RELATED APPLICATION

[0001] This application is an INTERNATIONAL APPLICATION (PCT) claiming priority to U.S. Provisional Patent Application Number 63/423,907 filed on 9 November 2022 and entitled “DEVICES AND METHODS FOR NEURAL STIMULATION,” and U.S.

Provisional Patent Application Number 63/424,066 filed on 09 November 2022 and entitled “DEVICES AND METHODS FOR NEURAL STIMULATION,” each of which are incorporated by reference, in their entirety, herein.

BACKGROUND

[0002] Nerve stimulation is known in the art to provide certain physiological effects on a subject. Different types of nerve stimulation include electrical nerve stimulation, chemical nerve stimulation, thermal nerve stimulation, and mechanical nerve stimulation. Electrical stimulation can be delivered as transcutaneously or percutaneously. Nerve stimulation is commonly used to alleviate pain experienced by a subject.

[0003] Cardiovascular disease is a leading cause of death globally and is responsible for about 25% of deaths in the United States. One in every 6 cardiovascular disease deaths is due to stroke, and more than 795,000 people in the United States have a stroke annually. Stroke is a leading cause of serious long-term disability, as stroke reduces mobility in more than half of stroke survivors aged 65 and over due to brain damage resulting from the stroke. Stroke-related costs in the United States came to nearly $46 billion between 2014 and 2015. Presently, there are few commercially available treatments available to treat a stroke prior to administration of an emergency therapy and to rehabilitate a subject recovering from a stroke.

SUMMARY

[0004] The lack of commercially available treatments available to treat an ischemic stroke and to rehabilitate subjects recovering from an ischemic stroke increases the severity of an ischemic stroke due to prolonged lack of oxygen to the region of the ischemic stroke, and the resulting brain damage. A non-invasive therapy which could increase the flow of blood or oxygen to the brain, and which could be administered shortly following diagnosis, before a reperfusion therapy is administered and during the recovery phase of a stroke would serve to significantly improve the treatment of ischemic stroke, improve subject outcomes, and reduce stroke-related costs. For instance, prolonged lack of oxygen to the penumbral tissue region of an ischemic stroke results in increased infarct core formation, increased brain damage. These are common negative subject outcomes because of the prolonged time between stroke diagnosis and administration of a reperfusion therapy. Similarly, the rapid reoxygenation of the penumbral tissue following administration of a reperfusion therapy may also result in a reperfusion injury, contributing to negative subject outcomes and high stroke-related costs.

[0005] It is appreciated by the inventors that nerve stimulation may be used to increase a flow of blood and oxygen to the brain or inhibit on other pathways that lead to cell death, and such an application may be useful in treating an ischemic stroke, and that non-invasive nerve stimulation may be applied quickly following diagnosis of stroke well before a reperfusion therapy can be administered. It is similarly appreciated by the inventors that nerve stimulation may be used to modulate a flow of blood and oxygen to the brain or inhibit on other pathways that lead to cell death, and such an application may be useful in treating, mitigating, or preventing a reperfusion injury resulting from a reperfusion therapy administered in conjunction with the treatment for an ischemic stroke. The devices, systems and methods described herein may be configured for treating a medical condition through a coordinated stimulation of two or more targeted nerves. The medical condition may comprise ischemic stroke, traumatic brain injury, intracranial hemorrhage (e.g., subarachnoid hemorrhage, subdural hematoma, epidural hematoma, intracerebral hemorrhage, etc.), vasospasm, cardiac arrhythmia, other conditions that involve loss of blood flow or ischemia, inflammatory diseases, conditions that can be managed through inflammatory modulation (e.g., rheumatoid arthritis, irritable bowel syndrome, sepsis, renal ischemia, trauma/hemorrhagic shock, acute lung injury, hyperinflammation, etc.), hypotension, disorders of consciousness, migraine, headache or other facial pain, other diseases that cause pain, neurological conditions (e.g., Alzheimer’s Disease, Mild Cognitive Impairment, etc.), ocular conditions, infectious diseases, auditory deficits, hypoxia, or a combination thereof. The devices, systems and methods described herein may be configured for rehabilitating a subject recovering from said medical condition. The devices, systems, and methods described herein may be configured to help ease intraprocedural complications or help regulate homeostasis in the central nervous system (CNS). [0006] Aspects disclosed herein provide a method of treating stroke, rehabilitating a subject recovering from a medical condition comprising: transcutaneously delivering a first stimulation energy, wherein the first stimulation energy is delivered: to a supraorbital branch of a trigeminal nerve, or to the supraorbital branch of the trigeminal nerve and to an auricular branch of a vagal nerve; transcutaneously delivering a second stimulation energy, wherein the first stimulation energy is delivered: to the auricular branch of the vagal nerve, or to the supraorbital branch of the trigeminal nerve and to an auricular branch of a vagal nerve, wherein the subject exhibits, relative to the medical condition, a reduction in recovery time, an increase in motor function, an increase in speech function, an increase in cognitive function, or combinations thereof, relative to a subject recovering from the medical condition who does not receive the first stimulation energy and the second stimulation energy.

[0007] The method may further comprise delivering the first simulation energy intermittently without regard to the task. The method may further comprise delivering the second simulation energy temporally with regard to the task. The second simulation energy may be delivered upon completion of the task. The second stimulation energy may be delivered during execution of the task.

[0008] The method may further comprise delivering the first simulation energy prior to completion of the task.

[0009] The method may further comprise delivering the first simulation energy during completion of the task. Delivering the first simulation energy during completion of the task may further comprise increasing the first stimulation energy during completion of the task. Delivering the first simulation energy during completion of the task may further comprise increasing the first stimulation energy during completion of the task proportional to a successful resistance motor function, wherein the task is completion of the resistance motor function. Increasing the first stimulation energy may comprise increasing the amplitude of the stimulation energy. Increasing the first stimulation energy may comprise increasing the amplitude of the stimulation energy to a maximum tolerable level when the task is attempted. The method may further comprise ceasing increasing the first stimulation energy upon completion of the task. The method may further comprise delivering the second simulation energy upon completion of the task. [0010] The method may further comprise delivering the first simulation energy prior to completion of the task and during completion of the task. The method may further comprise ceasing delivery of the first stimulation energy upon completion of the task. The method may further comprise delivering the second simulation energy upon completion of the task.

[0011] The first stimulation energy may be constantly applied during a treatment session.

[0012] The method may further comprise modulating the first stimulation energy during a treatment session.

[0013] The first stimulation energy and the second stimulation energy may be constantly applied during a treatment session. The first stimulation energy and the second stimulation energy may be both constantly applied after completion of the task. The first stimulation energy may be applied prior to the treatment session, and the second stimulation energy may be applied during performance of the task and after completion of the task.

[0014] The method may further comprise measuring the subject’s completion of the task with a device attached to the subject. The device may comprise a motion sensor, an accelerometer, a touch sensor, a goniometer, a capacitive sensor, a resistive sensor, an audio sensor, of combinations thereof.

[0015] The application of the first stimulation energy or the second stimulation energy may be modulated based upon subject electroencephalogram (EEG) parameters. The modulation of the first or second stimulation energy may comprise decreasing from a high frequency stimulation to a low frequency stimulation, increasing from a low frequency stimulation to a high frequency stimulation, changing from a burst duty cycle to a rapid duty cycle, changing from a rapid duty cycle to a burst duty cycle, or combinations thereof. The modulation may occur with respect to the second stimulation energy. The task may comprise a motor function, speech, or a cognitive task.

[0016] In some embodiments, the first stimulation and the second stimulation energy may be electrical. In some embodiments, one or more of the first or second stimulation energies may be provided at a frequency between 0.2 and 500 Hz. In some embodiments, one or more of the first or second stimulation energies may be provided at an amplitude of between 0.1 and 200 mA. In some embodiments, one or more of the first or second stimulation energies may be provided at a pulse width between 1 us and 2 s. In some embodiments, one or more of the first or second stimulation energies may be provided a charge of between 0.5 mC to 200 mC. In some embodiments, one or more of the first or second stimulation energies may be biphasic. [0017] In some embodiments, the device comprises a bracelet, or an appendage marker. In some embodiments, the method further includes administering a third stimulation energy with the device. In some embodiments, application of the first stimulation energy or the second stimulation energy is modulated based upon subject electroencephalogram (EEG) parameters, upon near-infrared spectroscopy, transcranial doppler ultrasound, completion of the task, or combinations thereof. In some embodiments, the medical condition is a stroke, treating a symptom of a stroke, a cerebral ischemia injury, a cerebral reperfusion injury, or combinations thereof. In some embodiments, the medical condition is rehabilitation after recovering from ischemic stroke, traumatic brain injury, intracranial hemorrhage (e.g., subarachnoid hemorrhage, subdural hematoma, epidural hematoma, intracerebral hemorrhage, etc.), vasospasm, cardiac arrhythmia, other conditions that involve loss of blood flow or ischemia, inflammatory diseases, conditions that can be managed through inflammatory modulation (e.g., rheumatoid arthritis, irritable bowel syndrome, sepsis, renal ischemia, trauma/hemorrhagic shock, acute lung injury, hyperinflammation, etc.), hypotension, disorders of consciousness, migraine, headache or other facial pain, other diseases that cause pain, neurological conditions (e.g., Alzheimer’s Disease, Mild Cognitive Impairment, etc.), ocular conditions, infectious diseases, auditory deficits, hypoxia, or a combination thereof.

[0018] Systems, methods, and devices disclosed herein may be configured facilitate provision of stimulation to one or more target nerve locations of a subject via one or more electrodes in contact with the subject's skin overlying the target nerve location(s). The stimulation may be electrical (e.g., current) in nature and, in some case, may be a biphasic and may be provided transcutaneously. The stimulation may be generated by, for example, a pulse generator and/or a control unit. The control unit may also be configured to control a characteristic and/or parameter of the stimulation provided to the one or more electrodes. At times, the one or more electrodes may be resident within a nerve stimulation delivery device worn on the subject's head. In some embodiments, the electrodes and/or subject may be monitored using, for example, an impedance measurement, to ensure that the electrodes are in contact with the subject's skin. When it is determined that an electrode is not properly in contact with a subject's skin, provision of the stimulation energy may be ceases so that, for example, the relevant electrode may be correctly attached to the patient's skin. In some cases, the stimulation may be configured and/or provided to induce a modulation of neurotransmitters of the subject while the subject may be performing and/or attempting to perform a rehabilitation task, induce cerebrovascular plasticity for the subject, induce neuroplasticity for the subject, and/or induce cortical reorganization for the subject all of which may aid in the subject's recovery from a medical condition.

[0019] In some embodiments, a first signal may be received by a control unit. The first signal may be, for example, a measurement communicated by a sensor to the control unit and/or an indication of an interaction with the subject and/or a user (e.g., caregiver, doctor, or therapist) with a user interface of the control unit.

[0020] A first stimulation signal may be provided to a first electrode via, for example, the control unit, for a first duration of time. The first electrode may be positioned on a subject's skin overlying a first target nerve location (e.g., a supraorbital branch of the subject's trigeminal nerve) and provision of the first stimulation energy may be responsive to (e.g., turned on or off) the first received signal.

[0021] Then, a second signal may be received. The second signal may be different from or the same as the first signal and/or may correspond to the first signal (e.g., the first signal may be pushing a button, and the second signal may be releasing the button). A second stimulation signal may be provided (e.g., by the control unit) to a second electrode for a second duration of time responsively to the second received signal. In some embodiments, the second electrode may be positioned on a subject's skin overlying the same and/or a different (e.g., a second) target nerve location, such as an auricular branch of the subject's vagus nerve. Alternatively, the second electrode may not be used, and the second stimulation signal may be provided to the first electrode, which may be positioned at the first target nerve location.

[0022] The first and/or second signals may be received from a device external to the control unit such as, for example, a sensor, a wearable device worn by the subject, and/or a device communicatively coupled to the first and/or second electrode. Additionally, or alternatively, the external device may be a motion sensor, an accelerometer, a touch sensor, a goniometers, a capacitive sensor, a resistive sensor, an audio sensor, an electrocardiogram (ECG) sensor or device, a blood pressure monitor, an electromyography (EMG) sensor or device, a strain gauge, an electroencephalography (EEG) sensor or device, a pulse oximeter, a respiratory sensor, a humidity sensor, a moisture sensor, and/or a heartrate monitor.

[0023] In some cases, the first target nerve location may be included in a first plurality of target neve locations (e.g., different positions overlying target locations of the supraorbital branch of the subject's trigeminal nerve) and the first electrode may be included in a first set of electrodes. In these cases, each electrode of the first set of electrodes may be positioned on a subject's skin overlying a different target nerve location of the first plurality of target nerve locations. Additionally, or alternatively, the second target nerve location may be included in a second plurality of target neve locations (e.g., different positions overlying target locations of an auricular branch of the subject's vagus nerve) and the second electrode may be included in a second set of electrodes. In these cases, each electrode of the second set of electrodes may be positioned on a subject's skin overlying a different target nerve location of the second plurality of target nerve locations.

[0024] In some embodiments, the first signal may indicate that the subject has initiated a rehabilitative task, and the second signal may indicate that the subject has concluded performance of the rehabilitative task. The rehabilitative task may be selected for performance by the subject as part of a rehabilitative treatment for a medical condition (e.g., stroke or neurological impairment) and may be, for example, a limb movement task, a speech task, and cognitive task.

[0025] In some embodiments, a length of the first duration of time may be longer than a length of the second duration of time. Alternatively, a length of the first duration of time may be shorter than a length of the second duration of time. Alternatively, a length of the first duration of time may be the same as a length of the second duration of time. Additionally, or alternatively, a length of the first duration of time and/or the second duration of time and/or a parameter of the first and/or second stimulation energy may be responsive to a physiological indicator of the subject. Exemplary physiological parameters a measurement of at least one of the subject's heart rate, level of hemoglobin oxygen saturation, cerebral blood flow, blood pressure, cerebral pulse pressure, intracranial pressure, an EEG parameter, an ECG parameter, an EMG parameter, respiratory rate\, and a combination thereof.

[0026] The first and/or second type of stimulation and/or stimulation energy may be, for example, an electrical signal in the form of, for example, a sine wave, a series of pulses, and/or biphasic. Parameters of the first and/or second stimulation energy include, but are not limited to, pulse width, amplitude, current, charge, frequency of modulation, and type of modulation.

[0027] In some embodiments, priming stimulation may be provided to the first and/or second electrode prior to providing the respective first and/or second stimulation energies to the respective first and/or seconds electrodes. The priming stimulation may be delivered for a set period of time that may be responsive to, for example, a type of therapy the patient is receiving, a tolerance of the subject to the stimulation energy, a characteristic of the target nerve location(s), a characteristic of skin overlaying the target nerve location, and a responsiveness of the patient to rehabilitation.

[0028] In some embodiments, a characteristic (e.g., duty cycle, intensity, current, amplitude, etc.) the first and/or second signal may be responsive to input from the subject, a caregiver of the subject, and a clinician. The input may be, for example, the pressing and/or releasing of a button, an input provided to a user interface coupled to a device (e.g., a control unit) providing the first and/or second stimulation energies to the respective first or second electrodes, and/or verbal or gestural input (e.g., waving a hand to disrupt and IR signal).

[0029] In some embodiments, the systems, methods, and devices disclosed herein may be used and/or performed while the subject is engaged in therapy designed to assist the subject in recovering from and/or improving a medical condition such as a neurological deficit or other medical condition caused by, for example, a stroke ischemic stroke, traumatic brain injury, intracranial hemorrhage, subarachnoid hemorrhage, subdural hematoma, epidural hematoma, intracerebral hemorrhage, vasospasm, cardiac arrhythmia, other conditions that involve loss of blood flow or ischemia, inflammatory diseases, conditions that can be managed through inflammatory modulation, rheumatoid arthritis, irritable bowel syndrome, sepsis, renal ischemia, trauma/hemorrhagic shock, acute lung injury, hyperinflammation, hypotension, disorders of consciousness, migraine, headache or other facial pain, other diseases that cause pain, neurological conditions, Alzheimer's Disease, Mild Cognitive Impairment, ocular conditions, infectious diseases, auditory deficits, hypoxia, or a combination thereof. In these embodiments, the methods disclosed herein may be executed while the subject is performing a rehabilitative task that may be related to rehabilitation of the subject from a medical condition and the subject's responsiveness to performance of a rehabilitative task (i.e., recovery from the medical condition) while the methods disclosed herein are executed may be improved (e.g., decrease in recovery time, increase in functionality, decrease in disability, etc.).

[0030] In some embodiments, a parameter for stimulation (e.g., electrical simulation and/or an electrical signa) to be provided to one or more target nerves of a subject via one or more electrodes of a nerve stimulation delivery device may be received. The parameter may be, for example, an amplitude, frequency, duration, pulse width, charge and/or wattage of the stimulation and, on some occasions, may be responsive to the subject's tolerance for the stimulation.

[0031] In some cases, the subject may be diagnosed with a medical condition and the parameter may be responsive to the medical condition and/or a treatment for the medical condition (e.g., physical or speech rehabilitation).

[0032] The one or more electrodes may be in contact with the subject's skin proximate to the one or more target nerve locations. In some instances, the one or more electrodes may include a first set of electrodes positioned within the nerve stimulation delivery device and configured to deliver a first portion of the stimulation to a first target nerve location of the one or more target nerve locations and a second set of electrodes positioned within the nerve stimulation delivery device and configured to deliver a second portion of the stimulation to a second target nerve location of the one or more target nerve locations. The first target nerve location may be proximate to a supraorbital branch of the subject's trigeminal nerve and/or a supratrochlear branch of the subject's trigeminal nerve and the second target nerve location may be proximate to an auricular branch of the subject's vagal nerve.

[0033] Then, stimulation as, for example, described herein, may be provided to the one or more electrodes by, for example, a pulse generator, in accordance with the parameter. At times, the stimulation may be provided in conjunction with the subject's engagement in performance of a rehabilitation task that may be related to rehabilitation of the subject from the medical condition.

[0034] In some embodiments, priming stimulation may be provided to the one or more electrodes in accordance with a priming nerve stimulation protocol prior to providing the stimulation to the one or more electrodes in accordance with the parameter. The priming stimulation may be provided for a period of time such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, and/or 30 minutes.

[0035] In some embodiments, a neural stimulation protocol including a plurality of parameters for the provision of the stimulation to the one or more electrodes may be received prior to providing the stimulation to the one or more electrodes in accordance with the parameter. Exemplary parameters include, but are not limited to, = amplitude, frequency, duration, pulse width, and charge of the stimulation provided by each electrode of the plurality of electrodes while the subject may be engaged in performing the rehabilitative task. At times, one or more of the plurality of parameters includes parameters for an alternating sequence of provision of a first and second stimulation. In some embodiments, the provided stimulation may include a first stimulation and a second stimulation. The first and second stimulations may be provided to the same and/or different electrodes. Additionally, or alternatively, the first and second stimulations may be different types of stimulation (e.g., may have different parameters). In these embodiments, the plurality of parameters may include a parameter for a duration of the first and/or second stimulation. In some instances, an indication of the subject's response (e.g., change in blood flow, cerebrovascular plasticity exhibited by the subject over time) to the stimulation may be received and another second parameter may be received in response to the indication.

[0036] In some embodiments, a processor may receive a first image of vasculature included in the subject's brain and a second image of vasculature included in the subject's brain, the second image may be taken at a later time (e.g., 2 weeks-1 year or least four weeks after the first image). The vasculature shown in the first image and the second image may be compared to determine a difference therebetween and a second parameter for stimulation to be provided to the one or more target nerves of the subject via one or more electrodes of the nerve stimulation delivery device may be determined responsively to the difference. Then, the processor may provide second parameter to the control unit.

[0037] In some embodiments, a control unit may receive a first signal and provide a first stimulation signal to an electrode for a first duration of time responsively to the first received signal. The electrode may be positioned on a subject's skin overlying a target nerve location. Then, a second signal may be received by the control unit and the control unit may provide a second stimulation signal to the electrode for a second duration of time responsively to the second received signal.

[0038] In another embodiment, a method for a patient recovering from a medical condition may include transcutaneously delivering a first stimulation energy, wherein the first stimulation energy may be delivered to a supraorbital branch of a trigeminal nerve, or to the supraorbital branch of the trigeminal nerve and to an auricular branch of a vagal nerve and transcutaneously delivering a second stimulation energy, wherein the second stimulation energy may be delivered to the auricular branch of the vagal nerve, or to the supraorbital branch of the trigeminal nerve and to an auricular branch of a vagal nerve. The patient may exhibit, relative to the medical condition, a reduction in recovery time, an increase in motor function, an increase in speech function, an increase in cognitive function, or combinations thereof, relative to a patient recovering from the medical condition who does not receive the first stimulation energy and the second stimulation energy. The reduction in recovery time or the increase in motor function may be measured by subject performance a task which has been negatively impacted by the stroke or injury.

[0039] At times, the first simulation energy may be delivered intermittently without regard to the task. Additionally, or alternatively, the second simulation energy may be delivered temporally with regard to the task. Additionally, or alternatively, the second simulation energy may be delivered upon completion of the task. Additionally, or alternatively, the first simulation energy may be delivered prior to completion of the task. Additionally, or alternatively, the first simulation energy may be delivered prior to and/or during performance of the task. Additionally, or alternatively, delivery of the first stimulation energy may be ceased upon completion of the task. Additionally, or alternatively, the second and/or second simulation energy may be delivered upon completion of the task.

[0040] In some embodiments, the first simulation energy and the second simulation energy may be delivered upon completion of the task, within 0.1 , 0.5, 1 , 1.5, 2, 3, 5, or 10 seconds.

[0041] In some embodiments, delivering the first simulation energy during completion of the task further comprises increasing the first stimulation energy during completion of the task. At times, delivering the first simulation energy during completion of the task further comprises increasing the first stimulation energy during completion of the task proportional to a successful resistance motor function, wherein the task may be completion of the resistance motor function. Increasing the first stimulation energy may include increasing the amplitude of the stimulation energy to, for example, a maximum tolerable level when the task may be attempted. In some cases, increasing the first stimulation energy may be ceased upon completion of the task. Additionally, or alternatively, the second simulation energy may be delivered upon completion of the task and/or the first stimulation energy may be constantly applied during a treatment session. Alternatively, the first stimulation energy may be modulated during a treatment session. Additionally, or alternatively, the second stimulation energy may be delivered during execution of the task. Additionally, or alternatively the first stimulation energy and the second stimulation energy are constantly applied during a treatment session. Additionally, or alternatively the first stimulation energy and the second stimulation energy may both constantly applied after completion of the task. Additionally, or alternatively the first stimulation energy may be applied prior to the treatment session, and the second stimulation energy may be applied during performance of the task and after completion of the task. Additionally, or alternatively the subject's completion of the task may be measured with a device, sensor, or virtual reality device, attached to the subject, or measuring the subject's completion of the task with a virtual reality device attached to the subject. Exemplary devices/sensors include, but are not limited to a motion sensor, an accelerometer, a touch sensor, a goniometer, a capacitive sensor, a resistive sensor, an audio sensor, of combinations thereof. The sensor/device may be embodied as, for example, a bracelet, patch, and/or appendage marker.

[0042] In some embodiments, a third stimulation energy that may be similar to the first and/or second stimulation energy may be provided with the device.

[0043] At times, stimulation applied by one or more of the devices and/or systems disclosed herein may be modulated based upon subject electroencephalogram (EEG) parameters, upon near-infrared spectroscopy measurements, transcranial doppler ultrasound measurements, completion of the task, or combinations thereof. The modulation of the stimulation, or stimulation energy may include decreasing from a high frequency stimulation to a low frequency stimulation, increasing from a low frequency stimulation to a high frequency stimulation, changing from a burst duty cycle to a rapid duty cycle, changing from a rapid duty cycle to a burst duty cycle, and/or combinations thereof. At times, decreasing from a high frequency stimulation to a low frequency stimulation, increasing from a low frequency stimulation to a high frequency stimulation, or the changing from a burst duty cycle to a rapid duty cycle may be done to coincide with physiological neural oscillations including low frequency oscillations or the sensorimotor rhythm and/or the modulation may occur with respect to the second stimulation energy.

[0044] In some embodiments, the stimulation (e.g., first and/or second) and/or stimulation energies disclosed herein may be electrical and may be provided at, for example, a frequency between 0.2 and 500 Hz, an amplitude of between 0.1 and 200 mA, a pulse width between 1 us and 2 s, a charge of between 0.5 mC to 200 mC and/or may be biphasic. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which:

[0046] FIG. 1A provides a block diagram of an exemplary neural stimulation system, in accordance with embodiments disclosed herein.

[0047] FIG. 1B provides a block diagram of exemplary components that may be included in a nerve stimulation delivery device of the system of FIG. 1A, in accordance with embodiments disclosed herein.

[0048] FIG. 1C provides a block diagram of an exemplary system that may be integrated into and/or attached to a nerve stimulation delivery device housing, in accordance with embodiments disclosed herein.

[0049] FIG. 1D provides a block diagram of an exemplary control unit that may be included in a nerve stimulation delivery device of the system of FIG. 1A, in accordance with embodiments disclosed herein.

[0050] FIG. 1E provides a side view of an exemplary subject’s head.

[0051] FIG. 2A provides a top view of an exemplary nerve stimulation delivery device showing its circuitry and electrodes, in accordance with embodiments disclosed herein. [0052] FIG. 2B provides a front-right perspective view of a subject wearing the nerve stimulation delivery device of FIG. 2A, in accordance with embodiments disclosed herein.

[0053] FIG. 2C provides a side view of subject’s left ear wearing the nerve stimulation delivery device of FIG. 2A, in accordance with embodiments disclosed herein.

[0054] FIG. 2D provides a diagram of a second nerve stimulation delivery device, in accordance with embodiments disclosed herein.

[0055] FIG. 2E provides a front-left perspective view of a subject wearing the nerve stimulation delivery device of FIG. 2D, in accordance with embodiments disclosed herein.

[0056] FIG. 3 provides a rear perspective view depiction of an exemplary nerve stimulation delivery device , in accordance with embodiments disclosed herein. [0057] FIG. 4 provides a flowchart illustrating an exemplary process for exposing a subject to stimulation as part of a stimulation tolerability assessment for the subject, in accordance with embodiments disclosed herein.

[0058] FIG. 5 provides a flowchart illustrating an exemplary process for exposing a subject to transcutaneous nerve stimulation as part of a priming nerve stimulation protocol for the subject, in accordance with embodiments disclosed herein.

[0059] FIG. 6 provides a flowchart illustrating an exemplary process for exposing a subject to transcutaneous nerve stimulation as part of a rehabilitation stimulation protocol for the subject and/or a method of treating the subject for a medical condition such as a motor or speech deficit caused by ischemic stroke, in accordance with embodiments disclosed herein.

[0060] FIG. 7 provides a flowchart illustrating an exemplary process for exposing a subject to transcutaneous nerve stimulation as, for example, a treatment for a medical condition, in accordance with embodiments disclosed herein.

[0061] FIG. 8A provides a graph that plots data time-averaged percent changes in MFV measurements and PI measurements taken by a first device and a second device. [0062] FIG. 8B provides a graph that plots changes in MFV from a prior baseline.

[0063] FIG. 8C provides a graph that plots change in PI from a prior baseline.

DETAILED DESCRIPTION

[0064] Rehabilitation from and/or recovery of deficits caused by neurological impairment and/or neurologically-related medical condition (at times collectively referred to herein as a “medical condition” herein) may be assisted by the development of new connections between neurons and/or brain regions via brain remodeling and/or neural plasticity. Often, rehabilitation programs designed to assist in recovery from medical conditions focus on motor learning and/or include task-specific repetitive rehabilitation protocols because they are associated with dendrite sprouting, synapse formation, axonal changes, and neurochemical production, which may contribute to improved neuroplasticity and/or cortical reorganization. Provision of neural stimulation to subjects in conjunction with their respective performance of rehabilitation protocols and/or tasks associated with rehabilitation protocols as disclosed herein may enhance dendrite sprouting, synapse formation, axonal changes, cerebrovascular architecture remodeling, and/or neurochemical production for these subjects, which may contribute to improved neuroplasticity, cerebrovascular plasticity, and/or cortical reorganization for these subjects, which may lead to improved rehabilitation outcomes and/or recovery of deficits caused by the medical condition.

[0065] The medical condition treated by the neural stimulation disclosed herein may comprise acute and/or chronic instances and/or symptoms of ischemic stroke, traumatic brain injury, intracranial hemorrhage (e.g., subarachnoid hemorrhage, subdural hematoma, epidural hematoma, intracerebral hemorrhage, etc.), cerebral palsy, vasospasm, cardiac arrhythmia, other conditions that involve loss of blood flow or ischemia, inflammatory diseases, conditions that can lead to secondary damage or involvement of the nervous system (e.g., rheumatoid arthritis, sepsis, renal ischemia, trauma/hemorrhagic shock, acute lung injury, hyperinflammation, etc.), hypotension, disorders of consciousness, migraine, headache or other facial pain, other diseases that cause pain, neurocognitive conditions (e.g., Alzheimer’s Disease, Mild Cognitive Impairment, etc.), neurodegenerative conditions (e.g., Multiple Sclerosis), ocular conditions, infectious diseases including sequalae (e.g. symptoms associated with COVID-19 infections), auditory deficits, hypoxia, central nervous system oncological lesions, injury secondary to neurosurgical or neurointerventional intervention, conditions that impair or hinder cerebral autoregulation, or a combination thereof. In some cases, the medical condition may comprise an acute phase during which an injury causing the medical condition may have occurred and a rehabilitation phase following an acute phase during which the rehabilitative treatment may be focused on repairing damage and/or recovering functionality (e.g., mobility, cognitive processing, etc.) impaired by the acute phase. The devices, systems, and methods described herein may be configured to provide treatment during the acute and/or rehabilitation phase. Additionally, or alternatively, the devices, systems, and methods described herein may be configured to help ease intraprocedural complications and/or help regulate homeostasis in the central nervous system (CNS) for a subject that may be undergoing treatment for the medical condition.

[0066] The neural stimulation (also referred to herein as “stimulation”) provided to subjects according to one or more processes disclosed herein may include stimulation of the supraorbital branch of the trigeminal nerve and/or the auricular branch of the vagus nerve. The stimulation may be provided via one or more electrodes, housed by a nerve stimulation delivery device , that are in contact with a subject’s skin. In some embodiments, the electrodes may be configured to provide electrical fields that decrease morbidity and/or tissue deoxygenation and degradation due to the medical condition. In some embodiments, the electrode may be configured to provide electrical fields that improve neurological recovery and/or development. This improvement may, or may not, be observable as a faster speed of neurological improvement and/or an ability to continue improvement during periods when improvement is not seen in previous clinical cases. At times, the nerve stimulation delivery device may comprise a rigid external frame that may, or may not, be adhered to the skin.

[0067] At times, the stimulation may be and/or include coordinated electrical stimulation of two or more target nerves of a subject via provision of electrical stimulation, or energy, in, for example, parallel, series, and/or a combination thereof to electrodes of a nerve stimulation delivery device. The stimulation may be delivered in any sequence over time. The stimulation delivery may be contingent on an electrode placement confirmation via one or more electrode monitors. The delivered electrical stimulation may comprise one or more stimulation parameters configured to be adjusted based on feedback from the subject. The feedback may comprise automatic detection of a subject physiological parameter or other subject response (e.g., muscle spasm or contraction detection). The feedback may comprise subject-provided input, such as verbal or visual (e.g., facial expression, gestures) communication. The feedback may comprise a physical mechanical trigger, which may or may not, occur in the course of rehabilitative or other therapy. The current for electrical stimulation may be generated and/or provided by a pulse generator.

[0068] The stimulation may be and/or include transcutaneous or minimally invasive stimulation of the auricular branch of the vagus nerve and/or branches of the trigeminal nerve. In some embodiments, the stimulation may slow progression of cerebral brain damage by increasing cerebral blood flow, down-regulating a subject’s immune response, modulating nitric oxide expression, and/or interrupting ischemic depolarization, in the setting of ischemic brain injury. In some embodiments, the stimulation may increase cerebral blood flow, promote cerebral angiogenesis, release neurotransmitters associated with attention and arousal (e.g., acetylcholine, norepinephrine, etc.), and reinforce new neural connection, in the setting of recovery from a brain injury or condition. At times, the stimulation may be delivered as a first stimulation energy that targets target nerve, or region of a nerve, (e.g., a supraorbital branch of a trigeminal nerve) and a second stimulation energy to another target nerve (e.g., an auricular branch of a vagal nerve) or region thereof. In some cases, a subject receiving stimulation according to one or more methods disclosed herein may be monitored using, for example, a physiological monitoring system such as an electroencephalogram (EEG), near-infrared spectroscopy, ultrasound, and/or other technology configured to detect and/or monitor cerebral blood flow, or any other key vital physiological indicators to, for example, monitor and provide safe and/or tolerable stimulation ranges and protocols.

[0069] In some embodiments, stimulation energy provided by one or more of the electrodes disclosed herein may be modulated by, for example, increasing and/or decreasing a frequency, modulation, pulse width, duration of stimulation energy delivery, and/or duty cycle parameters (e.g., a rapid duty cycle and/or a burst duty cycle), and/or combinations thereof. In some circumstances, the modulation may be responsive to, for example, a physiological parameter of the subject such as a heart rate, a level of hemoglobin oxygen saturation, a direct or indirect measurement of cerebral blood flow, a continuous blood pressure measurement, a cerebral pulse pressure, a measurement of intracranial pressure, and/or an EEG parameter. In some cases, the stimulation energy may be provided to a first set of electrodes positioned on a subject’s skin proximate to (i.e., overlying) a first target nerve (e.g., a supraorbital branch of a trigeminal nerve) and/or a second set of electrodes positioned on a subject’s skin proximate to (i.e., overlying) a second target nerve (e.g., an auricular branch of a vagal nerve).

[0070] “Target nerve,” as used herein, may refer to, for example, one or more of the following: 1) a single target nerve corresponding to one or more locations on a single branch of the target nerve; 2) a single target nerve corresponding to one or more locations on two different branches of the target nerve. For example, the supraorbital nerve comprises nerve branches located on both sides of a subject head, wherein systems and methods described herein may be configured to stimulate one or both branches.

[0071] The target nerve(s) may comprise a vagus nerve, a trigeminal nerve, a facial nerve, an auricular nerve, or a combination thereof. The target nerve(s) may comprise neural ganglion (ganglia) or nucleus (nuclei) comprising sphenopalatine ganglion, geniculate ganglion, otic ganglion, ciliary ganglion, nucleus ambiguous, spinal trigeminal nucleus, solitary nucleus, trigeminal ganglion, or some combination thereof. The vagus nerve may comprise an auricular branch, a pharyngeal nerve, a superior laryngeal nerve, superior cervical cardiac branches of the vagus nerve, or a combination thereof. The trigeminal nerve may comprise an auriculotemporal branch, a supratrochlear branch, a supraorbital branch, a maxillary branch, an ophthalmic branch, infraorbital branch, or a combination thereof. The facial nerve may comprise the greater petrosal nerve, nerve to the stapedius, chorda tympani, posterior auricular nerve, temporal branch, zygomatic branch, buccal branch, marginal mandibular branch, cervical branch, or a combination thereof. An auricular nerve may comprise the anterior branch of the greater auricular nerve, the posterior branch of the greater auricular nerve, a cutaneous branch, the nerve origin at the cervical plexus, or any combination thereof. In some embodiments, the target nerve(s), nucleus (nuclei), ganglion (ganglia), or some combination thereof comprises a sympathetic nerve, a parasympathetic nerve, a sensory nerve, a motor nerve, or a combination thereof. The target nerve(s) may comprise of sensory nerve fiber(s) Act, A , Ab, C, or a combination thereof. The target nerve fiber(s) may have diameters range from 0.2 to 25 pm.

[0072] Systems and methods described herein may be configured to target a nucleus (e.g., nucleus tractus solitarius (NTS) sensory nuclei in the brainstem, spinal trigeminal nucleus, the superior salivatory nucleus, or the rostral ventromedial medulla). Targeting a nucleus may comprise 1) appropriate charge density at a required depth, 2) minimally invasive approach, or 3) indirect activation through downstream stimulation (via peripheral nerves).

[0073] FIG. 1A is a block diagram of an exemplary neural stimulation system 100 that is configured to provide neural stimulation according to one or more methods, or processes, described herein. Neural stimulation system 100 includes a pulse generator 120 that may be configured to produce an electrical output that is provided to a nerve stimulation delivery device 110 via a control unit 130. Optionally, system 100 may include a display device 125 that may be configured to provide information to a subject using nerve stimulation delivery device 110. Display device 125 may be, for example, a touch screen or computer display device, a virtual reality headset and/or device, a speaker, and/or a microphone. Exemplary information provided to the subject via display device 125 includes, but is not limited to, instructions to stop and/or start performance of a task and/or instructions regarding how to perform a task.

[0074] In some embodiments, pulse generator 120 may be configured output discrete pulses of constant and/or controlled electrical current for transcutaneous electrical stimulation and/or activation of one or more target nerves and/or target locations along nerve(s) via communication with one or more electrodes, such as the electrodes disclosed herein, via contact between the skin of a subject that overlays the target nerve location(s) and/or target locations along nerve(s) and the one or more electrodes. Additionally, or alternatively, pulse generator 120 may be configured to output pulses of biphasic stimulation at variable and/or fixed frequency, current (e.g., current*time), and/or pulse width (i.e., pulse duration).

[0075] In some embodiments, biphasic stimulation produced by pulse generator 120 may comprise a first, or depolarization, phase and a second, or polarization phase. In some embodiments, the first and second phases may be asymmetric so that, for example, the second, polarization, phase has an amplitude of 40% of the first depolarization phase and a duration of 1/40% of the first phase such that the two phases are charge-balanced. Additionally, or alternatively, an interphase interval of the biphasic stimulation produced by pulse generator 120 may be fixed and/or variable and may have a duration of, for example, 200-1 OOOus. In some embodiments, the interphase interval may be different for different electrodes of a nerve stimulation delivery device and, in some cases, may be varied responsively to time action potentials of target nerves and/or target nerve locations so that, for example, an interphase interval for biphasic stimulation delivered to a first electrode (or first set of electrodes) has a first duration and an interphase interval for biphasic stimulation delivered to a second electrode (or a second set of electrodes) has a second duration. At times, the length of the first and second durations may be responsive to one or more nerve and/or subject characteristics including, but not limited to, subject tolerance to the stimulation, nerve size, type, and/or location, and/or the type of rehabilitation the subject is undergoing and/or participating in.

[0076] A duration of each pulse of stimulation may be variable and/or fixed and may last, for example, 30-4000ps in duration. Exemplary output currents of pulse generator 120 may range from 0.0-15mA with a maximum current density of 0-5 mA/cm ² . Pulses generated by pulse generator 120 may be rectangular and/or biphasic and each pulse may have a width within an exemplary range of 250-450us or 1ms-1s and may be delivered at a frequency within an exemplary range of 0-60Hz. Stimulation energies provided by pulse generator 120 may have a pulse width within a range of, for example, 100us-5.0ms, .1us, 0.2us, 0.5us, 1us, 2us, 5us, 10us, 20us, 1s, 2s, 5s, or 10s. A train of pulses may be delivered over, for example, 20-180s. At times, pulse generator 120 may comprise two or more components such as a bipolar constant current stimulator (e.g., the DS8R Bipolar Constant Current Stimulator) and a remote electrode selector (e.g., the D188 Remote Electrode Selector). [0077] Nerve stimulation delivery device 110 may be configured as a device that may non-invasively apply, or deliver, electrical stimulation (also referred to herein as “stimulation”) via a plurality of electrodes 152 in contact with a subject’s skin on and/or around the auricle and/or the forehead of a subject. Stimulation delivered to the subject’s skin may be configured to transcutaneously stimulate one or more underlying target nerves and/or target positions along the underlying nerves for the purpose of treating a medical condition. Plurality of electrodes 152 may receive the electrical stimulation from pulse generator 120 via control unit 130, wherein control unit 130 may control one or more parameters of the electrical stimulation provided to one or more of plurality of electrodes 152 as, for example, described herein.

[0078] FIG. 1B provides a block diagram of exemplary components that may be included in nerve stimulation delivery device 110 such as an optional sensor 140, a housing 150, a communication interface 156, a flexible substrate 154, an optional adhesive layer 158, and the plurality of electrodes 152 that may be physically and electrically coupled to flexible substrate 154 and/or communication interface 156. Optionally, nerve stimulation delivery device 110 may include pulse generator 120 and/or control unit 130, which may be positioned within housing 150 and/or be resident on an external (i.e., non-patient facing) side of housing 150. At times, pulse generator 120, control unit 130, a power source 131 (e.g., battery and/or coupling to an electrical main) one or more sensors 140, and/or communication interface 156 may be components of a system 101 that may be resident within a separate housing 151 as shown in FIG. 1C. System 101 may be integrated into and/or attached to 150 as shown in, for example, FIG. 2B. In some embodiments, housing 150 along with flexible substrate 154, an optional adhesive layer 158, and the plurality of electrodes 152 may be configured for a one-time use (i.e., disposable) while system 101 and/or components housed within housing 151 may be reusable via, for example, one or more couplings (e.g., snaps, clamps, tracks, clips, electrical couplings, electrical interfaces, etc.) that may removably attach housing 151 to housing 150 and/or enable electrical and/or communicative coupling of system 101 with one or more components of housing 150. [0079] Communication interface 156 may be embodied as, for example, a physical and/or electrical coupling to pulse generator 120. Additionally, or alternatively, communication interface 156 may be a wired and/or wireless communication and/or power coupling to, for example, control unit 130 and/or an external device (e.g., a computer and/or sensor). [0080] Housing 150 may be configured to hold and/or maintain a position one or more electrodes of plurality of electrodes 152 relative to each other and/or a subject when housing 150 is worn. In some embodiments, housing 150 may be configured to achieve and/or maintain adherence of one or more of plurality electrodes 152 to skin of a subject (e.g., subject 160 shown in FIG. 1E) that may be proximate to and/or overly one or more target nerve positions. Housing 150 may also be configured to provide a conduit between the plurality of electrodes 152 and control unit 130 and/or pulse generator 120 so that, for example, electrical stimulation may be delivered to one or more of the plurality of electrodes 152 for distribution through a subject’s skin to stimulate one or more underlying target nerve positions in accordance with, for example, one or more methods disclosed herein.

[0081] In some embodiments, housing 150 may be flexible and/or incorporate flexible materials that facilitate curving, or otherwise shaping, housing 150 to, for example, wrap around a subject’s head while accommodating a subject’s facial anatomy and/or facilitate proper placement of the plurality of electrodes 152 on the subject’s skin (e.g., forehead and/or ear) without, for example, breakage and/or loss of functionality. At times, housing 150 may be embodied as a headband, head covering, mask, or portion thereof that is configured to wrap around a subject’s head so that, when worn, one or more of the plurality of electrodes 152 are properly positioned to deliver stimulation to the subject’s skin and target nerve(s). For example, a center, or forehead, section of housing 150 may include one or more of the plurality of electrodes 152 that are positioned and/or configured to correspond to a position of target locations along a subject’s supraorbital nerve when worn and an ear section of housing 150 may include one or more electrodes of the plurality of electrodes 152 that are positioned and/or configured to correspond to a position of target locations along a subject’s vagus nerve when worn. A temple section of housing may extend laterally from the forehead section and connect the forehead and ear sections. In some embodiments, the temple section of housing 150 may make application and/or use of the device easier and/or quicker, by enabling housing 150 to wrap around the side of the subject’s face.

[0082] In some embodiments, housing 150 and/or the components housed within housing 150 may be configured to accommodate differing head sizes and/or anatomy. For example, housing 150 may be configured in small, medium, and large sizes to accommodate differently-sized heads and/or anatomical proportions. Additionally, or alternatively, housing 150 may be sized, shaped, and/or configured so that it does not cover a subject’s temporal bone and/or leaves regions (e.g., a transcranial temporal window) of the subject’s skin open to, for example, facilitate one or more measurements of brain activity and/or health before, during, and/or after receiving stimulation from nerve stimulation delivery device 110 without requiring removal of housing 150. These measurements may be taken using, for example, a transcranial Doppler ultrasound machine to assess one or more cerebral arteries.

[0083] Flexible substrate 154 may include a flexible circuit (not shown) and a protection and/or insulation layer (not shown). Flexible circuit 154 may be configured provide one or more conductive pathways (e.g., leads, wires, lines of conductive ink, etc.) that are configured to electrically and/or communicatively couple each of the plurality of electrodes 152 to pulse generator 120 (via, control unit 130) to, for example, communicate electrical simulation from pulse generator 120 to one or more of the plurality of electrodes 152. The protection/insulation layer of flexible substrate 154 may be configured to provide protection and/or insulation for the conductive pathways to, for example, prevent breakage and/or undesired electrical discharge (via, for example, contact with the subject’s skin) along the conductive pathways, particularly as flexible substrate 154 and/or housing 150 is bent or curved to, for example, wrap around a subject’s head and/or ear. The protection and/or insulation layer of flexible substrate may comprise, for example, a dielectric insulator and/or a thin polyethylene plastic such as Mylar A. In some embodiments, protection and/or insulation layer of flexible substrate 154 may provide structural support and spacing for one or more of the plurality of electrodes 152 and may, at times, be shaped to minimize the areas acting as a barrier between, for example, adhesive layer 158 of, and/or adhesive mechanism (e.g., tape and/or adhesive layer 158) for, housing 150 and a subject’s skin.

[0084] When housing 150 includes adhesive layer 158, it may be configured to temporarily adhere (e.g., in a manner similar to, for example, tape and/or a sticker) to a subject’s skin (e.g., forehead, temple, and/or ear) and maintain contact between plurality of electrodes 152 and the skin by forming a temporary bond with a suitable area of the subject’s skin positioned around the electrodes. The adhesive layer 158 may be configured to have a degree of tack that is strong enough to remain bonded to the subject’s skin when the subject moves his or her head but may still be removed from the subject without damaging the subject’s skin, housing 150, and/or a component thereof. At times, the adhesive layer 158 may be sized and/or configured to minimize application of the adhesive layer 158 to areas of skin that may be covered with the subject’s hair, such as the eyebrows, scalp, and sideburns. In some cases, the adhesive layer 158 may be configured to allow air and moisture to penetrate its barrier to improve wearing comfort and/or may be configured to be. In some embodiments, the adhesive layer 158 may comprise a medical grade tape adhesive and/or a silicone adhesive tape such as 3M medical grade silicone adhesive 2480.

[0085] At times, a size and/or shape of housing 150 may be configured so that it does not cover a subject’s temporal bone and/or leaves open portions of the subject’s head to ultrasonic interrogation via, for example, a transcranial Doppler ultrasound device so as to, for example, perform assessment of the subject’s cerebral arteries without removal of the device. For example, housing 150 may be configured so that it does not impede access for an ultrasound transducer (e.g., a 2 MHz TCD ultrasound transducer) when it is placed over the temporal area of the subject’s head just above the zygomatic arch and in front of the tragus of the ear, thereby permitting the ultrasonic transducer user to orient the transducer slightly upward, anteriorly to obtain a transcranial ultrasound measurement. In some embodiments, the shape of housing 150 may not overlie the subject’s eyes or prevent assessment of the subject’s face (e.g., assess facial droop). In some embodiments, housing 150 and/or components thereof may be configured to stretch, so that, for example, housing 150 may be shaped to accommodate the facial anatomy of the user and allow for slight adjustments to ensure one or more of the plurality of electrodes overlie the intended nerve targets.

[0086] One or more of the plurality of electrodes 152 may be configured to contact and/or adhere to a subject’s skin overlying a target location on the subject’s nerve(s). Once in position, one or more of the plurality of electrodes may be configured and transmit electrical stimulation provided by pulse generator 120 (via, for example, control unit 130) to the skin for communication to a target location the subject's nerve(s). One or more of the plurality of electrodes 152 may be embodied as a hydrogel electrode. The hydrogel may serve to conduct current between the one or more electrodes 152 and the skin, reduce impedance of this boundary, and/or improve the current distribution over a surface area of the respective electrode by increasing the contact area of the electrode with the skin. On some occasions, the hydrogel may include a conductive ink that fills an area of the electrode and/or may be constructed from a composite of conductive ink with an overlying hydrogel. In some cases, the hydrogel may be a multiuse high-tack hydrogel and/or hydrogel that may be used multiple times configured to enhance current transmission between pulse generator 120 and the subject’s skin to a target nerve.

[0087] Control unit 130 may be configured to control an operation of pulse generator 120 and/or nerve stimulation delivery device 110 according to, for example, one or more processes, methods, and/or protocols disclosed herein. At times, control unit 130 may be operated by, for example, a patient, therapist, caregiver, and/or clinician to initiate delivery of stimulation to one or more of the plurality of electrodes, terminate delivery, and/or control delivery of stimulation to one or more electrodes of a nerve stimulation delivery device such as the nerve stimulation delivery devices disclosed herein. A diagram of an exemplary control unit 130 is provided by FIG. 1D and includes one or more processing device(s) 132 that may be embodied as, for example, a processor, a FPGA, and/or an ASIC, a memory 134 configured to store one or sets of instructions for execution by processing device 132 and/or control unit 130, and a communication interface 136 configured to accept input from and/or provide output to a user and/or a component of system 100 and/or a component external to system 100, such as a computer and/or display device (not shown). Exemplary input to communication interface 136 includes, but is not limited to, instructions for operation of a component of system 100 such as a setting and/or parameter for the operation of nerve stimulation delivery device 110, pulse generator 120, and/or sensor(s) 140. Exemplary settings include, but are not limited to, a duty cycle, frequency, amplitude and/or pulse width of stimulation energies provided to one or more electrodes of nerve stimulation delivery device 110. Exemplary components of communication interface 136 include, but are not limited to, dials, meters, touch screens, keyboard, speakers, microphones, display screens, lights, and a wired and/or wireless communication port(s). For example, in some embodiments, communication interface 136 may include one or more switches 166, one or more port(s) 168, a first dial 164A, and/or a second dial 164B. Switches 166 may be configured to, for example, initiate and/or terminate delivery of electrical stimulation to one or more of the plurality of electrodes 152. In some embodiments, first and/or second dial 164A and 164B may be configured to receive input regarding a parameter (e.g., amplitude, pulse width, duration of stimulation delivery, and/or frequency) for the stimulation to be delivered via the one or more of the plurality of electrodes 152 and on some occasions, first dial 164A may be configured to control parameters for stimulation delivered by a first set of electrodes included in the plurality of electrodes 152 and second dial 164B may be configured to control parameters for stimulation delivered by a second set electrodes of the plurality of electrodes 152. Further details regarding the first and second sets of electrodes are provided below. [0088] Optionally, system 100 and/or nerve stimulation delivery device 110 may include one or more sensor(s) 140 configured to observe and/or measure a physiological indicator for a subject and/or an indication that the subject may (or may not) have performed an action and/or rehabilitation task. Exemplary sensor 140 include, but are not limited to, motion sensors, accelerometers, touch sensors, goniometers, capacitive sensors, resistive sensors, audio sensors, electrocardiogram (ECG) sensors, blood pressure monitors, electromyography (EMG) sensors, strain gauges, electroencephalography (EEG) sensors, pulse oximeters, respiratory sensors, humidity sensors, moisture sensors, heartrate monitors, and combinations thereof. On some occasions, sensor 140 may be attached to the subject and/or nerve stimulation delivery device 110 to measure and/or determine, for example, an orientation of nerve stimulation delivery device 110, a change in orientation and/or position of nerve stimulation delivery device 110 during use, whether the subject and/or nerve stimulation delivery device 110 has moved and, if so, a speed and/or direction of the movement, how much energy the subject is exerting to perform the task, changes in the subject’s heart rate as he or she performs a task, and/or whether the subject has completed a task or series of tasks.

[0089] Communication between two or more components of system 100 and/or between a component of system 100 and an external component may be facilitated by a wired and/or wireless communication coupling. Although shown as separate components, two or more components of system 100 may be resident within the same housing. For example, pulse generator 120 and/or control unit 130 may be integrated into nerve stimulation delivery device 110 and/or adhered to the external side thereof. [0090] FIG. 1E is a side view of an exemplary subject’s 160 head showing three regions on the subjects’ skin that correspond to particular subdural nerves, wherein subcutaneous tissue in a first region 161 is innervated by the auricular branch of the vagus nerve (ABVN), also known as Arnold’s nerve. Arnold's nerve arises from the superior vagal ganglion and is joined by a branch from the inferior ganglion of the glossopharyngeal nerve. Subcutaneous tissue in a second region 162 ascends the auriculotemporal nerve (ATN), which is a branch of the mandibular division of Cranial nerve V (Trigeminal nerve). The ATN arises from the mandibular nerve, it also communicates with the facial nerve (Cranial nerve VII). Subcutaneous tissue in a third region 163 is innervated with nerves that branch from the supraorbital nerve (arising from Cranial nerve V) and from the supratrochlear nerve pass through a notch/foramen superior to the orbit.

[0091] In addition, FIG. 1E provides an exemplary position of three transcranial temporal windows, wherein a rostral circle 170 represents an anterior transcranial temporal window, a middle circle 172 represents a middle transcranial temporal window, and a caudal circle 174 represents a posterior transcranial temporal window. In some embodiments, a position of one or more transcranial temporal windows on a subject (e.g., subject 160) may be found and/or marked (e.g., a dot or an arrow) with, for example, a pen (e.g., surgical pen or permanent marker) to facilitate application of housing 150 without obscuring the marked temporal window(s). Transcranial temporal windows 170, 171 , and/or 172 may be easy or difficult to find for individual subjects depending on, for example, one or more of the subject’s age, race, and/or gender. In some embodiments, a method of finding the transcranial temporal windows may include scanning a subject’s head (e.g., from left to right of the forehead above the eyes) with an ultrasound transducer (e.g., a 2 MHz transcranial ultrasound transducer) until a clear signal for the desired cerebral vessel, such as a unilateral middle cerebral artery (MCA), is found using, for example, sound and visual density of the ultrasound signals. Additionally, or alternatively, a transcranial temporal window for an MCA may be located anatomically by placing an ultrasound transducer over a subject’s temporal area just above the zygomatic arch and in front of the tragus of the ear with the transducer oriented slightly upward in the anterior direction until a clear signal for the desired cerebral vessel is found at the appropriate depth. An alternative method of finding a subject’s transcranial temporal window(s) includes examining the subject’s head while his or her mouth is opened and closed and/or the jaw muscles are clenched repeatedly while another person places their hand over the subject’s temple to feel for areas of the subject’s temple with the most flesh or muscle concentration, which may be an indication for where on the subject’s temple bone density is thinnest, which may be a landmark for locating one or more transcranial temporal window(s).

[0092] FIG. 2A provides a diagram of a subject-facing side of a first exemplary nerve stimulation delivery device 110A. Nerve stimulation delivery device 110A comprises a housing 150A (a subject-facing side of which may be covered with an adhesive and/or adhesive layer 158) that holds a first flexible substrate 154A, a first communication interface 156A, and plurality of electrodes 152, which comprises a right supraorbital nerve location upper triangular electrode 201 , a left supraorbital nerve location upper triangular electrode 203, a right supraorbital nerve location lower electrode 202, a left supraorbital nerve location lower electrode 204, a right vagus nerve location larger elliptical electrode 205, a left vagus nerve location larger elliptical electrode 207, a right vagus nerve location smaller elliptical electrode 206, a left vagus nerve location smaller elliptical electrode 208. Right supraorbital nerve location upper triangular electrode 201 , a left supraorbital nerve location upper triangular electrode 203, a right supraorbital nerve location lower electrode 202, a left supraorbital nerve location lower electrode 204 and portions of a first flexible substrate 154A coupled thereto are positioned within a forehead section 240A of housing 150A. Right vagus nerve location larger elliptical electrode 205 along with portions of first flexible substrate 154A coupled thereto are positioned with a large right vagus nerve portion 220B of housing 150A and right vagus nerve location smaller elliptical electrode 206 along with portions of first flexible substrate 154A coupled thereto are positioned with a small right vagus nerve portion 230B. Left vagus nerve location larger elliptical electrode 207 along with portions of first flexible substrate 154A coupled thereto are positioned with a large left vagus nerve portion 220A of housing 150A and left vagus nerve location smaller elliptical electrode 208 along with portions of first flexible substrate 154A coupled thereto are positioned with a small left vagus nerve portion 230A.

[0093] Communication interface 156A of nerve stimulation delivery device 110A may be embodied as a reinforced interface for communicative and/or electrical coupling to control unit 130 and/or pulse generator 120 and may include a tail that may comprise one or more conductive traces of plurality of electrodes 152 and may be configured to go over a back of subject’s 160 head (as shown in FIG. 2B). Communication interface 156A may include a portion of flexible substrate 154 but, in many cases, may not have include the adhesive layer 158.

[0094] At times, supraorbital nerve location upper triangular electrode 201 , left supraorbital nerve location upper triangular electrode 203, right supraorbital nerve location lower electrode 202, and left supraorbital nerve location lower electrode 204 may be grouped together into a set of supraorbital electrodes configured to provide stimulation to a subject’s forehead (i.e., third region 163) so that the supraorbital branch of the trigeminal nerve and/or positions along the trigeminal nerve may be stimulated via stimulation delivered by the set of supraorbital electrodes. The stimulation provided by the supraorbital set of electrodes may be referred to herein as trigeminal nerve stimulation (TNS) and, on some occasions, may be controlled by user input provided via first dial 164A of control unit 130. Additionally, or alternatively, right vagus nerve location larger elliptical electrode 205, left vagus nerve location larger elliptical electrode 207, right vagus nerve location smaller elliptical electrode 206, and left vagus nerve location smaller elliptical electrode 208 may be grouped together into second set of electrodes configured to provide stimulation to a left and right first and second region 161 and 162 so that the auricular branch of the subject’s vagus nerve and/or positions along the subject’s vagus nerve may be stimulated via stimulation delivered by the second set of electrodes, which may be referred to herein as vagus nerve stimulation (VNS) that, on some occasions, may be controlled by user input provided via second dial 164B of control unit 130.

[0095] FIG. 2B provides a side-perspective view of subject 160 with first nerve stimulation delivery device 110A positioned thereon, wherein forehead section 240A of housing 150A is positioned on subject’s 160 forehead below the hairline and above the eyes, large left vagus nerve portion 220A of housing 150A is positioned in front of subject’s 160 ear, and small left vagus nerve portion 230A is positioned within subject’s ear. As may be seen in FIG. 2B, communication interface 156A may be positioned over the top and back of subject’s 160 head so that it may be, for example, coupled to control unit 130 and/or pulse generator 120.

[0096] FIG. 2C provides a side view of subject’s 160 left ear wearing nerve stimulation delivery device 110A. The part of nerve stimulation delivery device 110A comprising the smallest electrode (i.e., left vagus nerve location smaller elliptical electrode 208) may be located in the subject’s cymba concha 302 and may fit snugly in the space below the antihelix 303 and above the helicis crus 304 and may be affixed thereto by adhesive layer 158 that covers left vagus nerve location smaller elliptical electrode 208. A portion of flexible substrate 154A proximate to left vagus nerve location smaller elliptical electrode 208 may have an “S-”like shape 306 configured to follow the contour of the subject’s helicis crus and increase surface area for adhesion of flexible substrate 154A proximate to left vagus nerve location smaller elliptical electrode 208 within the subject’s cavum concha 305. Flexible substrate 154A and adhesive layer 158 may exit the outer ear at the intertragic notch 301 and left vagus nerve location larger elliptical electrode 207 may be positioned in front of the subject’s tragus 307 and behind the hair of the sideburn 308 as shown. [0097] FIG. 2D provides a diagram of a second exemplary housing 150B for plurality of electrodes 152 and includes a headband 210, a left-side auricular extension 220, and a right-side auricular extension 230. Headband 210 may be sized, shaped, and/or configured to wrap around a subject’s head and may include one or more fastening mechanisms (e.g., Velcro, loops, hooks, snaps, etc.) 215 configured to facilitate affixing one side of headband 210 to the other when worn by a subject. Headband 210 may be configured to house the first and second sets of supraorbital electrodes and a corresponding portion of flexible substrate 154 (not shown) configured to hold the first and second sets of supraorbital electrodes in place and provide electrical stimulation thereto. Headband 210 may further include a plurality of openings sized, shaped, and positioned to correspond to a respective position of the first and second sets of supraorbital electrodes so that they are not covered, or obscured by headband 210. Additionally, or alternatively, first and second sets of supraorbital electrodes may be positioned on an exterior surface of headband 210 and may be electrically coupled to an underlying portion of flexible substrate 154 (not shown). Headband 210 may also include a left-side and a right-side notch sized and positioned so that headband 210 does not fit over, or obscure, a subject’s upper ear.

[0098] Left-side auricular extension 220A may be sized, shaped, and/or configured to house left-side set of auricular electrodes 207 and 208 along with portions of flexible substrate 154 configured to hold left-side set of auricular electrodes 207 and 208 in place and provide electrical stimulation thereto. In particular, left-side auricular extension 220 includes left vagus nerve location larger elliptical electrode 207 along with a first left-side segment of flexible substrate 154A that connects left vagus nerve location larger elliptical electrode 207 to a portion of flexible substrate 154 included within headband 210 (not shown). Left vagus nerve location larger elliptical electrode 207 and first left-side segment of flexible substrate 154A are positioned within a substantially rectangularly shaped left vagus nerve portion 255A of left-side auricular extension 220A. Left-side auricular extension 220A also includes a left-side curved extension 252B that houses left vagus nerve location smaller elliptical electrode 208 and a second left-side portion of flexible substrate 154B.

[0099] Right-side auricular extension 230 may be sized, shaped, and/or configured to house right-side set of auricular electrodes 205 and 206 along with portions of flexible substrate 154 configured to hold right-side set of auricular electrodes 205 and 206 in place and provide electrical stimulation thereto. In particular, right-side auricular extension 230 includes right vagus nerve location larger elliptical electrode 205 along with a first right-side segment of flexible substrate 154A that connects right vagus nerve location larger elliptical electrode 205 to a portion of flexible substrate 154 included within headband 210 (not shown). Right vagus nerve location larger elliptical electrode 205 and first right-side segment of flexible substrate 154A are positioned within a substantially rectangularly shaped right-side vagus nerve portion 255B of right-side auricular extension 230. Right-side auricular extension 230 also includes a right-side curved extension 252B that houses right vagus nerve location smaller elliptical electrode 208 and a second right-side portion of flexible substrate 154B.

[00100] In some embodiments, left-side auricular extension 220 and/or right-side auricular extension 230 may be detachable from headband 210 via, for example, one or more couplings (e.g., snaps, toggles, wired couplings, a track, a pin, and/or clasp). On some occasions, a subject may be fitted with headband 210 without left-side and/or right-side auricular extension 220 and/or 230 and then, once headband 210 and/or first and second sets of supraorbital electrodes are properly positioned, left-side and/or rightside auricular extension 220 and/or 230 may be attached to headband 210 and/or positioned around the subject’s ear as shown in, for example, FIG. 2E, which provides a left-side-perspective view of subject 160 wearing housing 150B with headband 210 wrapped around the subject’s 160 head so that the first and second sets of supraorbital electrodes are positioned against the skin of subject’s 160 forehead, notches within headband 210 are positioned proximate to subject’s 160 left and right ears, left-side auricular extension 220 is positioned proximate to subject’s 160 left-side auricular and right-side auricular extension 230 is positioned proximate to subject’s 160 right-side auricular. As may also be seen in FIG. 2E, headband 210 may further include housing 151.

[00101] FIG. 3 provides a rear perspective view of a system of retaining components 300 that includes a frame 310 sized, shaped, and configured to fit over one or more of the nerve stimulation delivery devices disclosed herein (e.g., nerve stimulation delivery device 110A) and be held in place with an elastic band 340 size, shaped, and configured to wrap around a back of a subject’s head when worn and exert a compressive force pulling frame 310 toward the subject’s skin. System 300 may be configured to facilitate adhesion of a housing like housing 150A to the subject’s skin and/or exert a force that maintains contact of one or more electrodes of the nerve stimulation delivery device with the subject’s skin and/or decreases a distance to the target nerves by displacing and/or compressing overlying tissue, which may decrease impedance between the nerve stimulation delivery device and skin interface.

[00102] Frame 310 may be constructed with a rigid and/or semi-rigid material that is sized, shaped, and/or configured to overly housing 150, 150A, and/or 150B and, in some embodiments, may include one or more depressions, or openings, sized, positioned, and/or arranged within frame 310 to correspond to a respective electrode of the nerve stimulation delivery device housing. For example, frame 310 includes a first opening 310 sized, shaped, and configured to correspond to electrode 201 ; a second opening 302 sized, shaped, and configured to correspond to electrode 202; a third opening 303 sized, shaped, and configured to correspond to electrode 203; a fourth opening 304 sized, shaped, and configured to correspond to electrode 204; a fifth opening 305 sized, shaped, and configured to correspond to electrode 205; and a sixth opening 306 sized, shaped, and configured to correspond to electrode 206. Frame 310 also includes left and right auricle frame extensions 320A and 320B sized, shaped, and configured to fit over respective left and right auricle extensions 220A and 220B and left and right auricle frame small right vagus nerve portion 330A and 330B sized, shaped, and configured to fit over respective left and right auricle frame small right vagus nerve portion 330A and 330B. In some embodiments, system 300 may include an additional head strap that may be positioned superiorly over the head of the subject between the ears to prevent the external frame from moving inferiorly.

[00103] In some embodiments, frame 310 may be manufactured using an injection molding and/or stamping process using, for example, suitable plastic including, but not limited to, polypropylene. At times, frame 310 may include adjustable components that allow repositioning of, for example, one or more components of frame 310. A force applied to the electrodes by system 300 may be generated as a result of the material properties of gram 310 and/or elastic band 340 and their respective size, shape, and configuration that may cause an interference fit between frame 310 and the electrodes of a nerve stimulation delivery device in contact with the subject’s skin. A force may be generated between the adjustable components and the rest of the headframe using a spring, such as a torsion spring. The spring may have a spiral-shaped configuration. The spiral may be a shape with windings about a central axis. The windings may gradually widen or tighten along the length. The spiral may be continuous. The spring may have a conical-shaped deployed configuration including, but not limited to, tubular, conical, frustoconical, or helical shapes. [00104] FIG. 4 is a flowchart illustrating an exemplary process 400 for exposing a subject to stimulation as part of a stimulation tolerability assessment for the subject. Process 400 may be performed by any system, system component, and/or device disclosed herein.

[00105] Optionally, an indication of a selected amplitude (e.g., 0.01-500mA) for stimulation to be delivered transcutaneously to nerves proximate to the subject’s for head, and/or ears may be received by, for example, a nerve stimulation delivery device control unit such as control unit 130 (step 405). In some embodiments, the indication of step 405 may be received via first and/or second dial(s) 164A and/or 164B. Step 405 may not be executed when, for example, an amplitude for the stimulation is pre-set to a desired level on the control unit (e.g., dial 164A and/or 164B are set to a desired amplitude prior to execution of step 410).

[00106] In step 410, an indication to initiate provision of the stimulation at the selected amplitude to a nerve stimulation delivery device may be received via, for example, a switch like switches 166 and/or one or more instructions received from a processor or computer. It may be ensured that the nerve stimulation delivery device is properly positioned on the subject prior to execution of step 410. In some embodiments, this may be done by visual inspection and/or determining a level of impedance for one or more electrodes of the nerve stimulation delivery device.

[00107] In step 415, stimulation energy of a fixed frequency (e.g., 0.01-800Hz) and the selected or pre-set amplitude may be provided to the nerve stimulation delivery device for a period of time (e.g., 0.5-180 seconds) sufficient to assess the subject’s tolerance to the stimulation. In some cases, the stimulation energy may be biphasic. In some embodiments, step 415 may be executed by, for example, the control unit via one or more ports, or interfaces, in communication with a pulse generator like pulse generator 120. In these embodiments, the control unit may act as a conduit and/or switch for stimulation generated by the pulse generator. The stimulation may be delivered to the subject via one or more electrodes present within the nerve stimulation delivery device as, for example, shown and described herein. While the stimulation is being provided in step 415, impedance for a circuit including the nerve stimulation delivery device and pulse generator may be measured and, when the impedance falls outside an expected range (e.g., too high, or too low) (step 420), execution of process 400 and/or step 415 may stop and/or an error message may be provided to a user (step 425). When the impedance is within an expected range (step 420), execution of step 415 may continue. [00108] Optionally, in step 430, an indication of an adjustment to the selected amplitude (e.g., 0.01 -500mA) for stimulation to be delivered to nerves proximate to the subject’s forehead and/or ears may be received by, for example, a nerve stimulation delivery device control unit such as nerve stimulation delivery device control unit 130. At times, the amplitude for the stimulation may be adjusted responsively (e.g., up, or down) to feedback from the subject regarding his or her tolerance for the stimulation and/or discomfort associated with receipt of the stimulation. When step 430 is not performed, process 400 may end when provision of the stimulation to the subject is complete. [00109] In step 435, an indication to initiate provision of the stimulation at the adjusted amplitude to the nerve stimulation delivery device may be received via, for example, a switch like switches 166 and/or one or more instructions received from a processor. Then, in step 440, stimulation of a fixed frequency (e.g., 0.01-800Hz) and the adjusted amplitude may be provided to the nerve stimulation delivery device for a period of time (e.g., 15-180 seconds) sufficient to assess the subject’s tolerance to the stimulation. At times, the stimulation energy provided in step 445 may be biphasic. In some embodiments, step 440 may be executed in a manner similar to execution of step 415. Optionally, while the stimulation is being provided in step 440, impedance for the circuit including the nerve stimulation delivery device and pulse generator may be measured and, when the impedance falls outside an expected range (e.g., too high, or too low) (step 445), execution of process 400 and/or step 440 may stop and/or an error message may be provided to a user (step 450). When the impedance is within an expected range (step 445), execution of step 440 may continue until execution of process 400 ends. [00110] Process 400 and/or portions thereof may be performed for different regions of a subject’s head, such as the forehead and proximate to the ears to, for example, assess the subject’s tolerance for stimulation at various regions of their head. A subject’s tolerance for stimulation may vary due to, for example, skin moisture level, barriers to current penetration such as oils, dirt, or makeup, or anatomic differences in cutaneous nerve distribution in different regions of the head that may lead to differing levels of sensation tolerability for different regions of the subject’s head. Similarly, subjects that are more susceptible to headache or migraine may desire a lower forehead stimulation level should the stimulation trigger a headache and/or migraine. Alternatively, these subjects may desire a higher stimulation level to prevent and/or treat a headache and/or migraine while also, for example, performing rehabilitation tasks in conjunction with treatment for ischemic stroke or other neurological conditions. [00111] Additionally, or alternatively, process 400 may be performed to elicit a physiological response of the subject and/or avoid one or more undesirable side effects. For example, it has been suggested that stimulation of the right cervical vagus nerve may affect cardiac modulation. While the auricular branch of the vagus nerve has not been shown to affect heart rhythm and, therefore, no cardiac modulation side effects are expected from provision of stimulation of the auricular branch of the vagus nerve, should modulation of a subject’s heart rhythm be observed, one or more features of the stimulation provided to the auricular branch of the vagus nerve may be adjusted (e.g., lower amplitude and/or termination of stimulation) to, for example, diagnose a source of the heart rhythm modulation and/or avoid the modulation.

[00112] FIG. 5 is a flowchart illustrating a process 500 for exposing a subject to transcutaneous nerve stimulation as part of a priming nerve stimulation protocol and/or process for the subject. In some cases, the neural priming stimulation (as may be delivered during execution of process 500) may be used to lower the resistivity of the vasculature of the subject receiving neural stimulation via, for example, one or more processes described herein. Lowering vascular resistivity in this way may increase cerebral blood flow during systole. Additionally, or alternatively, provision of neural priming stimulation to subjects who, for example, may have one or more risk factors associated with stroke or other neurological conditions, may decrease the respective subject’s pulsatility index (PI) as may be measured by, for example, a transcranial Doppler ultrasound of the middle cerebral arteries. This decrease in PI may be indicative of a lowered resistivity of the subject’s downstream microvasculature. Process 500 may be performed by any system, system component, and/or device disclosed herein.

[00113] Optionally, an indication of a selected upper limit, or maximum, amplitude (e.g., 0.1-500mA) for stimulation to be delivered to nerves proximate to the subject’s for head, and/or ears may be received by, for example, a nerve stimulation delivery device control unit such as nerve stimulation delivery device control unit 130 (step 505). In some embodiments, the indication of step 505 may be received via first and/or second dial(s) 164A and/or 164B. Step 505 may not be executed when, for example, a maximum amplitude for the stimulation is pre-set to a desired level on, for example, the control unit (e.g., dial 164A and/or 164B are set to a desired maximum amplitude prior to execution of step 510). At times, the maximum amplitude may be responsive to a subject’s tolerance for the stimulation as determined via, for example, execution of process 400. [00114] In step 510, an indication to initiate provision of the stimulation at the selected amplitude to a nerve stimulation delivery device may be received via, for example, a switch like switches 166 and/or one or more instructions received from a processor. Then, in step 515, stimulation energy of a variable frequency (e.g., 0.01-800Hz) and variable amplitude that does not exceed the maximum amplitude may be provided to the nerve stimulation delivery device for a period of time (e.g., 5-30 minutes). The stimulation energy of step 515 may be biphasic. A manner of executing step 515 may be similar to execution of step 415.

[00115] Optionally, while the stimulation is being provided in step 515, impedance for a circuit including the nerve stimulation delivery device and pulse generator may be measured and, when the impedance falls outside an expected range (e.g., too high, or too low) (step 520), execution of process 500 and/or step 515 may stop and/or an error message may be provided to a user (step 525). When the impedance is within an expected range (step 520), execution of step 515 may continue.

[00116] In some instances, the priming nerve stimulation applied via execution of process 500 may serve to reduce the resistivity of the subject’s cerebrovasculature, which may allow for greater cerebral perfusion and blood flow to impaired regions of the brain that may be targets for neuroplastic recovery. Additionally, or alternatively, the priming nerve stimulation applied via execution of process 500 may be performed before the performance of rehabilitative tasks to induce a lower cerebrovascular resistance state in the subject and improve the effectiveness of neuroplastic recovery during the rehabilitative tasks.

[00117] In some embodiments, processes 400, 500, and/or 600 may be sequentially performed for a subject during a therapy session using, for example, a nerve stimulation delivery device like the nerve stimulation delivery devices disclosed herein. In these embodiments, process 400 may be executed to assess the tolerability of the subject to the stimulation and set a stimulation level and/or one or more parameters for the stimulation to be provided when process(es) 500 and/or 600 are executed. For example, a stimulation parameter used during execution of process 500 may be responsive to a stimulation parameter set and/or determined via execution of process 400. Following execution of process 500, process 600 may be executed to deliver repetitive bursts of stimulation to the nerve stimulation delivery device in contact with the subject’s skin while the subject is performing, or attempting to perform, one or more rehabilitation tasks during the therapy session. The therapy session may be targeted to rehabilitation of any neurological deficit and/or responsive to a medical condition of the patient.

[00118] FIG. 6 is a flowchart illustrating a process 600 for exposing a subject to transcutaneous nerve stimulation as part of a rehabilitation stimulation protocol for the subject and/or a method of treating the subject for a medical condition such as a motor or speech deficit caused by ischemic stroke. Process 600 may be performed by any system, system component, and/or device disclosed herein.

[00119] Optionally, an indication of an amplitude (e.g., 0.01 -500mA) for stimulation to be delivered to nerves proximate to the subject’s for head, and/or ears may be received by, for example, a nerve stimulation delivery device control unit such as nerve stimulation delivery device control unit 130 (step 605). In some embodiments, step 605 may be executed in a manner similar to the execution of step 405 and/or 505. In some cases, the amplitude received in step 605 may be responsive to the subject’s tolerance as may be determined as a result of execution of step 400.

[00120] In step 610, an indication to initiate provision of the stimulation at the selected amplitude to a nerve stimulation delivery device may be received via, for example, a switch like switches 166 and/or one or more instructions received from a processor or computer. Additionally, or alternatively, the indication to initiate provision of the stimulation may be and/or include one or more measurements and/or inputs from a sensor like sensor 140 that may, for example, indicate that a rehabilitation task is being prepared for, is being performed, and/or is completed. Exemplary inputs include, but are not limited to, the subject’s blood pressure, blood oxygenation values, ECG measurements, an indication of movement of a muscle (e.g., a measurement from a muscle activation sensor (e.g., an EMG sensor) and/or a strain gauge) and/or an indication of detected motion and/or an indication of detected motion For example, a motion sensor may be configured to sense when a subject has bent his elbow to raise his hand to his face (e.g., in a manner similar to moving a fork into the subject’s mouth) and, an output from the motion sensor that indicates an initiation, completion, and/or cessation of this movement may be a trigger for initiating execution of step 615 and/or the indication received in step 610. Then, in step 615, a burst of stimulation energy of a fixed frequency (e.g., 0.01-800Hz) and a fixed amplitude may be provided to the nerve stimulation delivery device for a period of time (e.g., 0.5-30 seconds). In some cases, the stimulation energy may be biphasic. In some embodiments, step 610 may be executed before, during, and/or after the subject performs a therapeutic task selected to treat a medical condition of the subject.

[00121] Optionally, before and/or during the stimulation is provided in step 615, impedance for a circuit including the nerve stimulation delivery device and pulse generator may be measured and, when the impedance falls outside an expected range (e.g., too high, or too low) (step 620), execution of process 600 and/or step 615 may stop and/or an error message may be provided to a user (step 625). When the impedance is within an expected range (step 620), execution of step 615 may continue for a desired length of time.

[00122] FIG. 7 is a flowchart illustrating a process 700 for exposing a subject to transcutaneous nerve stimulation as, for example, a treatment for a medical condition such as a cognitive, motor, or speech deficit caused by ischemic stroke, neurological injury, and/or neurological impairment. Process 700 may be performed by any system, system component, and/or device disclosed herein.

[00123] In step 705, parameters for neural stimulation and/or a neural stimulation protocol for a subject may be received by, for example, a control unit like control unit 130 and/or a computer or processor in communication with a nerve stimulation delivery device like the nerve stimulation delivery device s disclosed herein. Exemplary parameters for neural stimulation include, but are not limited to, an amplitude, frequency, pulse width, and/or duration of neural stimulation to be provided to a nerve stimulation delivery device worn by the subject. Exemplary neural stimulation protocols may be one or more instructions regarding how and/or when to provide stimulation to the nerve stimulation delivery device. Exemplary neural stimulation protocols may include instructions regarding a sequence of parameters for stimulation provided to one or more which electrodes of a nerve stimulation delivery device , and/or how the stimulation may be responsive to one or more indications from, for example, a user, the subject, and/or a sensor like sensor 140. At times, the neural stimulation protocol(s) and/or parameter(s) may be tailored to subject using, for example, a result of execution of processes 400, 500, and/or 600, a diagnosis of subject, a rehabilitation program for the subject, trends in the subject’s responsiveness to neural stimulation therapy, known side effects for the subject when undergoing neural stimulation therapy, comorbidities of the subject, other treatments (e.g., medication, physical therapy, etc.) provided to the subject, who is administering the neural stimulation (e.g., the subject, a trained clinician, etc.), how compliant the subject is with his or her therapeutic regime, and/or where (e.g., home, at bedside in the hospital, in clinic, and/or at physical rehabilitation center) the stimulation therapy is being administered.

[00124] In some embodiments, the neural stimulation protocol of step 705 may include parameters specific to one or more electrodes and/or sets of electrodes of the nerve stimulation delivery device. For example, the neural stimulation protocol of step 705 may provide instructions for when and/or how stimulation is to be provided to individual electrodes and/or a first and second set of electrodes of the nerve stimulation delivery device.

[00125] In some cases, the neural stimulation protocol of step 705 may be a default protocol and/or one or more of a plurality of protocols associated with a characteristic of the subject and/or the medical condition the subject is receiving therapy for. For example, if the subject is receiving therapy for upper limb weakness, the protocol received in step 705 may be a default protocol associated with upper limb weakness that, on some occasions, may be adjusted according to one or more optional parameters received in step 705. In another example, if the subject is receiving therapy for cognitive impairment, the protocol received in step 705 may be a default protocol associated with cognitive impairment that, on some occasions, may be adjusted according to one or more optional parameters received in step 705.

[00126] Additionally, or alternatively, the neural stimulation protocol of step 705 may be responsive to, and/or adjusted for, input from one or more sensors (e.g., sensors 140) that, for example, may be coupled to and/or observe or measure the subject while he or she is performing rehabilitation tasks and/or during execution of process 700 or a portion thereof. For example, sensor characteristics (e.g., accuracy rate, lag time between subject movement and communication of motion detected by the sensor, sensor type, etc.) may be incorporated into a neural stimulation protocol. At times, a neural stimulation protocol may include one or more over-rides and/or instructions for terminating neural stimulation in response to a received input from a sensor. For example, if the subject is coupled to an electrocardiogram (ECG) machine and a reading from the ECG machine indicates that the subject’s heart rate is too high and/or is modulating at an unacceptable rate, then neural stimulation protocol may include instructions to stop providing stimulation to the nerve stimulation delivery device so that these conditions may be addressed by, for example, the subject and/or clinical staff.

[00127] Optionally, in step 710, an indication that the nerve stimulation delivery device is properly positioned on the subject’s anatomy may be received. At times, step 710 may be executed via, for example, measuring a level of impedance between electrodes of the nerve stimulation delivery device and a circuit providing stimulation to the nerve stimulation delivery device. Additionally, or alternatively, step 710 may be indirectly executed via, for example, receipt of an indication to initiate provision of the stimulation to the nerve stimulation delivery device (step 715) according to, for example, the neural stimulation parameters and/or a neural stimulation protocol received in step 705. In some embodiments, execution of step 715 may resemble execution of step 610. [00128] In step 720, stimulation energy may be provided to the nerve stimulation delivery device in accordance with the neural stimulation protocol(s) and/or parameter(s). In some cases, the stimulation energy may be biphasic. In some embodiments, step 710 may be executed before, during, and/or after the subject performs a therapeutic task selected to treat a medical condition of the subject according to, for example, the neural stimulation protocol(s) and/or parameter(s). At times, step 720 may be executed before, during, and/or after performance of a rehabilitative task by the subject.

[00129] Optionally, before and/or during the stimulation is provided in step 720, impedance for a circuit including the nerve stimulation delivery device and pulse generator may be measured and, when the impedance falls outside an expected range (e.g., too high, or too low) (step 725), execution of process 700 and/or step 715 may stop and/or an error message may be provided to a user (step 730). When the impedance is within an expected range (step 725), execution of step 715 may continue for a desired length of time.

[00130] Optionally, in step 735, one or more indication(s) of a subject’s response to the neural stimulation may be received and, in some embodiments, the neural stimulation protocol and/or parameters for the subject may be adjusted accordingly (step 740) and one or more of steps 710-735 may be repeated using the adjusted neural stimulation protocol and/or parameters for the subject. Exemplary indications of a subject’s response to the neural stimulation include, but are not limited to, measurements and/or observations of the subject taken shortly (e.g., 1s-30 minutes) before, during, and/or shortly (e.g., 1s-30 minutes) after the subject has received neural stimulation via the nerve stimulation delivery device (e.g., execution of step 720). Two exemplary measurements of this type include PI and blood mean flow velocity (MFV), and changes to PI and MFV may be measured using, for example, transcranial Doppler ultrasound monitoring. PI is equal to a difference between peak systolic blood velocity and minimum diastolic blood velocity divided by mean blood velocity during a cardiac cycle. PI may provide an indication of and/or be used to infer vascular resistivity. MFV is a measure indicating how fast blood is flowing through blood vessels in the area being examined. Analysis of combined PI and MFV measurements may indicate changes (e.g., increases or decreases) in cerebral blood flow. In some circumstances, a larger positive change in MFV measurements and/or a larger negative change in PI measurements during and/or following delivery of stimulation via the nerve stimulation delivery device may be indicative of increased cerebral blood flow caused by the stimulation and may demonstrate that the stimulation provided by the nerve stimulation delivery device is effectively stimulating the cerebral blood flow, which may induce, improve, and/or stimulate cerebrovascular plasticity and/or recovery from the medical condition.

[00131] Additionally, or alternatively, exemplary indications of a subject’s response to the neural stimulation that may be received in step 735 include, but are not limited to, measurements and/or observations of the subject taken following a multi-day (e.g., 7-30 days), multi-month (1-12 months), and/or multi-year (e.g., 1-20 years) execution of process 700 (i.e., the subject receives neural stimulation according to process 700 for days, months, and/or years). Exemplary measurements of this type may include imaging the subject’s brain via, for example, a magnetic resonance imaging (MRI) device and comparing these images over time (e.g., 1, 1.5, 2, 3, 6, 9, and/or 12 months) to, for example, observe and/or quantify changes in blood flow, cerebrovascular remodeling, global blood perfusion, vascular response, vascular size, and/or an extent of vascularization in the subject’s brain over time. These changes may, for example, indicate areas of new, or increased, neuronal growth and/or activity, which may be an indicator of recovery from the medical condition. For example, if cerebrovascular plasticity and/or vascular indicators are improved for a region of the brain that is damaged as a result of the medical condition are improved over time as a consequence of delivering stimulation via execution of process 700, these improvements may lead to, for example, improved functional recovery from the medical condition, increased neurogenesis, and/or reduced risk of cognitive decline, the subject regaining function in the damaged region of the brain. Additionally, or alternatively, a consequence of delivering stimulation via execution of process 700 may be to creation of extra collateral blood vessels, which may provide an additional reserve of blood vessels should the subject experience an acute event (e.g., stroke). Other exemplary measurement of this type include, but are not limited to, functional scores and assessments of quality of life, as may be indicated by, for example, a subject’s responses to one or more patient reported outcome documents designed to make such assessments and/or measurements.

[00132] Optionally, a feature of the stimulation (e.g., frequency and/or amplitude) provided to a nerve stimulation delivery device according to one or more methods disclosed herein (e.g., execution of step(s) 515, 615, and/or 720) may be adjusted during a therapy session and/or while the subject is performing a therapeutic task. For example, a feature of the stimulation may be adjusted during performance and/or upon completion of the task in a manner that may be proportional to a successful resistance motor function, an amplitude of the simulation energy may be increased to a maximum tolerable level when the task is attempted and/or provision of the simulation energy may cease upon completion of a task.

[00133] In some embodiments, such as for the treatment of acute incidences of the medical condition, process 500, 600, and/or 700 may be executed in a manner that increases cerebral blood flow for the subject and/or modulates depolarization events and/or neuroinflammation for the subject. For example, when treating an acute occurrence of the medical condition, the nerve stimulation delivery device may be activated/started upon placement on the subject and stimulation may be provided over a period of hours. In some circumstances, one or more features of the stimulation delivered to the subject may be dictated by a neural stimulation protocol, neural stimulation parameter, and/or a repeating algorithm that may be received in, for example, step 705 and/or adjusted in step 740. Additionally, or alternatively, the stimulation may be provided to the nerve stimulation delivery device using, for example, a repeating algorithm for a duration of, for example, hours and/or a portion of a therapy session. For example, in some embodiments when processes 600 or 700 are performed, the stimulation provided in step 615 or 720, respectively, may include provision of a first type of stimulation (e.g., TNS) for a first duration of time (e.g., 1-5 minutes) followed by provision of a second type of stimulation (e.g., VNS) for a second duration of time (e.g., 1-30 minutes) and this pattern may be repeated as needed and/or continuously through the duration of a therapy session. In another example, the stimulation provided in step 615 or 720, of processes 600 or 700 respectively, may include provision of a first type of stimulation (e.g., TNS) for a first duration of time (e.g., 1-5 minutes), followed by second duration of time (e.g., 1-5 minutes) wherein no stimulation is provided (e.g., an off-duty cycle), followed provision of a second type of stimulation (e.g., VNS) for a third duration of time (e.g., 1-30 minutes) and this pattern may be repeated as needed and/or continuously through the duration of a therapy session. In another example, the stimulation provided in step 615 or 720, of processes 600 or 700 respectively, include provision of a first (e.g., TNS) and a second type of stimulation (e.g., VNS) for a first duration of time (e.g., 15-30 minutes) on a 30-50% duty cycle followed by a short (e.g., 0.2-0.8s) burst of VNS and a short (e.g., 1-4s) burst of TNS after performance of each rehabilitation task.

[00134] Additionally,, or alternatively, in some embodiments, such as for the treatment of chronic incidences and/or symptoms of the medical condition, process 500, 600, and/or 700 may be executed in a manner that increases cerebral blood flow and may induce a corresponding modulation of neurotransmitters for a short duration of time (e.g., 0.5-20s) while the subject is performing and/or attempting to perform a rehabilitation task. In these embodiments, provision of stimulation to the subject’s nerve stimulation delivery device may be triggered by the subject’s performance and/or attempt to perform of the rehabilitation task, which may be observed by, for example, a clinician and/or one or more sensors, such as sensor 140. For example, process 600 and/or 700 may be executed to deliver stimulation to electrodes of the nerve stimulation delivery device proximate to a subject’s trigeminal nerve locations during performance of a rehabilitative task in the form of a movement of an upper limb (e.g., raise the limb from the subject’s side to over his or her head). A sensor (e.g., motion sensor and/or infrared sensor) that is observing the subject’s movement may provide the indication (step 610 and/or 715) to deliver the trigeminal nerve stimulation while the subject is moving his limb from his or her side to over his or her head. Once the subject has completed this task (i.e., his or her arm is over his or her head), provision of the trigeminal nerve stimulation may be stopped and may then be followed by a short burst of vagus nerve stimulation.

[00135] In another example, process 600 and/or 700 may be executed to deliver stimulation to electrodes of the nerve stimulation delivery device proximate to a subject’s trigeminal nerve locations before (e.g., 0-10s) performance of a rehabilitative task, which may be followed by delivery of a short burst of stimulation to electrodes proximate to the subject’s vagus nerve during the performance of the task.

[00136] In another example, process 600 and/or 700 may be executed to deliver stimulation to all electrodes of the nerve stimulation delivery device (e.g., the electrodes proximate to a subject’s trigeminal and vagus nerve locations) during a phase of performing a rehabilitative task. For example, stimulation may be delivered to all electrodes of the nerve stimulation delivery device during a certain phase of gait (e.g., when dorsiflexion of the ankle is desired during the toe-off to swing to heel strike phase) when the subject is performing the rehabilitative task of walking.

[00137] In yet another example, process 600 and/or 700 may be executed to deliver stimulation to electrodes of the nerve stimulation delivery device proximate to a subject’s trigeminal nerve locations before or during (e.g., 0-10s) performance of a rehabilitative speaking task. This trigeminal nerve stimulation may then be followed by delivery of a short burst of stimulation to electrodes proximate to the subject’s vagus nerve during the performance of the task.

[00138] In some embodiments, the stimulation provided via a nerve stimulation delivery devices like the nerve stimulation delivery devices disclosed herein using, for example, one or more processes disclosed herein may modulate and/or increase cerebrovascular autoregulation and/or vasculogenesis biochemical factors that, over time, may lead to the growth of new vasculature and/or better vascular response in a subject’s brain and/or a region of the subject’s brain that may have been damaged by the medical condition. For example, provision of stimulation to the trigeminal nerve alone or with the vagus nerve may trigger modulation and/or stimulation of vascular endothelial growth factor (VEGF), which may modulate and/or increase cerebrovascular autoregulation and/or vasculogenesis to, for example, accelerate recovery from the medical condition and/or restore function. Collectively, this may be seen as an improvement and/or inducement of cerebrovascular plasticity.

[00139] In one use case for the systems and devices disclosed herein, subjects diagnosed with an ischemic stroke and/or who present with chronic-stroke-like symptoms, such as paralysis, fatigue, memory problems and trouble speaking may be treated with one or more of the nerve stimulation delivery devices disclosed herein before, during, and/or after during a rehabilitation treatment session and/or performance of rehabilitation tasks with neural stimulation provided by a nerve stimulation delivery device like the nerve stimulation delivery devices disclosed herein.

[00140] Following diagnosis and initial treatment for acute stroke symptoms in, for example, a hospital or clinic, a subject may be treated for a medical condition (e.g., one or chronic stroke symptoms) resulting from the stroke during one or more rehabilitation sessions in which the subject is tasked with performing one or more actions to address the medical condition. For example, if a subject’s medical condition following stroke includes loss of fine motor skills in the right hand, during the rehabilitation session, the subject’s therapy protocol may include performance one or more rehabilitation tasks designed and/or selected to improve the subject’s right hand motor skills.

[00141] The subject may be coupled to a nerve stimulation delivery device like the nerve stimulation delivery devices disclosed herein in a manner that, for example, resembles how the nerve stimulation delivery device is coupled to in FIG. 2B, 2C, and/or 2E so that, for example, electrodes 206 and 208 are positioned to contact a left-side and a right-side first region 161 of the subject’s head, electrodes 206 and 207 are positioned to contact a left-side and a right-side second region 162 of the subject’s head, and electrodes 201 , 202, 203, and 204 are positioned to contact third region 163 of the subject’s head.

[00142] The nerve stimulation delivery device may include a sensor like sensor 140 and/or the subject may be provided with the sensor to, for example, hold and/or affix to his or her body as a wearable device (e.g., bracelet, stick-on patch, and/or anklet). Exemplary sensors include, but are not limited to, a motion sensor, an accelerometer, a touch sensor, a goniometer, a capacitive sensor, a resistive sensor, an audio sensor, a strain gauge, an EMG sensor, an EEG sensor, an ECG sensor, and combinations thereof. The sensor may be configured to measure one or more aspects of a subject’s performance, physiology, and/or completion of the task.

[00143] Optionally, the subject may be provided with a display device like display device 125 (e.g., a smart phone, tablet computer, and/or virtual reality device (e.g., a virtual reality headset)) that may be configured to cue the subject for performance and/or completion of a rehabilitation task. The cue may include auditory/visual instructions explaining the rehabilitation task to be performed by the subject and/or instruction to stop and/or start engaging in performance (or attempted performance) of the rehabilitation task. Delivery of neural stimulation provided by the nerve stimulation delivery device may be triggered in conjunction with, for example, provision of the cue for the task, receipt of a measurement from one or more of the sensors, and/or evaluation of a measurement from one or more of the sensors. Then, stimulation may be provided to the nerve stimulation delivery device in accordance with, for example, one or more processes described herein. For example, the stimulation delivered to the nerve stimulation delivery device may comprise administering about a 100% stimulation duty cycle for TNS and about a 100% VNS duty cycle constantly or continuously for a portion of and/or an entire rehabilitation session in which the subject is performing rehabilitation tasks. Additionally, or alternatively, the stimulation may be delivered to the subject in one or more treatment blocks lasting between 1 minute to 4 hours. Thereafter (i.e., following the 100% TNS and VNS), stimulation including an administration of about a 5-20% TNS duty cycle and about a 10% VNS duty cycle continuously (e.g., 4-24 hours), periodically (e.g., for 1-30 minutes every 4 hours), and/or for the duration of a treatment rehabilitation session may be provided. Stimulating the subject’s target nerves in this manner may, for example, increase the flow of blood to the subject’s brain, decreasing subject’s pain, and/or increase the subject’s efficacy in performance of one or more rehabilitation task(s).

[00144] In some cases, the stimulation provided by the nerve stimulation delivery device according to, for example, one or more processes described herein may be administered relative to the performance (or attempted performance) of a rehabilitation task, wherein TNS stimulation (e.g., first stimulation energy) may be applied while providing the subject with instruction regarding a rehabilitation task to be performed and/or cue to begin performance of the task and, when the subject successfully completes the task, VNS (e.g., second stimulation energy) may be provided.

Application of TNS stimulation (e.g., first stimulation energy) may occur in proportion to a resistance force (for example, if the task is bending the elbow from an extended to a retracted position, TNS may be applied at a lower level, and increased as the elbow continues to be bent; as the elbow is unbent, TNS may be decreased to a minimal level). Application of VNS (second stimulation energy) may occur after task completion. [00145] In some cases, provision of the stimulation in accordance with one or more processes described herein may include provision of TNS that is indirectly proportional to subject’s motor, or exertion, force while engaged in completion of a rehabilitation task such that when a task is tried TNS increases from a minimal amount to a maximum setting. If the subject is able to successfully complete the task, TNS stops increasing and VNS is performed after task completion. If the subject cannot perform the task and TNS has reached a maximum tolerable level, TNS decreases. Successful task completion may be measured by the sensor, (e.g., bracelet).

[00146] In some embodiments, processes 600 and/or 700 may be performed so that TNS levels and/or parameters are constant while the subject is participating in a therapy session. Additionally, or alternatively, processes 600 and/or 700 may be performed so that TNS amplitude and duty cycle may be modulated while VNS is modulated (high vs low frequency or rapid vs burst duty cycle) in a manner that is responsive to a subject’s EEG measurements (ex. Beta waves, delta waves, low frequency oscillations)).

[00147] In some cases, both TNS and VNS (e.g., nTNVS) is performed during a planning phase (beta wave and cognitive stage) prior to action and VNS is performed after execution of action. Additionally, or alternatively, processes 600 and/or 700 may be performed so that TNS is performed during a rehabilitative task planning phase (beta wave and cognitive stage) prior to action and/or attempted performance of the rehabilitative task and VNS is performed following execution of task and/or at the conclusion of attempting to perform the task. Additionally, or alternatively, processes 600 and/or 700 may be performed so that TNS is constantly delivered before and during a task and completion of the task is used to trigger the end of TNS and beginning of VNS, which may then be delivered for a set time period. Additionally, or alternatively, processes 600 and/or 700 may be performed so that VNS is performed both during the task and then after.

[00148] Additionally, or alternatively, processes 600 and/or 700 may be performed so that both TNS and VNS (e.g., nTNVS) is performed constantly during a rehabilitation session. Additionally, or alternatively, processes 600 and/or 700 may be performed so that VNS and TNS are applied together on task completion.

[00149] Additionally, or alternatively, processes 600 and/or 700 may be performed so that there is application of TNS overnight and VNS during the day, intermittently during the treatment rehab session, and/or in response to task completion.

[00150] Additionally, or alternatively, processes 600 and/or 700 may be performed so that TNS and/or VNS comprises subsensory stimulation and/or is provided along with other forms of stimulation (e.g., epidural stimulation to instigate low frequency oscillations or with peripheral nerve stimulation) during a rehabilitation session.

[00151] FIG. 8A provides a graph 801 that plots data time-averaged (over nine trials) percent changes in MFV measurements and PI measurements taken by a first device (i.e., a nerve stimulation delivery device like the nerve stimulation delivery devices disclosed herein) and a second device (i.e., the CEFALY® system available from Cefaly Technology of Seraing, Liege, Belgium) over time (measured in minutes) before, during, and after application of neural stimulation by the first and second devices during a one- minute neural stimulation window occurring between minutes 1 and 2 (as indicated by the shaded region on graph 801 ). The parameters for the application of neural stimulation over the one-minute neural stimulation window are the same for both the first and second devices.

[00152] In particular, graph 801 shows four plotted sets of data, wherein a first curve 810 (shown in black broken lines) corresponds to a percent change in MFV measurements taken over time by the first device; a second curve 820 of graph 801 corresponds to a percent change in PI measurements taken over time by the first device; a third curve 830 of graph 801 corresponds to a percent change in MFV measurements taken over time by the second device; and a fourth curve 840 of graph 801 corresponds to a percent change in PI measurements taken over time by the second device.

[00153] As may be seen in graph 801 , neural stimulation provided by the first device produces a greater increase in MFV and a greater reduction in PI of the one-minute neural stimulation window than the second device. This suggests the effectiveness of the first device increasing MFV and reducing PI may increase cerebral blood flow to an extent greater than the second device, which may lead to greater outcomes for treatment of a medical condition as disclosed herein by, for example, increasing blood flow and/or promoting the remodeling of cerebrovascular architecture and/or inducing forms of cerebrovascular plasticity. It is known that neuroplastic recovery following an injury is accompanied by indications of vascular recovery or angiogenesis, leading to improved perfusion, compared to earlier in a rehabilitation process. Similar effects on cerebrovasculature can be observed with improved vascular health with aerobic exercise.

[00154] In addition, graph 801 shows that, after the cessation of stimulation (i.e., between minute 2 and minute 3), stimulation produced by the second device yielded a larger increase in MFV and more negative response in PI than the first device whose measurements more closely resembled the pre-stimulation baseline (i.e., between minute 0 and minute 1).

[00155] With reference to FIG. 8B, the depiction of change in MFV from a prior baseline with a standard error of the mean is the lighter line for the CEFALY® device electrodes based stimulation and the darker line for stimulation using the device according to the disclosure herein. This graph comprises average values across nine trials for each nerve stimulation delivery device . The y-axis shows change in MFV as a percent of the baseline, and the x-axis shows four time points comprising a baseline time point, a stimulation time point, a post-stimulation time point, and a 3-minutes-post-stimulation time point. A larger positive change in MFV may be indicative of increased cerebral blood flow and effectiveness of the nerve stimulation delivery device . The device according to the disclosure herein had a larger positive change in MFV during the stimulation period and after the stimulation period both immediately and three minutes after, with (p<0.05), thus suggesting the effectiveness of the device described herein for treating ischemic stroke via increased cerebral blood flow may be greater than existing devices

[00156] With reference to FIG. 8C, the depiction of change in PI from a prior baseline with a standard error of the mean is lighter line for the CEFALY® device electrodes based stimulation and a darker line for stimulation using the device according to the disclosure herein. This graph comprises average values across nine trials for each nerve stimulation delivery device . The y-axis shows change in PI as a percent of the baseline, and the x-axis shows four time points comprising a baseline time point, a stimulation time point, a post-stimulation time point, and a 3-minutes-post-stimulation time point. A larger negative change in pulsatility may be indicative of increased cerebral blood flow and effectiveness of the nerve stimulation delivery device . The device described herein had a larger negative change in pulsatility during the stimulation period and after the stimulation period both immediately and three minutes after, with (p<0.05), thus suggesting the effectiveness of the device described herein for treating ischemic stroke via increased cerebral blood flow may be greater than existing devices.