WO2025101086A1

WO2025101086A1 - Systems and methods for treating respiratory conditions

Info

Publication number: WO2025101086A1
Application number: PCT/NZ2024/050125
Authority: WO
Inventors: Joseph BALFE; Yusuf Ozgur CAKMAK
Original assignee: Otago Innovation Ltd
Current assignee: Otago Innovation Ltd
Priority date: 2023-11-07
Filing date: 2024-11-07
Publication date: 2025-05-15
Anticipated expiration: 2026-05-07

Abstract

The present invention relates to methods of alleviating or preventing bronchoconstriction in a subject (including a subject in need thereof) comprising administering transdermally to the subject a stimulus to one or more of the subject's T1-T5 nerve dermatome(s) and/or angiosome(s), and related systems and devices.

Description

SYSTEMS AND METHODS FOR TREATING RESPIRATORY CONDITIONS

TECHNICAL FIELD

The present invention relates to providing therapeutic treatment through the stimulation to bodily tissues. In particular, the invention relates to devices, systems, and methods for selective administration of stimulation, such as electrical stimulation, for alleviating respiratory conditions and symptoms associated therewith, including for example alleviating or preventing bronchoconstriction.

BACKGROUND OF THE INVENTION

Bronchoconstriction is a potentially serious and life-threatening medical complication that many experience today. Bronchoconstriction can occur due to various causes, such as asthma complications and exercise and is also common in the field of anaesthesiology.

As one of the more common causes, asthma is a widespread chronic disorder affecting a significant portion of the global population, with an estimated 339 million individuals currently affected. Tragically, it claims the lives of over 1,000 people every day.

There are a number of known existing solutions for treating, preventing or alleviating bronchoconstriction. Some examples of these existing solutions include inhaled medications such as short-acting beta-agonists (SABAs), injected and/or oral medications such as oral corticosteroids, and invasive and expensive treatments such as bronchial thermoplasty.

However, with each of these existing solutions having their own limitations and drawbacks, patients at risk of bronchoconstriction are inevitably faced with having to tackle one or more challenges regardless of which solution they opt for. These limitations and drawbacks include:

1. Potential side effects: overuse or misuse of existing solutions, such as SABAs, can lead to tolerance and reduced effectiveness.

2. Non-adherence to medication: many individuals with bronchoconstriction-inducing conditions such as asthma struggle with adhering to their prescribed medication regimen. This nonadherence can lead to poor control of the condition, increased frequency of incidents (e.g., asthma attacks), and higher healthcare utilization.

3. subpar efficacy of medication: some medications (e.g., inhaled medication) are at times ineffective in accessing the constricted areas optimally, for example, due to the small airways becoming obstructed, meaning the patient can be put at risk and/or require emergency care.

4. Delayed medical care: in some cases, individuals experiencing bronchoconstriction may delay seeking medical care, leading to potentially severe consequences. Delays in obtaining help during the final stages of a bronchoconstriction incident (e.g., an asthma attack) can result in preventable deaths.

5. Suboptimal long-term care: bronchoconstriction-inducting conditions such as asthma typically require consistent long-term management and medical care. However, there is a significant gap in providing optimal care to individuals with such conditions, leading to suboptimal control of symptoms and increased risk of complications. Further, as mentioned briefly above, bronchoconstriction is a serious side effect and a life-threatening problem encountered in the field of anaesthesia. Effective management of bronchoconstriction during anaesthesia is crucial for patient safety and well-being.

Addressing these problems and/or needs requires the development of innovative and accessible solutions that ensure timely medical care, enhance long-term care and management, and effectively manage bronchoconstriction, for example, during exercise and in anaesthesia. By addressing these challenges, it is possible to significantly improve the quality of life for individuals with the tendency of experiencing bronchoconstriction (e.g., asthmatic patients) and reduce the burden of this condition on individuals, healthcare systems, and society as a whole.

The present invention thus seeks to provide a system and/or device and related methods for alleviating bronchoconstriction and/or one or more symptoms associated with bronchoconstriction, and/or to at least in part address the aforementioned drawbacks and/or needs, and/or to at least provide a useful alternative to existing solutions, or to at least provide the public with a useful choice.

SUMMARY OF THE INVENTION

According to a first aspect a method of alleviating, treating or preventing bronchoconstriction in a subject (including a subject in need thereof) is provided. The method comprises administering transdermally to the subject a stimulus to one or more of the subject's T1-T5 nerve dermatome(s) and/or angiosome(s).

According to a second aspect a method of promoting bronchodilation in a subject (including a subject in need thereof) is provided. The method comprises administering transdermally to the subject a stimulus to one or more of the subject's T1-T5 nerve dermatome(s) and/or angiosome(s).

According to a third aspect a method of alleviating, treating, or preventing bronchoconstriction or of eliciting or promoting bronchodilation in a subject (including a subject in need thereof) comprising administering transdermally to the subject a stimulus to one or more skin zones that are innervated by the T1-T5 dermatome(s) and/or angiosomes(s), such that the T1-T5 nerves are activated.

In some examples, the stimulus is transdermally administered to the T2 and/or T3 nerve dermatome(s) and/or corresponding angiosome(s).

In some examples, the stimulus is transdermally administered to modulate the T2 and/or T3 nerve activity or function.

According to a fourth aspect a method of alleviating, treating, or preventing bronchoconstriction in a subject (including a subject in need thereof) is provided. The method comprises administering transdermally to the subject a stimulus to modulate the T1-T5 nerve activity or function.

In some examples, the stimulus comprises or consists of an electrical stimulation.

In some examples, the stimulus comprises or consists of at least one electrical stimulation pulse or waveform. In some examples, the stimulus comprises magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s), photonic stimulation signal(s), and/or thermal stimulation signal(s).

In some examples, the method comprises alternating anode and cathode configurations of the stimulation, after one or more cycle(s) of stimulation.

In some examples, alternating the anode and cathode configurations alters the direction of the electrical field being produced.

In some examples, the method comprises altering the anode and cathode configurations of the stimulation, for example to alter the electrical field being produced, such as to alter the polarity, phase or relative phase, intensity, pulse frequency, wave train frequency, or duty cycle.

In various examples, the stimulation comprises one or more pulses or wave trains, including a stimulation provided by the interference of two continuous sine waves, with beat frequency matching the target pulse train. In one example of such a stimulation, the interference or modulation depth exceeds the activation threshold, while the inter-beat signals are below activation threshold or are of a frequency other than a frequency associated with activation.

In some examples, the method comprises determining a degree or severity of bronchoconstriction from the subject and initiating and/or adjusting the stimulus based on the determined degree or severity of bronchoconstriction.

In some examples, adjusting the stimulus comprises adjusting the duration and/or frequency of at least a portion of the stimulus.

In some examples, determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and/or expired air from the subject.

In some examples, determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and expired air from the subject and correlating the detected triggering sounds with the detected expiration and/or the determined bronchoconstriction. For example, detecting triggering sounds comprises the use of one or more acoustic sensors (including ultrasound) to detect "wheezing" or other sounds associated with bronchoconstriction, and/or capnography (which is based on expired air)-based bronchoconstriction determination.

As discussed herein, expiration and expired air and various parameters relating to expiration and expired air can be measured and/or monitored by any means, including audibly, by capnography, and/or by spirometry. Examples of such monitoring and/or measuring using capnography, for example using a capnometer to detect bronchoconstriction and/or determine one or more parameters associated with bronchoconstriction, such as the degree or severity of bronchoconstriction, are presented herein. In various examples, a capnometer is used. Capnometers provide a real-time continuous measurement of carbon dioxide (CO2) concentrations in respiratory gases, in which measurements of expired CO2 are plotted over time to produce a capnogram, displayed for example by means of a waveform display. Those skilled in the art will appreciate having the benefit of this disclosure that any methods of detecting, monitoring and/or measuring expiration and/or expired air are amenable to use herein.

In some examples, determining the degree or severity of bronchoconstriction comprises detecting any one or more of expiration, the subject's motion parameters and the subject's heart rate. In some examples, the expired air from the subject is configured to be detected using at least one stretch sensor on the outer skin of the subject.

In some examples, the sensor measures thoracic impedance. In some examples, determining the degree or severity of bronchoconstriction comprises determining and/or monitoring thoracic impedance of the subject.

In some examples, determining a degree or severity of bronchoconstriction comprises tracking and/or storing data associated with at least one heart rate sensor; and/or at least one motion sensor; and/or at least one stretch sensor.

In some examples, determining a degree or severity of bronchoconstriction comprises an analysis of data relating to the subject, such as tracked and/or stored data obtained in or by a method, device, or system as contemplated herein, or data relating to the subject provided by one or more external determinations or assessments. In one example, determining a degree or severity of bronchoconstriction comprises tracking and/or storing data and analysing data, such as stored data, relating to the subject, for example to provide personalised response, alleviation, or the like.

In some examples, at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapulae of the subject. In one example, at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapulae of the subject, targeting the nerve within the T3 dermatome. In one example, at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapulae of the subject to innervate the sympathetic nerves within the T3 dermatome and/or angiosome.

In some examples, at least a portion of the one or more skin zones comprise or correspond to the medial aspect of an arm of the subject, targeting the intercostobrachial nerve within the T2 dermatome.

In some examples, at least a portion of the one or more skin zones comprise or correspond to the medial aspect of each arm of the subject, bilaterally targeting the intercostobrachial nerve within the T2 dermatome.

According to a fifth aspect a method of alleviating, treating, or preventing bronchoconstriction in a chordate subject, is provided. The method comprises transdermally administering stimulation to dermatomes and/or angiosomes of the subject such that nerve endings associated with the T1-T5 sympathetic ganglions are stimulated and bronchial constriction is alleviated and/or prevented.

According to a sixth aspect a method of alleviating, treating, or preventing bronchoconstriction in a chordate subject, is provided. The method comprises transdermally administering stimulation to dermatomes and/or angiosomes of the subject such that the T1-T5 nerves are indirectly modulated, and bronchial constriction of the subject is reduced.

In some examples, the stimulation is transdermally administered to the T3 nerve dermatome and/or angiosome.

In some examples, the stimulation comprises or consists of an electrical stimulation.

In some examples, the stimulation comprises or consist of at least one electrical stimulation pulse or waveform. In some examples, the stimulation comprises magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s), photonic stimulation signal(s), and/or thermal stimulation signal(s).

In some examples, the method further comprises alternating anode and cathode configurations after one or more cycle(s) of stimulation.

In some examples, the method comprises determining a degree or severity of bronchoconstriction from the subject and initiating or adjusting the stimulation based on the determined degree or severity of bronchoconstriction.

In some examples, adjusting the stimulation comprises adjusting the duration and/or frequency of at least a portion of the stimulation.

In some examples, determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and expired air from the subject and correlating the detected triggering sounds with the detected expiration.

In some examples, determining the degree or severity of bronchoconstriction comprises detecting expiration using at least one stretch sensor on the outer skin of the subject.

In some examples, at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapula of the subject, targeting the nerve within the T3 dermatome.

According to a seventh aspect a method for alleviating, treating or preventing bronchoconstriction in a subject (including a subject in need thereof) is provided. The method comprises: placing one or more activation members in contact with an outer skin surface of the subject; applying at least one stimulation pulse or waveform to at least one of the one or more activation members, wherein the at least one stimulation pulse or waveform is configured to activate the T1-T5 nerves of the subject, such that bronchial constriction of the subject is reduced or prevented.

According to an eighth aspect a system for alleviating, treating, or preventing bronchoconstriction in a subject is provided, where the system is configured to perform the methods according to any one of the first to seventh aspects and their associated examples. According to a ninth aspect a system for alleviating, treating, or preventing bronchoconstriction in a subject, is provided. The system comprises: an activator comprising one or more activation members configured to be placed on the outer skin of the subject, the activator being configured to apply at least one stimulation pulse or waveform to at least one of the one or more activation members; and at least one detector configured to detect bronchoconstriction from the subject, wherein: the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T1-T5 dermatome(s) and/or angiosomes(s) associated with T1-T5 sympathetic ganglions, in use; and application of the at least one stimulation pulse or waveform is initiated or adjusted based on bronchoconstriction being detected by the at least one detector.

In some examples, the activator is wearable.

In some examples, the activator comprises an electro-stimulator.

In some examples, the one or more activation members comprise electrodes.

In some examples, the skin zones are positioned at the back and in-between the scapula of the subject.

In various examples, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T2 dermatome(s) and/or angiosomes(s) associated with T2 sympathetic ganglions.

In various examples, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T3 dermatome(s) and/or angiosomes(s) associated with T3 sympathetic ganglions.

In some examples, the activator is configured to apply stimulation at a frequency between 2Hz to 20kHz.

In some examples, the activator is configured to apply stimulation at a frequency between 10Hz and 200Hz.

In some examples, the activator is configured to apply two or more different stimulation frequencies. In certain examples, the activator is configured to apply two or more different stimulation frequencies in succession, with or without pause between application, and optionally for the same or different durations.

In some examples, the activator is configured to alternate between applying two or more different stimulation frequencies,

In some examples, the activator is configured to alternate between applying stimulation at frequencies of 10Hz, 80Hz and 200Hz.

In some examples, the activator is configured to alternate between applying stimulation at frequencies of any two or more of the group consisting of 10Hz, 80Hz, 120Hz, and 200Hz.

In some examples, the activator is configured to alternate between applying at least one dominant frequency within a poly-tone signal. In some examples, the activator is configured to alternate between one or more signals having significant or notable Fourier Transform peaks at or around frequencies of any one or more of the group consisting of 10Hz, 80Hz, 120Hz, and 200Hz. In various examples, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T2 dermatome(s) and/or angiosomes(s) associated with T2 sympathetic ganglions, and the activator is configured to apply stimulation at a frequency of between 10Hz and 200Hz. In one example, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T2 dermatome(s) and/or angiosomes(s) associated with T2 sympathetic ganglions, and the activator is configured to alternate between applying stimulation at frequencies of any two or more of the group consisting of 10Hz, 80Hz, 120Hz, and 200Hz. In one example, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T2 dermatome(s) and/or angiosomes(s) associated with T2 sympathetic ganglions, and the activator is configured to apply stimulation at a frequency of 80Hz.

In various examples, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T3 dermatome(s) and/or angiosomes(s) associated with T3 sympathetic ganglions, and the activator is configured to apply stimulation at a frequency of between 10Hz and 200Hz. In one example, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T3 dermatome(s) and/or angiosomes(s) associated with T3 sympathetic ganglions, and the activator is configured to alternate between applying stimulation at frequencies of any two or more of the group consisting of 10Hz, 80Hz, 120Hz, and 200Hz. In one example, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T3 dermatome(s) and/or angiosomes(s) associated with T3 sympathetic ganglions, and the activator is configured to apply stimulation at a frequency of 10Hz. In one example, the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T3 dermatome(s) and/or angiosomes(s) associated with T3 sympathetic ganglions, and the activator is configured to apply stimulation at a frequency of 200Hz.

In some examples, the activator is configured to apply the two or more different stimulation frequencies about every two minutes, for example, to apply different fundamental or interfered signals containing one or more significant Fourier transform peaks on timeframes of about two minutes. In some examples, the activator is configured to alternate between the two or more different stimulation frequencies every two minutes.

In some examples, the activator is configured to apply a direct current to at least one of the one or more activation members, prior to applying the at least one stimulation pulse or waveform.

In some examples, the activator is configured to apply a small-amplitude periodic or aperiodic (noisy or random) signal offset by a direct current bias to at least one of the one or more activation members, such as prior to applying the at least one stimulation pulse or waveform.

In some examples, the system is configured to provide any one or more of acoustic stimulation, thermal stimulation, mechanical stimulation, photonic stimulation, magnetic stimulation and electrical startle stimulation to the skin zone(s), prior to applying the at least one stimulation pulse or waveform.

In various examples, the mechanical stimulation comprises vibrational stimulation and/or stimulation via exertion of pressure, one or more shear waves, or one or more pressure wave. Mechanical stimulation includes (but is not limited to) skin vibration that can be induced by mechanical stimulus or other ways.

In some examples, the detector is wearable.

In some examples, the at least one activator and at least one detector are wearable. In certain examples, the at least one activator and the at least one detector are configured as a single wearable device.

In some examples, the at least one detector comprises at least one heart rate sensor and/or at least one motion sensor.

In some examples, the at least one heart rate sensor is configured to detect the occurrence and duration of acceleration and/or deceleration of the heart rate of the subject. In certain examples, occurrence or duration of heart rate variability is determined periodically, for example, at or for 1 - 10 second intervals or periods, for example, for 5 second periods at 10 second intervals, for 10 second periods at 20 second intervals, etc. Those skilled in the art will recognise that methods for monitoring heart rate variability are well established, and the manner in which heart rate variability is determined so as to provide meaningful data relating to heart rate variability is within the scope of the skilled addressee.

In some examples, the at least one heart rate sensor comprises at least one wearable sensor.

In some examples, the at least one wearable sensor comprises an ECG device and/or an accelerometer.

In some examples, the at least one wearable sensor measures or determines thoracic impedance.

In some examples, the at least one heart rate sensor comprises at least one non-contact sensor.

In some examples, the at least one non-contact sensor is any one or more of: infra-red sensor, laser sensor, ultrasound sensor and camera.

In some examples, the at least one motion sensor is configured to sense a change in motion parameters and the duration of which the change occurs.

In some examples, the at least one detector comprises at least one stretch sensor.

In some examples, the system is configured to track and/or store data from the at least one detector.

In some examples, the data being tracked and/or stored comprises data from any one or more of the at least one heart rate sensor; the at least one motion sensor; and the at least one stretch sensor.

In some examples, the system is configured to provide an alert upon detection of potential triggers based on previous data from the at least one detector.

In some examples, at least a portion of the one or more activation members are configured to be positioned to innervate the sympathetic nerves within the T3 dermatome and/or angiosome.

In some examples, at least a portion of the one or more activation members are configured to be positioned on the back and in-between the scapulae of the subject. For example, at least a portion of the one or more activation members are configured to be positioned on the back and in- between the scapulae of the subject to innervate the sympathetic nerves within the T3 dermatome and/or angiosome.

In some examples, at least a portion of the one or more activation members are configured to be positioned such that the at least one stimulation pulse or waveform is configured to be applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of the arm of the subject.

In some examples, at least a portion of the one or more activation members are configured to be positioned such that the at least one stimulation pulse or waveform is configured to be bilaterally applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of each arm of the subject.

In some examples, the activator comprises two or more activation members.

In some examples, the at least one stimulation pulse or waveform is configured to be applied to the two or more activation members interchangeably.

In some examples, the two or more activation members are positioned in multiple different locations on the subject.

In some examples, the multiple different locations on the subject comprise the right arm, left arm and/or the back of the thorax.

In some examples, the at least one stimulation pulse or waveform comprises at least one electrical stimulation pulse or waveform.

In some examples, the anode and cathode configuration of the at least one stimulation pulse or waveform is configured to alternate after one or more cycle(s) of stimulation.

In some examples, the alternating anode and cathode configurations alters the direction of the electrical field being produced.

In some examples, the at least one stimulation pulse or waveform comprises magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s), photonic stimulation signal(s), and/or thermal stimulation signal(s).

In some examples, the activator is configured to initiate or adjust the duration and/or frequency of at least a portion of the at least one stimulation pulse or waveform, based on data received from the at least one detector.

In some examples, the subject is suffering from or is predisposed to asthma.

In some examples, the subject is seeking to avoid or mitigate exercise-induced bronchoconstriction. In some examples, the subject is suffering from exercise-induced bronchoconstriction.

In some examples, the subject is or has been exposed to cold air.

In some examples, the subject is suffering from an emotional or psychological response, such as stress, or is seeking to mitigate an emotional or psychological response or one or more symptoms of an emotional or psychological response, such as stress.

In various examples, the subject is seeking to improve performance, such as athletic or physical performance. BRIEF DESCRIPTION OF THE DRAWINGS

A number of examples will now be shown, by way of example, with reference to the following drawings.

Figure 1 is an illustration showing particular locations of a subject which may be subjected to a stimulus, according to an example of the present invention.

Figure 2 shows a schematic of a system for alleviating, treating, or preventing bronchoconstriction, according to the example of Figure 1.

Figure 3 is an illustration showing particular locations of a subject which may be subjected to a stimulus, according to another example of the present invention.

Figure 4 shows a schematic of a system for alleviating, treating, or preventing bronchoconstriction, according to an example of Figure 3.

Figure 5 presents a representative healthy capnogram (left) and a representative bronchoconstriction capnogram (right). During bronchoconstriction, the decreased slope of Phase II and increased slope of Phase III produces a larger a angle and smaller 3 angle that is characteristic of an increase in bronchoconstriction.

Figure 6 presents an individual capnograph waveform output (during baseline) in MATLAB (2021b) obtained from a trial participant as described in Example 1, indicating the a angle, phase III gradient, and p angle (from left to right). The y-axis represents expired CO2 measured in millimetres of mercury (mmHg). The x-axis represents datapoints across time sampled at a rate of 20Hz.

Figure 7 presents a schematic diagram of the full experiment conducted for each participant as reported herein in Example 1. After enrolment and eligibility was confirmed, each participant was allocated to three days of experiments in a counterbalanced manner (which determined the order of stimulation session). The experiment began with a 6-min baseline period for capnograph and ECG recording. Once this was completed, the participant underwent an 8-min exercise challenge. Stimulation was then performed for 6-mins upon exercise cessation. At the end of post-exercise stimulation, the nasal cannula, running watch, and ECG device were removed from the participant and the experiment was concluded for the day (total roughly 30 to 35 min).

Figure 8 presents two graphs showing capnograph results from each trial participant before (last 2-min of baseline) and after (0-2-min of placebo stimulation) the exercise challenge as reported herein in Example 1. Each datapoint represents the mean a angle (left) or 8 angle (right) over a 2- minute period for each participant. ** = p < 0.01; **** = p < 0.0001.

Figure 9 presents a graph comparing the absolute effects (differences of differences from baseline) of TENS on p angle during the 2-4 min stimulation period in the trial reported herein in Example 1. Data are presented as means with error bars representing standard deviation. Post-hoc tests revealed that 10Hz TENS produced a significantly smaller absolute change in p angle compared to placebo-TENS during the 2-4 min stimulation period (p = 0.025). * = p < 0.05, ns = not significant. Figure 10 presents a graph comparing the absolute effects (differences of differences from baseline) of TENS on phase III slope during the 2-4 min stimulation period in the trial reported herein in Example 1. Data are presented as means with error bars representing standard deviation. Post-hoc tests revealed that 10Hz TENS produced a significantly smaller absolute change in phase III slope compared to placebo-TENS during the 2-4 min stimulation period (p = 0.0241). * = p < 0.05; ns = not significant.

Figure 11 presents a graph comparing the absolute effects (differences of differences from baseline) of TENS on RMSSD during the 0-2 min stimulation period in the trial reported herein in Example 1. Data are presented as means with error bars representing standard deviation. Post-hoc tests revealed that 10Hz TENS produced a significantly smaller absolute change in RMSSD compared to placebo-TENS during the 0-2 min stimulation period (p = 0.0175). There was no significant difference between the 10Hz and 80Hz stimulation sessions. * = p < 0.05; ns = not significant.

Figure 12 presents a graph comparing the absolute effects (differences of differences from baseline) of TENS on SI during the 0-2 min stimulation period in the trial reported herein in Example 1. Data are presented as means with error bars representing standard deviation. Post-hoc tests revealed no significant differences in the absolute changes in SI between each condition (placebo, 10Hz, and 80Hz). ns = not significant.

Figure 13 presents two graphs showing capnograph results from each trial participant before (last 2-min of baseline) and after (0-2-min of placebo stimulation) the exercise challenge as reported herein in Example 2. Each datapoint represents the mean a angle (left) or 8 angle (right) over a 2- minute period for each participant. **** = p < 0.0001.

Figure 14 presents two graphs showing capnograph results from each trial participant before (last 2-min of baseline) and after (0-2-min of placebo stimulation) the exercise challenge as reported herein in Example 3. Each datapoint represents the mean a angle (left) or 8 angle (right) over a 2- minute period for each participant. **** = p < 0.0001.

DETAILED DESCRIPTION

The present invention relates to devices, systems and methods for selective administration of stimulation (e.g., electrical stimulation) for alleviating, treating or preventing bronchoconstriction (and its associated symptoms) and/or for promoting or eliciting bronchodilation in a subject, such as a human subject and/or a subject in need thereof.

In humans, the airway smooth muscle is innervated by parasympathetic and sympathetic nerves that mediate bronchoconstriction and bronchodilation, respectively. Thus, stimulation of the sympathetic nerves can potentially be useful in eliciting or promoting bronchodilation in the small airways. In order to provide this stimulation, while still overcoming the aforementioned drawbacks and disadvantages of the existing solutions, the methods, devices and systems disclosed herein predominantly focus on the application of transcutaneous (i.e. , on or through the skin) stimulation for eliciting or promoting bronchodilation. Transcutaneous stimulation, such as Transcutaneous Electrical Nerve Stimulation (TENS), is essentially a non-invasive and drug-free method of treating symptoms by applying stimulation to the skin of the subject/patient. In the context of this disclosure, a subject/ patient includes but is not limited to humans and chordate subjects.

While the present disclosure is directed predominantly to alleviating, treating, or preventing bronchoconstriction by administering stimulation to the sympathetic nervous system (e.g., using TENS and/or other types of stimulation), it will be appreciated that the devices, systems, and methods disclosed herein can be utilised for alleviating, treating, or preventing symptoms of other diseases by applying the stimulation to the same or other nerves, such as parasympathetic, spinal, or cranial nerves and the like.

As mentioned above, sympathetic nerves can potentially be stimulated to elicit or promote bronchodilation in the small airways by, for example, modulating sympathetic nerve(s) that correspond with bronchial innervation. By subjecting the nerves to stimulation, it is essentially possible to normalise the activity or functioning of the nerves. Particular sympathetic nerve fibres, e.g., those originating from the T1-T5 spinal nerve, segmentally innervate their associated dermatome(s) and/or angiosome(s) (e.g., T1-T5 dermatome(s) and/or angiosome(s) in the case of the T1-T5 spinal nerves). Therefore, the effects of stimulating the associated dermatome(s) and/or angiosome(s) can potentially include and/or reach the small airways which are predominantly involved in asthma pathophysiology. As a result, administering stimulation (e.g., via TENS) to particular dermatome(s) and/or angiosome(s) (e.g., T1-T5) can provide the surprising and beneficial effect of eliciting or promoting bronchodilation in the small airways. These effects may be used to treat shortterm, acute cases of bronchoconstriction (e.g., exercise-induced bronchoconstriction, EIB) or longterm, chronic cases of bronchoconstriction (e.g., asthma).

Selected definitions

It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7). These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a sample" includes a plurality of samples, including mixtures thereof.

Those skilled in the art will appreciate the meaning of various terms of degree used herein. For example, as used herein in the context of referring to an amount (e.g., "about 9%"), the term "about" represents an amount close to and including the stated amount that still performs a desired function or achieves a desired result, e.g. "about 9%" can include 9% and amounts close to 9% that still perform a desired function or achieve a desired result. For example, the term "about" can refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, or within less than 0.01% of the stated amount. It is also intended that where the term "about" is used, for example with reference to a figure, concentration, amount, integer or value, the exact figure, concentration, amount, integer or value is also specifically contemplated.

The term "and/or" can mean "and" or "or".

The term "comprising" as used in this specification means "consisting at least in part of". When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises", and the terms "including", "include" and "includes" are to be interpreted in the same manner.

The term "consisting essentially of" when used in this specification refers to the features stated and allows for the presence of other features that do not materially alter the basic characteristics of the features specified.

The term "consisting of" as used herein means the specified materials or steps of the claimed invention, excluding any element, step, or ingredient not specified in the claim.

The terms "determining", "measuring", "evaluating", "assessing," "assaying," and "analyzing" can be used interchangeably herein to refer to any form of measurement and include determining if an element is present or not (e.g., detection). These terms can include both quantitative and/or qualitative determinations. Assessing may be relative or absolute. These terms can include use of the algorithms described herein. "Detecting the presence of" can include quantification such as determining the amount of something present, as well as determining whether it is present or absent.

While the present disclosure is directed predominantly to alleviating, treating, or preventing bronchoconstriction in a human subject, those skilled in the art having the benefit of this disclosure will appreciate that the methods, devices, and systems disclosed herein may be incorporated in various applications and arrangements for alleviating, treating, or preventing bronchoconstriction in non-human subjects.

Accordingly, as used herein, the term "subject" contemplates a chordate animal, usually a mammal, including a human, an agricultural animal, a companion animal, or indeed any chordate animal that would benefit from the application of the methods, devices, and systems herein described. Representative agricultural animals include caprine, ovine, bovine, cervine, and porcine. Representative companion animals include feline, equine, and canine. While the focus of this disclosure is on the treatment of human subjects, and reference to anatomical features herein should be interpreted accordingly, those skilled in the art will appreciate that one or more equivalent anatomical features may be found in non-human subjects, such that the methods, devices and systems described herein with reference to human subjects can readily be applied to non-human subjects. With regard to subjects, the methods, devices, and systems disclosed herein may be incorporated in various applications and arrangements for alleviating, treating, or preventing bronchoconstriction in any subject (such as a human subject) in need thereof or a subject who is desirous of, would benefit from, or considers there to be a benefit or a potential benefit in alleviating, treating, or preventing bronchoconstriction. Examples of subjects (such as human subjects) who may be in need of the methods, devices, and systems contemplated herein include those having or at risk of a medical condition associated with or caused or exacerbated by bronchoconstriction. Examples of other subjects, such as subjects who are desirous of, would benefit from, or consider there to be a benefit or a potential benefit in alleviating, treating, or preventing bronchoconstriction include athletes, performance or racing animals, underwater divers (such as saturation divers or those using modified atmospheres such as He-Ox divers), orators or singers, subjects seeking to ameliorate one or more emotional or psychological responses such as stress, and the like.

Examples of devices, systems, and methods disclosed herein relate to implementing the abovementioned stimulation and producing the associated desired affects, are described below. Moreover, as will be described in further detail below, the devices, systems, and methods disclosed herein also describe the use of any one or more of thermal, vibrational, photonic, ultrasound and magnetic stimulation, alternatively to or in combination with the electrical stimulation provided by TENS. Regardless, all of these methods demonstrate the potential for the development of an easily accessible, non-invasive, drug-free solution for treating, alleviating, or preventing bronchoconstriction by ensuring alveolar ventilation is maintained (e.g., by eliciting and/or promoting bronchodilation) during and/or upon determination of a bronchoconstriction event (e.g., an asthma attack). The solutions disclosed herein also have the ability of being configured as an automated and/or wearable devices.

Accordingly, in certain aspects the invention relates to a wearable device comprising at least one activator and at least one detector as disclosed herein.

In another aspect, the invention relates to a wearable device comprising at least one activator and/or at least one detector as described herein for use in a method contemplated herein.

In certain examples, including in a method as contemplated herein, the system or wearable device is worn by a subject in anticipation of the possible onset of bronchoconstriction. For example, the system or wearable device is worn by a subject, such as a subject suffering from or predisposed to asthma who is or expects to be exposed to a trigger for an asthma attack or who anticipates the onset of an asthma attack.

In another example (including for example in a method as contemplated herein), the system or wearable device is worn by a subject, such as a subject suffering from or predisposed to exercise- induced bronchoconstriction who is or expects to be at increased risk of exercise-induced bronchoconstriction, such as a subject who is exercising or is about to exercise. In certain examples (including for example in a method as contemplated herein), the system or wearable device is worn prophylactically.

In certain examples (including for example in a method as contemplated herein) the system or wearable device is worn for a period over which more than one administration of transdermal stimulus occurs. For example, the system or wearable device is worn continuously over multiple separate rounds of transdermal stimulation. For example, the system or wearable device is worn continuously over a treatment regimen comprising multiple separate periods of transdermal stimulation, wherein each period of transdermal stimulation comprises from about 1 s to about 10 minutes of stimulation.

Representative examples of treatment regimens contemplated herein are presented in the Examples - see in particular Example 1.

In certain examples (including for example in a method as contemplated herein), the system or wearable device is worn for the entirety of the period over which the onset, degree or severity of bronchoconstriction is determined and/or detected.

In certain examples (including for example in a method as contemplated herein), the system or wearable device is worn for the entirety of the period over which there is an increased likelihood of the onset of bronchoconstriction, or an increased likelihood of severe bronchoconstriction.

In certain examples (including for example in a method as contemplated herein) the system or wearable device is worn for the entirety of the period over which the onset of bronchoconstriction is anticipated, or over which an increased likelihood of severe bronchoconstriction is anticipated.

In certain examples, the methods contemplated herein are prophylactic.

In certain examples, including in a method as contemplated herein, the system or wearable device is worn by a subject for a period substantially longer than that over which a transdermal stimulus is applied. For example, the system or wearable device is worn by a subject for a period substantially longer than that over which a period of transdermal stimulus is applied.

Methods, devices, and systems for alleviating, treating, or preventing bronchoconstriction and/or eliciting or promoting bronchodilation in a subject (including a subject in need thereof) are disclosed herein. The methods, devices, and system can comprise or provide for administering transdermally (or transcutaneously) a stimulus (also referred to as "stimulation", "stimulation pulse", "stimulation waveform" herein) to the subject, for example via one or more skin zones.

In some examples, the stimulus is transdermally administered to one or more dermatome(s) and/or angiosome(s) of the subject's nerves. This may allow for the stimulus to be administered to one or more of the subject's cutaneous sympathetic nerves, as they may be distributed via their respective dermatome(s) and/or angiosome(s). This means that the nerve endings (e.g., of T1-T5) may be directly or indirectly activated by the stimulus being administered (or applied) to one or more respective or corresponding dermatome(s) and/or angiosome(s). In response to such stimulation, the nerve endings may "act back" and stimulate one or more nerves (e.g., the spinal nerve) through (e.g., indirect) activation of the shared bundle. Thus, the ability to obtain an (e.g., indirect) activation of the nerves via administering a non-invasive stimulation to the skin and/or the vasculature of the subject/ patient, provides a surprising and beneficial technical effect.

In some examples, the stimulus may be administered to specific/targeted dermatome(s) and/or angiosome(s) of the nerves in order to modulate the activity of the nerves that are of interest. This targeted application of the stimulus may be possible by administering the stimulus to one or more skin zones that are innervated by dermatome(s) or angiosome(s) associated with the nerves (e.g., the ganglion or ganglia) of interest. In some examples, the one or more skin zones may be positioned such that they are innervated by the T1-T5 dermatome(s) and/or angiosomes(s), such that the T1-T5 nerves are configured to be activated upon the stimulus being administered to the one or more skin zones. This arrangement would essentially allow for the administered stimulus to potentially modulate the T1-T5 nerve activity or function. In some examples, the one or more skin zones may be positioned such that the administered stimulus is configured to modulate the T2 and/or T3 nerve activity or function by, for example, having the T2 and/or T3 nerves being stimulated by proximity and/or shared bundling with sensory dermatome and/or angiosome stimulation.

In some examples, the stimulation is indirect stimulation of a specific and/or targeted dermatome(s) and/or angiosome(s), for example indirect stimulation of the dermatome and/or angiosome of the T2 nerve, for example by stimulation of the intercostobrachial nerve, for example by stimulation applied to the medial aspect and/or the ventral axial line of the upper limb.

In some examples, the stimulus (also referred to as "stimulation", "stimulation pulse", "pulse", "waveform", and the like) comprises or consists of an electrical stimulation and/or at least one electrical stimulation pulse or waveform. In some examples, the methods, devices and systems disclosed herein comprise or provide for altering or alternating the anode and cathode configurations of the stimulation, e.g., after one or more cycle(s) of stimulation. This may produce a beneficial technical effect as alternating the anode and cathode configuration may alter the direction of the electrical field being produced, which can potentially provide a burst of stimulation.

Accordingly, as contemplated herein electrical nerve stimulation including burst, continuous and interferential stimulation is contemplated.

Alternatively, or in addition to the electrical stimulation and/or at least one electrical stimulation pulse or waveform, the stimulus (or stimulation or stimulation pulse or waveform) may comprise any one or more of magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s), photonic stimulation signal(s), and/or thermal stimulation signal(s).

In certain examples, the duration of stimulation may be from about 1 s to about 30 minutes or more. In certain examples, the administration of stimulation comprises multiple separate periods of stimulation, wherein each period of stimulation may be from about 1 s to about 30 minutes.

The devices and systems disclosed herein may comprise an activator. The activator may comprise one or more activation members and/or may be provided in the form of an electro- stimulator such as an electro-stimulator configured to provide one or more electromagnetic signals. The one or more activation members may comprise one or more electrodes and/or may be configured to be placed on the outer skin of the subject. The activator may be configured to apply at least one stimulation pulse or waveform to the subject via at least one of the one or more activation members.

The systems and/or devices disclosed herein may be configured in various arrangements. Examples of these will be explained below to demonstrate their possible configurations and arrangements and to demonstrate how such systems and/or devices may operate.

Stimulation configuration

As explained above, selective placement of the one or more activation members corresponding to the appropriate dermatome(s) and/or angiosome(s) of the nerve(s) of interest, for example, placing one or more activation members on one or more skin zone which are innervated by the sympathetic nerves of the T3 dermatome and T1 angiosome, is unique and produces a surprising and beneficial technical effect. Thus, in some examples, the one or more activation members are configured to be placed on one or more skin zone(s) of interest.

The one or more skin zone(s) of interest may be innervated by the T1-T5 dermatome(s) and/or angiosomes(s) associated with T1-T5 nerves (e.g., the T1-T5 sympathetic ganglia). In some examples, the one or more skin zone(s) are positioned such that stimulus is transdermally administered to the sympathetic nerves of the Tl-5 dermatome and/or angiosome including the skin territories of the intercostal arteries, circumflex scapular artery, suprascapular artery, acromiothoracic artery, transverse cervical artery and/or internal thoracic artery.

In various examples, the one or more activation members are placed to innervate the sympathetic nerves of the T1 dermatome and/or T1 angiosome.

In various examples, the one or more activation members are placed to innervate the sympathetic nerves of the T2 dermatome and/or T2 angiosome. In one example, the one or more activation members are placed to innervate the intercostobrachial nerve.

In various examples, the one or more activation members are placed to innervate the sympathetic nerves of the T3 dermatome and/or T3 angiosome.

In various examples, the one or more activation members are placed to innervate the sympathetic nerves of the T4 dermatome and/or T4 angiosome.

In various examples, the one or more activation members are placed to innervate the sympathetic nerves of the T5 dermatome and/or T5 angiosome.

In various examples, any combination of two or more of the above are contemplated, such as positioning one or more activation members to innervate the sympathetic nerves of the T5 dermatome and the T1 angiosome, or to innervate the sympathetic nerves of the T3 dermatome and the T2 angiosome, etc.

In the example shown in Figure 1, at least a portion of the one or more skin zones may comprise or correspond to the back and in-between the scapula of the subject, targeting the nerve within the T3 dermatome and/or angiosome. In other words, at least a portion of the one or more skin zones may be positioned at the back and in-between the scapulae of the subject. This may be particularly beneficial in the case of alleviating, treating or preventing bronchoconstriction, as the sympathetic nerves which are positioned along the T3 nerve dermatome correspond with the lower bronchial tree innervation, which is essentially considered the main pathology of bronchoconstriction (e.g., asthmatic bronchoconstriction which occurs at the lower branchial tree). In some examples, the T3 dermatome is positioned at a lateral distance of approximately 5cm from the spine of the subject. The exact reference point for this measurement may be the lower border of the spinous process of the 3^rd thoracic vertebra.

Figure 3 shows another example, where at least a portion of the one or more skin zones alternatively or additionally (to those shown in Figure 1) comprise or correspond to the medial aspect of an arm of the subject, targeting the intercostobrachial nerve within the T2 dermatome. In other words, in this arrangement, the one or more activation members and therefore the stimulus (or at least one stimulation pulse or waveform) may be configured to be positioned and applied to the T2 dermatome on the medial aspect of the arm of the subject in order to modulate the intercostobrachial nerve.

In another example, alternatively or additionally (to those shown in Figure 1), at least a portion of the one or more skin zones (and therefore the one or more activation members) may be configured to be positioned such that the stimulus (or the at least one stimulation pulse or waveform) is configured to be bilaterally applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of each arm of the subject.

The schematics shown in Figures 2 and 4 outline examples of systems and/or devices that may be used for implementing the aforementioned (or similar) methods, according to the present invention.

Modes of Stimulation

In some examples, the stimulus is able to be adjusted by adjusting the duration and/or frequency of at least a portion of the stimulus.

The methods, devices, and systems disclosed herein can offer adjustable settings and/or configurations, allowing for the one or more stimuli to be customized. For example, the intensity, frequency, and/or duration of the stimulation (e.g., electrical impulses) can be modified based on the subject's needs, comfort level and tolerance. Such versatility enables the provision of various modes of operation, such as continuous, burst, or modulation mode, to provide varied patterns of stimulation as required.

In some examples, the activator may be configured to apply electrical stimulation at a frequency between 2Hz to 20kHz. More particularly, the activator may be configured to apply stimulation at a frequency between 10Hz and 200Hz. In some examples, the methods, devices, and systems disclosed herein are configured to alternate between applying two or more different frequencies of stimulation (e.g., electrical stimulation). In an example, the activator is configured to alternate between applying stimulation (e.g., electrical stimulation) at frequencies of 10Hz, 80Hz and 200Hz. In some examples, the methods, devices, and systems disclosed herein are configured to alternate between the two or more different frequencies of stimulation (e.g., electrical stimulation) every two minutes.

Alternatively or in addition to applying two or more frequencies of stimulation, the methods, devices, and systems disclosed herein may be configured to alternate between applying two or more different amplitudes of stimulation (e.g., electrical stimulation). In some examples, the methods, devices, and systems disclosed herein are configured to alternate between the two or more different amplitudes of stimulation (e.g., electrical stimulation) every two minutes.

In certain examples, the stimulus comprises one or more signals having a peak in Fourier space, such as a desired peak in Fourier space resulting from one or more signals having one or more different characteristics. It will be appreciated by those skilled in the art having the benefit of this disclosure that such a signal will have inherent linewidth, and may be the result of signals of different frequencies, periodicities, noise, or the like.

In one example, the stimulus comprises a signal having a selected waveform.

In various examples, the stimulus comprises a signal (such as a signal defined as a waveform or by its Fourier transform) comprising one or more of the following: one or more beat frequencies, one or more DC offsets or biases, a degree of aperiodicity, one or more variable sensitiser pulses, noise, one or more chirped frequency wavetrains, and the like.

In one example, the stimulation comprises one or more pairs of signals, the interference of which results in a peak in Fourier space within the desired frequency range.

In one example, the stimulation comprises a DC-bias, a DC offset, a DC offset field, a variable or varying DC offset field, and/or noise applied directly or indirectly to a DC signal, for example as periodic train sensitisation.

In one example, the stimulation comprises an aperiodic train of pulses or waveforms, for example, the applied train of pulses is aperiodic over at least a part of the applied duration. For example, the stimulation comprises an aperiodic or quasi-periodic train of pulses or waveforms having a random or quasi-random peak-to-peak perturbation, preferably while maintaining average periodicity at l/(target frequency).

By applying/administering stimulation (e.g., electrical stimulation) at different frequencies and/or amplitudes, e.g., with the aid of stimulation time (e.g., minutes) and/or angle-specific effect of specific frequencies, it is possible to increase (and ideally maximise) the capnogram 'alpha' (used to assess the ventilation/perfusion of the lung) and 'beta' (used to assess the extent of rebreathing) angles - see Figure 5. This are useful benchmarks which can be used as targets when assessing the efficacy of methods, devices and systems for alleviating, treating or preventing bronchoconstriction (e.g., by eliciting or promoting bronchodilation).

In some applications, it may be advantageous to allow for the nerves of the subject to be response to lower levels stimulation (e.g., lower levels of current of electrical stimulation). In terms of user experience, this can potentially result in a reduction of the likelihood of habituation and/or the subject building up tolerance to stimulation. Habituation can be undesirable as it may necessitate for higher levels of stimulation to be used, which can be detrimental to the experience for the subject, especially over a long period of time. In order to reduce the likelihood of habituation and/or the subject building up tolerance to stimulation, priming/pre-conditioning the nerves of the subject (e.g., the skin nerves) prior to applying the stimulation may be beneficial.

In some examples, in order to prime/pre-condition the nerves, the activator is configured to apply a direct current to at least one of the one or more activation members, prior to applying the at least one stimulation pulse or waveform. Alternatively or additionally, the system may be configured to provide any one or more of acoustic stimulation, thermal stimulation, mechanical stimulation, photonic stimulation, magnetic stimulation and electrical startle stimulation to the skin zone(s), prior to applying the at least one stimulation pulse or waveform.

Input and feedback mechanisms

In some examples, the application/administering of at least a portion of the stimulus is initiated and/or adjusted based on a determined degree or severity of bronchoconstriction and so the methods, devices, and systems for alleviating, treating, or preventing bronchoconstriction or for eliciting or promoting bronchodilation disclosed herein may comprise or provide for determining a degree or severity of bronchoconstriction from the subject. To achieve this, one or more variable(s) may be used (individually or in combination with each other) as at least a portion of an input and/or feedback mechanism to enhance the suitability of the stimulus for the subject and/or provide a solution that is able to be more tailored and personalised to the subject's needs. By utilising feedback, that includes but is not limited to bronchial response, heart rate/acceleration and/or motion parameters, in real-time, one or more of the stimuli may be tailored/personalised according to a trained algorithm, for example an algorithm trained with the aid of biosignal responses to earlier and/or realtime stimulation periods. Additionally or alternatively, the trained algorithm may utilize previous stimuli (from the same or previous stimulation sessions) and/or prediction algorithms for response forecasting and adjusting the parameters of the one or more stimuli.

In some examples, one or more variables/parameters are required to be determined and/or detected and so one or more sensors may be used for obtaining these variable(s)/parameter(s). In some examples, the devices and systems disclosed herein comprise at least one detector configured to detect bronchoconstriction from the subject. In some examples, the devices and systems disclosed herein are configured to provide an alert upon detection of potential triggers based on current and/or previous data from the at least one detector. Moreover, the methods, devices, and systems (e.g., the determining and/or at least one detector) may comprise or provide for at least one heart rate sensor and/or at least one motion sensor. The at least one heart rate sensor may be configured to detect the occurrence and duration of acceleration and/or deceleration of the heart rate of the subject. The at least one heart rate sensor may comprise at least one wearable sensor, for example an ECG device and/or an accelerometer. Additionally or alternatively, the at least one heart rate sensor comprises at least one non-contact sensor, such as any one or more of infra-red sensor, laser sensor, ultrasound sensor and camera. The at least one motion sensor may be configured to sense a change in the motion parameters and/or the duration of which the change occurs.

In some examples, methods, devices, and systems (e.g., the determining and/or at least one detector) comprise or provide for at least one heart rate sensor and/or at least one motion sensor at least one stretch sensor. In some examples, determining the degree or severity of bronchoconstriction may comprise detecting triggering sounds from the subject.

For example, the expired air (also referred to as "expiration" and "bronchial response") from the subject may be configured to be detected using at least one stretch sensor (e.g., on the outer skin of the subject), and/or the subject's motion parameters may be obtained using at least one motion sensor and/or the subject's heart acceleration/rate may be obtained using at least one heart rate sensor. In some examples, determining a degree or severity of bronchoconstriction comprises tracking and/or storing data associated with the one or more sensors (e.g., of the at least one detector). Thus, in the example provided above, determining a degree or severity of bronchoconstriction may comprise tracking and/or storing data associated with the at least one heart rate sensor; and/or the at least one motion sensor; and/or the at least one stretch sensor.

In various examples, the methods, devices, and systems contemplated herein comprise one or more stretch sensors to sense one or both of the expiration phase and/or the inspiration phase, for example so that expiration phase related wheezing (a signature of bronchoconstriction) can be detected or determined.

In another example, the methods, devices, and systems contemplated herein comprise one or more stretchable ultrasound sensors to detect bronchoconstriction by directly visualising the bronchioles.

In some examples, determining the degree or severity of bronchoconstriction comprises correlating and/or combining the one or more variable(s)/parameter(s). For example, one or more variable(s)/parameter(s) related to any one or more of the triggering sounds, expired air, motion, and heart acceleration/rate of the subject may be correlated and/or combined.

Alternatively or in addition to initiating and/or adjusting at least a portion of the stimulus based on the determined degree or severity of bronchoconstriction, at least a portion of the stimulus can be initiated and/or adjusted manually by the subject or another user. The manual initiation and/or adjustment of the stimulus may comprise the one or more variable(s) being manually entered by the subject or another user. In some examples, such manual entries may override/overrule any variable(s) obtained via the at least one detector. This can be useful in situations where the subject and/or another user experience acute bronchoconstriction that is not or cannot be detected (e.g., by the at least one detector and/or the one or more sensors) and manual intervention is necessary.

Moreover, the subject or another user may enter one or more variable(s) as an input and/or feedback to the system, if required. For example, as well as one or more variables/ parameters of the stimulus, one or more manually entered variable(s) may comprise (but are not limited to) gender, age, weight, height, and any medical conditions that the subject may have.

In some examples, the devices and/or systems disclosed herein may comprise a user interface (UI) that allows the subject or another user to view and/or enter one or more variable(s) as an input and/or feedback to the system, if required.

In some examples, the manual and/or the determined and/or the detected input (e.g., via one or more sensors) from the subject or another user may be provided via a separate device that may be connected to the stimulation system. For example, wearable or non-wearable smart devices (such as mobile phones and smart watches) may be connected to the stimulation system (e.g., via Bluetooth). In such configurations, the separate device may comprise at least a portion of the one or more sensors.

In certain examples, at least a portion of the stimulus can be initiated and/or adjusted on the basis of data relating to the subject, such as tracked and/or stored data relating to the subject. In certain examples, initiating and/or adjusting at least a portion of the stimulus comprises an analysis of data relating to the subject, such as an analysis of tracked and/or stored data obtained in or by a method, device, or system as contemplated herein, or data relating to the subject provided by one or more external determinations or assessments. In one example, initiation and/or adjustment of the stimulus comprises an analysis of tracked and/or stored data relating to the subject in conjunction with the determination of bronchoconstriction, such as the determination of the degree or severity of bronchoconstriction, for example to provide personalised response, alleviation, or the like.

Particularly contemplated applications

The methods, devices, and systems disclosed herein may be incorporated in various applications and arrangements for alleviating, treating, or preventing bronchoconstriction. For example, a medical device for eliciting or promoting bronchodilation can be provided for emergency situations where, for example, the subject/ patient is no longer responding to use of conventional methods of treating bronchoconstriction (e.g., using an inhaler).

Moreover, the medical device can be useful for eliciting or promoting bronchodilation when the subject/ patient is under general anaesthetic in order to alleviate, treat, or prevent bronchoconstriction.

In other examples, a device for eliciting or promoting bronchodilation can be provided for situations including non-medical situations where, for example, a degree of bronchodilation is desired or considered to be of benefit. Particularly contemplated examples include as part of a training session or regimen, such as of an athlete, where bronchodilation (for example to alleviate, treat, or prevent exercise-induced bronchoconstriction) is considered to be of benefit to the subject undergoing or about to undergo such training.

In certain examples, the methods and devices contemplated herein can be useful for eliciting or promoting bronchodilation prior to the training session, during training, or indeed after the training session, as needed or desired.

EXAMPLES

Example 1. Assessment of TENS stimulation of bronchodilation

This example presents an analysis of the effectiveness of transcutaneous electrical nerve stimulation (TENS) in the T-3 dermatome on segmental induction of bronchodilation of the small airways during exercise-induced bronchoconstriction (EIB).

Here, capnography was used to measure bronchoconstriction in endurance-trained athletes, in which EIB is prevalent even without a diagnosis of asthma. This allowed for the immediate identification of any changes in airway activity. Importantly, microstream capnography as used here can monitor activity of the small airways which are most implicated in asthma pathophysiology.

Materials and Methods

Participants

A total of 15 healthy endurance-trained athletes volunteered to participate in this pilot study. Participants were recruited by posters and word of mouth. All participants completed a pre-screening questionnaire for inclusion before each experimental session. The questionnaire covered overall health status, smoking history, caffeine intake, and exercise routine. All participants presented as healthy non-smokers and did not consume any caffeine within two hours of each experimental session. Participants were competitively involved in long-distance running (n = 8), football (n = 3), netball (n = 2), badminton (n = 1), and field hockey (n = 1), at a tertiary level or higher (see Table 1). Exclusion criteria were participants outside of the ages 19 to 39 years and anybody with a history of health conditions pertaining to the cardiovascular system (e.g., stroke, cardiac health issues such as myocardial infarction, hypertension, etc.). All participants gave informed, written consent to participate in the experiment. Ethical approval was obtained.

Table 1. Participant demographics and characteristics

Participants n = 15

Sex: n = male/female (%) 9/6 (60/40 %)

Mean age ± St.d. (years) 21.3 ± 1.72

Ethnicity

Maori n = 2

NZ European n = 7

Asian n = 6 Sport

Long-distance Running n = 8

Football n = 3

Netball n = 2

Badminton n = 1

Field Hockey n = 1

Exercise Challenge

On all three visits, the participants exercised on an off-the-shelf treadmill for eight minutes. The first two minutes were used as a warmup to reach 80 to 90% of maximum heart rate (HR) (220 minus age in years) and the speed was adjusted throughout the remaining six minutes to maintain HR between these limits. HR was monitored using a running watch which was primarily used within the first two minutes to ensure the participant reached the target intensity. Every effort was made to perform the exercise challenge at the same time of day, 72 hours apart for each participant. Transcutaneous Electrical Nerve Stimulation (TENS)

TENS was applied to the participants using electrodes attached to a TENS device with three different parameters; 80Hz, 10Hz, and placebo-TENS (electrodes attached to the skin but no current delivered; participants were instructed that the stimulation was at a sub-threshold amount). Two electrodes were placed bilaterally on the back within the T-3 dermatome (5 cm lateral to the lower border of the T-3 spinous process) immediately after the exercise challenge and the stimulation lasted for six minutes. The cathode was placed on the left side for all participants (as presented in Figure 1). The TENS current was adjusted to obtain a sense of tingling at an intensity that did not exceed the pain threshold. The strength of the TENS (amplitude) was between 9 mA and 13 mA which was strong enough to induce localized muscle twitches surrounding the electrodes. The pulse bandwidth was 175 pS width bipolar square waveform.

Capnography

Microstream capnography was performed with a sampling rate of 20Hz using a nasal cannula connected to a capnograph. Microstream capnography is based on molecular correlation spectroscopy, which results in a highly efficient and selective emission of infrared wavelengths exactly matching for CO2 absorption. Thus, only small samples of CO2 are required to monitor activity of the small airways which are most attributed to asthma pathophysiology.

Participants were instructed to keep their mouth closed during the baseline and stimulation recordings to maximise the accuracy of CO2 readings from the nasal cannula. Capnograph traces were obtained for the entire duration of each experimental session and analysed for changes in a angle, 8 angle, and phase III slope (mmHg/sec) in response to TENS stimulation. Capnograph outputs were processed in MATLAB (R2021b) to obtain individual values for each capnogram parameter. The peaks of each waveform were used to segment out each waveform. The maximum rise and decline gradients were extracted and a line was fit for each of phase II and phase 0, respectively. The plateau slope (phase III) was identified when the gradient was less than 20mmHg/sec and a line was also fit to this gradient. The a and P angles were then calculated between the intersections of these lines (see Figure 6).

Heart Rate Variability

An electrocardiograph (ECG, HRV sampling frequency 1000 Hz, ECG sampling frequency 500-1000 Hz) was used to measure HRV to capture various components of autonomic nervous system (ANS) activity. Time-domain measurements including root mean square of successive differences (RMSSD) and stress index (SI) were analysed. RMSSD is the primary time-domain measurement used to estimate parasympathetic responses reflected in HRV by measuring the successive differences between neighbouring R-R intervals. The SI represents an index of sympathetic activity, calculated by the square root of the Baevsky's SI model. Time-domain measurements were prioritized in this study as they are largely unaffected by respiratory rate. They were analysed in 2-minute segments because this is the minimum time window recommended by the literature for accurate HRV recordings. At the beginning of the experiment, the ECG was placed on the skin below the sternum and secured with a band encircling the torso to ensure for a fixed position. All ECG traces were obtained for the entire duration of each experimental session and analysed in Kubios HRV Premium, Version 3.2.0. Experimental Procedure

All participants were provided with the experimental proceedings and a consent form on the first visit. Participants also completed a pre-screening questionnaire for inclusion before each experimental session. Once the full experimental briefing was completed, the location of electrode placement was identified and marked with permanent marker on the skin. The participant was then fitted with the nasal cannula, running watch, and ECG device to begin the 6-min baseline recording. Participants were instructed to keep their mouth closed and stand on the treadmill as still as possible during the baseline period. After the baseline period, the treadmill was activated, and participants were able to open their mouth and begin the 8-min exercise challenge. Small adjustments in treadmill speed were made by the experimenter within the first 2-mins to achieve the targeted 80 to 90% maximum HR. After the 8-min exercise challenge, participants were instructed to close their mouth immediately upon exercise cessation and TENS electrodes were attached to the T-3 dermatome. Stimulation was performed for 6-mins post-exercise and the participants were required to keep their mouth closed while standing still for the duration of stimulation. At the end of post-exercise stimulation, the nasal cannula, running watch, and ECG device were removed from the participant. The experiment took approximately 30 to 35min to complete (see Figure 7).

Data Analysis

All data analyses were performed using Prism, model 9.4.1., by GraphPad Software Inc. (San

Diego, CA, USA). The number of participants recruited (n = 15) was based on a G-power analysis.

Normality of all data was confirmed using the Shapiro-Wilk correction. Data that did not pass the normality test used the Friedman test as a non-parametric alternative to repeated-measures ANOVA.

Dunn's multiple comparisons test was used to observe significant effects of data found in the Friedman's test.

Capnograph outputs were processed in MATLAB (R2021b) to obtain individual values for each capnogram parameter (see Figure 6). A one-tailed paired t-test was performed to compare mean a and P angles before (last 2-min of baseline) and after (0-2 min of placebo stimulation) the exercise challenge to determine whether the exercise challenge induced bronchoconstriction. Repeated- measures ANOVA was performed to observe changes in mean a angle, p angle, phase III slope (mmHg/sec), SI, and RMSSD across time segments (baseline, 0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation) within each condition (placebo, 10Hz, and 80Hz). Baseline analysis incorporated the last 2 minutes of each baseline recording. One-way ANOVA was also performed to compare absolute changes (from baseline) in a angle, P angle, phase III slope (mmHg/sec), SI, and RMSSD between conditions (placebo, 10Hz, and 80Hz) during each stimulation segment (0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation). Post-hoc Dunnett's tests were used to observe significant effects of data found in the ANOVA.

Results

Capnography

Each participant's results (mean a and P angles) before (last 2-min of baseline) and after (0- 2 min of placebo stimulation) the exercise challenge in the placebo session is presented in Figure 8. There was a significant increase in a angle from baseline to post-exercise (p = 0.0032), and a corresponding significant decrease in p angle from baseline to post-exercise (p < 0.0001). These results indicate that the exercise challenge was successful at inducing EIB. Effects of TENS on Capnogram Angle

The results from RM-ANOVA to observe changes in capnogram angle (a and P) across time segments (baseline, 0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation) within each condition (placebo, 10Hz, and 80Hz) are displayed in Table 2 below.

Table 2. Results from RM-ANOVA of capnogram angles (a and (3) during baseline, 0-2 min, 2- 4 min, and 4-6 min of stimulation within each condition (placebo, 10Hz, and 80Hz).

Reporting means ± standard deviation (st.d.), f-statistic, p-value, and post-hoc. * = p < 0.05; ** = p < 0.01; ***

= p < 0.001.

RM-ANOVA showed a significant difference in a angle across time segments in placebo (p = 0.027) and 10Hz (p = 0.0179) stimulation sessions. Post- hoc tests (Dunnett's test) revealed a significant increase in a angle from baseline to the 0-2 min stimulation period for both placebo (p = 0.0169) and 10Hz (p = 0.0408) stimulation sessions. There were no significant differences in a angle across time during the 80Hz stimulation session. For the b angle, RM-ANOVA showed a significant difference across time for placebo (p = 0.0005), 10Hz (p = 0.0007), and 80Hz (p = 0.0039) stimulation sessions. Post-hoc tests revealed that placebo-TENS significantly decreased the 8 angle from baseline during the 0-2 min (p = 0.0004) and 2-4 min (p = 0.0208) stimulation periods. However, there was only a significant decrease from baseline during the 0-2 min stimulation period for the 10Hz (p = 0.0020) and 80Hz (p = 0.0074) stimulation sessions. Taken together, these results indicate that 80Hz TENS recovered the a angle faster than 10Hz and placebo-TENS because there was no significant difference from baseline during the 0-2 min stimulation period. These results also indicate that 10Hz and 80Hz TENS recovered the 8 angle faster than placebo-TENS because there were no significant differences from baseline during the 2-4 min stimulation period for both frequencies. A differences of differences analysis was incorporated to compare the absolute effects of TENS on capnogram angle (a and 8) between conditions (placebo, 10Hz, and 80Hz) (see Table SI). Each participant's 'difference' value was obtained by subtracting the baseline value from the stimulation value. One-way ANOVA revealed no significant differences in the absolute changes in a angle across all three conditions (placebo, 10Hz, and 80Hz) for each stimulation time segment (0-2 min, 2-4 min, 4-6 min). However, there was a significant difference in the absolute change in 8 angle across conditions (placebo, 10Hz, and 80Hz) during the 2-4 min stimulation period (p = 0.0430). Post-hoc tests revealed that 10Hz TENS produced a significantly smaller absolute change in 8 angle compared to placebo-TENS during the 2-4 min stimulation period (p = 0.0253) (see Figure 9). Effects of TENS on Phase III Slope (Plateau Slope)

The results from RM-ANOVA to observe changes in the phase III slope (mmHg/sec) across time segments (baseline, 0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation) within each condition (placebo, 10Hz, and 80Hz) are displayed in Table 3 below.

Table 3. Results from RM-ANOVA of the phase III slope (mmHg/sec) during baseline, O-2 min, 2-4 min, and 4-6 min of stimulation within each condition (placebo, 10Hz, and 80Hz).

R

RM-ANOVA showed a significant difference in mmHg/sec across time segments in placebo (p = 0.0097), 10Hz (p = 0.0084), and 80Hz (p = 0.0265) stimulation sessions. Post-hoc tests (Dunnett's test) revealed a significant increase in mmHg/sec from baseline to the 0-2 min stimulation period for both placebo (p = 0.0167) and 10Hz (p = 0.0369) stimulation sessions. There were no significant differences in mmHg/sec during any stimulation period compared to baseline for the 80Hz stimulation session. These results indicate that 80Hz TENS recovered the phase III slope during the 0-2 min stimulation period faster than placebo-TENS. Further, a differences of differences analysis was incorporated to compare the absolute effects of TENS on phase III slope between conditions (placebo, 10Hz, and 80Hz) (data not shown). Each participant's 'difference' value was obtained by subtracting the baseline value from the stimulation value. One-way ANOVA revealed a significant difference in the absolute change in phase III slope across conditions during the 2-4 min stimulation period (p = 0.0419). Post-hoc tests revealed that 10Hz TENS produced a significantly smaller absolute change in phase III slope compared to placebo-TENS during the 2-4 min stimulation period (p = 0.0241) (see Figure 10).

Effects of TENS on HRV Time-Domain Parameters

The results from RM-ANOVA to observe changes in HRV time-domain parameters (SI and RMSSD) across time segments (baseline, 0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation) within each condition (placebo, 10Hz, and 80Hz) were recorded (data not shown). RM- ANOVA showed significant differences in SI across time for placebo (p = 0.0006), 10Hz (p = 0.0061), and 80Hz (p = 0.0010) stimulation sessions. Post- hoc tests (Dunnett's test) revealed significant increases in SI during all stimulation segments compared to baseline for all conditions. For RMSSD, Friedman's test showed significant differences across time for placebo (p = 0.0022) and 80Hz (p = 0.0006) stimulation sessions. Post-hoc tests (Dunn's test) revealed that placebo and 80Hz stimulation significantly decreased RMSSD during all stimulation segments compared to baseline. There were no significant differences in RMSSD across all stimulation segments for the 10Hz stimulation session. A differences of differences (from baseline) analysis was incorporated to compare the absolute effects of TENS on SI and RMSSD between conditions (placebo, 10Hz, and 80Hz, data not shown). Each participant's 'difference' value was obtained by subtracting the baseline value from the stimulation value. One-way ANOVA revealed a significant difference in the absolute change in RMSSD across conditions during the 0-2 min (p = 0.0185) and 2-4 min (p = 0.0452) stimulation periods. Post-hoc tests revealed that 10Hz TENS produced a significantly smaller absolute change in RMSSD compared to placebo-TENS during the 0-2 min stimulation period (p = 0.0175) (see Figure 11). There were no significant differences in the absolute change in RMSSD between any condition during the 2-4 min stimulation period. For the SI, there were no significant differences in the absolute changes between all conditions (see Figure 12).

Discussion

The results reported in this Example demonstrated that the exercise challenge was successful at inducing bronchoconstriction with a significant increase in a angle (p = 0.0032) and significant decrease in 8 angle (p < 0.0001) from baseline to post-exercise in the placebo session (see Figure 8). 80Hz TENS in the T-3 dermatome recovered the a angle during the 0-2 min stimulation period, and the 8 angle during the 2-4 min stimulation period faster than placebo-TENS post-exercise (see Table 2). Additionally, 80Hz TENS recovered the phase III slope during the 0-2 min stimulation period faster than placebo-TENS (see Table 3).

This study supports the inventors' view that 80Hz TENS in the T-3 dermatome can induce bronchodilation of the small airways by decreasing the a angle, increasing the P angle, and decreasing the phase III slope in the face of bronchoconstriction.

In addition, 10Hz TENS recovered the P angle during the 2-4 min stimulation period faster than placebo-TENS (see Table 2). With incorporation of a differences of differences analysis, 10Hz TENS showed significantly smaller absolute changes in p angle (p = 0.025, post-hoc) and phase III slope (p = 0.024, post-hoc) compared to placebo-TENS during the 2-4 min stimulation period (see Figures 11 and 12).

Thus, the present findings also support the inventors' view that 10Hz TENS is effective for modulating the small airways.

Based on the primary HRV analysis reported here the inventors believe, without wishing to be bound by any theory, that 80Hz TENS did not systemically modulate the ANS because the differences in SI and RMSSD across time were the same for both 80Hz and placebo-TENS. Further, and again without wishing to be bound by any theory, the inventors believe that 10Hz TENS modulated the PNS in a systemic manner to overcome suppression in response to the exercise challenge.

To establish whether the bronchial responses to TENS were mediated segmentally or systemically two approaches were undertaken. First, to establish whether the absolute changes in SI were more prominent in response to TENS compared to placebo-TENS, which in turn could explain the bronchodilatory responses observed with TENS. Second, to establish whether the 10Hz effect on the 8 angle and phase III slope could be explained by the systemic modulation of the PNS.

Differences of differences analyses were incorporated to compare the absolute changes in SI and RMSSD between conditions (placebo, 10Hz, and 80Hz).

Firstly, there were no significant differences in the absolute changes in SI between each condition. This indicates that the sympathetic response post-exercise occurred to the same extent for 10Hz, 80Hz, and placebo-TENS. Thus, bronchodilation in response to TENS cannot be explained by a systemic modulation of the SNS. Conversely, 10Hz TENS produced a significantly smaller absolute change in RMSSD compared to placebo-TENS during the 0-2 min stimulation period (p = 0.0175, post-hoc) (see Figure 11). This systemic modulation of parasympathetic activity did not correspond with bronchial responses observed with 10Hz TENS during the 2-4 min stimulation period.

Conclusion

In summary, this work demonstrated that TENS in the T-3 dermatome induced bronchodilation of the small airways during EIB. Microstream capnography was used to establish the capability of TENS to modulate the small airways for the therapeutic benefit of subjects such as asthmatic patients. Specifically, 80Hz TENS showed faster recovery of the a angle, 3 angle, and phase III slope in the face of EIB compared to placebo-TENS when analysed for changes within conditions. Modulating three aspects of the capnogram waveform is promising and ensures that these changes were not due to chance. In addition, 10Hz TENS showed significant improvements in the 3 angle and phase III slope compared to placebo-TENS when compared for absolute changes between conditions. The incorporation of HRV measurements indicated that 10Hz TENS systemically modulated the PNS. Conversely, 80Hz TENS did not systemically modulate the ANS, indicating that bronchodilation was achieved in a localised, segmental manner. This is a highly desirable outcome for clinical application.

These data support the inventors' view that localised, segmental stimulation of bronchodilation via the easily accessible, non-invasive, wearable and readily automated devices as contemplated herein, such as the particularly contemplated devices deployed to stimulate the T-3 dermatome, upon detection of bronchoconstriction is highly effective to improve alveolar ventilation, for example during an asthma attack.

Example 2. Assessment of TENS stimulation of bronchodilation

As above, capnography was used to measure bronchoconstriction in endurance-trained athletes, in which EIB is prevalent even without a diagnosis of asthma.

Materials and Methods

Participants and methodology was as described in Example 1 above, except that in this Example, TENS was applied to the participants using electrodes attached to a TENS device with three different parameters, being 120Hz, 200Hz, and placebo-TENS (electrodes attached to the skin but no current delivered; participants were instructed that the stimulation was at a sub-threshold amount). Results

Capnography

Each participant's results (mean a and 8 angles) before (last 2-min of baseline) and after (0-

2 min of placebo stimulation) the exercise challenge in the placebo session is presented in Figure 13.

There was a significant increase in a angle from baseline to post-exercise (p < 0.0001), and a corresponding significant decrease in p angle from baseline to post-exercise (p < 0.0001). These results indicate that the exercise challenge was successful at inducing EIB.

Effects of TENS on Capnogram Angle

The results from RM-ANOVA to observe changes in capnogram angle (a and (3) across time segments (baseline, 0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation) within each condition (placebo, 120Hz, and 200Hz) also indicate a significant increase in a angle from baseline to post-exercise (p = 0.0002, post-hoc) and a significant decrease in p angle from baseline to postexercise (p < 0.0001, post-hoc) in the placebo session (data not shown). Absolute Effects of TENS on Capnogram Angle Between Conditions (T-3; 120Hz and 200Hz)

A differences of differences (from baseline) analysis was incorporated to compare the absolute effects of TENS on capnogram angle (a and P) between conditions (placebo, 120 Hz, and 200 Hz) (see Table 4). Each participant's 'difference' value was obtained by subtracting the baseline value from the stimulation value. One-way ANOVA showed a significant difference in a angle across conditions during the 0-2 min (p = 0.0081) and 2-4 min (p = 0.0241) stimulation periods. Post-hoc tests (Dunnett's test) revealed that 200 Hz TENS produced a significantly smaller absolute change in a angle compared to placebo-TENS during the 0-2 min (p = 0.0048) and 2-4 min (p = 0.0160) stimulation periods (data not shown). 200 Hz TENS showed a negative absolute change in a angle during the 2-4 min stimulation period with a mean (± st.d.) of -0.605 ± 3.047, suggesting an improvement compared to baseline conditions (data not shown). For the P angle, one-way ANOVA showed a significant difference across conditions during the 0-2 min (p = 0.0350) and 2-4 min (p = 0.0098) stimulation periods. Post- hoc tests revealed that 200 Hz TENS produced a significantly smaller absolute change in p angle compared to placebo-TENS during the 0-2 min (p = 0.0288) and 2-4 min (p = 0.0126) stimulation periods (data not shown). Corresponding with the a angle results, 200 Hz TENS showed a positive absolute change in p angle during the 2-4 min stimulation period with a mean (± st.d.) of 0.037 ± 2.572, suggesting an improvement compared to baseline conditions (data not shown).

Table 4. One-way ANOVA to compare the absolute effects of TENS on capnogram angle between conditions (placebo, 120 Hz, and 200 Hz).

The means in Table 4 above represent differences from baseline measurements (baseline value subtracted from stimulation value). Reporting means ± standard deviation (st.d.), f-statistic, p-value, and post-hoc. *; p < 0.05, **; p < 0.01.

Conclusion

In summary, this work demonstrated that TENS in the T-3 dermatome induced bronchodilation of the small airways during EIB. Microstream capnography was used to establish the capability of TENS to modulate the small airways for the therapeutic benefit of subjects such as asthmatic patients. Specifically, 120Hz TENS showed faster recovery of the a angle and P angle in the face of EIB compared to placebo-TENS when analysed for changes within conditions. In addition, 200Hz TENS showed significant improvements in the a angle and the P angle compared to placebo- TENS when compared for absolute changes between conditions. These are highly desirable outcomes for clinical application.

Example 3. Assessment of TENS stimulation of bronchodilation

This example presents an analysis of the effectiveness of transcutaneous electrical nerve stimulation (TENS) in the T-2 dermatome on segmental induction of bronchodilation of the small airways during exercise-induced bronchoconstriction (EIB).

Materials and Methods

Participants and methodology was as described in Example 1 above, except that in this Example, TENS was applied to the participants using electrodes placed at the T-2 dermatome and attached to a TENS device with three different parameters, being 10Hz, 80Hz, and placebo-TENS (electrodes attached to the skin but no current delivered; participants were instructed that the stimulation was at a sub-threshold amount).

Results

Capnography

Each participant's results (mean a and 3 angles) before (last 2-min of baseline) and after (0-

2 min of placebo stimulation) the exercise challenge in the placebo session is presented in Figure 14.

Effects of TENS on Capnogram Angle

The results from RM-ANOVA to observe changes in capnogram angle (a and P) across time segments (baseline, 0-2 min stimulation, 2-4 min stimulation, and 4-6 min stimulation) within each condition (placebo, 10Hz, and 80Hz) also indicate a significant increase in a angle from baseline to post-exercise (p = 0.0004, post-hoc) and a significant decrease in p angle from baseline to postexercise (p < 0.0001, post-hoc) in the placebo session (data not shown).

Absolute Effects of TENS on Capnogram Angle Between Conditions (T-2; 10Hz and 80Hz).

A differences of differences (from baseline) analysis was incorporated to compare the absolute effects of TENS on capnogram angle (a and P) between conditions (placebo, 10 Hz, and 80 Hz) (see Table 5). Each participant's 'difference' value was obtained by subtracting the baseline value from the stimulation value. One-way ANOVA showed no differences in a angle or p angle during any stimulation period across all conditions. However, post-hoc tests (Dunnett's test) revealed that 80 Hz TENS produced a significantly smaller absolute change in p angle compared to placebo-TENS during the 2-4 min p = 0.0369) and 4-6 min p = 0.0377) stimulation periods (data not shown). 80 Hz TENS showed a positive absolute change in p angle during the 2-4 min stimulation period with a mean (± st.d.) of 0.416 ± 1.912, and during the 4-6 min stimulation period with a mean (± st.d.) of 0.370 ± 1.585, suggesting an improvement compared to baseline conditions.

Table 5. One-way ANOVA to compare the absolute effects of TENS on capnogram angle (a and P) between conditions (placebo, 10 Hz, and 80 Hz).

The means in Table 5 above represent differences from baseline measurements (baseline value subtracted from stimulation value). Reporting means ± standard deviation (st.d.), f-statistic, p-value, and post-hoc. *; p < 0.05.

Conclusion

The data presented in this Example demonstrated that TENS in the T-2 dermatome induced bronchodilation of the small airways during EIB. Specifically, 80 Hz TENS produced a significantly smaller absolute change in p angle in the face of EIB compared to placebo-TENS. These data support the inventors' view that localised, segmental stimulation of bronchodilation via the easily accessible, non-invasive, wearable and readily automated devices as contemplated herein, such as the particularly contemplated devices deployed to stimulate the T-2 dermatome, upon detection of bronchoconstriction is highly effective to improve alveolar ventilation, for example during an asthma attack.

Example 4. Meta-analysis of TENS stimulation of bronchodilation

This example presents a meta-analysis of the effectiveness of transcutaneous electrical nerve stimulation (TENS) described in Examples 1 to 3 above.

Results

Meta-analysis of absolute Effects of TENS on Capnogram parameters.

The results presented in Examples 1 to 3 above suggest that different frequencies of TENS in different (or the same) dermatomes can significantly improve the same capnogram parameters within the same stimulation time segments. This analysis investigates whether one or more of the exemplified interventions are superior to one another when compared by their respective significant absolute effects in a particular situation.

The following analyses incorporate data from the investigation of the effects of 10 Hz and 80 Hz TENS in the T-3 dermatome to provide a comprehensive understanding of the efficacy of particular combinations of frequencies and/or target dermatomes at improving capnogram parameters during EIB. Table 6 below displays the magnitude of absolute change from placebo for each capnogram parameter (a angle, 8 angle, and phase III slope) during each stimulation period (0-2 min, 2-4 min, and 4-6 min) for all investigated conditions to date. Each data point represents the mean absolute placebo value subtracted from the mean absolute stimulation value. The significant absolute effects are displayed (in bold text) to identify which capnogram parameters were significantly improved by multiple interventions during the same stimulation period.

In this context, the data presented in Table 6 indicates that the absolute effect of TENS on p angle was significantly improved by 10 Hz (T-3), 200 Hz (T-3) and 80 Hz (T-2) during the 2-4 min stimulation period compared to placebo-TENS. In addition, the absolute effect of TENS on phase III slope was significantly improved by 10 Hz (T-3) and 200 Hz (T-3) during the 2-4 min stimulation period compared to placebo-TENS.

Two additional statistical analyses were then performed. Firstly, an unpaired one-way ANOVA was used to compare the significant absolute effects of 10 Hz (T-3), 200 Hz (T-3), and 80 Hz (T-2) on P angle during the 2-4 min stimulation period to identify whether any of these interventions were superior for this aspect. Secondly, a two-tailed unpaired t-test was used to compare the significant absolute effects of 10 Hz (T-3) and 200 Hz (T-3) on phase III slope during the 2-4 min stimulation period to identify whether any of these interventions were superior for this aspect.

One-way ANOVA and post-hoc tests (Tukey's test) revealed no significant differences between the significant absolute effects on p angle for any condition (data not shown). The unpaired t-test showed no significant difference between the significant absolute effects on phase III slope for either condition (data not shown).

These results suggest that each of the 10 Hz (T-3), 200 Hz (T-3), and 80 Hz (T-2) interventions were potentially equally effective. Notably, 200 Hz (T-3) showed significant absolute effects on all capnogram parameters (a angle, 8 angle, and phase III slope) during the 0-2 min and 2- 4 min stimulation periods (see Table 6). In comparison, 10 Hz (T-3) showed significant absolute effects on the 8 angle and phase III slope during the 2-4 min stimulation period, and 80 Hz (T-2) showed a significant absolute effect on the 8 angle during the 2-4 min and 4-6 min stimulation periods. This analysis indicates that in these cohorts, 200 Hz (T-3) was fastest at inducing bronchodilation in the face of EIB when observed on a group level of analysis.

It is important note that for all interventions tested, the magnitude of absolute change from placebo was in the direction of improvement for every capnogram parameter during every stimulation period. For instance, every value for a angle and phase III slope displayed in Table 6 has a negative direction of magnitude, suggesting that all interventions were able to decrease, and thus, improve the a angle and phase III slope in the face of EIB. In addition, every value for the 8 angle has a positive direction of magnitude (except for 120 Hz at 4-6 mins: -0.2), suggesting that all interventions were able to increase, and thus, improve the 8 angle in the face of EIB.

Table 6. Magnitude of absolute effects of TENS on capnogram parameters across all conditions.

Note: Bold values represent the statistically significant absolute changes compared to placebo found in one-way ANOVA analyses. DD; differences of differences.

Each data point represents the mean absolute placebo value subtracted from the mean absolute stimulation value. *; p < 0.05, **; p < 0.01.

These data support the inventors' view that localised, segmental stimulation of bronchodilation via the easily accessible, non-invasive, wearable and readily automated devices as contemplated herein, such as the particularly contemplated devices deployed to stimulate the T-2 and/or T3 dermatome, upon detection of bronchoconstriction is highly effective to improve alveolar ventilation, for example during an asthma attack or at onset of exercise-induced bronchoconstriction.

Example 5. Comparison of bronchodilatory treatments

This example presents a comparison of the effectiveness of transcutaneous electrical nerve stimulation (TENS) as described in Examples 1 to 3 above compared to treatment with the bronchodilator salbutamol.

Exercise-induced bronchoconstriction (EIB) is a common issue in asthmatic patients, characterized by a temporary narrowing of the airways following exercise. Various bronchodilator interventions, including Salbutamol and other stimulations, are used to alleviate this condition. Spirometer-based FEV1: Forced Expiratory Volume in one second is a measure of how much air a person can forcibly exhale in one second. It is a key indicator of lung function and is often used to diagnose and monitor asthma. Higher FEV1 values indicate better lung function, while lower FEV1 values suggest airway obstruction or bronchoconstriction.

The LaForce et al., (2022) study provided specific baseline FEV1 values and percentage changes at the maximum effect time post-exercise for patients receiving Salbutamol. These data points were used to calculate the absolute improvement in FEV1 in comparison to placebo effects and subsequently convert this improvement to changes in the Phase-III slope (a capnography output parameter) using the correlation established by You et al., (1994). The Phase-III slope of the capnogram represents the alveolar plateau, reflecting the uniformity of gas exchange in the lungs. A steeper Phase-III slope indicates more uneven ventilation, often due to airway obstruction or bronchoconstriction.

Results

The LaForce et al., (2022) study provides key data on the mean baseline FEVl(Forced Expiration Volume 1) and the percentage change in FEV1 at the 5th minute post-exercise following Salbutamol administration and placebo. Using the correlation slope of 0.9 from You et al. (1994): 5^TH minute APhase-III Slope(differences of Salbutamol based improvement in comparison to the improvements in placebo) =0.3 mmHg/sec.

At 4-6 minutes post-exercise, different types of stimulations described herein (for example, the data presented in Examples 1 - 4 above) showed the following effects compared to placebo: arm stimulation at 10Hz showed a change of 0.4, thorax stimulation at 200Hz showed a change of 0.3, thorax stimulation at 10Hz showed a change of 0.3, and thorax stimulation at 80Hz showed a change of 0.4. These results indicate that various stimulation settings can achieve clinically relevant improvements in airway function, comparable to the effects reported for Salbutamol (0.3).

LaForce C, Chipps BE, Albers FC, et al. Albuterol/budesonide for the treatment of exercise-induced bronchoconstriction in patients with asthma: The TYREE study." Ann Allergy Asthma Immunol. 2022 Feb;128(2) : 169-177. You B, Peslin R, Duvivier C, Vu VD, Grilliat JP. "Expiratory capnography in asthma: evaluation of various shape indices." European Respiratory Journal, 7(2) : 318-323, 1994.

It should be noted that various changes and modifications to the presently preferred examples described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be included within the present invention.

The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features.

Aspects of the invention have been described by way of example only, and it should be appreciated that variations, modifications and additions may be made without departing from the scope of the invention, for example when present the invention as defined in the indicative claims. Furthermore, where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred in this specification.

Numbered paragraphs with particularly contemplated examples

1. A method of alleviating or preventing bronchoconstriction in a subject (including a subject in need thereof) comprising administering transdermally to the subject a stimulus to one or more of the subject's T1-T5 nerve dermatome(s) and/or angiosome(s).

2. A method of promoting bronchodilation in a subject (including a subject in need thereof), the method comprising administering transdermally to the subject a stimulus to one Por more of the subject's T1-T5 nerve dermatome(s) and/or angiosome(s).

3. A method of alleviating, treating, or preventing bronchoconstriction or of eliciting or promoting bronchodilation in a subject (including a subject in need thereof), comprising administering transdermally to the subject a stimulus to one or more skin zones that are innervated by the T1-T5 dermatome(s) and/or angiosomes(s), such that the T1-T5 nerves are activated.

4. The method of any one of the preceding numbered paragraphs, wherein the stimulus is transdermally administered to the T2 and/or T3 nerve dermatome(s) and/or corresponding angiosome(s).

5. The method of any one of the preceding numbered paragraphs, wherein the stimulus is transdermally administered to modulate the T2 and/or T3 nerve activity or function.

6. A method of alleviating, treating, or preventing bronchoconstriction in a subject (including a subject in need thereof) comprising administering transdermally to the subject a stimulus to modulate the T1-T5 nerve activity or function.

7. The method of any one of the preceding numbered paragraphs, wherein the stimulus comprises or consists of an electrical stimulation.

8. The method of any one of the preceding numbered paragraphs, wherein the stimulus comprises or consists of at least one electrical stimulation pulse or waveform. 9. The method of any one of numbered paragraphs 1 to 8, wherein the stimulus comprises magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s), photonic stimulation signal(s), and/or thermal stimulation signal(s).

10. The method of any one of numbered paragraphs 7 to 9, further comprising alternating anode and cathode configurations of the stimulation, after one or more cycle(s) of stimulation.

11. The method of numbered paragraph 10, wherein alternating the anode and cathode configurations alters the direction of the electrical field being produced.

12. The method of any one of the preceding numbered paragraphs, comprising determining a degree or severity of bronchoconstriction from the subject and initiating and/or adjusting at least a portion of the stimulus based on the determined degree or severity of bronchoconstriction.

13. The method of numbered paragraph 12, wherein adjusting the stimulus comprises adjusting the duration and/or frequency of at least a portion of the stimulus.

14. The method of numbered paragraph 12 or 13, wherein determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and/or expired air from the subject.

15. The method of numbered paragraph 12 or 13, wherein determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and/or expired air from the subject and correlating the detected triggering sounds with the detected expiration and/or the determined degree or severity of bronchoconstriction.

16. The method of any one of numbered paragraphs 12 to 15, wherein determining the degree or severity of bronchoconstriction comprises detecting any one or more of expiration, the subject's motion parameters and the subject's heart rate or acceleration.

17. The method of any one of numbered paragraphs 14 to 16, wherein expiration and/or the expired air from the subject is configured to be detected using at least one stretch sensor on the outer skin of the subject.

18. The method of any one of numbered paragraphs 12 to 17, wherein determining a degree or severity of bronchoconstriction comprises tracking and/or storing data associated with: at least one heart rate sensor; and/or at least one motion sensor; and/or at least one stretch sensor.

19. The method of numbered paragraph 3 or any one of numbered paragraphs 4 to 18 when dependent on numbered paragraph 3, wherein at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapulae of the subject, for example to innervate the sympathetic nerves within the T3 dermatome and/or angiosome.

20. The method of numbered paragraph 3 or any one of numbered paragraphs 4 to 19 when dependent on numbered paragraph 3, wherein at least a portion of the one or more skin zones comprises the medial aspect of at least one arm of the subject, targeting the intercostobrachial nerve within the T2 dermatome.

21. The method of numbered paragraph 3 or any one of numbered paragraphs 4 to 19 when dependent on numbered paragraph 3, wherein at least a portion of the one or more skin zones comprise or correspond to the medial aspect of each arm of the subject, bilaterally targeting the intercostobrachial nerve within the T2 dermatome.

22. A method of alleviating, treating, or preventing bronchoconstriction and/or promoting bronchodilation in a chordate subject, comprising transdermally administering stimulation to dermatomes and/or angiosomes of the subject such that nerve endings associated with the TITS sympathetic ganglions are stimulated and bronchial constriction is at least partially alleviated and/or prevented.

23. A method of alleviating, treating, or preventing bronchoconstriction and/or promoting bronchodilation in a chordate subject, comprising transdermally administering stimulation to dermatomes and/or angiosomes of the subject such that the T1-T5 nerves are indirectly modulated, and bronchial constriction of the subject is reduced.

24. The method of numbered paragraph 22 or 23, wherein the stimulation is transdermally administered to the T3 nerve dermatome and/or angiosome.

25. The method of any one of numbered paragraphs 22 to 24, wherein the stimulation comprises or consists of an electrical stimulation.

26. The method of any one of numbered paragraphs 22 to 24, wherein the stimulation comprises or consist of at least one electrical stimulation pulse or waveform.

27. The method of any one of numbered paragraphs 24 to 26, wherein the stimulation comprises any one or more of magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s) and/or thermal stimulation signal(s).

28. The method of any one of numbered paragraphs 22 to 27, further comprising alternating anode and cathode configurations after one or more cycle(s) of stimulation.

29. The method of numbered paragraph 28, wherein alternating the anode and cathode configurations alters the direction of the electrical field being produced.

30. The method of any one of the preceding numbered paragraphs, comprising determining a degree or severity of bronchoconstriction from the subject and initiating and/or adjusting the stimulation based on the determined degree or severity of bronchoconstriction.

31. The method of numbered paragraph 30, wherein adjusting the stimulation comprises adjusting the duration and/or frequency of at least a portion of the stimulation.

32. The method of numbered paragraph 30 or 31, wherein determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and/or expired air from the subject.

33. The method of numbered paragraph 30 or 31, wherein determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and expired air from the subject and correlating the detected triggering sounds with the detected expiration and/or the determined degree or severity of bronchoconstriction.

34. The method of any one of numbered paragraphs 30 to 33, wherein determining the degree or severity of bronchoconstriction comprises detecting any one or more of expiration, the subject's motion parameters and the subject's heart rate.

35. The method of any one of numbered paragraphs 32 to 34, wherein the expiration and/or expired air from the subject is configured to be detected using at least one stretch sensor on the outer skin of the subject. 36. The method of any one of numbered paragraphs 30 to 35, wherein determining a degree or severity of bronchoconstriction comprises tracking and/or storing data associated with: at least one heart rate sensor; and/or at least one motion sensor; and/or at least one stretch sensor.

37. The method of any one of numbered paragraphs 22 to 36, wherein at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapulae of the subject, targeting the nerve within the T3 dermatome.

38. The method of any one of numbered paragraphs 22 to 37, wherein at least a portion of the one or more skin zones comprise or correspond to the medial aspect of an arm of the subject, targeting the intercostobrachial nerve within the T2 dermatome.

39. The method of any one of numbered paragraphs 22 to 37, wherein at least a portion of the one or more skin zones comprise or correspond to the medial aspect of each arm of the subject, bilaterally targeting the intercostobrachial nerve within the T2 dermatome.

40. A method of treating or preventing bronchoconstriction in a subject (including a subject in need thereof) comprising: placing one or more activation members in contact with an outer skin surface of the subject; applying at least one stimulation pulse or waveform to at least one of the one or more activation members, wherein the at least one stimulation pulse is configured to activate the T1-T5 nerves of the subject, such that bronchial constriction of the subject is reduced or prevented.

41. A system for alleviating, treating, or preventing bronchoconstriction in a subject that is configured to perform the methods according to any one of the preceding numbered paragraphs.

42. A system for alleviating, treating, or preventing bronchoconstriction and/or promoting bronchodilation in a subject, the system comprising: an activator comprising one or more activation members configured to be placed on the outer skin of the subject, the activator being configured to apply at least one stimulation pulse to at least one of the one or more activation members; and at least one detector configured to detect bronchoconstriction from the subject, wherein: the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T1-T5 dermatome(s) and/or angiosomes(s) associated with T1-T5 sympathetic ganglions, in use; and application of the at least one stimulation pulse is initiated or adjusted based on bronchoconstriction being detected by the at least one detector.

43. The system of numbered paragraph 42, wherein the activator comprises an electro-stimulator.

44. The system of numbered paragraph 42 or 43, wherein the one or more activation members comprise electrodes.

45. The system of any one of numbered paragraphs 42 to 44, wherein at least a portion of the skin zones are positioned at the back and in-between the scapulae of the subject. 46. The system of any one of numbered paragraphs 42 to 45, wherein the activator is configured to apply stimulation at a frequency between 2 Hz to 20 kHz and/or to apply a stimulation the Fourier transform of which includes one or more peak frequencies between 2Hz and 20kHz.

47. The system of numbered paragraph 46, wherein the activator is configured to apply stimulation at a frequency between 10 Hz and 200 Hz and/or to apply a stimulation the Fourier transform of which includes one or more peak or notable frequencies between 10 Hz and 200 Hz.

48. The system of any one of numbered paragraphs 42 to 47, wherein the activator is configured to alternate between applying two or more different stimulation frequencies, and/or is configured to apply two or more stimulations, one or more of the Fourier transforms of which contains one or more peak or notable frequencies within a range of between 2 Hz and 20 kHz, and/or is configured to apply a poly-tone stimulus containing at least one fundamental or beat frequency or the Fourier transform of which has one or more peak or notable frequencies within a range of between 2 Hz and 20 kHz.

49. The system of numbered paragraph 48, wherein the activator is configured to alternate between applying stimulation at frequencies of 10Hz, 80Hz and 200Hz.

50. The system of numbered paragraph 48 or 49, wherein the activator is configured to alternate between the two or more different stimulation frequencies every two minutes.

51. The system of any one of numbered paragraphs 42 to 50, wherein the activator is configured to apply a direct current to at least one of the one or more activation members, prior to applying the at least one stimulation pulse or waveform.

52. The system of any one of numbered paragraphs 42 to 51, wherein the system is configured to provide any one or more of acoustic stimulation, thermal stimulation, mechanical stimulation, photonic stimulation, magnetic stimulation, ultrasonic stimulation, and electrical startle stimulation to the skin zone(s), prior to applying the at least one stimulation pulse or waveform.

53. The system of any one of numbered paragraphs 42 to 52, wherein the at least one detector comprises at least one heart rate sensor and/or at least one motion sensor.

54. The system of numbered paragraph 53, wherein the at least one heart rate sensor is configured to detect the occurrence and duration of acceleration and/or deceleration of the heart rate of the subject.

55. The system of numbered paragraph 53 or 54, wherein the at least one heart rate sensor comprises at least one wearable sensor.

56. The system of numbered paragraph 55, wherein the at least one wearable sensor comprises an ECG device and/or an accelerometer.

57. The system of any one of numbered paragraphs 53 to 56, wherein the at least one heart rate sensor comprises at least one non-contact sensor.

58. The system of numbered paragraph 57, wherein the at least one non-contact sensor comprises any one or more of: infra-red sensor, laser sensor, ultrasound sensor and camera.

59. The system of any one of numbered paragraphs 53 to 58, wherein the at least one motion sensor is configured to sense a change in motion and/or the duration over which the change occurs. 60. The system of any one of numbered paragraphs 42 to 59, wherein the at least one detector comprises at least one stretch sensor.

61. The system of any one of the numbered paragraphs 42 to 60, wherein the system is configured to track and/or store and/or analyse data from the at least one detector or data relating to the subject.

62. The system of numbered paragraph 61, wherein the data being tracked and/or stored comprises data from any one or more of: the at least one heart rate sensor; the at least one motion sensor; and the at least one stretch sensor.

63. The system of any one of numbered paragraphs 42 to 62, wherein the system is configured to provide an alert upon detection of potential triggers based on previous data from the at least one detector.

64. The system of any one of numbered paragraphs 42 to 63, wherein at least a portion of the one or more activation members are configured to be positioned on the back and in-between the scapulae of the subject, targeting the nerve within the T3 dermatome and/or angiosome.

65. The system of any one of numbered paragraphs 42 to 64, wherein at least a portion of the one or more activation members are configured to be positioned such that the at least one stimulation pulse is configured to be applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of the arm of the subject.

66. The system of any one of numbered paragraphs 42 to 64, wherein at least a portion of the one or more activation members are configured to be positioned such that the at least one stimulation pulse pr waveform is configured to be bilaterally applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of each arm of the subject.

67. The system of any one of numbered paragraphs 42 to 66, wherein the activator comprises two or more activation members.

68. The system of numbered paragraph 67, wherein the at least one stimulation pulse is configured to be applied to the two or more activation members interchangeably.

69. The system of numbered paragraph 67 or 68, wherein the two or more activation members are positioned in multiple different locations on the subject.

70. The system of numbered paragraph 69, wherein the multiple different locations on the subject comprise the right arm, left arm and/or the back of the thorax.

71. The system of any one of numbered paragraphs 42 to 70, wherein the at least one stimulation pulse comprises at least one electrical stimulation pulse.

72. The system of numbered paragraph 71, wherein the anode and cathode configuration of the at least one stimulation pulse is configured to alternate after one or more cycle(s) of stimulation.

73. The system of numbered paragraph 72, wherein the alternating anode and cathode configurations alters the direction of the electrical field being produced.

74. The system of any one of numbered paragraphs 42 to 73, wherein the at least one stimulation pulse comprises magnetic stimulation signal(s), ultrasound stimulation signal(s), photonic stimulation signal(s), vibrational stimulation signal(s) and/or thermal stimulation signal(s). The system of any one of numbered paragraphs 42 to 74, wherein the activator is configured to initiate or adjust the duration and/or frequency of at least a portion of the at least one stimulation pulse, based on data received from the at least one detector. The method or system of any one of the preceding numbered paragraphs, wherein the subject is suffering from or is predisposed to asthma. The method or system of any one of numbered paragraphs 1 to 75, wherein the subject is suffering from exercise-induced bronchoconstriction. The method or system of any one of the preceding numbered paragraphs, wherein the subject seeks to avoid or mitigate exercise-induced bronchoconstriction or seeks to promote bronchodilation. The method or system of numbered paragraph 78 wherein the subject is an athlete.

Claims

1. A method of alleviating or preventing bronchoconstriction or promoting bronchodilation in a subject (including a subject in need thereof) comprising administering transdermally to the subject a stimulus to one or more of the subject's T1-T5 nerve dermatome(s) and/or angiosome(s).

2. A method of alleviating, treating, or preventing bronchoconstriction in a subject (including a subject in need thereof) comprising administering transdermally to the subject a stimulus to modulate the T1-T5 nerve activity or function.

3. A method of alleviating, treating, or preventing bronchoconstriction and/or promoting bronchodilation in a chordate subject, comprising transdermally administering stimulation to dermatomes and/or angiosomes of the subject such that nerve endings associated with the TITS sympathetic ganglions are stimulated and/or the T1-T5 nerves are indirectly modulated, and bronchial constriction of the subject is at least partially alleviated and/or prevented.

4. The method of any one of the preceding claims, wherein the stimulus is transdermally administered to the T2 and/or T3 nerve dermatome(s) and/or corresponding angiosome(s) and/or to modulate the T2 and/or T3 nerve activity or function.

5. The method of any one of the preceding claims, wherein the stimulus comprises or consists of an electrical stimulation, and/or the stimulus comprises magnetic stimulation signal(s), ultrasound stimulation signal(s), vibrational stimulation signal(s), photonic stimulation signal(s), and/or thermal stimulation signal(s).

6. The method of claim 5, further comprising alternating anode and cathode configurations of the stimulation, after one or more cycle(s) of stimulation.

7. The method of any one of the preceding claims, comprising determining a degree or severity of bronchoconstriction from the subject and initiating and/or adjusting at least a portion of the stimulus based on the determined degree or severity of bronchoconstriction.

8. The method of claim 7, wherein adjusting the stimulus comprises adjusting the duration and/or frequency of at least a portion of the stimulus.

9. The method of claim 7 or 8, wherein determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and/or expired air from the subject.

10. The method of any one of claims 7 to 9, wherein determining the degree or severity of bronchoconstriction comprises detecting triggering sounds and/or expired air from the subject and correlating the detected triggering sounds with the detected expiration and/or the determined degree or severity of bronchoconstriction.

11. The method of any one of claims 7 to 10, wherein determining the degree or severity of bronchoconstriction comprises detecting any one or more of expiration, the subject's motion parameters and the subject's heart rate or acceleration.

12. The method of any one of claims 9 to 11, wherein expiration and/or the expired air from the subject is configured to be detected using at least one stretch sensor on the outer skin of the subject.

13. The method of any one of claims 7 to 12, wherein determining a degree or severity of bronchoconstriction comprises tracking and/or storing data associated with: at least one heart rate sensor; and/or at least one motion sensor; and/or at least one stretch sensor.

14. The method of any one of the preceding claims, wherein at least a portion of the one or more skin zones comprise or correspond to the back and in-between the scapulae of the subject, for example to innervate the sympathetic nerves within the T3 dermatome and/or angiosome.

15. The method of any one of the preceding claims, wherein at least a portion of the one or more skin zones comprises the medial aspect of at least one arm of the subject, targeting the intercostobrachial nerve within the T2 dermatome.

16. The method of any one of the preceding claims, wherein at least a portion of the one or more skin zones comprise or correspond to the medial aspect of each arm of the subject, bilaterally targeting the intercostobrachial nerve within the T2 dermatome.

17. A system for alleviating, treating, or preventing bronchoconstriction in a subject that is configured to perform the methods according to any one of the preceding claims.

18. A system for alleviating, treating, or preventing bronchoconstriction and/or promoting bronchodilation in a subject, the system comprising: an activator comprising one or more activation members configured to be placed on the outer skin of the subject, the activator being configured to apply at least one stimulation pulse to at least one of the one or more activation members; and one or more detectors configured to detect bronchoconstriction from the subject, wherein: the one or more activation members are configured to be placed on respective skin zone(s) that are innervated by the T1-T5 dermatome(s) and/or angiosomes(s) associated with T1-T5 sympathetic ganglions, in use; and application of the at least one stimulation pulse is initiated or adjusted based on bronchoconstriction being detected by at least one of the one or more detectors.

19. The system of claim 18, wherein the activator comprises an electro-stimulator and/or wherein the one or more activation members comprise electrodes.

20. The system of claim 18 or 19, wherein the activator, and/or one or more of one or more detectors, and/or both the activator and one or more of the one or more detectors are wearable and/or comprise a wearable device.

21. The system of any one of claims 18 to 20, wherein the activator is configured to apply stimulation at a frequency between 2 Hz to 20 kHz and/or to apply a stimulation the Fourier transform of which includes one or more peak frequencies between 2Hz and 20kHz.

22. The system of claim 21, wherein the activator is configured to apply stimulation at a frequency between 10 Hz and 200 Hz and/or to apply a stimulation the Fourier transform of which includes one or more peak or notable frequencies between 10 Hz and 200 Hz.

23. The system of any one of claims 18 to 22, wherein the activator is configured to alternate between applying two or more different stimulation frequencies, and/or is configured to apply two or more stimulations, one or more of the Fourier transforms of which contains one or more peak or notable frequencies within a range of between 2 Hz and 20 kHz, and/or is configured to apply a poly-tone stimulus containing at least one fundamental or beat frequency or the Fourier transform of which has one or more peak or notable frequencies within a range of between 2 Hz and 20 kHz.

24. The system of any one of claims 18 to 23, wherein the activator is configured to alternate between applying stimulation at any two or more frequencies selected from the group consisting of 10Hz, 80Hz, 120Hz, and 200Hz.

25. The system of any one of claims 18 to 24, wherein the system is configured to provide any one or more of acoustic stimulation, thermal stimulation, mechanical stimulation, photonic stimulation, magnetic stimulation, ultrasonic stimulation, and electrical startle stimulation to the skin zone(s), prior to applying the at least one stimulation pulse or waveform.

26. The system of any one of claims 18 to 25, wherein the at least one detector comprises at least one heart rate sensor and/or at least one motion sensor.

27. The system of claim 26, wherein the at least one heart rate sensor is configured to detect the occurrence and duration of acceleration and/or deceleration of the heart rate of the subject.

28. The system of claim 26 or 27, wherein the at least one heart rate sensor comprises at least one wearable sensor.

29. The system of claim 28, wherein the at least one wearable sensor comprises an ECG device and/or an accelerometer.

30. The system of claim 26 or 27, wherein the at least one heart rate sensor comprises at least one non-contact sensor.

31. The system of claim 30, wherein the at least one non-contact sensor comprises any one or more of: infra-red sensor, laser sensor, ultrasound sensor and camera.

32. The system of any one of claims 26 to 31, wherein the at least one motion sensor is configured to sense a change in motion and/or the duration over which the change occurs.

33. The system of any one of claims 18 to 32, wherein the one or more detector comprises at least one stretch sensor.

34. The system of any one of the claims 18 to 33, wherein the system is configured to track and/or store and/or analyse data from the detector or data relating to the subject.

35. The system of claim 34, wherein the data being tracked and/or stored comprises data from any one or more of: the at least one heart rate sensor; the at least one motion sensor; and the at least one stretch sensor.

36. The system of any one of claims 18 to 35, wherein the system is configured to provide an alert upon detection of potential triggers based on previous data from the at least one detector.

37. The system of any one of claims 18 to 36, wherein at least a portion of the one or more activation members: a) are configured to be positioned on the back and in-between the scapulae of the subject, targeting the nerve within the T3 dermatome and/or angiosome; and/or b) are configured to be positioned such that the at least one stimulation pulse is configured to be applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of the arm of the subject; and/or c) are configured to be positioned such that the at least one stimulation pulse pr waveform is configured to be bilaterally applied to the intercostobrachial nerve within the T2 dermatome on the medial aspect of each arm of the subject; and/or d) any combination of any two or more of a) to c) above.

38. The system of any one of claims 18 to 37, wherein the activator comprises two or more activation members, and the at least one stimulation pulse is configured to be applied to the two or more activation members interchangeably.

39. The system of any one of claims 18 to 38, wherein the activator comprises two or more activation members, and the two or more activation members are positioned in multiple different locations on the subject.

40. The system of any one of claims 18 to 40, wherein the at least one stimulation pulse comprises one or more of the following: at least one electrical stimulation pulse, at least one magnetic stimulation signal(s), at least one ultrasound stimulation signal(s), at least one photonic stimulation signal(s), at least one vibrational stimulation signal(s), at least one thermal stimulation signal(s), and/or any combination of any two or more thereof.

41. The system of any one of claims 18 to 40, wherein the activator is configured to initiate or adjust the duration and/or frequency of at least a portion of the at least one stimulation pulse, based on data received from the detector.

42. The method or system of any one of the preceding claims, wherein the subject is suffering from or is predisposed to asthma, exercise-induced bronchoconstriction, or both asthma and exercise-induced bronchoconstriction.

43. A wearable device comprising at least one activator and at least one detector as defined in any one of the preceding claims.

44. A wearable device comprising at least one activator and/or at least one detector as defined in any one of the preceding claims for use in a method according to any one of claims 1 to 16.