IMPROVE SLEEP

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to U.S. Provisional patent application 62/100,004, titled "SYSTEMS FOR TRANSDERMAL ELECTRICAL STIMULATION TO IMPROVE SLEEP AND METHODS OF USING THEM" filed on 1/5/2015.

[0002] This patent application may also be related to the following U.S. patent applications, which are herein incorporated by reference in their entirety: U.S. Application No. 14/956,193, titled

"TRANSDERMAL ELECTRICAL STIMULATION DEVICES FOR MODIFYING OR INDUCING COGNITIVE STATE", filed on 12/1/2015, which is a continuation of U.S. Patent Application No.

14/639,015, titled "TRANSDERMAL ELECTRICAL STIMULATION DEVICES FOR MODIFYING OR INDUCING COGNITIVE STATE," filed 3/4/2015, now U.S. patent no. 9,233,244, which is a continuation of U.S. Patent Application No. 14/320,461 , titled "TRANSDERMAL ELECTRICAL STIMULATION DEVICES FOR MODIFYING OR INDUCING COGNITIVE STATE," filed

6/30/2014, now U.S. patent no. 9,002,458, which claims priority to: U.S. Provisional Application No. 61/845,845, titled "TRANSCRANIAL ELECTRICAL STIMULATION SYSTEMS AND METHODS" filed 7/12/2013; U.S. Provisional Application No. 61/875,424, titled "TRANSCRANIAL ELECTRICAL STIMULATION SYSTEMS AND METHODS" filed 9/9/2013; U.S. Provisional Application No.

61/841 ,308, titled "TRANSCRANIAL ELECTRICAL STIMULATION SYSTEMS" filed 6/29/2013 ;

U.S. Provisional Application No. 61/907,394, titled "TRANSCRANIAL ELECTRICAL STIMULATION SYSTEMS AND METHODS" filed 1 1/22/2013; U.S. Provisional Application No. 61/888,910, titled "TRANSCRANIAL ELECTRICAL STIMULATION SYSTEMS AND METHODS" filed 10/9/2013; U.S. Provisional Application No. 61/975,1 18, titled "TRANSDERMAL ELECTRICAL STIMULATION SYSTEMS" filed 4/4/2014; U.S. Provisional Application No. 62/002,860, titled "TRANSDERMAL ELECTRICAL STIMULATION SYSTEMS FOR INDUCING COGNITIVE EFFECTS AND METHODS OF USING THEM" filed 5/25/2014; U.S. Provisional Application No. 62/002,909, titled "TRANSDERMAL ELECTRICAL STIMULATION SYSTEMS AND METHODS OF USING THEM" filed 5/25/2014; and U.S. Provisional Application No. 62/002,910, titled "TRANSDERMAL

ELECTRICAL STIMULATION ELECTRODE DEGRADATION DETECTION SYSTEMS AND METHODS OF USING THEM" filed 5/25/2014; this patent may also be related to U.S. patent application no. 14/634,664, titled "CANTILEVER ELECTRODES FOR TRANSDERMAL AND TRANSCRANIAL STIMULATION" and filed on 2/27/2015; U.S. patent application no. 14/634,661, titled "METHODS FOR ATTACHING AND WEARING A NEUROSTIMULATOR" filed on

2/27/2015; U.S. patent application no. 14/715, 461 , titled "WEARABLE TRANSDERMAL

NEUROSTIMULATOR HAVING CANTILEVERED ATTACHMENT" filed on 5/18/2015; U.S. patent application on. 14/715,470, titled "TRANSDERMAL NEUROSTIMULATOR ADAPTED TO REDUCE CAPAC1TIVE BUILD-UP" filed on 5/18/2015; U.S. patent application no. 14/715,476, titled "METHODS AND APPARATUSES FOR AMPLITUDE-MODULATED ENSEMBLE WAVEFORMS

FOR NEUROSTIMULATION" filed on 5/18/2015; and U.S. patent application no. 14/715,483, titled "METHODS AND APPARATUSES FOR CONTROL OF A WEARABLE TRANSDERMAL

NEUROSTIMULATOR TO APPLY ENSEMBLE WAVEFORMS" filed on 5/18/2015. Each of these patents and patent applications are herein incorporated by reference in their entirety.

INCORPORATION BY REFERENCE

[0003] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

FIELD OF THE INVENTION

[0004] The present invention relates to methods and systems for transdermal electrical

neuromodulation to modulate sleep. In particular described herein are neurostimulator apparatuses, generally wearable, configured to be applied to the user (e.g., the user's head and/or neck) to reduce sleep onset, lengthen sleep duration, improve sleep quality, and/or enhance the types and/or subtypes of sleep. In some variations these systems may improve sleep for subjects with sub-clinical or clinical sleep disturbances, including sleep disorders and sleep issues symptomatic to other diseases, disorders, or behaviors.

BACKGROUND

[0005] Sleep disturbances, including insomnia and sleeplessness, are known to affect a vast number of individuals. In addition, many individuals may wish to regulate or control their sleep as a lifestyle choice. Sleep disorders, as well sleep abnormalities symptomatic to a disorder, disease, behavior, or treatment (i.e. sleep issues that occur in response to ADHD treatment, chemotherapy, etc.) affect millions. Moreover, many individuals suffer from sub-clinical or undiagnosed sleep issues that severely affect health and well-being, causing a reduced quality of life. Currently, modulation of sleep and treatment of the symptoms of sleeping disorders is generally accomplished with pharmacological agents. Such agents may be expensive, have associated risk of overdose, and may have undesirable side effects. In addition some people are averse to using drugs to treat seemingly benign conditions such as insomnia and sleeplessness.

[0006] It would generally be advantageous to provide apparatuses (devices, systems) and methods for transdermal electrical stimulation for improving sleep. Specifically, there is a need for effective non- drug treatments (or enhancements for existing drug treatments) for sleep.

[0007] Described herein are transdermal electric stimulation (hereinafter "TES") apparatuses

(devices and systems) and methods of using them that may be useful in treating sleep. TES (e.g., applied through scalp electrodes) has been used to affect brain function in humans. TES has been shown to improve motor control and motor learning, improve memory consolidation during slow-wave sleep, regulate decision-making and risk assessment, affect sensory perception, and cause movements. TES has been used therapeutically in various clinical applications, including treatment of pain, depression, epilepsy, and tinnitus. Despite the research to date on TES neurostimulation, existing methods and apparatuses for TES are lacking for applications related to the modulation of sleep.

[0008] For example, U.S. patent application 13/423,380 titled "Device for converting music signal to electrical stimulation" by inventor Liang describes systems for adapting music therapy insomnia treatments by converting the analog auditory signal to a time-varying voltage signal delivered to transdermal electrodes targeting acupuncture points. However, audible waveforms of music appropriate for use as a musical therapy intervention for sleep are poorly adapted to transdermal electrical stimulation targeting peripheral nerves. An analog-adapted signal as described by Liang would likely lack high transient peak currents (i.e. pulsing) that may be effective for activating peripheral nerves, and further may be quite uncomfortable due to the presence of significant power in low frequencies (100s of Hz) without duty cycle limitations.

[0009] U.S. patent application 12/616,513, titled "Deep brain stimulation for sleep and movement disorders" by inventors Wu et al. describes an implantable electrical stimulation system targeting the substantia nigra to treat sleep disorders. The sleep stage of a patient is tracked and stimulation is modulated according to the patient's sleep stage. Such implantable systems have a greater cost and risk relative to noninvasive designs. Further, this invention requires some form of sleep tracking to modulate the applied electrical stimulation. It would be desirable to modulate sleep without requiring such tracking. Similarly, U.S. patent No. 8,612,005 to inventors Rezai et al. titled "Neurostimulation for affecting sleep disorders" describes another technique for affecting a sleep disorder by stimulating a deep nucleus via an implanted electrode. Another implanted electrical treatment is described in U.S. patent 5,335,657 to inventors Terry Jr., et al. titled "Therapeutic treatment of sleep disorder by nerve stimulation". This patent describes an implanted vagal nerve stimulator for treating sleep disorders.

[00010] Although non-invasive electrical stimulation devices to treat sleep have been proposed, such devices have not found wide use because they are not effective and/or they result in pain or discomfort during or after use. For example, U.S. patent 3,648,708 to inventor Haeri titled "Electrical therapeutic device" describes a device to be operated by a medical professional that delivers pulsed or alternating currents at lower frequencies (less than or equal to 250 Hz) for inducing relaxation or sleep. This invention is lacking at least due to the requirement for operation by a medical professional (unsuitability for self-actuation) and limitation to low frequencies that may limit the intensity of stimulation due to discomfort. Discomfort (e.g., due to skin irritation and/or muscle twitching) is believed to decrease with increasing frequency in a range above 250 Hz, thus low-frequency stimulation may be uncomfortable.

[00011] Similarly, U.S. patent 3,255,753 to inventor Wing titled "Electrical sleep machine and sleep inducing method" uses a rechargeable battery to power an electrical stimulator and a self-timer as safety features that enable self-operation of the device. The pulses delivered are square pulses, generally less than 40 Hz. Such stimulation is likely to be uncomfortable and/or ineffective for inducing or improving sleep. Discomfort or pain invariably induces physiological arousal in a user and makes falling asleep more difficult.

[00012] U.S. patent No. 4,418,687 to inventors Matsumoto et al. titled "Electric sleep inducer" describes another low frequency (< 14 Hz) electrical stimulator for inducing sleep by broadly inhibiting the cerebral cortex. This invention is inspired by the work by Gilyarovsky and colleagues in the mid-19th century that used low (< 150 Hz) frequency stimulation to induce sleep.

[00013] U.S. patent No. 8,029,431 to inventor Tononi et al. titled "Method and apparatus for promoting restorative sleep" also operates at brain rhythm (low frequencies), employing magnetic stimulation to entrain brain rhythms at slow-wave (delta) frequencies for enhancing restorative sleep. Such low- frequency magnetic systems may not target peripheral nerves (cranial nerves, vagal nerve, etc.) that can modulate autonomic function and brain state, but may operate under a different regime.

Similarly, U.S. patent application 1 1/025,928 to inventor Wang titled "Method for moderation of sleep disorder" describes methods for treating a sleep disorder using a magnetic head acupuncture headgear (see also U.S. patent No. 6,280,454 to Wang) for electrical stimulation at 0.3-3.4 kHz using many electrodes implanted on the scalp. These methods require a magnetic material, cap, or a large number of electrode locations making them difficult to operate and apply.

[00014] Finally, U.S. patent No. 5,792,067 to inventor Karell titled "Apparatus and method for mitigating sleep and other disorders through electromuscular stimulation" describes a system and method of using an electrode placed on the user's palate or pharynx to mitigate snoring, apnea, etc. As implied by the title, this invention stimulates the muscles, e.g., within the oral cavity, to reduce snoring and/or apnea, and the internal (in the mouth) placement and the energy applied are likely to be uncomfortable, and does not directly modulate sleep (e.g., onset, duration, quality, etc.).

[00015] Thus, in general, it would be advantageous to provide apparatuses and methods for transdermal electrical stimulation for improving sleep that are both effective and comfortable for a user. SUMMARY OF THE DISCLOSURE

[00016] The present invention relates to methods and apparatuses for improving sleep. Improving sleep may refer to reducing the time to fall asleep, including reducing sleep onset, increasing/causing drowsiness, and causing sleep. Improving sleep may also or alternatively include lengthening the duration of sleep or of certain portions of the sleep cycle (e.g., any of sleep stages: 1 , 2, 3, 4 and REM sleep, slow wave sleep, etc.), reducing sleep interruptions (wakening), or the like.

[00017] In general, these methods may include applying the wearable TES applicator to the subject, and applying appropriate TES prior to falling asleep and/or during sleep. The TES applicator is typically applied by the patient herself, and in some variations the patient may manually adjust one or more of the TES waveform parameters to enhance comfort. The attachment sites for the electrodes may include at least one location on the head (e.g., the temple) and may also include a second location on the subject's head or neck (e.g., back of the neck). Alternatively two electrode locations may be on the neck; one electrode location may be on the subject's neck and a second electrode location may be below the neck; or two electrodes may be on the subject's skin below the neck.

[00018] For example, a method of non-invasively reducing sleep onset and increasing sleep duration may include attaching a first electrode to a subject's head or neck at a first location and a second electrode to the subject's head or neck at a second location, wherein the first and the second electrode are coupled to a transdermal electrical stimulation (TES) applicator worn by the subject. Once applied, the TES applicator may be used to apply an electrical stimulation between the first and second electrodes for a stimulation duration. The applied electrical stimulation may be an 'ensemble waveform' as described herein and described in U.S. application no. 14/715,476, filed 5/18/2015 (now US-2015-0328461), previously incorporated by reference in its entirety. For example, the electrical stimulation may have a peak amplitude of greater than 3 mA, a frequency of greater than 250 Hz, and a duty cycle of greater than 10%. The application of the electrical stimulation may be continued for a stimulation duration of at least one minute to enhance sleepiness, sustain sleep or to enhance sleepiness and sustain sleep. For example, the stimulation duration (the time during which the TES waveform is being applied by the applicator) may be between 1 minute and 120 minutes, between 1 minute and 90 minutes, between 1 minute and 60 minutes, etc., or may be between any lower value (where the lower value may be 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 90, 105, 120, etc. minutes) and an upper value (where the upper value may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 90, 105, 120, 150, etc. minutes), and the lower value is always lower than the upper value.

[00019] The wearable TES applicator may be attached by any appropriate method, including adhesively attaching, attaching using a strap, attaching via a garment such as a hat, band, etc., attaching via a bandage or wrap, or the like. As mentioned, the first electrode may be attached to the subject's head, e.g., to the subject's temple region, forehead region, etc. The first electrode may be on or attached directly to the body of the wearable TES applicator. The second electrode may also be attached to the subject's head or neck; for example, the second electrode may be attached to the subject's neck above the subject's vertebra prominens.

[00020] Any of these methods may allow the subject (who may also be referred to as the user) to select a set of parameters for the electrical stimulation to be applied. Any individual or combination of parameters may be modulated/set by the user, and this modulation may be performed before and/or during the application of the stimulation. For example, a subject may modify one or more parameters such as: stimulation duration, frequency, peak amplitude, duty cycle, capacitive discharge on or off, and DC offset. The adjustment may be made within a fixed predetermined range of values (e.g., for frequency, the subject may adjust the frequency between a minimum value, such as 250 Hz, and a maximum value, such as 40 kHz, or any sub-range therebetween).

[00021] The TES applicator may be worn (and energy applied) while the subject is awake, before sleeping, and/or while the subject sleeps. In some variations, the apparatus (including the first and second electrodes and TES applicator) may be removed prior to the subject sleeping. [00022] TES ensemble waveforms appropriate for enhancing sleep are described in greater detail below. In general, these TES ensemble waveforms may be monophasic or biphasic (or both during different periods); in particular the sleep-improving TES ensemble waveforms may include biphasic electrical stimulation. This biphasic electrical stimulation may be asymmetric with respect to positive and negative going phases. Sleep-enhancing TES waveforms may also have a duty cycle (e.g., time on relative to time off) of between 10% and 90%, e.g., a duty cycle of between 30% and 60%. The peak amplitude of the applied current may also be controlled. In general, the peak amplitude may be greater than 3 mA (greater than 4 mA, greater than 5 mA, greater than 6 niA, greater than 7 mA, greater than 8 mA, etc. or between about 3 mA and about 30 mA, between 3mA and 20 mA, between 5mA and 30 mA, between 5 mA and 20 mA, etc.).

[00023] As mentioned above, any of the stimulation parameters (e.g., peak current amplitude, frequency, DC offset, percent duty cycle, capacitive discharge, etc.) may be changed during the ensemble waveform, so that sub-periods of different parameters may be consecutively applied. The frequency may be between 250 Hz and 40 kHz (e.g., a minimum of: 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 3000, 4000, 5000, etc. Hz and a maximum of 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 15000, 20000, 25000, 30000, 35000, 40000 Hz, where the minimum is always less than the maximum).

[00024] As mentioned, any appropriate stimulation duration may be used. For example, the step of continuing application of the electrical stimulation for a stimulation duration may include continuing for a stimulation duration of at least five minutes.

[00025] Any of the TES ensemble waveforms described herein may be modulated by amplitude modulation, using an appropriate AM carrier frequency. For example, applying the TES waveform(s) may comprise applying electrical stimulation having amplitude modulation, and the amplitude modulation may generally have a frequency of less than 250 Hz (e.g., between 0.01 Hz and 250 Hz, 1 Hz and 250 Hz, 5 Hz and 200 Hz, 10 Hz and 200 Hz, etc.).

[00026] In some variations, applying the TES sleep-improving ensemble waveform may include applying electrical stimulation having a burst mode. A bursting mode may include periods where the applied TES stimulation is quiescent ("off). Note that although the majority of the examples described herein include the use of ensemble waveforms in which one or more (though often just one) stimulation parameter changes during different, predefined component waveforms that are sequentially applied as the ensemble waveform, in some variations only a single component waveform is applied. Similarly, a component waveform may vary continuously or discretely (by steps) for one or more component waveforms.

[00027] For example, described herein are methods of non-invasively reducing sleep onset that may include: placing a first electrode of a wearable transdermal electrical stimulation (TES) applicator on a subject's temple region and a second electrode on a back of the subject's neck; activating the wearable TES applicator to deliver a biphasic electrical stimulation between the first and second electrodes having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater, wherein the biphasic electrical stimulation is asymmetric with respect to positive and negative going phases; and reducing sleep onset by applying the biphasic electrical stimulation between the first and second electrodes for 10 seconds or longer.

[00028] For example, a method of non-invasively inducing sleep in a subject may include: placing a first electrode of a wearable transdermal electrical stimulation (TES) applicator on the subject's skin on the subject's temple region and a second electrode on a back of the subject's neck above a vertebra prominens; activating the wearable TES applicator to deliver a biphasic electrical stimulation having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater, wherein the biphasic electrical stimulation is asymmetric with respect to positive and negative going phases; and inducing sleep by applying the biphasic electrical stimulation between the first and the second electrodes for 10 seconds or longer.

[00029] A method of maintaining sleep in a subject may include: placing a first electrode of a wearable transdermal electrical stimulation (TES) applicator on the subject's skin on the subject's temple region and a second electrode on a back of the subject's neck above a vertebra prominens; activating the wearable TES applicator to deliver a biphasic electrical stimulation having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater, wherein the biphasic electrical stimulation is asymmetric with respect to positive and negative going phases; and maintaining a state of sleep in the subject by applying the biphasic electrical stimulation between the first and second electrodes for 10 seconds or longer while the subject is asleep.

[00030] Any of the method components described above may be incorporated into any of these exemplary methods as well. For example, attaching the TES applicator and/or electrodes may refer to adhesively attaching, mechanically attaching or the like. In general, the TES applicator may be applied directly to the body (e.g., coupling the body to the skin or clothing of the patient directly) or indirectly, e.g., attaching to the body only by coupling with another member (e.g., electrode) that is already attached or attachable to the body.

[00031] In any of the methods described herein, the user may be allowed and/or required to select the waveform ensemble from a list of possible waveform ensembles, which may be labeled to indicate name, content, efficacy, and/or the like. As already mentioned, the subject may be permitted or allowed (e.g., using a wearable electronic and/or handheld electronic apparatus) to select and/or modify one or more parameters for the electrical stimulation to be applied, wherein the parameters may include one or more of: stimulation duration, frequency, peak amplitude, and duty cycle.

[00032] The electrodes and TES applicator may be worn while the subject sleeps, or removed prior to sleeping. For example, any of these methods may include removing the first and second electrodes and TES applicator prior to the subject sleeping.

[00033] In general, reducing sleep onset or inducing sleep may include: increasing drowsiness and/or increasing the desire to sleep. Activating may include delivering the biphasic electrical stimulation while the subject is awake. Thus, in any of these methods described herein, the method may include monitoring the subject's sleep. As mentioned, sleep may be monitored using the wearable TES applicator and/or using a separate monitor. For example, monitoring the subject's sleep may be done using the wearable TES applicator having a sensor coupled to the TES applicator to measure the subject's autonomic function, or communicating with the TES applicator (but separate). Monitoring may include one or more of: actimetry, galvanic skin resistance, heart rate, heart rate variability, or breathing rate. Monitoring may include monitoring the subject's sleep using a sensor that is worn by the subject, coupled to the subject's bed, or remotely monitoring the subject without physical contact with the subject.

[00034] Any of the methods described herein may be automatically or semi-automatically controlled, and may include processing of feedback from any of the sensors to regulate the application of TES, including modifying one or more TES waveform parameter based on the sensed values. For example, any of these methods may include automatically stopping activation of the wearable TES applicator when the subject is asleep based on a physiological measurement or sleep state monitoring, and/or automatically stopping activation of the wearable TES applicator when the subject is asleep following a fixed delay (e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8min, 9 min, 10 min, 15 min, 20 min, etc.). Activating may include activating the wearable TES applicator when the subject is asleep based on a physiological measurement or sleep state monitoring.

[00035] Any of the methods described herein may be methods to treat a sleep disorder or a sleep- related disorder. For example, any of these methods may include a step of treating a sleep disorder in the subject. Examples of such sleep disorders include: idiopathic hypersomnia, insomnia, post-traumatic stress disorder, anxiety, emotional distress, depression, bipolar disorder, schizophrenia; restless leg syndrome and periodic limb movement disorder; circadian rhythm disorders; sleeping sickness;

parasomnia; shift work and jet lag; and hypersomnia.

[00036] In any of these variations, the apparatus may be specifically adapted for comfort, convenience or utility during and before sleeping. For example, in apparatuses in which there is a visible (e.g., light) indicator such as an LED, screen, or the like, the light may be dimmed or turned off during operation and/or following operation, and/or when sleep is detected. For example, any of these methods may include dimming or turning off a visual indicator (e.g., an LED or screen) of the transdermal electrical stimulator when the wearable TES system is activated.

[00037] Although the stimulation parameters may be adjusted or modified by the subject wearing the apparatus, any of these method may include modifying, by a party that is not the subject, a stimulation parameter of the wearable TES device while the subject is sleep, wherein the stimulation parameter includes one or more of: stimulation duration, frequency, peak amplitude, duty cycle, capacitive discharge, DC offset, etc.

[00038] As mentioned, the apparatus and methods may also be adapted to automatically adapt stimulation parameters. For example, any of these methods may include automatically modifying a stimulation parameter of the wearable TES device based on the subject's sleep quality being below a threshold value, where sleep quality is defined by one or more of: sleep latency, amount and/or sequence of sleep stages, sleep amount, autonomic state, EEG activity, EMG activity, movements, and time during the day when sleep occurs, further wherein the stimulation parameter includes one or more of: stimulation duration, frequency, peak amplitude, duty cycle, capacitive discharge, DC offset, etc.

[00039] Any of these methods may also include automatically stopping, starting or modulating the wearable TES applicator based on a measure of sleep quality detected from the subject, where sleep quality is defined by one or more of: sleep latency, amount and/or sequence of sleep stages, sleep amount, time during the day when sleep occurs, and other sleep quality or quantity metric. The sleep quality used to start, stop, or modulate the transdermal electrical stimulation may be based on a measurement of one or more of the subject's: activity, stress, immune system function, autonomic state, or other physiological assessment.

[00040] Placing may comprise placing the first and second electrodes before or during a nap.

[00041] In operation, the wearable TES applicator may automatically or manually triggered to deliver the biphasic electrical stimulation when the subject wakes up. The apparatus may also be configured to transmit a notification (directly or via a user computing device) that reminds the subject to wear the TES applicator before bed, for example, transmitting a notification that reminds the subject to wear the TES applicator before bed based on input from a location sensor in the TES applicator or wirelessly connected to the TES applicator that detects when the subject is in their bedroom.

[00042] The methods described herein may also include providing a metric to the subject showing a sleep quality metric, wherein the sleep quality metric is one or more of: sleep onset time, length of sleep, sleep latency, total length or percentage of REM sleep, total length or percentage of NREM sleep, total length or percentage of slow wave (deep) sleep, length of sleep cycles, number and/or length of night awakenings, and morning wake time.

[00043] Any of the methods described herein may include automatically adjusting the biphasic electrical stimulation based on an average or detected amount of time before the subject falls asleep. The devices described herein may also be configured to perform any of these steps such as automatically adjusting the electrical stimulation.

[00044] In addition, any of the methods described herein may also include concurrently delivering a calming sensory stimulus when activating the wearable TES applicator, such as concurrently delivering a calming sensory stimulus when activating the wearable TES applicator, wherein the calming sensory stimulus is one or more of auditory stimulus, olfactory stimulus, thermal stimulus, and mechanical stimulus.

[00045] Also described herein are wearable transdermal electrical stimulation (TES) applicators for facilitating, inducing, and/or maintaining sleep in a subject. These apparatuses may be configured to perform any of the methods described herein. In general, these apparatuses may include: a body; a first electrode; a second electrode (the apparatuses may be part of a separate but attachable, e.g., disposable, electrode assembly that couples to the body); and a TES control module at least partially within the body. The TES control module may include a processor, a timer and a waveform generator, and the TES control module may be adapted to deliver an electrical (e.g., biphasic, asymmetric) stimulation signal for a stimulation duration (e.g., 10 seconds or longer) between the first and second electrodes. The electrical stimulation which may be a TES ensemble waveform, may have a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater, wherein the biphasic transdermal electrical stimulation is asymmetric with respect to positive and negative going phases. The wearable TES applicator may generally be lightweight (e.g., may weigh less than 50 grams, etc.). Any of the TES applicators described herein may include at least one sensor coupled to the body for sleep monitoring of the subject.

[00046] Any appropriate sleep-enhancing TES waveform(s) may be used. For example, the duty cycle may be between 10% and 90%. The transdermal electrical stimulation may have a frequency greater than 250 Hz, 500 Hz, 750 Hz, 5 kHz, etc. The transdermal electrical stimulation may comprise amplitude modulation, as discussed above, having a frequency of less than 250 Hz. The transdermal electrical stimulation may include a burst mode, such as a burst mode having a frequency of bursting that is less than 250 Hz.

[00047] Any of the apparatuses described herein may be specifically adapted for sleep, as mentioned above. In some variations this may include having the TES waveform(s) pre-programmed, and/or including feedback for monitoring the subject's sleep, and/or for using any sleep-related data on the subject in modifying/controlling the applied stimulation. The apparatus may include at least one sensor that measures the subject's autonomic function, wherein the measurement of autonomic function may measure one or more of: galvanic skin resistance, heart rate, heart rate variability, or breathing rate. The at least one sensor may comprise a sensor to detect the subject's movements (e.g., uniaxial or multi-axial accelerometer, etc.). A movement sensor may be configured to detect the subject's movements in communication with the controller; the movement sensor may be worn by the subject, coupled to the subject's bed, or may detect movements remotely without direct or indirect physical contact with the subject.

[00048] The TES control module may be configured to automatically stop delivery of the biphasic electrical stimulation when the subject is asleep based on a measurement from a sensor, for example, when the subject is asleep at a fixed delay (e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 12 min, 15 min, 30 min, 45 min, 1 hr, etc.).

[00049] The TES control module ("TES controller") may be configured to automatically start delivery of the biphasic electrical stimulation when the subject is asleep based on a physiological measurement derived from the at least one sensor.

[00050] Any of these devices may include a visual indicator (e.g., light, screen, etc., including LED(s), displays, etc.) that is configured to be turned down or turned off when the wearable TES system is activated.

[00051] The TES controller may also be configured to automatically stop, start or modify delivery of the biphasic electrical stimulation based on sleep quality being below a threshold value, wherein sleep quality is defined by a TES control module (or computing device communicatively connected to the TES control module) based on data from the at least one sensor and correspond to one or more of: sleep latency, amount and/or sequence of sleep stages, sleep amount, and time during the day when sleep occurs. The TES controller may also be configured to automatically or manually deliver the biphasic electrical stimulation if the subject wakes up.

BRIEF DESCRIPTION OF THE DRAWINGS

[00052] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[00053] FIG. 1 schematically illustrates a base waveform which may be repeated and modified according to waveform parameters to form component waveforms which may be combined to form ensemble waveforms, as described herein.

[00054] FIGS. 2A-2F show electrode positions for one configuration ("Configuration 3") on a model user head that may be used with the methods and apparatuses of enhancing sleep described herein.

[00055] FIG. 3A illustrates one example of a neurostimulator that may be configured for use with

(and may deliver) the ensemble waveforms described herein.

[00056] FIGS. 3B-3G illustrate another example of a neurostimulator as described herein.

[00057] FIGS. 3H-3K illustrates a first example of one variation of an electrode assembly.

[00058] FIG. 3L illustrates the application of an electrode assembly that may be worn on the subject's head, and/or head and neck to enhance sleep.

[00059] FIG. 3M illustrates the neurostimulator device worn on the subject's head.

[00060] FIGS. 4A-4D show electrode positions for another configuration ("Configuration 4") on a model user head that may be used with the methods and apparatuses of enhancing sleep described herein.

[00061] FIG. 5 shows components of a portable, wired TES neurostimulator system.

[00062] FIG. 6 shows components of a TES neurostimulator system that connects wirelessly to a control unit comprising a microprocessor.

[00063] FIG. 7 shows a workflow for configuring, actuating, and ending a TES session.

[00064] FIGS. 8A-8D show electrode positions for another configuration ("Configuration 6") on a model user head that may be used with the methods and apparatuses of enhancing sleep described herein.

[00065] FIG. 9 is a graph showing an improvement in overall sleep (using the Pittsburg Sleep Quality

Index, PSQI) following the methods described herein in a user population (n=10). Higher scores (e.g., PSQI of greater than 5, up to a maximum score of 21) are considered a poor sleep quality. Subjects used for this study had a PSI of just over 5. Following treatment with either of two experimental TES protocols ("low F" or "high F"), the PSQI scores improved.

[00066] FIGS. 1 OA- IOC compare the time to Wake after Sleep Onset (WASO, FIG. 10A), percentage of time awake (FIG. 10B), and self-reported WASO (FIG. IOC) of subjects in the trial illustrated in FIG. 9 that received either treatment A (Low F) or treatment B (High F).

[00067] FIGS. 1 1 A-l 1 C show heart rate variability (HRV) power in very low, low, and high frequency bands, respectively. Changes in heart rate variability may indicate modulation of the subject's autonomic nervous system. In these experiments, comparing between the two effective stimulation regimes (low F and high F), 10 subjects (n=10) were examined.

[00068] FIGS. 12A-12C illustrate anxiety, depression and stress, respectively, from patients (n=10) treated as shown above in FIG. 9. The measures are based on the DASS (Depression, Anxiety and Stress Scale), a clinical measure between 0 and 3.

[00069] FIGS. 12D-12G illustrate positive affectivity (FIG. 12D), negative affectivity (FIG. 12E), irritability (FIG. 12F), and fatigue (FIG. 12G) in the same patients described in FIGS. 12A-12C.

Affectivity was measured on 5 point scale (FIGS. 12D and 12E), irritability was measured on a 0 to 3 scale (FIG. 12F) and fatigue was measured on a 0 to 10 scale (FIG. 12G).

[00070] FIGS. 13A and 13B illustrate a comparison between different (effective) sleep enhancing stimulation protocols on the number of naps (FIG. 13 A) and in-the-moment stress (FIG. 13B).

[00071] FIGS. 14A and 14B compare measures of morning amylase and morning Cortisol, respectively between different sleep-enhancing stimulation protocols. Both protocols are significantly different compared to baseline (not shown) and may be different from each other, consistent with the results shown in FIGS. 9-13B (amylase: p=0.036; Cortisol: p=0.040). Morning saliva was assayed within 30 minutes of waking for each patient. There were no differences between patients in afternoon or evening Cortisol.

[00072] FIG. 15A is a table with waveform parameters of another example of a "high F" ensemble waveform as described herein. FIG. 15B is a table with another variation of an ensemble waveform similar to that shown in FIG. 15 A. FIG. 15C is a table with another variation of an ensemble waveform as shown in FIGS. 15A-15B.

[00073] FIG. 16 is a table showing another example of an ensemble waveform that may be adapted for use as a sleep enhancing TES waveform. This variation is consistent with the low F ensemble waveform described herein.

[00074] FIG. 17 is a table illustrating one example of a very low F ensemble waveform as described herein.

DESCRIPTION OF THE INVENTION

[00075] In general, described herein are methods and apparatuses (devices and systems) for transdermal electrical stimulation (TES) to enhance sleep, including reducing sleep onset (e.g., increasing drowsiness, reducing sleep onset latency, and inducing sleep) and/or increasing the duration and/or quality of sleep in a subject. The quality of sleep may be related to the length and/or proportion of one or more sleep stages during a subject's sleeping session. In particular, as described herein, the TES may be applied during and/or immediately prior to (e.g., within 30 min, 25 min, 20 min, 15 min, 10 min, 5 min, etc.) a desired sleep time, such as when the subject is preparing or has prepared to sleep (e.g., lying down, etc.). The stimulation parameters of the applied TES (duration, amplitude, frequency, percent duty cycle, bipolar/unipolar, DC offset, AC component/AC frequency, presence of capacitance discharge, etc.) and location of stimulation on the subject (attachment site of the electrodes) as well as the function and feel of the TES applicator (weight, placement, and shape of the applicator) may affect the efficacy with respect to enhancing sleep, and are described herein.

[00076] As will be described in greater detail below, particular ranges of stimulation parameters (frequency, peak current amplitude, duty cycle) of TES waveforms applied using a wearable TES applicator worn on the subject's head and/or neck have been found to be effective, while stimulation outside of these parameters, and/or at different locations, may not be as effective. In general, stimulation at greater than 10% duty cycle (e.g., between 10 and 90%, between 20 and 80%, between 30 and 80%, etc.), at a frequency that is 100 Hz or greater (e.g., 150 Hz or greater, 200 Hz or greater, 250 Hz or greater, 300 Hz or greater, 400 Hz or greater, 500 Hz or greater, 600 Hz or greater, 700 Hz or greater, 750 Hz or greater, 800 Hz or greater, 1 kHz or greater, 2 kHz or greater, 5 kHz or greater, etc., and in particular, 250 Hz or greater), and a peak amplitude of 3 mA or greater (e.g., 4 mA or greater, 5 mA or greater, 6 mA or greater, 7 mA or greater, 8 mA or greater, 9 mA or greater, 10 mA or greater, etc.) are particularly effective. Because such stimulation parameters (e.g., low frequency at relatively high peak current amplitudes) may be painful and thus prevent drowsiness or sleep, it may be particularly useful to modulate the applied TES so that it can be comfortably tolerated, even before sleeping. For example, the applied TES waveform may be biphasic and in some variations asymmetric, with respect to positive and negative going phases. In some variations a capacitive discharge (e.g., a rapid depolarization component to discharge capacitance built up on the electrodes (and in the body) may be applied during the pulsed application (e.g., on each or a subset, e.g., during positive going pulses, negative pulses, etc., of the TES stimulation)).

[00077] Particular types of TES waveforms delivered to a subject (e.g., to the head and/or neck) may improve the quantity and quality of sleep. In such cases, users wake up feeling more rested, with a more positive mood, less anxiety, and less stress (both as self-reported and as assessed by biochemical assay of saliva). For example, 15 minute TES waveforms delivered through a wearable TES applicator attached with an anode at the forehead/temple area and cathode on the neck of a subject (delivering a pulsed waveform with variable frequency, generally between 250 Hz and 1 1 kHz at between 2-12 mA peak current in asymmetric, biphasic pulses) showed a significant improvement in sleep, e.g., reducing sleep onset (time to fall asleep), duration (lengthening the duration of sleep) and quality (e.g., self-reported assessments) of subject's sleep compared to baseline or to non-effective (sham) TES waveforms.

[00078] Described herein are methods and apparatuses for transdermal electrical stimulation (e.g., neurostimulation) using TES stimulation protocols and electrode configurations that facilitate the passage into sleep, accelerate the induction of sleep, improve the restorative quality of sleep, and/or enhance the likelihood of maintaining a state of sleep in a subject. Apparatuses described herein may generally include a neurostimulator for delivering transdermal electrical stimulation, appropriate dermal electrodes that connect electrically to the neurostimulator for transmitting the electrical stimulation to the subject, and, optionally, a controller unit that may be connected to the neurostimulator in a wired or wireless manner (including user computing devices such as a smartphone, tablet, wearable device (e.g. smartwatch or Google Glass), or computer). The TES apparatuses for improving sleep described herein are configured to deliver appropriate TES waveforms and to couple transdermal electrodes with an appropriate configuration for inducing a drowsy or sleeping state in a subject. Methods for improving sleep in a subject (e.g., one or more of: reducing sleep onset, facilitating the passage into sleep, inducing sleep, enhancing the likelihood of maintaining sleep, modifying the quality of sleep, etc.) using a TES system before or during sleep are described. Also described herein are wearable TES apparatuses (e.g., neurostimulators) that are configured specifically to enhance sleep.

[00079] These neurostimulators may be capable of autonomous function and/or controllable via a wired or wireless connection to a computerized user device (e.g. smartphone, tablet, laptop, other wearable device). The neurostimulator may be configured specifically to deliver stimulation within a range of parameters, including intensity and frequency, determined to be effective for inducing, enhancing, or promoting sleep while minimizing pain and discomfort due to the relatively large magnitude stimulation provided. For example, an apparatus (such as a TES applicator) may include a control module having circuitry (e.g., hardware), software and/or firmware that allows the apparatus to apply signals within an effective range, including, for example, one or more processors, timers, and waveform generators.

[00080] Relative to existing systems for transdermal electrical stimulation for improving sleep, the systems and methods described herein induce more powerful effects for treating and affecting (not limited to treatment or diagnosis of any medical condition) sleep. These apparatuses may use replaceable, disposable (e.g., consumable) electrodes and may also use appropriate electrical stimulation parameters; this combination may mitigate discomfort, enabling higher peak currents to be delivered for stimulating transdermally without delivering irritating or painful stimuli that may wake a subject. Higher peak currents typically provide a more robust effect.

[00081] A neurostimulation system as described herein may include two or more parts: (1 ) a lightweight (e.g., less than lOOg, less than 75g, less than 50g, less than 40g, less than 30g, less than 25g, less than 20g, etc.), wearable (or portable), neurostimulator device (neurostimulator) that is configured to be worn on a subject (generally on the head or neck) or portable and coupled to the subject and includes processor(s) and/or controller(s) to prepare the TES waveform(s) to be applied; and (2) a

consumable/disposable electrode assembly to deliver the TES waveform(s) to the wearer. In some variations a third component may be a controller that is separate from but communicates with the neurostimulator. For example, in some variations the controller may be a user device that wirelessly communicates with the neurostimulator. In some variations the controller is a mobile

telecommunications device (e.g., smartphone or tablet) being controlled by an application that sends instructions and exchanges 2-way communication signals with the neurostimulator. For example, the controller may be software, hardware, or firmware, and may include an application that can be downloaded by the user to run on a wireless-connectable (e.g., by Bluetooth) device (e.g., smartphone or tablet) to allow the user to select the waveforms delivered by the neurostimulator, including allowing real-time or short latency (e.g., less than one second, less than 500 ms, etc.) modulation of the delivered neurostimulation to enhance sleep as described herein. Alternatively, the electrodes may be reusable and integrated in a single assembly with a TES controller.

[00082] The methods and apparatuses described herein may induce a calm or relaxed mental state and may facilitate, induce, or maintain a state of sleep in a subject. This class of cognitive effects includes those associated with relaxation and a calm mental state, for example: a state of calm, including states of calm that can be rapidly induced (e.g., within about 5 minutes of starting delivery of the TES waveforms). In some variations, these effects may include a care-free state of mind; a mental state free of worry; induction of sleep; a slowing of the passage of time; enhanced physiological, emotional, or and/or muscular relaxation; enhanced concentration; inhibition of distractions; increased cognitive and/or sensory clarity; a dissociated state; a state akin to mild intoxication by a psychoactive compound (i.e. alcohol); a state akin to mild euphoria induced by a psychoactive compound (i.e. a morphine); the induction of a state of mind described as relaxed and pleasurable; enhanced enjoyment of auditory and visual experiences (i.e. multimedia); reduced physiological arousal; increased capacity to handle emotional or other stressors; a reduction in psychophysiological arousal as associated with changes in the activity of the hypothalamic-pituitary-adrenal axis (HPA axis) and/or reticular activating system and/or by modulating the balance of activity between the sympathetic and parasympathetic nervous systems generally associated with a reduction in biomarkers of stress, anxiety, and mental dysfunction; anxiolysis; a state of high mental clarity; enhanced physical performance; promotion of resilience to the deleterious consequences of stress; a physical sensation of relaxation in the periphery (i.e. arms and/or legs); a physical sensation of being able to hear your heart beating, and the like.

[00083] More interestingly, in some variations, the TES waveforms may enhance sleep as suggested herein shortly after the session (application of TES) has ended; during the session, sleepiness/relaxation may not be felt, and in fact the application may be mildly uncomfortable. The discomfort may be minimized as described herein, and may be short-lived; once application of these (typically lower frequency) stimulation waveforms has stopped, an enhancement of sleep may be affected.

[00084] The apparatuses (systems and devices) and methods described herein allow the reproducible enhancement of sleep, as described herein. The effect resulting from the methods and devices described may depend, at least in part, on the positioning of the electrodes. It may be particularly advantageous with the TES waveform parameters described herein to apply the electrodes on the subject's head, neck and head, or neck and elsewhere on the body other than the head. Described below are three configurations for enhancing sleep. These configurations are exemplary and are not meant to be limiting with regard to configurations that can induce these cognitive effects and thus improve sleep in a subject.

[00085] FIGS. 2A-2F illustrate a first electrode configuration for enhancing sleep in a subject 200 and may be referred to herein for convenience as "configuration 3". A first electrode is positioned on the subject's skin near the subject's temple area (e.g., above and slightly to the right of the right eye, or to the left of the subject's left eye) and a second electrode is placed on the subject's neck (e.g., on a superior portion of the neck center as in Fig. 2E). Beneficial embodiments comprise electrodes for the neck having an area of at least about 20 cm ² and an electrode having area at least about 10 cm ² (optimally at least about 20 cm ² ) near the right temple. TES stimulation of this region may result in enhancing a calm or relaxed mental state. FIGS. 2 A and 2B show the broad outlines of effective areas for a temple electrode 202 and neck electrode 201 , 203 (though the actual electrodes within these areas would be smaller than the regions outlined). For example, effective electrode size and positions may be as shown in FIG. 2C, wherein rectangular temple electrode 205 and circular electrode (on the right side of the neck) 204 are applied to the subject. In another example of effective electrode size and positions shown in FIG. 2D, a small circular temple electrode 206 and elongated oval electrode (on the right side of the neck) 207 are applied to the subject. In a third example of effective electrode size and positions shown in FIGS. 2E-2F, an oval temple electrode 209 and roughly rectangular electrode (centered on the superior portion of the neck) 208 are applied to the subject.

[00086] FIGS. 4A-4D illustrate a second electrode configuration for enhancing sleep in subject 4500 and may be referred to herein for convenience as "configuration 4". A first electrode is positioned on the subject's skin near the bridge of the subject's nose 4501 and a second electrode is positioned on the subject's body further than a few inches from the first electrode 4502, 4503, 4504 (e.g., on the subject's head or neck, including the forehead or temple). One advantage of this configuration is that electrode placement is relatively easy for a user to do themselves. FIG. 4A shows model subject 4500 with a round anode electrode placed between the eyes on the bridge of the nose 4501. In a preferred embodiment, the anode electrode is less than 1 " across and flexible in order to conform to the curvature of the area near the bridge of the nose of a subject. The anode electrode may be round, elliptical, square, rectangular, or an irregular shape configured for ease of placement on the curved areas of the nose. In a preferred embodiment, a second electrode (e.g., cathode) is located at a site selected from the list including, but not limited to: temple 4502 (as shown in FIG. 4B), forehead 4504 (FIG. 4C), neck 4503 (FIG. 4D), mastoid, shoulder, arm, or elsewhere on the face, head, neck, or body below the neck. A second electrode can be placed on either side of the body. In some embodiments, multiple cathode electrodes can be used. The forehead electrode can be easily affixed using a mirrored surface or front-facing smartphone (or tablet) camera, and the cathode positioning may not need to be precise.

[00087] FIGS. 8A-D illustrate a third electrode configuration for enhancing sleep in a subject 800 and may be referred to herein for convenience as "configuration 6". According to an embodiment, subjects treated with TES using Configuration 6 experience different forms of neuromodulation with distinct cognitive effects depending on the waveform and intensity delivered. In embodiments, systems and methods for TES using Configuration 6 electrically couple an electrode to the subject 800 between the eyes at the bridge of the nose 801 ('nasal' electrode) and a second electrode near the midline on the forehead, superior to the nasal electrode. In an embodiment, the nasal electrode is an anode and the forehead electrode is a cathode. The more superior electrode may be medial and close to the bridge of the nose 802 (FIG. 8A), medial and more superior relative to the bridge of the nose 803 (FIG. 8B), shifted left or right relative to the midline and superior to the bridge of the nose 804 (FIG. 8C), or larger and more superior relative to the bridge of the nose 805 (FIG. 8D). In contrast to other configurations, the anode and cathode can be switched and the beneficial neuromodulation effects still achieved in subjects. In a preferred embodiment, systems and methods with this electrode configuration deliver different electrical stimulation wavefomis to achieve distinct cognitive effects. TES using an alternating (or pulsed biphasic) transdermal electrical stimulation current at a frequency between 3 kHz and 15 kHz (i.e. between 3 kHz and 5 kHz) at an intensity greater than 4 mA induces neuromodulation in a subject with cognitive effects including, but not limited to, those in the following list: increased drowsiness; increased desire to sleep: induction of sleep; induction of a relaxed state of mind; and induction of a calm state of mind. TES using an alternating transdermal electrical stimulation current at a frequency less than 3 kHz (preferably between 750 Hz and 1 kHz) at an intensity greater than 1 mA induces neuromodulation with cognitive effects including, but not limited to, those in the following list: increased energy and enhanced wakefulness, and is thus not a beneficial set of waveform parameters to use with this configuration for facilitating, inducing, or maintaining a state of sleep.

[00088] Alternative electrode configurations for inducing or enhancing sleep include: a first electrode on the neck and a second electrode on the shoulder (i.e. deltoid, upper arm, etc.); one electrode on each shoulder (i.e. deltoid, upper arm, etc.); and two electrodes on the neck.

[00089] FIG. 7 shows an exemplary workflow for configuring, actuating, and ending a TES session for improving sleep. According to an embodiment of the present invention, user input on TES device or wirelessly connected control unit 700 is used to select desired cognitive effect 701 which determines electrode configuration setup 702 to achieve the desired cognitive effect, including selection of electrodes or a TES system that contains electrodes and determination of correct positions for electrodes. As described above, configurations 3, 4, and 6 are three exemplar configurations beneficial for improving sleep. In an embodiment, configuration instructions to user 703 are provided by one or more ways selected from the list including but not limited to: instructions provided via user interface; kit provided to user; wearable system configured to contact TES electrodes to appropriate portions of a user's body; electrode choice and positioning done autonomously by user (e.g. due to previous experience with TES); assistance provided by skilled practitioner of TES; and instructions provided via other means.

[00090] Based on these instructions or knowledge, a user or other individual or system positions electrodes on body 704. In some embodiments, the TES session starts 707 automatically after electrodes are positioned on the body. In other embodiments, the impedance of the electrodes 705 is checked by a TES system before the TES session starts 707. In some embodiments, after impedance of the electrodes 705 is checked by a TES system, user actuates TES device 706 before the TES session starts 707. In other embodiments, after positioning electrodes on the body 704 the user actuates the TES device 706 to start the TES session 707. Once the TES session starts, the next step is to deliver electrical stimulation with specified stimulation protocol 708. In some embodiments, a user actuates end of TES session 709. In other embodiments, the TES session ends automatically when the stimulation protocol completes 710.

[00091] FIG. 5 shows a schematic illustration of a portable, wired TES neurostimulator 500.

According to an embodiment, adherent electrodes 501 connect to TES controller 504 via connectors 502 and wires 503. TES controller 504 has several components including battery or protected AC power supply 505, fuse and other safety circuitry 507, memory 508, microprocessor 509, user interface 510, current control circuitry 506, and waveform generator 51 1.

[00092] FIG. 6 shows an embodiment of a TES system comprising adherent or wearable TES neurostimulator 600 that communicates wirelessly with microprocessor-controlled control unit 609 (e.g. a smartphone running an Android or iOS operating system such as an iPhone or Samsung Galaxy, a tablet such as an iPad, a personal computer including, but not limited to, laptops and desktop computers, or any other suitable computing device). In this exemplary embodiment, adherent or wearable neurostimulator 600 holds two or more electrodes in dermal contact with a subject with one or more of: an adhesive, a shaped form factor that fits on or is worn on a portion of a user's body (e.g. a headband or around-the-ear 'eyeglass' style form factor). In an exemplar embodiment, adherent or wearable neurostimulator 600 comprises components: battery 601, memory 602, microprocessor 603, user interface 604, current control circuitry 605, fuse and other safety circuitry 606, wireless antenna and chipset 607, and waveform generator 616. Microprocessor-controlled control unit 609 includes components: wireless antenna and chipset 610, graphical user interface 61 1 , one or more display elements to provide feedback about a TES session 612, one or more user control elements 613, memory 614, and microprocessor 66. In an alternate embodiment the neurostimulator 600 may include additional or fewer components. One of ordinary skill in the art would appreciate that neurostimulator could be comprised of a variety of components, and embodiments of the present invention are contemplated for use any such component.

[00093] An adherent or wearable neurostimulator 600 may be configured to communicate bidirectionally with wireless communication protocol 608 to microprocessor-controlled system 609. The system can be configured to communicate various forms of data wirelessly, including, but not limited to, trigger signals, control signals, safety alert signals, stimulation timing, stimulation duration, stimulation intensity, other aspects of stimulation protocol, electrode quality, electrode impedance, and battery levels. Communication may be made with devices and controllers using methods known in the art, including but not limited to, RF, WIFI, WiMax, Bluetooth, BLE, UHF, NHF, GSM, CDMA, LAN, WAN, or another wireless protocol. Pulsed infrared light as transmitted for instance by a remote control is an additional wireless form of communication. Near Field Communication (NFC) is another useful technique for communicating with a neuromodulation system or neuromodulation puck. One of ordinary skill in the art would appreciate that there are numerous wireless communication protocols that could be utilized with embodiments of the present invention, and embodiments of the present invention are contemplated for use with any wireless communication protocol.

[00094] Adherent or wearable neurostimulators 609 may or may not include a user interface 604 and may be controlled exclusively through wireless communication protocol 608 to control unit 609. In an alternate embodiment, adherent or wearable neurostimulator 609 does not include wireless antenna and chipset 607 and is controlled exclusively through user interface 604. One skilled in the art will recognize that alternative neurostimulator systems can be designed with multiple configurations while still being capable of delivering electrical stimulation transdermally into a subject. [00095] In general, any appropriate neurostimulation system may use (and/or be configured to use or operate with) the ensemble waveforms as described herein for enhancing sleep. FIGS. 3A, and 3B-3M describe and illustrate an example of a neurostimulation system (neurostimulator, electrodes, controller) that may be used. For example, a neurostimulation system may include a lightweight, wearable, neurostimulator device (neurostimulator) that is configured to be worn on the head and a

consumable/disposable electrode assembly; in addition a device that may be worn and/or held by the user ("user device") which includes a processor and wireless communication module may be used to control the application of neurostimulation by the wearable neurostimulator. The neurostimulator and/or user device may be particularly adapted to deliver the ensemble waveforms as described herein. For example, the user device may present a list of ensemble waveforms and allow the user to select among them in order to select a desired cognitive effect. The ensemble waveforms may be ordered by the desired effect (e.g., enhancing sleep onset, improving sleep quality, etc.) and/or by time and/or by ranking, etc.

Further, the user device may be adapted to communicate with the wearable neurostimulator and may transmit an identifier of the selected ensemble waveform, and/or waveform parameters that define all of a portion (e.g., component waveforms or portions of component waveforms) of the ensemble waveform, as well as any user adjustments such as user modification to the perceived intensity to be used to modify the actual waveforms delivered by, for example, attenuating the ensemble waveform parameters. Thus, for example, the user device may be configured to send, and the neurostimulator to receive, the ensemble waveform parameters (duration, ramping parameter/ramping time, capacitive discharge parameters, current amplitude, frequency, percent duty cycle, percent charge imbalance, etc.).

[00096] The user device may also be referred to herein as a controller, and the controller (user device or user computing device) is typically separate from but communicates with the neurostimulator. For example, in some variations the controller may be a user device that wirelessly communicates with the neurostimulator. In some variations the controller is a mobile telecommunications device (e.g., smartphone or tablet) or wearable electronics (e.g., Google glass, smart watch, etc.), being controlled by an application that sends instructions and exchanges 2-way communication signals with the

neurostimulator. Any of these embodiments may be referred to as handheld devices, as they may be held in a user's hand or worn on the user's person. However, non-handheld control user devices (e.g., desktop computers, etc.) may be used as well. The user device may be a general purpose device (e.g., smartphone) running application software that specifically configures it for use as a controller, or it may be a custom device that is configured specifically (and potentially exclusively) for use with the neurostimulators described herein. For example, the controller may be software, hardware, or firmware, and may include an application that can be downloaded by the user to run on a wireless-connectable (i.e. by Bluetooth) device (e.g., handheld device such as a smartphone or tablet) to allow the user to select the waveforms delivered by the neurostimulator, including allowing real-time modulation of the delivered neurostimulation to modify the user's cognitive state as described herein.

[00097] The neurostimulator may apply an ensemble waveform for about 3-30 min (or longer) that is made up of different "blocks" having repeated waveform characteristics; the waveform ensemble may include transition regions between the different blocks. In general, at least some of the waveform blocks

(and in some variations most or all of them) generally have a current amplitude of > 3 mA (e.g., > 3 mA, greater than 4 mA, greater than 5 mA, between 5 mA and 40 mA, between 5 mA and 30 mA, between 5 mA and 22 mA, etc.), and a frequency of > 100 Hz (e.g., between 750 Hz and 25 kHz, between 750 Hz and 20 kHz, between 750 Hz and 15 kHz, etc.), the current is typically biphasic and is charge imbalanced, and has a duty cycle of between 1 -90% (e.g., between 10-90%, between 30-80%, between 30-60%, etc.). One or more of these characteristics may be changed during stimulation over timescales of every few seconds to minutes as the ensemble waveform shifts between subsequent component waveforms.

[00098] When worn, the system may resemble the system shown in FIG. 3M, having an electrode assembly attached at two locations (points or regions) on the subject's head and/or neck) and a neurostimulator attached to the electrode assembly, as shown; in some variations a separate controller may be attached to coordinate the application of stimulation.

[00099] As will be described in greater detail herein, the neurostimulator may be lightweight (e.g., less than 30g, less than 25g, less than 20g, less than 18g, less than 15g, etc.), and self-contained, e.g. enclosing the circuitry, power supply, and wireless communication components such as a rechargeable battery and charging circuit, Bluetooth chip and antenna, microcontroller, and current source configured to deliver waveforms with a duration of between 10 seconds and tens of minutes. A neurostimulator may also include safety circuitry. The neurostimulator may also include circuits to determine that the electrode is attached and what "kind" of electrode it is (i.e., for configuration 3 vs. configuration 4; or indicating the batch and/or source of manufacture, etc.). FIGS. 3A and 3B-3G illustrate two variations of a neurostimulator.

[000100] For example, FIG. 3A illustrates a first example of a neurostimulator as described herein. In FIG. 3 A, the neurostimulator is shown with a pair of electrodes attached. A first electrode 601 is coupled directly to the body 603 of the TES applicator 602, and a second electrode 606 is connected by a cable or wire 604 to the body 603 of the applicator 602. These electrodes are separate from each other, and may be replaceable/disposable. Different shaped electrodes 607 may be used with the same re-usable neurostimulator. The neurostimulator in this example includes a rigid outer body, to which the pair of electrodes is attachable, making electrical contact via one or more plug-type connectors.

[000101] FIGS. 3B-3G illustrate another embodiment of a neurostimulator as described herein. In this variation the neurostimulator is also a lightweight, wearable neurostimulator that attaches to an electrode, and includes contacts for making an electrical connection with two (or potentially more) electrically active regions (e.g., anodic and cathodic regions) on the electrode(s). However, in this example, the neurostimulator is configured to operate with a cantilevered electrode apparatus, and to attach both mechanically and electrically to the electrode apparatus at a region that is off-center on the bottom (underside or skin-facing side) of the neurostimulator, allowing one end region to be held securely to the skin while the other edge region is not pinned in this way. The "floating" end may therefore adjust slightly to different curvatures of the head, even while the electrode assembly (which may be flexible) is securely held to the skin. Thus, this cantilevered attachment mechanism may enhance comfort and adjustability of the device. In addition, the neurostimulator device may be configured specifically so that it can be comfortably worn at the user's temple, even in users wearing glasses. For example, the apparatus may be configured so that the skin-facing side (which connects to the electrode assembly via one or more connectors) is curved with a slightly concave surface having a slight twist angle. This curve shape may help the apparatus fit more snugly (more uniformly) to the surface of the temple. In addition, one end of the device (the end to be positioned in-line with the edge of the user's eye and the user's ear) may be thinner (e.g., less than 2 cm, less than 1.5 cm, less than 1 cm, less than 0.8 cm, etc.) than the opposite end, which may be worn higher up on the temple.

[000102] For example, FIGS. 3B-3G illustrate front, back, left side, right side, top and bottom perspective views, respectively of a variation of a neurostimulation device (neurostimulator or electrical stimulator) that may be used with cantilever electrode apparatuses. The overall shape of the

neurostimulator may be triangular, and particularly the surface of the neurostimulator (though curved/concave and twisted) adapted to connect to the electrode apparatus and face the patient may be three-sided (e.g., roughly triangular). This roughly triangular shape may include rounded edges, and the thickness of the stimulator (in the direction perpendicular to the surface contacting the cantilever electrode apparatus) may vary, e.g., be thinner along one side, and particularly the side (the portion between the orbital edge and the auricular edge) that will extend laterally from the edge of the eye in the direction of the ear. This shape may also be beneficial when helping to fit/be worn on most people in a region of the face/head that tends to not have hair. Both adhesive and conductive hydrogel that may cover an active electrode region function more effectively on skin with little or no hair. This thin lower corner (the orbital/auricular corner) may fit between the eyebrow and hairline, while the wider portion is positioned up in the forehead area where there is less likely to be hair.

[000103] In FIGS. 3B-3G the various edges of the neurostimulator are labeled, based on where the apparatus will be worn by the subject, as is illustrated in FIG. 3M. In general, the side of the unit worn toward the ear is the auricular edge, the side worn highest on the forehead is the superior edge, and the side worn nearest the eye/eyebrow is the orbital edge. The overall shape of the neurostimulator is triangular (including rounded edges). As used herein triangular includes shapes having rounded/smooth transitions between the three sides, as illustrated. The subject-facing surface is specifically contoured to fit in the predefined orientation, making it difficult or impossible for a subject to misapply, and risk placing the active region of the attached cantilever electrode apparatus in the wrong place. When attaching the cantilever electrode apparatus to the neurostimulator, the cantilever electrode apparatus may flex or bend so that it is contoured to match the curved and twisted surface. This surface is a section of a saddle shape, in which there is an axis of curvature around which the surface is concavely curved, and an axis of twisting, which may distort the curved surface (the two axes may be different or the same).

[000104] Within the housing, any of the neurostimulators described herein may include a processor (e.g., microprocessor) or controller, a wireless communication module that is connected to the processor, and a power source (e.g., battery, etc.). The power source may be configured to provide power to the internal circuitry and/or the circuitry driving current between anodic and cathodic regions of the electrodes when worn by the user. The power supply may be a high-voltage power supply, e.g., able to provide up to 60 V across these electrode terminals. In general, the apparatus may also include circuitry that is configured to regulate the energy (e.g., current) delivered as required by the processor, which may in turn receive instructions via the wireless communications module from a controller. The controller may also communicate information, and in particular information about the electrodes, including confirming that the electrode assembly is connected and/or what type (e.g., calm, energy, make/model, batch, etc.) of electrode assembly is attached, and an indicator of the contact with the user's skin (e.g., conductance, a parameter proportional to conductance, or a value from which an estimate of the conductance of the electrode(s) may be derived).

[000105] The electrode assembly may mechanically and/or electrically connect to the

neurostimulator, e.g., by snapping to the underside of the neurostimulator at one or more (e.g., two) connectors such as snap receivers. Thus in some variations the neurostimulator may be held onto the subject's (user's) head by the electrode assembly; the electrode assembly may be adhesively connected to the user's head and/or neck to form an electrical contact with the desired regions on the user, and the neurostimulator may be connected e.g., adhesively and/or electrically, to the electrode assembly. As described below, the connectors between the neurostimulator and the electrode assembly may be positioned in a particular and predetermined location that allows the neurostimulator to be robustly connected to the electrode assembly and therefore the user's head/neck without disrupting the connection, and while permitting the system to be worn on a variety of different body shapes.

[000106] Electrode assemblies are generally described in detail below, along with specific examples and variations. In particular, described herein are electrode assemblies that are thin (e.g., generally less than 4 mm, less than 3 mm, less than 2 mm, less than 1 mm, etc. thick, which may not include the thickness of the connectors that may extend proud from the thin electrode assembly), and flexible, and may be flat (e.g., formed in a plane). For example, they may be printed on a flex material, such as the material used to print a flex circuit. In use, they can be wrapped around the head to contact it in at least two locations (e.g. at the temple and on the back of the neck). The electrode assembly may include a connector (electrical and/or mechanical) that extends proud of the otherwise flat/planar surface to connect the active regions of the electrode assembly to the neurostimulator. For example, the neurostimulator may be mechanically and electrically connected by one or more snaps extending from the front of the electrode assembly. In some examples, one snap connects to a first active electrode region (anodic or cathodic region) that is surrounded by an adhesive to adhere the active region to the user's head. A second electrode region (anodic or cathodic) on a separate part of the electrode assembly may be electrically connected to the other connector. For example, the second electrode region may be adapted to fit either on a region across the user's neck at the base of the hairline, e.g., near the midline of the neck (calm electrode configuration).

[000107] The electrode apparatus may be printed (e.g., by flexographic printing, laser printing with conductive ink, silk-screening, etc.) on a flexible (e.g. plastic) substrate (flex substrate) and may also include a pair of connectors (snaps) on the side opposite the skin-facing electrodes. The electrode active regions on the back of the assembly may include a layer of conductor (e.g., silver), over which a layer of Ag/AgCl is placed that is sacrificial and acts as a pH buffer. A next layer of hydrogel overlays the Ag/AgCl electrode so that it can uniformly transfer charge across the active region into the skin. A portion of the electrode assembly around the active electrode area may have an adhesive that permits good contact with a user's skin.

[000108] There may be multiple configurations (e.g., shapes) of the electrode assembly, and, as described in greater detail herein, the electrode assembly may generally be formed on a flexible material ('flex circuit' material) and mechanically and electrically connected to the neurostimulator.

[000109] FIGS. 3H-3 illustrate one variation of a cantilever electrode apparatus ("electrode apparatus") that may be used with a neurostimulator and may be worn on a subject's head. This variation is adapted to connect to a user's temple region and the back of a user's neck. In this example, the cantilever electrode apparatus 400 includes a plurality of electrode portions (two are shown) 403, 405. In FIG. 3H, a front perspective view is shown. The front side is the side that will face away from the subject when worn. The cantilever electrode apparatus is thin, so that the electrode portions include a front side (visible in FIGS. 3H and 31) and a back side (visible in FIG. 3 ). As shown in the side view of FIG. 3 J, the device has a thin body that includes the electrode portions 403, 405 as well as an elongate body region 407 extending between the two electrode portions. The elongate body is also thin (having a much larger diameter and height than thickness). The thickness is shown in FIG. 3 J.

[000110] In this example, two connectors 415, 417 (electrical and mechanical connectors, shown in this example as snaps) extend from the front of the cantilever electrode apparatus. The front of the first electrical portion 403 may also include an optional foam and/or adhesive material 421 through which the snaps extend proud of the first electrical portion. The first electrical portion is shaped and sized so that the snaps will connect to plugs (ports, holders, opening, female mating, etc.) on the electrical stimulator. As described above, the connectors may be separated by between about 0.6 and about 0.9 inches (e.g., between about 0.7 and about 0.8 inches, etc., shown in FIG. 3H-3K as about 0.72 inches). The second electrode portion may also include a foam or backing portion 423. This foam/backing region may be optional. In some variations the separation between the connectors is not limited to 0.7 to 0.8, but may be larger (e.g., between 0.7 and 1.2 inches, 0.7 and 1.1 inches, 0.7 and 1.0 inches, 0.7 and 0.9 inches, etc.) or smaller (e.g., between 0.2 and 0.7, 0.3 and 0.7, 0.4 and 0.7, 0.5 and 0.7, 0.6 and 0.7 inches, etc.).

[000111] FIG. 3 K shows a back view of this first example of a cantilever electrode apparatus. In this example, the first 403 and second 405 electrode portions are also shown and include active regions 433, 435. The active regions are bordered by adhesive 440. The first 403 electrode portion includes, on the back (patient-contacting) side, a first active region 433, which is bounded, e.g., around its entire circumference, or at least on, by an adhesive 440. The active region may include a conductive material (e.g., electrically conductive gel). Similarly, the back of the second electrode portion 405 includes the second active region 435 surrounded on two sides by an adhesive material 440 that extends to the edge of the electrode region. The adhesive may be any biocompatible adhesive that can releasably hold the material to the skin. [000112] In general the elongate body region connecting the two electrode portions may be any appropriate length, but is generally longer than a few inches (e.g., longer than about 2 inches, longer than about 3 inches, longer than about 4 inches, longer than about 5 inches, longer than about 6 inches, longer than about 7 inches, longer than about 8 inches, longer than about 9 inches, etc.). The elongate body region may also be bent or curved, as illustrated in FIGS. 3H-3K. The bend or curve, in which the elongate body may even double back on itself, may allow the material to flex or bend to allow it to be adjustably positioned over and/or around the subject's head, as shown in FIGS. 3L and 3M, for example.

[000113] FIG. 3L illustrates a cantilever electrode apparatus (similar to those shown in FIGS. 1 A and 4A) worn on a subject's head. As illustrated, the apparatus is positioned with the first electrode portion adhesively attached at the temple region and a second electrode portion attached to a region behind the head (e.g., neck region, not shown). A neurostimulator (not shown in FIG. 3L) may be attached to the cantilever electrode apparatus either before or after it is applied to the subject. As shown in FIG. 3M, the neurostimulator may be attached to the front side of the cantilever electrode apparatus by snapping onto the proud connectors, while the elongate body region 407 is bent to extend behind the subject's head and down to a portion on the midline of the back of the patient's neck. Both the first electrode portion and the second electrode portion may be adhesively held with the electrically active regions against the skin, allowing the neurostimulator to apply energy, and in particular the waveforms as described in application 14/320,443, titled "TRANSDERMAL ELECTRICAL STIMULATION METHODS FOR MODIFYING OR INDUCING COGNITIVE STATE" and filed on 6/30/2014, and herein incorporated by reference in its entirety.

[000114] In use, a user may interact with a controller (e.g., a smartphone controlled by application software/firmware) that pairs with the neurostimulator (e.g. by Bluetooth). The user may operate the controller to select the operational mode, e.g., the type of cognitive effect to be induced, including enhancing the quality of sleep or reducing sleep onset latency, and/or the device could automatically detect based on the configuration of an electrode to which the apparatus is attached. The user may select, for example, from a set of ensemble waveforms which ensemble waveform to execute. There may be separate waveforms to evoke a desired experience/effect (e.g., "calm" ensemble waveforms for reducing anxiety so that a subject may fall asleep vs. "drowsy" ensemble waveforms that are likely to induce sleep in a subject). An ensemble waveform may generally be between about 3-90 min (e.g., between about 3- 60 min, between about 5-60 min, between about 5-40 min, etc., between about 3-25 minutes, etc.) long, or longer (e.g., greater than 3 min, greater than 5 min, greater than 10 min, greater than 12 min, etc.). In general, an ensemble waveform may be broken up into segments with specific pulsing parameters, e.g., current amplitude, frequency, duty cycle, charge imbalance, shorting/capacitive discharge, etc., and these parameters may change at pre-specified times for subsequent component waveforms. Once the user selects an ensemble waveform, the user can start the neurostimulation and the user can control or change the perceived intensity (e.g., by dialing the perceived intensity up or down), pause, or stop the session using the phone (app). In general, the perceived intensity can be scaled by the user between 0-100% of a target perceived intensity (e.g., a target current, frequency, duty cycle, charge imbalance, and/or shorting/capacitive discharge), using a control such as one or more buttons, sliders, dials, toggles, etc., that may be present on the controller (e.g., smartphone) in communication with the neurostimulator. The controller may also allow a user to activate ("on demand") a waveform configuration that is designed to evoke a predetermined response. For example, the control device could be adapted to display one or more icons to trigger phosphenes or an intensification of the perceived cognitive effect or skin sensation intensity. In addition, the controller may be configured to allow the user to press an icon to help in applying the electrode apparatus and/or neurostimulator. For example, activating this control may cause the smartphone to activate a front-facing camera on the phone to help the user to attach the apparatus to the head. During or after a session, a user can access help screens, a profile page, social sharing interfaces (i.e. tweet your experience), feedback about a session, and analysis & history of previous use. In general, the system may also be configured to pass data to and from the controller and/or the neurostimulator and to/from a remote server via the Internet. These data may include user information, waveform data, information about the function or state of the hardware device or electrode assembly, etc.

[000115] The neurostimulator may apply an ensemble waveform for about 3-30 min (or longer) that is made up of different "blocks" having repeated waveform characteristics; the waveform ensemble may include transition regions between the different blocks. In general, at least some of the waveform blocks (and in some variations most or all of them) generally have a current amplitude of > 3 mA (e.g., between 5 mA and 40 mA, between 5 mA and 30 mA, between 5 mA and 22 mA, etc.), and a frequency of >100 Hz (e.g., between 250 Hz and 15 kHz, between 750 Hz and 25 kHz, between 750 Hz and 20 kHz, between 750 Hz and 15 kHz, etc.), the current is typically biphasic and is charge imbalanced, and has a duty cycle of between 1 -90% (e.g., between 10-90%, between 30-80%, between 30-60%, etc.). One or more of these characteristics may be changed during stimulation over timescales of every few seconds to minutes. FIG. 1 shows an exemplary cycle of a waveform for TES comprising a positive-going pulse of duration t _p , a negative-going pulse of duration t _n , and a total pulse duration of t _c . As shown in FIG. 1 the peak of the positive- and negative-going pulses may be equal (absolute value). The duty cycle percentage may be defined as (t _p + t„)/t _c and the charge imbalance percentage may be defined as (tp - 1„)/ (t _p + t,,).

[000116] In general, the TES control module may be specifically adapted to deliver a biphasic electrical stimulation signal of 10 seconds or longer between the first and second electrodes, where the signal has a frequency of 100 Hz or greater (e.g., 200 Hz or greater, 400 Hz or greater, 450 Hz or greater, 500 Hz or greater, 600 Hz or greater, 700 Hz or greater, etc.; optimally 750 Hz or greater, including 1 kHz or greater, 2 kHz or greater, 3 kHz or greater, 4 kHz or greater, 5 kHz or greater, 7.5 kHz or greater, 10 kHz or greater, 20 kHz or greater, etc.) and an intensity of 2 mA or greater (e.g., 3 mA or greater, 4 m A or greater, 5 mA or greater, 6 mA or greater, 7 mA or greater, 8 mA or greater, 9 mA or greater, 10 mA or greater, etc.). The control module may also be configured to reduce pain when applying the stimulation by controlling the duty cycle (e.g., the percent of time that the current applied is non-zero, and/or greater than zero), e.g. so that the duty cycle of the applied energy is greater than 10 percent (e.g., greater than 15 percent, greater than 20 percent, greater than 30 percent) and less than 90 percent (e.g., less than 75 percent, greater less than 70 percent, less than than 60 percent). In addition, the control module may be configured so that the applied current is biphasic and/or is not charge balanced (e.g., has a

DC offset, also referred to as DC bias, so that the mean amplitude of the applied waveform is non-zero). Alternatively or in addition, the control module (TES control module) may be configured to deliver waveforms biphasically asymmetric (i.e. not having the same pulse in the positive and negative direction) and/or to discharge capacitance built up on the electrodes (and in the body), e.g., by occasionally or periodically "shorting" the electrodes, and/or by applying an opposite current(s). In general, a control module may be configured to generate stimulation that includes these parameters, and may be configured to prevent stimulation outside of these parameters, in order to avoid inducing pain.

[000117] Described herein is a method of enhancing sleep, including facilitating falling asleep (e.g., reducing sleep onset time, increasing drowsiness, facilitating the passage into sleep in a subject, etc.), Such methods may generally include: placing a first electrode of a wearable transdermal electrical stimulation (TES) applicator on the subject's skin in a first region (e.g., on a temple region on a first side of the subject's body); placing a second electrode of the TES applicator on a second location (e.g., on the back of the subject's neck above the vertebra prominens); activating the wearable TES applicator to deliver a transdermal electrical stimulation having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 raA or greater. The biphasic transdermal electrical stimulation may be asymmetric with respect to positive and negative going phases; and facilitating the passage into sleep by applying the biphasic transdermal electrical stimulation between the first and second electrodes for 10 seconds or longer.

[000118] Also described herein are methods of inducing sleep in a subject, which may include: placing a first electrode of a wearable transdermal electrical stimulation (TES) applicator on the subject's skin (e.g., on a temple region on a first side of the subject's body); placing the second electrode on the subject (e.g., on the back of the subject's neck above the vertebra prominens); activating the wearable TES applicator to deliver a transdermal electrical stimulation having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater. The stimulation may be biphasic transdermal electrical stimulation that is asymmetric with respect to positive and negative going phases. The method may generally include inducing sleep by applying the biphasic transdermal electrical stimulation between the first and second electrodes for 10 seconds or longer.

[000119] Also described herein is a method of maintaining sleep in a subject, the method comprising: placing a first electrode of a wearable transdermal electrical stimulation (TES) applicator on the subject's skin on a temple region on a first side of the subject's body; placing the second electrode on the back of the subject's neck above the vertebra prominens; activating the wearable TES applicator to deliver a transdermal electrical stimulation having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 5 mA or greater, wherein the biphasic transdermal electrical stimulation is asymmetric with respect to positive and negative going phases; and maintaining a state of sleep in the subject by applying the biphasic transdermal electrical stimulation between the first and second electrodes for 10 seconds or longer while the subject is asleep. [000120] As mentioned above, any of the portable transdermal electrical stimulation (TES) applicators descried herein for facilitating, inducing, and/or maintaining sleep in a subject may include: a body; a first electrode; a second electrode; and a TES control module at least partially within the body and comprising a processor, a timer and a waveform generator, wherein the TES control module is adapted to deliver a biphasic electrical stimulation signal of 10 seconds or longer between the first and second electrodes having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater, wherein the biphasic transdermal electrical stimulation is asymmetric with respect to positive and negative going phases.

[000121] For example, a wearable transdermal electrical stimulation (TES) applicators for facilitating, inducing, and/or maintaining sleep in a subject may include: a body; a first electrode; a second electrode; a TES control module at least partially within the body and comprising a processor, a timer and a waveform generator, wherein the TES control module is adapted to deliver a biphasic electrical stimulation signal of 10 seconds or longer between the first and second electrodes having a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or greater, wherein the biphasic transdermal electrical stimulation is asymmetric with respect to positive and negative going phases; and a wireless receiver connected to the TES control module; wherein the wearable TES applicator weighs less than 50 grams.

[000122] Any of these apparatuses may be specifically adapted for use as a sleep-modifying apparatus. For example, in some variations, the apparatus includes one or more sensor that determine the sleep state (e.g., awake, asleep, drowsy, etc.) of the subject wearing the apparatus. Sensors may include one or more accelerometers, heart rate sensors, electroencephalogram (EEG) sensors, electromyogram (EMG, including electrooculogram EOG), etc. As used herein, a sensor may also include hardware and/or software for interpreting and/or modifying the resulting signals, including but not limited to filtering physiological signals, amplifying physiological signals, etc.

[000123] The methods and apparatuses (devices, systems) described herein may use a TES waveform having one or more characteristics from the list including: a duty cycle between 30% and 60%; a frequency greater than 5 kHz or greater than 10 kHz; an amplitude modulation, including amplitude modulation with a frequency less than 250 Hz; and a burst mode wherein stimulation pauses intermittently (i.e. on for 100 ms, off for 900 ms; on for 500 ms, off for 500 ms; and other more complex pulsing patterns, including chirping and patterns repeating at 250 Hz or lower frequency).

[000124] The methods and apparatuses (devices, systems) described herein are useful for facilitating the passage into sleep and/or inducing sleep and may include inducing one or more of the following states in the subject: increased drowsiness; increased desire to sleep: and enhanced state of calmness and carefreeness (i.e. reduced anxiety) when preparing to fall asleep, attempting to fall asleep, or actually passing into a state of sleep.

[000125] The apparatuses (devices, systems) described herein may be activated while the subject is awake (before they fall asleep) or may be put on by the user before sleep but not activated until after the user has fallen asleep. For embodiments configured to deliver TES before a subject falls asleep, a visual indicator (i.e. LED or screen) of the transdermal electrical stimulator (or a connected user device such as a smartphone running an app that controls the transdermal electrical stimulator) may be turned down or turned off when the wearable TES system is activated for facilitating the passage into sleep of the subject.

[000126] Some versions of the methods and systems described herein include sleep monitoring of the subject. Sleep monitoring may comprise using a sensor (which may be included as part of the apparatus or used along with the apparatus) to measure a subject's brain rhythms (i.e. EEG), autonomic function

(including sensors to measure one or more of: galvanic skin resistance, heart rate, heart rate variability, or breathing rate), and/or movements, including movement sensors worn by the subject, coupled to the subject's bed, or configured to detect movements remotely without direct or indirect physical contact with the subject (i.e. via ultrasound or a microphone). Variations of the systems and methods described herein may further comprise an automatic modification of a transdermal electrical stimulation waveform based on the amount of time required for a subject to fall asleep. Thus, any of the apparatuses described herein may be configured to feed the sensor information back to control (e.g., turn on/off) and/or modify the

TES stimulation applied.

[000127] For example, in some embodiments of the invention, a subject will fall asleep within a short period of time (i.e. less than 15 minutes; less than 10 minutes; less than 5 minutes). A TES stimulation may stop automatically when the subject is asleep, as detected by a sleep monitoring function and related components of the system. For example, TES may automatically stop when the subject is asleep at a fixed delay (alarm mode), based on a sleep state (or series of sleep states) experienced by the user, or by control of a third party (i.e. a sleep clinic technician who controls the system remotely via an Internet connection). In another example, TES may be automatically or manually (i.e. from a quick start button that can be pressed quickly and easily to minimize likelihood of waking) triggered if a subject wakes up, even briefly, so that the subject can get back to sleep quickly.

[000128] In some variations of the systems and methods described herein, a TES waveform may be started, stopped, or modified based on sleep quality being below a threshold value, where sleep quality is defined by one or more of: sleep latency, amount and/or sequence of sleep stages, sleep amount, and time during the day when sleep occurs. The sleep quality measurement may be a measurement of sleep quality from the current bout of sleep and/or from one or more previous bouts of sleep. In other variations of the systems and methods described herein, a TES waveform may be started, stopped, or modified based on a measurement of the subject's physiology or cognitive state including but not limited to: activity, stress, immune system function, diet, and mood. The methods and apparatuses (devices, systems) described herein may be configured for use before or during a nap and/or to enhance the function of the immune system (i.e. by improving the quality and/or quantity of slow-wave sleep in the subject).

[000129] In addition to 'lifestyle' applications (i.e. for general use by subjects, not for treating or diagnosing any medical condition), the TES apparatuses (systems, devices) and methods described herein for facilitating, inducing, and/or maintaining sleep in a subject may be used to treat a sleep disorder in a patient, including but not limited to: insomnia, including insomnias as a symptom of a psychiatric or mood disorder such as post-traumatic stress disorder, anxiety, emotional distress, depression, bipolar disorder, or schizophrenia; restless leg syndrome and periodic limb movement disorder; circadian rhythm disorders; sleeping sickness; parasomnia; shift work and jet lag; and hypersomnia. The TES apparatuses (systems, devices) and methods described herein for facilitating, inducing, and/or maintaining sleep in a patient may also be used to treat a disorder, disease, or symptom not generally described as a sleep disorder but for which sleep abnormalities occur in the patient, including but not limited to: posttraumatic stress disorder, a neurodegenerative disease such as Alzheimer's disease, a neurodevelopmental disorder such as Down syndrome, autism spectrum disorder, and Rett's syndrome; alcoholism; drug addiction; menopause; pregnancy; menstruation; attention-deficit disorders, including attention-deficit hyperactivity disorder; medication that affects the ability to fall asleep, including chemotherapeutic agents; and age-related sleep changes.

[000130] The systems and methods described herein may further comprise a notification that reminds the subject to wear a neurostimulator before bed and configure it for improving sleep. For example, the notification to the subject may be based on input from a location sensor in the neurostimulator or a device wirelessly connected to the neurostimulator to detect that a user is in their bedroom and a clock to determine whether the user is in their bedroom during a time when they generally go to sleep. In other embodiments, the system or method may further comprise a calming sensory stimulus (i.e. an auditory stimulus, including binaural beat, and olfactory stimuli) and/or may further comprise an alarm that wakes a subject during an identified phase of light sleep to remind the user to remove the sleep-promoting TES system.

[000131] When a subject wakes (i.e. in the morning), feedback may be provided to the subject showing how the subject's use of transdermal electrical stimulation before and/or during sleep affected a sleep quality metric selected from the group including but not limited to: sleep onset time, length of sleep, sleep latency, total length or percentage of REM sleep, total length or percentage of NREM sleep, total length or percentage of slow wave (deep) sleep, length of sleep cycles, number and/or length of night awakenings, and morning wake time.

EXAMPLES

[000132] As mentioned above, in general the use of certain TES waveforms applied prior to sleeping may improve the quantity and/or quality of sleep. In the morning, users typically wake up feeling more rested, with a more positive mood, less anxiety, and less stress (both as self-reported and as assessed by biochemical assay of saliva). FIGS. 9-14B illustrate exemplary data comparing various TES waveform that may be used to enhance sleep, including comparing to a control ("baseline") stimulation in which only sham TES was applied.

[000133] For example, FIG. 9 illustrates an example of an overall assessment of the effect of two exemplary TES waveforms within a range of parameter values found to enhance sleep, compared to baseline. Comparison is made using the Pittsburg Sleep Quality Index (PSQI). In this example, the assessments compared, in a 1 -week crossover design with no washout period, baseline (no TES before sleep) and two different 15-minute TES waveforms delivered through a configuration wherein an anode is at the forehead / temple area and cathode on the neck of a subject, similar to that shown in FIGS. 2A-2F.

One waveform tested was referred to as 'high F' (or alternatively as 'Program B' or relaxCES) and is a pulsed waveform with variable frequency, generally between 3 kHz and 11 kHz. FIG. 15A-15C describe three example of complete ensemble waveforms that may be similar to the "high F" TES waveforms used.

[000134] The tables shown in FIG. 15A-15C lists the waveform parameters for each of the component waveforms. In this example the ensemble waveform is configured with short circuiting on (meaning that a capacitive discharge pulse occurs in the opposite direction after each of the biphasic pulses). In one example, the system transfers chunks (e.g., 400 ms segments) securely between the user device and the worn neurostimulator every about 400 ms (or on multiples of about 400 ms), including the

neurostimulation start frequency, end frequency, starting amplitude, end amplitude, start duty cycle, end duty cycle, start percent charge imbalance, end charge imbalance, etc. The timing of wireless communication chunks at about 400 ms should not be construed as limiting the timing of communication between a controller unit and the neurostimulator. FIG. 15B illustrates a second example of a calm ensemble waveform having a slightly longer running time, running over 12 minutes. Similarly, 15C illustrates a third example of a calm ensemble waveform having a yet longer running time (over 16 minutes).

[000135] A second waveform tested in this study was referred to as 'low F' (or alternatively as 'Program A'). This second waveform has a lower pulsing frequency, variable but generally 750 Hz. FIG. 16 illustrates an example of a TES ensemble waveform such as the low F variations described herein.

[000136] In FIG. 9, a comparison of PSQI for n=10 subjects examined between baseline (no TES), high F and low F ensemble waveforms show a significant improvement of both low F and high F waveforms compared to baseline (and to other TES waveforms having parameters outside of the ranges described herein, data not shown). In general, a PSQI of greater than 5 is considered to reflect poor sleep quality.

[000137] In addition to the low F and high F parameters, acute studies performed in the afternoon used alternative 15 minute TES ensemble waveforms with even lower frequency, e.g., 500 Hz, pulsing (full set of parameters below). Surprisingly, 5 of 10 people fell asleep during the 15 minute vibe. This effect appears to be stronger for lower frequencies (e.g., 'low F') compared to higher frequency ('high F') ensembles, for which subjects tend to fall asleep after the vibe completes (though it is not that uncommon to fall asleep during a sleep-inducing waveform). Subject's self-reported feeling increased sleepiness (e.g., very heavy drowsy physical feelings, "face is extremely relaxed, words are slowed down and shoulders drop," feeling as though the subject woke up from a nap physically relaxed and mentally alert, etc.). In this example, the parameters (for 'very low F' stimulation) included stimulating at 500 Hz for a 15 min ensemble, having a peak current of 3.5 mA. The (illustrated in the table of FIG. 17) had a frequency of 500 Hz for 4 min and 30 sec, switching to a frequency of 550 Hz for 30 seconds (and repeating for 3 cycles of this). The duty cycle, as defined above, was 25 to 35% depending on patient comfort (they could self-adjust). The charge imbalance as defined above as the percent DC offset (see FIG. 1) was 3%. Capacitive discharging was set to "on" so that a brief capacitive discharging pulse was emitted during a portion of each positive- or negative- going pulse.

[000138] In each of the sleep studies discussed herein the subject ages ranged between 18 and 50 years old. Subjects were monitoring using one or more sleep sensors (e.g., 7 wore Actigraph sleep sensors, Phillips Actiwatch; 7 wore HRV monitor, Polar chest strap). Integrated sensors (e.g., motion sensors, etc.) in the wearable apparatus could alternatively or additionally be used. In some examples, the procedure included seven nights of each protocol. In practice, subjects may use these apparatuses for multiple nights (e.g., 2 nights, 3 nights, 1 week, 2 weeks, one month, etc.) concurrently to enhance sleep.

[000139] For example, seven nights of Program B (e.g., using a high F ensemble TES waveform similar to that shown in FIG. 15 A, running for 15 min. beginning prior to falling asleep) and seven nights of Program A (e.g., using a low F, approximately 750 Hz, pulsing TES waveform for 15 min., similar to FIG. 16, prior to falling asleep). In the studies shown in FIGS. 9-14B, morning and evening logs were kept for study duration, sleep monitoring (e.g., Actigraph and Polar chest strap, measuring HR and HRV) was performed for the study duration during sleep. Baseline, 7 Day and 14 Day general health screening was done, assessing (by self-reporting): overall sleep score (FIG. 9), Stress, Anxiety, Depression, Fatigue and the like (FIGS. 12A-12G).

[000140] For example, as partially reflected in FIGS. lOA-lOC, comparison between low F and high F stimulation protocols suggests that the improved sleep quality (compared to baseline) in these two exemplary stimulation protocols may come in part due to fewer awakenings, fewer unknown awakenings, and in particular, fewer awakenings caused by needing to use a bathroom. See, e.g., FIG. 10A, showing a bar graph of WASO in minutes, and FIG. 10B, showing comparison between the percentage of time, and FIG. IOC, showing the self-reported WASO events.

[000141] Similarly, FIGS. 11 A-l 1 C illustrate heart rate variability (FIG. 11 A, showing HRV in very low frequency bands (e.g., oVLF of 57.5 to 75), HRV power in the low-frequency band, FIG. 1 IB shows pLF (between 15 and 20), while FIG. 1 1C compares the pHF indicating slight differences between the low F and high F protocols.

[000142] FIGS. 14A and 14B compare two empirical measures of sleep quality, morning amylase and morning Cortisol, between the high F and low F groups. This biochemical analysis included collecting saliva on mornings during the treatment period for each of the high F and low F parameters. The user collected saliva was processed by a third party for alpha-amylase and Cortisol, both of which are known to correlate to acute and chronic stress. The lower frequency regime (Low F) showed a slightly greater effect compared to the high F regime, consistent with the other (self-reported) data, e.g., in FIGS. 1 1A-13B.

[000143] In general, the methods of improving sleep by TES stimulation described herein show that, relative to baseline, both low F and high F TES ensemble waveforms improved sleep quality as assessed by the Pittsburgh Sleep Quality Index (for which higher scores correspond to lower quality sleep).

Further, the Low F waveforms led to fewer awakenings and reduced the length of awake time after sleep onset relative to the high F waveform (see, e.g., FIGS. lOA-lOC), and the low F waveforms caused a reduction in power in the very low frequency band relative to high F. Hear rate variability (HRV) in the low frequency and high frequency bands is slightly higher after low F TES waveform than the high F waveform. These frequency bands are typically described as high frequency (HF) brain activity, from 0.15 to 0.4 Hz, low frequency (LF) brain activity, from 0.04 to 0.15 Hz, and the very low frequency (VLF) brain activity, from 0.0033 to 0.04 Hz.

[000144] In general, the high F and low F waveforms were relatively similar, though both improved over baseline. For example, improvements were seen in the time it takes to fall asleep (sleep onset latency), reductions in the occurrence of nightmares, increased total sleep time, and improved mood. In a previous study, high F beat baseline on all above metrics except for those related to middle of the night and early morning awakenings.

[000145] Thus, in general, the application of TES before bed using either low F or high F waveforms led to improvements in subject's mood and energy in the morning as assessed with the positive and negative affect schedule (PANAS) scale. These beneficial effects on mood may include reduced anxiety (FIG. 12A), reduced depressive feelings (FIG. 12B), reduced stress (FIG. 12C), increased positive affect (FIG. 12D), reduced negative affect (FIG. 12E), reduced irritability (FIG. 12F), and reduced fatigue (FIG. 12G). Application of TES as described herein before sleeping may also improve depression, anxiety and stress, as indicated by the Depression, Anxiety and Stress Scale (DASS), a clinical measure with a 0 to 3 scale used for FIGS 12A-12G. Affectivity was measured on a 5 point scale, ranging from 1 to 5, irritability was measured on a 0 to 3 scale, and fatigue was measured on a 0 to 10 scale.

[000146] The self-reported scores for PANAS and DASS are consistent with the biochemical markers examined (e.g., decreased Awakening Amylase and Increased Awakening Cortisol) for the high F, low F and very low F TES stimulation. Cortisol is on a diurnal pattern with its peak 30 min after waking; generally, the higher the morning rise in Cortisol, the more 'normal' the indicator is, whereas a blunted rise in morning Cortisol may be indicative of a disease state such as depression, post-traumatic stress disorder (PTSD), anxiety and/or sleep deprivation. In general, the majority (e.g., 2/3 or more) of subjects reported feeling more rejuvenated, less drowsy, less anxious, and less stressed the next day. Over 2/3 of subjects also reported having an easier time falling asleep and/or getting more sleep following the use of the TES methods described herein.

[000147] The TES waveforms that may be applied (e.g., to the subject's neck or head and neck) to enhance sleep as described herein include a range of parameters that may be adjusted for both efficacy and comfort. The data described herein suggest that in some variations it may be beneficial to provide relatively low frequency (e.g., 250 Hz to 750 Hz, 250 to 1 kHz, 250 to 3 kHz, 250 to 5 kHz, etc.) stimulation at relatively high current (e.g., >3 mA, greater than 4 mA, greater than 5 mA, etc.); however these two parameters alone, low frequency and high current, typically result in painful and/or unpleasant sensations on the head and/or neck when applied there. In order to achieve a combination of low (250-

750 Hz) frequency and high current (>3 mA, 3-40 mA, >5 mA, etc.) it may be beneficial to include one or more of the modulation schemes described herein, including DC offset (biphasic, asymmetric stimulation in which the positive and negative going pulses are different durations and/or amplitudes), percent duty- cycles (e.g., between 10-80%, etc.) and the use of an AC (carrier) frequency (<250 Hz). In some variations, the use of just one or two of these modulation schemes may be sufficient (e.g., using just a DC offset and a percent duty cycle between 10-80%, or just a DC offset and an AC carrier frequency < 250

Hz, or just a percent duty cycle between 10-80% and an AC carrier frequency of <250 Hz), while in some variations, all three may or must be used.

[000148] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[000149] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as "/".

[000150] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

[000151] Although the terms "first" and "second" may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.

[000152] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising" means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term "comprising" will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[000153] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or

"approximately," even if the term does not expressly appear. The phrase "about" or "approximately" may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/- 0.1 % of the stated value (or range of values), +/- 1 % of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 1 1 , 12, 13, and 14 are also disclosed.

[000154] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims. [000155] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.