Patent Abstract:
A mouthpiece for providing non-invasive neuromodulation to a patient, the mouthpiece including an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar exterior top surface and internal structural members disposed within the housing, the internal structural members elastically responding to biting forces generated by the patient, a spacer attached to the top surface of the housing for limiting contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing, and a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue.

Full Description:
FIELD OF THE INVENTION 
       [0001]    In general, the invention relates to devices and methods for non-invasive neurostimulation of a subject&#39;s brain. More specifically, the invention relates to devices and methods for non-invasive neurostimulation of a subject&#39;s brain to effect treatment of various maladies. 
       BACKGROUND OF THE INVENTION 
       [0002]    Traumatic brain injury (TBI) is a leading cause of disability around the world. Each year in the United States, about two million people suffer a TBI, with many suffering long term symptoms. Long term symptoms can include impaired attention, impaired judgment, reduced processing speed, and defects in abstract reasoning, planning, problem-solving and multitasking. 
         [0003]    A stroke is a loss of brain function due to a disturbance in the blood supply to the brain. Every year, about 800,000 people in the United States will have a stroke. Stroke is a leading cause of long-term disability in the United States, with nearly half of older stroke survivors experiencing moderate to severe disability. Long term effects can include seizures, incontinence, vision disturbance or loss of vision, dysphagia, pain, fatigue, loss of cognitive function, aphasia, loss of short-term and/or long-term memory, and depression. 
         [0004]    Multiple sclerosis (MS) is a disease that causes damage to the nerve cells in the brain and spinal cord. Globally, there are about 2.5 million people who suffer from MS. Symptoms can vary greatly depending on the specific location of the damaged portion of the brain or spinal cord. Symptoms include hypoesthesia, difficulties with coordination and balance, dysarthria, dysphagia, nystagmus, bladder and bowel difficulties, cognitive impairment and major depression to name a few. 
         [0005]    Alzheimer&#39;s disease (AD) is a neurodegenerative disorder affecting over 25 million people worldwide. Symptoms of AD include confusion, irritability, aggression, mood swings, trouble with language, and both short and long term memory loss. In developed countries, AD is one of the most costly diseases to society. 
         [0006]    Parkinson&#39;s disease (PD) is a degenerative disorder of the central nervous system, affecting more than 7 million people globally. Symptoms of PD include tremor, bradykinesia, rigidity, postural instability, cognitive disturbances, and behavior and mood alterations. 
         [0007]    One approach to treating the long term symptoms associated with TBI, stroke, MS, AD, and PD is neurorehabilitation. Neurorehabilitation involves processes designed to help patients recover from nervous system injuries. Traditionally, neurorehabilitation involves physical therapy (e.g., balance retraining), occupational therapy (e.g., safety training, cognitive retraining for memory), psychological therapy, speech and language therapy, and therapies focused on daily function and community re-integration. 
         [0008]    Another approach to treating the long term symptoms associated with TBI, stroke, MS, AD, and PD is neurostimulation. Neurostimulation is a therapeutic activation of part of the nervous system. For example, activation of the nervous system can be achieved through electrical stimulation, magnetic stimulation, or mechanical stimulation. Typical approaches focused mainly on invasive techniques, such as deep brain stimulation (DBS), spinal cord stimulation (SCS), cochlear implants, visual prosthesis, and cardiac electrostimulation devices. Only recently have non-invasive approaches to neurostimulation become more mainstream. 
         [0009]    Despite many advances in the areas of neurorehabilitation and neurostimulation, there exists an urgent need for treatments that employ a combined approach, including both neurorehabilitation and neurostimulation to improve the recovery of patients having TBI, stroke, multiple sclerosis, Alzheimer&#39;s, Parkinson&#39;s, depression, memory loss, compulsive behavior, or any other neurological impairment. 
       SUMMARY OF THE INVENTION 
       [0010]    The invention, in various embodiments, features methods and devices for combining non-invasive neuromodulation with traditional neurorehabilitation therapies. Clinical studies have shown that methods combining neurostimulation with neurorehabilitation are effective in treating the long term neurological impairments due to a range of maladies such as TBI, stroke, MS, AD, and PD. 
         [0011]    In one aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having (i) a non-planar exterior top surface and (ii) internal structural members disposed within the housing, the internal structural members elastically responding to biting forces generated by the patient. The mouthpiece also includes a spacer attached to the top surface of the housing for limiting contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing. The mouthpiece also includes a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. In some embodiments, the mouthpiece also includes ribs aligned parallel to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes ribs aligned perpendicular to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes ribs aligned parallel to a longitudinal axis of the elongated housing and ribs aligned perpendicular to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes an interpenetrating network of ribs, with at least some of the ribs aligned parallel to a longitudinal axis of the elongate housing and at least some of the ribs aligned perpendicular to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes pockets in a posterior portion of the elongated housing formed by the interpenetrating network of ribs. In some embodiments, the mouthpiece also includes integrated circuits located in the pockets. In some embodiments, the ribs have a rectangular cross section. In some embodiments, the ribs are comprised of arches. In some embodiments, the mouthpiece also includes one or more columns extending away from an interior surface of the elongated housing, the one or more columns configured to contact the mounted printed circuit board. In some embodiments, the structural elements can withstand a force of 700 Newtons without causing plastic deformation of the mouthpiece. In some embodiments, the mouthpiece also includes a rectangular sheet embedded on an interior surface of the elongated housing and located in a posterior region of the elongated housing, the rectangular sheet connecting the interpenetrating network of ribs. In some embodiments, the mouthpiece also includes a curvilinear sheet embedded on an interior surface of the elongated housing and located in a region connecting the anterior region and the posterior region of the elongated housing, the curvilinear sheet connecting the ribs aligned parallel to a longitudinal axis of the elongated housing. 
         [0012]    In another aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having (i) a non-planar exterior top surface and (ii) internal structural members disposed within the housing, the internal structural members elastically responding to biting forces generated by the patient. The mouthpiece also includes a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. In some embodiments, the mouthpiece also includes ribs aligned parallel to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes ribs aligned perpendicular to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes ribs aligned parallel to a longitudinal axis of the elongated housing and ribs aligned perpendicular to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes an interpenetrating network of ribs, with at least some of the ribs aligned parallel to a longitudinal axis of the elongate housing and at least some of the ribs aligned perpendicular to a longitudinal axis of the elongated housing. In some embodiments, the mouthpiece also includes pockets in a posterior portion of the elongated housing formed by the interpenetrating network of ribs. In some embodiments, the mouthpiece also includes integrated circuits located in the pockets. In some embodiments, the ribs have a rectangular cross section. In some embodiments, the ribs are comprised of arches. In some embodiments, the mouthpiece also includes one or more columns extending away from an interior surface of the elongated housing, the one or more columns configured to contact the mounted printed circuit board. In some embodiments, the structural elements can withstand a force of 700 Newtons without causing plastic deformation of the mouthpiece. 
         [0013]    In another aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar interior top surface and internal fins located between the non-planar interior top surface and a bottom surface defined by a perimeter of the elongated housing, the internal fins forming a channel at the anterior region of the elongated housing. The mouthpiece also includes a spacer attached to the top surface of the housing for minimizing contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing. The mouthpiece also includes a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The mouthpiece also includes a cable having a first segment disposed within the housing and a second segment extending from the housing, the cable mounted in an s-shaped pattern along the channel formed by the internal fins, one end of the first segment of the cable connected to the printed circuit board. In some embodiments, the mouthpiece also includes a right angled grommet mounted to an anterior region of the elongated housing, the grommet surrounding the cable as it exits the channel formed by the internal fins, the grommet forcing the cable to make an approximately ninety degree turn as it exits the elongated housing. In some embodiments, the cable forms two consecutive s-shapes along the channel formed by the internal fins. In some embodiments, the mouthpiece also includes a grommet mounted to an anterior region of the elongated housing, the grommet surrounding the cable as it exits the channel formed by the internal fins. In some embodiments, the mouthpiece also includes a cylindrically symmetric elastomeric element, the elastomeric element surrounding a portion of the cable and having trench in a central portion thereof and surrounded by two regions having radii that decrease in relation to a distance from the trench. In some embodiments, the mouthpiece also includes an aperture located at an anterior region of the elongated housing, the aperture configured to form mechanical connection with the trench. In some embodiments, the mouthpiece also includes a cap, the cap having an elastomeric portion in contact with the printed circuit board and a rigid portion in contact with the elongated housing, the cap in cooperation with the elongated housing forming an aperture at an anterior region of the mouthpiece, the aperture configured to form mechanical connection with the trench. In some embodiments, the mouthpiece also includes a valley located in the interior surface of the elongated housing, the valley configured to receive the cable. In some embodiments, the mouthpiece also includes an elastomeric sleeve, the elastomeric sleeve in contact with the cable, and an anterior region of the elongated housing, the elastomeric sleeve providing resistance to bending and tensile strains in the cable. 
         [0014]    In another aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar interior top surface and a bottom surface defined by a perimeter of the elongated housing. The mouthpiece also includes a spacer attached to the top surface of the elongated housing for minimizing contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing. The mouthpiece also includes a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The mouthpiece also includes a first elastomeric ring located along an interior sidewall of the elongated housing, the first elastomeric ring forming a sealing surface with the printed circuit board. The mouthpiece also includes a plurality of mechanical protrusions extending from the interior sidewall of the elongated housing, the mechanical protrusions in contact with the printed circuit board. The mouthpiece also includes a cable having a first segment disposed within the housing and a second segment extending from the housing, one end of the first segment of the cable connected to the printed circuit board. In some embodiments, the mouthpiece also includes a valley located in the interior surface of the elongated housing, the valley configured to receive the cable. In some embodiments, the mouthpiece also includes internal fins extending from the interior top surface of the elongated housing, the internal fins forming a channel at an anterior region of the elongated housing. In some embodiments, the cable forms at least two consecutive s-shapes along the channel formed by the internal fins. In some embodiments, the mouthpiece also includes a second elastomeric ring attached to the first elastomeric ring, the second elastomeric ring surrounding a portion of the cable and forming a connection between an anterior portion of the elongated housing and the cable. In some embodiments, the mouthpiece also includes a second elastomeric ring attached to the first elastomeric ring, the second elastomeric ring surrounding a portion of the cable and forming a connection between an anterior portion of the elongated housing and the cable, the second elastomeric ring causing the cable to exit the mouthpiece at an angle of 90 degrees. 
         [0015]    In another aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar interior top surface and internal fins located between the non-planar interior top surface and a bottom surface defined by a perimeter of the elongated housing, the internal fins forming a channel at the anterior region of the elongated housing. The mouthpiece also includes a printed circuit board mounted to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The mouthpiece also includes a cable having a first segment disposed within the housing and a second segment extending from the housing, the cable mounted in an s-shaped pattern along the channel formed by the internal fins, one end of the first segment of the cable connected to the printed circuit board. In some embodiments, the mouthpiece also includes a right angled grommet mounted to an anterior region of the elongated housing, the grommet surrounding the cable as it exits the channel formed by the internal fins, the grommet forcing the cable to make an approximately ninety degree turn as it exits the elongated housing. In some embodiments, the cable forms two consecutive s-shapes along the channel formed by the internal fins. In some embodiments, the mouthpiece also includes a grommet mounted to an anterior region of the elongated housing, the grommet surrounding the cable as it exits the channel formed by the internal fins. In some embodiments, the mouthpiece also includes a cylindrically symmetric elastomeric element, the elastomeric element surrounding a portion of the cable and having trench in a central portion thereof and surrounded by two regions having radii that decrease in relation to a distance from the trench. In some embodiments, the mouthpiece also includes an aperture located at an anterior region of the elongated housing, the aperture configured to form mechanical connection with the trench. In some embodiments, the mouthpiece also includes a cap, the cap having an elastomeric portion in contact with the printed circuit board and a rigid portion in contact with the elongated housing, the cap in cooperation with the elongated housing forming an aperture at an anterior region of the mouthpiece, the aperture configured to form mechanical connection with the trench. In some embodiments, the mouthpiece also includes a valley located in the interior surface of the elongated housing, the valley configured to receive the cable. In some embodiments, the mouthpiece also includes an elastomeric sleeve, the elastomeric sleeve in contact with the cable, and an anterior region of the elongated housing, the elastomeric sleeve providing resistance to bending and tensile strains in the cable. 
         [0016]    In another aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar exterior top surface. The mouthpiece also includes a spacer attached to the top surface of the housing for minimizing contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing. The mouthpiece also includes a first printed circuit board mounted to a bottom portion of the elongated housing, the first printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The mouthpiece also includes a rim extending from a bottom portion of the elongated housing, the rim surrounding a perimeter of the first printed circuit board and having a u-shaped cross section. The mouthpiece also includes a well shaped to accommodate an adhesive, the adhesive bonding the first printed circuit board to the elongate housing. In some embodiments, a portion of the rim rests below the first printed circuit board and prevents a patient&#39;s teeth from contacting the printed circuit board. In some embodiments, the first printed circuit board is non-planar and the plurality of electrodes are located on a non-planar surface of the first printed circuit board. In some embodiments, the first printed circuit board has a curved shape and the plurality of electrodes are located on a curved surface of the first printed circuit board. In some embodiments, the plurality of electrodes has a first density at an anterior region of the first printed circuit board and a second density at a posterior region of the first printed circuit board, wherein the first density is greater than the second density. In some embodiments, the mouthpiece also includes a second printed circuit board mounted above the first printed circuit board. In some embodiments, the rim is an integral part of the elongated housing. In some embodiments, the rim is dimensioned to define the glue well between the bottom portion of the elongated housing and the perimeter of the first printed circuit board. In some embodiments, the rim is concentric with the perimeter of the first printed circuit board. In some embodiments, the rim covers a bottom portion of the first printed circuit board along the perimeter thereof. In some embodiments, the rim covers a side portion of the first printed circuit board along the perimeter thereof. In some embodiments, the rim covers a bottom portion and a side portion of the first printed circuit board along the perimeter thereof. 
         [0017]    In another aspect, the invention features a mouthpiece for providing non-invasive neuromodulation to a patient. The mouthpiece includes an elongated housing having an anterior region and a posterior region, the elongated housing having a non-planar exterior top surface. The mouthpiece also includes a spacer attached to the top surface of the housing for minimizing contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing. The mouthpiece also includes a first printed circuit board mounted to a bottom portion of the elongated housing, the first printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The mouthpiece also includes a rim extending from a bottom portion of the elongated housing, the rim surrounding a perimeter of the first printed circuit board. The mouthpiece also includes a beveled well configured to accommodate an adhesive, the adhesive bonding at least two orthogonal surfaces of the first printed circuit board to the elongated housing. In some embodiments, a portion of the rim rests below the first printed circuit board and prevents a patient&#39;s teeth from contacting the first printed circuit board. In some embodiments, the first printed circuit board is non-planar and the plurality of electrodes are located on a non-planar surface of the first printed circuit board. In some embodiments, the first printed circuit board has a curved shape and the plurality of electrodes are located on a curved surface of the first printed circuit board. In some embodiments, the plurality of electrodes has a first density at an anterior region of the first printed circuit board and a second density at a posterior region of the first printed circuit board, wherein the first density is greater than the second density. In some embodiments, the mouthpiece also includes a second printed circuit board mounted above the first printed circuit board. In some embodiments, the rim is an integral part of the elongated housing. In some embodiments, the rim is dimensioned to define the glue well between the bottom portion of the elongated housing and the perimeter of the first printed circuit board. In some embodiments, the rim is concentric with the perimeter of the first printed circuit board. In some embodiments, the rim covers a bottom portion of the first printed circuit board along the perimeter thereof. In some embodiments, the rim covers a side portion of the first printed circuit board along the perimeter thereof. In some embodiments, the rim covers a bottom portion and a side portion of the first printed circuit board along the perimeter thereof. 
         [0018]    In another aspect, the invention features a method of manufacturing a mouthpiece, the mouthpiece providing non-invasive neuromodulation to a patient. The method includes providing an elongated housing having internal fins located between a non-planar interior top surface and a bottom surface defined by a perimeter of the elongated housing, the internal fins forming a channel at the anterior region of the elongated housing. The method also includes attaching a spacer to the top surface of the elongated housing for minimizing contact between a patient&#39;s upper teeth and the exterior top surface of the elongated housing. The method also includes mounting a cable in an s-shaped pattern along the channel formed by the internal fins. The method also includes mounting a printed circuit board to a bottom portion of the elongated housing, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The method also includes connecting one end of the cable to the printed circuit board. In some embodiments, the method also includes forming a 90 degree bend in the cable at an exit of elongated housing. In some embodiments, the method also includes threading the cable through an elastomeric element located at the exit of the elongated housing. In some embodiments, the method also includes forming two consecutive s-shapes along the cable. In some embodiments, the method also includes mounting a cylindrically symmetric elastomeric element to the cable, the elastomeric element surrounding a portion of the cable and having a trench in a central portion thereof and surrounded by two regions having radii that decrease in relation to a distance from the trench. In some embodiments, the method also includes forming an aperture at an anterior region of the elongated housing, the aperture configured to form mechanical connection with the trench. In some embodiments, the method also includes providing a cap having an elastomeric portion and a rigid portion. In some embodiments, the method also includes contacting the elastomeric portion of the cap with the printed circuit board and contacting the rigid portion of the cap with the elongated housing. In some embodiments, the method also includes cooperatively forming an aperture with the cap and the elongated housing, the aperture forming a mechanical connection with the trench. In some embodiments, the method also includes forming a valley located in the interior surface of the elongated housing. In some embodiments, the method also includes receiving a cable in the valley. In some embodiments, the method also includes forming an elastomeric sleeve around the cable, the elastomeric sleeve in contact with an anterior region of the elongated housing, the elastomeric sleeve providing resistance to bending and tensile strains in the cable. In some embodiments, the method also includes applying an adhesive along the perimeter of the printed circuit board, the adhesive bonding at least two orthogonal surfaces of the first printed circuit board to the elongated housing. 
         [0019]    In another aspect, the invention features a method of manufacturing a mouthpiece, the mouthpiece providing non-invasive neuromodulation to a patient. The method includes providing an elongated housing having a plurality of mechanical protrusions extending from an interior sidewall thereof and first elastomeric ring located along an interior sidewall of the elongated housing. The method also includes attaching a spacer to the top surface of the elongated housing for minimizing contact between a patient&#39;s upper teeth and a top surface of the elongated housing. The method also includes contacting a printed circuit board to the first elastomeric ring of the elongated housing to form a seal, the printed circuit board having a plurality of electrodes for delivering subcutaneous local electrical stimulation to the patient&#39;s tongue. The method also includes providing a cable having a first segment disposed within the housing and a second segment extending from the housing. The method also includes connecting one end of the first segment of the cable connected to the printed circuit board. In some embodiments, the method also includes forming a 90 degree bend in the cable at an exit of elongated housing. In some embodiments, the method also includes threading the cable through an elastomeric element located at the exit of the elongated housing. In some embodiments, the method also includes forming two consecutive s-shapes along the cable. In some embodiments, the method also includes mounting a cylindrically symmetric elastomeric element to the cable, the elastomeric element surrounding a portion of the cable and having a trench in a central portion thereof and surrounded by two regions having radii that decrease in relation to a distance from the trench. In some embodiments, the method also includes forming an aperture at an anterior region of the elongated housing, the aperture configured to form mechanical connection with the trench. In some embodiments, the method also includes forming a valley located in the interior surface of the elongated housing. In some embodiments, the method also includes receiving a cable in the valley. In some embodiments, the method also includes forming an elastomeric sleeve around the cable, the elastomeric sleeve in contact with an anterior region of the elongated housing, the elastomeric sleeve providing resistance to bending and tensile strains in the cable. 
         [0020]    As used herein, the terms “approximately,” “roughly,” and “substantially” mean±10%, and in some embodiments, ±5%. Reference throughout this specification to “one example,” “an example,” “one embodiment,” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the example is included in at least one example of the present technology. Thus, the occurrences of the phrases “in one example,” “in an example,” “one embodiment,” or “an embodiment” in various places throughout this specification are not necessarily all referring to the same example. Furthermore, the particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0021]    The advantages of the invention described above, together with further advantages, may be better understood by referring to the following description taken in conjunction with the accompanying drawings. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. 
           [0022]      FIG. 1  is a drawing of a patient engaged in a non-invasive neurostimulation therapy session according to an illustrative embodiment of the invention. 
           [0023]      FIGS. 2A and 2B  are diagrams showing a neurostimulation system according to an illustrative embodiment of the invention. 
           [0024]      FIG. 2C  is a diagram showing a neurostimulation system according to an illustrative embodiment of the invention. 
           [0025]      FIG. 3A  is a diagram showing a more detailed view of the neurostimulation system depicted in  FIGS. 2A and 2B . 
           [0026]      FIG. 3B  is a diagram showing a more detailed view of the neurostimulation system depicted in  FIG. 2C . 
           [0027]      FIG. 3C  is a diagram showing a more detailed view of an electrode array. 
           [0028]      FIG. 3D  is a graph showing an exemplary sequence of pulses for effecting neurostimulation of a patient. 
           [0029]      FIG. 4A  is a flow chart illustrating a method in accordance with one embodiment for operating a neurostimulation system. 
           [0030]      FIG. 4B  is a flow chart illustrating a method in accordance with one embodiment for operating a neurostimulation system. 
           [0031]      FIG. 5A  is a diagram showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0032]      FIG. 5B  is a diagram showing a side view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0033]      FIG. 5C  is a diagram showing a top view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0034]      FIG. 5D  is a diagram showing a bottom view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0035]      FIGS. 5E and 5F  are diagrams showing a bottom view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0036]      FIG. 6A  is a diagram showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0037]      FIG. 6B  is a diagram showing a bottom view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0038]      FIG. 6C  is a diagram showing a glue well in accordance with an illustrative embodiment of the invention. 
           [0039]      FIG. 6D  is a diagram showing a glue well in accordance with an illustrative embodiment of the invention. 
           [0040]      FIG. 7A  is a diagram showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0041]      FIG. 7B  is a diagram showing a bottom view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0042]      FIG. 7C  is a diagram showing a sectional view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0043]      FIGS. 8A and 8B  are diagrams showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0044]      FIG. 8C  is a diagram showing a sectional view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0045]      FIG. 8D  is a diagram showing a sectional view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0046]      FIGS. 9A and 9B  are diagrams showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0047]      FIG. 9C  is a diagram showing a sectional view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0048]      FIGS. 10A and 10B  are diagrams showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0049]      FIG. 10C  is a diagram showing a sectional view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0050]      FIGS. 11A and 11B  are diagrams showing an isometric view of a mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0051]      FIG. 11C  is a diagram showing an isometric view of the mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0052]      FIG. 12  is a flow chart illustrating a method in accordance with one embodiment for manufacturing a mouthpiece. 
           [0053]      FIGS. 13A-B  are diagrams showing an overmolded mouthpiece in accordance with an illustrative embodiment of the invention. 
           [0054]      FIG. 14  is a diagram showing an overmolded mouthpiece in accordance with an illustrative embodiment of the invention. 
       
    
    
     DETAILED DESCRIPTION 
       [0055]      FIG. 1  shows a patient  101  undergoing non-invasive neuromodulation therapy (NINM) using a neurostimulation system  100 . During a therapy session, the neurostimulation system  100  non-invasively stimulates various nerves located within the patient&#39;s oral cavity, including at least one of the trigeminal and facial nerves. In combination with the NINM, the patient engages in an exercise or other activity specifically designed to assist in the neurorehabilitation of the patient. For example, the patient can perform a physical therapy routine (e.g., moving an affected limb, or walking on a treadmill) engage in a mental therapy (e.g., meditation or breathing exercises), or a cognitive exercise (e.g., computer assisted memory exercises) during the application of NINM. The combination of NINM with an appropriately chosen exercise or activity has been shown to be useful in treating a range of maladies including, for example, traumatic brain injury, stroke (TBI), multiple sclerosis (MS), balance, gait, vestibular disorders, visual deficiencies, tremor, headache, migraines, neuropathic pain, hearing loss, speech recognition, auditory problems, speech therapy, cerebral palsy, blood pressure, relaxation, and heart rate. For example, a useful non-invasive neuromodulation (NINM) therapy routine has been recently developed as described in U.S. Pat. No. 8,849,407, the entirety of which is incorporated herein by reference. 
         [0056]      FIGS. 2A and 2B  show a non-invasive neurostimulation system  100 . The non-invasive neurostimulation system  100  includes a controller  120  and a mouthpiece  140 . 
         [0057]    The controller  120  includes a receptacle  126  and pushbuttons  122 . The mouthpiece  140  includes an electrode array  142  and a cable  144 . The cable  144  connects to the receptacle  126 , providing an electrical connection between the mouthpiece  140  and the controller  120 . In some embodiments, the controller  120  includes a cable. In some embodiments, the mouthpiece  140  and the controller  120  are connected wirelessly (e.g., without the use of a cable). During operation, a patient activates the neurostimulation system  100  by actuating one of the pushbuttons  122 . In some embodiments, the neurostimulation system  100  periodically transmits electrical pulses to determine if the electrode array  142  is in contact with the patient&#39;s tongue and automatically activates based on the determination. After activation, the patient can start an NINM treatment session, stop the NINM treatment session, or pause the NINM treatment session by pressing one of the pushbuttons  122 . In some embodiments, the neurostimulation system  100  periodically transmits electrical pulses to determine if the electrode array  142  is in contact with the patient&#39;s tongue and automatically pauses the NINM treatment session based on the determination. During an NINM treatment session, the patient engages in an exercise or other activity designed to facilitate neurorehabilitation. For example, during an NINM treatment session, the patient can engage in a physical exercise, a mental exercise, or a cognitive exercise. In some embodiments, the controller  120  has pushbuttons on both arms. In some embodiments, a mobile device can be used in conjunction with the controller  120  and the mouthpiece  140 . The mobile device can include a software application that allows a user to activate the neurostimulation system  100  and start or stop an NINM treatment session by for example, pressing a button on the mobile device, or speaking a command into the mobile device. The mobile device can obtain patient information and treatment session information before, during, or after an NINM treatment session. In some embodiments, the controller  120  includes a secure cryptoprocessor that holds a secret key, to be described in more detail below in connection with  FIGS. 9A and 9B . The secure cryptoprocessor is in communication with a microcontroller. The secure cryptoprocessor can be tamper proof. For example, if outer portions of the cryptoprocessor are removed in an attempt to access the secret key, the cryptoprocessor erases all memory, preventing unauthorized access of the secret key. 
         [0058]      FIG. 2C  shows a non-invasive neurostimulation system  100 . As shown, a mobile device  121  is in communication with a mouthpiece  140 . More specifically, the mobile device  121  includes a processor running a software application that facilitates communications with the mouthpiece  140 . The mobile device  121  can be, for example, a mobile phone, a portable digital assistant (PDA), or a laptop. The mobile device  121  can communicate with the mouthpiece  140  by a wireless or wired connection. During operation, a patient activates the neurostimulation system  100  via the mobile device  121 . After activation, the patient can start an NINM treatment session, stop the NINM treatment session, or pause the NINM treatment session by manipulating the mobile device  121 . During an NINM treatment session, the patient engages in an exercise or activity designed to provide neurorehabilitation. For example, during an NINM treatment session, the patient can engage in a physical exercise, a mental exercise, or a cognitive exercise. 
         [0059]      FIG. 3A  shows the internal circuitry housed within the controller  120 . The circuitry includes a microcontroller  360 , isolation circuitry  379 , a universal serial bus (USB) connection  380 , a battery management controller  382 , a battery  362 , a push-button interface  364 , a display  366 , a real time clock  368 , an accelerometer  370 , drive circuitry  372 , tongue sense circuitry  374 , audio feedback circuitry  376 , vibratory feedback circuitry  377 , and a non-volatile memory  378 . The drive circuitry  372  includes a multiplexor, and an array of resistors to control voltages delivered to the electrode array  142 . The microcontroller  360  is in electrical communication with each of the components shown in  FIG. 3A . The isolation circuitry  379  provides electrical isolation between the USB connection  380  and all other components included in the controller  120 . Additionally, the circuitry shown in  FIG. 3A  is in communication with the mouthpiece  140  via the external cable  144 . During operation, the microcontroller  360  receives electrical power from battery  362  and can store and retrieve information from the non-volatile memory  378 . The battery can be charged via the USB connection  380 . The battery management circuitry controls the charging of the battery  362 . A patient can interact with the controller  120  via the push-button interface  122  that converts the patient&#39;s pressing of a button (e.g. an info button, a power button, an intensity-up button, an intensity-down button, and a start/stop button) into an electrical signal that is transmitted to the microcontroller  360 . For example, a therapy session can be started when the patient presses a start/stop button after powering on the controller  120 . During the therapy session, the drive circuitry  372  provides an electrical signal to the mouthpiece  140  via the cable  144 . The electrical signal is communicated to the patient&#39;s intraoral cavity via the electrode array  142 . The accelerometer  370  can be used to provide information about the patient&#39;s motion during the therapy session. Information provided by the accelerometer  370  can be stored in the non-volatile memory  378  at a coarse or detailed level. For example, a therapy session aggregate motion index can be stored based on the number of instances where acceleration rises above a predefined threshold, with or without low pass filtering. Alternatively, acceleration readings could be stored at a predefined sampling interval. The information provided by the accelerometer  370  can be used to determine if the patient is engaged in a physical activity. Based on the information received from the accelerometer  370 , the microcontroller  360  can determine an activity level of the patient during a therapy session. For example, if the patient engages in a physical activity for 30 minutes during a therapy session, the accelerometer  370  can periodically communicate (e.g. once every second) to the microcontroller  360  that the sensed motion is larger than a predetermined threshold (e.g. greater than 1 m/s 2 ). In some embodiments, the accelerometer data is stored in the non-volatile memory  378  during the therapy session and transmitted to the mobile device  121  after the therapy session has ended. After the therapy session has ended, the microcontroller  360  can record the amount of time during the therapy session in which the patient was active. In some embodiments, the recorded information can include other data about the therapy session (e.g., the date and time of the session start, the average intensity of electrical neurostimulation delivered to the patient during the session, the average activity level of the patient during the session, the total session time the mouthpiece has been in the patient&#39;s mouth, the total session pause time, the number of session shorting events, and/or the length of the session or the type of exercise or activity performed during the therapy session) and can be transmitted to a mobile device. A session shorting event can occur if the current transmitted from the drive circuitry to the electrode array  142  exceeds a predetermined threshold or if the charge transmitted from the drive circuitry to the electrode array exceeds a predetermined threshold over a predetermined time interval. After a session shorting event has occurred, the patient must manually press a pushbutton to resume the therapy session. The real time clock (RTC)  368  provides time and date information to the microcontroller  360 . In some embodiments, the controller  120  is authorized by a physician for a predetermined period of time (e.g., two weeks). The RTC  368  periodically communicates date and time information to the microcontroller  360 . In some embodiments, the RTC  368  is integrated with the microcontroller. In some embodiments, the RTC  368  is powered by the battery  362 , and upon failure of the battery  362 , the RTC  368  is powered by a backup battery. After the predetermined period of time has elapsed, the controller  120  can no longer initiate the delivery of electrical signals to the mouthpiece  140  and the patient must visit the physician to reauthorize use of the controller  120 . The display  366  displays information received by the microcontroller  360  to the patient. For example, the display  366  can display the time of day, therapy information, battery information, time remaining in a therapy session, error information, and the status of the controller  120 . The audio feedback circuitry  376  and vibratory feedback circuitry  377  can give feedback to a user when the device changes state. For example, when a therapy session begins, the audio feedback circuitry  376  and the vibratory feedback circuitry  377  can provide auditory and/or vibratory cues to the patient, notifying the patient that the therapy session has been initiated. Other possible state changes that may trigger audio and/or vibratory cues include pausing a therapy session, resuming a therapy session, the end of a timed session, canceling a timed session, or error messaging. In some embodiments, a clinician can turn off one or more of the auditory or vibratory cues to tailor the feedback to an individual patient&#39;s needs. The tongue sense circuitry  374  measures the current passing from the drive circuitry to the electrode array  142 . Upon sensing a current above a predetermined threshold, the tongue sense circuitry  374  presents a high digital signal to the microcontroller  360 , indicating that the tongue is in contact with the electrode array  142 . If the current is below the predetermined threshold, the tongue sense circuitry  374  presents a low digital signal to the microcontroller  360 , indicating that the tongue is not in contact or is in partial contact with the electrode array  142 . The indications received from the tongue sense circuitry  374  can be stored in the non-volatile memory  378 . In some embodiments, the display  366  can be an organic light emitting diode (OLED) display. In some embodiments, the display  366  can be a liquid crystal display (LCD). In some embodiments, a display  366  is not included with the controller  120 . In some embodiments, neither the controller  120  nor the mouthpiece  140  includes a cable, and the controller  120  communicates wirelessly with the mouthpiece  140 . In some embodiments, neither the controller  120  nor the mouthpiece  140  includes an accelerometer. In some embodiments, the drive circuitry  372  is located within the mouthpiece. In some embodiments, a portion of the drive circuitry  372  is located within the mouthpiece  140  and a portion of the drive circuitry  372  is located within the controller  120 . In some embodiments, neither the controller  120  nor the mouthpiece  140  includes tongue sense circuitry  374 . In some embodiments, the mouthpiece  140  includes a microcontroller and a multiplexer. 
         [0060]      FIG. 3B  shows a more detailed view of  FIG. 2C . The mouthpiece  140  includes a battery  362 , tongue sense circuitry  374 , an accelerometer  370 , a microcontroller  360 , drive circuitry  372 , a non-volatile memory  378 , a universal serial bus controller (USB)  380 , and battery management circuitry  382 . During operation, the microcontroller receives electrical power from battery  362  and can store and retrieve information from the non-volatile memory  378 . The battery can be charged via the USB connection  380 . 
         [0061]    The battery management circuitry  382  controls the charging of the battery  362 . A patient can interact with the mouthpiece  140  via the mobile device  121 . The mobile device  121  includes an application (e.g. software running on a processor) that allows the patient to control the mouthpiece  140 . For example, the application can include an info button, a power button an intensity-up button, an intensity-down button, and a start/stop button that are presented to the user visually via the mobile device  121 . When the patient presses a button presented by the application running on the mobile device  121 , a signal is transmitted to the microcontroller  360  housed within the mouthpiece  140 . For example, a therapy session can be started when the patient presses a start/stop button on the mobile device  121 . During the therapy session, the drive circuitry  372  provides an electrical signal to an electrode array  142  located on the mouthpiece  140 . The accelerometer  370  can be used to provide information about the patient&#39;s motion during the therapy session. The information provided by the accelerometer  370  can be used to determine if the patient is engaged in a physical activity. Based on the information received from the accelerometer  370 , the microcontroller  360  can determine an activity level of the patient during a therapy session. For example, if the patient engages in a physical activity for 30 minutes during a therapy session, the accelerometer  370  can periodically communicate (e.g. once every second) to the microcontroller  360  that the sensed motion is larger than a predetermined threshold (e.g. greater than 1 m/s 2 ). After the therapy session has ended, the microcontroller  360  can record the amount of time during the therapy session in which the patient was active. In some embodiments, the accelerometer  370  is located within the mobile device  121  and the mobile device  121  determines an activity level of a patient during the therapy session based on information received from the accelerometer  370 . The mobile device can then record the amount of time during the therapy session in which the patient was active. The mobile device  121  includes a real time clock (RTC)  368  that provides time and date information to the microcontroller  360 . In some embodiments, the mouthpiece  140  is authorized by a physician for a predetermined period of time (e.g., two weeks). After the predetermined period of time has elapsed, the mouthpiece  140  can no longer deliver electrical signals to the patient via the electrode array  142  and the patient must visit the physician to reauthorize use of the mouthpiece  140 . In some embodiments, the mouthpiece  140  includes pushbuttons (e.g., an on/off button) and a patient can manually operate the mouthpiece  140  via the pushbuttons. After a therapy session, the mouthpiece  140  can transmit information about the therapy session to a mobile device. 
         [0062]    In some embodiments, the mouthpiece  140  does not include a USB controller  380  and instead communicates only via wireless communications with the controller. 
         [0063]      FIG. 3C  shows a more detailed view of the electrode array  142 . The electrode array  142  can be separated into 9 groups of electrodes, labelled a-i, with each group having 16 electrodes, except group b which has 15 electrodes. Each electrode within the group corresponds to one of 16 electrical channels. During operation, the drive circuitry can deliver a sequence of electrical pulses to the electrode array  142  to provide neurostimulation of at least one of the patient&#39;s trigeminal or facial nerve. The electrical pulse amplitude delivered to each group of electrodes can be larger near a posterior portion of the tongue and smaller at an anterior portion of the tongue. For example, the pulse amplitude of electrical signals delivered to groups a-c can be 19 volts or 100% of a maximum value, the pulse amplitude of electrical signals delivered to groups d-f can be 14.25 volts or 75% of the maximum value, the pulse amplitude of electrical signals delivered to groups g-h can be 11.4 volts or 60% of the maximum value, and the pulse amplitude of electrical signals delivered to group i can be 9.025 volts or 47.5% of the maximum value. In some embodiments, the maximum voltage is in the range of 0 to 40 volts. The pulses delivered to the patient by the electrode array  142  can be random or repeating. The location of pulses can be varied across the electrode array  142  such that different electrodes are active at different times, and the duration and/or intensity of pulses may vary from electrode. For oral tissue stimulation, currents of 0.5-50 mA and voltages of 1-40 volts can be used. In some embodiments, transient currents can be larger than 50 mA. The stimulus waveform may have a variety of time-dependent forms, and for cutaneous electrical stimulation, pulse trains and bursts of pulses can be used. Where continuously supplied, pulses may be 1-500 microseconds long and repeat at rates from 1-1000 pulses/second. Where supplied in bursts, pulses may be grouped into bursts of 1-100 pulses/burst, with a burst rate of 1-100 bursts/second. 
         [0064]    In some embodiments, pulsed waveforms are delivered to the electrode array  142 .  FIG. 3D  shows an exemplary sequence of pulses that can be delivered to the electrode array  142  by the drive circuitry  372 . A burst of three pulses, each spaced apart by 5 ms is delivered to each of the 16 channels. The pulses in neighboring channels are offset from one another by 312.5 μs. The burst of pulses repeats every 20 ms. The width of each pulse can be varied from 0.3-60 is to control an intensity of neurostimulation (e.g., a pulse having a width of 0.3 is will cause a smaller amount of neurostimulation than a pulse having a width of 60 μs). 
         [0065]      FIG. 4A  shows a method of operation  400  of a controller  120  as described in  FIGS. 2A, 2B and 3A . A patient attaches a mouthpiece  140  to a controller  120  (step  404 ). The patient turns on the controller  120  (step  408 ) using, for example, a power button. The patient places the controller  120  around his/her neck (step  412 ) as shown in  FIG. 1B . The patient places a mouthpiece  140  in his/her mouth (step  416 ). The patient initiates a therapy session by pressing a start/stop button (step  420 ). During the therapy session, the controller  120  delivers electrical signals to the mouthpiece  140 . The patient calibrates the intensity of the electrical signals (step  424 ). The patient raises the intensity of the electrical signals delivered to the mouthpiece by pressing an intensity-up button until the neurostimulation is above the patient&#39;s sensitivity level. The patient presses an intensity-down button until the neurostimulation is comfortable and non-painful. After the calibration step, the patient performs a prescribed exercise (step  428 ). The exercise can be cognitive, mental, or physical. In some embodiments, physical exercise includes the patient attempting to maintain a normal posture or gait, the patient moving his/her limbs, or the patient undergoing speech exercises. Cognitive exercises can include “brain training” exercises, typically computerized, that are designed to require the use of attention span, memory, or reading comprehension. Mental exercises can include visualization exercises, meditation, relaxation techniques, and progressive exposure to “triggers” for compulsive behaviors. 
         [0066]    In some embodiments, the patient can rest for a period of time during the therapy session (e.g. the patient can rest for 2 minutes during a 30 minute therapy session). After a predetermined period of time (for example, thirty minutes) has elapsed, the therapy session ends (step  432 ) and the controller  120  stops delivering electrical signals to the mouthpiece  140 . In some embodiments, the intensity of electrical signals increases from zero to the last use level selected by the patient over a time duration in the range of 1-5 seconds after the patient starts a therapy session by pressing the start/stop button. In some embodiments, the intensity of electrical signals is set to a fraction of the last use level selected by the patient (e.g. ¾ of the last level selected) after the patient starts a therapy session by pressing the start/stop button. In some embodiments, the intensity of electrical signals increases from zero to a fraction of the last use level selected by the patient (e.g. ¾ of the last level selected) over a time duration in the range of 1-5 seconds after the patient starts a therapy session by pressing the start/stop button. In some embodiments, the intensity of electrical signals increases instantaneously from zero to the last use level selected by the patient after the patient starts a therapy session by pressing the start/stop button. 
         [0067]    In some embodiments, the mouthpiece  140  is connected to the controller  120  after the controller  120  is turned on. In some embodiments, the mouthpiece  140  is connected to the controller  120  after the controller  120  is donned by the patient. In some embodiments, the patient calibrates the intensity of the electrical signals before initiating a therapy session. In some embodiments, a patient performs an initial calibration of the intensity of electrical signals in the presence of a clinician and does not calibrate the intensity of the electrical signals during subsequent treatments performed in the absence of a clinician. 
         [0068]      FIG. 4B  shows a method of operation  449  of the non-invasive neurostimulation system  100  described in  FIGS. 2C and 3B . A patient activates a mobile device  121  (step  450 ). The patient places a mouthpiece  140  in his/her mouth (step  454 ). The patient initiates a therapy session by pressing a start/stop button within an application running on the mobile device  121  (step  458 ). During the therapy session, circuitry within the mouthpiece  140  delivers electrical signals to an electrode array  142  located on the mouthpiece  140 . The patient calibrates the intensity of the electrical signals (step  462 ). The patient first raises the intensity of the electrical signals delivered to the mouthpiece  140  by pressing an intensity-up button located within an application running on the mobile device  121  until the neurostimulation is above the patient&#39;s sensitivity level. The patient presses an intensity-down button running within an application on the mobile device  121  until the neurostimulation is comfortable and non-painful. After the calibration step, the patient performs a prescribed exercise (step  464 ). The exercise can be cognitive, mental, or physical. In some embodiments, the patient can rest for a period of time during the therapy session (e.g. the patient can rest for 5 minutes during a 30 minute therapy session). After a predetermined period of time (for example, thirty minutes) has elapsed, the therapy session ends (step  468 ) and the circuitry located within the mouthpiece  140  stops delivering electrical signals to the electrode array  142 . In some embodiments, the calibration of the intensity of the electrical signals takes place before the patient initiates a therapy session. 
         [0069]      FIGS. 5A-5F  show a mouthpiece  500 . The mouthpiece  500  includes a housing  504 , a spacer  508 , a transition region  520 , a posterior region  524 , an anterior region  528 , a printed circuit board  532 , internal circuitry  533 , an electrode array  542 , and a cable  544 . The housing  504  includes an outer shell  505 , longitudinal ribs  550 , transverse ribs  551 , columns  552 , valleys  553 , shoring  554 , pockets  555 , and a platform  558 . The mouthpiece  500  has three regions, a posterior region  524 , a transition region  520 , and an anterior region  528 . The transition region  520  smoothly connects the anterior region  528  with the posterior region  524 . The printed circuit board  532  attaches to the bottom side of the housing  504 . The internal circuitry  533  is mounted to the top side of the printed circuit board  532  and is covered by the housing  504 . The cable  544  is in communication with the internal circuitry  533  and the internal circuitry  533  is in communication with the electrode array  542 . The outer shell  505  of the housing  504  has an exemplary thickness in the range of 0.5 to 2 mm. The outer shell can be made of glass filled nylon, nylon, acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyether ether ketone (PEEK), alloy metal, or metal, having a compression strength in the range of 375 to 590 N. In some embodiments, the outer shell  505  has two different thicknesses. For example, the anterior region of the outer shell  505  can have a thickness in the range of 1.2 to 2 mm and the posterior region can have a thickness in the range of 0.5 to 1.2 mm. The thickness of the outer shell  505  can vary smoothly in the transition region such that there are no discontinuities or steps in the thickness of the outer shell  505 . In some embodiments, the thickness of the outer shell  505  in the anterior region is chosen to withstand biting by the patient. In some embodiments, the thickness of the outer shell  505  in the posterior region is selected to provide retention of the mouthpiece  500 , thereby preventing accidental ejection of the mouthpiece  500 . By itself, the outer shell  505  cannot withstand biting forces from the patient (e.g., the outer shell undergoes significant deflections and/or experiences plastic deformation). The longitudinal ribs  550 , transverse ribs  551 , columns  552 , shoring  554 , and platform  558  can provide structural support for the outer shell  505  to prevent damage due to biting by the patient. The longitudinal ribs  550  can extend longitudinally along the housing  504 . The longitudinal ribs  550  can be regularly spaced, creating valleys  553  therebetween as shown in  FIG. 5E . Internal circuitry  533  can be located in the valleys  553 . In an exemplary embodiment, the longitudinal ribs  550  have a width in the range of 0.5 to 2 mm, and a height that varies from approximately 6 mm in the posterior region  524  to 1 mm in the anterior region  528 . In some embodiments, the longitudinal ribs are irregularly spaced, with the spacing between ribs being larger towards the perimeter of the outer shell  505  and smaller towards a central portion of the outer shell  505 . In some embodiments, the longitudinal ribs are separated by a distance in the range of 4 to 9.0 mm as measured from center to center. The transverse ribs  551  can be located in the posterior region  524  and traverse a width of the housing  504 . The transverse ribs can be spaced regularly, as shown in  FIG. 5E . In an exemplary embodiment, the transverse ribs  551  have a width of in the range of 0.5 to 1.5 mm, and a height of in the range of 4 to 7 mm. In some embodiments, the transverse ribs  551  can intersect with the longitudinal ribs  550 , creating pockets  555  as shown in  FIG. 5E . Internal circuitry  533  can be located in the pockets  555 . In some embodiments, the transverse ribs are irregularly spaced, with the spacing between ribs being larger towards the perimeter of the outer shell  505  and smaller towards a central portion of the outer shell  505 . The column  552  can have a rectangular cross section and be located in an anterior region  528  of the housing  504 . In some embodiments, one or more columns  552  are regularly spaced and traverse a width of the housing  504 . The columns  552  can provide resistance to compressive forces exerted on the mouthpiece  500 , thereby providing protection of the internal circuitry  533 . The columns  552  can have a thickness in the range of 0.5 to 2 mm. In some embodiments, the height of the columns  552  is greater than the thickness of the internal circuitry  533 , thereby providing a clearance between the internal circuitry  533  and the outer shell  505 . In some embodiments, the height of the columns  552  is at least 1 mm greater than the thickness of the internal circuitry  533 . In some embodiments, the platform  558  is directly connected to one or more longitudinal ribs and one or more transverse ribs, thereby providing increased capacity to withstand shear and compressive loads. The thickness of the platform  558  can be in the range of 1.5 to 3.5 mm. In some embodiments, the shoring  554  includes a layer of material with a thickness greater than the thickness of the outer shell  505 . The thickness of the shoring  554  can be in the range of 0.5 to 2 mm. In some embodiments, the thickness of the outer shell  505  is smaller in the region of the shoring  554  than in other regions to accommodate the spacer  508 . For example, the thickness of the outer shell can be 1.5 mm in the anterior and posterior regions and 0.5 mm in the region of the shoring  554 . During operation, a patient places a portion of the mouthpiece  500  in his/her mouth to engage in an NINM therapy session. The patient bites down on the mouthpiece  500  with his/her front teeth to secure a position of the mouthpiece. The patient&#39;s bottom teeth contact the printed circuit board  532  and the patient&#39;s tongue contacts the electrode array  542 . In some embodiments, the patient relaxes his/her mouth to secure a position of the mouthpiece. The internal circuitry delivers electrical neurostimulation signals to the patient&#39;s tongue via the electrode array  542 . In some embodiments, the spacer  508  can provide a soft and comfortable bite surface so that stress is not concentrated at small areas where the patient&#39;s teeth contact the mouthpiece  500  during biting. For example, the spacer  508  can be made from thermoplastic polyurethane (TPU), thermoplastic elastomer (TPE), or silicone. In some embodiments, the transverse ribs  551  are located in the anterior region and traverse a width of the housing  504 . 
         [0070]      FIGS. 6A-6B  show a more detailed view of the outer shell  505 . The outer shell includes a glue well  570 , internal fins  561  and  562 , and a central longitudinal axis  590 . The internal fins include at least one pair of entrance fins  561 . The entrance fins  561  can be symmetric about the longitudinal axis  590  and can guide the cable  544  along the longitudinal axis  590  without causing substantial bending thereof. A glue, adhesive, or epoxy can provide a rigid mechanical connection between the cable  544  and the entrance fins  561 . For example, the glue, adhesive, or epoxy can be a UV cured adhesive, or cyanoacrylate. The internal fins also in include an even number of guiding fins  562 . In some embodiments, the internal fins include an odd number of guiding fins  562 . For example, the internal fins can include three guiding fins. In some embodiments, the guiding fins  562  are not symmetric about the longitudinal axis  590 , with each guiding fin  562  causing an approximately 90 degree bend in the cable  544 , and each bend having a radius of curvature approximately equal to two diameters of the cable  544 . In some embodiment, each guiding fin  562  causes a bend in the cable  544  of greater than 90 degrees, but less than 180 degrees. The guiding fins  562  are in mechanical contact with the cable  544  and provide frictional resistance that compensates for any tensile strain applied to the cable, for example due to longitudinal forces applied along the cable  544 . In some embodiments, the guiding fins  562  provide frictional resistance of at least 100 Newtons. In some embodiments, the guiding fins provide frictional resistance greater than the weight of the mouthpiece. In some embodiments, the guiding fins provide frictional resistance greater than the forces required to disconnect the mouthpiece  140  from the controller  120 . In some embodiments, a rubber grommet  563  provides an elastic mechanical attachment between the outer shell  505  and the cable  544  with the outer shell  505  providing a resistance that counteracts any bending strain applied to the cable  544  (e.g., the patient may accidentally pull or tug on the cable while the mouthpiece  500  is secured within the patient&#39;s mouth). In some embodiments, the spacer  508  includes an elastomeric element that provides a mechanical connection between the cable  544  and the entrance fins  561 . The elastomeric element provides a frictional force that provides a frictional resistance that counteracts any bending stress applied to the cable  544 . In some embodiments, the cable  544  can exit the outer shell at a 90 degree angle and be attached to the outer shell by an epoxy, the epoxy providing mechanical resistance of up to 100 Newtons to accommodate bending strains induced by the patient. In some embodiments, the cable  544  is attached to the outer shell by an adhesive or glue. In some embodiments, the cable  544  can exit the outer shell at a 90 degree angle and be mechanically attached to the outer shell by a right-angled elastomeric element, the right-angled elastomeric element interlocking with the outer shell and providing mechanical resistance of up to 100 Newtons to accommodate both bending and tensile strains induced by the patient. 
         [0071]      FIG. 6C  shows a more detailed cross sectional view of the glue well  570 . The glue well  570  is located along an outer boundary of the outer shell  505  and accommodates an adhesive (e.g., a biomedical compatible epoxy or glue) that provides a mechanical connection between the printed circuit board  532  and the outer shell  505 . The glue well  570  includes a beveled lip  571 , and a discontinuously connected cross-section that includes a concave portion  572  and a vertical portion  573  that intersect to form a lowest point of the glue well  570 . In some embodiments, the shape of the glue well can be trapezoidal. In some embodiments, the shape of the glue well can be wedged. In some embodiments, the shape of the glue well can be triangular. In some embodiments, the shape of the glue well can be rectangular. In some embodiments, a portion of the glue well can overhang the printed circuit board  532 , thereby protecting portions of the printed circuit board from the teeth of the patient. In some embodiments, the adhesive is in contact with the outer shell  505  and the top of the printed circuit board  532 . In some embodiments, the adhesive is in contact with the outer shell  505  and the top and side portions of the printed circuit board  532 . In some embodiments, the glue well is shaped such that the adhesive is in contact with the outer shell  505  and the side portions of the printed circuit board  532 , but only has negligible contact with the top portion of the printed circuit board  532  (e.g., the glue well can have a width greater than a depth). 
         [0072]      FIG. 6D  shows an embodiment where the outer shell  505  includes two glue wells,  570  and  574 . A first glue well  570  and a second glue well  574  are located along an outer boundary of the outer shell  505  and accommodate an adhesive (e.g., a biomedical compatible epoxy) that provides a mechanical connection between the printed circuit board  532  and the outer shell  505 . The second glue well  574  is designed to accommodate a glue or adhesive that overflows from the first glue well  570 , thereby preventing glue or adhesive from overflowing onto the bottom side of the printed circuit board. A step  578  is positioned between the first and second glue well to define the height of the first glue well. 
         [0073]      FIGS. 7A-7C  show a mouthpiece  700 . The mouthpiece  700  includes an outer shell  705  having a central longitudinal axis  790 , a spacer  708 , a cable  744 , a sleeve  764 , exit fins  761 , a glue well  770 . The sleeve  764  is integrated with the cable  744  and mechanically couples the cable  744  with the outer shell  705 . The sleeve  764  includes two tapered outer portions  765  and a gap  766  separating the two tapered outer portions. 
         [0074]    The cable  744  can be pulled towards the outer shell  705  until the gap  766  is aligned with an outer boundary of the mouthpiece  700 . Once aligned with the outer shell  705 , the sleeve  764  provides a mechanical resistance of up to 100 Newtons to counteract both tensile and bending stresses applied to the cable  744 . The cable  744  may additionally be clamped between the printed circuit board  732  and the outer shell  705  as shown in  FIG. 7C . The additional clamping can provide additional mechanical resistance to tensile stresses applied to the cable  744 . 
         [0075]      FIGS. 8A-8D  show a mouthpiece  800 . The mouthpiece  800  includes an outer shell  805 , a spacer  808 , a printed circuit board  832 , a cable  844 , a sleeve  864 , a glue well  870 , and a clamp  809 . A posterior portion of the cable  844  is connected to the printed circuit board  832  via solder, ribbon connector, or other mechanical connection. The sleeve  864  is integrated with the cable  844  and mechanically couples the cable  844  with the outer shell  805  and clamp  809 . The sleeve  864  is similar to the sleeve  764 , having two tapered outer portions and a gap. Instead of being pulled through the outer shell  805  as shown in  FIG. 7 , the sleeve  864  is secured by a clamp  809  that connects to a bottom portion of the outer shell  805 . The clamp  809  mechanically secures the printed circuit board  832  to the outer shell  805  and in addition, secures the sleeve  864  to the outer shell  805 . In some embodiments, adhesive or glue is added to the glue well  870  to secure the printed circuit board  832  to the outer shell  805 . The sleeve  864  provides mechanical resistance (up to 100 Newtons) to bending stresses and tensile stresses in the cable  844 . The clamp  809  includes a rigid plastic portion  809   b  and an elastomeric portion  809   a . The rigid plastic portion  809   b  provides structural integrity, while the elastomeric portion  809   a  provides a sealing mechanism. For example, the clamp  809  can be placed into contact with the outer shell  805  as shown in  FIG. 8D . A narrow protrusion  810  extends from the rigid plastic portion  809   b  of the clamp  809 , the narrow protrusion  810  interlocking with a recessed portion  806  of the outer shell  805 . The elastomeric portion  809   a  contacts the outer shell  805 , the glue well  870 , and the printed circuit board  832 , forming an air tight seal. The air tight seal can protect portions of the printed circuit board  832  from moisture. In some embodiments, the clamp  809  is secured to the outer shell  805  by adding an adhesive or glue to the glue well  870  that contacts both the outer shell and the clamp. 
         [0076]      FIGS. 9A-9C  show a mouthpiece  900 . The mouthpiece  900  includes an outer shell  905 , a printed circuit board  932 , a cable  944 , a glue well  970 , a boot  945 . The outer shell  905  includes a valley  971  and a glue well  970 . The valley  971  guides the cable  944  within the outer shell  905 , and the glue well  970  accommodates an epoxy or other adhesive to provide a mechanical connection between the printed circuit board  932 , the outer shell  905 , and the cable  944 . The shape of the glue well  970  can be a wedge shape to advantageously provide an interface between the adhesive or epoxy and the printed circuit board  932 , the outer shell  905 , and the cable  944 . A protrusion  946  extends from the outer shell  905  and interlocks with a recessed portion  947  of the boot  945 . The interlocked boot  945  is in mechanical contact along an outer diameter of the cable  944  (e.g., the interlocked boot  945  can be in contact with the outer diameter of the cable  944  for a distance in the range of 0.5 to 10 mm). In some embodiments, the interlocked boot  945  can be overmolded, or glued onto the cable  944 . In some embodiments, the interlocked boot  945  is mechanically coupled to the cable  944 . The interlocked boot  945  can provide mechanical resistance to tugging or pulling (e.g., up to 100 Newtons) of the cable by the patient. In some embodiments, the interlocked boot can provide resistance to both bending strains and tensile strains. In some embodiments, the boot  945  can cover the glue well  970 . In some embodiments, the boot  945  can be extended to cover portions of the printed circuit board  932  that are not covered by an electrode array. 
         [0077]      FIGS. 10A-10C  show a mouthpiece  1000 . The mouthpiece  1000  includes an outer shell  1005 , a printed circuit board  1032 , a cable  1044 , a valley  1071 , a sealing ring  1081 , and clips  1080 . Epoxy and/or adhesives are not present in mouthpiece  1000 . The printed circuit board  1032  contacts the sealing ring  1081  and is held in place by clips  1080 . The clips  1080  can have vertical sidewall and a downward sloping overhang as shown in  FIG. 10B . In some embodiments, the clips are spaced along an inner boundary of the outer shell  1005 . The cable  1044  is electrically connected to the printed circuit board  1032 . Additionally, the sealing ring  1081  forms an aperture at an anterior region of the outer shell  1005 , with the cable  1044  passing through the aperture. The valley  1071  guides the cable  1044  from the printed circuit board  1132  to the aperture. The aperture is in contact with the cable  1044  and provides resistance to tugging or pulling of the cable  1044  by the patient. In some embodiments, the aperture can provide resistance to both bending and tensile strains on the cable  1044 . In some embodiments, the sealing ring  1081  is composed of a low durometer elastomer such as TPE, TPU, or silicone. In some embodiments, the sealing ring can be replaced by a glue well or a layer of glue. 
         [0078]      FIGS. 11A-11C  show a mouthpiece  1100 . The mouthpiece  1100  includes an outer shell  1105 , a printed circuit board  1132 , a cable  1144 , and a fastener  1191 . The outer shell includes a glue well  1170 , a valley  1171 , and a port  1172  shaped to accommodate the fastener  1191 . The glue well  1170  can accommodate an epoxy or other adhesive that connects the outer shell  1105  to the printed circuit board  1132 . The cable  1144  is attached to the printed circuit board  1132  via solder, ribbon cable, or other mechanical connector. The cable rests in the valley  1171  before exiting at port  1172 . An O-ring surrounds the cable  1144  at the port  1172 . The fastener  1191  attaches to the outer shell  1105  at the position of the port  1172 . The fastener applies a force to the O-ring that holds the cable in place at the port. The O-ring together with the fastener  1172  protect the cable from pulling or tugging by the patient. In some embodiments, the O-ring and the fastener  1172  provide resistance to both bending and tensile strain. In some embodiments, an epoxy or adhesive surrounds the cable  1144  at the port  1172 . 
         [0079]      FIG. 12  shows a method  1200  of manufacturing a mouthpiece such as the mouthpiece shown in  FIG. 5 . Initially, a housing is provided (step  1204 ). A spacer is attached to the housing (step  1208 ). In some embodiments, the spacer is molded directly onto the housing. In some embodiments, the spacer attached to the housing via an adhesive or glue. The housing is attached to the printed circuit board (step  1212 ). In some embodiments, the housing is molded directly onto the printed circuit board. The molded housing can wrap around the edge of the printed circuit board and create a lip on the bottom side of the printed circuit board for better engagement. In some embodiments, features can be added to the printed circuit board (e.g., countersunk holes, beveled edge of the board, stepped edge of the board, tongue and groove edge of the board) such that when the molded housing is molded onto the board, the plastic hardens around the features to create better engagement. In some embodiments, the housing is attached to the printed circuit board via an adhesive and/or mechanical clips. In some embodiments, the housing is attached to the printed circuit board by a mechanical bond. In some embodiments, the housing is attached to the printed circuit board by a chemical bond. In some embodiments, the attached housing covers and encapsulates surface mounted electronics on the printed circuit board, while leaving the electrode array exposed such that the electrode array can be placed in contact with a patient&#39;s tongue for NINM therapy. A cable is provided (step  1216 ). The cable is connected to the printed circuit board (step  1220 ). In some embodiments, the cable is connected to the printed circuit board prior to the housing being molded onto the printed circuit board. The cable can be partially encapsulated by the housing after the molding process. In some embodiments, the housing is molded onto the printed circuit board in two steps. In a first step a first shot of plastic can be molded onto the board, where the mold temperatures and pressures are low enough that it is not hazardous to the electrical components on the board. The first shot can be used to pot the components, thereby protecting them. The first shot can be a softer material (TPE, TPU) or a rigid material with a lower mold pressure and/or temperature (Polyamide, Polyolefin). A second shot is molded over at least a portion of the first shot, where mold temperatures and pressures are higher than the first shot. This second shot may be of harder, more durable materials (e.g., nylon or glass filled nylon, ABS, PC, etc.). In some embodiments, the housing is molded onto, and completely surrounds the printed circuit board, such that only the electrode array is not covered by the housing. In this situation, the printed circuit board material would not come into contact with the patient, thereby protecting the patient in the case of harmful printed circuit board materials. In some embodiments, the electrode array is non-planar with the printed circuit board (e.g., the electrode array can protrude by a distance in the range of 0.1 to 1 mm from the printed circuit board). In some embodiments, the electrode array is an array of pins that protrude from the printed circuit board. The array of pins remains exposed after molding the housing onto the printed circuit board. 
         [0080]      FIGS. 13A and 13B  show a mouthpiece  1300  that has been manufactured by overmolding a housing  1304  directly onto a printed circuit board  1332 . The mouthpiece  1300  includes a spacer  1308  and a cable  1344 . In some embodiments, the printed circuit  1332  board includes features for mechanically engaging the molded housing  1304  (e.g., a beveled edge of the board, a stepped edge of the board, a notched edge of the board etc.). In some embodiments, the molded housing  1304  can wrap around the edge of the printed circuit board  1332  and create a lip on the bottom side of the printed circuit board to mechanically engage the printed circuit board  1332 . In some embodiments, the printed circuit board includes countersunk holes  1340 . The countersunk holes are filled with plastic as the housing  1304  is molded onto the printed circuit board. A rivet forms inside the countersunk hole  1340 , with the rivet being an integral portion of the housing  1304 . The tapered shape of the rivet provides a force that holds the printed circuit board  1332  in mechanical contact with the housing  1304 . 
         [0081]      FIG. 14  shows a mouthpiece  1400  according to a two shot injection molding manufacturing method wherein a shot refers to the volume of material that is used to fill a mold cavity and compensate for material shrinkage. The mouthpiece  1400  includes a housing  1404 , a printed circuit board  1432 , a cable  1444 , and a frame  1450 . The frame  1450  is formed around the printed circuit board (one or both sides)  1432  during a first shot, which provides a seal between the printed circuit board and the external environment. The housing  1404  is formed around the printed circuit board  1432  and frame  1450  during a second shot, thereby encapsulating the components on the printed circuit board  1432  and chemically bonding to the frame  1450 . The first and second shots can be rigid, elastomeric, or a combination of both. 
         [0082]    The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting of the inventive concepts. It will be understood that, although the terms first, second, third etc. are used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the present application. 
         [0083]    While the present inventive concepts have been particularly shown and described above with reference to exemplary embodiments thereof, it will be understood by those of ordinary skill in the art, that various changes in form and detail can be made without departing from the spirit and scope of the present inventive concepts described and defined by the following claims.

Technology Classification (CPC): 0