Functional near-infrared spectroscopy and external nerve stimulation for screening and treatment of neuropsychiatric and neurological disorders.

Abstract

This disclosure relates to a method, device, and system used for identifying and treating responders to external nerve stimulation via a combination of a skin electrode assembly and a functional near-infrared spectroscopy (fNIRS) device. More specifically, this specification discloses a method for cutaneous stimulation of the trigeminal nerve, occipital nerve, vagus nerve, facial nerve and / or any of their branches, and a method for measuring cerebral blood flow in a target brain region.

Description

Technical Field

[0001] Technical Field

[0001] This disclosure generally relates to medical devices and systems for identifying responders to neuropsychiatric and neurological disorders and treating such disorders, and methods of using them. More specifically, methods, devices and systems configured to treat neurological and / or neuropsychiatric disorders via external nerve stimulation are provided, where treatment of neurological and / or neuropsychiatric disorders includes configuring stimulation parameters to cause an increase or decrease in a patient's cerebral blood flow ("CBF"). Devices and systems configured to stimulate the superficial sensory branches of cranial nerves, and methods of their application, will be described.

Background Art

[0002] Background

[0002] Mental disorders or neuropsychiatric disorders, such as depressive disorders (DD), also sometimes referred to as depression, or anxiety disorders, have conventionally been treated by drug therapy and psychotherapy. Neurological disorders and diseases such as epileptic disorders characterized by epileptic seizures, acute or chronic brain injury, coma, chronic headache or migraine, movement disorders and related disorders are treated by drug therapy and sometimes by brain surgery.

[0003]

[0003] Electrical stimulation is a newly emerging therapy for treating some diseases. In recent years, it has been found that external cutaneous electrical stimulation is useful for treating various neuropsychiatric and neurological disorders, as described, for example, in U.S. Pat. Nos. 8,380,315, 8,688,220 and 10,639,468. However, electrical stimulation devices do not respond to related neurological diseases.

[0004]

[0004] Many clinical neurological and neuropsychiatric disorders are associated with abnormal blood flow patterns in the brain. These include epilepsy, migraine, aging, schizophrenia, bipolar disorder, major depressive disorder, motor disorders, and attention-deficit / hyperactivity disorder (ADHD). One consequence of abnormal blood flow is an imbalance between oxygen supply and demand in the brain. This is thought to play a significant role in the development of neurological events common to various disorders. Therefore, it is advantageous to employ a system or method for monitoring such abnormal blood flow patterns in order to identify responders to external skin stimuli, with the intention of correcting abnormal or insufficient blood flow patterns in order to provide clinical benefit. Responsive stimulation, which detects neural activity and selectively applies electrical stimulation, is particularly advantageous. [Overview of the project] [Means for solving the problem]

[0005] overview

[0005] One aspect of the subject matter of the present disclosure addresses the above-mentioned need by providing a system for identifying and treating responders to external nerve stimulation. In one or more embodiments, the system includes a pulse generator or nerve stimulator; a skin electrode assembly that communicates with the pulse generator; a functional near-infrared spectroscopy (fNIRS) device configured to measure cerebral blood flow (CBF) in a target brain region and generate an output signal corresponding to the CBF in the target brain region; and a control device configured to process the output signal to generate visual feedback corresponding to the CBF in the target brain region.

[0006]

[0006] In some embodiments, the skin electrode assembly comprises a first electrode having at least one contact configured to be positioned on the skin in a first region of the patient's face, and a second electrode having at least one contact configured to be positioned on the skin in a second region of the patient's face, wherein the first and second electrodes are each configured to be in contact with a portion of the patient's face that overlaps with the skin distribution of the trigeminal nerve, occipital nerve, vagus nerve, facial nerve and / or any of their branches.

[0007]

[0007] In other embodiments, the skin electrode assembly includes a first contact pair configured to be positioned in a first area of ​​the patient's face, a second contact pair configured to be positioned in a second area of ​​the patient's face, and an insulating connection area connecting the first contact pair and the second contact pair, wherein the first and second contact pairs are configured to contact a portion of the patient's face that overlaps with the skin distribution of at least one branch of the ophthalmic nerve, infraorbital nerve, mental nerve, occipital nerve, vagus nerve, or facial nerve.

[0008]

[0008] Another aspect of the present disclosure provides a method for evaluating the use of external nerve stimulation for the treatment of neuropsychiatric or neurological disorders. The method includes bringing a first area of ​​a patient's face into contact with a skin electrode assembly; applying an electrical signal to the skin electrode assembly with specified operating parameters to treat a neuropsychiatric or neurological disorder; measuring cerebral blood flow (CBF) in a target brain region using a functional near-infrared spectroscopy (fNIRS) device; and determining that the CBF has changed in the target brain region.

[0009] Brief explanation of the drawing

[0009] The configuration and operation of this disclosure, as well as further purposes and advantages, can be understood by referring to the following description in relation to the attached drawings. [Brief explanation of the drawing]

[0010] [Figure 1A]

[0010] The locations of some branches (nerves) of the trigeminal nerve, and the locations of the major foramina for the superficial branches of the trigeminal nerve are shown. [Figure 1B]

[0010] The locations of some branches (nerves) of the trigeminal nerve, and the locations of the major foramina for the superficial branches of the trigeminal nerve are shown. [Figure 2]

[0011] One embodiment of a system including an electrode assembly provided by aspects of this disclosure is shown. [Figure 3A]

[0012] Figure 2 shows a magnified view of the electrode assembly. [Figure 3B]

[0013] The typical dimensions of the electrode assembly in Figure 3A are shown. [Figure 4A]

[0014] Figure 2 shows various embodiments of the skin electrode assembly. [Figure 4B]

[0014] Various embodiments of the skin electrode assembly shown in Figure 2 are illustrated. [Figure 4C]

[0014] Various embodiments of the skin electrode assembly shown in Figure 2 are illustrated. [Figure 5]

[0015] Another embodiment of the electrode assembly that can be used in the system shown in Figure 2 is presented. [Figure 6]

[0016] One embodiment of the system according to the present disclosure is shown. [Figure 7]

[0017] This shows fNIRS data from healthy adult males acquired at baseline (before stimulation) during verbal fluency testing. [Figure 8]

[0018] Figure 7 shows eTNS or fNIRS data of a healthy adult male during stimulation, according to the embodiments of this disclosure. [Modes for carrying out the invention]

[0011] Detailed explanation

[0019] According to one or more embodiments, screening and identifying responders to external skin stimuli is achieved by using a combination of a skin electrode assembly and a functional near-infrared spectroscopy (fNIRS) device. In some embodiments, this combination is used to tailor the treatment delivery to the patient to more optimally produce beneficial changes in the cerebral blood flow pattern. Advantageously, monitoring of cerebral blood flow can be achieved by periodically using fNIRS, a non-invasive imaging technique, and the fNIRS results can be used to predict patients who will respond to external skin stimuli.

[0012]

[0020] In various embodiments, the treatment includes electrical stimulation. According to some embodiments, the electrical stimulation can regulate blood flow in the brain. By stimulating specific brain structures, a pattern of blood flow changes can be produced, including an increase or decrease in blood flow in the target brain region. Thus, the regulation of CBF can be used for the treatment of neuropsychiatric disorders and / or neurological disorders.

[0013]

[0021] In some embodiments, the neurological disorders that may be treated include one or more of movement disorders (e.g., tremors characteristic of Parkinson's disease), migraine, or chronic pain. In some embodiments, the neuropsychiatric disorders that may be treated include one or more of schizophrenia, obsessive-compulsive disorder, depression, attention deficit disorder (ADD), ADHD, autism and autism spectrum disorder (ASD), substance use disorder and related behavioral addictions, eating disorders and obsessive-compulsive disorder (OCD), psychotic disorders, or cognitive disorders. The neurological or neuropsychiatric disorders that may be treated according to the present disclosure include any neurological or neuropsychiatric disorder that is directly or indirectly affected by changes in CBF.

[0014]

[0022] Generally, substantially all pharmacological treatments targeting brain cells for neurological and neuropsychiatric disorders are considered to be combinable with the embodiments herein. In particular, these embodiments can be adapted to be used for the treatment of disorders such as brain tumors, acute brain injuries, chronic brain injuries, movement disorders, tardive dyskinesia and other dyskinesias, seizure-related disorders, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, anxiety, ADHD, post-traumatic stress disorder, cognitive and behavioral disorders, and other disorders directly or indirectly affected by changes in CBF.

[0015]

[0023] Referring to Figures 1A and 1B, the trigeminal nerve is the largest cranial nerve and has extensive connections to the brainstem and other brain structures. The trigeminal nerve has three major sensory branches that run across the face, all of which are bilateral and highly accessible. The supraorbital nerve or ophthalmic nerve is often referred to as the V1 branch. The infraorbital nerve or maxillary nerve is often referred to as the V2 branch. The mandibular nerve (known as the mental branch) is referred to as the V3 branch. The supraorbital nerve supplies sensory information regarding pain, temperature, and light touch to the skin of the forehead, upper eyelids, the anterior part of the nose, and the eyes. The infraorbital branch supplies sensory information regarding pain, temperature, and light touch to the lower eyelids, cheeks, and upper lip. The mental branch supplies similar sensory modalities to the skin of the lower half of the face (e.g., the jaw and tongue) and lips.

[0016]

[0024] These branches exit the skull through three foramina, as shown in Figures 1A and 1B. The supraorbital nerve or ophthalmic nerve emerges from foramina 1 (supraorbital foramen or notch), approximately 2.1–2.6 cm (adult) from the nasal midline, located directly above the orbital protuberance below the eyebrow. The infraorbital branch or maxillary nerve emerges from foramina 2 (infraorbital foramen), approximately 2.4–3.0 cm (adult) from the nasal midline, and the mental nerve emerges from foramina 3 (mental foramen), approximately 2.0–2.3 cm (adult) from the nasal midline. The nasal nerve is a branch of the ophthalmic nerve. Other sensory branches, including the zygomatic-facial branch, zygomatic-orbital branch, zygomatic-temporal branch, and auricular-temporal branch, arise from other foramina.

[0017]

[0025] Fibers from the three main branches converge to form the trigeminal ganglion. From there, the fibers ascend within the brainstem at the pons level, synapsing with the principal sensory nuclei of the pons, the trigeminal mesencephalic nuclei, and the trigeminal spinal tract nuclei and trigeminal spinal tract. Pain fibers descend within the trigeminal spinal tract nuclei and trigeminal spinal tract, then ascend to the posteromedial ventral nucleus (VPM) of the thalamus. Light touch sensory fibers are thick myelinated fibers that ascend to the posterolateral ventral nucleus (VPL) of the thalamus. Afferent sensory fibers project from the trigeminal nuclei to the thalamus and the major cerebral cortex.

[0018]

[0026] The trigeminal nucleus has reciprocal projections to the nucleus tractus solitarius (NTS), locus coeruleus, major cerebral cortex, and vagus nerve. The NTS receives afferent input from the vagus and trigeminal nerves. The NTS integrates input from multiple input sources and projects to the brainstem and forebrain structures, including the locus coeruleus.

[0019]

[0027] The locus coeruleus is a pair of nuclear structures located in the dorsal pons, directly below the floor of the fourth ventricle. It has extensive axonal projections to numerous brainstem, subcortical, and cortical structures and is a crucial component of the reticular activating system. The locus coeruleus is a central part of the brainstem's noradrenergic pathway and produces the neurotransmitter norepinephrine. Norepinephrine plays a vital role in regulating attention, arousal, blood pressure, and heart rate, as well as mood.

[0020]

[0028] In some embodiments, the connection between the trigeminal nerve and the locus coeruleus, thalamus, amygdala, anterior cingulate cortex, and other central nervous system structures, as described above, may be related to the potential role of the trigeminal nerve in neuropsychiatric disorders, including mood (such as depression), anxiety (such as post-traumatic stress disorder), and other cognitive and behavioral disorders. Therefore, skin stimulation of the trigeminal nerve may be effective in treating these neuropsychiatric disorders.

[0021] [0029 In various embodiments, the connections between the trigeminal nerve, locus coeruleus, nucleus tractus solitarius and tractus solitarius, thalamus, and major cerebral cortex may be related to the potential role of the trigeminal nerve in a number of neurological disorders, including coma and brain injury, paroxysmal disorders, headaches, migraines, and motor disorders, as may be apparent to those skilled in the art. Therefore, skin stimulation of the trigeminal nerve with individually adjusted settings and parameters within a predefined range may be effective in treating multiple neurological disorders.

[0022]

[0030] The occipital nerves are cranial nerves that originate in the neck and run to the occipital and posterior temporal regions. The three main occipital nerves are the greater occipital nerve, the lesser (or small) occipital nerve, and the third (or least small) occipital nerve. The greater occipital nerve ascends toward the parietal region. It innervates the occipital scalp up to the apex of the skull, the ears, and the skin directly above the parotid gland. Therefore, the greater occipital nerve supplies sensation to the scalp in the parietal region, above the ears, and above the parotid gland. The lesser occipital nerve ascends toward the temporal region. The lesser occipital nerve branches into two types of branches: communicating branches and cutaneous branches. The communicating branches are interconnected with the communicating branches of the greater occipital nerve. The cutaneous branches include the auricular branches, mastoid branches, and occipital branches. These branches provide sensation to the lateral parts of the scalp and the skin around the outer ear. The third occipital nerve runs from near the neck, around the back of the head, and towards the ear. This nerve supplies sensation to the scalp in the lower center of the back of the head. The third occipital nerve is susceptible to damage from whiplash injuries.

[0023]

[0031] The greater occipital nerve, along with the lesser occipital nerve and the third occipital nerve, is generally associated with occipital neuralgia, cervicogenic headache, and migraine. Occipital neuralgia is a type of headache characterized by paroxysmal, stabbing pain in the posterior scalp. Cervicogenic headache is perceived in the head from a cervical origin. Migraine causes severe, throbbing pain or a pulsating sensation, usually occurring on one side of the head. For treatment, stimulation may be applied along the occipital nerve in the back of the head, or to the apex or upper part of the skull.

[0024]

[0032] The vagus nerve is a cranial nerve that regulates visceral functions such as digestion, heart rate, and respiratory rate, as well as vasomotor activity and specific reflexes such as coughing, sneezing, swallowing, and vomiting. When the vagus nerve is activated, acetylcholine (ACh) is released at synaptic junctions with secretory cells, intrinsic nerve fibers, and smooth muscle. ACh binds to nicotinic and muscarinic receptors, stimulating muscle contraction in the parasympathetic nervous system.

[0025]

[0033] The vagus nerve originates in the brain and branches in multiple directions toward the neck and trunk, performing functions such as transmitting sensory information from the skin of the ear, controlling muscles used in swallowing and speech, and influencing the immune system. The right vagus nerve passes anterior to the subclavian artery and posterior to the sternoclavicular joint before entering the rib cage. The left vagus nerve runs downward between the left common carotid artery and the left subclavian artery, passing posterior to the sternoclavicular joint before entering the rib cage.

[0026]

[0034] Several branches of the vagus nerve diverge in the neck. The pharyngeal branch provides motor innervation to most of the muscles of the pharynx and soft palate. The superior laryngeal nerve branches into an internal and an external branch. The external laryngeal nerve innervates the cricothyroid muscle of the larynx. The internal laryngeal nerve provides sensory innervation to the larynx, pharynx, and upper larynx. The recurrent laryngeal nerve ascends towards the larynx after curving below the right subclavian artery. It innervates most of the intrinsic muscles of the larynx. Within the thoracic cavity, the right vagus nerve forms the posterior vagal trunk, and the left vagus nerve forms the anterior vagal trunk. Branches from the vagal trunk contribute to the formation of the esophageal plexus, which innervates the smooth muscles of the esophagus. Within the thoracic cavity, two more branches diverge: the left recurrent laryngeal nerve and the cardiac branch. The left recurrent laryngeal nerve ascends, curving below the aortic arch and innervating most of the intrinsic muscles of the larynx. The cardiac branch innervates the regulation of heart rate and provides visceral sensation to organs. The vagus trunk enters the abdomen. In the abdomen, the vagus trunk branches and terminates, supplying branches that innervate the esophagus, stomach, and small and large intestines (up to the splenic flexure). Vagus nerve stimulation may be used to treat seizures, epilepsy, depression, stroke, headaches, migraines, cardiac arrhythmias, heart failure, and autoimmune diseases.

[0027]

[0035] The facial nerve is a cranial nerve that provides a pathway from the brain to specific muscles of the face. It controls the muscles that help create facial expressions such as raising the eyebrows, smiling, or frowning. This nerve is also involved in the sense of taste in the tongue. The facial nerve has five branches responsible for different motor functions. The frontal branch (temporal branch) controls the muscles of the forehead. The zygomatic branch helps close the eyes. The buccal branch enables movement of the nose, blinking, and raising the upper lip and corners of the mouth to create a smile. The mandibular marginal branch controls the movement of the lower lip (like a frown) and passes through the middle ear to help with responses to loud noises. The cervical branch controls movement of the chin and the lower corners of the mouth. Facial nerve stimulation is sometimes used in the treatment of stroke.

[0028]

[0036] To consider some embodiments of methods, systems, and devices using skin electrodes according to aspects of the present disclosure, we now refer to Figures 2A to 5, which illustrate various embodiments of systems and devices that can be used for skin stimulation of the trigeminal nerve, occipital nerve, vagus nerve, facial nerve and / or their branches to modulate CBF, as well as methods of using them.

[0029]

[0037] According to one aspect of this disclosure, a method is provided for treating neuropsychiatric and / or neuropathy using external trigeminal nerve stimulation ("eTNS"). Broadly speaking, the method for treating neuropsychiatric and / or neuropathy with eTNS comprises placing an external electrode on or near at least one of the foramina or branches of the trigeminal nerve (Figures 1A and 1B), and stimulating the electrode using a stimulator or pulse generator for a set period of time with specified operating parameters. The electrode does not need to be applied to the main branch of the nerve, but can be applied to a skin area innervated by that nerve, which may be several inches away from the main branch. In one embodiment, the external electrodes are positioned above the foramen of the supraorbital or ophthalmic nerve (Figure 1A, foramen 1) because unilateral or bilateral stimulation of the trigeminal nerve is possible by placing a single or separate electrode on the right and / or left side of the patient's face (for example, by placing an electrode assembly such as two separate electrodes, a single pair electrode, or two sets of electrodes, each having at least one contact, on the patient's forehead or other area of ​​the face). In one embodiment, the electrode assembly is configured for unilateral stimulation. In one embodiment, the electrode assembly is configured for bilateral stimulation. In some embodiments, the functions of different brain structures on the left and right sides may not be identical (for example, language expression is most commonly localized in the language center of the left hemisphere, and damage to that location results in a catastrophic loss of speech ability, while damage to the corresponding area on the right side may not cause such severe functional loss and may result in subtle functional changes), so bilateral stimulation may produce an effect equal to or greater than unilateral stimulation. Also, a synergistic effect may occur with bilateral stimulation. In some embodiments, two separate electrodes or a single counter electrode may be positioned on the forehead. In alternative embodiments, the electrodes may be positioned above the infraorbital foramen (infraorbital nerve or maxillary nerve) (Figure 1A, foramen 2) or the mental foramen (mental nerve or mandibular nerve) (Figure IB, foramen 3). In yet another embodiment, stimulation may be applied unilaterally to one foramen of the trigeminal nerve. In other embodiments, a method for treating neuropsychiatric and / or neuropathy includes positioning external electrodes above multiple foramen and simultaneously stimulating different trigeminal nerves.In other embodiments, the electrodes may be positioned in the patient's facial region (right and / or left) corresponding to the supratrochlear nerve, subtrochlear nerve, zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbital nerve, nasal nerve and / or auricular temporal nerve and / or their respective foramina.

[0030]

[0038] According to one aspect of this disclosure, a method for treating neuropsychiatric and / or neurological disorders by eTNS includes selecting patient-specific values ​​of stimulation operating parameters for each individual patient within a defined range. In one embodiment, the values ​​of the operating parameters are selected so that the patient experiences a stimulating sensation such as mild tingling on the forehead and scalp without feeling discomfort or pain. In one embodiment, the values ​​of the operating parameters are selected so as to minimize skin irritation, burns, and undesirable effects on the brain and / or cranial nerves. In one embodiment, the method for selecting the operating parameters includes evaluating variables such as electrode configuration and size, pulse duration, electrode current, duty cycle, and stimulation frequency, which are important factors in ensuring that the total charge, charge density, and charge per phase are well within acceptable limits for the skin, nerves, and brain. For example, to minimize skin irritation, it is not sufficient to simply specify the total current; the current density must also be defined. Furthermore, the selection of electrical stimulation parameters, electrode design, and inter-electrode distance is chosen so as to prevent or minimize the penetration of current into the lower part of the skull, while ensuring that the electrical stimulation zone includes the ophthalmic nerve or other cranial nerves (approximately 3-4 mm below the skin surface).

[0031]

[0039] As will be described in more detail with respect to Figures 2A to 5, the electrodes are connected to lead wires to transmit electrical stimulation from the nerve stimulator. In some embodiments, nerve stimulation can be provided using an electric nerve stimulator with the following exemplary settings: a frequency of 20 to 150 Hz, a current of 1 to 10 mA, a pulse duration (pulse width) of 50 to 250 microseconds, a duty cycle of 10% to 50%, and at least one hour per day. For patient comfort and low power consumption, stimulation parameters at the lower end of these ranges may be used. In other embodiments, different operating parameter values ​​may be used. In another embodiment, a single external electrode may be used. In some embodiments, as will be described in more detail, a portable external stimulator that can be attached to the patient's clothing is used.

[0032]

[0040] In one embodiment, as can be seen from Figures 2 to 5, the system 200 for treating neuropsychiatric and / or neurological disorders via eTNS includes an electrode assembly 100, an electrical cable or wire 120, and an external nerve stimulator or pulse generator 122. In some embodiments, the pulse generator may be an internal pulse generator. The electrode assembly may be configured for bilateral simultaneous and asynchronous stimulation of the ophthalmic nerve. In other embodiments, the electrode assembly may be configured for unilateral or bilateral stimulation of one or more branches of the trigeminal nerve, as disclosed elsewhere in this specification. The nerve stimulator or pulse generator may be any type of stimulator, signal generating device. In the illustrated embodiment, the generator 122 is portable and attached to the patient 20's belt. However, portable pulse generators may be used, or non-portable pulse generators may be used. As shown in Figure 2, the electrode assembly 100 can be connected to the external stimulator 122 by lead wires 124 connected to the electrical cable 120, or wirelessly. In one embodiment, an electrical cable or wire 120 is configured to provide a physical and electrical connection between the generator 122 and the electrode assembly 100 via a lead wire 124. In other embodiments, the generator 122 and the electrode assembly 100 communicate wirelessly (i.e., wires 120 and lead wires 124 are not used). The system 200 or its elements, such as the electrode assembly 100, may be part of a kit. In some embodiments, the kit may include instructions relating to the electrode system and / or the placement of the system. In some embodiments, the kit may also include instructions relating to the treatment of neuropsychiatric or neurological disorders in the manner disclosed herein.

[0033]

[0041] In some embodiments, the system 200 may also include a regulating device to ensure the safe use of the system. This regulating device is configured to be attached to the pulse generator 122 and is configured to control the maximum charge equilibrium output current to less than approximately 30–50 mA in order to minimize current penetration into the brain and to increase patient tolerance. This regulating device may be internally programmed to range from 0.25–5.0 mA, 0–10 mA, or 0–15 mA, depending on the surface area, placement, and orientation of the electrodes, and whether the electrodes are stimulating near or adjacent to the skull, or away from the skull (mentalis muscle), and the current range may be higher or lower. Current TENS units stimulate with output currents up to 100 mA, which generates currents that may penetrate the skull and may not be well tolerated.

[0034]

[0042] In some embodiments, the electrode assembly 100 further includes a retaining element 130 configured to secure the electrode assembly to the patient's forehead. In one embodiment, the retaining element 130 may be an elastic band or strap. In another embodiment, the electrode assembly 100 may be secured in place by a hat or cap, which also serves to conceal the electrode assembly from view. In yet another embodiment, the electrode assembly may be secured by an adhesive, such as adhesive tape, an adhesive backing surrounding the conductive area, or an adhesive conductive gel.

[0035]

[0043] In some embodiments, the electrode assembly includes an electrode having at least one contact. In some embodiments, a single electrode may have multiple contacts. In some embodiments, the electrode assembly includes a pair of electrodes having a pair of contacts. In some embodiments, the electrode assembly may be a strip electrode having at least one contact. In some embodiments, the strip electrode may have multiple contacts.

[0036]

[0044] The electrode assembly 100 shown in Figures 2 to 3B is also referred to as a bilateral supranorbital electrode. As shown in Figures 2 to 3B, the electrode assembly 100 includes a first contact pair 112a, 112b positioned in a first region of the patient's face and a second contact pair 114a, 114b positioned in a second region of the patient's face. In some embodiments, the first region is the right side of the patient's face and the second region is the left side of the patient's face. The first contact pair includes a first upper contact 112a and a first lower contact 112b, and the second contact pair includes a second upper contact 114a and a second lower contact 114b. The first and second contact pairs are connected to each other by an insulating connection region 116. The electrode assembly 100 includes an inner contact surface 118 that contacts the patient's skin in four contact regions, each contact region corresponding to one of the four contacts 112a, 112b, 114a, and 114b. The inner contact surface 118, which includes four contact areas, contains a buffering gel-like adhesive that provides good conductivity with minimal skin irritation. An example of such a gel is a commercially available hydrogel from AmGel Technologies (AmGel Technologies, Fallbrook, CA, USA).

[0037]

[0045] In one embodiment, the electrode assembly 100 is configured to stimulate both the right and left ophthalmic nerves simultaneously or asynchronously. The insulated connection area 116 assists the patient in aligning the electrode assembly 100 with the midline of the nose, ensuring that the electrode assembly 100 is properly positioned on both ophthalmic nerves, which are located on average about 2.1–2.6 cm from the midline of the nose in adult patients. Thus, the electrode assembly can be accurately positioned (e.g., by the patient themselves) without knowing the location of the ophthalmic nerves or key landmarks associated with the nerves, thereby reducing the possibility of insufficient stimulation due to incorrect electrode positioning.

[0038]

[0046] By positioning the first contact pair 112a, 112b and the second contact pair 114a, 114b on either side of the nasal midline, it is ensured that the stimulating current flows anterograde, i.e., towards the afferent ophthalmic nerve or supraorbital nerve. Furthermore, the configuration of this electrode assembly 100 allows for the localization of the response to stimulation, which may differ on the left and right sides of the midline, making it possible to stimulate the contact pairs 112a / 112b and 114a / 114b independently and / or unilaterally. In other words, the electrode assembly disclosed herein allows for the individual adjustment of the current for the first and second regions, or the right and left sides, depending on the application, thereby reducing asymmetric stimulation and / or the perception of asymmetric stimulation. Figures 4A to 4C show other embodiments of the electrode assembly 100, which can be used to stimulate other branches of the trigeminal nerve, such as the right ophthalmic nerve and / or the left ophthalmic nerve and / or the zygomaticofacial nerve and / or the auricular-temporal nerve, as disclosed herein. It can be understood that a single electrode with one or more contacts, or multiple electrodes with one or more contacts, may be used. Bilateral supraorbital electrodes are specifically configured for bilateral supraorbital stimulation. These electrodes are scalable based on the site of use, stimulation parameters, and input from computer modeling to neutralize, minimize, or bring current penetration into the brain to a safe level. Because skin irritation may occur, a similar configuration can be applied unilaterally to provide relief on one side of the forehead to increase skin tolerance and reduce the risk of irritation. Other configurations of size and inter-electrode distance can also be considered for different branches of the trigeminal nerve, as shown in Figures 4A to 4C. In one embodiment, the auriculotemporal nerve and / or zygomatic facial nerve can be stimulated using a strip electrode with at least two contacts. In other embodiments, the auriculotemporal nerve and / or zygomatic facial nerve may be stimulated using two separate electrodes.

[0039]

[0047] For stimuli that generate single-polarity electrical pulses (single-phase, i.e., all positive pulses or all negative pulses), the upper contacts 112a, 114a and lower contacts 112b, 114 have fixed polarity. For stimuli that generate alternating-polarity electrical pulses (two-phase, i.e., alternating positive and negative pulses or pulse trains), the upper contacts 112a, 114a and lower contacts 112b, 114b have alternating polarity. The lower electrode also typically functions as the cathode in the preceding phase of the stimulation pulse. In the case of single-phase stimulation, the lower electrode is generally the cathode.

[0040]

[0048] As can be seen from Figure 3B, each of the contacts 112a, 112b, 114a, and 114b is sized to deliver electrical pulses over a sufficiently large surface area to minimize skin damage caused by excessive current and / or charge density and to minimize or eliminate penetration of current beyond the inner surface of the skull. The distance between the first pair of contacts 112a, 112b and the second pair of contacts 114a, 114b is configured to stimulate the ophthalmic nerve while minimizing or eliminating the supply of current to the surface of the brain. In one embodiment, the midpoint of each contact is located approximately 2.5 cm (range 1.5 cm to 3.5 cm) from the nasal midline. Electrode sizes and inter-electrode distances may differ between children and adults, and between men and women, based on anatomical differences. In one embodiment, the electrodes are approximately 32.5 mm long and 12.5 mm high, with, for example, an electrode-to-electrode distance of 17.5 mm between the upper electrode pair 112a and 114a, and an electrode-to-electrode distance of 20 mm between the upper electrode 112a and the lower electrode 112b. In other embodiments, the electrode length may be greater than or less than 32.5 mm, and the height may be greater than or less than 12.5 mm. In yet another embodiment, the electrode-to-electrode distance may be in the range of greater than 20 mm and / or less than 17.5 mm. In various embodiments, the surface area of ​​each of the contacts 112a, 112b, 114a, and 114b is approximately 0.5 cm². 2 ~about 20cm 2The distances may be within a range of approximately 0.5 cm to approximately 10 cm. In various embodiments, the distance between contact 112a and contact 112b, and the distance between contact 114a and contact 114b, may be within a range of approximately 0.5 cm to approximately 10 cm. Those skilled in the art will recognize that one or more of the above distances can be used as boundaries for the distance range.

[0041]

[0049] Figure 5 shows another embodiment of the electrode assembly 100. As shown in Figure 5, the patient 10 has two separate electrodes 12 attached to the forehead, one above each eyebrow, corresponding to the foramen of the ophthalmic nerve.

[0042]

[0050] Those skilled in the art will understand that various adaptations and modifications to the embodiments of electrode assembly 100 described above are within the scope and spirit of this disclosure. For example, one embodiment of the device includes a unilateral electrode assembly configured for unilateral stimulation of the ophthalmic nerve. The electrode assembly may also be configured for stimulation of the maxillary nerve or the mandibular nerve. Alternatively, an electrode assembly configured to simultaneously stimulate multiple trigeminal nerve branches is also within the scope of this disclosure. In one embodiment, the system or electrode assembly disclosed herein may be configured to stimulate the auricular-temporal nerve. In one embodiment, the system or electrode assembly disclosed herein may be configured to stimulate the zygomatic facial nerve.

[0043]

[0051] Those skilled in the art will also understand how to modify and use the electrode assembly 100 to stimulate the occipital nerve, vagus nerve, facial nerve, and / or any of their branches. In short, these other nerves are closely related to the trigeminal nerve, and stimulating them in addition to, or instead of, the trigeminal nerve is expected to increase the effect of the stimulation and target additional brain regions. This can improve the effectiveness of the stimulation and enable the treatment of additional indications.

[0044]

[0052] During use, the electrode assembly 100 is positioned on the forehead of the patient 20 such that the insulated connection area 116 coincides with the midline of the patient's nose. In some embodiments, the electrode assembly 100 is positioned above the supraorbital foramen, located above the orbital ridge, approximately 2.1–2.6 cm lateral to the nasal midline. The electrode assembly 100 can then be connected to an external nerve stimulator 122 via lead wires 124 and an electrical cable 120. In other embodiments, the electrode assembly 100 is connected to the nerve stimulator 122 via a wireless connection. Stimulation is then applied based on patient-specific operating parameters determined according to the method described herein.

[0045]

[0053] According to one aspect of this disclosure, a method for treating a neuropsychiatric disorder or neurological disorder using the electrode assembly 100 is provided, as described above. In one embodiment, the method for treating a neuropsychiatric disorder and / or neurological disorder includes positioning the electrode assembly 100 on the forehead of a patient, connecting the electrode assembly 100 to an external stimulator 122, and stimulating the electrode assembly 100 at defined values ​​of operating parameters disclosed herein.

[0046]

[0054] According to one aspect of this disclosure, a method for treating neuropsychiatric and / or neurological disorders is provided using an embodiment of the electrode assembly described herein. In one embodiment, the method for treating neuropsychiatric and / or neurological disorders includes positioning the electrode assembly in a first region of the patient's face, connecting the electrode assembly to an external stimulator, and stimulating the electrode assembly at defined values ​​of operating parameters disclosed herein. In one embodiment, the first region is the region corresponding to the auriculotemporal nerve. In one embodiment, the first region is the region corresponding to the zygomatic facial nerve. In one embodiment, the first region is the region corresponding to the supraorbital nerve.

[0047]

[0055] In one embodiment, the bilateral supraorbital electrodes 100 shown in Figures 2-3A stimulated the greater cerebral cortex at a stimulation frequency of approximately 20 Hz to 300 Hz, with a pulse duration of 50 microseconds (μsec) to 250 μsec, at a rate of 25 mA / cm². 2 Output current density of less than 10 microcoulombs / cm² 2 The brain is stimulated with an output charge density of less than 1, for at least 30 minutes to 1 hour per day. Generally, this stimulation results in zero or negligible charge density in the greater cerebral cortex. In some cases, the stimulation may be provided for less than 30 minutes per day. Those skilled in the art will understand that one or more of the above parameters can be used as boundaries for parameter ranges.

[0048]

[0056] According to one aspect of this disclosure, a method for treating epilepsy and related seizure disorders, as well as other neurological disorders and diseases, by eTNS includes selecting optimal values ​​for the operating parameters of the stimulation for each individual patient. In one embodiment, nerve stimulation is provided using an electrical stimulator with the following exemplary settings: a frequency of 20–150 Hz, a current of 5–15 mA, a pulse duration of 50–250 microseconds, a duty cycle of 10%–50%, and at least one hour per day. In another embodiment, nerve stimulation is provided using an electrical stimulator with the following exemplary settings: a frequency of 20–150 Hz, a current of 1–10 mA, a pulse duration of 50–250 μsec, a duty cycle of 10%–50%, and at least one hour per day.

[0049]

[0057] In various embodiments, the stimulus is delivered with a predetermined pulse width (or pulse duration) or a range of pulse widths. The stimulus can be configured to provide pulse widths within any range between a lower limit of about 10 microseconds and an upper limit of about 3 seconds. In various embodiments, the stimulus can be configured to provide pulse widths greater than and / or less than one or more of the following: 50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 225 μs, 250 μs, and up to 500 μs. Those skilled in the art will understand that one or more of the above times can be used as boundaries for pulse width ranges.

[0050]

[0058] In some embodiments, the stimulation amplitude is provided as a voltage-controlled or current-controlled stimulus. In other embodiments, the stimulation amplitude may be provided as a capacitive discharge. In various embodiments, the current amplitude can be any range within the range of approximately 30 to 35 mA, with a lower limit of approximately 300 μA, depending on the electrode surface area, inter-electrode distance, stimulated branch, and the modeling data described above. In various embodiments, the amplitude can be 50 μA, 75 μA, 100 μA, 125 μA, 150 μA, 175 μA, 200 μA, 225 μA, 250 μA, 275 μA, 300 μA, 325 μA, 350 μA, 375 μA, 400 μA, 425 μA, 450 μA, 475 μA, 500 μA, 525 μA, 550 μA, 575 μA, 600 μA, 625 μA, 650 μA, 675 μA, 70 The amplitude range can be greater than and / or less than one or more of the following: 0 μA, 725 μA, 850 μA, 875 μA, 900 μA, 925 μA, 950 μA, 975 μA, 1 mA, 2 mA, 3 mA, 4 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, 10 mA, 11 mA, 12 mA, 13 mA, 14 mA, 15 mA, 16 mA, 17 mA, 18 mA, 19 mA, and 20 mA. Those skilled in the art will understand that one or more of the above amplitudes can be used as boundaries for the amplitude range.

[0051]

[0059] In various embodiments, the stimulus can be delivered at one or more frequencies or within a frequency range. The stimulus can be set to be delivered at any frequency within the range of approximately 500 Hz upper limit and approximately 10 Hz lower limit. In various embodiments, the stimulus can be set to be delivered at frequencies lower and / or higher than one or more of 50 Hz, 45 Hz, 40 Hz, 35 Hz, 30 Hz, 25 Hz, 20 Hz, 15 Hz, or 10 Hz. In various embodiments, the stimulus can be set to be delivered at frequencies higher and / or lower than one or more of 20 Hz, 30 Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 125 Hz, 150 Hz, and up to 300 Hz. Those skilled in the art will understand that one or more of the above frequencies can be used as frequency range boundaries.

[0052]

[0060] In various embodiments, the stimulus is delivered with a specific duty cycle or duty cycle range ranging from 100% to about 5%. In various embodiments, the stimulus can be set to be delivered with a duty cycle range greater and / or less than one or more of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a duty cycle of 10% to 50% may be preferred to ensure nerve preservation. In some embodiments, a duty cycle of up to 100% may be useful in certain situations. Those skilled in the art will understand that one or more of the above percentages can be used as boundaries for duty cycle ranges.

[0053]

[0061] In other embodiments, different values ​​for the operating parameters may be used. In one embodiment, the values ​​of the operating parameters are selected so that the patient experiences a stimulating sensation such as a mild tingling on the forehead and scalp without feeling discomfort or pain. Nerve stimulation parameters are an important element in the treatment method. In one embodiment, the values ​​of the operating parameters are selected so as to minimize skin irritation, burns, and undesirable effects on the brain and / or ophthalmic nerve. In one embodiment, the method for selecting the operating parameters includes evaluating variables such as electrode shape and size, pulse duration, electrode current, duty cycle, and stimulation frequency, each of which is an important element in ensuring that the total charge, charge density, and charge per phase are well within acceptable safety limits for the skin, nerves, and brain. For example, to minimize skin irritation, it is not sufficient to simply consider the total current; the current density must be defined. Furthermore, it is important to select the electrical stimulation parameters, electrode design, and inter-electrode distance so that the electrical stimulation zone includes the ophthalmic nerve (approximately 3-4 mm deep) or other target nerves, while preventing or minimizing current penetration beneath the skull.

[0054]

[0062] Stimulation is performed at the values ​​of the operating parameters described above. These values ​​may vary depending on the treatment being addressed, but the systems and devices disclosed herein perform stimulation at parameters that prevent or minimize the penetration of current beneath the surface of the skull and / or into the brain.

[0055]

[0063] In some embodiments, the use of external electrodes for trigeminal nerve stimulation allows for the identification of individuals who are likely to benefit from a minimally invasive system, in addition to the optimal predetermined location and parameters based on individual differences. Various neurological diagnostic methods, imaging methods, or cutaneous nerve mapping methods may clarify individual anatomical differences and allow for the optimization of stimulation for efficacy and / or safety. Furthermore, the use of minimally invasive systems may enable the screening and identification of individuals who are likely to benefit from implantable systems such as deep brain stimulation. This can be conceptualized by relating the three approaches as Stage I (external TNS of the trigeminal nerve), Stage II (implantable TNS of the superficial trigeminal nerve), and Stage III (deep brain stimulation), so that Stage I can screen Stage II, and Stage II can screen Stage III. By monitoring patients for evidence of beneficial therapeutic effects, such as a reduction in symptom severity, treatment outcomes at one stage can be used to determine the effectiveness of treatment at a higher, more invasive stage.

[0056]

[0064] In another aspect of this disclosure, a method for evaluating the use of external nerve stimulation for the treatment of a patient's neuropsychiatric or neurological disorder is disclosed. Referring to Figure 6, the method may include applying a skin system 605 to a patient for stimulating the trigeminal nerve, occipital nerve, vagus nerve, facial nerve, and / or any branch thereof, and monitoring the patient for at least one of evidence of a beneficial therapeutic response and / or evidence of tolerance to external nerve stimulation therapy. In one or more embodiments, monitoring the patient for evidence of a beneficial therapeutic response includes detecting changes in CBF via an fNIRS device 610.

[0057]

[0065] fNIRS is a known technique that uses near-infrared light to measure hemoglobin blood flow in the brain and is therefore not described in detail herein. This technique is non-invasive, requires little restraint of the patient being measured, and allows for relatively simple measurements without the need for a selection of a test environment. This technique is a type of functional neuroimaging technique that provides a relatively non-invasive, safe, portable, and low-cost method for indirect and direct monitoring of brain activity. By measuring changes in near-infrared light, fNIRS allows researchers to monitor blood flow in the anterior part of the brain.

[0058]

[0066] More technically, fNIRS enables functional imaging of brain activity (or activation) through monitoring blood oxygenation and blood volume in the prefrontal cortex. This is achieved by measuring changes in the concentrations of oxygenated and deoxygenated hemoglobin (Hb), as well as changes in the redox state of cytochrome c oxidase (Cyt-Ox), based on their distinct intrinsic spectra in the near-infrared region of 700–1000 nm.

[0059]

[0067] During operation, the fNIRS device 610 is typically mounted on the patient's forehead and can be monitored by connecting directly to a computer 615 or by connecting to a portable computing device 615 (also referred to herein as a control device 615 or control unit 615), which records data as the patient engages in a predetermined cognitive task. The recorded data is then analyzed for changes in cerebral blood flow or its oxygenation levels before, during, and after performing the task. Hypotheses about how brain activity is affected by a particular task, behavior, or treatment can then be tested.

[0060]

[0068] To measure changes in blood flow within the brain, fNIRS uses optical sensors that detect oxygenated blood. fNIRS employs an array of optical sensors called a "light source" and a "detector." The light source illuminates the brain with light, and the detectors detect the light signals transmitted from the light source to measure changes in blood flow.

[0061]

[0069] When brain activity increases, blood flow to specific brain regions increases. As blood flows to activated brain regions, it carries oxygen molecules. fNIRS measures these changes in oxygenated blood and can determine whether or not a brain region was activated during a specific task, or if it was activated at that time. Because oxygenated blood appears red or near-infrared, fNIRS is called "near-infrared."

[0062]

[0070] According to one or more embodiments, the patient's CBF is measured at multiple brain locations. For example, CBF can be measured at multiple channel locations, including the prefrontal cortex, right temporal lobe, left temporal lobe, left parietal lobe, and right parietal lobe, left occipital lobe, and right occipital lobe.

[0063]

[0071] In some embodiments, CBF is initially measured during the performance of a cognitive task (e.g., playing a video game) to establish a baseline for subsequent CBF measurements. Based on this CBF data, patients can be screened to determine their response to external nerve stimulation. For example, a patient can be treated with external nerve stimulation while simultaneously measuring CBF to determine whether the stimulation is increasing or decreasing CBF in specific parts of the brain.

[0064]

[0072] In one or more embodiments, responders to external nerve stimulation are identified using fNIRS technology. In exemplary embodiments, fNIRS technology is used to verify whether a patient responds to eTNS. In one or more embodiments, an electrical signal is applied to the trigeminal nerve, CBF is measured, and changes in CBF are determined. Changes in CBF indicate that the patient is responding to eTNS treatment. In some embodiments, changes in CBF include an increase in CBF to the right prefrontal cortex or a decrease in CBF to the right or left temporal lobe. In one embodiment, changes in CBF include an increase in CBF to the right prefrontal cortex and a decrease in CBF to the right or left temporal lobe.

[0065]

[0073] In some embodiments, a control device 615 or control unit 615 may be used to instruct the electrode assembly 605 to deliver a stimulus, which is then measured by the fNIRS device 610 to verify the effect or progression of the stimulus. In some embodiments, the control device 615 can perform a number of advantageous operations related to the present invention. In particular, the control device 615 can specify and set operating parameters in the skin electrode assembly 605, upload or receive data, or instruct the electrode assembly 605 to perform a predetermined operation or change the operating mode at the request of a user operating the electrode assembly 605, in order to adapt the function of the device to meet the needs of the patient.

[0066]

[0074] In exemplary embodiments, the control device 615 is equipped to receive external measurements from other devices, including an fNIRS device 610. For example, the fNIRS device 610 may upload measurements to the control device 615 periodically or in real time. In some embodiments, the software operating program of the control device 615 includes tools for analyzing and processing recorded fNIRS data to help physicians develop operating parameters optimized for specific patients.

[0067]

[0075] In some embodiments, the control device 615 is configured to drive one or more electrodes to apply an electric current to a site that can induce an increase or decrease in the patient's CBF. In some embodiments, the control device 615 configures the stimulation to cause an increase or decrease in the patient's CBF in order to treat the patient.

[0068]

[0076] In one or more embodiments, the control device 615 is primarily a commercially available personal computer, laptop computer, or workstation having a central processing unit (CPU), keyboard, mouse, and display, and running a standard operating system such as Microsoft Windows®, Linux®, Unix®, or Apple OS®. It is also intended that a dedicated programmer device with a custom software package (which may not use a standard operating system) can be developed. The control device 615 can also be embodied as a dedicated microchip, which may reside on a device plugged into a computer, for example, via a USB port.

[0069]

[0077] Advantageously, the present invention enables the use of electrical stimulation to induce changes in CBF to treat neuropsychiatric and neurological disorders. The stimulation pattern can be beneficially modified to enhance blood flow in nerve pathways or alter CBF. In one embodiment, automated measurements are performed, the measurements are recorded, and later transmitted to a control device 615 via wireless telemetry. These measurements can be used by clinicians to adjust the treatment to suit a given patient being treated.

[0070]

[0078] Simulation studies may be conducted to evaluate the effects of different stimulus operating parameters. For example, the control device 615 applies programmed stimuli within a preset range of acceptable operating parameters (pulse amplitude, pulse width, etc.), which are then modified or adjusted, and the effects of these changes are monitored. Thus, the present invention can be realized as a brain-modulating system that treats disease conditions by providing stimulus signals having variable operating parameters such as intensity. To optimize patient treatment, it is intended that the operating parameters of the stimulus signals provided by the treatment (e.g., targeted nerve branches, frequency, amplitude, pulse width, duty cycle, duration, and / or waveform, etc.) can be adjusted.

[0071] Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), Autism and Autism Spectrum Disorder (ASP)

[0079] While not intended to be bound by any particular theory, neuroimaging studies suggest that dysfunction in several brain regions is involved in the pathophysiology and treatment response of these disorders, which generally begin in early childhood. As defined by the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 4th edition, 2000), attention-deficit / hyperactivity disorder (ADHD) is characterized by symptoms of inattention, hyperactivity, and impulsivity, whereas the diagnosis of ADD (now formally known as ADHD / inattentive type) does not include the features of hyperactivity and impulsivity. Previous studies have shown that ADD and ADHD involve abnormalities in multiple regions, including the anterior cingulate cortex (ACC) and parietal cortex (e.g., Makris et al., 2010, J Atten Disord 13(4):407-13; Dickstein SG, et al. 2006 J Child Psychol Psychiatry. 47(10):1051-62). As defined by the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 4th edition, 2000), autism (also known as autistic disorder) is characterized by widespread impairments in areas such as reciprocal social interaction skills and communication skills, or the presence of stereotyped behaviors, interests, and activities. ASD includes related diagnoses such as Asperger's syndrome, which has most of the characteristics except for language developmental delay.Areas involved in autism and ASD include the ACC, prefrontal cortex, temporal cortex, and parietal cortex (e.g., Hall GB, Szechtman H, Nahmias C. 2003. Am J Psychiatry. 160(8):1439-41; McAlonan GM, et al. 2005. Brain. 128(Pt 2):268-76; Cherkasova MV, Hechtman L. 2009. Can J Psychiatry. 54(10):651-64; Konrad K, et al. 2006. Biol Psychiatry. 59(7):643-51). Individuals with ADHD are generally unable to increase blood flow to the prefrontal cortex in response to tasks requiring cognitive concentration.

[0072]

[0080] In one or more embodiments, fNIRS data from healthy adult males were acquired in Figure 7 during a verbal fluency test at baseline (before stimulation), and in Figure 8 during or after stimulation using eTNS. In Figure 8, the use of eTNS dramatically increased oxygenated blood flow in channels 36, 46, and 47 in the prefrontal cortex. Conversely, the use of eTNS decreased temporal blood flow in the right and left temporal lobes. These findings are consistent with previous positron emission tomography (PET) scan data collected by the applicant.

[0073]

[0081] Based on these findings, and without intending to be constrained by theory, we can hypothesize that patients who do not respond to eTNS will not show a dramatic increase in prefrontal cortex blood flow on fNIRS. On the other hand, in patients who do respond to eTNS, a dramatic increase in blood flow in these channels will be observed as soon as the stimulus is turned on.

[0074]

[0082] Those skilled in the art will understand that various adaptations and modifications of the preferred embodiments described above can be made without departing from the scope and spirit of this specification. Stimulation of target nerves can be achieved by applying many forms of energy, such as magnetic or ultrasonic waves, to the skin. Therefore, it should be understood that the subject matter of this specification may be carried out in ways other than those specifically described herein.

Claims

1. A system for identifying and treating responders to external nerve stimulation, pulse generator, A skin electrode assembly that communicates with the pulse generator, A first electrode having at least one contact point, configured to be placed on the skin in a first region of the patient's face, A second electrode having at least one contact point is configured to be positioned on the skin in a second region of the patient's face, Equipped with, The first electrode and the second electrode are configured to contact a portion of the patient's face that overlaps with the skin distribution of the trigeminal nerve, occipital nerve, vagus nerve, facial nerve and / or any of their branches, respectively. Skin electrode assembly and A functional near-infrared spectroscopy (fNIRS) device configured to measure cerebral blood flow (CBF) in a target brain region and generate an output signal corresponding to the CBF in the target brain region, A control device configured to process the output signal and generate visual feedback corresponding to the CBF of the target brain region, A system equipped with these features.

2. The system according to claim 1, wherein the first electrode and the second electrode are configured to contact a portion of the patient's face that overlaps with the skin distribution of the same branch of the ophthalmic nerve, infraorbital nerve, mental nerve, occipital nerve, vagus nerve, or facial nerve.

3. The system according to claim 1, wherein the first electrode and the second electrode are configured to contact a portion of the patient's face that overlaps with the skin distribution of different branches of the ophthalmic nerve, infraorbital nerve, mental nerve, occipital nerve, vagus nerve, or facial nerve.

4. The system according to claim 1, further comprising a wire that operably connects the pulse generator and the skin electrode assembly.

5. The system according to claim 1, further comprising an adjustment device configured to adjust the maximum charge equilibrium output current to less than approximately 30 to 50 mA.

6. The pulse generator emits approximately 25 mA / cm² in the cerebral cortex at a frequency of approximately 20 to 300 Hz and a pulse duration of approximately 50 to 500 microseconds. ２ The following output current densities and approximately 10 microcoulombs / cm² are observed. ２ The system according to claim 1, configured to apply an electrical signal at the following output charge density.

7. A system for identifying and treating responders to external nerve stimulation, A nerve stimulator, A skin electrode assembly comprising: a first contact pair configured to be positioned in a first region of the patient's face; a second contact pair configured to be positioned in a second region of the patient's face; and an insulating connection region connecting the first contact pair and the second contact pair, wherein the first contact pair and the second contact pair are configured to contact a portion of the patient's face that overlaps with the skin distribution of at least one branch of the ophthalmic nerve, infraorbital nerve, mental nerve, occipital nerve, vagus nerve, or facial nerve; A functional near-infrared spectroscopy (fNIRS) device configured to measure cerebral blood flow (CBF) in a target brain region and generate an output signal corresponding to the CBF in the target brain region, A control device configured to process the output signal and generate visual feedback corresponding to the CBF of the target brain region, A system equipped with these features.

8. The system according to claim 7, further comprising a cable and lead wires that operably connect the nerve stimulator and the skin electrode assembly.

9. The system according to claim 7, further comprising an adjustment device that adjusts the current output to minimize or prevent current penetration beneath the surface of the skull.

10. The system according to claim 7, further comprising a retaining element configured to fix the skin electrode assembly to the forehead of the patient.

11. A method for evaluating the use of external nerve stimulation for the treatment of neuropsychiatric disorders or neurological disorders, The first area of ​​the patient's face is brought into contact with the skin electrode assembly, wherein the skin electrode assembly is A first electrode having at least one contact point is configured to be placed on the skin in a first region of the patient's face. Equipped with, The first electrode is configured to contact a portion of the patient's face that overlaps with the skin distribution of at least one branch of the ophthalmic nerve, infraorbital nerve, mental nerve, occipital nerve, vagus nerve, or facial nerve, To treat the aforementioned neuropsychiatric disorder or neurological disorder, an electrical signal is applied to the skin electrode assembly with specified operating parameters, Using a functional near-infrared spectroscopy (fNIRS) device, we measure cerebral blood flow (CBF) in a target brain region, It is determined that the CBF has changed in the aforementioned target brain region, Methods that include...

12. The method according to claim 11, wherein the target brain region includes one or more of the prefrontal cortex, the right temporal lobe, or the left temporal lobe.

13. The method according to claim 12, wherein determining that the CBF has changed in the target brain region includes determining that the CBF has increased in the right prefrontal cortex and that the CBF has decreased in the right temporal lobe and the left temporal lobe.

14. The method according to claim 11, comprising adjusting the operating parameters to optimize the treatment of the neuropsychiatric disorder or the neurological disorder.

15. The method according to claim 14, wherein the operating parameters include one or more of the following: a branch of the ophthalmic nerve, infraorbital nerve, mental nerve, occipital nerve, vagus nerve, or facial nerve; the frequency of an electrical signal; the amplitude of an electrical signal; the pulse width of an electrical signal; the duty cycle of an electrical signal; or the waveform of an electrical signal.

16. The method according to claim 11, wherein the neuropsychiatric disorder is selected from mood disorders, cognitive disorders, behavioral disorders, or anxiety disorders.

17. The method according to claim 16, wherein the behavioral disorder includes attention-deficit hyperactivity disorder (ADHD).

18. The method according to claim 11, wherein the neurological disorder is selected from epilepsy, seizure-related disorders, acute brain injury, chronic brain injury, chronic daily headache, migraine, migraine and headache-related disorders, and motor disorders.

19. The method according to claim 11, wherein the step of applying an electrical signal includes applying an electrical signal with a frequency of approximately 20 to 300 Hz, a current of 0.05 to 5 milliamperes (mA), and a pulse duration of 500 microseconds or less.

20. The step of applying an electrical signal involves a frequency of approximately 20–300 Hz, a pulse duration of approximately 50–500 microseconds, and an electrical current of approximately 25 mA / cm² in the cerebral cortex. ２ The following output current densities and approximately 10 microcoulombs / cm² are observed. ２ The method according to claim 19, comprising applying an electrical signal at the following output charge density.

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