Trigeminal nerve stimulation as treatment for neurodevelopmental disorders and for increasing cognitive performance

Abstract

The present disclosure relates to methods used for the treatment of neurodevelopmental disorders and for increasing the cognitive performance of a patient without a neurodevelopmental disorder via stimulation of the superficial elements of the trigeminal nerve. More specifically, cutaneous methods of stimulation of the superficial branches of the trigeminal nerve located extracranially in the face, namely the supraorbital, supratrochlear, infraorbital, auriculotemporal, zygomaticotemporal, zygomaticoorbital, zygomaticofacial, infraorbital, nasal and mentalis nerves (also referred to collectively as the superficial trigeminal nerve) are disclosed herein.

Description

PCT / US25 / 12424 21 January 2025 (21.01.2025)TRIGEMINAL NERVE STIMULATION AS TREATMENT FOR NEURODEVELOPMENTAL DISORDERS AND FOR INCREASING COGNITIVE PERFORMANCETECHNICAL FIELD

[0001] The present disclosure generally relates to cutaneous neuromodulation devices and systems and methods of using the same to treat neurodevel opmental disorders such as dyslexia and to increase cognitive performance in patients without neurodevelopmental disorders. More specifically, methods for the treatment of neurodevelopment disorders, such as dyslexia, via external trigeminal nerve stimulation are provided. Devices and systems configured for stimulation of superficial sensory branches of cranial nerves and their methods of application are also described.BACKGROUND

[0002] Neurodevelopmental disorders, also known as developmental disabilities, are a group of conditions associated primarily with neurologic function and the brain. About 1 in 6 children in the United States have a developmental disability of developmental delay.

[0003] Neurodevelopmental disorders are a heterogeneous group of conditions but include dyslexia, autism, learning disabilities, cerebral palsy, attention deficit hyperactivity disorder (ADHD), and other conditions. For most of these conditions, the only interventions are behavioral and talk-therapy based. Pharmaceutical interventions can be used to help manage symptoms, but do not address the core symptoms of the disorder.

[0004] The trigeminal nerve is the fifth cranial nerve, and the largest and most complex of all the cranial nerves, with distal connections to the internal carotid artery that help regulate blood flow in the cortex, as well as connections in the brainstem to the vagus nerve and connections to the midbrain, thalamus, and cortex. External trigeminal nerve stimulation (eTNS) is a therapeutic modality where patients apply a wearable patch to their face to stimulate the trigeminal nerve. Previous work has shown that electrical stimulation of the trigeminal nerve acutely increases regional cerebral blood flow (rCBF) in the right prefrontal cortex. It has also been demonstrated that nightly therapy with eTNS increases electrical activity across the frequency spectrum in the F4 electrode on quantitative EEG (qEEG), even when the device is not in use. Further, a doubleblind randomized controlled trial of children with ADHD demonstrated that the increase inPCT / US25 / 12424 21 January 2025 (21.01.2025)qEEG power measured by the F4 electrode could be correlated with clinical improvement in ADHD symptoms. Importantly, there is a connection between ADHD, dyslexia, learning disabilities, and autism that is not fully understood, with these conditions often overlapping and co-occurring in the same individuals. Accordingly, there is a need for improved methods of treating neurodevelopmental disorders.SUMMARY

[0005] One aspect of the subject matter of the present disclosure addresses the aforementioned needs by providing a method of treating neurodevelopmental disorders and systems and devices configured to stimulate the ophthalmic (supraorbital), infraorbital and mentalis branch(es) of the trigeminal nerve, and more specifically by providing a method of treating neurodevelopmental disorders using eTNS.

[0006] In some embodiments, the present disclosure is directed to a method of treating a neurodevelopmental disorder in a patient, the method including: attaching an electrode assembly cutaneously to the patient so as to contact the skin surface overlying the cutaneous distribution of at least one of the branches of the trigeminal nerve; and applying adjustable electrical signals to at least one of the patient’s trigeminal nerves through the at least one electrode to stimulate or activate the right prefrontal cortex of the patient.

[0007] In one or more embodiments, applying electrical signals to the electrode assembly includes applying electrical signals at a frequency between 20 and 300 Hertz, at a pulse duration between 50 and 250 microseconds, at an output current density of not greater than 25 mA / cm2and an output charge density of not greater than 10 micro Coulomb / cm2at the cerebral cortex.

[0008] In certain embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over a supraorbital nerve. In various embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over an auriculotemporal nerve. In several embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over a zygomaticofacial nerve.

[0009] In some embodiments, the neurodevelopmental disorder is dyslexia. In other embodiments, the neurodevelopmental disorder is one or more of dyslexia, autism, learning disabilities, cerebral palsy, or ADHD.PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0010] In one or more embodiments, the electrical signals are applied while the patient is performing a cognitive task, such as reading, inductive reasoning, practicing making connections, backward thinking, sequencing and grouping, practicing observation and description, practicing pattern recognition, problem solving, practicing memory retrieval, writing, creative thinking, drawing, practicing reversibility, socializing, practicing procedural knowledge, singing, doing mathematics, using deductive reasoning, instrumental learning, playing games, planning, cooking, or practicing manual dexterity. In an exemplary embodiment, the electrical signals are applied while the patient is reading or writing.

[0011] In certain embodiments, the electrical signals are applied daily to the patient. In some embodiments, the electrical signals are applied while the patient is asleep or during the evening.

[0012] Another aspect of the subject matter of the present disclosure includes providing a method of increasing cognitive performance in a patient by stimulating the ophthalmic (supraorbital), infraorbital and mentalis branch(es) of the trigeminal nerve.

[0013] In some embodiments, the present disclosure is directed to a method of increasing cognitive performance in a patient without a neurodevelopmental disorder, the method including: attaching an electrode assembly cutaneously to the patient so as to contact the skin surface overlying the cutaneous distribution of at least one of the branches of the trigeminal nerve; and applying adjustable electrical signals to at least one of the patient’s trigeminal nerves through the at least one electrode to stimulate or activate the right prefrontal cortex of the patient.

[0014] In one or more embodiments, applying electrical signals to the electrode assembly includes applying electrical signals at a frequency between 20 and 300 Hertz, at a pulse duration between 50 and 250 microseconds, at an output current density of not greater than 25 mA / cm2and an output charge density of not greater than 10 micro Coulomb / cm2at the cerebral cortex.

[0015] In certain embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over a supraorbital nerve. In various embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over an auriculotemporal nerve. In several embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over a zygomaticofacial nerve.

[0016] In one or more embodiments, the electrical signals are applied while the patient is performing a cognitive task, such as reading, inductive reasoning, practicing makingPCT / US25 / 12424 21 January 2025 (21.01.2025)connections, backward thinking, sequencing and grouping, practicing observation and description, practicing pattern recognition, problem solving, practicing memory retrieval, writing, creative thinking, drawing, practicing reversibility, socializing, practicing procedural knowledge, singing, doing mathematics, using deductive reasoning, instrumental learning, playing games, planning, cooking, or practicing manual dexterity. In an exemplary embodiment, the electrical signals are applied while the patient is reading or writing.

[0017] In certain embodiments, the electrical signals are applied daily to the patient. In some embodiments, the electrical signals are applied while the patient is asleep or during the evening.

[0018] Yet another aspect of the subject matter of the present disclosure includes providing a method of improving the accuracy and fluency of reading in a patient with dyslexia by trigeminal nerve stimulation. In one or more embodiments, the method includes stimulating the ophthalmic (supraorbital), infraorbital and / or mentalis branch(es) of the trigeminal nerve. In some embodiments, the method includes attaching an electrode assembly cutaneously to the patient so as to contact the skin surface overlying the cutaneous distribution of at least one of the branches of the trigeminal nerve; and applying adjustable electrical signals to at least one of the patient’s trigeminal nerves through the at least one electrode to stimulate or activate the right prefrontal cortex of the patient.

[0019] In one or more embodiments, applying electrical signals to the electrode assembly includes applying electrical signals at a frequency between 20 and 300 Hertz, at a pulse duration between 50 and 250 microseconds, at an output current density of not greater than 25 mA / cm2and an output charge density of not greater than 10 micro Coulomb / cm2at the cerebral cortex.

[0020] In certain embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over a supraorbital nerve. In various embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over an auriculotemporal nerve. In several embodiments, the electrode assembly is attached to the patient so as to contact the skin surface over a zygomaticofacial nerve.

[0021] In various embodiments, the electrical signals are applied daily to the patient. In several embodiments, the electrical signals are applied while the patient is asleep or during the evening.PCT / US25 / 12424 21 January 2025 (21.01.2025)BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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:

[0023] Figs. 1A 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;

[0024] Fig. 2 shows an embodiment of a system including an electrode assembly provided according to embodiments of the present disclosure;

[0025] Fig. 3 A depicts an enlarged view of the electrode assembly of Fig. 2;

[0026] Fig. 3B depicts representative dimensions of the electrode assembly of Fig. 3 A;

[0027] Figs. 4A-4C depict various embodiments of the cutaneous electrode assembly of Fig. 2;

[0028] Fig. 5 shows another embodiment of an electrode assembly that may be used with the system of Fig. 2;

[0029] Fig. 6 summarizes one embodiment of current, charge, current density, and charge density parameters for a subject exposed to cutaneous stimulation of the supraorbital nerve according to embodiments of the present disclosure;

[0030] Fig. 7 is a writing sample of a patient before trigeminal nerve stimulation according to embodiments of the present disclosure;

[0031] Fig. 8 is a writing sample of a patient after trigeminal nerve stimulation according to embodiments of the present disclosure;

[0032] Fig. 9 shows the GORT-4™ results of a patient before and after trigeminal nerve stimulation according to embodiments of the present disclosure; and

[0033] Fig. 10 provides a summary of the GORT-4™ results in Fig. 9 according to embodiments of the present disclosure.DETAILED DESCRIPTION

[0034] The present disclosure relates to methods, devices and systems used for the treatment of neurodevel opmental disorders such as dyslexia. More specifically, cutaneous methods of stimulation of the superficial branches of the trigeminal nerve located extracraniallyPCT / US25 / 12424 21 January 2025 (21.01.2025)in the face, namely the supraorbital, supratrochlear, infraorbital, auriculotemporal, zygomaticotemporal, zygomaticoorbital, zygomaticofacial, infratrochlear, nasal and mentalis nerves (also referred to collectively as the superficial trigeminal nerve) are disclosed herein. Methods for the treatment of neurodevelopmental disorders by eTNS (external trigeminal nerve stimulation) are also provided. Systems and devices configured for therapeutic stimulation of the trigeminal nerve or branches thereof, such as the superficial trigeminal nerve, and their methods of application are also described. The unique anatomy of the trigeminal nerve, and its direct and indirect connections with key areas of the brainstem, thalamus, amygdala, insula, anterior cingulate and other cortical and subcortical areas involved with sensory processing, attention, emotion, cognition, and autonomic function, may allow the use of external stimulation for a variety of neurodevelopmental conditions in which stimulation may be desirable. The methods, systems and devices described herein may be noninvasive or minimally invasive.

[0035] Some brain stimulation methods aim to generate currents in large volumes of the cortex and treat the brain as a bulk conductor, for example, ECT (electroconvulsive therapy) at the whole-lobe level and rTMS (repetitive transcranial magnetic stimulation) at the large regional level (i.e., dorsolateral prefrontal cortex). Additionally, deep brain stimulation is generally predicated on stimulation of small but regional volumes that lead to discharges in a very large number of cells. The systems, devices and methods of the present disclosure send minimal, if any, current into the brain; instead, signals are sent into the brain in order to modify the activity of relevant neuroanatomical structures. Without wishing to be bound by any particular theory, the electrical pulses generate signals in the cutaneous branches of the trigeminal nerve and the electric fields are generally confined to the skin tissue and there is minimal, if any, leakage into the brain. These electrical pulses trigger a cascade of change in neuronal signaling events that involve very limited and precise recruitment of specific networks of neurons. Thus, the systems, devices and methods as disclosed herein utilize the brain's existing infrastructure to transmit signals to the targets of interest. In the context of this disclosure, minimal current penetration means (1) a charge density of approximately 0 uC / cm2at the cerebral cortex, or (2) calculated, measured, or modeled charge densities below the following thresholds at the cerebral cortex: (a) at currents, charge densities, or charge per phase not likely to cause direct activation of pyramidal neurons and axons; and (b) to prevent brain injury, a charge density of less than lOpC / cm2in one embodiment, and, in other embodiments, a charge density of less than 1.0PCT / US25 / 12424 21 January 2025 (21.01.2025)pC / cm2and in some embodiments, a charge density of less than 0.001 to 0.1 gC / cm2, and at combinations of charge density and charge per phase not known to cause brain injury. In some embodiments, a lower charge density may be used when the central nervous system of an individual patient is sufficiently sensitive to lower levels of stimulation that the lower level will still permit clinical benefit to accrue.

[0036] The following description is provided to enable any person skilled in the art to make and use the subject matter of this disclosure. Various modifications, however, will remain readily apparent to those skilled in the art, since the general principles of the disclosed subject matter have been defined herein specifically to describe: (1) methods of treating neurodevelopmental disorders by trigeminal nerve stimulation, (2) a system and an electrode assembly configured for cutaneous trigeminal nerve stimulation; and (3) methods of increasing cognitive performance in a patient without a neurodevelopmental disorder by trigeminal nerve stimulation.

[0037] With reference to Figs. 1A and IB, the trigeminal nerve is the largest cranial nerve, and has extensive connections with brainstem and other brain structures. The trigeminal nerve 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.

[0038] 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 thePCT / US25 / 12424 21 January 2025 (21.01.2025)ophthalmic nerve. Other sensory branches, including the zygomaticofacial, zygomaticoorbital, zygomaticotemporal, and auriculotemporal, arise from other foramina.

[0039] 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.

[0040] 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.

[0041] 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 axonal projections 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.

[0042] While not wishing to be bound by any particular theory, 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 neurodevelopmental disorders. Thus, cutaneous stimulation of the trigeminal nerve could be effective in the treatment of neurodevelopmental disorders.

[0043] The present disclosure is directed to the use and application of a noninvasive neurostimulation modality to treat the core symptoms of neurodevelopmental disorders including dyslexia, autism, learning disabilities, cerebral palsy, and ADHD. Neurodevelopmental disorders are a group of conditions that affect how the brain functions and develops, causing difficulties in a person’s social, cognitive, and emotional functioning.PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0044] In an exemplary embodiment, the neurodegenerative disorder that is treated by eTNS is dyslexia. Dyslexia or reading developmental disorder (RDD) is a brain-based difficulty in acquiring fluent reading skills and affects roughly 10-15% of the population. Dyslexia also affects reading accuracy, reading comprehension, spelling skills, and math skills. There are numerous definitions based on the number of symptoms from normal to severe or profound. Dyslexia is truly a spectrum of symptoms like autism. Treatments vary as much as the symptoms, but most include different types of reading instruction.

[0045] In general, dyslexia occurs when an individual has significant difficulty with speed and accuracy of word decoding. Comprehension of text and spelling are also affected. The diagnosis of dyslexia involves the use of reading tests, but the continuum of reading performance suggests that any cutoff point is arbitrary. The IQ score does not play a role in the diagnosis of dyslexia. The cognitive difficulties of dyslexics include problems with speech perception, basic sound recognition, and manipulation in a language, language memory, and learning the sounds of letters.

[0046] Dyslexia is a neurological condition with a genetic basis. There are abnormalities in the brains of dyslexic individuals. There are also differences in the electrophysiological and structural characteristics of the brains of dyslexics.

[0047] As used herein, “dyslexia” is a specific learning disability that primarily affects the skills involved in accurate and fluent word reading and spelling. The term “treating” or the like includes delaying, alleviating, mitigating, or reducing the intensity, progression, or worsening of one or more attendant symptoms of a disorder or condition and / or alleviating, mitigating, or impeding one or more causes of a disorder or condition. Treatment under the present disclosure may be a preventative treatment, prophylactic treatment, remission of treating or ameliorating treatment.

[0048] In one embodiment, the present disclosure is directed to treating and / or improving the symptoms of neurodevelopmental disorders in patients in need thereof. A patient is any person who is under medical care or treatment, and may be an adult or a child. In one or more embodiments, the neurodevelopment disorder is dyslexia.

[0049] In non-dyslexic individuals, the left temporal / occipital lobe is enlarged relative to the right and is responsible for language, reading, and speech. Neuroimaging studies show thatPCT / US25 / 12424 21 January 2025 (21.01.2025)these areas are activated during reading tasks, and individuals who suffer strokes in these regions have problems with these types of activities.

[0050] In contrast, individuals with dyslexia do not activate their left temporal / occipital region to the same degree as non-dyslexics when performing these same tasks. They also tend to lack the normal brain asymmetry. Instead, dyslexics appear to compensate by using different parts of their brain for reading. Specifically, dyslexic individuals have been shown to activate the right prefrontal cortex during reading tasks, and the degree of right prefrontal cortex activation has been positively correlated with better long-term reading outcomes. Therefore, activating the right prefrontal cortex by eTNS to treat dyslexia is a non-intuitive mechanism because this is not activating the brain regions typically associated with reading and language processing. Instead, eTNS acts by augmenting activation of the right prefrontal cortex brain regions that dyslexic brains use as an alternative.

[0051] In other words, left occipital cortex function is impaired in patients with dyslexia. To compensate, patients rely on the right prefrontal cortex during reading tasks. eTNS acts by facilitating this compensatory mechanism. According to various aspects of the present disclosure, eTNS increases activation of the right prefrontal cortex to improve reading accuracy and fluency, for example, in patients with dyslexia. Use of eTNS activates the right prefrontal cortex both acutely and over the long term.

[0052] Patients with dyslexia who successfully learned to read tended to activate their rPFC during reading tasks, while those who were unsuccessful did not. Use of eTNS happens to stimulate a brain region associated with successful outcomes in dyslexia.

[0053] In various embodiments, patients use eTNS during cognitive tasks, such as reading and writing, as a means to boost right prefrontal cortex activity and achieve improved long-term outcomes in cognitive tasks. In some embodiments, patients use eTNS at night while sleeping to activate the right prefrontal cortex. Advantageously, eTNS can be used as a tool for improving the core symptoms of neurodevelopment disorders (such as dyslexia) that is used on a daily or nightly basis for a set period of time and can also be used while the task is being performed under the theory that activation of the right prefrontal cortical brain region during the task will more strongly activate the relevant brain networks and more rapidly improve performance and retention than if eTNS was not being used.PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0054] In one or more embodiments, eTNS is used as a learning tool for cognitive enhancement in patients without neurodevelopment disorders who seek to more rapidly acquire complex cognitive and physical skills such as reading, writing, memorizing facts, and playing an instrument. Cognitive performance is a measure of how well a brain functions. Increased cognitive performance can be evidenced by improvement in memory, reasoning, and / or problemsolving skills. Stimulating the right prefrontal cortex advantageously enhances cognitive functions related to attention, decision-making, and working memory.

[0055] According to one aspect of the present disclosure, a method of treating neurodevelopmental disorders using eTNS is provided. Broadly speaking, the method of treating neurodevel opmental disorders by eTNS includes positioning external electrodes over or near at least one of the foramina or branches of the trigeminal nerve (Figs. 1A and IB), and stimulating the electrodes using a stimulator 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 the foramina 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 (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. 1 A, Foramen 2) or the mentalisPCT / US25 / 12424 21 January 2025 (21.01.2025)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.

[0056] In other embodiments, the method of treating neurodevelopmental disorders includes 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.

[0057] According to one aspect of the present disclosure, the method of treating neurodevelopmental disorders by eTNS includes 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 the brain, and / or the cranial nerves are minimized. In one embodiment, the method of selecting operational parameters includes 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 interelectrode 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.

[0058] 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 superficial branches of the trigeminal nerve and methods of using the same.PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0059] 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.

[0060] In one embodiment, as can be understood from Figs. 2-5, a system 200 for treatment of neurodevel opmental disorders via TNS 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. 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 non-portable pulse generator may be used. As shown in Fig. 2, the electrode assembly 100 is connectable 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 neurodevelopmental disorder according to a method as disclosed herein.

[0061] 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 belowPCT / US25 / 12424 21 January 2025 (21.01.2025)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 mA's, which result in currents which may penetrate the skull and which may not be well tolerated.

[0062] 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.

[0063] In some embodiments, the electrode assembly includes 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.

[0064] 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 includes a first upper contact 112a and a first lower contact 112b, while the second pair of contacts 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 insulative connection region 116. The electrode assembly 100 includes 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 including the four contact areas includes a buffered gel-like adhesive that provides good electrical conductivityPCT / US25 / 12424 21 January 2025 (21.01.2025)with minimum skin irritation, an example of such gel includes the commercially available hydrogels from AmGel Technologies (AmGel Technologies, Fallbrook, CA, USA).

[0065] 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.

[0066] 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 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 and second regions or right and left sides, as applicable, thereby reducing asymmetric stimulation and / or perceived asymmetric stimulation.

[0067] 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 toPCT / US25 / 12424 21 January 2025 (21.01.2025)stimulate the auriculotemporal and / or zygomaticofacial nerve. In other embodiments, two separate electrodes may be used to stimulate the auriculotemporal and / or zygomaticofacial nerve.

[0068] 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.

[0069] 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 for children and adults, males and females based on anatomical differences. In 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.PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0070] 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.

[0071] 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 includes 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.

[0072] 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.

[0073] According to one aspect of the present disclosure, there is provided a method of treatment of neurodevel opmental disorders using the electrode assembly 100, as described above. In one embodiment, the method of treating neurodevelopmental disorders 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 the operational parameters as disclosed herein.

[0074] According to another aspect of the present disclosure, there is provided a method for increasing cognitive performance in a patient without a neurodevelopmental disorder using the electrode assembly 100, as described above. In one embodiment, the method of increasingPCT / US25 / 12424 21 January 2025 (21.01.2025)cognitive performance in a patient without a neurodevelopmental 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 the operational parameters as disclosed herein.

[0075] According to one aspect of the present disclosure, there is provided a method of treatment of neurodevelopmental disorders using an embodiment of the electrode assembly as described herein. In one embodiment, the method of treating neurodevelopmental disorders includes 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.

[0076] According to another aspect of the present disclosure, there is provided a method of increasing cognitive performance in a patient without a neurodevelopmental disorder using an embodiment of the electrode assembly as described herein. In one embodiment, the method of increasing cognitive performance in a patient without a neurodevelopmental disorder includes 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.

[0077] 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 / cm2 and an output charge density of less than lOp Coulomb / cm2 at the cerebral cortex for at least one-half to one hour per day. In general, the stimulation would yield no or negligible charge densities at the cerebral cortex. In 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.PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0078] 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 recognize that one or more of the above times can be used as a border of a range of pulse widths.

[0079] 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 of skill in the art will recognize that one or more of the above amplitudes can be used as a border of a range of amplitudes.

[0080] 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.

[0081] 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, thePCT / US25 / 12424 21 January 2025 (21.01.2025)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.

[0082] 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 is important 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.

[0083] The stimulation is carried out at the above-described values of the operational parameters. The values of the operational parameters are advantageously selected such that a patient will experience a stimulation sensation, such as mild tingling over the forehead and scalp, without causing the patient unbearable discomfort or pain. 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.

[0084] In some embodiments, an external device may be used to identify the location of the branch or branches of the trigeminal nerve that will be targeted in an individual patient forPCT / US25 / 12424 21 January 2025 (21.01.2025)stimulation by the implanted electrode assembly disclosed herein. The external device may be used for mapping and targeting the desired branch or branches of the trigeminal nerve and for identifying the individual stimulation parameters that are optimal for efficacy and safety. In one embodiment, the device may include a plurality of external (transcutaneous) TNS electrodes. The practitioner approximates the location of the target branch and affixes the electrodes to the patient's skin above the target location. Stimulation may be applied and the actual location or preferred (optimal) stimulation location of the target branch or branches may be determined Stimulation parameters may also be established. Once the location and / or stimulation parameters have been established via the external device, that data may be used to help guide the placement of the implanted electrodes for an individual patient and to establish the customized stimulation parameters for that patient.

[0085] In addition, 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 other 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.

[0086] A method of evaluating the use of trigeminal nerve stimulation for treatment of a neurodevelopmental disorder in a patient is disclosed herein. The method may include applying a cutaneous system for stimulation of the trigeminal nerve to the patient and monitoring the patient for at least one of evidence of a useful therapeutic response or evidence of tolerability of TNS treatment, providing a subcutaneous electrode assembly or system, and implanting thePCT / US25 / 12424 21 January 2025 (21.01.2025)subcutaneous electrode assembly or system in the patient for treatment of a neurodevelopmental disorder.

[0087] A method of evaluating the use of deep brain stimulation for treatment of a neurodevelopmental disorder in a patient is disclosed herein. The method may include applying a cutaneous system for stimulation of the trigeminal nerve to the patient and monitoring the patient for at least one of evidence of a useful therapeutic response or evidence of tolerability of TNS treatment thereby generating external measurement criteria, providing a subcutaneous electrode assembly or system, implanting the subcutaneous electrode assembly or system in the patient for treatment of a neurodevelopmental disorder, monitoring the patient for at least one of a useful therapeutic response or tolerability of the implanted device, thereby generating extracranial measurement criteria, and analyzing the external measurement criteria and extracranial measurement criteria to determine whether the patient will benefit from deep brain stimulation.

[0088] The following examples are presented to set forth more clearly the subject matter of this disclosure without imposing any limits on the scope thereof and to illustrate the clinical benefits of trigeminal nerve stimulation for the treatment of neurodevelopmental disorders. In the first example, a patient was treated using cutaneous electrodes for bilateral supraorbital stimulation. In the second example, a patient with severe dyslexia was treated by TNS with external cutaneous electrodes.Example 1

[0089] Fig. 6 summarizes current, charge, current density and charge density recorded in a subject during exposure to cutaneous stimulation of the supraorbital nerve. Fig. 6 illustrates representative parameters for bilateral supraorbital stimulation recorded in a subject using an EMS 7500 stimulator, 120 HZ, 150-250 psec, Tyco superior silver electrodes 1.25", placed one inch from the midline above the eyebrows. Data recorded with Fluke Oscilloscope, 50 mV / div, resistor = 10.1 Q. In general, these findings show that, as the pulse width increased, the maximum tolerable current decreased.

[0090] Cutaneous electrical stimulation of the supraorbital branch of the trigeminal nerve with round 1.25-inch TENS patch electrodes results in current densities and charge density / phase that are well within the limits of safety. In general, the maximum current comfortably tolerated by TNS patients studied previously is approximately 25 mA, and patients typically are stimulated at an amplitude setting well below 25 mA (6-10 mA).PCT / US25 / 12424 21 January 2025 (21.01.2025)

[0091] The 1.25-inch TENS electrodes are circular electrodes with a radius of 1.59 cm. The surface area can be calculated as A = nr 2 = [n] * [1.59 cm]2 = 7.92 cm2. Using these electrodes, typical stimulation current ranges from 6 - 10 mA at pulse durations of 150-250 psec.

[0092] Current Density: In a typical subject, stimulation currents of 6-10 mA result in current densities ranging from 0.76 to 1.3 mA / cm2. McCreery et al have established a maximum safe current density of 25mA / cm at the stimulating electrode for transcranial electrical stimulation. Assuming even higher currents of up to 25 mA with electrodes of surface area 7.92 cm2, current densities may range to a maximum of 3.16mA / cm2. From 0.76 mA / cm2to3.16mA / cm2, TNS delivers a current density 8-33 times less than the maximum safe allowable current density. Charge Density (Charge density / phase): Yuen et al have identified a safe limit for charge density / phase delivered at the cerebral cortex of 40 pC / cm2. [Yuen et al 1981] and more recently McCreery et al. (McCreery et al 1990) have identified 10 pC / cm2as the safe limit. Assuming 10 mA at 250 psec, the charge density / phase is [0.010A] x [250 psec] / 7.92 = 0.32 pC / cm2at the stimulating electrode. Assuming even higher levels of stimulation, 25mA at 250 psec, the maximum charge density per phase is 0.79 pC / cm2. At these levels, the charge density is generally 12 to 120-fold less at the stimulating electrode than the maximum allowed at the cerebral cortex. Since the cortex is a minimum of 10-13 mm from the stimulating electrodes, and given the interposed layers of skin, fat, bone, dura, and CSF, the actual charge densities will be significantly lower. This is of importance in avoiding the undesired passage of current directly through brain tissue as a bulk conductor.

[0093] As shown in Fig. 6, stimulation intensity responses in a subject with electrodes of surface area 7.92 cm2, at pulse durations between 150-250 psec, results in current densities at the scalp well below currently recommended current densities for transcranial stimulation, which are 25 mA / cm2, and charge densities at the scalp significantly lower than safe charge densities at the cerebral cortex (0.15-0.18 pC / cm2).Example 2

[0094] A nine-year-old girl with severe dyslexia and significant problems with reading and writing, despite intensive intervention, underwent eTNS therapy. The parameters that were used were 120 Hz, 30 seconds on and 30 seconds off, 250 microseconds pulse width, square charge balanced waveform, delivered 8 hours nightly. Fig. 7 is her writing sample before she started eTNS therapy. The topic was to summarize her reading group’s book. The writing samplePCT / US25 / 12424 21 January 2025 (21.01.2025)is typical of the girl’s work prior to eTNS therapy. She used a word processor to type 8-10 sentences (the minimum required in the assignment) because writing things by hand required too much effort and was often illegible. As can be seen, the writing is robotic, formulaic, and strained in style.

[0095] Fig. 8 is the first page of a four-page handwritten sample from the girl after four weeks of therapy with eTNS. The topic of the assignment was to share a spring break experience. She was on eTNS therapy when she wrote the assignment and it took her two days to complete. As can be seen, the writing sample is radically different both in the volume written (even though the assignment requirements were the same as in Fig. 7) and in the complexity and richness of the writing itself. Prior to therapy with eTNS, the girl was never observed to write in this manner.

[0096] Fig. 9 provides the results of the Gray Oral Reading Test-4 (GORT-4™) of the girl after eight weeks of daily eTNS therapy. Fig. 10 provides a summary of the results of the GORT-4™, and shows dramatic improvements in reading accuracy and fluency. The girl’s reading accuracy jumped to the 50th percentile from the 25th percentile, and her reading fluency increased from the 16th percentile to the 37th percentile.

[0078] 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

PCT / US25 / 12424 21 January 2025 (21.01.2025)THE CLAIMS1. A method for treating a neurodevel opmental disorder by trigeminal nerve stimulation, comprising:attaching an electrode assembly to a patient, the electrode assembly comprising: a first pair of contacts configured for placement on a first region of the 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 trigeminal nerve; andapplying electrical signals to the electrode assembly at specified operational parameters to treat a neurodevelopmental disorder by stimulating the right prefrontal cortex of the patient.

2. The method of claim 1, wherein 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 about 25 mA / cm2and an output charge density of not greater than about 10 micro-Coulomb / cm2.

3. The method of claim 1, wherein the electrode assembly is attached to the patient so as to contact the skin surface over a supraorbital nerve.

4. The method of claim 1, wherein the electrode assembly is attached to the patient so as to contact the skin surface over an auriculotemporal nerve.

5. The method of claim 1, wherein the electrode assembly is attached to the patient so as to contact the skin surface over a zygomaticofacial nerve.

6. The method of claim 1, wherein the neurodevelopmental disorder is dyslexia.PCT / US25 / 12424 21 January 2025 (21.01.2025)7. The method of claim 1, wherein applying the electrical signals comprises applying the electrical signals while the patient is performing a task.

8. The method of claim 8, wherein the task comprises reading or writing.

9. The method of claim 1, wherein applying the electrical signals comprises applying the electrical signals daily.

10. The method of claim 1, wherein applying the electrical signals comprises applying the electrical signals while the patient is asleep.

11. A method for increasing cognitive performance in a patient without a neurodevelopment disorder by trigeminal nerve stimulation, comprising:attaching an electrode assembly to a patient, the electrode assembly comprising: a first pair of contacts configured for placement on a first region of the 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 trigeminal nerve; andapplying electrical signals to the electrode assembly at specified operational parameters to increase cognitive performance by stimulating the right prefrontal cortex of the patient.

12. The method of claim 11, wherein 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 about 25 mA / cm2and an output charge density of not greater than about 10 micro-Coulomb / cm2.

13. The method of claim 11, wherein the electrode assembly is attached to the patient so as to contact the skin surface over a supraorbital nerve.PCT / US25 / 12424 21 January 2025 (21.01.2025)14. The method of claim 11, wherein the electrode assembly is attached to the patient so as to contact the skin surface over an auriculotemporal nerve.

15. The method of claim 11, wherein the electrode assembly is attached to the patient so as to contact the skin surface over a zygomaticofacial nerve.

16. The method of claim 11, wherein applying the electrical signals comprises applying the electrical signals while the patient is performing a task.

17. The method of claim 16, wherein the task comprises reading or writing.

18. The method of claim 11, wherein applying the electrical signals comprises applying the electrical signals daily.

19. The method of claim 11, wherein applying the electrical signals comprises applying the electrical signals while the patient is asleep.

20. A method for improving the accuracy and fluency of reading in a patient with dyslexia by trigeminal nerve stimulation, comprising:attaching an electrode assembly to a patient, the electrode assembly comprising: a first pair of contacts configured for placement on a first region of the 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 trigeminal nerve; andapplying electrical signals to the electrode assembly at specified operational parameters to stimulate the right prefrontal cortex of the patient.

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