve, the vagal nerve, a brainstem structure, a thalamic structure, a cortical structure, or the spinal cord.