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

Abstract

The present disclosure relates to methods, devices and systems used for the identification and treatment of responders to external nerve stimulation via a combination of a cutaneous electrode assembly and a functional near-infrared spectroscopy (fNIRS) device. More specifically, cutaneous methods of stimulation of the trigeminal nerve, the occipital nerve, the vagus nerve, the facial nerve, and / or any branch thereof and measurement of cerebral blood flow at targeted brain areas are disclosed herein.

Description

FUNCTIONAL NEAR-INFRARED SPECTROSCOPY AND EXTERNAL NERVE STIMULATION FOR SCREENING AND TREATMENT OF NEUROPSYCHIATRIC AND NEUROLOGICAL DISORDERSTECHNICAL FIELD

[0001] The present disclosure generally relates to medical devices and systems and methods of using the same for identifying responders to and for treatment of neuropsychiatric and neurological disorders. More specifically, methods, devices, and systems configured for the treatment of neurological and / or neuropsychiatric disorders, via external nerve stimulation are provided, where treatment of the neurological and / or neuropsychiatric disorder includes configuring stimulation parameters to cause an increase or a decrease in cerebral blood flow (“CBF”) of a patient. Devices and systems configured for stimulation of superficial sensory branches of cranial nerves and their methods of application are described.BACKGROUND

[0002] Psychiatric or neuropsychiatric disorders, for example depressive disorders (DD) sometimes referred to as depression, or anxiety disorders, are traditionally treated with pharmacotherapy and psychotherapy. Neurological disorders and conditions, such as seizure disorders that are characterized by epileptic seizures, acute or chronic brain injury, coma, chronic headache or migraine, movement and related disorders, may be treated with medications and, in certain cases, brain surgery.

[0003] Electrical stimulation is an emerging therapy for treating several diseases. Recently, external cutaneous electrical stimulation has been found to be useful in the treatment of various neuropsychiatric and neurological diseases, as described for example in U.S. Patent Nos. 8,380,315; 8,688,220; and 10,639,468. Electrical stimulation devices, however, are not responsive to relevant neurological conditions.

[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, movement disorders, and attention deficit hyperactivity disorder (ADHD). One result of abnormal blood flow is an imbalance between cerebral oxygen supply and demand. This is thought to play an important role in thegeneration of neurological events common to various disorders. It would therefore be advantageous to employ a system or method to monitor such abnormal blood flow patterns to identify responders to external cutaneous stimulation with the intention of correcting the abnormal or insufficient blood flow patterns to provide clinical benefit. Responsive stimulation, in which neurological activity is detected and electrical stimulation is applied selectively, would be particularly advantageous.SUMMARY

[0005] One aspect of the subject matter of the present disclosure addresses the aforementioned needs 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 a neurostimulator; a cutaneous electrode assembly in electrical communication with the pulse generator; a functional near-infrared spectroscopy (fNIRS) device configured to measure cerebral blood flow (CBF) at targeted brain areas and to generate an output signal corresponding to CBF in the targeted brain areas; and a control device configured to process the output signal to produce visual feedback corresponding to the CBF in the targeted brain areas.

[0006] In some embodiments, the cutaneous electrode assembly includes a first electrode comprising at least one contact configured for cutaneous placement at a first region of a patient’s face, and a second electrode comprising at least one contact configured for cutaneous placement at a second region of the patient’s face, wherein the first electrode and second electrode are each configured to contact a portion of the patient’s face overlying the cutaneous distribution of the trigeminal nerve, the occipital nerve, the vagus nerve, the facial nerve, and / or any branch thereof.

[0007] In other embodiments, the cutaneous electrode assembly includes a first pair of contacts configured for placement on a first region of a patient’s face; a second pair of contacts configured for placement on a second region of the patient’s face; and an insulating connection region connecting the first pair of contacts and the second pair of contacts, wherein the first pair of contacts and the second pair of contacts are configured to contact a portion of the patient’s face overlying the cutaneous distribution of at least one branch of the ophthalmic nerve, the infraorbital nerve, the mentalis nerve, the occipital nerve, the vagus nerve, or the facial nerve.

[0008] Another aspect of the present disclosure provides a method for evaluating the use of external nerve stimulation for treatment of a neuropsychiatric or neurological disorder. Themethod includes contacting a first region of a patient’s face with a cutaneous electrode assembly, applying electrical signals to the cutaneous electrode assembly at specified operational parameters to treat the neuropsychiatric or neurological disorder; measuring, with a functional near-infrared spectroscopy (fNIRS) device, cerebral blood flow (CBF) at targeted brain areas; and determining that the CBF has changed at the targeted brain areas.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The present disclosure, both as to its organization and manner of operation, together with further objects and advantages, may be understood by reference to the following description, taken in connection with the accompanying drawings, in which:

[0010] Figs. 1 A and IB illustrate the location of several branches (nerves) of the trigeminal nerve and the location of the major foramina for the superficial branches of the trigeminal nerve;

[0011] Fig. 2 shows an embodiment of a system including an electrode assembly provided according to aspects of the present disclosure;

[0012] Fig. 3 A depicts an enlarged view of the electrode assembly of Fig. 2;

[0013] Fig. 3B depicts representative dimensions of the electrode assembly of Fig. 3 A;

[0014] Figs. 4A-4C depict various embodiments of the cutaneous electrode assembly of Fig. 2;

[0015] Fig. 5 shows another embodiment of an electrode assembly that may be used with the system of Fig. 2;

[0016] Fig. 6 shows an embodiment of a system according to aspects of the present disclosure;

[0017] Fig. 7 illustrates fNIRS data of a healthy adult male taken during a verbal fluency test at baseline (pre-stimulation); and

[0018] Fig. 8 illustrates fNIRS data of the healthy adult male of Fig. 7 during eTNS or stimulation according to aspects of the present disclosure.DETAILED DESCRIPTION

[0019] According to one or more embodiments, screening for and identifying responders to external cutaneous stimulation is accomplished by use of a combination of a cutaneouselectrode assembly and a functional near-infrared spectroscopy (fNIRS) device. Tn some embodiments, the combination is used to adjust therapy delivery to a patient to more optimally bring about beneficial changes in brain blood flow patterns. Advantageously, monitoring of the brain blood flow can be accomplished by the periodic use of the non-invasive imaging technique fNIRS, and the results of fNIRS can be used to predict which patients will respond to external cutaneous stimulation.

[0020] In various embodiments, therapy includes electrical stimulation. According to certain embodiments, electrical stimulation can modulate blood flow in the brain. Stimulation of certain brain structures can produce patterns of blood flow changes including increases or reductions of blood flow in targeted brain areas. Accordingly, modulation of CBF may be employed for treatment of neuropsychiatric and / or neurological disorders.

[0021] In some embodiments, the neurological disorders that may be treated include one or more of movement disorders (e.g., the tremors characterizing Parkinson’s disease), migraine headaches, or chronic pain. In certain 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 disorders (ASD), substance use disorders and related behavioral addictions, eating disorders and obsessive compulsive disorder (OCD), psychotic disorders, or dementing disorders. The neurological or neuropsychiatric disorders that may be treated according to the present disclosure include any neurological or neuropsychiatric disorders that are directly or indirectly affected by changes in CBF.

[0022] In general, it is believed that substantially all pharmacological treatments aimed at cerebral cells for neurological and neuropsychiatric disorders are amenable for use with the embodiments of the present disclosure. In particular, these embodiments may be adapted for use in the treatment of disorders such as brain tumors, acute brain injury, chronic brain injury, movement disorders, tardive 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 that are directly or indirectly affected by changes in CBF.

[0023] With reference to Figs. 1 A and IB, the trigeminal nerve is the largest cranial nerve, and has extensive connections with brainstem and other brain structures. The trigeminalnerve has three major sensory branches over the face, all of which are bilateral, and highly accessible. The supraorbital nerve, or ophthalmic nerve, is frequently referred to as the Vi division. The infraorbital branch, or maxillary nerve, is commonly referred to as the V2 division. The mandibular nerve (also known as the mentalis branch) is referred to as the V3 division. The supraorbital nerve supplies sensory information about pain, temperature, and light touch to the skin of the forehead, the upper eyelid, the anterior part of the nose, and the eye. The infraorbital branch supplies sensory information about pain, temperature, and light touch sensation to the lower eyelid, cheek, and upper lip. The mentalis branch supplies similar sensory modalities to the skin of the lower face (e.g. jaw and tongue) and lips.

[0024] These branches exit the skull through three foramina, as shown in Figs. 1 A and IB. The supraorbital nerve or ophthalmic nerve exits at foramen 1 (the supraorbital foramen or notch), approximately 2 1-2.6 cm from the nasal midline (in adults), and is located immediately above the orbital ridge that is located below the eyebrow. The infraorbital branch or maxillary nerve exits at foramen 2 (the infraorbital foramen), approximately 2.4-3.0 cm from the nasal midline (in adults), and the mentalis nerve exits at foramen 3 (the mentalis foramen), approximately 2.0-2.3 cm from the nasal midline (in adults). The nasal nerve is a division of the ophthalmic nerve. Other sensory branches, including the zygomaticofacial, zygomaticoorbital, zygomaticotemporal, and auriculotemporal, arise from other foramina.

[0025] Fibers from the three major branches join together to form the trigeminal ganglion. From there, fibers ascend into the brainstem at the level of the pons to synapse with the main sensory nucleus of the pons, the mesencephalic nucleus of V, and the spinal nucleus and tract of V. Pain fibers descend in the spinal nucleus and tract of V, and then ascend to the ventral posterior medial nucleus (VPM) of the thalamus. Light touch sensory fibers are large, myelinated fibers, which ascend to the ventral posterior lateral (VPL) nucleus of the thalamus. Afferent sensory fibers project from the trigeminal nuclei to the thalamus and the cerebral cortex.

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

[0027] The locus coeruleus is a paired nuclear structure in the dorsal pons, and is located just beneath the floor of the fourth ventricle. The locus coeruleus has extensive axonalprojections to a broad number of brainstem, sub-cortical and cortical structures, and is an important part of the reticular activating system. The locus coeruleus is a core part of the brainstem noradrenergic pathway, and produces the neurotransmitter norepinephrine.Norepinephrine plays a key role in attention, alertness, blood pressure and heart rate regulation, and mood.

[0028] In certain embodiments, the connections between the trigeminal nerve and the locus coeruleus, thalamus, amygdala, anterior cingulate, and other central nervous system structures as described above may be relevant to a 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. Thus, cutaneous stimulation of the trigeminal nerve could be effective in the treatment of these neuropsychiatric disorders.

[0029] In various embodiments, the connections between the trigeminal nerve, locus coeruleus, nucleus and tractus solitarius, thalamus, and cerebral cortex, may be relevant to a potential role of the trigeminal nerve in numerous neurological disorders, including coma and brain injury, seizure disorders, headache, migraine, and movement disorders, as may be apparent to one skilled in the art. Thus, cutaneous stimulation of the trigeminal nerve at custom tailored settings and parameters within a predefined range could be effective in the treatment of multiple neurological disorders.

[0030] The occipital nerves are cranial nerves that originate in the neck and extend up the back and back sides of the head. The three major occipital nerves are the greater occipital nerve, the lesser (or small) occipital nerve, and the third (or least) occipital nerve. The greater occipital nerve extends upward toward the top of the head. The greater occipital nerve innervates the skin of the back of the scalp up to the vertex of the skull, the ear, and the skin just above the parotid gland. Because of that it supplies sensation to the scalp at the top of the head, over the ear and over the parotid glands. The lesser occipital nerve extends upward and toward the sides of the head. The lesser occipital nerve gives off two types of branches: communicating and cutaneous. The communicating branches interconnect with the communicating branches of the greater occipital nerve. The cutaneous branches include the auricular, mastoid and occipital branches. These branches provide sensory supply to the skin of the lateral portion of the scalp and the skin around the external ear. The third occipital nerve extends from near the neck around the back ofthe head toward the ear. This nerve provides sensation to the skin on the middle lower back of your scalp. The third occipital nerve is vulnerable to damage from whiplash.

[0031] The greater occipital nerve, together with the lesser occipital nerve and the third occipital nerve, are commonly associated with occipital neuralgia, cervicogenic headaches, and migraine headaches. Occipital neuralgia is a type of headache characterized by a paroxysmal stabbing pain in the posterior area of the scalp. Cervicogenic headaches are perceived in the head from a source in the neck. Migraine headaches cause severe throbbing pain or a pulsing sensation, usually on one side of the head. Stimulation can be applied along the occipital nerves at the back of the head or on the top or superior portion of the skull for treatment.

[0032] The vagus nerve is the cranial nerve responsible for the regulation of internal organ functions, such as digestion, heart rate, and respiratory rate, as well as vasomotor activity, and certain reflex actions, such as coughing, sneezing, swallowing, and vomiting. Its activation leads to the release of acetylcholine (ACh) at the synaptic junction with secreting cells, intrinsic nervous fibers, and smooth muscles. ACh binds to nicotinic and muscarinic receptors and stimulates muscle contractions in the parasympathetic nervous system.

[0033] The vagus nerve originates in the brain and branches out in multiple directions to the neck and torso, where it is responsible for actions such as carrying sensory information from the skin of the ear, controlling the muscles that you use to swallow and speak and influencing your immune system. The right vagus nerve passes anterior to the subclavian artery and posterior to the sternoclavicular joint, entering the thorax. The left vagus nerve passes inferiorly between the left common carotid and left subclavian arteries, posterior to the sternoclavicular joint, entering the thorax.

[0034] Several branches of the vagus nerve arise in the neck. The pharyngeal branches provide motor innervation to the majority of the muscles of the pharynx and soft palate. The superior laryngeal nerve splits into internal and external branches. The external laryngeal nerve innervates the cricothyroid muscle of the larynx. The internal laryngeal provides sensory innervation to the laryngopharynx and superior part of the larynx. The recurrent laryngeal nerve hooks underneath the right subclavian artery, then ascends towards to the larynx. It innervates the majority of the intrinsic muscles of the larynx. In the thorax, the right vagus nerve forms the posterior vagal trunk, and the left forms the anterior vagal trunk. Branches from the vagal trunks contribute to the formation of the esophageal plexus, which innervates the smooth muscle of theesophagus. Two other branches arise in the thorax: the left recurrent laryngeal nerve and the cardiac branches. The left recurrent laryngeal nerve hooks under the arch of the aorta, and ascends to innervate the majority of the intrinsic muscles of the larynx. The cardiac branches innervate regulate heart rate and provide visceral sensation to the organ. The vagal trunks enter the abdomen. In the abdomen, the vagal trunks terminate by dividing into branches that supply the esophagus, stomach and the small and large bowel (up to the splenic flexure). Vagus nerve stimulation may be used treat seizures, epilepsy, depression, stroke, headaches, migraines, cardiac arrythmias, heart failure, and autoimmune disorders.

[0035] The facial nerve is a cranial nerve and a pathway from the brain to certain muscles in the face. It controls muscles that help make expressions like raising an eyebrow, smiling or frowning. This nerve is also responsible for the tongue’s taste sensations. The facial nerve has five branches that perform distinct motor functions. The frontal (temporal) branch controls forehead muscles. The zygomatic branch helps close the eyes. The buccal branch allows movement of the nose, blinking, and raising the upper lip and corners of the mouth to make a smile. The marginal mandibular branch draws you lower lip down (like a frown) and travels through your middle ear to help respond to loud noises. The cervical branch controls movement in the chin and lower corners of the mouth. Facial nerve stimulation can be used to treat stroke.

[0036] For a discussion of certain embodiments of methods, systems and devices using cutaneous electrodes according to aspects of the present disclosure, reference is now made to Figs. 2A-5, which show various embodiments of the systems and devices that may be used for the cutaneous stimulation of the trigeminal nerve, the occipital nerve, the vagus nerve, the facial nerve, and / or any branch thereof to modulate CBF, and methods of using the same.

[0037] According to one aspect of the present disclosure, a method of treating neuropsychiatric and / or neurological disorders using external trigeminal nerve stimulation (“eTNS”) is provided. Broadly speaking, the method of treating neuropsychiatric and / or neurological disorders by eTNS includes positioning external electrodes over or near at least one of the foramina or branches of the trigeminal nerve (Figs. 1 A and IB), and stimulating the electrodes using a stimulator or pulse generator for a fixed time at specified operational parameters. The electrodes need not be applied at the main branch of the nerve, they can be applied in the area of the skin supplied by that nerve, which may be inches away from the main branch of the nerve. In one embodiment, the external electrodes are positioned over theforamina of the supraorbital or ophthalmic nerves (Fig. 1 A, Foramen 1 ) since unilateral stimulation or bilateral stimulation of the trigeminal nerve is achievable by placing single or separate electrodes on the right and / or left sides of a patient’s face (e.g. by placing an electrode assembly, such as two separate electrodes, a single paired electrode or two pairs of electrodes, each electrode having at least one contact, over the forehead or other region of the patient’s 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, bilateral stimulation may offer similar or better efficacy than unilateral stimulation because the function of different brain structures may not be the same on right and left (e.g. verbal expression is most commonly localized to speech centers in the left hemisphere, and injury there produces catastrophic loss of the ability to speak, while damage to the corresponding region on the right does not produce this profound loss of function, but may alter subtle functions). There may also be synergistic effects that arise with bilateral stimulation. In some embodiments, two separate electrodes or a single paired electrode may be placed over the forehead. In alternative embodiments, the electrode can be positioned over the foramina of the infraorbital foramen (infraorbital or maxillary nerves) (Fig. 1A, Foramen 2) or the mentalis foramen (mentalis or mandibular nerves) (Fig. IB, Foramen 3). In yet other embodiments, the stimulation can be unilaterally applied to one foramen of the trigeminal nerves. In other embodiments, the method of treating neuropsychiatric and / or neurological disorders comprises positioning external electrodes over a plurality of foramina and simultaneously stimulating different trigeminal nerves. In other embodiments, electrodes may be positioned at a region of the patient’s face (on the right and / or left side) corresponding with the supratrochlear nerve, infratrochlear nerve, zygomaticotemporal, zygomaticofacial, zygomaticoorbital, nasal, and / or auriculotemporal nerves and / or their respective foramina.

[0038] According to one aspect of the present disclosure, the method of treating neuropsychiatric and / or neurological disorders by eTNS comprises selecting patient specific values for the operational parameters for the stimulation of each individual patient within a defined range. In one embodiment, the values of the operational parameters are selected such that a patient will experience a stimulation sensation, such as a mild tingling over the forehead and scalp without being in discomfort or in pain. In one embodiment, the values of the operational parameters are selected such that skin irritation, burns, and undesired effects on thebrain, and / or the cranial nerves are minimized. Tn one embodiment, the method of selecting operational parameters comprises evaluating variables such as the configuration and size of the electrode, the pulse duration, the electrode current, the duty cycle and the stimulation frequency; which are important factors in ensuring that the total charge, the charge density, and charge per phase are well within accepted limits for the skin, nerve and brain. For example, to minimize skin irritation, it is not sufficient to merely state the total current, but the current density needs to be defined. Additionally, selection of the electrical stimulation parameters, electrode design, and inter-electrode distance are chosen such that the electrical stimulation zone includes the ophthalmic or other cranial nerves (approximately 3-4 mm below the skin surface), while preventing or minimizing current penetration beneath the skull bone as described above.

[0039] As described in more detail below with respect to Figs. 2A-5, the electrodes connect to leads for conveying the electrical stimuli from a neurostimulator. In some embodiments, the neurostimulation may be provided using an electrical neurostimulator at the following exemplary settings: frequency 20-150 Hz, current 1-10 mA, pulse duration (pulse width) of 50-250 microseconds, a duty cycle of 10% to 50%, for 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 values of the operational parameters may be used. In alternative embodiments, a single external electrode can be used. In some embodiments, as described in more detail below, a portable external stimulator, which can be attached to a patient’s clothing, is used.

[0040] In one embodiment, as can be understood from Figs. 2-5, a system 200 for treatment of neuropsychiatric and / or neurological disorders via eTNS includes an electrode assembly 100, electrical cable or wire 120 and an external neurostimulator or pulse generator 122. In some embodiments, the pulse generator may be an internal pulse generator. The electrode assembly may be configured for the bilateral simultaneous and asynchronous stimulation of the ophthalmic nerves. 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 herein. The neurostimulator or pulse generator may be any type of appropriate stimulating, signal -generating device. In the illustrated embodiment, the generator 122 is portable and attached to the belt of a patient 20. However, either a portable or nonportable pulse generator may be used. As shown in Fig. 2, the electrode assembly 100 isconnectable to an external stimulator 122 either by lead wires 124 connected to an electrical cable 120 or wirelessly. That is, in one embodiment, the electrical cable or wire 120 is configured to provide a physical and electrical link between the generator 122 and the electrode assembly 100 via lead wires 124. In other embodiments, the generator 122 and the electrode assembly 100 communicate wirelessly (i.e. the wire 120 and leads 124 are not used). The system 200 or elements thereof, such as the electrode assembly 100, may be part of a kit. In some embodiments, the kit may also include instructions for placement of the electrode system and / or system. In some embodiments, the kit may also include instructions for treatment of a neuropsychiatric or neurological disorder according to a method as disclosed herein.

[0041] In some embodiments, the system 200 may also include a regulation device to ensure safe use of the system. The regulation device is configured to be attached to the pulse generator 122 and is configured to govern the maximum charge balanced output current below approximately 30-50mA to minimize current penetration to the brain and increase patient tolerance. The regulation device may be internally programmed to range from 0.25- 5.0 mA, 0 - 10mA, 0-15mA, depending on the surface area, placement, and orientation of the electrode, and whether the electrode is stimulating near or adjacent to the skull, or away from the skull, (mentalis), where current ranges may be higher or lower. Current TENS units stimulate with maximum output currents of up to 100 mAs, which result in currents which may penetrate the skull and which may not be well tolerated.

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

[0043] In some embodiments, the electrode assembly comprises an electrode with at least one contact. In some embodiments, a single electrode may have a plurality of contacts. In some embodiments, the electrode assembly comprises pair of electrodes with a pair of contacts. In some embodiments, the electrode assembly may be a strip electrode with at least one contact. In some embodiments, the strip electrode may include a plurality of contacts.

[0044] The electrode assembly 100 shown in Figs. 2-3B is also referred to as a bilateral supraorbital electrode. As illustrated in Figs. 2-3B, the electrode assembly 100 includes a first pair of contacts 112a, 112b for placement on a first region of the patient’s face, and a second pair of contacts 114a, 114b for placement on 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 pair of contacts comprises a first upper contact 112a and a first lower contact 112b, while the second pair of contacts comprises a second upper contact 114a and a second lower contact 114b. The first and second contact pairs are connected to each other by an insulative connection region 116. The electrode assembly 100 comprises an inner contact surface 118 that comes into contact with a patient’s skin at four contact areas, each corresponding to one of the four contacts 112a, 112b, 114a, 114b. The inner contact surface 118 comprising the four contact areas includes a buffered gel -like adhesive that provides good electrical conductivity with minimum skin irritation, an example of such gel includes the commercially available hydrogels from AmGel Technologies (AmGel Technologies, Fallbrook, CA, USA).

[0045] In one embodiment, the electrode assembly 100 is configured to stimulate both the right and left ophthalmic nerves either simultaneously or asynchronously. The insulative connection region 116 serves to assist a patient in lining up the electrode assembly 100 with the midline of the nose to ensure proper placement of the electrode assembly 100 over both ophthalmic nerves, which lie on the average about 2.1 to 2.6 cm from the nasal midline of an adult patient. Thus, the electrode assembly can be placed accurately (e.g. by the patient) without knowledge of the location of the ophthalmic nerve or key landmarks relative to the nerve, thereby reducing the possibility of inadequate stimulation due to errors in positioning of the electrodes.

[0046] The placement of the first contact pair 112a, 112b and the second contact pair 114a, 114b on opposite sides of the nasal midline assures that stimulation current moves orthodromically or in the direction of the afferent ophthalmic or supraorbital nerve. Furthermore, this configuration of the electrode assembly 100 allows the contact pairs 112a / l 12b and 114a / l 14b to be stimulated independently and / or unilaterally, as the response to stimulus may be localized and thus varied from one side of the midline to the other side. That is, the presently disclosed electrode assembly permits individual adjustment of current for the first andsecond regions or right and left sides, as applicable, thereby reducing asymmetric stimulation and / or perceived asymmetric stimulation. Figs. 4A-4C illustrate other embodiments of the electrode assembly 100, which configurations may be used to stimulate the right and / or left ophthalmic nerve and / or other branches of the trigeminal nerve as disclosed herein, such as the zygomaticofacial and / or the auriculotemporal nerves. It can be appreciated that a single electrode with one or more contacts or multiple electrodes with one or more contacts may be used. The bilateral supraorbital electrode is specially configured for bilateral supraorbital stimulation. It is scalable based on the location of use, stimulation parameters and input from computer modeling so as to negate or minimize or render safe, current penetration into the brain. As skin irritation may occur, a similar configuration could be applied unilaterally, so as to provide relief to one side of the forehead, to promote skin tolerability and to reduce the risk of irritation. Other configurations of size and inter electrode distance can be conceived for different branches of the trigeminal nerve, as shown in Figs. 4A-4C. In one embodiment, a strip electrode with at least two contacts may be used to stimulate the auriculotemporal and / or zygomaticofacial nerve. In other embodiments, two separate electrodes may be used to stimulate the auriculotemporal and / or zygomaticofacial nerve.

[0047] For stimulations wherein electrical pulses of a single polarity (monophase - either all positive pulses or all negative pulses) are generated, the upper contacts 112a, 114a and lower contacts 112b, 114 have fixed polarities. For stimulations wherein electrical pulses of alternating polarities (biphase - alternating positive and negative pulses or pulse trains) are generated, the upper contacts 112a, 114a and lower contacts 112b, 114b have alternating polarities. Also, the inferior electrode typically serves as the cathode for the leading phase of the stimulating pulse. In the case of a monophasic stimulation, the inferior electrode generally becomes the cathode.

[0048] As can be understood from Fig. 3B, each of the contacts 112a, 112b, 114a, 114b is sized to deliver an electrical pulse over a large enough surface area to minimize any skin injury due to excess current density and / or charge density, and to minimize or eliminate current penetration beyond the inner surface of the skull bone. The distance between the first contact pair 112a, 112b and the second contact pair 114a, 114b is configured to stimulate the ophthalmic nerves while minimizing or eliminating current delivery to the surface of the brain. In one embodiment, the mid-point of each of the contacts is approximately 2.5 cm (range 1.5 cm to 3.5 cm) from the nasal midline. The electrode size and the inter-electrode distance may vary forchildren and adults, males and females based on anatomical differences. Tn one embodiment, the electrode is approximately 32.5mm in length by 12.5mm in height and the inter-electrode distance between, for example, the upper pair of electrodes 112a, 114a is 17.5 mm and the interelectrode distance between, for example, the upper electrode 112a and the lower electrode 112b is 20mm. In other embodiments, the length of the electrode may be greater than or less than 32.5mm and greater than or less than 12.5 mm in height. In still other embodiments, the inter electrode distance can be in a range greater than 20mm and / or less than 17.5mm. In various embodiments, the surface area of each of the contacts 112a, 112b, 114a, and 114b can be within a range of about 0.5 cm2to about 20 cm2. In various embodiments, the distance between the contacts 112a and 112b and the distance between contacts 114a, and 114b can be in a range of about 0.5 cm to about 10 cm. Those of skill in the art will recognize that one or more of the above distances can be used as a border of a range of distances.

[0049] Fig. 5 illustrates another embodiment of the electrode assembly 100. As shown in Fig. 5, a patient 10 is wearing two separate electrodes 12 on the forehead, one over each eyebrow, corresponding to the foramina of the ophthalmic nerves.

[0050] Those skilled in the art will appreciate that various adaptations and modifications of the above-described embodiments of the electrode assembly 100 are within the scope and spirit of the present disclosure. For example, one embodiment of the present device comprises a unilateral electrode assembly configured for the unilateral stimulation of ophthalmic nerves. Also, the instant electrode assembly can also be configured for the stimulation of the maxillary nerves or the mandibular nerves. Alternatively, an electrode assembly configured for the simultaneous stimulation of a plurality of trigeminal nerve branches is also within the scope of the present disclosure. In one embodiment, the system or electrode assembly as disclosed herein may be configured to stimulate the auriculotemporal nerve. In one embodiment, the system or electrode assembly as disclosed herein may be configured to stimulate the zygomaticofacial nerve.

[0051] Those skilled in the art will also appreciate how to modify and use the electrode assembly 100 to stimulate the occipital nerve, the vagus nerve, the facial nerve, and / or any branch thereof. In brief, these other nerves are closely related to the trigeminal and stimulating them in addition or as an alternative to the trigeminal would be expected to increase the effect ofstimulation and also target additional brain regions. This could improve the efficacy of the stimulation and also allow for treatment of additional indications.

[0052] In use, the electrode assembly 100 is positioned over the forehead of the patient 20 such that the insulative connection region 116 lines up with the midline of the patient’s nose. In some embodiments, the electrode assembly 100 is placed over the supraorbital foramina, located over the orbital ridge approximately 2.1-2.6 cm lateral to nasal midline. The electrode assembly 100 may then be connected to the external neurostimulator 122 via lead wires 124 and the electrical cable 120. In other embodiments, the electrode assembly 100 is connected to the neurostimulator 122 via a wireless connection. Stimulation according to patient specific operational parameters as determined according to the methods described herein is then applied.

[0053] According to one aspect of the present disclosure, there is provided a method of treatment of neuropsychiatric or neurological disorders using the electrode assembly 100, as described above. In one embodiment, the method of treating neuropsychiatric and / or neurological disorders comprises 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 the operational parameters as disclosed herein.

[0054] According to one aspect of the present disclosure, there is provided a method of treatment of neuropsychiatric and / or neurological disorders using an embodiment of the electrode assembly as described herein. In one embodiment, the method of treating the neuropsychiatric and / or neurological disorders comprises positioning the electrode assembly at a first region of a face of a patient, connecting the electrode assembly to an external stimulator, and stimulating the electrode assembly at defined values of the operational parameters as disclosed herein. In one embodiment, the first region is a region corresponding to the auriculotemporal nerve. In one embodiment, the first region is a region corresponding to the zygomaticofacial nerve. In one embodiment, the first region is a region corresponding to the supraorbital nerve.

[0055] In one embodiment, the bilateral supraorbital electrode 100 illustrated in Figs. 2- 3A is stimulated at a stimulus frequency between about 20 Hz and about 300 Hz, at a pulse duration between 50 microseconds (psec) and 250 psec, at an output current density of less than 25 mA / cm2and an output charge density of less than 10pCoulomb / cm2at the cerebral cortex for at least one-half to one hour per day. In general, the stimulation would yield no or negligiblecharge densities at the cerebral cortex. Tn some cases, stimulation can be provided for less than one-half hour per day. Those of skill in the art will recognize that one or more of the above parameters can be used as a border of a range of parameters.

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

[0057] In various embodiments, the stimulation is delivered at a specific pulse width or range of pulse widths (or pulse duration). The stimulation can be set to deliver pulse widths in any range within a lower limit of about 10 microseconds and an upper limit of about 3 seconds. In various embodiments, the stimulation can be set to deliver pulse widths in the range greater than and / or less than one or more of 50 ps, 60 ps, 70 ps, 80 ps, 90 ps, 100 ps, 125 ps, 150 ps, 175 ps, 200 ps, 225 ps, 250 ps, up to 500 ps. Those of skill in the art will recognized that one or more of the above times can be used as a border of a range of pulse widths.

[0058] In some embodiments, the stimulation amplitude is delivered as a voltage or current controlled stimulation. In other embodiments it can be delivered as a capacitive discharge. In various embodiments, the current amplitude can be in any range within a lower limit of about 300 pA and an upper limit of about 30mA-35mA, depending on the surface area of the electrodes, inter-electrode distance, the branch(es) stimulated, and the modeling data as described above.. In various embodiments, the amplitude can be in a range greater than and / or less than one or more of 50pA, 75 pA, 100 pA, 125 pA, 150 pA, 175 pA, 200 pA, 225 pA, 250 pA, 275 pA, 300 pA, 325 pA, 350 pA, 375 pA, 400 pA, 425 pA, 450 pA, 475 pA, 500 pA, 525 pA, 550 pA, 575 pA, 600 pA, 625 pA, 650 pA, 675 pA, 700 pA, 725 pA, 850 pA, 875 pA, 900 pA, 925 pA, 950 pA, 975 pA, 1 mA, 2 mA, 3 mA, 4 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, 10 mA, 11mA, 12mA, 13mA, 14mA, 15mA, 16mA, 17mA, 18mA, 19mA and 20 mA. Those ofskill in the art will recognize that one or more of the above amplitudes can be used as a border of a range of amplitudes.

[0059] In various embodiments, the stimulation can be delivered at one or more frequencies, or within a range of frequencies. The stimulation can be set to be delivered at frequencies in any range within an upper limit of about 500 Hz and a lower limit of about 10 Hz. In various embodiments, the stimulation can be set to be delivered at frequencies less than, and / or greater 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 stimulation can be set to be delivered at frequencies greater than, and / or less than, one or more of 20Hz, 30Hz, 40Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 125 Hz, 150 Hz, up to 300 Hz. Those of skill in the art will recognize that one or more of the above frequencies can be used as a border of a range of frequencies.

[0060] In various embodiments, the stimulation is delivered at a specific duty cycle or range of duty cycles within a range from 100% down to about 5%. In various embodiments, the stimulation can be set to be delivered at a duty cycle in the range greater than 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, to ensure preservation of the nerve, a duty cycle of 10% to 50% may be preferable. In some embodiments, duty cycles up to 100% may be useful in particular circumstances. Those of skill in the art will recognize that one or more of the above percentages can be used as a border of a range of duty cycles.

[0061] In other embodiments, different values of the operational parameters may be used. In one embodiment, the values of the operational parameters are selected such that a patient will experience a stimulation sensation, such as a mild tingling over the forehead and scalp without being in discomfort or in pain. The neurostimulation parameters are important factors in the treatment method. In one embodiment, the values of the operational parameters are selected to minimize skin irritation, burns, undesired effects on the brain and / or the ophthalmic nerves. In one embodiment, the method of selecting operational parameters comprises evaluating variables such as the configuration and size of the electrode, the pulse duration, the electrode current, the duty cycle and the stimulation frequency, each of which are important factors in ensuring that the total charge, the charge density, and charge per phase are well within accepted safety limits for the skin, nerve and brain. For example, to minimize skin irritation, it is not sufficient to merely consider the total current, but the current density needs to be defined. Additionally, it isimportant to select the electrical stimulation parameters, electrode design, and inter-electrode distance, such that the electrical stimulation zone includes the ophthalmic nerve (approximately 3 -4mm deep), or other target nerve, while preventing or minimizing current penetration beneath the skull bone.

[0062] The stimulation is carried out at the above-described values of the operational parameters. These values may vary according to the treatment of interest; however, the systems and devices disclosed herein stimulate at parameters where current penetration below the surface of the skull and / or into the brain is prevented or minimized.

[0063] In some embodiments, the use of external electrodes for stimulation of the trigeminal nerve may identify individuals who are likely to derive therapeutic benefit from a minimally invasive system in addition to the optimal specific locations and parameters of stimulation based on person-to-person variability. Various neurodiagnostic, imaging, or cutaneous nerve mapping methods may be able to delineate differences in individual anatomy to optimize stimulation for efficacy and / or safety. Furthermore, the use of a minimally invasive system may allow screening and identification of those individuals who are likely to derive benefit from implantable systems, such as deep brain stimulation. This can be conceptualized as linking the three approaches as stage I (external TNS of the trigeminal nerve), stage II (implanted TNS of the superficial trigeminal nerve), and stage III (deep brain stimulation), such that stage I can screen for stage II, and stage II for stage III. By monitoring a patient for evidence of useful therapeutic effect, such as by reduction in the severity of symptoms, the results of treatment at one stage may be used to judge the likely effect of treatment with a more invasive treatment from a higher stage.

[0064] According to another aspect of the present disclosure, a method of evaluating the use of external nerve stimulation for treatment of a neuropsychiatric or neurological disorder in a patient is disclosed herein. Referring to Fig. 6, the method may include applying a cutaneous system 605 for stimulation of the trigeminal nerve, the occipital nerve, the vagus nerve, the facial nerve, and / or any branch thereof to the patient and monitoring the patient for at least one of evidence of a useful therapeutic response or evidence of tolerability of external nerve stimulation treatment. In one or more embodiments, monitoring the patient for evidence of a useful therapeutic response includes sensing a change in CBF via a fNIRS device 610.

[0065] fNIRS is a well-known technique for measuring hemoglobin flow inside a brain using near-infrared light, and is therefore not shown in detail herein The technique is non-invasive and requires little restraint of the patient to be measured, enabling comparatively simple measurement without test environment selection. This technique is a type of functional neuroimaging technology that offers a relatively non-invasive, safe, portable, and low-cost method of indirect and direct monitoring of brain activity. By measuring changes in nearinfrared light, fNIRS allows researchers to monitor blood flow in the front part of the brain.

[0066] More technically, fNIRS allows functional imaging of brain activity (or activation) through monitoring of blood oxygenation and blood volume in the pre-frontal cortex. It does this by measuring changes in the concentration of oxy- and deoxy-hemoglobin (Hb) as well as the changes in the redox state of cytochrome-c-oxidase (Cyt-Ox) by their different specific spectra in the near-infrared range between 700-1000 nm.

[0067] In operation, the fNIRS device 610 is typically attached to the patient’s forehead and can be monitored either connected directly to a computer 615, or a portable computing device 615 (also referred to herein as a control device 615 or a control unit 615) that records the patient’s data as he or she engages in specific cognitive tasks. The data is recorded and then analyzed for changes in the blood flow or its oxygenation levels of the brain before, during, and after the task. Hypotheses can then be tested about how brain activity is being affected by certain tasks, behaviors, or treatments.

[0068] To measure the changes in blood flow in the brain, fNIRS uses light sensors to detect oxygenated blood. With fNIRS, an array of light sensors called “sources” and “detectors” are used. Sources send light into the brain, and detectors detect the light signal sent from a source to measure changes in blood flow.

[0069] Increased activity in the brain will cause increased blood flow to a particular brain region. When blood is flowing to an active brain region, it carries oxygen molecules with it. fNIRS measures these changes in oxygenated blood, and can tell if or when a brain region is active during a particular task. fNIRS is called “near-infrared” because oxygenated blood is red or near-infrared in color.

[0070] According to one or more embodiments, the CBF of a patient is measured at a plurality of brain locations. For example, the CBF can be measured at a plurality of channel locations, including in the pre-frontal region, the right temporal lobe, the left temporal lobe, the left parietal lobe, and the right parietal lobe, the left occipital lobe, and the right occipital lobe

[0071] Tn some embodiments, CBF is first measured during cognitive task execution (e.g., playing video games) to establish a baseline for subsequent CBF measurements. Based on the 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 and simultaneously, the patient’s CBF can be measured to determine whether the stimulation is increasing or decreasing CBF to certain parts of the brain.

[0072] In one or more embodiments, responders to external nerve stimulation are identified using fNIRS technology. In an exemplary embodiment, fNIRS technology is used to verify if a patient responds to eTNS. In one or more embodiments, electrical signals are applied to the trigeminal nerve, CBF is measured, and a change in CBF is determined. A change in CBF indicates that the patient is responding to eTNS treatment. In some embodiments, the change in CBF comprises an increase in CBF to the right pre-frontal cortex or a decrease in CBF to the right temporal lobe or the left temporal lobe. In one embodiment, the change in CBF comprises an increase in CBF to the right pre-frontal cortex and a decrease in CBF to the right temporal lobe or the left temporal lobe.

[0073] In certain embodiments, a control device 615 or a control unit 615 may be used to command the electrode assembly 605 to deliver stimulation, after which measurements are taken by a fNIRS device 610 to verify the effects or progress of the stimulation. In several embodiments, the control device 615 is capable of performing a number of advantageous operations in connection with the present invention. In particular, the control device 615 is able to specify and set operational parameters in the cutaneous electrode assembly 605 to adapt the function of the device to meet the patient’s needs, upload or receive data, or command the electrode assembly 605 to perform specific actions or change modes as desired by a user operating the electrode assembly 605.

[0074] In an exemplary embodiment, the control device 615 is equipped to receive external measurements from other devices, including a fNIRS device 610. For example, a fNIRS device 610 may upload measurements to the control device 615 either periodically or in realtime. In some embodiments, the software operating program of the control device 615 includes tools for the analysis and processing of recorded fNIRS data to assist a physician in developing optimized operational parameters for each specific patient.

[0075] Tn several embodiments, the control device 615 is adapted to drive one or more electrodes to apply a current to the site capable of inducing an increase or a decrease in CBF of the patient. In some embodiments, the control device 615 configures the stimulation so as to cause an increase or decrease in CBF of the patient, so as to treat the patient.

[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 operation system such as Microsoft Windows®, Linux®, Unix®, or Apple OS®. It is also envisioned that a dedicated programmer apparatus with a custom software package (which may not use a standard operating system) could be developed. The control device 615 can also be embodied into a specialized microchip, which can reside on a device which is plugged into a computer, for example, via a USB port.

[0077] Advantageously, the present invention provides for use of electrical stimulation to produce changes in CBF to treat neuropsychiatric and neurological disorders. The stimulation pattern may be beneficially changed to enhance blood flow in neural pathways or alter CBF. In an embodiment, automatic measurements are taken, measurements are recorded, and later transferred to a control device 615 via wireless telemetry. These measurement may be used by a clinician to tailor therapy to the specific patient being treated.

[0078] Simulation studies may be performed to assess the effect of different simulation operational parameters. For example, the control device 615 applies stimulation as programmed within a preset range of allowed operational parameters (pulse amplitude, pulse width, etc.), the operational parameters are changed or adjusted, and the effect of the change monitored. Accordingly, the present invention can be realized as a brain modulation system that treats disease states by providing a stimulation signal that has operational parameters, such as intensity, that may be varied. It is contemplated that the operational parameters of the stimulation signal (e.g, the nerve branch(es) targeted, frequency, amplitude, pulse width, duty cycle, duration, and / or waveform) provided by the therapy can be adjusted to optimize treatment of a patient.Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), Autism, and Autism Spectrum Disorders (ASP)

[0079] Without wishing to be bound by any particular theory, neuroimaging studies have implicated dysfunction in several brain regions in the pathophysiology and treatment response of these disorders, which commonly arise early in life. As defined by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 4th edition, 2000), attention deficit / hyperactivity disorder (ADHD) is marked by symptoms of inattention, hyperactivity, and impulsivity, while the diagnosis of ADD (now formally ADHD / inattentive type) lacks the hyperactivity and impulsivity features. In ADD and ADHD, prior research has found 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 S G, et al. 2006 J Child Psychol Psychiatry. 47(10):1051-62). As defined by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 4th edition, 2000), autism (also termed autistic disorder) is characterized by pervasive deficits in development in areas such as reciprocal social interaction skills, communication skills, or the presence of stereotyped behavior, interests, and activities. ASD includes related diagnoses such as Asperger’s Syndrome, in which most features are present but not a delay in language development. Regions implicated in Autism and ASD include ACC, frontal cortex, temporal cortex, and parietal cortex (e.g., Hall G B, Szechtman H, Nahmias C. 2003. Am J Psychiatry. 160(8): 1439-41; McAlonan G M, et al. 2005. Brain. 128(Pt 2):268- 76; Cherkasova M V, Hechtman L. 2009. Can J Psychiatry. 54(10):651-64; Konrad K, et al. 2006. Biol Psychiatry. 59(7):643-51.) Patients with ADHD are generally unable to increase prefrontal cortex blood flow in response to tasks that require cognitive focus.

[0080] According to one or more embodiments, fNIRS data of a healthy adult male was taken during a verbal fluency test at baseline (pre-stimulation) in Fig. 7 and during eTNS or stimulation in Fig. 8. In Fig. 8, there is a dramatic increase in oxygenated blood flow in channels 36, 46, and 47 in the pre-frontal cortex with use of eTNS. Conversely, there was a decrease in temporal blood flow in the right temporal lobe and the left temporal lobe with use of eTNS. These findings are consistent with previous positron emission tomography (PET) scan data collected by Applicant.

[0081] Based on these findings and without wishing to be bound by theory, it can be hypothesized that patients who do not respond to eTNS will not exhibit a dramatic rise in prefrontal cortex blood flow on fNIRS. Alternatively, in those patients that do respond to eTNS, adramatic rise in blood flow in these channels will be observed as soon as the stimulation is turned on.

[0082] Those skilled in the art will appreciate that various adaptations and modifications of the above described preferred embodiments may be configured without departing from the scope and spirit of this disclosure. Stimulation of the target nerve may be accomplished by cutaneous application of energy in many forms, such as magnetic or ultrasonic. Therefore, it is to be understood that the subject matter of this disclosure may be practiced other than as specifically described herein.

Claims

WHAT IS CLAIMED IS:

1. A system for identifying and treating responders to external nerve stimulation, the system comprising: a pulse generator; a cutaneous electrode assembly in electrical communication with the pulse generator, the assembly comprising: a first electrode comprising at least one contact configured for cutaneous placement at a first region of a patient’s face, a second electrode comprising at least one contact configured for cutaneous placement at a second region of the patient’s face, wherein the first electrode and second electrode are each configured to contact a portion of the patient’s face overlying the cutaneous distribution of the trigeminal nerve, the occipital nerve, the vagus nerve, the facial nerve, and / or any branch thereof; a functional near-infrared spectroscopy (fNIRS) device configured to measure cerebral blood flow (CBF) at targeted brain areas and to generate an output signal corresponding to CBF in the targeted brain areas; and a control device configured to process the output signal to produce visual feedback corresponding to the CBF in the targeted brain areas.

2. The system of claim 1, wherein the first electrode and the second electrode are configured to contact a portion of the patient’s face overlying the cutaneous distribution of a same branch of the ophthalmic nerve, the infraorbital nerve, the mentalis nerve, the occipital nerve, the vagus nerve, or the facial nerve.

3. The system of claim 1, wherein the first electrode and the second electrode are configured to contact a portion of the patient’s face overlying the cutaneous distribution of a different branch of the ophthalmic nerve, the infraorbital nerve, the mentalis nerve, the occipital nerve, the vagus nerve, or the facial nerve.

4. The system of claim 1 , further comprising a wire operably connecting the pulse generator and the cutaneous electrode assembly.

5. The system of claim 1, further comprising a regulating device configured to regulate the maximum charge balanced output current below approximately 30-50 mA.

6. The system of claim 1, wherein the pulse generator is configured to apply electrical signals at a frequency between approximately 20 and 300 Hertz, at a pulse duration between approximately 50 and 500 microseconds, at an output current density of not greater than approximately 25 mA / cm2and an output charge density of not greater than approximately 10 microCoulomb / cm2at the cerebral cortex.

7. A system for identifying and treating responders to external nerve stimulation, the system comprising: a neurostimulator; a cutaneous electrode assembly comprising: a first pair of contacts configured for placement on a first region of a patient’s face; a second pair of contacts configured for placement on a second region of the patient’s face; and an insulating connection region connecting the first pair of contacts and the second pair of contacts, wherein the first pair of contacts and the second pair of contacts are configured to contact a portion of the patient’s face overlying the cutaneous distribution of at least one branch of the ophthalmic nerve, the infraorbital nerve, the mentalis nerve, the occipital nerve, the vagus nerve, or the facial nerve; a functional near-infrared spectroscopy (fNIRS) device configured to measure cerebral blood flow (CBF) at targeted brain areas and to generate an output signal corresponding to CBF in the targeted brain areas; and a control device configured to process the output signal to produce visual feedback corresponding to the CBF in the targeted brain areas.

8. The system of claim 7, further comprising a cable and lead wires operably connecting the neurostimulator and the cutaneous electrode assembly.

9. The system of claim 7, further comprising a regulation device configured to regulate current output to minimize or prevent current penetration below the surface of the skull bone.

10. The system of claim 7, further comprising a retainer element configured to secure the cutaneous electrode assembly to the patient’s forehead.

11. A method for evaluating the use of external nerve stimulation for treatment of a neuropsychiatric or neurological disorder, comprising: contacting a first region of a patient’s face with a cutaneous electrode assembly, the cutaneous electrode assembly comprising: a first electrode comprising at least one contact configured for cutaneous placement at a first region of the patient’s face, wherein the first electrode is configured to contact a portion of the patient’s face overlying the cutaneous distribution of at least one branch of the ophthalmic nerve, infraorbital nerve, mentalis nerve, occipital nerve, vagus nerve, or facial nerve, applying electrical signals to the cutaneous electrode assembly at specified operational parameters to treat the neuropsychiatric or neurological disorder; measuring, with a functional near-infrared spectroscopy (fNIRS) device, cerebral blood flow (CBF) at targeted brain areas; and determining that the CBF has changed at the targeted brain areas.

12. The method of claim 11, wherein the targeted brain areas comprises one or more of the pre-frontal cortex, right temporal lobe, or left temporal lobe.

13. The method of claim 12, wherein determining that the CBF has changed at the targeted brain areas comprises determining that the CBF has increased in the right pre-frontal cortex and the CBF has decreased in the right temporal lobe and the left temporal lobe.

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

15. The method of claim 14, wherein the operational parameters comprise one or more of a branch of the ophthalmic nerve, infraorbital nerve, mentalis nerve, occipital nerve, vagus nerve, or facial nerve, a frequency of an electrical signal, an amplitude of an electrical signal, a pulse width of an electrical signal, a duty cycle of an electrical signal, or a wave form of an electrical signal.

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

17. The method of claim 16, wherein the behavioral disorder comprises attention deficit hyperactivity disorder (ADHD).

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

19. The method of claim 11, wherein the step of applying electrical signals comprises applying electrical signals at a frequency between approximately 20 and 300 Hertz, at a current of 0.05 to 5 milliamperes (mA) and at a pulse duration of less than or equal to 500 microseconds.

20. The method of claim 19, wherein the step of applying electrical signals comprises applying electrical signals at a frequency between approximately 20 and 300 Hertz, at a pulse duration between approximately 50 and 500 microseconds, at an output current density of not greater than approximately 25 mA / cm2and an output charge density of not greater than approximately 10 microCoulomb / cm2at the cerebral cortex.

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