Nerve stimulation for treating migraine and other headache conditions

Abstract

To provide systems and methods for treatment and prevention of migraine and other headache conditions.SOLUTION: A method for treating migraines using transcutaneous peripheral nerve stimulation comprises: positioning a first peripheral nerve effector on a skin surface proximate to a median nerve of an arm or wrist of a patient; positioning a second peripheral nerve effector on a skin surface proximate to a nerve other than the median nerve of the arm or wrist of the patient; receiving EEG data relating to the patient; generating parameters of a first electrical stimulation signal and a second electrical stimulation signal, where generating parameters comprises analyzing the EEG data relating to the patient; and transcutaneously delivering the first electrical stimulation signal to the first peripheral nerve effector to stimulate the nerve other than the median nerve.SELECTED DRAWING: Figure 1F

Description

Incorporation by Reference

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 750,204, filed October 24, 2018, which is incorporated by reference herein in its entirety. This application also incorporates by reference in its entirety U.S. Patent No. 9,452,287 to Rosenbluth et al., U.S. Patent Application Publication No. 9,802,041 to Wong et al., U.S. Patent Application Publication No. 2018 / 0169400 to Wong et al., and U.S. Patent Application Publication No. 2018 / 0236217 to Hamner et al., each of which is incorporated by reference in its entirety. [Technical field]

[0002] FIELD OF THE DISCLOSURE

[0002] Embodiments of the present invention relate generally to cranial pain treatment, such as migraine, further including cephalgia and headache, and more particularly to systems and methods for treating migraine, cephalgia, headache, and other headache conditions via non-invasive peripheral nerve stimulation. [Background technology]

[0003] Migraine is a brain disorder of dysregulation of sensory processing associated with autonomic neuropathy. It is a neurovascular disorder with symptoms including unilateral pulsating cranial pain, hypersensitivity to light, sound, and smell, nausea, and dysfunction of the autonomic nervous, cognitive, emotional, and motor systems. Migraine can be triggered both internally or externally, including by factors such as stress, hormonal changes, lack of sleep, malnutrition, or sensory overload. In about one-third of cases, symptoms such as aura precede the onset of a migraine episode. Up to 16% of the world's population suffers from migraines, which are most common in women and have a strong genetic component.

[0004] Migraine headaches affect over 39 million Americans and are the second leading cause of neurological disability. Current treatments are often ineffective or worsen symptoms, and preventive pharmacological medications are effective in only about 50% of patients. Long-term efficacy is also poor, with only 25% benefiting at 6 months and 14% benefiting at 12 months in some studies.

[0005] Migraine pathogenesis is multifactorial, and episodes are thought to be triggered by activation of nociceptors that innervate the cerebral vasculature by mechanical, electrical and / or chemical provocation. Nociceptors that innervate the vasculature consist of C- and A-fibers that contain neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). Nociceptors originate in the trigeminal ganglion and reach intracranial structures via the trigeminal nerve.

[0006] The hypothalamus is deeply involved in migraine attacks, including increased susceptibility, seizure induction, and symptomatic symptoms. Orexins (alternatively called hypocretins) are a pair of hypothalamic neuropeptides that are exclusively synthesized in cell bodies of the lateral hypothalamus. Anatomically, the orexin system is tightly integrated with other brain systems involved in migraine pathophysiology, including the trigeminovascular system. The orexinergic system may contribute to altered homeostatic mechanisms that may affect seizure susceptibility, prodromal and associated symptoms, and migraine nociception. Thus, this system may be a potential therapeutic target for migraine. Summary of the Invention

[0007] Some embodiments of the present invention relate generally to the treatment of migraines, cephalgias, headaches, and other cranial pain, and more particularly to systems and methods for treating migraines, cephalgias, headaches, and other cranial pain via non-invasive peripheral nerve stimulation. In some embodiments, a system for treating a migraine in a patient is disclosed herein. The system may include or consist essentially of a peripheral nerve stimulator including a pulse generator, and at least two electrodes configured to deliver electrical neuromodulation (e.g., to nerves, acupressure points, or meridians in the patient's limbs or ears). As disclosed herein, the patient's ear is anatomically distinct and separate from the patient's head. In some embodiments, stimulation is not delivered to the patient's head, but rather to the patient's ear, lower limbs, or upper limbs. Upper limb neuromodulation (e.g., stimulation) may, in some embodiments, be across the upper arm, the upper arm and the lower arm, or only below the elbow (e.g., only one or more of the forearm, wrist, and / or fingers), and the stimulator may be configured accordingly. Neuromodulation (e.g., stimulation) may, in some embodiments, be sufficient to alleviate one or more of pulsating cranial pain, hypersensitivity to light, sound, and smell, nausea, and dysfunction of the autonomic nervous system, cognitive system, emotional system, and motor system. In some embodiments, neuromodulation (e.g., stimulation) may be therapeutic (e.g., after the onset of symptoms) and / or prophylactic / preventative (e.g., when the patient is not currently experiencing any symptoms). The system may also include one, two, or more sensors. The stimulator and / or sensor may be implantable within the patient or may be wearable with no implantable components. In some embodiments, the stimulator and / or sensor may be through the skin or transcutaneous.

[0008] As used herein, neuromodulation can include both excitatory (eg, stimulation) and inhibitory (eg, blocking) therapies on one or more nerves.

[0009] In some embodiments, the systems and methods for treating migraines may include, or consist essentially of, any number of the features disclosed herein.

[0010] In some embodiments, a transcutaneous method for treating migraine with selective activation is disclosed herein. The method may, for example, include or consist essentially of placing a first peripheral nerve effector on the skin of a patient's limb and transcutaneously delivering a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficiently to modify at least one neural pathway associated with migraine or headache conditions, including but not limited to the orexinergic pathway and / or the trigeminovascular pathway. An episodic migraine patient may have measurable orexin in cerebrospinal fluid (CSF). The first electrical nerve stimulation signal may preferentially or selectively activate only on or above the A alpha, Abeta, A delta, B, or C fibers of the first peripheral nerve. The first peripheral nerve may be an upper limb nerve, such as the median nerve, radial nerve, medial cutaneous nerve, lateral cutaneous nerve, musculocutaneous nerve, or ulnar nerve, a cranial or cervical nerve, such as the auricular nerve, specifically the auricular branch of the vagus nerve (ABVN), the vagus nerve, specifically the cervical vagus nerve, the trigeminal nerve, specifically the supraorbital nerve, the occipital nerve, or the pterygopalatine ganglion, or a lower limb nerve, such as the tibial nerve, the saphenous nerve, the common peroneal nerve, the femoral nerve, the sacral nerve, the sciatic nerve, and the sural nerve. In some embodiments, the first peripheral nerve does not include any one or more of the aforementioned nerves, or any one or more of the nerves described elsewhere herein. The first electrical nerve stimulation signal may include burst or continuous stimulation, and in some cases, a selected waveform, which may be a biphasic square wave or a sine wave. The pulse width may be, for example, about 50 μs to about 100 μs, about 150 μs to about 200 μs, about 300 μs to about 400 μs, or other ranges including any two of the foregoing values. In some embodiments, the electrical stimulation signal may have a frequency of about 5-50 Hz, 50-150 Hz, 150-250 Hz, 250-500 Hz, 500-1000 Hz, 1000-2500 Hz, and overlapping ranges therein, including, for example, about 5 Hz or less or at least about 5 Hz, about 250 Hz or less or at least about 250 Hz, or about 2000 Hz or less or at least about 2000 Hz.In some embodiments, the first peripheral nerve effector may include at least a first and a second electrode. In some cases, the electrodes may be substantially aligned along the length of the nerve axon. In some embodiments, the method may include placing a second peripheral nerve effector on the skin of the patient's limb and transcutaneously delivering a second electrical nerve stimulation signal to the second peripheral nerve effector to stimulate the second peripheral nerve sufficiently to modify at least one neural pathway associated with the migraine or headache condition. In some embodiments, the headache condition may be one or more of sinus headache, cluster headache, tension headache, rebound headache, daily persistent headache, post-traumatic headache, chronic daily headache, occipital neuralgia, persistent hemicrania, and the like. In some embodiments, the system stimulates one or more peripheral nerves to balance activity of the patient's parasympathetic or sympathetic nervous system. The second peripheral nerve is different from the first peripheral nerve and may be selected from, for example, any of the nerves described elsewhere herein and / or may not include any of the nerves described elsewhere herein. The method may also include receiving input regarding the patient's autonomic nervous system activity, including, for example, receiving data from a sensor measuring the patient's heart rate variability, and / or receiving data from a sensor measuring at least one of the patient's electrodermal activity, temperature measurements, and ECG information. The method may also include placing any number of peripheral nerve effectors on one or more of the C5, C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, L1, L2, L3, L4, L5, S1, S2, S3, and / or S4 dermatomes. In some embodiments, the peripheral nerve effector may be placed in a patient's extremity offset from one or more nerves, such as the median, radial, or ulnar nerve, to target a target nerve, such as a cutaneous nerve. In some embodiments, the electrical nerve stimulation signal may preferentially or selectively activate only one of the A alpha, Abeta, A delta, B, or C fibers of a first peripheral nerve.

[0011] In some embodiments, a wearable transcutaneous system for treating migraine or other headache conditions by selective activation is also disclosed herein. The system may include or consist essentially of any number of the following features, or other features disclosed elsewhere herein. The system may include, for example, a controller, a first peripheral nerve effector configured to be placed on the skin of a patient's extremity, and / or at least one biomedical sensor or data input source configured to provide feedback information. The controller may be configured to transcutaneously generate a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition. The first electrical nerve stimulation signal may preferentially or selectively activate one or more of A-alpha, Abeta, A-delta, or C-fibers of the first peripheral nerve. The system may also include a second peripheral nerve effector configured to be placed on the skin of a patient's extremity. The controller may be configured to transcutaneously generate a second electrical nerve stimulation signal to a second peripheral nerve effector to stimulate the second peripheral nerve sufficiently to modify at least one neural pathway associated with a migraine or headache condition. The second electrical nerve stimulation signal may preferentially activate one or more of A-alpha, A-beta, A-delta, B, or C fibers of the second peripheral nerve. The feedback information may include, for example, heart rate variability and / or galvanic skin response. The first peripheral nerve may be an upper limb nerve, such as the median nerve, radial nerve, medial cutaneous nerve, lateral cutaneous nerve, musculocutaneous nerve, or ulnar nerve, a cranial or cervical nerve, such as the auricular nerve, specifically the ABVN, the vagus nerve, specifically the cervical vagus nerve, the trigeminal nerve, specifically the supraorbital nerve, the occipital nerve, or the pterygopalatine ganglion, or a lower limb nerve, such as the tibial nerve, the saphenous nerve, the common peroneal nerve, the femoral nerve, the sacral nerve, the sciatic nerve, and the sural nerve. The first electrical nerve stimulation signal may include burst or continuous stimulation and, in some cases, a selected waveform, which may be a biphasic square wave or a sine wave.The pulse width may be, for example, about 50 μs to about 100 μs, about 150 μs to about 200 μs, about 300 μs to about 400 μs, or other ranges including any two of the aforementioned values. In some embodiments, the electrical stimulation signal may have a frequency of about 5-50 Hz, 50-100 Hz, 100-250 Hz, 250-500 Hz, 500 Hz to 1000 Hz, 1000-3000 Hz, and ranges therebetween (e.g., including about 5 Hz, about 250 Hz, or about 2,000 Hz or less). In some embodiments, the first peripheral nerve effector may include at least a first and a second electrode. In some cases, the electrodes may be substantially aligned along the length of the nerve axon. In some embodiments, the system may include a second peripheral nerve effector configured to be placed on the skin of the patient's extremity and configured to deliver a second electrical nerve stimulation signal transcutaneously to the second peripheral nerve effector to stimulate the second peripheral nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop and balance activity of the patient's parasympathetic or sympathetic nervous system. The second peripheral nerve may be different from the first peripheral nerve and may be selected, for example, from any of the nerves described elsewhere herein. The system may also be configured to receive input regarding the patient's autonomic nervous system activity, including, for example, receiving data from a sensor measuring the patient's heart rate variability and / or receiving data from a sensor measuring at least one of the patient's electrodermal activity, temperature measurements, and ECG information.

[0012] Also disclosed herein is a method for treating migraine and headache conditions, comprising: placing a first peripheral nerve effector on the skin of a patient's upper extremity to stimulate a first peripheral nerve selected from the group consisting of the patient's median nerve, radial nerve, or ulnar nerve; placing a second peripheral nerve effector on the skin of the patient's upper extremity to stimulate a second peripheral nerve different from the first peripheral nerve; delivering a first electrical nerve stimulation signal transcutaneously to a first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one neural pathway associated with a migraine or headache condition; and / or transcutaneously delivering a second electrical nerve stimulation signal to a second peripheral nerve effector to stimulate the second peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition. The method may include, or consist essentially of, a first electrical nerve stimulation signal and a second electrical nerve stimulation signal. The first and second electrical nerve stimulation signals may be coordinated such that stimulation from the first and second peripheral nerve effectors simultaneously activate the brachial plexus. The second electrical nerve stimulation signal may occur simultaneously or substantially simultaneously with the delivery of the first electrical nerve stimulation signal. The delivery of the second electrical nerve stimulation signal may be offset in time from the delivery of the first electrical nerve stimulation signal, such as by about 0.5 to 10 milliseconds (e.g., about 1 to 3 milliseconds, optionally 1.0 milliseconds to about 2.1 milliseconds, and overlapping ranges therein). The method may also include performing a nerve conduction study to measure nerve conduction velocities of the first and second peripheral nerves. The offset may be determined from the measured nerve conduction velocities of the first and second peripheral nerves. The nerve stimulation signals may be delivered in an alternating and / or rhythmic pattern, such as at a frequency (e.g., an alternating frequency) of about 3 Hz to about 15 Hz. In some embodiments, a frequency of about 1-20 Hz may be used. The nerve stimulation signal may be delivered in a pseudo-random pattern and / or adjusted based on feedback received regarding the patient's autonomic balance. The feedback may include the patient's measured heart rate variability, such as, for example, the ratio of absolute low frequency to absolute high frequency of the patient's heart rate variability. The first peripheral nerve effector and the second peripheral nerve effector span multiple dermatomes of the patient, such as any of the dermatomes described herein. The dermatomes may be stimulated at predetermined intervals.

[0013] In some embodiments, a wearable system for treating migraine and headache conditions is also disclosed herein. The system may include or consist essentially of any number of the following features or other features disclosed elsewhere herein. The system may include any number of controllers, a first peripheral nerve effector configured to be placed on the skin of a patient's limb, a second peripheral nerve effector configured to be placed on the skin of a patient's limb, and at least one biomedical sensor or data input source configured to provide feedback information. The controller may be configured to transcutaneously generate a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop associated with a migraine episode or headache condition. The controller may also be configured to transcutaneously generate a second electrical nerve stimulation signal to the second peripheral nerve effector to stimulate the second peripheral nerve sufficient to modify at least one neural pathway associated with a migraine episode or headache condition. The controller may also be configured to adjust the first electrical nerve stimulation signal and the second electrical nerve stimulation signal such that stimulation from the first peripheral nerve effector and stimulation from the second peripheral nerve effector activate the brachial plexus simultaneously, e.g., simultaneously or substantially simultaneously with the delivery of the first electrical nerve stimulation signal. The controller may be configured to deliver the second electrical nerve stimulation signal offset in time from the delivery of the first electrical nerve stimulation signal, such as by about 1.0 to about 2.1 milliseconds, 0.5 to 10 milliseconds (e.g., about 1 to 3 milliseconds). The controller may be configured to deliver the electrical nerve stimulation signal in an alternating, random, pseudo-random, and / or rhythmic pattern, such as at a frequency (e.g., an alternating frequency) of about 3 Hz to about 15 Hz. In some embodiments, a frequency of about 1 to 20 Hz may be used. The controller may be configured to adjust at least one of the first electrical nerve stimulation signal and the second electrical nerve stimulation signal based on feedback received regarding the patient's autonomic balance. The feedback may be, for example, the patient's measured heart rate variability, for example the ratio of the absolute low frequency to the absolute high frequency of the patient's heart rate variability.The controller may be configured to receive recorded measurements related to nerve conduction velocity of the first peripheral nerve and the second peripheral nerve and adjust the first electrical nerve stimulation signal and the second electrical nerve stimulation signal based on the recorded measurements.

[0014] In some embodiments, a fully or partially transcutaneous system and method for treating migraine or other neurological conditions is provided. The technology can be partially transcutaneous and partially subcutaneous. In some embodiments, the system and method includes a first neuroeffector that delivers a first neuromodulation signal to modify at least one neural pathway associated with the condition, including but not limited to the orexinergic pathway and / or the trigeminovascular pathway. The first neuromodulation signal may preferentially or selectively activate only on or above the A alpha, Abeta, A delta, B, or C fibers of the first peripheral nerve. The first peripheral nerve may be an upper limb nerve, such as the median nerve, radial nerve, medial cutaneous nerve, lateral cutaneous nerve, musculocutaneous nerve, or ulnar nerve, for example, an auricular nerve, specifically the auricular branch of the vagus nerve (ABVN), a vagus nerve, specifically the cervical vagus nerve, a trigeminal nerve, specifically a cranial or cervical nerve, such as the supraorbital nerve, the occipital nerve, or the pterygopalatine ganglion, or a lower limb nerve, such as the tibial nerve, the saphenous nerve, the common peroneal nerve, the femoral nerve, the sacral nerve, the sciatic nerve, and the sural nerve. The first neuromodulation signal may include burst or continuous stimulation, and in some cases, a selected waveform, which may be a biphasic square wave or a sine wave. The pulse width may be, for example, about 50 μs to about 100 μs, about 150 μs to about 200 μs, about 300 μs to about 400 μs, or other ranges including any two of the aforementioned values. In some embodiments, the electrical stimulation signal may have a frequency of about 5-50 Hz, 50-150 Hz, 150-250 Hz, 250-500 Hz, 500-1000 Hz, 1000-2500 Hz, and overlapping ranges therein (e.g., including about 5 Hz, about 250 Hz, or about 2,000 Hz). In some embodiments, the first neural effector may include at least a first and a second electrode. In some cases, the electrodes may be substantially aligned along the length of the neural axon. In some embodiments, the systems and methods may include delivering a second neuromodulation signal to stimulate the second nerve sufficient to modify at least one neural pathway. In some embodiments, the system modulates one or more nerves to balance activity of the patient's parasympathetic or sympathetic nervous system.The systems and methods may also include receiving input regarding the patient's autonomic nervous system activity, including, for example, receiving data from a sensor measuring the patient's heart rate variability, and / or receiving data from a sensor measuring at least one of the patient's electrodermal activity, temperature measurements, and ECG information. The systems and methods may also include placing any number of peripheral nerve effectors on one or more of the C5, C6, C7, C8, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, L1, L2, L3, L4, L5, S1, S2, S3, and / or S4 dermatomes. In some embodiments, the nerve effectors may be offset from one or more nerves, such as the median, radial, or ulnar nerve, and placed on the patient's extremity to target a target nerve, such as a cutaneous nerve. In some embodiments, the neuromodulatory signal may preferentially (activate, inhibit, etc.) or selectively (activate, inhibit, etc.) affect only one of the A-alpha, Abeta, A-delta, B, or C fibers of the first nerve.

[0015] In some embodiments, a method of treating migraine and headache conditions is disclosed herein, the method comprising: placing a first peripheral nerve effector on the skin of a patient's upper extremity to stimulate a first peripheral nerve selected from the group consisting of one of the patient's median nerve, radial nerve, and ulnar nerve; placing a second peripheral nerve effector on or in the patient's ear to stimulate a second peripheral nerve associated with the patient's parasympathetic pathway, such as the ABVN; transcutaneously delivering a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition; and transcutaneously delivering a second electrical nerve stimulation signal to the second peripheral nerve effector to stimulate the second peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition. The method may include or consist essentially of any number of: a first electrical neurostimulation signal; a second electrical neurostimulation signal; and a second electrical neurostimulation signal. The first and second electrical neurostimulation signals may be configured to balance activity of the patient's parasympathetic and sympathetic nervous systems. The method may also include monitoring the patient's sympathetic and parasympathetic activity. The method may also include adjusting the first electrical neurostimulation signal upon identifying abnormal sympathetic activity of the patient. The method may also include adjusting the second electrical neurostimulation signal upon identifying abnormal parasympathetic activity of the patient. In one embodiment, third, fourth and additional signals are used.

[0016] In some embodiments, systems for treating migraine and headache conditions (including, but not limited to, wearable systems) are also disclosed herein. The systems may include or consist essentially of any number of the following features, or other features disclosed elsewhere herein. The systems may include a first peripheral nerve effector configured to be placed on the skin of a patient's limb, a second peripheral nerve effector configured to be placed on or in the patient's ear, and / or at least one biomedical sensor or data input source configured to provide feedback information. The controller may be configured to transcutaneously generate a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition. The controller may also be configured to transcutaneously generate a second electrical nerve stimulation signal to the second peripheral nerve effector to stimulate a second peripheral nerve associated with the patient's parasympathetic pathway, such as the ABVN, to modify at least one neural pathway associated with the migraine or headache condition. The controller may also be configured to adjust the first electrical neurostimulation signal and the second electrical neurostimulation signal to balance activity of the patient's parasympathetic and sympathetic nervous systems. The controller may be configured to adjust the first electrical neurostimulation signal upon identifying abnormal sympathetic and / or parasympathetic activity of the patient.

[0017] Also disclosed herein is a method for treating migraine and headache conditions. The method may include, or consist essentially of, assessing at least one of the sympathetic and parasympathetic nerve activity of a subject, determining the presence of abnormal sympathetic or parasympathetic nerve activity in the subject, stimulating a first nerve operably connected to the brachial plexus in the presence of abnormal sympathetic nerve activity, sufficient to have a therapeutic effect on migraine or other headache conditions, and stimulating the ABVN in the presence of abnormal parasympathetic nerve activity, sufficient to have a therapeutic effect on migraine or other headache conditions. The stimulation may be only electrical transcutaneous stimulation in some cases, and may include stimulating or inhibiting neural activity of the first nerve. In the presence of both abnormal sympathetic and abnormal parasympathetic nerve activity, the stimulation may include both the first nerve and the ABVN. Assessing at least one of the sympathetic and parasympathetic nerve activity of the subject includes measuring the HRV of the subject, such as with a wrist-worn device, and may also include measuring heart rate and / or electrodermal activity. The first nerve can be, for example, a median, radial, ulnar, median cutaneous, lateral cutaneous, or other nerve discussed herein.

[0018] Also disclosed herein is a method of treating migraine or other headache conditions, which may include, or consist essentially of, electrically stimulating a first peripheral nerve, assessing at least one of sympathetic and parasympathetic activity of a subject, determining abnormal sympathetic or parasympathetic activity of the subject, and adjusting the electrical stimulation based on assessing the at least one of the sympathetic and parasympathetic activity. Adjusting the electrical stimulation may include identifying abnormal sympathetic or parasympathetic activity in the patient and adjusting a frequency of stimulation of the first nerve, and / or discontinuing electrical stimulation of the first nerve and initiating electrical stimulation of a second nerve.

[0019] Systems and methods are also disclosed for providing neural stimulation of one, two, or more peripheral nerve targets that modulate vagal tone, such as the auricular branch of the vagus nerve (ABVN), where the stimulation is activated in phase with a portion of the respiratory cycle with measurements from a sensor that detects an event or phase of the respiratory cycle.

[0020] Some embodiments include, or consist essentially of, a method of treating migraine or other headache conditions using a combination of pharmacotherapy and transcutaneous electrical stimulation, comprising administering to a patient an amount of one, two, or more pharmacological agents, including, but not limited to, triptans, ergot, CGRP inhibitors, and combinations thereof; placing a first peripheral nerve effector on the skin of the patient's extremity; and transcutaneously delivering a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition; and any number thereof. The triptan can be, for example, one or more of sumatriptan (Imitrex), rizatriptan (Maxalt), almotriptan (Axert), naratriptan (Amerge), zolmitriptan (Zomig), frovatriptan (Frova), and eletriptan (Relpax). The ergot can be, for example, ergotamine and caffeine combination (Migergot, Cafergot), or dihydroergotamine (DHE45, Migranal). The CGRP inhibitor can be erenumab-aooe (Aimovig), eptinezumab (ALD 403), fremanezumab (TEV-48125), or galcanezumab (LY 2951742).

[0021] Also disclosed herein is a combination medication and electrical stimulation system for treating migraine or other headache conditions, which may include or consist essentially of any number of features, for example, as disclosed herein. The system may include or consist essentially of, for example, a device (such as a wearable device) including a controller, a first peripheral nerve effector configured to be placed on the skin of a patient's limb, and at least one biomedical sensor or data input source configured to provide feedback information. The controller may be configured to transcutaneously generate a first electrical nerve stimulation signal to the first peripheral nerve effector to stimulate the first peripheral nerve sufficient to modify at least one neural pathway associated with the migraine or headache condition. The system may also include a triptan, ergot, CGRP inhibitor, or combinations thereof for administration to the patient.

[0022] In some embodiments, the embodiments described herein selectively target peripheral nerves of one or more fiber types and / or coordinate stimulation of multiple peripheral nerves so that action potentials arrive at the same target location (e.g., in the brachial plexus) at the same time or substantially the same time. The embodiments described herein may have one or more of the following advantages: greater therapeutic benefit with less discomfort, use of lower currents (e.g., less power and improved battery life), and increased likelihood of patient compliance. In some embodiments, the embodiments described herein include multiple peripheral nerve stimulation, promoting sympatho-vagal balance with at least one peripheral nerve that regulates the sympathetic nervous system and at least one peripheral nerve that regulates the parasympathetic nervous system. The embodiments described herein may advantageously have the ability to selectively regulate either the sympathetic and / or parasympathetic arms of the autonomic nervous system in response to detected sympathetic and / or parasympathetic overactivity. In some embodiments, the peripheral nerve stimulation may advantageously have a synergistic effect when combined with medications including triptans, ergots, or CGRP inhibitors. The effect may include an enhanced response to treatment, a lower dose of the triptan, ergot, or CGRP inhibitor required to achieve the effect, and therefore fewer adverse reactions, etc. In some embodiments, combination therapy may be beneficial to shorten the time it takes to achieve a therapeutic effect (e.g., by at least 10%, 25%, 50% or more, or overlapping ranges therein), or to prolong the therapeutic effect (e.g., by at least 10%, 20%, 40% or more, or overlapping ranges therein), or to improve the overall benefit (e.g., a greater reduction in the magnitude or frequency of migraine symptoms).

[0023] In some embodiments, a device is provided that adjusts the stimulation modality to enhance efficacy based on a predetermined characteristic or feature of the neurological or physiological data measured from the sensor and / or previous responses by the subject. In some embodiments, one or more sensors are provided to adjust the parameters of the operating mode. In some embodiments, it is beneficial to shorten the time it takes to achieve a therapeutic effect (e.g., at least 10%, 25%, 50% or more, or overlapping ranges therein), or to prolong the therapeutic effect (e.g., at least 10%, 20%, 40% or more, or overlapping ranges therein), or to improve the overall benefit (e.g., a greater reduction in the magnitude or frequency of migraine symptoms).

[0024] Alternatively or additionally, and without being limited by theory, treatments involving stimulation as disclosed herein may cause a neurohormonal response. The neurohormonal response may include changes (increases or decreases) in the production of norepinephrine, epinephrine, acetylcholine, and / or inflammatory cytokines. Inflammatory cytokines may include interleukins, high mobility group box 1 proteins, and / or tumor necrosis factor alpha. The neurohormonal response may also be caused by afferent and / or efferent nerve stimulation of the median, radial, ulnar, or vagus nerves, cutaneous nerves, or sympathetic nerves. In one embodiment, one or more of norepinephrine, epinephrine, acetylcholine, and / or inflammatory cytokines are reduced by at least about 5%, 10-20%, 20-40%, 40-60% or more (including overlapping ranges therein) following treatment with the devices disclosed herein compared to pre-treatment.

[0025] In some embodiments, the systems and methods are configured to treat migraine symptoms but are not configured or do not treat tremors or movement disorders (including but not limited to Parkinson's disease). Some of the embodiments described herein do not include one, some, or all of the following features: (i) sensors configured to assess patient movement and / or collect movement data; (ii) accelerometers, gyroscopes, magnetometers, inertial measurement units; (iii) EMG or other muscle sensors. In some embodiments, the systems and methods are not configured for or located on the upper arm and / or are not configured for neuromodulation of the forehead skin surface. In some embodiments, the systems and methods are not configured or do not modulate descending (e.g., efferent) neural pathways and only modulate ascending (e.g., afferent) neural pathways. In some embodiments, the systems and methods are not configured or do not modulate nerves only at the ventral side of the wrist. In some embodiments, the systems and methods do not include an implantable component. In some embodiments, the systems and methods are not configured for stimulation through the skin or subcutaneously, but only for transcutaneous neuromodulation. In some embodiments, the systems and methods are not configured for or do not treat cardiac disorders, including, but not limited to, hypertension, angina, ischemia, myocardial infarction, congestive heart failure, and / or arrhythmia. In some embodiments, the systems and methods are not configured for neuromodulation only (e.g., stimulating the ventral side of the wrist), rather, some configurations may neuromodulate (e.g., delivering stimulation between two or more of the ventral, dorsal, and / or lateral sides of the wrist to target medial nerves).

[0026] In some embodiments, the system and method are not configured to and will not stimulate any number of the following puncture points: top of the head (Du 20 Baihui), forehead (GB.14 Yangbai), behind the ear (GB.20 Fengchi), above the ear (GB.8 Shuaigu), dorsum of the forearm (SJ.5 Waiguan), top of the hand between the thumb and index finger (LI.4 Hegu), toes (GB.41 Linqi), ankle (GB.37 Guangming), top of the foot (St.44 Neiting), foot (Liv.3 Taichong), (St.8 Touwei), temple (GB.4 Hanyan), top of the hand between the thumb and index finger (LI.4 Hegu), elbow (LI.11 Quchi), and shin (St.36 Zusanli).

[0027] In some embodiments, receiving electroencephalogram (EEG) data on the patient and generating parameters of the first burst electrical stimulation signal and / or the second burst electrical stimulation signal at least in part by analyzing the EEG data on the patient is particularly advantageous for enabling customized stimulation based on specific abnormal neuronal oscillations that may contribute to migraine or other headache pathologies. In some embodiments, the EEG data may be recorded with a single channel, two channels, four channels, eight channels, sixteen channels, thirty-two channels, or a system having more than thirty-two channels, with one or more channels positioned over a predetermined region of interest.

[0028] In some embodiments, utilizing peripheral neuromodulation to balance sympathetic activity by decreasing sympathetic activity and increasing parasympathetic activity is particularly advantageous by restoring balance to the autonomic nervous system, thus reducing the symptom burden associated with migraine and other headache conditions.

[0029] In some embodiments, transcutaneous neuromodulation at the arm and / or wrist (e.g., median, ulnar, and / or radial nerve stimulation), under the upper arm (e.g., distal to the upper arm / elbow), and two or more of the ventral, dorsal, and lateral sides of the arm and / or wrist may be particularly advantageous in suppressing sympathetically stimulated blood pressure increases and premotor sympathetic firing in the rostral ventrolateral medulla (rVLM). The median, ulnar, and / or radial nerves may provide more convergent input to sympathetic neurons of the cardiovascular premotor cortex, for example, in the rVLM.

[0030] In some embodiments, a method of treating a neurological condition using neuromodulation is disclosed, the method including placing a first neural effector on a skin surface adjacent to the median nerve on a patient's arm or wrist; placing a second nerve effector on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; receiving data relating to a patient, the data optionally being EEG data; generating parameters of the first neuromodulation signal and the second neuromodulation signal, where generating the parameters includes analyzing data related to the patient; delivering a first neuromodulation signal to a first neural effector to modulate a median nerve; delivering a second neuromodulation signal to a second neural effector to modulate a nerve other than the median nerve, thereby treating a neurological condition; The number of bits may include any number of bits.

[0031] In some embodiments, disclosed is a method for treating a neurological condition, comprising: placing a first nerve effector on a patient's skin on an arm or wrist distal to the upper arm to modulate a first nerve selected from the patient's median nerve, radial nerve, or ulnar nerve; placing a second nerve effector on or in the patient's ear to modulate the auricular branch of the vagus nerve of the patient; delivering a first burst signal to a first neural effector to modulate the first nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop associated with a neurological condition; delivering a second burst signal to a second neural effector to modulate the second nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop associated with the neurological condition; wherein the first signal and the second signal are configured to balance activity of the patient's sympathetic nervous system and parasympathetic nervous system; The number of bits may include any number of bits.

[0032] In some embodiments, the method may include any number of the following features, where the first and / or the second neural effector are peripheral nerve effectors, the first and / or the second neural effector are electrodes, the first and / or the second neural effector deliver a stimulating electrical signal, the neurological condition is a headache, such as a migraine, the neurological condition is pulsatile sensation, the neurological condition is pulsatile sensation, a third, fourth and / or fifth neural effector are provided, the first signal has a frequency of about 5 Hz or less and the second signal has a frequency of about 5 Hz or greater, and the method does not utilize an implantable component and includes only transcutaneous neuromodulation.

[0033] In some embodiments, a method of treating migraine headaches using transcutaneous peripheral nerve stimulation may include any number of: placing a first peripheral nerve effector on a skin surface of a patient's arm or wrist in proximity to the median nerve; placing a second peripheral nerve effector on a skin surface of the patient's arm or wrist in proximity to a nerve other than the median nerve; transcutaneously delivering a first electrical stimulation signal to the first peripheral nerve effector to stimulate the median nerve; and transcutaneously delivering a second electrical stimulation signal to the second peripheral nerve effector to stimulate the nerve other than the median nerve.

[0034] In some embodiments, a wearable device for treating migraine headaches using transcutaneous peripheral nerve stimulation may include any number of a first peripheral nerve effector configured to be placed on a skin surface proximate to the median nerve on a patient's arm or wrist, a second peripheral nerve effector configured to be placed on a skin surface proximate to a nerve other than the median nerve on a patient's arm or wrist, and a controller calibrated to transcutaneously deliver a first electrical stimulation signal to the first peripheral nerve effector to stimulate the median nerve and to transcutaneously deliver a second electrical stimulation signal to the second peripheral nerve effector to stimulate a nerve other than the median nerve.

[0035] In some embodiments, a method of treating or preventing headaches using transcutaneous peripheral nerve stimulation is disclosed that includes placing a first peripheral nerve effector on a skin surface adjacent to a first nerve on a patient's arm or wrist, and transcutaneously delivering a first electrical stimulation signal to the first peripheral nerve effector to stimulate the first nerve.

[0036] In some embodiments, a wearable device for treating or preventing headaches using transcutaneous peripheral nerve stimulation is disclosed, the wearable device including any number of first peripheral nerve effectors configured to be placed on a skin surface proximate to the median nerve on a patient's arm or wrist, and a controller configured to transcutaneously deliver a first electrical stimulation signal to the first peripheral nerve effector to stimulate the median nerve and to transcutaneously deliver a second electrical stimulation signal to the second peripheral nerve effector to stimulate a nerve other than the median nerve.

[0037] In some embodiments, a method of treating a neurological condition using neuromodulation is disclosed that includes placing a first neuroeffector on a skin surface proximate to a median nerve on a patient's arm or wrist, placing a second neuroeffector on the skin surface proximate to a nerve other than the median nerve on the patient's arm or wrist, receiving data related to the patient, generating parameters for a first neuromodulation signal and a second neuromodulation signal, where generating the parameters includes analyzing the data related to the patient, delivering the first neuromodulation signal to the first neuroeffector to modulate the median nerve, and delivering the second neuromodulation signal to the second neuroeffector to modulate the nerve, thereby treating the neurological condition. [Brief description of the drawings]

[0038] The novel, non-limiting features of the invention are set forth with particularity in the following claims. A better understanding of the features and advantages of some embodiments of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0039] [Figure 1A] Various views of embodiments of devices and systems are shown that provide peripheral nerve stimulation targeted to individual nerves to prevent or treat migraines and other headache conditions. [Figure 1B] Various views of embodiments of devices and systems are shown that provide peripheral nerve stimulation targeted to individual nerves to prevent or treat migraines and other headache conditions. [Figure 1C] Various views of embodiments of devices and systems are shown that provide peripheral nerve stimulation targeted to individual nerves to prevent or treat migraines and other headache conditions. [Figure 1D] Various views of embodiments of devices and systems are shown that provide peripheral nerve stimulation targeted to individual nerves to prevent or treat migraines and other headache conditions.

[0040] [Figure 1E] FIG. 1 illustrates a block diagram of one embodiment of a device and system for providing peripheral nerve stimulation and sensing biological measures used to customize or modify the delivery of electrical stimulation.

[0041] [Figure 1F] 1 illustrates generally the relationships between selected peripheral nerves, spinal levels, and neural pathways associated with migraine and other headache conditions. [Figure 1G] 1 illustrates generally the relationships between selected peripheral nerves, spinal levels, and neural pathways associated with migraine and other headache conditions. [Figure 1H] 1 illustrates generally the relationships between selected peripheral nerves, spinal levels, and neural pathways associated with migraine and other headache conditions.

[0042] [Figure 2A] FIG. 1 illustrates an embodiment of a stimulation device having electrodes that can be positioned on a wearable band, according to some embodiments of the present invention.

[0043] [Figure 3A] 1 illustrates various embodiments of a monitoring unit and a treatment unit forming a two-part treatment system. [Figure 3B] 1 illustrates various embodiments of a monitoring unit and a treatment unit forming a two-part treatment system.

[0044] [Figure 3C] FIG. 1 is a schematic diagram illustrating selected anatomical structures associated with the ear, including the area innervated by the auricular branch of the vagus nerve (ABVN).

[0045] [Figure 3D] FIG. 1 illustrates an embodiment of an auricle stimulation device.

[0046] [Figure 4A] 1 illustrates one embodiment of a two-part system having a single monitoring unit and multiple treatment units. [Figure 4B] 1 illustrates one embodiment of a two-part system having a single monitoring unit and multiple treatment units. [Figure 4C] 1 illustrates one embodiment of a two-part system having a single monitoring unit and multiple treatment units. [Figure 4D] 1 illustrates one embodiment of a two-part system having a single monitoring unit and multiple treatment units.

[0047] [Figure 4E] FIG. 1 illustrates a schematic diagram of an embodiment of an EEG system capable of recording data from one or more predetermined regions of interest.

[0048] [Figure 5A] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5B] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5C] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5D] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5E] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5F] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5G] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5H] 1 illustrates an embodiment of a wearable therapeutic system. [Figure 5I] 1 illustrates an embodiment of a wearable therapeutic system.

[0049] [Figure 6] FIG. 1 illustrates an embodiment of a wearable treatment system that uses the cloud to transmit and receive data between the treatment system, a secondary patient device, and a physician.

[0050] [Figure 7] FIG. 7 is a block diagram illustrating the individual components of the treatment unit, band, and base station shown in FIG.

[0051] [Figure 8A] 1 shows meridian points on the human body that can be used as locations for stimulation. [Figure 8B] 1 shows meridian points on the human body that can be used as locations for stimulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] Without being limited by theory, migraine is a brain disorder of dysregulation of sensory processing associated with autonomic involvement, and triggering may be driven by an imbalance in autonomic activity. This is an imbalance between sympathetic and parasympathetic activity within the autonomic nervous system. This imbalance may result from overactivity or underactivity of the sympathetic and / or parasympathetic limbs of the autonomic nervous system. Electrical stimulation affecting the autonomic nervous system, including the systems and methods disclosed herein, may provide therapeutic benefit by restoring balance to the autonomic nervous system and thus reducing the burden of symptoms associated with migraine and other headache conditions. Without being limited by theory, migraine may be a chronic sympathetic dysfunction in an anatomically intact system. Sympathetic dysfunction may be associated with an imbalance of cotransmitters. Chronic stimulation of the sympathetic nervous system depletes norepinephrine and increases the release of other cotransmitters. Migraine symptoms may be caused by overactivation of the sympathetic nervous system, resulting in differential release of cotransmitters. Thalamocortical arrhythmias may be an underlying cause of migraine headaches that can be observed in EEG measurements as low-frequency cortical oscillations. During interictal periods, resting-state EEGs of migraine patients tend to shift from the alpha range (e.g., 8-12 Hz) to the theta range (e.g., 4-8 Hz). These abnormal neuronal oscillation patterns may be responsible for the symptoms associated with migraine headaches (e.g., photo / phonophobia and vertigo, etc.) during both ictal and / or interictal periods. The lack of sensory input results in a thalamocortical column-specific reduction in information processing, allowing for a slowing of resting-state thalamocortical activity from alpha to theta frequencies, as less information needs to be processed. For example, neuromodulation (e.g., stimulation) of the median nerve may provide direct synaptic-mediated sensory input to thalamocortical circuits to increase information processing. Pattern or burst stimulation of the median or other nerves may favorably modulate resting-state cortical oscillation frequencies to a more normal, healthy state, e.g., from theta range to the alpha range. Sympathetic overactivation may be an underlying cause of migraine headaches (see attached slides). Pattern or burst stimulation of the median nerve can reduce sympathetic outflow at both acute (e.g., about 30 minutes) and chronic (e.g., about 2 weeks) time points.Therapeutic benefits improve over time with repeated daily use, so treatment can be used for both symptomatic relief and prevention. Diversity across migraine locations Allodynia and hyperalgesia are mediated by sensitized thalamic neurons that process nociceptive information from the cranial meninges along with sensory information from the scalp, face, body, and skin of the limbs. Pattern stimulation of one or more peripheral nerves (e.g., median, radial, ulnar, etc.) that project to the thalamus may attenuate sensitization by providing additional sensory input to disrupt, block, or mediate the nociceptive information from the cranial meninges that induces migraine.

[0053] Also, without being limited by theory, vagus nerve stimulation may modulate the trigeminal nucleus to suppress inflammation. Sensitization of the brainstem trigeminal sensory complex may underlie primary brain dysfunction in migraine by upregulating cortical excitability. Vagal afferents project to the nucleus tractus solitarii (NTS) and the spinal trigeminal nucleus (Sp5), regions that regulate the excitability of the trigeminal sensory complex and its connectivity with higher brain structures. The trigeminal sensory nucleus may be involved in neurogenic inflammation during migraine, which is characterized by vasodilation. VNS may modulate the trigeminal sensory pathway to restore migraine pathophysiology and reduce headache frequency and severity. Increased activation of the raphe nucleus and locus coeruleus may suppress nociceptive processing in the sensory trigeminal nucleus. Human skin is well innervated by autonomic nerves, and neuromodulation (e.g., stimulation) of nerves or meridian points as disclosed herein may potentially be useful in the treatment of migraine or other headache conditions. For example, peripheral or distal limb afferent nerves, including but not limited to the median nerve, are connected by neural circuits to the hypothalamic arcuate nucleus.

[0054] Alternatively or additionally, median nerve stimulation can regulate the orexinergic pathway for coma, which is a neural pathway related to the development and treatment of migraine. Activation of the orexinergic network can be used to treat migraine. Alternatively or additionally, and without being limited by theory, antidromic stimulation of autonomic or visceral efferent nerve fibers in the arm, leg, neck, or tragus can regulate sympathetic outflow and / or regulate vagal tone. Specifically, sympathetic afferent and / or efferent nerves can be specifically regulated, for example, by targeting c-fibers in the periphery of the body.

[0055] Alternatively or additionally, and without being limited by theory, electrical neuromodulation, e.g., stimulation of peripheral nerves, either somatic, autonomic, afferent, and / or efferent, may reduce susceptibility to migraine attacks.

[0056] Alternatively or additionally, respiration-gated auricular stimulation has been demonstrated to target brain networks involved in migraine headaches and shows therapeutic promise. In some embodiments, systems and methods for providing neural stimulation of one, two, or more peripheral nerve targets that modulate vagal tone, parasympathetic outflow, vagal brainstem regions, sympathetic outflow, or sympathetically mediated brainstem regions, where stimulation is activated in phase with a portion of respiration by measuring the respiratory cycle. In particular, the systems and methods may use a detection device to detect respiratory cycles over time. If there is a predetermined relationship or correlation between the detected activity and a threshold (such as a match, rate of change of activity, or within a predetermined range), the stimulation device is instructed to provide stimulation to at least one or more peripheral nerves. Stimulation may be advantageously correlated with a detected respiratory phase, such as exhalation, resulting in an increase in the potential synergistic effect of stimulation, thus improving therapeutic benefit.

[0057] For example, as shown in Figures 1A-1E, some embodiments relate to devices and systems that provide peripheral nerve stimulation targeting individual nerves. Some embodiments include devices and systems 10 that allow for customization and optimization of electrical therapy to an individual. In particular, the described devices 10 may be configured for electrical stimulation of the median, radial, ulnar, peroneal, saphenous, tibial, and / or other nerves or meridians accessible in the limbs to treat migraine and other headache conditions. Targeting these specific nerves and utilizing appropriately customized stimulation results in more effective treatment. In some embodiments, the treatment may reduce or eliminate the number, dosage, and / or frequency of medications a patient may need to take for a chronic migraine or headache condition, advantageously reducing side effects / potential toxicity. In some embodiments, the treatment may have unexpected synergistic effects when combined with one, two, or more pharmacological agents, such as triptans, ergots, or CGRP inhibitors. In some embodiments, triptans, ergots, or CGRP inhibitors may be administered orally, intravenously, or by another route along with peripheral nerve stimulation protocols as described herein for unexpected synergistically beneficial effects in the treatment of migraine or other headache conditions.

[0058] Peripheral or distal limb afferent nerves, including but not limited to the median nerve, are connected via neural pathways to sensitized peripheral and central neurons that are connected to the hypothalamus, as shown diagrammatically in Figures 1F-H.

[0059] 1A-1E illustrate embodiments of a device and system 10 that provides percutaneous peripheral nerve neuromodulation, e.g., targeted stimulation of one, two, three, or more individual nerves, to treat migraines or other headache conditions. In some embodiments, the device 10 is designed and configured to be worn on the wrist or arm. In some embodiments, the device 10 is configured to be placed under the upper arm / elbow. In some embodiments, electronics located within a watch-like housing 12 measure heart rate, movement, and / or electrodermal activity and also generate electrical stimulation waveforms. Electrical contacts within the band 14 and / or housing 12 transmit the stimulation waveform to disposable electrodes 16. The location of the contacts within the band 12 are positioned to target one or more specific nerves, such as the median, radial, and / or ulnar nerves, at the wrist. The electronics housing 12 may also have a digital display screen to provide feedback to the wearer of the device regarding stimulation and sensor measurements, derived characteristics, and history.

[0060] In some embodiments, the therapeutic device 10 is a wrist-worn device that may include, for example, 1) an array of electrodes 16 that encircles the wrist; 2) a skin interface to ensure good electrical contact to the person; 3) an electronics box or housing 12 that contains a stimulator or pulse generator 18, sensors 20, and other associated electronics such as a controller or processor 22 for executing instructions, memory 24 for storing instructions, a user interface 26 that may include a display and buttons, a communications module 28, a battery 30 that may be rechargeable, and optionally an induction coil 32 for charging the battery 30; and / or 4) a band to hold all the components together and secure the device tightly around the individual's wrist.

[0061] In FIG. 1D, the electrodes 16 are arranged circumferentially around the wrist, e.g., excited and neuromodulated on both sides of the wrist, with the electric field extending through the wrist, which allows for excitation of nerves deeper in the tissue. Thus, the circumferential array is compact, allowing for a bandwidth approximately the same size as the electrode width, and therefore advantageous for a wearable device. In some embodiments, the advantage of having the configurability of the array is that it can reach the same nerves, but fit into a more compact form factor than traditional median nerve excitation. While the devices described herein may be described and illustrated with electrodes arranged circumferentially or longitudinally, it should be understood that either electrode configuration may be used by the device. Additionally, while the devices may be described and illustrated with two, three or more electrodes, it should be understood that the device may have only two electrodes, or may have more than two electrodes. Some devices may be designed to stimulate only a single nerve, such as the median nerve, and some devices may be designed to stimulate more than two nerves.

[0062] Without being limited by theory, transcutaneous neuromodulation at the arm and / or wrist (e.g., median and / or radial nerve stimulation) may advantageously suppress sympathetically stimulated blood pressure increases and premotor sympathetic firing in the rostral ventrolateral medulla (rVLM). For example, the median and / or radial nerves may provide more convergent inputs to cardiovascular premotor sympathetic neurons in the rVLM.

[0063] 2A illustrates one embodiment of a wearable band 900 having integrated electrodes 902, 904. The integrated electrodes 902, 904 may be dry electrodes that electrically connect to a removable controller 910 via a flexible circuit embedded in the band. In some cases, dry electrodes may be more suitable for long-term use electrodes that may be used for several months, such as at least 1, 2, or 3 months, before the band needs replacing. In some embodiments, the band may be a disposable band that may be used for a relatively long period of time before replacing.

[0064] Embodiments of the invention may include devices, systems and methods for measuring and collecting biological data (e.g., heart rate, heart rate variability, ECG, galvanic skin response, temperature, and / or blood pressure), analyzing the data to interpret how these measurements may affect migraine or other headache conditions, and providing peripheral nerve stimulation targeting one or more individual nerves, such as the median, ulnar, radial, and / or ABVN, to treat or prevent migraine or other headache conditions, where the stimulation applied may or may not be modified based on the measurement data.

[0065] Embodiments of the treatment system may be flexible or adaptable to be worn at various locations on the body instead of or in addition to the arm or wrist, for example to access specific nerves such as the median or saphenous nerve at the wrist or elbow, or the ABVN at the ear, or the tibial nerve near the knee or ankle, or various nerves such as the radial and / or ulnar nerve, or various acupressure or meridian points as shown in Figures 8A and 8B.

[0066] In some embodiments, the electrodes may be placed near the Neiguan or PC 5-6 or PE 5 or PE6 acupressure points, preferably about three finger widths proximal to the wrist crease, for myofascial innervation. Alternatively, the electrodes may be placed distally on the arm where the median nerve is closer to the skin surface, which may require less power and provide a more comfortable transcutaneous simulation.

[0067] An embodiment of the treatment system may include any number of three components: (1) a monitoring unit having sensors, circuitry, and optionally a power source and / or microcontroller; (2) a treatment unit having a stimulator (e.g., pulse generator), circuitry, power source, and microcontroller; and (3) a skin interface having electrodes and electrical connections for electrically connecting to the treatment unit. In some embodiments, all three components are separate components that may be reversibly attached to each other to form a wearable treatment system. In some embodiments, any two of the components may be combined or integrated to form a wearable two-part system that may be reversibly attached to each other. Note that some functions may cross over, for example, the electrodes of the skin interface may be used as sensors to measure electrical activity (e.g., EMG and ECG), as well as impedance. In some embodiments, any one of the removable components may be disposable and / or sent back to the manufacturer for recycling. In some embodiments, the sensors may be separate, such as an effort belt attached to the chest to measure respiratory phase and rate, which may wirelessly communicate with the stimulator.

[0068] In some embodiments, some or all of the components of the treatment system may be implantable, transcutaneous, and / or transcutaneous. For example, a stimulation electrode may be implanted near the target nerve. Power may be provided to the electrode via a wired connection or wirelessly. The implanted electrode may have various shapes to direct the flow of current to the target nerve, including but not limited to a nerve cuff, or an electrode that may be cylindrical or flat (plate-like). The stimulation electrode may be inserted transcutaneously or transcutaneously. Alternatively, a sensor may be implanted in a location that may continuously measure electrical activity, such as the chest or wrist, transcutaneously, and / or transcutaneously. The implanted components may also communicate with other components of the treatment system via a wired connection or wirelessly.

[0069] One embodiment is a two-part system 310 including a monitor unit 312, which in some embodiments may be wearable, and a treatment unit 314, as shown in FIG. 3A. In some embodiments, the treatment unit 314 may be detachable and reversibly attachable to the wearable monitor unit 312. The treatment unit 314 may include an electrical stimulation signal generator 316, a power source 318, and a microprocessor and / or microcontroller 320 for controlling the stimulation. The treatment unit 314 may reversibly connect to and communicate with the wearable monitor 312 directly and / or wirelessly. In some embodiments, the treatment unit 314 may remain separate from the wearable monitor unit 312 and may communicate wirelessly with the wearable monitor unit 312. In some embodiments, the treatment unit 314 may have a data / power port 315, such as a USB port, that allows a user to charge the power source 318, update software and / or parameters on the microcontroller 320, and / or retrieve data from memory on the wearable monitoring unit 312 and / or treatment unit 314. In some embodiments, the data / power port may be located on the wearable monitoring unit 312, or on both the wearable monitoring unit 312 and the treatment unit 314. In some embodiments, the wearable monitoring unit 312 and / or treatment unit 314 may wirelessly communicate with an external computing device to update software and / or parameters and / or retrieve data.

[0070] In some embodiments, the wearable monitor unit 312 may have a housing with a user interface 322 that encloses one or more sensors 324. In some embodiments, the wearable monitor 312 may be used to measure heart rate, rhythm, heart rate variability (HRV), or other measurements that correlate or relate to migraine, other headache conditions, or autonomic nervous system responses. In some embodiments, the wearable monitor 312 may have one or more electrodes 326 disposed at the base of the housing that contacts the patient's skin. Additionally or alternatively, the wearable monitor 312 may have a band 328 or other fastening mechanism with one or more electrodes on the skin-facing side of the band 328. In some embodiments, the wearable monitor unit 312 has two or three electrodes, or at least two or three electrodes. In some embodiments, the wearable monitor unit 312 is unpowered and relies on a power source 318 in the treatment unit 314 for power. In other embodiments, both the wearable monitor unit 312 and the treatment unit 314 have power sources. In some embodiments, only the wearable monitor unit 312 has a power source and the treatment unit relies on power from the monitoring unit.

[0071] In some embodiments, as shown in FIG. 3B, the treatment unit 314 may have the capability to directly contact the wearer's skin and provide electrical stimulation of target nerves, such as the median, radial, ulnar, and / or ABVN, using electrodes 326. In some embodiments, the treatment unit 314 has two or three electrodes, or at least two or three electrodes. These electrodes 326 may be located on the housing of the treatment unit 314, and / or the treatment unit 314 may also have a band 328 or fixation mechanism with electrodes 326. In some embodiments, if the treatment unit 314 has electrodes 326, the wearable monitor unit 312 does not have electrodes. In some embodiments, both the monitor unit and the treatment unit may have electrodes. As described above, the treatment unit 314 may have a stimulator 316, a power source 318, and a microcontroller 320. The wearable monitor unit 312 may have a user interface 322 and one or more sensors 324, and optionally a power source 330 and a microcontroller 321. In some embodiments, if the monitor unit has a power source 330 and / or a microcontroller 321, the treatment unit does not have a power source and / or a microcontroller. In some embodiments, the wearable monitor unit 312 is a smart watch or other wearable device, such as an Apple Watch or an Android-based smart watch, with an application that allows the wearable device to communicate with the treatment unit and function as a monitor unit. In some embodiments, the wearable monitor unit 312 can communicate wirelessly with the treatment unit 314, and one or both of these devices can also communicate wirelessly with an external computing device. In some embodiments, one or both of the wearable monitor unit 312 and the treatment unit 314 may have a data / power port 315. In some embodiments, the wearable monitor unit 312 and the treatment unit 314 may connect to each other via the data / power port 315.

[0072] In some embodiments, the sensor may be located in or on the treatment unit instead of the monitoring unit. In some embodiments, the sensor may be located on both the treatment unit and the monitoring unit. In some embodiments, the sensor or sensors may be located on a separate wearable device, such as a sensor on a band that may be worn around the arm, leg, neck, or chest, or a sensor implanted in the body that may communicate via a wired or wireless connection with the treatment unit and / or the monitoring unit.

[0073] In some embodiments, the monitor unit may instead be carried by the user, e.g., in the user's hand or pocket, rather than being worn. For example, the monitor unit carried by the user may be a smartphone, such as an Android smartphone or an iPhone.

[0074] In some embodiments, the two-part system or monitor unit can instruct the user to perform an action such as sitting down and relaxing their arms, remaining still, or attempting to remain still while the wearable monitor unit takes a measurement using one of the sensors.

[0075] In some embodiments, the user interface may include a display. In some embodiments, the display may be a touch screen display or a capacitive sensor. In some embodiments, the display may be an array of LED lights. In some embodiments, the user interface may include one or more buttons, dials, and / or a keyboard.

[0076] In some embodiments, the electrodes may be, for example, dry contacts (e.g., fabric, metal, silicone, or any other plastic impregnated with conductive fillers, or a combination), may use a conductive gel (e.g., a hydrogel), may have a wet electrode surface (e.g., a sponge containing water or a conductive liquid or gel), or may have fine microneedles. In some embodiments, the electrodes may have a foam support.

[0077] In some embodiments, the monitor unit may be a wearable monitor having a housing with a user interface. The housing may use multiple sensors to collect, store, and analyze biological measurements about the wearer, including, but not limited to, blood pressure, movement (e.g., accelerometer, gyroscope, magnetometer, bending sensor), muscle activity (e.g., EMG using electrodes), cardiovascular rhythm measurements (e.g., heart rate, heart rate variability, or ECG, ventricular and / or atrial dyssynchrony using electrodes to measure cardiac rhythm abnormalities), skin conductance (e.g., skin conductance response, galvanic skin response, using electrodes), respiratory rate and phase, skin temperature, pupil diameter, and sleep state (e.g., wakefulness, light sleep, deep sleep, REM). Cardiac rhythm measurements may be recorded using optical, electrical, and / or accelerometer-based sensors. In particular, studies have shown that increased stress levels can increase blood pressure. Respiration measurements may be recorded with mechanical, electrical, impedance, acoustic, ultrasound, infrared, or video-based measurements. Activities such as exercise may also affect the onset of migraine or headache conditions, and measuring accelerometry (movement), heart rate, etc. may help identify these activities and normalize measurements by similar activities. Thus, using standard statistical analysis, machine learning, deep learning, or big data techniques such as logistic regression or naive Bayes classifiers, these biological measures may be analyzed to assess a person's condition, such as level of stress, which may serve as a predictor of migraine or headache attacks. In some embodiments, the device may provide stimulation based on the measurement of one or more biological measures, a determination of the person's condition, and / or a prediction of a migraine or headache attack.

[0078] In some embodiments, the responsiveness of the stimulation may depend on one, two, or more sensors housed in the device to collect, store, and analyze biological measurements about the wearer, including, but not limited to, movement (e.g., accelerometers, gyroscopes, magnetometers, bending sensors), ground reaction forces or foot pressure (e.g., force sensors or pressure insoles), muscle activity (e.g., EMG), cardiovascular measurements (e.g., heart rate, heart rate variability (HRV), photoplethysmography (PPG), or ECG and / or ventricular and / or atrial dyssynchrony using electrodes to measure cardiac rhythm abnormalities), skin conductance (e.g., skin conductance response, galvanic skin response), respiration rate, skin temperature, pupil diameter, and sleep state (e.g., wakefulness, light sleep, deep sleep, REM). Using standard statistical analysis, machine learning, deep learning, or big data techniques such as logistic regression or naive Bayes classifiers, these biological measures can be analyzed to assess the wearer's activity state, such as sedentary vs. active, stress levels, etc., which may serve as predictors of migraine or headache attacks.

[0079] Sympathetic and parasympathetic activity may be measured by several methods, including microneurography (MSNA), catecholamine testing, heart rate, HRV, or galvanic skin response. HRV may provide a quick and effective approximation of autonomic activity in the body. HRV may be determined by analyzing the time interval between heartbeats (also known as RR intervals). Heart rate may be accurately captured, for example, via a recording device such as a chest strap or finger sensor. The difference between successive RR intervals may provide a picture of cardiac health and autonomic activity. Generally speaking, healthier hearts have greater variability between successive RR intervals. This beat-to-beat data may also be used to indicate an individual's sympathetic and parasympathetic activity levels. With frequency domain analysis, heartbeat frequencies may be separated into distinct bands. High frequency signals (approximately 0.15-0.4 Hz) may reflect almost exclusively parasympathetic activity, while low frequency signals (approximately 0.04-0.15 Hz) may represent a mix of sympathetic and parasympathetic activity. Therefore, taking the ratio of high frequency (HF) and low frequency (LF) signals may provide an approximation of sympathetic tone. In some embodiments, HRV may be analyzed, for example, under time domain and geometric domain methods in addition to frequency domain methods. In some embodiments, an increase in heart rate variability may mean an increase in parasympathetic response and / or a decrease in sympathetic response. A decrease in heart rate variability may mean a decrease in parasympathetic response and / or an increase in sympathetic response. In some embodiments, the system may sense an increase or decrease in HRV of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, 100% or more relative to a baseline value (or a target desired HRV value) and configure changes in one, two or more stimulation modality parameters accordingly. In some embodiments, the one, two or more stimulation modalities may be configured to modulate, such as an increase or decrease in stimulation to one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, Response to treatment can be ascertained by sensing an increase or decrease in parasympathetic or sympathetic tone, including, but not limited to, an increase or decrease in HRV, a change in the high frequency content of HRV, and a change in the ratio of high frequency to low frequency content of HRV. In some embodiments, the balance of parasympathetic and sympathetic activity can be assessed by frequency analysis of heart rate variability measured by pulse plethysmography using an LED light source and light sensor placed in a device that measures variations in light levels due to blood flow targeting one of the major blood vessels around the knee or arm or neck or ear, in other embodiments. In some embodiments, heart rate can be measured using an accelerometer-based sensor or an electrical-based sensor, as well as a single or multi-lead ECG monitor.

[0080] In some cases, a large source of error in optical measurements of heart rate is motion artifacts due to relative motion between the optical sensor and the blood vessel being measured. In some embodiments, the optical heart rate sensor has an adhesive on the side of the housing that contacts the wearer's skin to reduce the relative motion between the sensor and the target blood vessel.

[0081] HRV measurements in subjects with chronic migraine or headache may be significantly different compared to controls. With frequency domain analysis, heartbeat frequencies may be separated into distinct bands. High frequency signals (about 0.15 Hz to about 0.4 Hz) may reflect almost exclusively parasympathetic activity, while low frequency signals (about 0.04 Hz to about 0.15 Hz) may represent a mixture of sympathetic and parasympathetic activity. In some embodiments, taking the ratio of high frequency (HF) signals to low frequency (LF) signals provides an approximation of sympathetic tone. Very low frequency (VLF) signals (about 0.004 Hz to about 0.040 Hz) may also be evaluated to assess parasympathetic activity. The total output of HRV in the frequency domain may be evaluated to assess autonomic activity.

[0082] Sympathetic and parasympathetic function may also be assessed, for example, by analyzing the mean normal-normal intervals (e.g., all intervals between adjacent QRS complexes of the measured cardiac rhythm, including the number of interval differences of consecutive NN intervals greater than 50 milliseconds, the square root of the mean squared difference of consecutive NN intervals, and the standard deviation of the NN intervals).

[0083] In some embodiments, sympathetic activity can also be assessed using more traditional techniques such as measuring the change in blood pressure before releasing and before starting the gripping movement, or measuring the change in blood pressure before and after immersing the hand in a cold water bath (e.g., cold pressor test). Parasympathetic activity can be assessed by measuring the heart rate response during deep breathing, or the heart rate response to standing from a lying or sitting position (orthostatic), or by repositioning the person's body, for example, using a tilt table. Both sympathetic and parasympathetic activity can be assessed during the Valsalva maneuver (e.g., blowing into a mercury manometer and maintaining a pressure of about or at least about 40 mmHg), or during orthostatic heart rate response (e.g., going from a lying or sitting position to a standing position).

[0084] In some embodiments, one, two, or more additional sensors are disposed within the device, including electrical and / or accelerometer sensors in contact with the wearer's skin to measure cardiac activity, or pressure sensors to measure vascular changes, used in combination with an optical sensor to improve the fidelity of the heart rate measurement.

[0085] In some embodiments, the systems and devices have memory and a processor for extracting RR intervals from the sensor data, calculating the variability of the RR intervals, transforming the data into the frequency domain, and calculating high frequency signals, low frequency signals, and ratios of high frequency signals to low frequency signals.

[0086] In some embodiments, the heart rate sensor may store the collected data for a specified period of time to ensure that the data collected is appropriate for heart rate variability calculations. The specified period of time may range from 1 to 60 seconds and may extend to 10 minutes or more.

[0087] In some embodiments, electrodermal activity, also known as galvanic skin response or skin conductance response, may be measured using sensors such as electrodes. Hereinafter, galvanic skin response and electrodermal activity are used synonymously. Galvanic skin response is a change in the electrical resistance of the skin caused by emotional stress and can be measured with a sensitive galvanometer. Without being limited by theory, skin resistance varies with the state of the sweat glands in the skin. Sweating is controlled by the sympathetic nervous system, and skin conductance can be an indicator of psychological or physiological arousal. When the sympathetic nervous system is highly excited, sweat gland activity also increases, which increases skin conductance. In this way, skin conductance can be a measure of emotional and sympathetic responses and can send feedback data to a controller, which then adjusts the stimulation, for example to reduce sympathetic nervous system activity. Other non-limiting parameters related to sympathetic and / or parasympathetic nervous system activity that may be sensed include, for example, sweating at certain times of the day and / or night, sleep states detected, for example, by an EEG sensor, e.g., an EEG headband (determining whether sympathetic and / or parasympathetic activity is particularly high or low, potentially correlating sleep states such as stage 1, 2, 3, 4, or REM), and / or movement. In some embodiments, a diagnostic and / or combined diagnostic / stimulation device may be configured to measure a person's heart rate and galvanic skin response to improve an estimate of the person's autonomic activity. This estimate of autonomic activity may be used to adjust the stimulation applied as a therapy, including, but not limited to, stimulation frequency, stimulation burst adjustments, selected neural targets, duration of a stimulation session, or time of day when stimulation is applied. In some embodiments, a wearable device, such as a wrist-worn device, may include both an electrodermal activity (EDA) sensor and a heart rate sensor. This combination of data may, in some embodiments, advantageously and synergistically provide an improved estimate of sympathetic and parasympathetic activity over a single measure alone. In some embodiments, the system may include multiple sensors for measuring electrodermal activity in conjunction with heart rate and HRV.Data from multiple sensors may be analyzed by a hardware or software processor and combined to provide a more accurate estimate of sympathetic and / or parasympathetic activity. In some embodiments, the EDA and HR sensors may be placed in a wrist-worn device that communicates with the stimulation device via a wired or wireless connection or transmits data to a centralized remote server (e.g., the cloud). In particular, stimulation parameters such as frequency or pulse width, neural target location (e.g., radial, ulnar or ABV nerves), or dosing regimen (e.g., duration or time of day of stimulation session) may be adjusted based on the estimate of sympathetic and / or parasympathetic activity. In some embodiments, significant changes in sympathetic and / or parasympathetic activity may be used to predict the onset of a migraine or headache, and the device may initiate stimulation to prevent or shorten the duration of the episode. Adjustments may be made in real time or in subsequent stimulation sessions. In some embodiments, the stimulation frequency may be adjusted to increase or decrease autonomic activity regulated by a single specific nerve or multiple nerves. For example, in some embodiments, relatively low frequency stimulation of a target nerve (e.g., below threshold, e.g., about 5 Hz) may potentially inhibit the nerve and thus reduce sympathetic activity, while higher frequency stimulation (e.g., above threshold, e.g., about 5 Hz) may potentially even excite the nerve and thus increase sympathetic activity. In some embodiments, the stimulation frequency may be, for example, about 20 Hz, 15 Hz, 10 Hz, 5 Hz, 4 Hz, 3 Hz, 2 Hz, 1 Hz or less, or a range including any two of the aforementioned values. Furthermore, the pulse width of the stimulation waveform may be adjusted to recruit more or less specific fiber types, including cutaneous fibers, which may inhibit sympathetic activity. The same effect may occur with the same or other target nerves to modulate parasympathetic activity. In other words, in some embodiments, relatively low frequency stimulation of a target nerve (e.g., below threshold, e.g., about 5 Hz) can potentially inhibit the nerve and thus decrease parasympathetic activity, while higher frequency stimulation (e.g., above threshold, e.g., about 5 Hz) can potentially excite the nerve and thus increase parasympathetic activity.Without being limited by theory, for example, depending on the stimulation parameters, in some cases stimulating a target nerve may increase or decrease sympathetic activity, parasympathetic activity, or both. In some embodiments, stimulation of the saphenous nerve may affect sympathetic activity and stimulation of the tibial nerve may affect parasympathetic activity.

[0088] In some embodiments, stimulation of one, two, or more nerves in the upper and / or lower limbs may be combined with stimulation of the ABVN, for example via the auriculotemporal nerve or tragus, to modulate vagal activity and restore balance to the autonomic nervous system. In alternative embodiments, the system may stimulate only the ABVN. FIG. 3C shows selected anatomical structures of the ear 390, including a relatively medial region of the ear 390 generally innervated by the auriculotemporal nerve 399, the tragus 398, the helix 397, the concha 396, a region 395 at the lower and lateral edge of the ear generally innervated by the greater auricular nerve, and a more central region 394 near the auriculotemporal nerve or tragus 398 generally innervated by the ABVN. In some embodiments, any number of the aforementioned anatomical locations of the ear may be neuromodulated or configured to be neuromodulated. In some embodiments, any number of the aforementioned anatomical locations of the ear are not neuromodulated or are not configured to be neuromodulated.

[0089] Stimulation of the concha or tragus may be performed non-invasively, for example, via a plug, earpiece, or other device, which may in some cases include electrodes for transcutaneous electrical stimulation. FIG. 3D shows an embodiment of a tragus stimulator 392 having an earphone configuration placed within the tragus 398 of the ear 390. The stimulator 392 may be wired as shown, or wireless in other embodiments. The stimulator 392 may include a distal ear receptacle portion 389 that may include a cathode 387 and an anode 388, a hub 386 proximate the receptacle portion 389, and a conduit 388 to a source of electromagnetic energy, such as electrical energy. In some embodiments, the auricle stimulator 392 includes one or more sensors for measuring parameters related to stimulation and / or physiological function, as discussed elsewhere herein. The auricle stimulator 392 may be unilateral or bilateral (e.g., placed in both ears).

[0090] In some embodiments, the system may include multiple stimulators that communicate wirelessly with each other to provide synchronized, patterned stimulation. In some embodiments, the multiple stimulators may be electrically connected with multiple electrode pairs to stimulate multiple nerves simultaneously. In one embodiment, the system may include a wrist stimulator to target the median nerve and an ear stimulator to target the ABVN. Each stimulator in the system may communicate with each other via wired or wireless connections. The multiple stimulators may provide synchronized stimulation to multiple nerves. Stimulation may be, for example, burst, offset, or alternating between multiple nerves.

[0091] The device may also respond to episodes of symptoms, including unilateral pulsating cranial pain, hypersensitivity to light, sound and smell, nausea, and possibly dysfunction of the autonomic nervous system, cognitive, emotional and motor systems. If more episodes occur per day, treatment may be increased, for example, by increasing the stimulation amplitude, duration of stimulation, or number of treatment sessions.

[0092] The number of episodes of symptoms may be detected in various ways to control the stimulation applied by the system and device. In some embodiments, the patient may enter an event associated with the symptom, including, but not limited to, unilateral pulsating cranial pain, hypersensitivity to light, sound and smell, and nausea events on the mobile device.

[0093] One embodiment of the system may centrally store biological measurements from multiple wearers on a server system (e.g., cloud) along with other relevant demographic data about each user including age, weight, height, gender, ethnicity, etc. The data collected from multiple wearers may be analyzed using standard statistical analysis, machine learning, deep learning, or big data techniques such as logistic regression or naive Bayes classifiers (or other classifiers) to improve prediction of migraine or headache attacks by determining correlations between biological measures and other recorded symptom events and migraine or headache events. These correlations may be used to set parameters of the stimulation waveform applied by the treatment unit, determine the best time to apply the stimulation therapy, and / or adapt the stimulation waveform applied by the treatment unit in real time.

[0094] In one embodiment of the system, the wearable monitor automatically detects and records medication dosage and consumption to (1) track patient compliance, (2) evaluate treatment effectiveness in combination with migraine or headache episode records, and (3) determine or predict migraine or headache attacks. Medication dosage and consumption may be detected and recorded in multiple ways, including (1) using a visual scanner to record markings on a pill pack or bottle each time medication is consumed, (2) a smart pill cap with a force sensor and a radio transmitter to detect each time medication is consumed from a pill bottle, (3) an RFID chip of similar size and shape to the pill consumed with each dose of medication that is activated by ingestion and communicates with the monitor device, (4) an RFID chip embedded in a sugar pill consumed with each dose of medication that is activated by ingestion and communicates with the monitor device, (5) a pill with visual coding that is scanned and recorded by a camera on the monitor unit each time medication is consumed, or (6) having the patient record medication consumption on the device.

[0095] The system may also record the patient's satisfaction after each stimulation session or after a specified period of time, such as a day, week, or month, via an input on the device that provides additional information to assist in the feedback application of the therapy. In some cases, if the person is satisfied, the therapy is maintained with the current stimulation waveform and level. In other cases, this may mean that the stimulation therapy may need to be optimized, for example by changing stimulation parameters such as waveform frequency or amplitude.

[0096] In some embodiments, the wearable monitor may have visual, auditory, tactile (e.g., compression band), or vibrotactile cues to notify the wearer of important events based on the analysis of biological measures, including, but not limited to, prediction of a migraine or headache attack, and / or increases in stress levels, heart rate, heart rate variability, or other parameters. The cue system may also notify the wearer of other predefined events or reminders set by the wearer.

[0097] In some embodiments, the wearable monitor and / or treatment unit may be in the form of a wrist band or watch, a ring, a glove, an arm or arm band or cuff, a knee band, a sock, a leg or leg cuff, an earpiece / headphone, a headband, a necklace or neckband, or a conforming patch that fits multiple locations on the body. In some embodiments, the wearable monitor and / or treatment unit is not in the form of a patch. In some embodiments, the wearable monitor and / or treatment unit extends completely circumferentially around the anatomical location.

[0098] In one embodiment, the wearable monitor may have a processing unit and memory to collect, store, process, and analyze the biological measurements along with other data input by the wearer.

[0099] In some embodiments, the wearable monitor may take user input regarding events including dietary history, medication history, caffeine intake, alcohol intake, sodium intake, etc. The monitor may use an accelerometer to measure certain movements, gestures, or tapping patterns to record user input at certain prompts. Other touch sensors such as resistive strips or pressure sensitive screens may be used to measure certain gestures to record user input. These gesture-based means for recording user input minimize the complexity of the steps required to enter user data into the device. The data may be stored in memory and processed by a processing unit. In some embodiments, the data may be transmitted from the wearable monitor to an external computing device.

[0100] In one embodiment, the wearable monitor and / or treatment unit may connect with other applications such as calendars and activity logs to sync and track events, or saved calendars may be saved and stored on the device. In some embodiments, the wearable monitor and / or treatment unit may communicate with various computing devices, such as, for example, smart phones, smart watches, tablets, laptop computers, or desktop computers that have these applications. In some embodiments, the wearable monitor may include a portable blood pressure monitor.

[0101] In one embodiment, the monitor unit and / or treatment unit may have a GPS or similar device to track the wearer's location and assess the activity. GPS measurements may be combined with a mapping or location system to determine the context of the wearer's activity (e.g., gym, office, home) and / or to determine elevation changes during a particular activity, such as running or cycling.

[0102] In some embodiments, as shown in FIGS. 4A-4D, a single monitor unit 412 may be used with multiple treatment units 414 having different sizes, shapes, colors, markings and / or capabilities, including different battery capacities and power outputs. Different wearers and use scenarios may require different amounts of stimulation duration and power, making smaller or larger treatment units more desirable, giving the wearer options to meet their needs in different scenarios. In some embodiments, the treatment units 414 may also have different programming, including treatments that may be adapted to different stimulation parameters and / or different types of treatment. In some embodiments, the treatment units may be tailored to provide different intensities of treatment, such as, for example, one unit for a short, low intensity duration treatment, another unit for a long, high intensity treatment, or one unit for various usage patterns or dosing regimens, such as one unit for daily stimulation and one unit for weekly stimulation. The different features and capabilities of the treatment units may correspond to different sizes, shapes, colors, and / or markings. The carrying case 432 may be used to hold a set of treatment units, such as a set of treatment units that differ in battery capacity and power output or some other characteristic.

[0103] In one embodiment, the treatment unit has its own charging station that can charge multiple treatment units simultaneously. The charging station may have a custom direct electrical connection to the treatment units or may wirelessly charge the treatment units in close proximity. Similarly, in some embodiments, the charging station may charge the monitoring units in a similar manner.

[0104] In one embodiment, the wearable monitor may track parameters related to the stimulation provided by the treatment unit, including the time of stimulation, the duration of the stimulation session, and the power used by the treatment unit. This data may be stored in a memory within the wearable monitor, processed by the wearable monitor, and / or transmitted to an external computing device.

[0105] In one embodiment, the treatment unit may use a switch or electrical sensor to detect the connection of the electrodes, (1) ensure that the proper and unique electrodes are installed (i.e., do not use different or incorrect types of electrodes) communicating a unique code, e.g., via RFID, encoded EEPROM chip, resistive or capacitive based ID, binary identifier, or surface pattern, (2) regulate the number of uses or electrode life of each electrode to prevent overuse, and (3) prevent use of the device without electrodes to prevent small shocks. In some embodiments, the treatment unit and / or monitor unit may have identifiers that may be sent to and from each other or to an external computing device. The identifiers enable one unit to determine the features, capabilities, and / or configuration of the other device, including the electrode configurations described above, using appropriate treatment parameters, and may also use component life or expiration dates that may be based on voltage measurements, time, number of treatment sessions, or other parameters. In some embodiments, instead of using identifiers, the features, capabilities, and / or configuration of one device may be transmitted to the other device from one device directly, or via input to a user interface, or via an external computing device.

[0106] Other components of the treatment system, including the band, treatment unit, monitoring unit, and skin interface, may each have one or more identifiers that perform the functions described above. These identifiers may encode various information described herein, as well as predetermined dosing regimens, initialization routines, calibration routines, or specific parameters. The identifiers may be associated with look-up tables that store the encoded information.

[0107] In some embodiments, the wearable monitor and / or treatment unit may communicate with an external computer or device (e.g., a tablet, smart phone, smart watch, or custom base station that includes a charger and communication connections) to store data. The communication between the monitor and the external device may be a direct physical connection or a wireless communication connection such as Bluetooth or GSM or cellular.

[0108] In one embodiment of the device, the treatment unit has an array of electrodes and one or more sensors, such as a pressure sensor, between the treatment unit and the wearer's wrist to measure the contact pressure of the electrodes and / or the skin interface around them. Consistent pressure of the skin interface is particularly important for the comfort of dry electrode materials. This pressure data can be analyzed to determine which electrodes in the array stimulate the appropriate nerves, or to detect changes in skin contact due to movement or other conditions and switch stimulation of the electrode array to an optimal position. These methods can be used to (1) evaluate poor electrode contact and (2) adjust the amplitude of stimulation based on the pressure measurements.

[0109] Increasing the contact pressure between the device and the wearer's skin and / or stimulating with electrodes having adequate contact pressure or pressure above a contact pressure threshold can (1) increase the surface area of ​​contact and reduce discomfort; (2) activate peripheral nerve fibers for deep somatic pain, reduce discomfort from stimulation and activate superficial pain fibers; (3) reduce the stimulation amplitude required to improve stimulation of the target nerve (e.g., the electrode is physically closer to the nerve due to compression of the surrounding tissue); or (4) reduce the effects of skin movement.

[0110] In some embodiments, certain fiber types within one or more nerves may be selectively activated (e.g., generating action potentials in such specific fiber types) to restore autonomic balance by specifically modulating the sympathetic and parasympathetic limbs of the autonomic nervous system (e.g., selectively only one or more of A alpha, Abeta, A delta, B and / or C fibers). In some embodiments, the systems and methods stimulate or do not substantially stimulate A alpha, Abeta, A delta, B fibers or C fibers.

[0111] Disclosed herein in some embodiments are wearable systems and methods that can utilize transcutaneous sensory stimulation in the form of burst patterns (e.g., theta burst patterns for treating migraine or headache conditions, and / or various other conditions, including but not limited to those disclosed herein. Non-invasive peripheral nerve theta burst stimulation can be effective in promoting cortical or spinal plasticity, in some cases more efficiently than continuous stimulation, to reduce symptoms and improve an individual's quality of life.

[0112] In some embodiments, the stimulation includes a pattern of electromagnetic stimulation of a peripheral nerve. Pattern stimulation can be burst stimulation, such as an on / off pattern that repeats at regular intervals (e.g., on for 10 ms, off for 20 ms, etc.), or non-burst pattern stimulation, which can be more complex in some embodiments, such as stochastic patterns or sinusoidal envelopes. Electromagnetic stimulation can include, for example, electrical energy, mechanical energy (e.g., vibration), magnetic energy, ultrasonic energy, radio frequency energy, thermal energy, optical energy (e.g., infrared or ultraviolet energy, etc.), and / or microwave energy, or combinations thereof. In some embodiments, stimulation is limited to only electrical energy (e.g., no magnetic or other types of energy are applied). Peripheral stimulation can include transdermal, transdermal, and / or implanted stimulation.

[0113] In some embodiments, the stimulation comprises non-invasive transcutaneous electrical pattern or burst stimulation of peripheral nerves, including afferent and / or efferent nerves. Without being limited by theory, burst stimulation of peripheral nerves may unexpectedly result in one or more of greater efficacy, greater plasticity, increased resistance or tolerance, reduced habituation effects, increased comfort, and / or reduced processing time required to achieve the same beneficial effect, as compared to conventional or continuous stimulation. Burst stimulation of peripheral nerves, including afferent nerves, may in some cases deliver more effective therapy by remotely accelerating plasticity in one or more central nervous system (e.g., brain and / or spinal cord) circuits, in other words, by creating plasticity in neural circuits for a period of time much longer than the duration of a stimulation session, such as, for example, about or at least about 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months, or more. In some cases, peripheral stimulation may be more convenient and comfortable for the user than central stimulation (e.g., transcranial stimulation and / or spinal cord stimulation) and may be more suitable for home and ambulatory use.

[0114] In some embodiments, the burst stimulation comprises theta burst stimulation. Theta burst stimulation (TBS) is a patterned form of repetitive stimulation that uses high frequency pulses separated by varying interburst intervals. Originally used for the induction of long-term potentiation in hippocampal learning and memory studies, theta burst stimulation in the form of repetitive magnetic stimulation (rTMS) has been demonstrated to induce plasticity non-invasively in humans in the motor, sensory and visual cortex. Depending on various parameters including the duration and continuity of stimulation, long-term potentiation or long-term depression (LTP / LTD)-like effects can be observed, which are surrogate measures of synaptic efficacy. The number of sessions and the interval between individual sessions of stimulation can also affect the duration of the induced response. The level of muscle relaxation before or during stimulation can also affect the direction or amplitude of the resulting plasticity induction, suggesting that there are homeostatic mechanisms in place that adjust the threshold for plasticity depending on previous synaptic activity. The effective modulation of neural plasticity demonstrated with theta burst stimulation may have great potential for the treatment of various neurological disorders and may affect other central neural circuits.

[0115] In some embodiments, the intra-burst frequency can be about or at least about 10 Hz, 20 Hz, 30 Hz, 40 Hz, 50 Hz, 100 Hz, 250 Hz, 500 Hz, 1 kHz, or more, or a range including any two of the foregoing frequencies. In some embodiments, the intra-burst frequency can vary between about 10 Hz and about 20 kHz. The intra-burst frequency can also be varied randomly or pseudo-randomly during the burst to reduce habituation and / or increase comfort. In other embodiments, the intra-burst frequency can be about 10 Hz to about 250 Hz, about 50 Hz to about 150 Hz, about 10 Hz to about 100 Hz, about 100 Hz to about 150 Hz, about 50 Hz to about 250 Hz, less than about 100 Hz, 95 Hz, 90 Hz, 85 Hz, 80 Hz, 75 Hz, 70 Hz, 65 Hz, 60 Hz, 55 Hz, 55 Hz, or about 50 Hz to about 1000 Hz, or a range including any two of the frequencies disclosed in this paragraph to maximize therapeutic response, improve comfort, reduce habituation, and / or reduce power consumption of the electrical stimulation device.

[0116] In some embodiments, burst stimulation is applied to one or more nerves, and the inter-burst frequency may be from about 1 Hz to about 20 Hz, e.g., from about 4 Hz (250 ms between the onset of each burst) to about 12 Hz (83 ms), e.g., from about 4 Hz (250 ms) to about 8 Hz (142 ms), which includes about 5 Hz (200 ms), or in some embodiments, from about 3.5 Hz to about 7.5 Hz, or from about 6 Hz to about 10 Hz, which are commonly accepted as theta band frequencies.

[0117] In some embodiments, the inter-session frequency can be from about 1 minute to about 12 hours, e.g., from about 5 minutes to about 120 minutes, from about 5 minutes to about 60 minutes, from about 10 minutes to about 30 minutes, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 90, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, or 720 minutes, or a range incorporating any two of the foregoing values.

[0118] In some embodiments, a repetitive pattern of stimulation known as four-pulse stimulation may be used, which includes four pulses at a short interval frequency (1.5 ms interstimulus interval) repeated at about 0.2 Hz for a period of time (e.g., about 30 minutes). Four-pulse stimulation has been shown to induce long-term plasticity. Variation of intra-burst frequency using this paradigm may affect the direction of induced plasticity. These repetitive small pulses may be anywhere between 2 to 10 or more pulses.

[0119] Other burst patterns besides theta burst stimulation may be used instead or in addition. Some non-limiting examples include delta (0-4 Hz), alpha (8-12 Hz), beta (12-30 Hz), and gamma (30-100 Hz) inter-burst frequencies. In some embodiments, neuromodulation (e.g., stimulation) with bursts at alpha frequencies may advantageously increase oscillation frequency. In some embodiments, neuromodulation (e.g., stimulation) with bursts at theta frequencies may advantageously disrupt low frequency oscillations, which may be associated with migraine pathology. In some embodiments, neuromodulation (e.g., stimulation) with bursts at beta or gamma frequencies may disrupt increased ambient beta / gamma activity.

[0120] In some embodiments, initial calibration and / or periodic or continuous closed-loop adjustment of the burst stimulation frequency may be performed, for example, based on pre-treatment, during-treatment, and / or post-treatment EEG assessments (e.g., calculating or otherwise determining the dominant oscillation frequency using either in-house or at-home assessments, and / or EEG monitoring during resting-state ictal or interictal periods). The closed-loop adjustment may be performed on a time scale of seconds, minutes, hours, days, weeks, or months. The controller may be configured to vary the burst frequency between two or more frequencies, including gradient, random, Gaussian, and others, for example as disclosed elsewhere herein.

[0121] In some embodiments, the dominant frequency of abnormal neuronal oscillations is calculated from EEG data recorded during resting state (e.g., intermediate state) before stimulation. EEG data may be recorded from one or more predefined regions of interest, including but not limited to Fp1, Fp2, F3, F4, F7, F8, C3, C4, T3, T4, T5, T6, P3, P4, M1, M2, O1, and O2, as shown in FIG. 4E. The dominant frequency is then used as a stimulation parameter, such as, for example, a limited pattern or burst frequency, a stimulation frequency, and / or a pulse width. In some embodiments, the dominant frequency of abnormal neuronal oscillations may be calculated from EEG data collected over 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 60, or 90 minutes. In embodiments, the dominant frequency of abnormal neuronal oscillations may be recalculated every 1, 2, 5, 7, 14, 30, 31, 60, or 90 days, or every 6, 9, or 12 months or more, or a range incorporating any two of the aforementioned values.

[0122] In some embodiments, the response to the treatment may be observed with an EEG assessment after a specified time (e.g., about 1, 2, 3, 4, 5, 6, or 7 days or less, 2, 3, 4 weeks, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more, or a range incorporating any two of the foregoing values). For example, a first initial EEG assessment may be performed prior to the initial treatment. A second EEG assessment may be performed during or after the treatment session, and stimulation parameters are adjusted based at least in part on the second EEG assessment. In some embodiments, the second EEG assessment may continue for a period of time during or after the treatment session, and stimulation parameters are adjusted in real time based at least in part on the EEG data received from the second EEG assessment.

[0123] In some embodiments, the peripheral burst stimulation may include a sine wave, square, rectangular, triangular, sawtooth, or other waveform.

[0124] In some embodiments, burst transcutaneous peripheral electrical stimulation may be preferred over burst transcutaneous peripheral magnetic stimulation in some cases. In some cases, transcutaneous peripheral electrical stimulation may be advantageous because magnetic theta bursts require more power and / or may be a heavier device. Electrical stimulation may advantageously provide for portable, at-home use and more precise stimulation of the target nerve by controlling the current flow between electrodes or by using a transcutaneous needle. In some embodiments, stimulation may be provided at a fixed burst frequency without measuring / adjusting the frequency of measurement of physiological or pathological parameters or symptoms associated with the subject.

[0125] In one embodiment, the timing of individual sessions of stimulation may be altered to extend the duration of plasticity. Session intervals may be between a lower threshold of approximately 1 minute and an upper threshold of approximately 24 hours. Varying the session intervals of theta burst stimulation may have the profound effect of altering the interval between stimulation sessions. An extension of the symptom improvement period may improve the tolerance of chronic repetitive stimulation. In some embodiments, the session intervals may be randomized between a lower threshold and an upper threshold. In some embodiments, the session intervals may be increased from a lower threshold or value to an upper threshold or value. In some embodiments, the session intervals may be decreased from an upper threshold or value to a lower threshold or value. In some embodiments, the session intervals may be altered according to a predetermined algorithm or schedule. In some embodiments, the session intervals may be altered based on feedback based on data from an accelerometer or electromyogram. In some embodiments, the session intervals may be altered based on feedback based on symptom tracking and / or measures of autonomic activity (e.g., HRV, EDA). The intervals may also be optimized using machine learning algorithms such as deep learning, naive Bayes networks, neural networks, and / or crowd-sourced or otherwise aggregated data sets from multiple users with data (e.g., device usage, symptom tracking, autonomic nervous activity) stored on a remote centralized server (e.g., the cloud).

[0126] In some embodiments, alternating stimulation of the nerves at the wrist (e.g., radial, median, and / or ulnar nerves), or ear, may be performed in a rhythmic or pseudorandom pattern. Without being limited by theory, bursts in a rhythmic pattern may improve the efficiency of therapeutic benefit by promoting plasticity of the corticospinal circuitry. Rhythmic or pseudorandom burst patterns may prevent neural habituation that occurs with constant stimulation. In some embodiments, the rhythmic burst patterns may synchronize electrical phases of the cardiac cycle, such as P waves, R waves, QRS complexes, ST segments, and T waves, to cardiac rhythmic events detected by a heart rate monitor in the system, including, but not limited to, P waves, R waves, QRS complexes, ST segments, and T waves.

[0127] In some embodiments, median, radial, and / or ulnar stimulation may be combined for synergistic effects in the brachial plexus. The median, radial, and ulnar nerves innervate various levels of the spinal cord in the brachial plexus, and the pathways go to various target locations and organs. Some embodiments may provide simultaneous or delayed timed stimulation to the median, radial, and / or ulnar nerves to control targeting within the brachial plexus, providing a synergistic effect of neural activation in the brachial plexus resulting in the stellate ganglion and sympathetic chain. This synergistic effect may provide the advantage of greater therapeutic benefit with less discomfort and less current (e.g., less power for longer battery life). The timing of stimulation may be simultaneous or may involve a delay to compensate for differences in conduction velocities of different nerves so that the signals arrive at the brachial plexus at the same time. Without being limited by theory, simultaneous or near simultaneous activation of the brachial plexus may enhance stimulation through neural pathways. For example, the mean conduction velocities of the radial, median, and ulnar sensory nerves are about 51 m / s, 60 m / s, and 63 m / s, respectively. Based on the variation in nerve length from the wrist to the brachial plexus from the 1st percentile female to the 99th percentile male, this may require a stimulation delay of about 1.3 to about 1.7 ms between the median and radial nerves, about 0.3 to about 0.4 ms between the median and ulnar nerves, and about 1.6 ms to about 2.1 ms between the radial and ulnar nerves. In some embodiments, the stimulation delay between the first and second nerves may be about 0.3 ms to about 1.7 ms, or about 0.2 ms to about 2.0 ms, about 1.2 ms to about 2.1 ms, or about 1 ms to about 2 ms. Combined subthreshold stimulation of the median, radial, and / or ulnar nerves may advantageously require subthreshold stimulation of the individual nerves, resulting in a synergistic effect at the brachial plexus. In some embodiments, the system may include nerve conduction velocity measurements by applying a stimulation source to a distal portion of the nerve and a measurement electrode to a proximal portion of the nerve, measuring the individual nerve conduction velocities and modifying the timed delays based on the individual measurements.

[0128] In some embodiments, the system may include an electrode configuration for stimulating nerves (e.g., radial, median, and / or ulnar) in an alternating pattern that may be rhythmic or pseudorandom. For rhythmic alternating patterns, the alternating frequency may be in the range of 1-100 Hz, which has been shown to improve treatment efficacy by promoting plasticity of corticospinal circuits. In some embodiments, device embodiments may include an electrode configuration for alternating stimulation of nerves (e.g., radial, median, and / or ulnar) and adjusting stimulation parameters (e.g., stimulation frequency, alternating frequency, stimulation duration, stimulation time per day) based on an assessment of autonomic balance, for example, by measuring heart rate variability (HRV) and analyzing sympatho-vagal balance as the ratio of absolute low frequency (LF) to absolute high frequency (HF) power, or LF / HF of the measured HRV, as described elsewhere herein.

[0129] 5A-5I show another embodiment of a two-part treatment system including a disposable band 500 and a treatment unit 502 that may be reversibly attached to the disposable band 500. The disposable band 500 may have two or more electrodes 504 disposed on a skin-facing or inner surface of the band and a receptacle 506 or receiving portion for reversibly receiving the treatment unit 502. Within the band 500 are wires and / or conductive traces that form a flexible circuit 505 that extends from the electrodes 504 to the receptacle 506 to electrically connect the electrodes 504 to the treatment unit 502 when the treatment unit 502 is placed within the receptacle 506. In some embodiments, the wires and / or conductive traces of the flexible circuit 505 are arranged in a wavy or undulating pattern to improve bending ability. In some embodiments, shown in FIG. 5F, the receptacle 506 may have one or more electrical contacts, such as one or more pin holes 507, for receiving one or more complementary electrical contacts, such as pins 509, from the treatment unit 502. The flexible circuit 505 may extend into the pin holes 507 such that an electrical connection is made when a pin is inserted into the pin holes 507. In some embodiments, as shown in FIGS. 5G-5I, the receptacle 506 may have a clip, retaining lip, magnet, snap fit, twist fit, hook, latch, sliding mechanism, or other securing mechanism to reversibly secure the treatment unit 502 to the band 500. FIG. 5G shows a clip 511, which may or may not be spring loaded, to form a snap fit around the treatment unit 502. FIG. 5H shows a flexible lip 513 around the opening of the receptacle that may be used to hold the treatment unit 502 after it is inserted into the receptacle 506. 5I shows a magnet 515 that may be positioned in a complementary position within the treatment unit 502 and the receptacle. In some embodiments, the clip, magnet, snap-fit ​​mechanism, twist-fit mechanism, hook, or other fastening mechanism may be made of metal or some other conductive material and electrically connected to the electrodes via wires and / or conductive traces.The electrodes 504 may be dry electrodes or may be coated with a conductive gel.

[0130] In some embodiments, the treatment unit 502 may include a battery, which may be rechargeable, and electronics for delivering electrical stimulation to the patient's nerves via the electrodes. The electronics may include a stimulator and a microcontroller, and may include memory and one or more sensors, such as a blood pressure sensor and / or a sensor for measuring heart rate and / or heart rate variability and / or galvanic skin response, or one, two or more ECG electrodes for measuring dyssynchrony. In some embodiments, the device may sense the impedance of the electrodes to assess the integrity of the electrode-skin interface. In some embodiments, there may be electrical indications (e.g., reading the chip, pressing the sensor on the connector, etc.) to detect the integrity of the connection between the band and the treatment unit. In some embodiments, the treatment unit 502 may have one or more LEDs, mini OLED screens, LCS, or indicators 501 that may indicate the status of the treatment unit 502, such as whether the treatment unit 502 is connected to the band 500, the remaining power in the battery of the treatment unit 502, whether stimulation is being delivered, the stimulation level, whether data is being transmitted, whether sensor measurements are being made, whether a calibration routine is being performed, whether the treatment unit 502 is initialized, whether the treatment unit 502 is paired with another device, such as a smart watch and / or smart phone, whether the battery is being charged, etc. In some embodiments, the treatment unit 502 may also include a user interface 503, such as one or more buttons.

[0131] FIG. 5B illustrates a kit including a wrist-worn device that may be sent to a user. The kit may include multiple bands 500 of different sizes, shapes, colors, etc. to accommodate patients with different wrist sizes or other body part sizes such as ankles, arms, fingers, and legs, and to accommodate different types of connected accessories such as secondary displays (e.g., smart watches). In some embodiments, the kit has three bands to accommodate most wrist sizes. In some embodiments, the kit has two bands to cover most sizes. Additionally, the kit may include one or more electronic units 502. When multiple electronic units 502 are provided in the kit, the battery capacities of the different electronic units 502 may be different to accommodate different types of use. For example, a relatively low capacity battery may be used for on-demand stimulation, while a relatively high capacity battery may be used for automated and / or responsive stimulation driven by a microcontroller. In some embodiments, only a single electronic unit is provided. In other embodiments, multiple electronic units are provided while a single band is provided. The kit may also include a charger 508 for charging the treatment unit 502. In some embodiments, the charger 508 may inductively charge the treatment unit 502. In other embodiments, the charger 508 may charge the treatment unit with a charging cable that may be inserted into a power port on the treatment unit. In some embodiments, the treatment unit 502 may dock with the charger 508 for charging.

[0132] FIG. 5C illustrates an embodiment in which a smart watch 510, such as an Apple Watch, is reversibly or permanently affixed to the band 500, which may also have the treatment unit 502. In some embodiments, the smart watch 510 may provide a display and user interface for the treatment unit 502. The smart watch 510 may communicate wirelessly with the treatment unit 502, such as via Bluetooth or Wi-Fi, or via a direct connection via a data port in the smart watch and a data port in the treatment unit 502. In some embodiments, the electronic unit 502 and / or the smart watch 510 may communicate with a smartphone 512 to transmit data or update software and / or stimulation parameters of the treatment unit 502 and / or the smart watch 510, as described herein. In some embodiments, the band 500 and treatment unit 502 are permanently affixed or integrated, while the smart watch 510 is reversibly attachable to the band 500. The smart phone 512 and / or smart watch 510 may include applications, which may be downloaded via the cloud or a computer, configured to interface with the treatment unit 502.

[0133] 5D and 5E show that the wearable two-part system can be worn and used throughout the day. When the battery power of the treatment unit is low, the treatment unit 502 can be recharged with the charger 508. Charging can be performed overnight, or when the battery is low, or whenever desired. In some embodiments, the treatment unit can be removed from the band before charging. In some embodiments, the user can replace a treatment unit with a low charge with a treatment unit with a high charge so that the user can always wear the treatment unit.

[0134] In some embodiments, the kit shown in FIG. 5B may be used as a diagnostic test kit. The patient may initially wear the treatment system for about, at least about, or about 1 day to about 90 days or less, or about or at least about 1, 2, 3, 4, 5, 6, 9, 12 months or more, or for a predefined period of time. This initial period is used to collect data using sensors in the treatment unit and / or band to characterize the patient's symptoms or other relevant measures or other disease variables, and to evaluate the patient's response to treatment during the test period to identify how well the patient is responding to various treatments. The sensor data may be stored in memory in the treatment unit and / or transmitted over a network to a cloud or server or to another computing device that can be accessed by the patient's physician, company, or another third party.

[0135] FIG. 6 illustrates an embodiment of a system for treating migraines or other headache conditions using a wearable therapeutic device. As described above, the therapeutic device may have two parts: a band 500 and a treatment unit 502. A base station 600, which may replace the charger in the kit described above, may be used to charge the therapeutic device and to transmit and receive data to the therapeutic device and to the cloud 602. Communication between the base station 600 and the therapeutic device may be wireless communication, such as via Bluetooth and / or Wi-Fi, communication between the base station 600 and the cloud 602 may be via a cellular network, for example, using a 3G or 4G connection, or via a wired connection to the Internet, using DSL or cable or Ethernet. A physician or other user may view and / or search the data stored in the cloud 602 using an online portal or physician web portal 604. Additionally, a physician may prescribe and / or modify a treatment plan on the treatment unit 502 via the cloud 602 and the base station 600 using the web portal 604.

[0136] In some embodiments, the base station 600 is used to transmit and receive relatively large amounts of data that may require high bandwidth, such as transmission of raw data from the therapy device, which may be about 10-100 Mb / day, or about 10, 20, 30, 40, or 50 Mb / day. In some embodiments, the data may be stored in a memory in the base station 600 and transmitted at other intervals, such as weekly or twice a week, with increasing bandwidth of transmission. High bandwidth transmission of raw data may occur daily while the therapy device is charging, such as overnight during a normal charging period. In some embodiments, the raw data may be processed by the cloud and / or by a physician into processed data and sent back to the therapy device.

[0137] In some embodiments, the system may optionally include a portable computing device 606, such as a smart phone or tablet, to provide the patient with a secondary display and user interface to more easily control the therapy device and run applications to view raw and processed data. The portable computing device may be used to make patient or physician adjustments to the therapy device, such as adjusting stimulation parameters and dosing, and may receive device status data from the therapy device, including data related to the device, such as when they were used, errors, when they were set and delivered, therapy parameters, such as amplitude, etc. In some embodiments, the portable computing device 606 may receive processed data from the cloud 602, for example, via a cellular network and / or via an internet connection using Wi-Fi.

[0138] FIG. 7 illustrates various components that may be included in the treatment unit 700, band 702, and base station 704. These components are described in detail above and below as one particular embodiment. For example, the treatment unit 700 includes one or more indicators 706, which may be, for example, LEDs, and a user interface 708, which may be a push button. The treatment unit 700 may also have a stimulator 710 having a stimulating electrical device and may include the ability to measure current and voltage. The treatment unit 700 may also have a battery 712, which may be rechargeable and may be recharged using a charging circuit 714, which may be inductive. The treatment unit 710 may further include a processor 716 and memory 718 for storing and executing programs and instructions to achieve the functions described herein. The treatment unit 710 may also include a sensor 720, such as a blood pressure sensor, and a communication module 722, which may be wireless and may communicate with the base station 704 and / or a secondary display / computing device.

[0139] The band 702 may have electrodes 724 and may include memory for storing identifying information or may include some other form of identifier 726 as described herein.

[0140] The base station 704 may include a charging circuit 728 that may be inductive and may transmit power to a complementary charging circuit 714 of the treatment unit 700. The base station 704 may also have a processor and memory for storing and executing instructions and programs. The base station 704 may further include a communication module 732, which may be cellular, for communicating with the cloud, and another communication module 734, which may be wireless and may be used to communicate with the treatment unit.

[0141] In some embodiments, the device may be a biological sensor, such as a heart rate or breathing monitor worn on the body, which may include an integrated neurostimulator. In some embodiments, the neurostimulator and sensor devices may be separate devices that communicate wirelessly. In some embodiments, the device may measure biological measurements over minutes, hours, days, weeks, and / or months to determine if the patient's condition is increasing, decreasing, or staying the same. In some embodiments, the measurements are time-averaged over a period that may be days, weeks, or months. In some embodiments, sensors such as motion sensors, IMUs, or GPS may be used to detect patient activity that may affect other measurements. However, some embodiments do not include a motion sensor. In some embodiments, the sensor may be an electrode that measures a galvanic skin response that may correlate with stress, a known trigger of migraines or headaches. In some embodiments, measurements are collected at the same time each day under the same conditions to improve consistency of measurements and reduce variability. In some embodiments, a stimulator is applied to one wrist or arm or ear to stimulate one peripheral nerve in the arm, such as the median nerve or ABVN, or a specific nerve location, such as an acupressure point or meridian.

[0142] In other embodiments, as shown in FIG. 8A and FIG. 8B, a stimulation device is applied to both the wrist / arm or ear to stimulate nerves in the wrist and / or arm, such as the median nerve or acupressure points, bilaterally. In some embodiments, the device may be worn on the wrist, forearm, or upper arm, or on the leg below the knee, above the knee, or near the ankle, or in the ear, or above the tragus. In some embodiments, two bilateral devices may be operated simultaneously to stimulate both nerves simultaneously. The stimulation parameters of each device may be the same or different. The two devices may communicate wirelessly to synchronize or offset waveforms between the devices. In some embodiments, the two bilateral devices may be operated in alternation such that only one device delivers stimulation at a time. The alternating devices may stimulate alternately on an hourly, daily, weekly, or monthly basis, and the frequency of alternation may be changed based on sensor measurements.

[0143] In some embodiments, the stimulation parameters of the devices described herein are amplitudes of about 1 mA to about 20 mA, such as about 1 mA to about 10 mA, or about 2 mA to about 5 mA. In some embodiments, the frequency can be about 1 Hz to about 100 kHz, about 1 Hz to about 150 Hz, or about 1 Hz to about 10 Hz. In some embodiments, the pulse width can be about 10 μS to about 1000 μs. In some embodiments, the pulse interval can be about 0 μS to about 1000 μs. In some embodiments, the frequency can be high frequency stimulation and can include frequencies of about 100 Hz to about 100 kHz. In some embodiments, the stimulation waveform is biphasic (i.e., the positive portion of the pulse is substantially immediately followed by the negative portion of the pulse, or vice versa), or monophasic square wave, sine wave, triangle wave, or other shape. Other embodiments can include curvilinear waveforms that can have periods of rise and / or fall to or from maximum amplitude. In some embodiments, the stimulation is symmetrical or asymmetrical. In some embodiments, the asymmetric waveform may be configured to be charge balanced, such that the area under the positive going pulse is equal to the area under the negative going pulse. In some embodiments, the leading pulse has a positive or negative polarity.

[0144] In some embodiments, the system is not configured to stimulate the trigeminal nerve (the method does not stimulate the trigeminal nerve). In some embodiments, the system is not configured to be placed on the forehead, other parts of the head, and / or neck (the method does not include placement of a stimulation component on the forehead, other parts of the head, and / or neck). In some embodiments, the system does not include self-adhesive electrodes. In some embodiments, the electrodes of the system are not magnetically connected to a stimulation device. In some embodiments, the systems and methods deliver only electrical energy, such as only transcutaneous electrical energy, and do not include any one or more of magnetic energy (including, for example, transcranial magnetic stimulation (TMS)), ultrasound energy, RF energy, microwave energy, and / or thermal energy. In some embodiments, the system does not include an implanted component. In some embodiments, the system is not configured to be placed on the upper arm (the method does not include placement of a stimulation component on the upper arm). However, some embodiments may include any number of the preceding features of this paragraph.

[0145] When a feature or element is referred to herein as being "on" another feature or element, it may be directly on the other feature or element, or there may be intervening features and / or elements present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. When a feature or element is referred to as being "connected," "attached," or "coupled" to another feature or element, it will also be understood that it may be directly connected, attached, or coupled to the other feature or element, or there may be intervening features or elements present. In contrast, when a feature or element is referred to as being "directly connected," "directly attached," or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or illustrated with respect to one embodiment, the features and elements so described or illustrated may apply to other embodiments as well. Those skilled in the art will also understand that a reference to a structure or feature located "adjacent" to another feature may have portions that overlap or underlie the adjacent feature.

[0146] The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the present invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising", as used herein, specify the presence of the stated features, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0147] Spatially relative terms such as "under," "below," "lower," "over," "upper," and the like may be used herein for ease of description to describe the relationship of one element or feature to another element or feature as shown in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is inverted, elements described as being "under" or "beneath" other elements or features may be oriented "over" the other elements or features. Thus, the exemplary term "under" may encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, terms such as "upwardly," "downwardly," "vertical," "horizontal," etc. are used herein for descriptive purposes only, unless otherwise specified.

[0148] Although the terms "first" and "second" may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element described below can be referred to as a second feature / element, and similarly, a second feature / element described below can be referred to as a first feature / element without departing from the teachings of the present invention.

[0149] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" mean that various components may be used jointly in methods and articles (e.g., apparatus and compositions and apparatuses that include methods). For example, the term "comprising" is understood to mean the inclusion of any described elements or steps but not the exclusion of any other elements or steps. However, some embodiments may consist of or consist essentially of any number of the described elements or steps disclosed herein.

[0150] As used in this specification and claims, including as used in the examples, unless expressly specified otherwise, all numbers may be read as if they were preceded by the word "about" or "approximately", even if the term does not appear explicitly. The phrase "about" or "approximately" may be used when describing a size and / or location to indicate that the described value and / or location is within a reasonable expected range of values ​​and / or locations. For example, a numerical value may have values ​​of + / -0.1% of the described value (or range of values), + / -1% of the described value (or range of values), + / -2% of the described value (or range of values), + / -5% of the described value (or range of values), + / -10% of the described value (or range of values), etc. Any numerical value set forth herein should also be understood to include approximately that value unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical ranges recited herein are intended to include all subranges subsumed therein. As would be well understood by one of ordinary skill in the art, when a value is disclosed, it is also understood that "less than or equal to" the value, "greater than or equal to" the value, and possible ranges between the values ​​are also disclosed. For example, when a value "X" is disclosed, "less than or equal to" and "greater than or equal to X" (e.g., where X is a number) are also disclosed. It is also understood that throughout this application, data is provided in several different formats, and this data represents endpoints and starting points, as well as ranges for any combination of data points. For example, when a specific data point "10" and a specific data point "15" are disclosed, it is understood that greater than, greater than, less than, less than, less than, and equal to 10 and 15, as well as between 10 and 15, are considered to be disclosed. It is also understood that each unit between two specific units is also disclosed. For example, when 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0151] Although various exemplary embodiments have been described above, any of a number of modifications may be made to the various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which the various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be skipped entirely. Any feature of the various apparatus and system embodiments may be included in some embodiments and not in other embodiments. Thus, the foregoing description has been provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as described in the claims.

[0152] The examples and illustrations contained herein show, by way of illustration and not limitation, specific embodiments in which the subject matter may be practiced. As noted above, other embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the subject matter of the present invention may be individually or collectively referred to herein by the term "invention" when more than one is actually disclosed, merely for convenience and without any intention of spontaneously limiting the scope of the present application to any single invention or inventive concept. Thus, although specific embodiments have been illustrated and described herein, any configuration calculated to achieve the same purpose may be substituted for the specific embodiment illustrated. The present disclosure is intended to cover any and all adaptations or modifications of the various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon review of the above description. The methods disclosed herein include specific actions taken by a practitioner. However, they may also include, explicitly or implicitly, any third-party instruction of those actions. For example, an act such as "transcutaneously stimulate an afferent peripheral nerve" includes "directing stimulation of the afferent peripheral nerve."

Claims

1. 1. A method of treating migraine headaches using transcutaneous peripheral nerve stimulation, comprising: placing a first peripheral nerve effector on a skin surface adjacent to the median nerve on the patient's arm or wrist; placing a second peripheral nerve effector on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; receiving EEG data relating to the patient; generating parameters of a first electrical stimulation signal and a second electrical stimulation signal, where generating the parameters includes analyzing the EEG data for the patient; delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the nerve of the median nerve; delivering the second electrical stimulation signal transcutaneously to the second peripheral nerve effector to stimulate the nerve other than the median nerve; The method includes:

2. 10. The method of claim 1, wherein the first electrical stimulation signal has a frequency of about 5 Hz or less than about 5 Hz.

3. The method of claim 1 , wherein the first and second electrical stimulation signals comprise burst stimulation signals.

4. The method of claim 3 , wherein the burst stimulation signal is an alpha burst stimulation signal.

5. The method of claim 3 , wherein the burst stimulation signal is a theta burst stimulation signal.

6. The method of claim 1 , wherein the EEG data is received from an EEG headband.

7. The method of claim 1 , wherein the method does not include stimulation of the patient's upper arm.

8. The method of claim 1 , wherein the method does not include receiving motion data regarding the patient.

9. 10. The method of claim 1, wherein placing the first peripheral nerve effector and placing the second peripheral nerve effector occur on at least two of a ventral side of the arm or wrist, a dorsal side of the arm or wrist, and a lateral side of the arm or wrist.

10. 10. The method of claim 1, wherein transcutaneously delivering the first electrical stimulation signal and the second electrical stimulation signal is therapeutically effective to modify at least one neural pathway associated with a migraine headache.

11. 11. The method of claim 10, wherein transcutaneously delivering the first electrical stimulation signal and the second electrical stimulation signal is therapeutically effective to disrupt thalamocortical arrhythmias associated with migraine headaches.

12. 10. The method of claim 1 , wherein receiving EEG data comprises receiving a first set of EEG data prior to a treatment session and receiving a second set of EEG data during or after a treatment session, the method further comprising adjusting the parameters of one or both of the first electrical stimulation signal and the second electrical stimulation signal based at least in part on the second set of EEG data.

13. 13. The method of claim 1, wherein the first and second peripheral nerve effectors are coupled to one another on a wearable band.

14. 13. The method of any one of claims 1 to 12, wherein the method also prevents the onset of a migraine headache.

15. 1. A wearable device for treating migraine headaches using transcutaneous peripheral nerve stimulation, comprising: a first peripheral nerve effector configured to be placed on a skin surface adjacent to the median nerve of a patient's arm or wrist; a second peripheral nerve effector configured to be placed on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; A controller, receiving EEG data relating to the patient; a controller configured to generate parameters of a first electrical stimulation signal and a second electrical stimulation signal based on the EEG data for the patient; delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the median nerve; delivering the second electrical stimulation signal transcutaneously to the second peripheral nerve effector to stimulate the nerve other than the median nerve; 13. A wearable device comprising:

16. 16. The apparatus of claim 15, wherein the first electrical stimulation signal has a frequency of less than about 5 Hz.

17. 16. The apparatus of claim 15, wherein the first and second electrical stimulation signals comprise burst stimulation signals.

18. The device of claim 15 , wherein the device is not configured to stimulate the upper arm of the patient.

19. The apparatus of claim 15 , wherein the controller is not configured to receive motion data regarding the patient.

20. The device of claim 15 , wherein the first and second peripheral nerve effectors are coupled to one another on a wearable band.

21. 16. The device of claim 15, wherein the controller is configured such that transcutaneously delivering the first electrical stimulation signal and the second electrical stimulation signal is therapeutically effective to modify at least one neural pathway associated with a migraine headache.

22. 22. The device of claim 21, wherein the controller is configured such that transcutaneously delivering the first electrical stimulation signal and the second electrical stimulation signal is therapeutically effective for disrupting thalamocortical arrhythmias associated with migraine headaches.

23. 1. A transdermal method for treating or preventing a migraine headache in a patient, comprising: placing a first peripheral nerve effector on the patient's skin on the patient's arm or wrist distal to the upper arm to stimulate a first peripheral nerve selected from the group consisting of one of the patient's median nerve, radial nerve, and ulnar nerve; placing a second peripheral nerve effector on or in the patient's ear to stimulate the auricular branch of the vagus nerve of the patient; delivering a first burst electrical nerve stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the first peripheral nerve sufficiently to modify at least one brain or spinal cord autonomic feedback loop associated with migraine headache; and transcutaneously delivering a second burst electrical nerve stimulation signal to the second peripheral nerve effector to stimulate the second peripheral nerve sufficiently to modify the at least one brain or spinal cord autonomic feedback loop associated with a migraine headache; wherein the first electrical neurostimulation signal and the second electrical neurostimulation signal are configured to balance activity of the patient's parasympathetic nervous system and sympathetic nervous system to reduce or prevent migraine symptoms; Further herein, the method does not utilize an implantable component and involves only transcutaneous stimulation. Percutaneous methods.

24. 24. The method of claim 23, further comprising monitoring the patient's sympathetic and parasympathetic activity.

25. 25. The method of any one of claims 23 to 24, further comprising adjusting the first electrical neurostimulation signal upon identifying abnormal sympathetic activity in the patient.

26. 26. The method of any one of claims 23 to 25, further comprising adjusting the second electrical neurostimulation signal upon identifying abnormal parasympathetic activity in the patient.

27. 27. The method of any one of claims 23-26, further comprising modifying at least one of the first burst electrical neurostimulation signal and the second burst electrical neurostimulation signal based in part on analyzing EEG data obtained from the patient.

28. 28. The method of any one of claims 23 to 27, wherein at least one of the first burst electrical neurostimulation signal and the second burst electrical neurostimulation signal has a frequency of about 5 Hz or less than about 5 Hz.

29. 1. A wearable system for treating or preventing migraine headaches, comprising: a first peripheral nerve effector configured for placement on the skin of a patient's arm or wrist and distal to the patient's upper arm to stimulate the patient's median nerve; a second peripheral nerve effector configured to be placed on or in the patient's ear to stimulate the auricular branch of the patient's vagus nerve; and at least one biomedical sensor or data input source configured to provide feedback information; wherein the controller is configured to generate a first burst electrical nerve stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the median nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop associated with migraine; wherein the controller is configured to generate a second burst electrical nerve stimulation signal transcutaneously to the second peripheral nerve effector to stimulate the auricular branch of the vagus nerve of the patient to modify at least one brain or spinal cord autonomic feedback loop associated with migraine; wherein the controller is configured to adjust the first electrical neurostimulation signal and the second electrical neurostimulation signal to balance activity of the patient's parasympathetic and sympathetic nervous systems to reduce or prevent migraine symptoms; wherein the device is not configured for implantation within the patient. Wearable system.

30. 30. The system of claim 29, wherein the controller is configured to adjust the first electrical neurostimulation signal upon identifying abnormal sympathetic nerve activity in the patient.

31. 31. The system of claim 29 or 30, wherein the controller is configured to adjust the first electrical neurostimulation signal upon identifying abnormal parasympathetic activity in the patient.

32. 32. The system of claim 29, wherein the feedback information comprises real-time feedback information.

33. 33. The system of any one of claims 29 to 32, wherein the feedback information comprises the patient's autonomic nervous system activity.

34. 34. The system of any one of claims 29 to 33, wherein the feedback information comprises heart rate variability.

35. 35. The system of any one of claims 29 to 34, wherein the feedback information comprises EEG data of the patient.

36. 36. The system of any one of claims 29 to 35, wherein at least one of the first burst electrical neurostimulation signal and the second burst electrical neurostimulation signal has a frequency of about 5 Hz or less than about 5 Hz.

37. 1. A method of treating or preventing headache using transcutaneous peripheral nerve stimulation, comprising: placing a first peripheral nerve effector on a skin surface of a patient's arm or wrist adjacent to a first nerve; receiving EEG data relating to the patient; generating parameters of a first burst electrical stimulation signal and a second burst electrical stimulation signal, wherein generating the parameters includes analyzing the EEG data for the patient; delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the first nerve; The method includes:

38. 38. The method of claim 37, wherein receiving EEG data comprises receiving a first set of EEG data prior to a treatment session and receiving a second set of EEG data during or after a treatment session, the method further comprising adjusting the parameters of the first electrical stimulation signal based at least in part on the second set of EEG data.

39. 39. The method of any one of claims 37 to 38, wherein the first electrical stimulation signal has a frequency of about 5 Hz or less than about 5 Hz.

40. 40. The method of any one of claims 37 to 39, wherein the burst stimulation signal is an alpha burst stimulation signal.

41. 40. The method of any one of claims 37 to 39, wherein the burst stimulation signal is a theta burst stimulation signal.

42. 42. The method of any one of claims 37 to 41, wherein the EEG data is received from an EEG headband.

43. 43. The method of any one of claims 37 to 42, wherein the method does not include stimulation of the patient's upper arm.

44. 44. The method of any one of claims 37 to 43, wherein the method does not include receiving motion data regarding the patient.

45. 45. The method of any one of claims 37 to 44, wherein transcutaneously delivering the first electrical stimulation signal and the second electrical stimulation signal is therapeutically effective to modify at least one neural pathway associated with a migraine headache.

46. 46. ​​The method of claim 45, wherein transcutaneously delivering the first electrical stimulation signal and the second electrical stimulation signal is therapeutically effective to disrupt thalamocortical arrhythmias associated with migraine headaches.

47. 47. The method of any one of claims 37 to 46, wherein the first and second peripheral nerve effectors are coupled to one another on a wearable band.

48. 1. A wearable device for treating or preventing headaches using transcutaneous peripheral nerve stimulation, comprising: a first peripheral nerve effector configured to be placed on a skin surface adjacent to the median nerve of a patient's arm or wrist; A controller, receiving EEG data relating to the patient; a controller configured to generate parameters of a first burst electrical stimulation signal based on the EEG data for the patient; delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the median nerve; 16. A wearable device comprising:

49. 49. The apparatus of claim 48, wherein the first electrical stimulation signal has a frequency of less than about 5 Hz.

50. 50. The apparatus of any one of claims 48 to 49, wherein the apparatus is not configured to stimulate the upper arm of the patient.

51. 51. The apparatus of any one of claims 48 to 50, wherein the controller is not configured to receive motion data regarding the patient.

52. 52. The device of any one of claims 48 to 51, wherein the first and second peripheral nerve effectors are coupled to one another on a wearable band.

53. 53. The apparatus of any one of claims 48 to 52, wherein the controller is configured such that transcutaneously delivering the first electrical stimulation signal is therapeutically effective for modifying at least one neural pathway associated with a migraine headache.

54. 54. The apparatus of claim 53, wherein the controller is configured such that transcutaneously delivering the first electrical stimulation signal is therapeutically effective for disrupting thalamocortical arrhythmias associated with migraine headaches.

55. 1. A method of transcutaneously stimulating a peripheral nerve for treating or preventing migraine or other chronic headache conditions, comprising: placing a first peripheral nerve effector on the skin of a patient's limb or in the ear of the patient; delivering a first electrical nerve stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the first peripheral nerve sufficiently to modify at least one neural pathway associated with a migraine or headache condition; The method includes:

56. 56. The method of claim 55, wherein the neural pathway is associated with at least one of the orexinergic pathway or the trigeminovascular pathway.

57. 57. The method of any one of claims 55 to 56, wherein the first peripheral nerve effector is positioned on the upper extremity below the elbow.

58. 58. The method of claim 57, wherein the first peripheral nerve effector is positioned on an upper extremity proximate the wrist.

59. 1. A method for providing neuromodulatory function for the treatment or prevention of migraine or other headache conditions, comprising: receiving a signal from a detection device detecting cardiac and / or pulmonary activity of the patient; comparing said received signal to a reference threshold determined algorithmically from previously received signals to find a predetermined relationship; if the predetermined relationship is found, transmitting a neuromodulation signal to an electrode electrically coupled to a first peripheral nerve of the patient to achieve the neuromodulation function; The method includes:

60. 60. The method of claim 59, further comprising converting the signal from the detection device into an electrical signal.

61. 61. The method of any one of claims 59 to 60, wherein the first peripheral nerve effector is positioned on an upper extremity below the elbow.

62. 62. The method of claim 61, wherein the first peripheral nerve effector is positioned on an upper extremity proximate the wrist.

63. 1. A method of treating a neurological condition using neuromodulation, comprising: placing a first nerve effector on a skin surface adjacent to a median nerve on a patient's arm or wrist; placing a second nerve effector on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; receiving data relating to the patient, said data optionally being EEG data; generating parameters of a first neuromodulation signal and a second neuromodulation signal, wherein generating the parameters includes analyzing the data related to the patient; delivering the first neuromodulation signal to the first neuroeffector to modulate the median nerve; delivering the second neuromodulation signal to the second neuroeffector to modulate the nerve other than the median nerve; thereby treating said neurological condition. The method includes:

64. 1. A method of treating a neurological condition, comprising: placing a first nerve effector on the patient's skin at the patient's arm distal to the upper arm or wrist to modulate a first nerve selected from the patient's median nerve, radial nerve, and ulnar nerve; placing a second neuroeffector on or in the patient's ear to modulate the auricular branch of the vagus nerve of the patient; delivering a first burst signal to the first neural effector to modulate the first nerve sufficient to modify at least one brain or spinal cord autonomic feedback loop related to the neurological condition; delivering a second burst signal to the second neuroeffector to modulate the second nerve sufficient to modify the at least one brain or spinal cord autonomic feedback loop related to the neurological condition; wherein the first signal and the second signal are configured to balance activity of the patient's parasympathetic nervous system and sympathetic nervous system. method.

65. the first and / or second nerve effector are peripheral nerve effectors; the first and / or second neuro-effector is an electrode; the first and / or second neuroeffector deliver a stimulating electrical signal; the neurological condition is a headache, such as a migraine; the neurological condition is pulsatile sensation; the neurological condition is pulsatile sensation; a third, fourth, and / or fifth neuro-effector is provided; the first signal has a frequency of about 5 Hz or less than about 5 Hz; the second signal has a frequency of about 5 Hz or greater; The method does not utilize an implantable component and involves only transcutaneous neuromodulation.

65. The method of claim 63 or 64, further comprising one or more of the following features:

66. 1. A method of treating migraine headaches using transcutaneous peripheral nerve stimulation, comprising: placing a first peripheral nerve effector on a skin surface adjacent to the median nerve on the patient's arm or wrist; placing a second peripheral nerve effector on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the median nerve; delivering the second electrical stimulation signal transcutaneously to the second peripheral nerve effector to stimulate the nerve other than the median nerve; The method includes:

67. 1. A wearable device for treating migraine headaches using transcutaneous peripheral nerve stimulation, comprising: a first peripheral nerve effector configured to be placed on a skin surface adjacent to the median nerve of a patient's arm or wrist; a second peripheral nerve effector configured to be placed on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; and A controller, delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the median nerve; delivering the second electrical stimulation signal transcutaneously to the second peripheral nerve effector to stimulate the nerve other than the median nerve; 16. A wearable device comprising:

68. 1. A method of treating or preventing headache using transcutaneous peripheral nerve stimulation, comprising: placing a first peripheral nerve effector on a skin surface of a patient's arm or wrist adjacent to a first nerve; delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the first nerve; The method includes:

69. 1. A wearable device for treating or preventing headaches using transcutaneous peripheral nerve stimulation, comprising: a first peripheral nerve effector configured to be placed on a skin surface adjacent to the median nerve of a patient's arm or wrist; A controller, delivering the first electrical stimulation signal transcutaneously to the first peripheral nerve effector to stimulate the median nerve; a controller configured to transcutaneously deliver the second electrical stimulation signal to the second peripheral nerve effector to stimulate the nerve other than the median nerve; 16. A wearable device comprising:

70. 1. A method of treating a neurological condition using neuromodulation, comprising: placing a first nerve effector on a skin surface adjacent to a median nerve on a patient's arm or wrist; placing a second nerve effector on a skin surface of the patient's arm or wrist adjacent to a nerve other than the median nerve; receiving data relating to the patient; generating parameters of a first neuromodulation signal and a second neuromodulation signal, wherein generating the parameters includes analyzing the data related to the patient; delivering the first neuromodulation signal to the first neuroeffector to modulate the median nerve; delivering the second neuromodulation signal to the second neuroeffector to modulate the nerve; thereby treating said neurological condition; and The method includes:

Images