Patent Description:
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.

A stroke is a loss of brain function due to a disturbance in the blood supply to the brain. Every year, about <NUM>,<NUM> 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.

Multiple sclerosis (MS) is a disease that causes damage to the nerve cells in the brain and spinal cord. Globally, there are about <NUM> 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.

Alzheimer's disease (AD) is a neurodegenerative disorder affecting over <NUM> 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.

Parkinson's disease (PD) is a degenerative disorder of the central nervous system, affecting more than <NUM> million people globally. Symptoms of PD include tremor, bradykinesia, rigidity, postural instability, cognitive disturbances, and behavior and mood alterations.

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.

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. A publication by Yuri P. Danilov et al describes a system for intraoral application of neurostimulation (<NPL>).

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's, Parkinson's, depression, memory loss, compulsive behavior, or any other neurological impairment.

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.

<FIG> shows a patient <NUM> undergoing non-invasive neuromodulation therapy (NINM) using a neurostimulation system <NUM>. During a therapy session, the neurostimulation system <NUM> non-invasively stimulates various nerves located within the patient'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 <CIT>.

<FIG> show a non-invasive neurostimulation system <NUM>. The non-invasive neurostimulation system <NUM> includes a controller <NUM> and a mouthpiece <NUM>. The controller <NUM> includes a receptacle <NUM> and pushbuttons <NUM>. The mouthpiece <NUM> includes an electrode array <NUM> and a cable <NUM>. The cable <NUM> connects to the receptacle <NUM>, providing an electrical connection between the mouthpiece <NUM> and the controller <NUM>. In some embodiments, the controller <NUM> includes a cable. In some embodiments, the mouthpiece <NUM> and the controller <NUM> are connected wirelessly (e.g., without the use of a cable). During operation, a patient activates the neurostimulation system <NUM> by actuating one of the pushbuttons <NUM>. In some embodiments, the neurostimulation system <NUM> periodically transmits electrical pulses to determine if the electrode array <NUM> is in contact with the patient'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 <NUM>. In some embodiments, the neurostimulation system <NUM> periodically transmits electrical pulses to determine if the electrode array <NUM> is in contact with the patient'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 <NUM> has pushbuttons on both arms. In some embodiments, a mobile device can be used in conjunction with the controller <NUM> and the mouthpiece <NUM>. The mobile device can include a software application that allows a user to activate the neurostimulation system <NUM> 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 <NUM> includes a secure cryptoprocessor that holds a secret key, to be described in more detail below in connection with <FIG>. 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.

<FIG> shows a non-invasive neurostimulation system <NUM>. As shown, a mobile device <NUM> is in communication with a mouthpiece <NUM>. More specifically, the mobile device <NUM> includes a processor running a software application that facilitates communications with the mouthpiece <NUM>. The mobile device <NUM> can be, for example, a mobile phone, a portable digital assistant (PDA), or a laptop. The mobile device <NUM> can communicate with the mouthpiece <NUM> by a wireless or wired connection. During operation, a patient activates the neurostimulation system <NUM> via the mobile device <NUM>. 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 <NUM>. 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.

<FIG> shows the internal circuitry housed within the controller <NUM>. The circuitry includes a microcontroller <NUM>, isolation circuitry <NUM>, a universal serial bus (USB) connection <NUM>, a battery management controller <NUM>, a battery <NUM>, a push-button interface <NUM>, a display <NUM>, a real time clock <NUM>, an accelerometer <NUM>, drive circuitry <NUM>, tongue sense circuitry <NUM>, audio feedback circuitry <NUM>, vibratory feedback circuitry <NUM>, and a non-volatile memory <NUM>. The drive circuitry <NUM> includes a multiplexor, and an array of resistors to control voltages delivered to the electrode array <NUM>. The microcontroller <NUM> is in electrical communication with each of the components shown in <FIG>. The isolation circuitry <NUM> provides electrical isolation between the USB connection <NUM> and all other components included in the controller <NUM>. Additionally, the circuitry shown in <FIG> is in communication with the mouthpiece <NUM> via the external cable <NUM>. During operation, the microcontroller <NUM> receives electrical power from battery <NUM> and can store and retrieve information from the non-volatile memory <NUM>. The battery can be charged via the USB connection <NUM>. The battery management circuitry controls the charging of the battery <NUM>. A patient can interact with the controller <NUM> via the push-button interface <NUM> that converts the patient'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 <NUM>. For example, a therapy session can be started when the patient presses a start/stop button after powering on the controller <NUM>. During the therapy session, the drive circuitry <NUM> provides an electrical signal to the mouthpiece <NUM> via the cable <NUM>. The electrical signal is communicated to the patient's intraoral cavity via the electrode array <NUM>. The accelerometer <NUM> can be used to provide information about the patient's motion during the therapy session. Information provided by the accelerometer <NUM> can be stored in the non-volatile memory <NUM> 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 <NUM> can be used to determine if the patient is engaged in a physical activity. Based on the information received from the accelerometer <NUM>, the microcontroller <NUM> can determine an activity level of the patient during a therapy session. For example, if the patient engages in a physical activity for <NUM> minutes during a therapy session, the accelerometer <NUM> can periodically communicate (e.g. once every second) to the microcontroller <NUM> that the sensed motion is larger than a predetermined threshold (e.g. greater than <NUM>/s<NUM>). In some embodiments, the accelerometer data is stored in the non-volatile memory <NUM> during the therapy session and transmitted to the mobile device <NUM> after the therapy session has ended. After the therapy session has ended, the microcontroller <NUM> 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'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 <NUM> 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) <NUM> provides time and date information to the microcontroller <NUM>. In some embodiments, the controller <NUM> is authorized by a physician for a predetermined period of time (e.g., two weeks). The RTC <NUM> periodically communicates date and time information to the microcontroller <NUM>. In some embodiments, the RTC <NUM> is integrated with the microcontroller. In some embodiments, the RTC <NUM> is powered by the battery <NUM>, and upon failure of the battery <NUM>, the RTC <NUM> is powered by a backup battery. After the predetermined period of time has elapsed, the controller <NUM> can no longer initiate the delivery of electrical signals to the mouthpiece <NUM> and the patient must visit the physician to reauthorize use of the controller <NUM>. The display <NUM> displays information received by the microcontroller <NUM> to the patient. For example, the display <NUM> can display the time of day, therapy information, battery information, time remaining in a therapy session, error information, and the status of the controller <NUM>. The audio feedback circuitry <NUM> and vibratory feedback circuitry <NUM> can give feedback to a user when the device changes state. For example, when a therapy session begins, the audio feedback circuitry <NUM> and the vibratory feedback circuitry <NUM> 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's needs. The tongue sense circuitry <NUM> measures the current passing from the drive circuitry to the electrode array <NUM>. Upon sensing a current above a predetermined threshold, the tongue sense circuitry <NUM> presents a high digital signal to the microcontroller <NUM>, indicating that the tongue is in contact with the electrode array <NUM>. If the current is below the predetermined threshold, the tongue sense circuitry <NUM> presents a low digital signal to the microcontroller <NUM>, indicating that the tongue is not in contact or is in partial contact with the electrode array <NUM>. The indications received from the tongue sense circuitry <NUM> can be stored in the non-volatile memory <NUM>. In some embodiments, the display <NUM> can be an organic light emitting diode (OLED) display. In some embodiments, the display <NUM> can be a liquid crystal display (LCD). In some embodiments, a display <NUM> is not included with the controller <NUM>. In some embodiments, neither the controller <NUM> nor the mouthpiece <NUM> includes a cable, and the controller <NUM> communicates wirelessly with the mouthpiece <NUM>. In some embodiments, neither the controller <NUM> nor the mouthpiece <NUM> includes an accelerometer. In some embodiments, the drive circuitry <NUM> is located within the mouthpiece. In some embodiments, a portion of the drive circuitry <NUM> is located within the mouthpiece <NUM> and a portion of the drive circuitry <NUM> is located within the controller <NUM>. In some embodiments, neither the controller <NUM> nor the mouthpiece <NUM> includes tongue sense circuitry <NUM>. In some embodiments, the mouthpiece <NUM> includes a microcontroller and a multiplexer.

<FIG> shows a more detailed view of <FIG>. The mouthpiece <NUM> includes a battery <NUM>, tongue sense circuitry <NUM>, an accelerometer <NUM>, a microcontroller <NUM>, drive circuitry <NUM>, a non-volatile memory <NUM>, a universal serial bus controller (USB) <NUM>, and battery management circuitry <NUM>. During operation, the microcontroller receives electrical power from battery <NUM> and can store and retrieve information from the non-volatile memory <NUM>. The battery can be charged via the USB connection <NUM>. The battery management circuitry <NUM> controls the charging of the battery <NUM>. A patient can interact with the mouthpiece <NUM> via the mobile device <NUM>. The mobile device <NUM> includes an application (e.g. software running on a processor) that allows the patient to control the mouthpiece <NUM>. 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 <NUM>. When the patient presses a button presented by the application running on the mobile device <NUM>, a signal is transmitted to the microcontroller <NUM> housed within the mouthpiece <NUM>. For example, a therapy session can be started when the patient presses a start/stop button on the mobile device <NUM>. During the therapy session, the drive circuitry <NUM> provides an electrical signal to an electrode array <NUM> located on the mouthpiece <NUM>. The accelerometer <NUM> can be used to provide information about the patient's motion during the therapy session. The information provided by the accelerometer <NUM> can be used to determine if the patient is engaged in a physical activity. Based on the information received from the accelerometer <NUM>, the microcontroller <NUM> can determine an activity level of the patient during a therapy session. For example, if the patient engages in a physical activity for <NUM> minutes during a therapy session, the accelerometer <NUM> can periodically communicate (e.g. once every second) to the microcontroller <NUM> that the sensed motion is larger than a predetermined threshold (e.g. greater than <NUM>/s<NUM>). After the therapy session has ended, the microcontroller <NUM> can record the amount of time during the therapy session in which the patient was active. In some embodiments, the accelerometer <NUM> is located within the mobile device <NUM> and the mobile device <NUM> determines an activity level of a patient during the therapy session based on information received from the accelerometer <NUM>. The mobile device can then record the amount of time during the therapy session in which the patient was active. The mobile device <NUM> includes a real time clock (RTC) <NUM> that provides time and date information to the microcontroller <NUM>. In some embodiments, the mouthpiece <NUM> 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 <NUM> can no longer deliver electrical signals to the patient via the electrode array <NUM> and the patient must visit the physician to reauthorize use of the mouthpiece <NUM>. In some embodiments, the mouthpiece <NUM> includes pushbuttons (e.g., an on/off button) and a patient can manually operate the mouthpiece <NUM> via the pushbuttons. After a therapy session, the mouthpiece <NUM> can transmit information about the therapy session to a mobile device. In some embodiments, the mouthpiece <NUM> does not include a USB controller <NUM> and instead communicates only via wireless communications with the controller.

<FIG> shows a more detailed view of the electrode array <NUM>. The electrode array <NUM> can be separated into <NUM> groups of electrodes, labelled a-i, with each group having <NUM> electrodes, except group b which has <NUM> electrodes. Each electrode within the group corresponds to one of <NUM> electrical channels. During operation, the drive circuitry can deliver a sequence of electrical pulses to the electrode array <NUM> to provide neurostimulation of at least one of the patient'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 <NUM> volts or <NUM>% of a maximum value, the pulse amplitude of electrical signals delivered to groups d-f can be <NUM> volts or <NUM>% of the maximum value, the pulse amplitude of electrical signals delivered to groups g-h can be <NUM> volts or <NUM>% of the maximum value, and the pulse amplitude of electrical signals delivered to group i can be <NUM> volts or <NUM>% of the maximum value. In some embodiments, the maximum voltage is in the range of <NUM> to <NUM> volts. The pulses delivered to the patient by the electrode array <NUM> can be random or repeating. The location of pulses can be varied across the electrode array <NUM> 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. <NUM>-<NUM> mA and voltages of <NUM>-<NUM> volts can be used. In some embodiments, transient currents can be larger than 50mA. 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 <NUM>-<NUM> microseconds long and repeat at rates from <NUM>-<NUM> pulses/second. Where supplied in bursts, pulses may be grouped into bursts of <NUM>-<NUM> pulses/burst, with a burst rate of <NUM>-<NUM> bursts/second.

In some embodiments, pulsed waveforms are delivered to the electrode array <NUM>. <FIG> shows an exemplary sequence of pulses that can be delivered to the electrode array <NUM> by the drive circuitry <NUM>. A burst of three pulses, each spaced apart by <NUM> is delivered to each of the <NUM> channels. The pulses in neighboring channels are offset from one another by <NUM>. The burst of pulses repeats every <NUM>. The width of each pulse can be varied from. <NUM>-<NUM> to control an intensity of neurostimulation (e.g., a pulse having a width of. <NUM> will cause a smaller amount of neurostimulation than a pulse having a width of <NUM>).

<FIG> shows a method of operation <NUM> of a controller <NUM> as described in <FIG> and <FIG>. A patient attaches a mouthpiece <NUM> to a controller <NUM> (step <NUM>). The patient turns on the controller <NUM> (step <NUM>) using, for example, a power button. The patient places the controller <NUM> around his/her neck (step <NUM>) as shown in FIG. The patient places a mouthpiece <NUM> in his/her mouth (step <NUM>). The patient initiates a therapy session by pressing a start/stop button (step <NUM>). During the therapy session, the controller <NUM> delivers electrical signals to the mouthpiece <NUM>. The patient calibrates the intensity of the electrical signals (step <NUM>). 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'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 <NUM>). 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.

In some embodiments, the patient can rest for a period of time during the therapy session (e.g. the patient can rest for <NUM> minutes during a <NUM> minute therapy session). After a predetermined period of time (for example, thirty minutes) has elapsed, the therapy session ends (step <NUM>) and the controller <NUM> stops delivering electrical signals to the mouthpiece <NUM>. 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 <NUM>-<NUM> 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. <NUM>/<NUM> 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. <NUM>/<NUM> of the last level selected) over a time duration in the range of <NUM>-<NUM> 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.

In some embodiments, the mouthpiece <NUM> is connected to the controller <NUM> after the controller <NUM> is turned on. In some embodiments, the mouthpiece <NUM> is connected to the controller <NUM> after the controller <NUM> 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.

<FIG> shows a method of operation <NUM> of the non-invasive neurostimulation system <NUM> described in <FIG> and <FIG>. A patient activates a mobile device <NUM> (step <NUM>). The patient places a mouthpiece <NUM> in his/her mouth (step <NUM>). The patient initiates a therapy session by pressing a start/stop button within an application running on the mobile device <NUM> (step <NUM>). During the therapy session, circuitry within the mouthpiece <NUM> delivers electrical signals to an electrode array <NUM> located on the mouthpiece <NUM>. The patient calibrates the intensity of the electrical signals (step <NUM>). The patient first raises the intensity of the electrical signals delivered to the mouthpiece <NUM> by pressing an intensity-up button located within an application running on the mobile device <NUM> until the neurostimulation is above the patient's sensitivity level. The patient presses an intensity-down button running within an application on the mobile device <NUM> until the neurostimulation is comfortable and non-painful. After the calibration step, the patient performs a prescribed exercise (step <NUM>). 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 <NUM> minutes during a <NUM> minute therapy session). After a predetermined period of time (for example, thirty minutes) has elapsed, the therapy session ends (step <NUM>) and the circuitry located within the mouthpiece <NUM> stops delivering electrical signals to the electrode array <NUM>. In some embodiments, the calibration of the intensity of the electrical signals takes place before the patient initiates a therapy session. <FIG> show a mouthpiece <NUM>. The mouthpiece <NUM> includes a housing <NUM>, a positioning pad <NUM>, a transition region <NUM>, a posterior region <NUM>, an anterior region <NUM>, a printed circuit board <NUM>, internal circuitry, an electrode array <NUM>, and a cable <NUM>. The housing <NUM> includes chamfered or beveled surfaces <NUM>, rounds <NUM>, and a plateau <NUM>. The mouthpiece <NUM> has three regions, a posterior region <NUM>, a transition region <NUM>, and an anterior region <NUM>. The lengths of the posterior region, the transition region, and the anterior region are shown in <FIG> as LP, LT, and LA respectively. The maximum heights of the posterior region and the anterior region are shown in <FIG> as HP and HA respectively. The maximum widths of the posterior region and the anterior region are shown in <FIG> as WP and WA respectively. In some embodiments, LP is approximately <NUM>, LT is approximately <NUM>, LA is approximately <NUM>, HP is approximately <NUM>, HA is approximately <NUM>, WP is approximately <NUM>, and WA is approximately <NUM>. In some embodiments, LP is in the range of <NUM> - <NUM>, LT is in the range of <NUM> to <NUM>, LA is in the range of <NUM> to <NUM>, HP is in the range of <NUM> to <NUM>, HA is in the range of <NUM> to <NUM>, WP is in the range of <NUM> to <NUM>, and WA is in the range of <NUM> to <NUM>. The positioning pad <NUM> is attached to the housing <NUM> and can form a mesa in an anterior region <NUM> of the mouthpiece <NUM>. The transition region <NUM> smoothly connects the anterior region <NUM> with the posterior region <NUM>. The printed circuit board <NUM> attaches to the bottom side of the housing <NUM>. In some embodiments, the printed circuit board <NUM> can be attached to the housing <NUM> by an adhesive. In some embodiments, the housing <NUM> is molded directly onto the printed circuit board <NUM>. The internal circuitry is mounted to the top side of the printed circuit board <NUM> and is surrounded by the housing <NUM>. The cable <NUM> is in communication with the internal circuitry and the internal circuitry is in communication with the electrode array <NUM>.

During operation, a patient opens his/her mouth and places a portion of the mouthpiece <NUM> in his/her mouth to engage in an NINM therapy session. The patient relaxes his/her mouth to secure a position of the mouthpiece. In some embodiments, the patient bites down on the positioning pad <NUM> with his/her front teeth to secure a position of the mouthpiece. The patient's bottom teeth can contact the printed circuit board <NUM> and the patient's tongue contacts the electrode array <NUM>. The internal circuitry delivers electrical neurostimulation signals to the patient's tongue via the electrode array <NUM>. In some embodiments, the patient's molars contact a region of the printed circuit board <NUM> containing the electrode array <NUM>.

The location of the center of gravity of the mouthpiece <NUM> determines if the mouthpiece <NUM> can rest in a patient's mouth when there is no biting force applied by the patient (e.g., when the patient's mouth is open or in a relaxed position). If the center of gravity is located in an anterior region of the mouthpiece, the mouthpiece tends to fall out of the patient's mouth in the absence of an applied biting force or external mounting apparatus. If the center of gravity is located in a posterior portion of the mouthpiece, the mouthpiece will tend to rest within the patient's mouth, even in the absence of an applied biting force. Adjusting the center of gravity of the mouthpiece <NUM> can be achieved by various approaches including adjusting the density and/or volume of the anterior and posterior regions of the mouthpiece. In some embodiments, the length and/or position of the transition region <NUM> can be adjusted to locate the center of gravity within the posterior region <NUM> of the mouthpiece. In some embodiments, the posterior region of the mouthpiece corresponds to the region of the mouthpiece that rests behind the patient's teeth during an NINM therapy session. In some embodiments, the center of gravity is located behind the patient's teeth during an NINM therapy session. In some embodiments, the patient's teeth act as a fulcrum and the center of gravity of the mouthpiece rests behind the patient's teeth to allow the mouthpiece to remain in the patient's mouth, even when the patient's mouth is in a relaxed state. In some embodiments, the patient's lips act as a fulcrum and the center of gravity of the mouthpiece rests behind the patient's lips to allow the mouthpiece to remain in the patient's mouth, even when the patient's mouth is in a relaxed state.

In some embodiments, the density throughout the mouthpiece <NUM> is approximately constant and a volume of the posterior region is adjusted to locate the center of gravity of the mouthpiece within the posterior region. For example, the posterior region of the mouthpiece can have an approximately equal average length, but a larger average height and/or average width than the anterior region of the mouthpiece, resulting in a center of gravity located within the posterior region. In another example, the posterior region of the mouthpiece can have an approximately equal average width, but a larger average height and/or average length than the anterior region of the mouthpiece, resulting in a center of gravity located within the posterior region. In yet another example, the posterior region of the mouthpiece can have an approximately equal average height, but a larger average width and/or average length than the anterior region of the mouthpiece, resulting in a center of gravity located within the posterior region. In some embodiments, a chamfer or bevel located on the housing <NUM> can be adjusted to change the volume of the posterior region (e.g., increasing the size of the bevel can in turn decrease the volume of the posterior region). In some embodiments, the location of the transition region can be adjusted to change the volume of the posterior region. For example, the location of the transition region <NUM> can determine the length of the posterior region and the anterior region. For example, by moving the transition region <NUM> towards the anterior region <NUM>, the length and volume of the anterior region decrease while the length and volume of the posterior region increase, causing the center of gravity of the mouthpiece <NUM> to move towards the posterior region. In another example, by moving the transition region <NUM> towards the posterior region <NUM>, the length and volume of the posterior region decrease while the length and volume of the anterior region increase, causing the center of gravity of the mouthpiece <NUM> to move towards the anterior region. In some embodiments, the mouthpiece can be constructed from one or more of the following materials: glass filled nylon, nylon, thermoplastic polyurethane (TPU), thermoplastic elastomer (TPE), silicone, acrylonitrile butadiene styrene (ABS), and polycarbonate.

In some embodiments, the average density of the posterior region is smaller than the average density of the anterior region. The volume of the posterior region can be adjusted to locate the center of gravity of the mouthpiece within the posterior region. For example, the center of gravity can be moved to the posterior region of the mouthpiece by increasing the volume of the posterior region (e.g. by increasing the length, height, or width of the posterior region) until the product of the density of the posterior region and the volume of the posterior region is greater than the product of the density of the anterior region and the volume of the anterior region.

In some embodiments, the average density of the posterior region or anterior region is adjusted to locate the center of gravity of the mouthpiece within the posterior region (e.g., a high density material such as polytetrafluroethylene (PTFE), metal, or a metal alloy can be added and/or substituted into the posterior region to increase the average density of the posterior region). For example, the volume of the posterior region can be the same as the volume of the anterior region and the average density of the posterior region can be adjusted to be greater than the average density in the anterior region such that the center of gravity of the mouthpiece is located within the posterior region. In another example, the volume of the posterior region can be less than the volume of the anterior region and the average density of the posterior region can be adjusted to be greater than the average density in the anterior region such that the center of gravity of the mouthpiece is located within the posterior region. In yet another example, the volume of the posterior region can be greater than the volume of the anterior region and the average density of the posterior region can be adjusted to be greater than or equal to the average density in the anterior region such that the center of gravity of the mouthpiece is located within the posterior region. For example, the center of gravity can be moved to the posterior region of the mouthpiece by increasing the volume of the posterior region (e.g. by increasing the length, height, or width of the posterior region) until the volume of the posterior region is greater than the volume of the anterior region.

In some embodiments, the average density of the anterior region can be reduced to locate the center of gravity within the posterior region of the mouthpiece. For example, at least one portion of material can be removed from the interior of the anterior region of the mouthpiece, the removed portion being replaced by a material having a lower density than the removed portion (e.g., polyethylene, polypropylene, air, or vacuum), resulting in a decreased average density of the anterior region. The removal of material from the anterior region can be repeated until the product of the average density of the posterior region and the volume of the posterior region is greater than the product of the average density of the anterior region and the volume of the anterior region.

In some embodiments, a number of components can be added or removed from the printed circuit board <NUM> to adjust the center of gravity. For example, any number of resistors, capacitors, or integrated circuits can be removed from an anterior portion of the printed circuit board <NUM> such that the center of gravity of the mouthpiece is located within a posterior region <NUM> of the mouthpiece <NUM>. In some embodiments, a second printed circuit board is added to the posterior region of the mouthpiece <NUM> such that the center of gravity of the mouthpiece is located within a posterior region <NUM> of the mouthpiece <NUM>. The second printed circuit board can be located above the printed circuit board <NUM>. In some embodiments, stainless steel or other metal weights are added to the printed circuit board <NUM> such that the center of gravity of the mouthpiece is located within a posterior region <NUM> of the mouthpiece <NUM>.

In some embodiments, the weight of the cable <NUM> can be adjusted <NUM> such that the center of gravity of the mouthpiece is located within a posterior region <NUM> of the mouthpiece <NUM>. For example, the weight of the cable <NUM> can be adjusted by selecting the density of the material forming the cable. In some embodiments, a cable strain relief mechanism can be adjusted such that the center of gravity of the mouthpiece is located within a posterior region <NUM> of the mouthpiece <NUM>. For example, the total amount of material and density of material included in a strain relief mechanism can be selected to locate the center of gravity of the mouthpiece within a posterior region <NUM> of the mouthpiece <NUM>.

In some embodiments, the shape of the mouthpiece provides forces that resist pulling of the mouthpiece <NUM> out of the patient's relaxed mouth. The width of the anterior region (WA) and the height of the anterior region (HA) are selected to allow the anterior region to pass through the patient's relaxed mouth without substantially contacting the patient's inner cheeks or lips. The width of the posterior region (WP) and the height of the posterior region (HP) are selected to cause the posterior region to make substantial contact with the patient's lips and/or inner cheeks. As the mouthpiece <NUM> is pulled out of the mouth, the inner cheeks and lips will be caused to open and/or deform, exerting forces on the mouthpiece that resist the pulling of the mouthpiece <NUM> out of the patient's mouth.

In some embodiments, the height of the posterior region <NUM> is selected such that the patient's teeth block the posterior region <NUM> from exiting the patient's mouth while the patient's mouth is in a relaxed state. The patient can open his/her jaw to unblock the posterior region <NUM> from exiting the patient's mouth. In some embodiments, the transition region, the chamfered or beveled surfaces <NUM>, the rounds <NUM>, and the plateau <NUM> are shaped to form a surface that substantially conforms to the roof of the patient's mouth, with a thin layer of saliva forming in between and facilitating a suction force that holds the mouthpiece <NUM> in the patient's mouth.

<FIG> show a mouthpiece <NUM> having a longitudinal axis <NUM> and a posterior boundary <NUM>. The mouthpiece <NUM> includes a housing <NUM>, a positioning pad <NUM>, a bottom locator <NUM>, a top locator <NUM>, a transition region <NUM>, a posterior region <NUM>, an anterior region <NUM>, an electrode array <NUM>, internal circuitry, and a printed circuit board <NUM>. The electrode array <NUM> includes one or more posterior electrodes <NUM> that are nearest to the posterior boundary <NUM>. The mouthpiece <NUM> is similar to the mouthpiece <NUM> with the exception of the two additional locators <NUM> and <NUM>. During operation a patient inserts the mouthpiece <NUM> into his/her mouth and bites down on the mouthpiece. The internal circuitry delivers electrical neurostimulation signals to the patient's tongue via the electrode array <NUM> which contacts the patient's tongue.

The locators <NUM> and <NUM> can be used to position the mouthpiece <NUM> within the patient's mouth along the longitudinal axis <NUM>. For example, the top locator <NUM> can include a trench traversing the width of the mouthpiece <NUM> that accommodates the patient's upper teeth. The patient can adjust the mouthpiece <NUM> until the patient's upper teeth contact the trench. Once the trench is in contact with the patient's upper teeth, the patient can bite down on the mouthpiece <NUM>. The patient's upper teeth can remain in contact with the trench, securing the position of the mouthpiece along a longitudinal axis <NUM> of the mouthpiece <NUM>. The trench can have a depth between. <NUM> and <NUM> and a cross section shaped like an inverted step, a "U" or a "V". In some embodiments, the bottom locator <NUM> includes a trench that accommodates the patient's lower teeth. The position of the locators <NUM>, <NUM> can be chosen to prevent the posterior region of the mouthpiece <NUM> from contacting any of the patient's anatomy that might cause gagging (e.g., the patient's tonsils, throat, or circumvallate papillae). Additionally, the position of the locators <NUM>, <NUM> can be chosen to optimize the overlap between the patient's tongue and the electrode array <NUM>. In some embodiments, the locators <NUM>, <NUM> are elongated crests, trenches, or a combination thereof. In some embodiments, the locators <NUM> and <NUM> are integral with the positioning pad <NUM> and/or the housing <NUM>. In some embodiments, the bottom locator <NUM> is shaped to accommodate the tip of the patient's tongue. In some embodiments, the top and bottom locators <NUM>, <NUM> are shaped to accommodate the patient's lips. In some embodiments, the locators <NUM>, <NUM> include an array of elongated crests, trenches, or a combination thereof and the patient chooses a locator most suitable to his/her anatomy (e.g., to optimize comfort or efficacy of the NINM therapy session).

In some embodiments, the transition region <NUM> can serve as a top locator <NUM>. The patient can insert the mouthpiece into his/her mouth until the transition region <NUM> is in contact with his/her upper palate. The transition region <NUM> can be shaped to substantially conform to the patient's upper palate.

The position of the top locator <NUM> and the bottom locator <NUM> can be chosen based on the length of the patient's tongue. For example, for a patient having a tongue length of <NUM> inches (e.g., from the oropharynx to the tip), the locator may be positioned <NUM> inches from a posterior boundary <NUM> of the mouthpiece. In some embodiments, the position of the locator may be chosen based the electrode array <NUM>. For example, the locator may be positioned <NUM> away from the anterior edge of the electrode array <NUM>. In some embodiments, the housing <NUM> is composed of a plastic material having a hardness of shore 90A. In some embodiments, the positioning pad <NUM> is a biocompatible material having a hardness of shore 30A. In some embodiments, the top and bottom locators prevent accidental ejection of the mouthpiece <NUM>. In some embodiments, the distance from the posterior electrodes <NUM> to the posterior boundary is less than <NUM>.

<FIG> show a mouthpiece <NUM>. Mouthpiece <NUM> includes similar elements as mouthpiece <NUM> (e.g. mouthpiece <NUM> includes a housing <NUM> which is similar to the housing <NUM> of mouthpiece <NUM>). In some embodiments, the height of the posterior region <NUM> is sized to accommodate two printed circuit boards. In some embodiments, a positioning pad is included on a bottom portion of transition region <NUM> or the anterior region <NUM>. Additionally, the operation of the mouthpiece <NUM> is similar to that described above in reference to <FIG> where similarly referenced elements have the same functionality (e.g., the electrode array <NUM> has the same functionality as the electrode array <NUM>). In some embodiments, the patient bites down on the positioning pad <NUM> with his/her front teeth and additionally, bites upward on a positioning pad located on the bottom of the mouthpiece <NUM> with his/her bottom teeth to secure a position of the mouthpiece. The positioning pad located on the bottom of the mouthpiece <NUM> can be located between the electrode array <NUM> and the cable <NUM>.

In some embodiments, the printed circuit board <NUM> is non-planar. In some embodiments, the printed circuit board <NUM> is mechanically attached to the housing <NUM> without the use of screws or fasteners. In some embodiments, the width of the mouthpiece is at least <NUM> to accommodate the average tracheal diameter of a healthy male and additionally, to prevent choking by the patient.

<FIG> show a mouthpiece <NUM>. Mouthpiece <NUM> includes similar elements as mouthpiece <NUM> (e.g. mouthpiece <NUM> includes a housing <NUM> which is similar to the housing <NUM> of mouthpiece <NUM>). In some embodiments, a positioning pad is included on a bottom portion of the posterior region <NUM>. The operation of the mouthpiece <NUM> is similar to that described above in reference to <FIG> where similarly referenced elements have the same functionality (e.g., the electrode array <NUM> has the same functionality as the electrode array <NUM>).

<FIG> show a mouthpiece <NUM>. Mouthpiece <NUM> includes similar elements as mouthpiece <NUM> (e.g. mouthpiece <NUM> includes a housing <NUM> which is similar to the housing <NUM> of mouthpiece <NUM>). The mouthpiece <NUM> also includes a collection of low profile scallops <NUM> located within the positioning pad <NUM>. The operation of the mouthpiece <NUM> is similar to that described above in reference to <FIG> where similarly referenced elements have the same functionality (e.g., the electrode array <NUM> has the same functionality as the electrode array <NUM>). In some embodiments, the patient can position the mouthpiece using the low profile scallops <NUM>. The patient can bite down on the positioning pad <NUM> with his/her front teeth, aligning his/her front teeth with one of the low profile scallops <NUM> shown in <FIG>. For example, a first patient may find that biting down on the most anterior low profile scallop <NUM> provides the greatest overlap of the tongue with the electrode array <NUM>. A second patient, having a different mouth geometry than the first patient, may find that biting down on the most posterior low profile scallop <NUM> provides the greatest overlap of the tongue with the electrode array <NUM>. The low profile scallop <NUM> can be shaped to accommodate the patient's upper teeth. For example, the low profile scallops <NUM> can have an ovular shape that approximates the shape of at least one tooth bottom. In some embodiments, the scallops <NUM> provide a corrugated surface to facilitate mechanical stability. In some embodiments, the width of the scallops is slightly smaller than the width of the positioning pad (e.g., the width of the scallops can be <NUM>% less than the width of the positioning pad). In some embodiments, the length of each scallop can be <NUM>. In some embodiments, the length of each scallop is in the range of <NUM> to <NUM>. In some embodiments, the height of the scallops is in the range of <NUM> to <NUM>. In some embodiments, each scallop is spaced apart by at least <NUM>, but not more than <NUM>.

<FIG> show a mouthpiece <NUM>. The mouthpiece <NUM> includes similar elements as mouthpiece <NUM> (e.g. mouthpiece <NUM> includes a positioning pad <NUM> which is similar to the positioning pad <NUM> of mouthpiece <NUM>). Additionally, the housing <NUM> includes raised regions <NUM>. The operation of the mouthpiece <NUM> is similar to that described above in reference to <FIG> where similarly referenced elements have the same functionality (e.g., the electrode array <NUM> has the same functionality as the electrode array <NUM>). In some embodiments, the patient can position the mouthpiece via the raised regions <NUM>. The raised regions can be shaped to accommodate the patient's fingers. The patient can adjust the position of the mouthpiece <NUM> by gripping the raised regions <NUM>. In some embodiments, the raised regions are spaced apart by about <NUM>-<NUM>.

Claim 1:
A method of placing a mouthpiece for delivering non-invasive neuromodulation in a patient's mouth, the method comprising:
providing a mouthpiece to the patient, the mouthpiece comprising:
an elongated housing having an anterior region with a substantially constant first width and a posterior region with a substantially constant second width, the elongated housing having a non-planar exterior top surface and a transition region connecting the anterior region and posterior region, the transition region having a width that varies smoothly between the first width and the second width;
a positioning pad attached to the top surface of the housing such that, in use, the patient can bite down on the positioning pad to secure a position of the mouthpiece in which the posterior region of the mouthpiece rests behind the patient's teeth;
a first locator disposed along the anterior region of the positioning pad, the first locator engaging the patient's upper teeth to securely position the mouthpiece in the patient's mouth;
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's tongue, wherein the center of gravity of the mouthpiece is located in the posterior region; and
a second locator traversing an anterior region of the printed circuit board, the second locator mechanically coupling to the patient's lower teeth to securely position the mouthpiece in the patient's mouth;
placing a portion of the mouthpiece in the patient's mouth;
manually adjusting the mouthpiece until the posterior region of the mouthpiece rests behind the patient's teeth; and
securing the position of the mouthpiece by the patient biting down on the positioning pad.