US 20170182285A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0182285 A1 TYLER et al. (43) Pub. Date: Jun. 29, 2017
(54) SYSTEMIS AND METHODS FOR on May 18, 2015, now Pat. No. 9,517,351, said TRANSIDERMAL ELECTRICAL application No. 15/264.224 is a continuation-in-part STMULATION TO IMPROVE SLEEP of application No. 15/169,445, filed on May 31, 2016. (60) Provisional application No. 62/308.845, filed on Mar. (71) Applicants: William J. TYLER, Newton, MA 15, 2016, provisional application No. 62/100,004, (US); Alyssa M. BOASSO, Brookline, filed on Jan. 5, 2015, provisional application No. MA (US); Hailey M. MORTIMORE, 61/729,851, filed on Nov. 26, 2012, provisional ap Boston, MA (US); Rhonda S. SILVA, plication No. 61/765,795, filed on Feb. 17, 2013, Boston, MA (US): Sumon K. PAL, provisional application No. 61/767.945, filed on Feb. Boston, MA (US); Jonathan 22, 2013, provisional application No. 61/770,479, CHARLESWORTH, Menlo Park, CA filed on Feb. 28, 2013, provisional application No. (US); Linh M. AVEN, Boston, MA 61/841.308, filed on Jun. 29, 2013, provisional appli (US) cation No. 61/845,845, filed on Jul. 12, 2013, provi (72) Inventors: William J. TYLER, Newton, MA sional application No. 61/875.424, filed on Sep. 9, (US); Alyssa M. BOASSO, Brookline, 2013, provisional application No. 61/900,880, filed MA (US); Hailey M. MORTIMORE, on Nov. 6, 2013, provisional application No. 61/875, Boston, MA (US); Rhonda S. SILVA, 891, filed on Sep. 10, 2013, provisional application Boston, MA (US): Sumon K. PAL, No. 61/888,910, filed on Oct. 9, 2013, provisional Boston, MA (US); Jonathan application No. 61/907.394, filed on Nov. 22, 2013, CHARLESWORTH, Menlo Park, CA provisional application No. 62/076,459, filed on Nov. (US); Linh M. AVEN, Boston, MA (Continued) (US) Publication Classification (21) Appl. No.: 15/460,138 (51) Int. C. A6M 2L/02 (2006.01) (22) Filed: Mar. 15, 2017 A61N L/36 (2006.01) A61N L/04 (2006.01) Related U.S. Application Data (52) U.S. C. (63) Continuation-in-part of application No. PCT/ CPC ...... A61M 21/02 (2013.01); A61N I/0456 US2016/012128, filed on Jan. 5, 2016, Continuation (2013.01); A61N I/36025 (2013.01); A61M in-part of application No. 15/264.224, filed on Sep. 2021/0072 (2013.01) 13, 2016, which is a continuation-in-part of applica tion No. 14/558,604, filed on Dec. 2, 2014, now Pat. (57) ABSTRACT No. 9,440,070, which is a continuation-in-part of Methods and apparatuses for improving sleep by transder application No. 14/091,121, filed on Nov. 26, 2013, mal electrical stimulation (TES). In general, described now Pat. No. 8,903,494, said application No. 15/264, herein are methods for applying TES to a subject, and 224 is a continuation-in-part of application No. particularly the Subjects head (e.g., temple/forehead region) 15/170,878, filed on Jun. 1, 2016, said application No. and/or neck with an TES waveform adapted to improve 15/264.224 is a continuation-in-part of application sleep, including reducing sleep onset (falling to sleep) more No. 14/715,470, filed on May 18, 2015, now Pat. No. quickly and/or lengthening the duration of sleep. TES wave 9,474,891, said application No. 15/264.224 is a con form(s) particularly well Suited to enhancing sleep are also tinuation-in-part of application No. 14/715,476, filed described herein.
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Related U.S. Application Data No. 62/099.960, filed on Jan. 5, 2015, provisional application No. 62/100,022, filed on Jan. 5, 2015, 6, 2014, provisional application No. 62/169,522, filed provisional application No. 61/994,860, filed on May on Jun. 1, 2015, provisional application No. 62/169, 17, 2014, provisional application No. 62/100,029. 523, filed on Jun. 1, 2015, provisional application No. filed on Jan. 5, 2015, provisional application No. 62/170,111, filed on Jun. 2, 2015, provisional appli 62/168,615, filed on May 29, 2015, provisional appli cation No. 62/268,084, filed on Dec. 16, 2015, pro cation No. 62/190,211, filed on Jul. 8, 2015, provi visional application No. 62/002.910, filed on May 25, sional application No. 62/200.256, filed on Aug. 3, 2014, provisional application No. 627076,459, filed 2015, provisional application No. 62/213,949, filed on Nov. 6, 2014, provisional application No. 62/075, on Sep. 3, 2015, provisional application No. 62/099, 896, filed on Nov. 6, 2014, provisional application 950, filed on Jan. 5, 2015. Patent Application Publication Jun. 29, 2017. Sheet 1 of 31 US 2017/0182285 A1
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Carrets zang$ saauan Sy su pue3sy Patent Application Publication Jun. 29, 2017. Sheet 31 of 31 US 2017/0182285 A1 : i. . 3. 2 N w t euese Luoy effuel Oueole f US 2017/0182285 A1 Jun. 29, 2017 SYSTEMIS AND METHODS FOR TRANSCRANIAL ELECTRICAL STIMULATION SYS TRANSIDERMAL ELECTRICAL TEMS AND METHODS, filed Oct. 9, 2013: U.S. Provi STIMULATION TO IMPROVE SLEEP sional Patent Application No. 61/907.394, titled “TRAN SCRANIAL ELECTRICAL STIMULATION SYSTEMS CROSS REFERENCE TO RELATED AND METHODS, filed Nov. 22, 2013. Each of these APPLICATIONS applications is herein incorporated by reference in its 0001. This patent application claims priority to U.S. entirety. Provisional Patent Application No. 62/308,845, titled 0004 U.S. patent application Ser. No. 14/558,604 also TRANSDERMAL ELECTRICAL NEUROMODULA claims the benefit of U.S. Provisional Patent Application No. TION OF THE TRIGEMINAL SENSORY NUCLEAR 62/076,459, titled “CANTILEVER ELECTRODES FOR COMPLEX IMPROVES SLEEP QUALITY AND TRANSDERMAL AND TRANSCRANIAL STIMULA MOOD,” filed Mar. 15, 2016, which is herein incorporated TION,” filed Nov. 6, 2014, which is herein incorporated by by reference in its entirety. reference in its entirety. 0002 This application also claims priority as a continu 0005 U.S. patent application Ser. No. 15/264,224 is also ation-in-part of International Patent Application No. PCT/ a continuation-in-part of U.S. patent application Ser. No. US2016/012128, titled “SYSTEMS AND METHODS FOR 15/170,878, titled “APPARATUSES AND METHODS FOR TRANSDERMAL ELECTRICAL STIMULATION TO NEUROMODULATION, filed Jun. 1, 2016, Publication IMPROVE SLEEP filed Jan. 5, 2016, Publication No. WO No. US-2016-0346545-A1, which claims priority to each of 2016/11 1974, which claims priority to U.S. Provisional the following: U.S. Provisional Patent Application No. Patent Application No. 62/100,004, titled “SYSTEMS FOR 62/169,522, titled “SYSTEMS AND METHODS FOR TRANSDERMAL ELECTRICAL STIMULATION TO NEUROMODULATION TO TRANSFORM CONCUR IMPROVE SLEEP AND METHODS OF USING THEM, RENT SENSORY EXPERIENCES.” filed Jun. 1, 2015: filed Jan. 5, 2015, each of which are herein incorporated by U.S. Provisional Patent Application No. 62/169,523, titled reference in its entirety. APPARATUSES AND METHODS FOR NEUROMODU 0003. This application also claims priority as a continu LATION,” filed Jun. 1, 2015; U.S. Provisional Patent Appli ation-in-part to U.S. patent application Ser. No. 15/264.224, cation No. 62/170,111, titled “SYSTEMS AND METHODS titled APPARATUSES AND METHODS FOR NEURO NEUROMODULATION WITH FACIAL AND MASTOID MODULATION,” filed Sep. 13, 2016, which is a continu ELECTRODES, filed Jun. 2, 2015; and U.S. Provisional ation-in-part of U.S. patent application Ser. No. 14/558,604, Patent Application No. 62/268,084, titled “SYSTEMS AND titled “WEARABLE TRANSDERMAL ELECTRICAL METHODS FOR NEUROMODULATION WITH FACIAL STIMULATION DEVICES AND METHODS OF USING AND MASTOID ELECTRODES, filed Dec. 16, 2015. THEM, filed Dec. 2, 2014, now U.S. Pat. No. 9,440,070, Each of these applications is herein incorporated by refer which is a continuation-in-part of U.S. patent application ence in its entirety. Ser. No. 14/091,121, titled “WEARABLE TRANSDER 0006 U.S. patent application Ser. No. 15/264.224 is also MAL ELECTRICAL STIMULATION DEVICES AND a continuation-in-part of U.S. patent application Ser. No. METHODS OF USING THEM, filed Nov. 26, 2013, now 14/715,470, titled “TRANSDERMAL NEUROSTIMULA U.S. Pat. No. 8,903,494, which claims the benefit of U.S. TORADAPTED TO REDUCECAPACITIVE BUILD-UP Provisional Patent Application No. 61/729,851, titled “DIS filed May 18, 2015, now U.S. Pat. No. 9,474,891, which POSABLE AND SEMI-DISPOSABLE TRANSCRANIAL claims priority to U.S. Provisional Patent Application No. ELECTRICAL STIMULATION SYSTEMS, filed Nov. 26, 62/002,910, titled “TRANSDERMAL ELECTRICAL 2012; U.S. Provisional Patent Application No. 61/765,795, STIMULATION ELECTRODE DEGRADATION DETEC titled TRANSCRANIAL ELECTRICAL STIMULATION TION SYSTEMS AND METHODS OF USING THEM, SYSTEMS, filed Feb. 17, 2013: U.S. Provisional Patent filed May 25, 2014: U.S. Provisional Patent Application No. Application No. 61/767,945, titled “TRANSCRANIAL 62/076,459, titled “CANTILEVER ELECTRODES FOR NEUROMODULATION SYSTEMS, filed Feb. 22, 2013; TRANSDERMAL AND TRANSCRANIAL STIMULA U.S. Provisional Patent Application No. 61/770,479, titled TION,” filed Nov. 6, 2014: U.S. Provisional Patent Appli TRANSCRANIAL NEUROMODULATION CONTROL cation No. 62/099,950, titled “CANTILEVER ELEC LER AND DELIVERY SYSTEMS, filed Feb. 28, 2013; TRODES FORTRANSDERMAL AND TRANSCRANIAL U.S. Provisional Patent Application No. 61/841,308, titled STIMULATION, filed Jan. 5, 2015; U.S. Provisional Pat TRANSCRANIAL ELECTRICAL STIMULATIONS ent Application No. 62/075,896, titled “SYSTEMS AND SYSTEMS, filed Jun. 29, 2013: U.S. Provisional Patent METHODS FOR NEUROMODULATION, filed Nov. 6, Application No. 61/845,845, titled “TRANSCRANIAL 2014: U.S. Provisional Patent Application No. 62/099.960, ELECTRICAL STIMULATION SYSTEMS AND METH titled METHODS AND APPARATUSES FOR USER ODS.” filed Jul. 12, 2013: U.S. Provisional Patent Applica CONTROL OF NEUROSTIMULATION, filed Jan. 5, tion No. 61/875,424, titled “TRANSCRANIAL ELECTRI 2015; U.S. Provisional Patent Application No. 62/100,022, CAL STIMULATION SYSTEMS AND METHODS, filed titled “WEARABLE TRANSDERMAL NEUROSTIMU Sep. 9, 2013: U.S. Provisional Patent Application No. LATOR, filed Jan. 5, 2015. Each of these applications is 61/900,880, titled “NEUROMODULATION CONTROL herein incorporated by reference in its entirety. AND USER INTERFACE SYSTEMS, filed Nov. 6, 2013; 0007 U.S. patent application Ser. No. 15/264,224 is also U.S. Provisional Patent Application No. 61/875,891, titled a continuation-in-part of U.S. patent application Ser. No. SYSTEMS AND METHODS FOR TRANSCRANIAL 14/715,476, titled “METHODS AND APPARATUSES FOR ELECTRICAL STIMULATION DURING A PERFOR AMPLITUDE-MODULATED ENSEMBLE WAVE MANCE OR GROUP INVENT.” filed Sep. 10, 2013: U.S. FORMS FOR NEUROSTIMULATION, filed May 18, Provisional Patent Application No. 61/888,910, titled 2015, now U.S. Pat. No. 9,517,351, which claims priority to US 2017/0182285 A1 Jun. 29, 2017 the following provisional patent applications: U.S. Provi 0012. The present invention relates to methods and sys sional Patent Application No. 61/994,860, titled “SYS tems for transdermal electrical neuromodulation to modulate TEMS, DEVICES, AND METHODS FOR TRANSDER sleep. In particular described herein are neurostimulator MAL ELECTRICAL STIMULATION WAVEFORM apparatuses, generally wearable, configured to be applied to DESIGN AND USE, filed May 17, 2014, and U.S. Provi the user (e.g., the user's head and/or neck) to reduce sleep sional Patent Application No. 62/100,029, titled “METH onset, lengthen sleep duration, improve sleep quality, and/or ODS AND APPARATUSES FOR DELIVERY OF enhance the types and/or subtypes of sleep. In some varia ENSEMBLE WAVEFORMS, filed Jan. 5, 2015. Each of tions these systems may improve sleep for Subjects with these applications is herein incorporated by reference in its Sub-clinical or clinical sleep disturbances, including sleep entirety. disorders and sleep issues symptomatic to other diseases, 0008 U.S. patent application Ser. No. 15/264.224 is also disorders, or behaviors. a continuation-in-part of U.S. patent application Ser. No. 15/169,445, titled “METHODS AND APPARATUSES FOR BACKGROUND TRANSDERMAL ELECTRICAL STIMULATION, filed 0013 Sleep disturbances, including insomnia and sleep May 31, 2016, Publication No. US-2016-0346530-A1, lessness, are known to affect a vast number of individuals. which claims priority to each of the following: U.S. Provi In addition, many individuals may wish to regulate or sional Patent Application No. 62/168,615, titled “METH control their sleep as a lifestyle choice. Sleep disorders, as ODS AND APPARATUSES FOR TRANSDERMAL well sleep abnormalities symptomatic to a disorder, disease, ELECTRICAL STIMULATION, filed May 29, 2015; U.S. behavior, or treatment (i.e. sleep issues that occur in Provisional Patent Application No. 62/190,211, titled response to ADHD treatment, chemotherapy, etc.) affect METHODS AND APPARATUSES FOR TRANSDER millions. Moreover, many individuals suffer from sub-clini MAL ELECTRICAL STIMULATION, filed Jul. 8, 2015: cal or undiagnosed sleep issues that severely affect health U.S. Provisional Patent Application No. 62/200.256, titled and well-being, causing a reduced quality of life. Currently, METHODS AND APPARATUSES FOR TRANSDER modulation of sleep and treatment of the symptoms of MAL ELECTRICAL STIMULATION, filed Aug. 3, 2015: sleeping disorders is generally accomplished with pharma and U.S. Provisional Patent Application No. 62/213,949, cological agents. Such agents may be expensive, have titled METHODS AND APPARATUSES FOR TRANS associated risk of overdose, and may have undesirable side DERMAL ELECTRICAL STIMULATION, filed Sep. 3, effects. In addition some people are averse to using drugs to 2015. Each of these applications is herein incorporated by treat seemingly benign conditions Such as insomnia and reference in its entirety. sleeplessness. 0009. This application may also be related to one or more 0014. It would generally be advantageous to provide of the following applications: U.S. patent application Ser. apparatuses (devices, systems) and methods for transdermal No. 14/320,443, titled “TRANSDERMAL ELECTRICAL electrical stimulation for improving sleep. Specifically, there STIMULATION METHODS FOR MODIFYING OR is a need for effective non-drug treatments (or enhancements INDUCING COGNITIVE STATE, filed Jun. 30, 2014, for existing drug treatments) for sleep. now U.S. Pat. No. 9,014,811; U.S. patent application Ser. 0015 Described herein are transdermal electric stimula No. 14/320,461, titled “TRANSDERMAL ELECTRICAL tion (hereinafter “TES) apparatuses (devices and systems) STIMULATION DEVICES FOR MODIFYING OR and methods of using them that may be useful in treating INDUCING COGNITIVE STATE, filed Jun. 30, 2014, sleep. TES (e.g., applied through scalp electrodes) has been now U.S. Pat. No. 9,002,458; U.S. patent application Ser. used to affect brain function in humans. TES has been shown No. 14/639,015, titled “TRANSDERMAL ELECTRICAL to improve motor control and motor learning, improve STIMULATION DEVICES FOR MODIFYING OR memory consolidation during slow-wave sleep, regulate INDUCING COGNITIVE STATE, filed Mar. 4, 2015, now decision-making and risk assessment, affect sensory percep U.S. Pat. No. 9,233,244; U.S. patent application Ser. No. tion, and cause movements. TES has been used therapeuti 14/634,551, titled “METHODS FOR USER CONTROL OF cally in various clinical applications, including treatment of NEUROSTIMULATION TO MODIFY A. COGNITIVE pain, depression, epilepsy, and tinnitus. Despite the research STATE, filed Feb. 27, 2015, now U.S. Pat. No. 9,399,126. to date on TES neurostimulation, existing methods and Each of these applications is herein incorporated by refer apparatuses for TES are lacking for applications related to ence in its entirety. the modulation of sleep. 0016 For example, U.S. patent application Ser. No. INCORPORATION BY REFERENCE 13/423.380 titled “DEVICE FOR CONVERTING MUSIC 0010 All publications and patent applications mentioned SIGNAL TO ELECTRICAL STIMULATION” by inventor in this specification are herein incorporated by reference in Liang describes systems for adapting music therapy insom their entirety to the same extent as if each individual nia treatments by converting the analog auditory signal to a publication or patent application was specifically and indi time-varying Voltage signal delivered to transdermal elec vidually indicated to be incorporated by reference. trodes targeting acupuncture points. However, audible waveforms of music appropriate for use as a musical therapy FIELD OF THE INVENTION intervention for sleep are poorly adapted to transdermal electrical stimulation targeting peripheral nerves. An analog 0011. This invention relates generally to methods and adapted signal as described by Liang would likely lack high apparatuses for noninvasive neuromodulation, and more transient peak currents (i.e. pulsing) that may be effective for specifically to configurations and methods for transdermal activating peripheral nerves, and further may be quite electrical stimulation systems adapted to improve sleep and uncomfortable due to the presence of significant power in mood. low frequencies (100s of Hz) without duty cycle limitations. US 2017/0182285 A1 Jun. 29, 2017 0017 U.S. patent application Ser. No. 12/616,513, titled Wang titled “METHOD FOR MODERATION OF SLEEP DEEP BRAIN STIMULATION FOR SLEEP AND DISORDER describes methods for treating a sleep disorder MOVEMENT DISORDERS’ by inventors Wu et al. using a magnetic head acupuncture headgear (see also U.S. describes an implantable electrical stimulation system tar Pat. No. 6,280,454 to Wang) for electrical stimulation at geting the Substantia nigra to treat sleep disorders. The sleep 0.3-3.4 kHz using many electrodes implanted on the scalp. stage of a patient is tracked and stimulation is modulated These methods require a magnetic material, cap, or a large according to the patient’s sleep stage. Such implantable number of electrode locations making them difficult to systems have a greater cost and risk relative to noninvasive operate and apply. designs. Further, this invention requires some form of sleep (0022. Finally, U.S. Pat. No. 5,792,067 to inventor Karell tracking to modulate the applied electrical stimulation. It titled APPARATUS AND METHOD FOR MITIGATING would be desirable to modulate sleep without requiring such SLEEP AND OTHER DISORDERS THROUGH ELEC tracking. Similarly, U.S. Pat. No. 8,612,005 to inventors TROMUSCULAR STIMULATION” describes a system Rezai et al. titled “NEUROSTIMULATION FOR AFFECT and method of using an electrode placed on the user's palate ING SLEEP DISORDERS' describes another technique for or pharynx to mitigate Snoring, apnea, etc. As implied by the affecting a sleep disorder by Stimulating a deep nucleus via title, this invention stimulates the muscles, e.g., within the an implanted electrode. Another implanted electrical treat oral cavity, to reduce Snoring and/or apnea, and the internal ment is described in U.S. Pat. No. 5,335,657 to inventors (in the mouth) placement and the energy applied are likely Terry Jr., et al. titled “THERAPEUTIC TREATMENT OF to be uncomfortable, and does not directly modulate sleep SLEEP DISORDER BY NERVE STIMULATION. This (e.g., onset, duration, quality, etc.). patent describes an implanted vagal nerve stimulator for 0023 Thus, in general, it would be advantageous to treating sleep disorders. provide apparatuses and methods for transdermal electrical 0018. Although non-invasive electrical stimulation stimulation for improving sleep that are both effective and devices to treat sleep have been proposed, such devices have comfortable for a user. not found wide use because they are not effective and/or they result in pain or discomfort during or after use. For example, SUMMARY OF THE DISCLOSURE U.S. Pat. No. 3,648,708 to inventor Haeri titled “ELECTRI 0024. The present invention relates to methods and appa CAL THERAPEUTIC DEVICE describes a device to be ratuses for improving sleep. Improving sleep may refer to operated by a medical professional that delivers pulsed or reducing the time to fall asleep, including reducing sleep alternating currents at lower frequencies (less than or equal onset, increasing/causing drowsiness, and causing sleep. to 250 Hz) for inducing relaxation or sleep. This invention Improving sleep may also or alternatively include length is lacking at least due to the requirement for operation by a ening the duration of sleep or of certain portions of the sleep medical professional (unsuitability for self-actuation) and cycle (e.g., any of sleep stages: 1, 2, 3, 4 and REM sleep, limitation to low frequencies that may limit the intensity of slow wave sleep, etc.), reducing sleep interruptions (wak stimulation due to discomfort. Discomfort (e.g., due to skin ening), or the like. irritation and/or muscle twitching) is believed to decrease 0025. In general, these methods may include applying the with increasing frequency in a range above 250 Hz, thus wearable TES applicator to the Subject, and applying appro low-frequency stimulation may be uncomfortable. priate TES prior to falling asleep and/or during sleep. The 0019. Similarly, U.S. Pat. No. 3,255,753 to inventor TES applicator is typically applied by the patient herself, Wing titled “ELECTRICAL SLEEP MACHINE AND and in Some variations the patient may manually adjust one SLEEP INDUCING METHOD uses a rechargeable battery or more of the TES waveform parameters to enhance com to power an electrical stimulator and a self-timer as safety fort. The attachment sites for the electrodes may include at features that enable self-operation of the device. The pulses least one location on the head (e.g., the temple) and may also delivered are square pulses, generally less than 40 Hz. Such include a second location on the Subject's head or neck (e.g., stimulation is likely to be uncomfortable and/or ineffective back of the neck). Alternatively two electrode locations may for inducing or improving sleep. Discomfort or pain invari be on the neck; one electrode location may be on the ably induces physiological arousal in a user and makes Subject's neck and a second electrode location may be below falling asleep more difficult. the neck; or two electrodes may be on the subject’s skin 0020 U.S. Pat. No. 4,418,687 to inventors Matsumoto et below the neck. al. titled “ELECTRIC SLEEPINDUCER describes another 0026. For example, a method of non-invasively reducing low frequency (<14 Hz) electrical stimulator for inducing sleep onset and increasing sleep duration may include sleep by broadly inhibiting the cerebral cortex. This inven attaching a first electrode to a Subject's head or neck at a first tion is inspired by the work by Gilyarovsky and colleagues location and a second electrode to the Subjects head or neck in the mid-19th century that used low (<150 Hz) frequency at a second location, wherein the first and the second stimulation to induce sleep. electrode are coupled to a transdermal electrical stimulation 0021 U.S. Pat. No. 8,029,431 to inventor Tononi et al. (TES) applicator worn by the subject. Once applied, the TES titled METHOD AND APPARATUS FOR PROMOTING applicator may be used to apply an electrical stimulation RESTORATIVE SLEEP” also operates at brain rhythm (low between the first and second electrodes for a stimulation frequencies), employing magnetic stimulation to entrain duration. The applied electrical stimulation may be an brain rhythms at slow-wave (delta) frequencies for enhanc 'ensemble waveform as described herein and described in ing restorative sleep. Such low-frequency magnetic systems U.S. application Ser. No. 14/715,476, filed May 18, 2015 may not target peripheral nerves (cranial nerves, vagal (now Publication No. US-2015-0328461), previously incor nerve, etc.) that can modulate autonomic function and brain porated by reference in its entirety. For example, the elec state, but may operate under a different regime. Similarly, trical stimulation may have a peak amplitude of greater than U.S. patent application Ser. No. 11/025,928 to inventor 3 mA, a frequency of greater than 250 Hz, and a duty cycle US 2017/0182285 A1 Jun. 29, 2017 of greater than 10%. The application of the electrical stimu percent duty cycle, capacitive discharge, etc.) may be lation may be continued for a stimulation duration of at least changed during the ensemble waveform, so that Sub-periods one minute to enhance sleepiness, Sustain sleep or to of different parameters may be consecutively applied. The enhance sleepiness and Sustain sleep. For example, the frequency may be between 250 Hz, and 40 kHz (e.g., a stimulation duration (the time during which the TES wave minimum of: 250, 300, 350, 400, 450, 500, 550, 600, 650, form is being applied by the applicator) may be between 1 700, 750, 800, 850, 900,950, 1000, 1500, 2000, 3000, 4000, minute and 120 minutes, between 1 minute and 90 minutes, 5000, etc. HZ and a maximum of 350, 400, 450, 500, 550, between 1 minute and 60 minutes, etc., or may be between 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, any lower value (where the lower value may be 0.5, 1, 2, 3, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 12000, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 15000, 20000, 25000, 30000, 35000, 40000 Hz, where the 50, 55, 60, 75,90, 105,120, etc. minutes) and an upper value minimum is always less than the maximum). (where the upper value may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 0032. As mentioned, any appropriate stimulation dura 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75,90, 105, tion may be used. For example, the step of continuing 120, 150, etc. minutes), and the lower value is always lower application of the electrical stimulation for a stimulation than the upper value. duration may include continuing for a stimulation duration 0027. The wearable TES applicator may be attached by of at least five minutes. any appropriate method, including adhesively attaching, 0033. Any of the TES ensemble waveforms described attaching using a strap, attaching via a garment Such as a hat, herein may be modulated by amplitude modulation, using an band, etc., attaching via a bandage or wrap, or the like. As appropriate AM carrier frequency. For example, applying mentioned, the first electrode may be attached to the sub the TES waveform(s) may comprise applying electrical jects head, e.g., to the Subjects temple region, forehead stimulation having amplitude modulation, and the amplitude region, etc. The first electrode may be on or attached directly modulation may generally have a frequency of less than 250 to the body of the wearable TES applicator. The second HZ (e.g., between 0.01 Hz and 250 Hz, 1 Hz and 250 Hz, 5 electrode may also be attached to the subject’s head or neck; HZ and 200 Hz, 10 Hz and 200 Hz, etc.). for example, the second electrode may be attached to the 0034. In some variations, applying the TES sleep-im subject’s neck above the subject’s vertebra prominens. proving ensemble waveform may include applying electrical 0028. Any of these methods may allow the subject (who stimulation having a burst mode. A bursting mode may may also be referred to as the user) to select a set of include periods where the applied TES stimulation is qui parameters for the electrical stimulation to be applied. Any escent (“off”). Note that although the majority of the individual or combination of parameters may be modulated/ examples described herein include the use of ensemble set by the user, and this modulation may be performed waveforms in which one or more (though often just one) before and/or during the application of the stimulation. For stimulation parameter changes during different, predefined example, a Subject may modify one or more parameters such component waveforms that are sequentially applied as the as: stimulation duration, frequency, peak amplitude, duty ensemble waveform, in some variations only a single com cycle, capacitive discharge on or off, and DC offset. The ponent waveform is applied. Similarly, a component wave adjustment may be made within a fixed/predetermined range form may vary continuously or discretely (by steps) for one of values (e.g., for frequency, the Subject may adjust the or more component waveforms. frequency between a minimum value. Such as 250 Hz, and 0035. For example, described herein are methods of a maximum value. Such as 40 kHz, or any Sub-range non-invasively reducing sleep onset that may include: plac therebetween). ing a first electrode of a wearable transdermal electrical 0029. The TES applicator may be worn (and energy stimulation (TES) applicator on a Subject's temple region applied) while the Subject is awake, before sleeping, and/or and a second electrode on a back of the Subject's neck; while the Subject sleeps. In some variations, the apparatus activating the wearable TES applicator to deliver a biphasic (including the first and second electrodes and TES applica electrical stimulation between the first and second electrodes tor) may be removed prior to the Subject sleeping. having a duty cycle of greater than 10 percent, a frequency 0030 TES ensemble waveforms appropriate for enhanc of 250 Hz or greater, and an intensity of 3 mA or greater, ing sleep are described in greater detail below. In general, wherein the biphasic electrical stimulation is asymmetric these TES ensemble waveforms may be monophasic or with respect to positive and negative going phases; and biphasic (or both during different periods); in particular the reducing sleep onset by applying the biphasic electrical sleep-improving TES ensemble waveforms may include stimulation between the first and second electrodes for 10 biphasic electrical stimulation. This biphasic electrical seconds or longer. stimulation may be asymmetric with respect to positive and 0036. For example, a method of non-invasively inducing negative going phases. Sleep-enhancing TES waveforms sleep in a Subject may include: placing a first electrode of a may also have a duty cycle (e.g., time on relative to time off) wearable transdermal electrical stimulation (TES) applicator of between 10% and 90%, e.g., a duty cycle of between 30% on the Subject's skin on the Subject's temple region and a and 60%. The peak amplitude of the applied current may second electrode on a back of the subject’s neck above a also be controlled. In general, the peak amplitude may be vertebra prominens; activating the wearable TES applicator greater than 3 mA (greater than 4 m.A, greater than 5 mA. to deliver a biphasic electrical stimulation having a duty greater than 6 m.A, greater than 7 mA, greater than 8 mA. cycle of greater than 10 percent, a frequency of 250 Hz or etc. or between about 3 mA and about 30 mA, between 3 mA greater, and an intensity of 3 mA or greater, wherein the and 20 mA, between 5 mA and 30 mA, between 5 mA and biphasic electrical stimulation is asymmetric with respect to 20 mA, etc.). positive and negative going phases; and inducing sleep by 0031. As mentioned above, any of the stimulation param applying the biphasic electrical stimulation between the first eters (e.g., peak current amplitude, frequency, DC offset, and the second electrodes for 10 seconds or longer. US 2017/0182285 A1 Jun. 29, 2017 0037. A method of maintaining sleep in a subject may cally stopping activation of the wearable TES applicator include: placing a first electrode of a wearable transdermal when the Subject is asleep based on a physiological mea electrical stimulation (TES) applicator on the subject’s skin Surement or sleep state monitoring, and/or automatically on the Subject's temple region and a second electrode on a stopping activation of the wearable TES applicator when the back of the subject’s neck above a vertebra prominens; Subject is asleep following a fixed delay (e.g., 1 min, 2 min, activating the wearable TES applicator to deliver a biphasic 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 electrical stimulation having a duty cycle of greater than 10 min, 20 min, etc.). Activating may include activating the percent, a frequency of 250 Hz or greater, and an intensity wearable TES applicator when the subject is asleep based on of 3 mA or greater, wherein the biphasic electrical stimula a physiological measurement or sleep state monitoring. tion is asymmetric with respect to positive and negative 0043 Any of the methods described herein may be going phases; and maintaining a state of sleep in the Subject methods to treat a sleep disorder or a sleep-related disorder. by applying the biphasic electrical stimulation between the For example, any of these methods may include a step of first and second electrodes for 10 seconds or longer while the treating a sleep disorder in the Subject. Examples of Such Subject is asleep. sleep disorders include: idiopathic hypersomnia, insomnia, 0038 Any of the method components described above post-traumatic stress disorder, anxiety, emotional distress, may be incorporated into any of these exemplary methods as depression, bipolar disorder, Schizophrenia; restless leg Syn well. For example, attaching the TES applicator and/or drome and periodic limb movement disorder, circadian electrodes may refer to adhesively attaching, mechanically rhythm disorders; sleeping sickness; parasomnia; shift work attaching or the like. In general, the TES applicator may be and jet lag; and hypersomnia. applied directly to the body (e.g., coupling the body to the 0044. In any of these variations, the apparatus may be skin or clothing of the patient directly) or indirectly, e.g., specifically adapted for comfort, convenience or utility attaching to the body only by coupling with another member during and before sleeping. For example, in apparatuses in (e.g., electrode) that is already attached or attachable to the which there is a visible (e.g., light) indicator Such as an LED, body. screen, or the like, the light may be dimmed or turned off 0039. In any of the methods described herein, the user during operation and/or following operation, and/or when may be allowed and/or required to select the waveform sleep is detected. For example, any of these methods may ensemble from a list of possible waveform ensembles, include dimming or turning off a visual indicator (e.g., an which may be labeled to indicate name, content, efficacy, LED or screen) of the transdermal electrical stimulator when and/or the like. As already mentioned, the subject may be the wearable TES system is activated. permitted or allowed (e.g., using a wearable electronic 0045 Although the stimulation parameters may be and/or handheld electronic apparatus) to select and/or adjusted or modified by the Subject wearing the apparatus, modify one or more parameters for the electrical stimulation any of these method may include modifying, by a party that to be applied, wherein the parameters may include one or is not the Subject, a stimulation parameter of the wearable more of stimulation duration, frequency, peak amplitude, TES device while the subject is sleep, wherein the stimula and duty cycle. tion parameter includes one or more of stimulation dura 0040. The electrodes and TES applicator may be worn tion, frequency, peak amplitude, duty cycle, capacitive dis while the subject sleeps, or removed prior to sleeping. For charge, DC offset, etc. example, any of these methods may include removing the 0046. As mentioned, the apparatus and methods may also first and second electrodes and TES applicator prior to the be adapted to automatically adapt stimulation parameters. Subject sleeping. For example, any of these methods may include automati 0041. In general, reducing sleep onset or inducing sleep cally modifying a stimulation parameter of the wearable may include: increasing drowsiness and/or increasing the TES device based on the subjects sleep quality being below desire to sleep. Activating may include delivering the bipha a threshold value, where sleep quality is defined by one or sic electrical stimulation while the subject is awake. Thus, in more of sleep latency, amount and/or sequence of sleep any of these methods described herein, the method may stages, sleep amount, autonomic state, EEG activity, EMG include monitoring the Subject's sleep. As mentioned, sleep activity, movements, and time during the day when sleep may be monitored using the wearable TES applicator and/or occurs, further wherein the stimulation parameter includes using a separate monitor. For example, monitoring the one or more of Stimulation duration, frequency, peak ampli subjects sleep may be done using the wearable TES appli tude, duty cycle, capacitive discharge, DC offset, etc. cator having a sensor coupled to the TES applicator to 0047 Any of these methods may also include automati measure the Subjects autonomic function, or communicat cally stopping, starting or modulating the wearable TES ing with the TES applicator (but separate). Monitoring may applicator based on a measure of sleep quality detected from include one or more of actimetry, galvanic skin resistance, the subject, where sleep quality is defined by one or more of: heart rate, heart rate variability, or breathing rate. Monitor sleep latency, amount and/or sequence of sleep stages, sleep ing may include monitoring the Subjects sleep using a amount, time during the day when sleep occurs, and other sensor that is worn by the subject, coupled to the subjects sleep quality or quantity metric. The sleep quality used to bed, or remotely monitoring the Subject without physical start, stop, or modulate the transdermal electrical stimulation contact with the subject. may be based on a measurement of one or more of the 0042 Any of the methods described herein may be Subjects: activity, stress, immune system function, auto automatically or semi-automatically controlled, and may nomic state, or other physiological assessment. include processing of feedback from any of the sensors to 0048 Placing may comprise placing the first and second regulate the application of TES, including modifying one or electrodes before or during a nap. more TES waveform parameter based on the sensed values. 0049. In operation, the wearable TES applicator may For example, any of these methods may include automati automatically or manually triggered to deliver the biphasic US 2017/0182285 A1 Jun. 29, 2017 electrical stimulation when the Subject wakes up. The appa 0055 Any of the apparatuses described herein may be ratus may also be configured to transmit a notification specifically adapted for sleep, as mentioned above. In some (directly or via a user computing device) that reminds the variations this may include having the TES waveform(s) subject to wear the TES applicator before bed, for example, pre-programmed, and/or including feedback for monitoring transmitting a notification that reminds the Subject to wear the Subjects sleep, and/or for using any sleep-related data on the TES applicator before bed based on input from a location the Subject in modifying/controlling the applied stimulation. sensor in the TES applicator or wirelessly connected to the The apparatus may include at least one sensor that measures TES applicator that detects when the subject is in their the Subject's autonomic function, wherein the measurement bedroom. of autonomic function may measure one or more of gal 0050. The methods described herein may also include Vanic skin resistance, heart rate, heart rate variability, or providing a metric to the Subject showing a sleep quality breathing rate. The at least one sensor may comprise a sensor metric, wherein the sleep quality metric is one or more of to detect the Subject's movements (e.g., uniaxial or multi sleep onset time, length of sleep, sleep latency, total length axial accelerometer, etc.). A movement sensor may be or percentage of REM sleep, total length or percentage of configured to detect the Subject's movements in communi NREM sleep, total length or percentage of slow wave (deep) cation with the controller; the movement sensor may be sleep, length of sleep cycles, number and/or length of night worn by the subject, coupled to the subject’s bed, or may awakenings, and morning wake time. detect movements remotely without direct or indirect physi 0051. Any of the methods described herein may include cal contact with the subject. automatically adjusting the biphasic electrical stimulation 0056. The TES control module may be configured to based on an average or detected amount of time before the automatically stop delivery of the biphasic electrical stimu subject falls asleep. The devices described herein may also lation when the Subject is asleep based on a measurement be configured to perform any of these steps such as auto from a sensor, for example, when the Subject is asleep at a matically adjusting the electrical stimulation. fixed delay (e.g., 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 0052. In addition, any of the methods described herein 7 min, 8 min, 9 min, 10 min, 12 min, 15 min, 30 min, 45 min, may also include concurrently delivering a calming sensory 1 hr., etc.). stimulus when activating the wearable TES applicator, such 0057 The TES control module (“TES controller) may as concurrently delivering a calming sensory stimulus when be configured to automatically start delivery of the biphasic activating the wearable TES applicator, wherein the calming electrical stimulation when the Subject is asleep based on a sensory stimulus is one or more of auditory stimulus, physiological measurement derived from the at least one olfactory stimulus, thermal stimulus, and mechanical stimu SSO. lus. 0.058 Any of these devices may include a visual indicator 0053 Also described herein are wearable transdermal (e.g., light, Screen, etc., including LED(S), displays, etc.) that electrical stimulation (TES) applicators for facilitating, is configured to be turned down or turned off when the inducing, and/or maintaining sleep in a Subject. These appa wearable TES system is activated. ratuses may be configured to perform any of the methods 0059. The TES controller may also be configured to described herein. In general, these apparatuses may include: automatically stop, start or modify delivery of the biphasic a body; a first electrode; a second electrode (the apparatuses electrical stimulation based on sleep quality being below a may be part of a separate but attachable, e.g., disposable, threshold value, wherein sleep quality is defined by a TES electrode assembly that couples to the body); and a TES control module (or computing device communicatively con control module at least partially within the body. The TES nected to the TES control module) based on data from the at control module may include a processor, a timer and a least one sensor and correspond to one or more of sleep waveform generator, and the TES control module may be latency, amount and/or sequence of sleep stages, sleep adapted to deliver an electrical (e.g., biphasic, asymmetric) amount, and time during the day when sleep occurs. The stimulation signal for a stimulation duration (e.g., 10 sec TES controller may also be configured to automatically or onds or longer) between the first and second electrodes. The manually deliver the biphasic electrical stimulation if the electrical stimulation which may be a TES ensemble wave Subject wakes up. form, may have a duty cycle of greater than 10 percent, a frequency of 250 Hz or greater, and an intensity of 3 mA or BRIEF DESCRIPTION OF THE DRAWINGS greater, wherein the biphasic transdermal electrical stimu lation is asymmetric with respect to positive and negative 0060. The novel features of the invention are set forth going phases. The wearable TES applicator may generally with particularity in the claims that follow. A better under be lightweight (e.g., may weigh less than 50 grams, etc.). standing of the features and advantages of the present Any of the TES applicators described herein may include at invention will be obtained by reference to the following least one sensor coupled to the body for sleep monitoring of detailed description that sets forth illustrative embodiments, the subject. in which the principles of the invention are utilized, and the 0054 Any appropriate sleep-enhancing TES waveform accompanying drawings of which: (s) may be used. For example, the duty cycle may be 0061 FIG. 1 schematically illustrates a base waveform between 10% and 90%. The transdermal electrical stimula which may be repeated and modified according to waveform tion may have a frequency greater than 250 Hz, 500 Hz, 750 parameters to form component waveforms which may be HZ, 5 kHz, etc. The transdermal electrical stimulation may combined to form ensemble waveforms, as described herein. comprise amplitude modulation, as discussed above, having 0062 FIGS. 2A-2F show electrode positions for one a frequency of less than 250 Hz. The transdermal electrical configuration (“Configuration 3') on a model user head that stimulation may include a burst mode, such as a burst mode may be used with the methods and apparatuses of enhancing having a frequency of bursting that is less than 250 Hz. sleep described herein. US 2017/0182285 A1 Jun. 29, 2017 0063 FIG. 3A illustrates one example of a neurostimu 007.9 FIGS. 14A and 14B compare measures of morning lator that may be configured for use with (and may deliver) amylase and morning cortisol, respectively between differ the ensemble waveforms described herein. ent sleep-enhancing stimulation protocols. Both protocols 0064 FIGS. 3B-3G illustrate another example of a neu are significantly different compared to baseline (not shown) rostimulator as described herein. and may be different from each other, consistent with the 0065 FIGS. 3H-3K illustrates a first example of one results shown in FIGS. 9-13B (amylase: p=0.036; cortisol: variation of an electrode assembly. p=0.040). Morning saliva was assayed within 30 minutes of 0066 FIG.3L illustrates the application of an electrode waking for each patient. There were no differences between assembly that may be worn on the subject’s head, and/or patients in afternoon or evening cortisol. head and neck to enhance sleep. 0080 FIG. 15A is a table with waveform parameters of 0067 FIG. 3M illustrates the neurostimulator device another example of a “high F ensemble waveform as worn on the subjects head. described herein. 0068 FIGS. 4A-4D show electrode positions for another 0081 FIG. 15B is a table with another variation of an configuration ("Configuration 4') on a model user head that ensemble waveform similar to that shown in FIG. 15A. may be used with the methods and apparatuses of enhancing 0082 FIG. 15C is a table with another variation of an sleep described herein. ensemble waveform as shown in FIGS. 15A-15B. 0069 FIG. 5 shows components of a portable, wired TES I0083 FIG. 16 is a table showing another example of an neurostimulator System. ensemble waveform that may be adapted for use as a sleep 0070 FIG. 6 shows components of a TES neurostimula enhancing TES waveform. This variation is consistent with tor system that connects wirelessly to a control unit com the low F ensemble waveform described herein. prising a microprocessor. I0084 FIG. 17 is a table illustrating one example of a very 0071 FIG. 7 shows a workflow for configuring, actuat low F ensemble waveform as described herein. ing, and ending a TES Session. I0085 FIGS. 18A and 18B show experimental designs 0072 FIGS. 8A-8D show electrode positions for another implemented for testing the effects of nightly repeated, configuration ("Configuration 6') on a model user head that self-administered transdermal electrical neuromodulation of may be used with the methods and apparatuses of enhancing trigeminal and cervical nerve sensory afferents on sleep and sleep described herein. mood as described herein. 0073 FIG. 9 is a graph showing an improvement in 0086 FIGS. 19A and 19B show acute transdermal neu overall sleep (using the Pittsburgh Sleep Quality Index, romodulation of trigeminal and cervical afferents prior to PSQI) following the methods described herein in a user sleep onset significantly reduces stress and anxiety. In FIG. population (n=10). Higher scores (e.g., PSQI of greater than 19A, depression, anxiety and stress are illustrated, while 5, up to a maximum score of 21) are considered a poor sleep FIG. 19B shows exemplary effects on refreshment and quality. Subjects used for this study had a PSI of just over drowsiness. 5. Following treatment with either of two experimental TES I0087 FIG. 20 is a table summarizing results from a first protocols (“low F or “high F'), the PSQI scores improved. experiment illustrating the effects of nightly TEN on morn 0074 FIGS. 10A-10C compare the time to Wake after ing arousal, affect, and mental health. Sleep Onset (WASO, FIG. 10A), percentage of time awake I0088 FIG. 21 is a table summarizing results from a (FIG. 10B), and self-reported WASO (FIG. 10C) of subjects second experiment illustrating impact of nightly TEN and in the trial illustrated in FIG.9 that received either treatment sham treatment on morning arousal, affect, and sleep quality A (Low F) or treatment B (High F). compared to baseline nights. 0075 FIGS. 11A-11C show heart rate variability (HRV) 0089 FIGS. 22A and 22B illustrate the effects of self power in very low, low, and high frequency bands, respec administered trigeminal and cervical afferent neuromodula tively. Changes in heart rate variability may indicate modu tion prior to sleep onset significantly improves mood and lation of the Subject's autonomic nervous system. In these increases sleep time. In FIG.22A, effects on depression and experiments, comparing between the two effective stimula anxiety are compared. FIG. 22B illustrate effects on stress tion regimes (low F and high F), 10 subjects (n=10) were and sleep time. examined. (0090 FIG. 23 illustrates the effect of nightly TEN influ 0076 FIGS. 12A-12C illustrate anxiety, depression and ences autonomic nervous system activity overnight indi stress, respectively, from patients (n=10) treated as shown cated by changes heart rate variability (pVLF on the left, above in FIG. 9. The measures are based on the DASS pHF on the right). (Depression, Anxiety and Stress Scale), a clinical measure 0091 FIGS. 24A and 24B are actigraphy graphs showing between 0 and 3. that TEN significantly improves sleep quality. FIG. 24A 0077 FIGS. 12D-12G illustrate positive affectivity (FIG. shows number of wakeups, WASO (min), and % time 12D), negative affectivity (FIG. 12E), irritability (FIG. 12F), awake. FIG. 24B shows RR (msec), RMSDD and pLF. and fatigue (FIG. 12G) in the same patients described in 0092 FIGS. 25A-25C illustrate low-frequency TEN FIGS. 12A-12C. Affectivity was measured on 5 point scale improves the efficacy of trigeminal and cervical afferent (FIGS. 12D and 12E), irritability was measured on a 0 to 3 modulation for improving sleep quality. FIG. 25A shows the scale (FIG. 12F) and fatigue was measured on a 0 to 10 scale effect on number of wakeups, WASO (min), and % time (FIG. 12G). awake, FIG. 25B shows the DASS and FIG. 25C shows the 0078 FIGS. 13A and 13B illustrate a comparison effect on waking cortisol and morning SAA. between different (effective) sleep enhancing stimulation 0093 FIG. 26 is an example of a schematic illustrating protocols on the number of naps (FIG. 13A) and in-the interfacing with the ascending reticular activating system moment stress (FIG. 13B). through the trigeminal sensory nuclear complex. US 2017/0182285 A1 Jun. 29, 2017 0094 FIG. 27 illustrates the effects of a low-frequency attached with an anode at the forehead/temple area and TEN waveform on subjective relaxation (subjective calm cathode on the neck of a Subject (delivering a pulsed ratings on the left) and heart rate variability (on the right). waveform with variable frequency, generally between 250 HZ and 11 kHz at between 2-12 mA peak current in DESCRIPTION OF THE INVENTION asymmetric, biphasic pulses) showed a significant improve 0095. In general, described herein are methods and appa ment in sleep, e.g., reducing sleep onset (time to fall asleep), ratuses (devices and systems) for transdermal electrical duration (lengthening the duration of sleep) and quality stimulation (TES) to enhance sleep, including reducing (e.g., self-reported assessments) of subjects sleep compared sleep onset (e.g., increasing drowsiness, reducing sleep to baseline or to non-effective (sham) TES waveforms. onset latency, and inducing sleep) and/or increasing the 0098. Described herein are methods and apparatuses for duration and/or quality of sleep in a Subject. The quality of transdermal electrical stimulation (e.g., neurostimulation) sleep may be related to the length and/or proportion of one using TES stimulation protocols and electrode configura or more sleep stages during a subjects sleeping session. In tions that facilitate the passage into sleep, accelerate the particular, as described herein, the TES may be applied induction of sleep, improve the restorative quality of sleep, during and/or immediately prior to (e.g., within 30 min, 25 and/or enhance the likelihood of maintaining a state of sleep min, 20 min, 15 min, 10 min, 5 min, etc.) a desired sleep in a subject. Apparatuses described herein may generally time. Such as when the Subject is preparing or has prepared include a neurostimulator for delivering transdermal elec to sleep (e.g., lying down, etc.). The stimulation parameters trical stimulation, appropriate dermal electrodes that connect of the applied TES (duration, amplitude, frequency, percent electrically to the neurostimulator for transmitting the elec duty cycle, bipolar/unipolar, DC offset, AC component/AC trical stimulation to the Subject, and, optionally, a controller frequency, presence of capacitance discharge, etc.) and unit that may be connected to the neurostimulator in a wired location of stimulation on the subject (attachment site of the or wireless manner (including user computing devices Such electrodes) as well as the function and feel of the TES as a Smartphone, tablet, wearable device (e.g. Smartwatch or applicator (weight, placement, and shape of the applicator) Google Glass), or computer). The TES apparatuses for may affect the efficacy with respect to enhancing sleep, and improving sleep described herein are configured to deliver are described herein. appropriate TES waveforms and to couple transdermal elec 0096. As will be described in greater detail below, par trodes with an appropriate configuration for inducing a ticular ranges of Stimulation parameters (frequency, peak drowsy or sleeping State in a subject. Methods for improving current amplitude, duty cycle) of TES waveforms applied sleep in a subject (e.g., one or more of reducing sleep onset, using a wearable TES applicator worn on the subjects head facilitating the passage into sleep, inducing sleep, enhancing and/or neck have been found to be effective, while stimu the likelihood of maintaining sleep, modifying the quality of lation outside of these parameters, and/or at different loca sleep, etc.) using a TES system before or during sleep are tions, may not be as effective. In general, stimulation at described. Also described herein are wearable TES appara greater than 10% duty cycle (e.g., between 10 and 90%, tuses (e.g., neurostimulators) that are configured specifically between 20 and 80%, between 30 and 80%, etc.), at a to enhance sleep. frequency that is 100 Hz or greater (e.g., 150 Hz or greater, 0099. These neurostimulators may be capable of autono 200 Hz or greater, 250 Hz or greater, 300 Hz or greater, 400 mous function and/or controllable via a wired or wireless Hz or greater, 500 Hz or greater, 600 Hz or greater, 700 Hz connection to a computerized user device (e.g. Smartphone, or greater, 750 Hz or greater, 800 Hz or greater, 1 kHz or tablet, laptop, other wearable device). The neurostimulator greater, 2 kHz or greater, 5 kHz or greater, etc., and in may be configured specifically to deliver stimulation within particular, 250 Hz or greater), and a peak amplitude of 3 mA a range of parameters, including intensity and frequency, or greater (e.g., 4 mA or greater, 5 mA or greater, 6 mA or determined to be effective for inducing, enhancing, or pro greater, 7 mA or greater, 8 mA or greater, 9 mA or greater, moting sleep while minimizing pain and discomfort due to 10 mA or greater, etc.) are particularly effective. Because the relatively large magnitude stimulation provided. For Such stimulation parameters (e.g., low frequency at rela example, an apparatus (such as a TES applicator) may tively high peak current amplitudes) may be painful and thus include a control module having circuitry (e.g., hardware), prevent drowsiness or sleep, it may be particularly useful to Software and/or firmware that allows the apparatus to apply modulate the applied TES so that it can be comfortably signals within an effective range, including, for example, tolerated, even before sleeping. For example, the applied one or more processors, timers, and waveform generators. TES waveform may be biphasic and in some variations 0100 Relative to existing systems for transdermal elec asymmetric, with respect to positive and negative going trical stimulation for improving sleep, the systems and phases. In some variations a capacitive discharge (e.g., a methods described herein induce more powerful effects for rapid depolarization component to discharge capacitance treating and affecting (not limited to treatment or diagnosis built up on the electrodes (and in the body) may be applied of any medical condition) sleep. These apparatuses may use during the pulsed application (e.g., on each or a Subset, e.g., replaceable, disposable (e.g., consumable) electrodes and during positive going pulses, negative pulses, etc., of the may also use appropriate electrical stimulation parameters; TES stimulation)). this combination may mitigate discomfort, enabling higher 0097. Particular types of TES waveforms delivered to a peak currents to be delivered for stimulating transdermally Subject (e.g., to the head and/or neck) may improve the without delivering irritating or painful stimuli that may wake quantity and quality of sleep. In Such cases, users wake up a Subject. Higher peak currents typically provide a more feeling more rested, with a more positive mood, less anxiety, robust effect. and less stress (both as self-reported and as assessed by 0101. A neurostimulation system as described herein may biochemical assay of saliva). For example, 15 minute TES include two or more parts: (1) a lightweight (e.g., less than waveforms delivered through a wearable TES applicator 100 g, less than 75 g, less than 50g, less than 40 g, less than US 2017/0182285 A1 Jun. 29, 2017 30 g, less than 25 g, less than 20 g, etc.), wearable (or lived; once application of these (typically lower frequency) portable), neurostimulator device (neurostimulator) that is stimulation waveforms has stopped, an enhancement of configured to be worn on a subject (generally on the head or sleep may be affected. neck) or portable and coupled to the Subject and includes 0104. The apparatuses (systems and devices) and meth processor(s) and/or controller(s) to prepare the TES wave ods described herein allow the reproducible enhancement of form(s) to be applied; and (2) a consumable/disposable sleep, as described herein. The effect resulting from the electrode assembly to deliver the TES waveform(s) to the methods and devices described may depend, at least in part, wearer. In some variations a third component may be a on the positioning of the electrodes. It may be particularly controller that is separate from but communicates with the advantageous with the TES waveform parameters described neurostimulator. For example, in Some variations the con herein to apply the electrodes on the Subjects head, neck troller may be a user device that wirelessly communicates and head, or neck and elsewhere on the body other than the with the neurostimulator. In some variations the controller is head. Described below are three configurations for enhanc a mobile telecommunications device (e.g., Smartphone or ing sleep. These configurations are exemplary and are not tablet) being controlled by an application that sends instruc meant to be limiting with regard to configurations that can tions and exchanges 2-way communication signals with the induce these cognitive effects and thus improve sleep in a neurostimulator. For example, the controller may be soft Subject. ware, hardware, or firmware, and may include an application 0105 FIGS. 2A-2F illustrate a first electrode configura that can be downloaded by the user to run on a wireless tion for enhancing sleep in a subject 200 and may be referred connectable (e.g., by Bluetooth) device (e.g., Smartphone or to herein for convenience as “configuration 3. A first tablet) to allow the user to select the waveforms delivered by electrode is positioned on the subject’s skin near the sub the neurostimulator, including allowing real-time or short jects temple area (e.g., above and slightly to the right of the latency (e.g., less than one second, less than 500 ms, etc.) right eye, or to the left of the subjects left eye) and a second modulation of the delivered neurostimulation to enhance electrode is placed on the Subject’s neck (e.g., on a Superior sleep as described herein. Alternatively, the electrodes may portion of the neck center as in FIG.2E). Beneficial embodi be reusable and integrated in a single assembly with a TES ments comprise electrodes for the neck having an area of at controller. least about 20 cm and an electrode having area at least 0102 The methods and apparatuses described herein may about 10 cm (optimally at least about 20 cm) near the right induce a calm or relaxed mental state and may facilitate, temple. TES stimulation of this region may result in enhanc induce, or maintain a state of sleep in a subject. This class ing a calm or relaxed mental state. FIGS. 2A and 2B show of cognitive effects includes those associated with relaxation the broad outlines of effective areas for a temple electrode and a calm mental state, for example: a state of calm, 202 and neck electrode 201, 203 (though the actual elec including States of calm that can be rapidly induced (e.g., trodes within these areas would be smaller than the regions within about 5 minutes of starting delivery of the TES outlined). For example, effective electrode size and positions waveforms). In some variations, these effects may include a may be as shown in FIG. 2C, wherein rectangular temple care-free state of mind; a mental state free of worry; induc electrode 205 and circular electrode (on the right side of the tion of sleep; a slowing of the passage of time; enhanced neck) 204 are applied to the subject. In another example of physiological, emotional, or and/or muscular relaxation; effective electrode size and positions shown in FIG. 2D, a enhanced concentration; inhibition of distractions; increased small circular temple electrode 206 and elongated oval cognitive and/or sensory clarity; a dissociated State; a state electrode (on the right side of the neck) 207 are applied to akin to mild intoxication by a psychoactive compound (i.e. the subject. In a third example of effective electrode size and alcohol); a state akin to mild euphoria induced by a psy positions shown in FIGS. 2E-2F, an oval temple electrode choactive compound (i.e. a morphine); the induction of a 209 and roughly rectangular electrode (centered on the state of mind described as relaxed and pleasurable; enhanced superior portion of the neck) 208 are applied to the subject. enjoyment of auditory and visual experiences (i.e. multime 0106 FIGS. 4A-4D illustrate a second electrode configu dia); reduced physiological arousal; increased capacity to ration for enhancing sleep in subject 4500 and may be handle emotional or other stressors; a reduction in psycho referred to herein for convenience as “configuration 4. A physiological arousal as associated with changes in the first electrode is positioned on the subject’s skin near the activity of the hypothalamic-pituitary-adrenal axis (HPA bridge of the subject’s nose 4501 and a second electrode is axis) and/or reticular activating system and/or by modulat positioned on the subject’s body further than a few inches ing the balance of activity between the sympathetic and from the first electrode 4502, 4503, 4504 (e.g., on the parasympathetic nervous systems generally associated with Subject's head or neck, including the forehead or temple). a reduction in biomarkers of stress, anxiety, and mental One advantage of this configuration is that electrode place dysfunction; anxiolysis; a state of high mental clarity; ment is relatively easy for a user to do themselves. FIG. 4A enhanced physical performance; promotion of resilience to shows model subject 4500 with a round anode electrode the deleterious consequences of stress; a physical sensation placed between the eyes on the bridge of the nose 4501. In of relaxation in the periphery (i.e. arms and/or legs); a a preferred embodiment, the anode electrode is less than 1" physical sensation of being able to hear your heartbeating, across and flexible in order to conform to the curvature of and the like. the area near the bridge of the nose of a subject. The anode 0103 More interestingly, in some variations, the TES electrode may be round, elliptical, square, rectangular, or an waveforms may enhance sleep as Suggested herein shortly irregular shape configured for ease of placement on the after the session (application of TES) has ended; during the curved areas of the nose. In a preferred embodiment, a session, sleepiness/relaxation may not be felt, and in fact the second electrode (e.g., cathode) is located at a site selected application may be mildly uncomfortable. The discomfort from the list including, but not limited to: temple 4502 (as may be minimized as described herein, and may be short shown in FIG. 4B), forehead 4504 (FIG. 4C), neck 4503 US 2017/0182285 A1 Jun. 29, 2017 (FIG. 4D), mastoid, shoulder, arm, or elsewhere on the face, ways selected from the list including but not limited to: head, neck, or body below the neck. A second electrode can instructions provided via user interface; kit provided to user; be placed on either side of the body. In some embodiments, wearable system configured to contact TES electrodes to multiple cathode electrodes can be used. The forehead appropriate portions of a user's body; electrode choice and electrode can be easily affixed using a mirrored surface or positioning done autonomously by user (e.g. due to previous front-facing Smartphone (or tablet) camera, and the cathode experience with TES); assistance provided by skilled prac positioning may not need to be precise. titioner of TES; and instructions provided via other means. 0107 FIGS. 8A-D illustrate a third electrode configura 0110 Based on these instructions or knowledge, a user or tion for enhancing sleep in a subject 800 and may be referred other individual or system positions electrodes on body 704. to herein for convenience as “configuration 6”. According to In some embodiments, the TES session starts 707 automati an embodiment, subjects treated with TES using Configu cally after electrodes are positioned on the body. In other ration 6 experience different forms of neuromodulation with embodiments, the impedance of the electrodes 705 is distinct cognitive effects depending on the waveform and checked by a TES system before the TES session starts 707. intensity delivered. In embodiments, systems and methods In some embodiments, after impedance of the electrodes 705 for TES using Configuration 6 electrically couple an elec is checked by a TES system, user actuates TES device 706 trode to the subject 800 between the eyes at the bridge of the before the TES session starts 707. In other embodiments, nose 801 (nasal electrode) and a second electrode near the after positioning electrodes on the body 704 the user actu midline on the forehead, superior to the nasal electrode. In ates the TES device 706 to start the TES Session 707. Once an embodiment, the nasal electrode is an anode and the the TES session starts, the next step is to deliver electrical forehead electrode is a cathode. The more superior electrode stimulation with specified stimulation protocol 708. In some may be medial and close to the bridge of the nose 802 (FIG. embodiments, a user actuates end of TES session 709. In 8A), medial and more superior relative to the bridge of the other embodiments, the TES session ends automatically nose 803 (FIG. 8B), shifted left or right relative to the when the stimulation protocol completes 710. midline and superior to the bridge of the nose 804 (FIG. 8C). 0111 FIG. 5 shows a schematic illustration of a portable, or larger and more Superior relative to the bridge of the nose wired TES neurostimulator 500. According to an embodi 805 (FIG. 8D). In contrast to other configurations, the anode ment, adherent electrodes 501 connect to TES controller 504 and cathode can be switched and the beneficial neuromodu via connectors 502 and wires 503. TES controller 504 has lation effects still achieved in subjects. In a preferred several components including battery or protected AC power embodiment, systems and methods with this electrode con supply 505, fuse and other safety circuitry 507, memory 508, figuration deliver different electrical stimulation waveforms microprocessor 509, user interface 510, current control to achieve distinct cognitive effects. TES using an alternat circuitry 506, and waveform generator 511. ing (or pulsed biphasic) transdermal electrical stimulation 0112 FIG. 6 shows an embodiment of a TES system current at a frequency between 3 kHz and 15 kHz (i.e. comprising adherent or wearable TES neurostimulator 600 between 3 kHz and 5 kHz) at an intensity greater than 4 mA that communicates wirelessly with microprocessor-con induces neuromodulation in a Subject with cognitive effects trolled control unit 609 (e.g. a Smartphone running an including, but not limited to, those in the following list: Android or iOS operating system such as an iPhone or increased drowsiness; increased desire to sleep: induction of Samsung Galaxy, a tablet Such as an iPad, a personal sleep; induction of a relaxed state of mind; and induction of computer including, but not limited to, laptops and desktop a calm state of mind. TES using an alternating transdermal computers, or any other Suitable computing device). In this electrical stimulation current at a frequency less than 3 kHz exemplary embodiment, adherent or wearable neurostimu (preferably between 750 Hz and 1 kHz) at an intensity lator 600 holds two or more electrodes in dermal contact greater than 1 mA induces neuromodulation with cognitive with a subject with one or more of an adhesive, a shaped effects including, but not limited to, those in the following form factor that fits on or is worn on a portion of a user's list: increased energy and enhanced wakefulness, and is thus body (e.g. a headband or around-the-ear eyeglass style not a beneficial set of waveform parameters to use with this form factor). In an exemplar embodiment, adherent or configuration for facilitating, inducing, or maintaining a wearable neurostimulator 600 comprises components: bat state of sleep. tery 601, memory 602, microprocessor 603, user interface 0108. Alternative electrode configurations for inducing 604, current control circuitry 605, fuse and other safety or enhancing sleep include: a first electrode on the neck and circuitry 606, wireless antenna and chipset 607, and wave a second electrode on the shoulder (i.e. deltoid, upper arm, form generator 616. Microprocessor-controlled control unit etc.); one electrode on each shoulder (i.e. deltoid, upper arm, 609 includes components: wireless antenna and chipset 610, etc.); and two electrodes on the neck. graphical user interface 611, one or more display elements 0109 FIG. 7 shows an exemplary workflow for config to provide feedback about a TES session 612, one or more uring, actuating, and ending a TES session for improving user control elements 613, memory 614, and microprocessor sleep. According to an embodiment of the present invention, 66. In an alternate embodiment the neurostimulator 600 may user input on TES device or wirelessly connected control include additional or fewer components. One of ordinary unit 700 is used to select desired cognitive effect 701 which skill in the art would appreciate that neurostimulator could determines electrode configuration setup 702 to achieve the be comprised of a variety of components, and embodiments desired cognitive effect, including selection of electrodes or of the present invention are contemplated for use any Such a TES system that contains electrodes and determination of component. correct positions for electrodes. As described above, con 0113. An adherent or wearable neurostimulator 600 may figurations 3, 4, and 6 are three exemplar configurations be configured to communicate bidirectionally with wireless beneficial for improving sleep. In an embodiment, configu communication protocol 608 to microprocessor-controlled ration instructions to user 703 are provided by one or more system 609. The system can be configured to communicate US 2017/0182285 A1 Jun. 29, 2017 various forms of data wirelessly, including, but not limited 0116. The user device may also be referred to herein as a to, trigger signals, control signals, safety alert signals, stimu controller, and the controller (user device or user computing lation timing, stimulation duration, Stimulation intensity, device) is typically separate from but communicates with the other aspects of stimulation protocol, electrode quality, neurostimulator. For example, in some variations the con electrode impedance, and battery levels. Communication troller may be a user device that wirelessly communicates may be made with devices and controllers using methods with the neurostimulator. In some variations the controller is known in the art, including but not limited to, RF, WIFI, a mobile telecommunications device (e.g., Smartphone or WiMax, Bluetooth, BLE, UHF, NHF, GSM, CDMA, LAN, tablet) or wearable electronics (e.g., Google glass, Smart WAN, or another wireless protocol. Pulsed infrared light as watch, etc.), being controlled by an application that sends transmitted for instance by a remote control is an additional instructions and exchanges 2-way communication signals wireless form of communication. Near Field Communica with the neurostimulator. Any of these embodiments may be tion (NFC) is another useful technique for communicating referred to as handheld devices, as they may be held in a with a neuromodulation system or neuromodulation puck. users hand or worn on the user's person. However, non One of ordinary skill in the art would appreciate that there handheld control user devices (e.g., desktop computers, etc.) are numerous wireless communication protocols that could may be used as well. The user device may be a general be utilized with embodiments of the present invention, and purpose device (e.g., Smartphone) running application soft embodiments of the present invention are contemplated for ware that specifically configures it for use as a controller, or use with any wireless communication protocol. it may be a custom device that is configured specifically (and 0114. Adherent or wearable neurostimulators 609 may or potentially exclusively) for use with the neurostimulators may not include a user interface 604 and may be controlled described herein. For example, the controller may be soft exclusively through wireless communication protocol 608 to ware, hardware, or firmware, and may include an application control unit 609. In an alternate embodiment, adherent or that can be downloaded by the user to run on a wireless wearable neurostimulator 609 does not include wireless connectable (i.e. by Bluetooth) device (e.g., handheld device antenna and chipset 607 and is controlled exclusively such as a smartphone or tablet) to allow the user to select the through user interface 604. One skilled in the art will waveforms delivered by the neurostimulator, including recognize that alternative neurostimulator systems can be allowing real-time modulation of the delivered neurostimu designed with multiple configurations while still being lation to modify the user's cognitive state as described capable of delivering electrical stimulation transdermally herein. into a subject. 0117 The neurostimulator may apply an ensemble wave 0115. In general, any appropriate neurostimulation sys form for about 3-30 min (or longer) that is made up of tem may use (and/or be configured to use or operate with) different “blocks” having repeated waveform characteris the ensemble waveforms as described herein for enhancing tics; the waveform ensemble may include transition regions sleep. FIGS. 3A, and 3B-3M describe and illustrate an between the different blocks. In general, at least some of the example of a neurostimulation system (neurostimulator, waveform blocks (and in some variations most or all of electrodes, controller) that may be used. For example, a them) generally have a current amplitude of >3 mA (e.g., >3 neurostimulation system may include a lightweight, wear mA, greater than 4 m.A, greater than 5 mA, between 5 mA able, neurostimulator device (neurostimulator) that is con and 40 mA, between 5 mA and 30 mA, between 5 mA and figured to be worn on the head and a consumable/disposable 22 mA, etc.), and a frequency of 100 Hz (e.g., between 750 electrode assembly; in addition a device that may be worn HZ and 25 kHz, between 750 Hz, and 20 kHz, between 750 and/or held by the user (“user device') which includes a HZ and 15 kHz, etc.), the current is typically biphasic and is processor and wireless communication module may be used charge imbalanced, and has a duty cycle of between 1-90% to control the application of neurostimulation by the wear (e.g., between 10-90%, between 30-80%, between 30-60%, able neurostimulator. The neurostimulator and/or user etc.). One or more of these characteristics may be changed device may be particularly adapted to deliver the ensemble during stimulation over timescales of every few seconds to waveforms as described herein. For example, the user device minutes as the ensemble waveform shifts between subse may present a list of ensemble waveforms and allow the user quent component waveforms. to select among them in order to select a desired cognitive 0118 When worn, the system may resemble the system effect. The ensemble waveforms may be ordered by the shown in FIG. 3M, having an electrode assembly attached at desired effect (e.g., enhancing sleep onset, improving sleep two locations (points or regions) on the Subjects head quality, etc.) and/or by time and/or by ranking, etc. Further, and/or neck) and a neurostimulator attached to the electrode the user device may be adapted to communicate with the assembly, as shown; in Some variations a separate controller wearable neurostimulator and may transmit an identifier of may be attached to coordinate the application of stimulation. the selected ensemble waveform, and/or waveform param 0119) As will be described in greater detail herein, the eters that define all of a portion (e.g., component waveforms neurostimulator may be lightweight (e.g., less than 30 g, less or portions of component waveforms) of the ensemble than 25 g, less than 20 g, less than 18 g., less than 15 g, etc.), waveform, as well as any user adjustments such as user and self-contained, e.g. enclosing the circuitry, power Sup modification to the perceived intensity to be used to modify ply, and wireless communication components such as a the actual waveforms delivered by, for example, attenuating rechargeable battery and charging circuit, Bluetooth chip the ensemble waveform parameters. Thus, for example, the and antenna, microcontroller, and current source configured user device may be configured to send, and the neurostimu to deliver waveforms with a duration of between 10 seconds lator to receive, the ensemble waveform parameters (dura and tens of minutes. A neurostimulator may also include tion, ramping parameter/ramping time, capacitive discharge safety circuitry. The neurostimulator may also include cir parameters, current amplitude, frequency, percent duty cuits to determine that the electrode is attached and what cycle, percent charge imbalance, etc.). “kind' of electrode it is (i.e., for configuration 3 vs. con US 2017/0182285 A1 Jun. 29, 2017 figuration 4; or indicating the batch and/or source of manu people in a region of the face/head that tends to not have facture, etc.). FIGS. 3A and 3B-3G illustrate two variations hair. Both adhesive and conductive hydrogel that may cover of a neurostimulator. an active electrode region function more effectively on skin 0120 For example, FIG. 3A illustrates a first example of with little or no hair. This thin lower corner (the orbital/ a neurostimulator as described herein. In FIG. 3A, the auricular corner) may fit between the eyebrow and hairline, neurostimulator is shown with a pair of electrodes attached. while the wider portion is positioned up in the forehead area A first electrode 601 is coupled directly to the body 603 of where there is less likely to be hair. the TES applicator 602, and a second electrode 606 is (0123. In FIGS. 3B-3G the various edges of the neuro connected by a cable or wire 604 to the body 603 of the stimulator are labeled, based on where the apparatus will be applicator 602. These electrodes are separate from each worn by the subject, as is illustrated in FIG. 3M. In general, other, and may be replaceable/disposable. Different shaped the side of the unit worn toward the ear is the auricular edge, electrodes 607 may be used with the same re-usable neuro the side worn highest on the forehead is the Superior edge, stimulator. The neurostimulator in this example includes a and the side worn nearest the eye/eyebrow is the orbital rigid outer body, to which the pair of electrodes is attachable, edge. The overall shape of the neurostimulator is triangular making electrical contact via one or more plug-type con (including rounded edges). As used herein triangular nectOrS. includes shapes having rounded/smooth transitions between 0121 FIGS. 3B-3G illustrate another embodiment of a the three sides, as illustrated. The Subject-facing Surface is neurostimulator as described herein. In this variation the specifically contoured to fit in the predefined orientation, neurostimulator is also a lightweight, wearable neurostimu making it difficult or impossible for a subject to misapply, lator that attaches to an electrode, and includes contacts for and risk placing the active region of the attached cantilever making an electrical connection with two (or potentially electrode apparatus in the wrong place. When attaching the more) electrically active regions (e.g., anodic and cathodic cantilever electrode apparatus to the neurostimulator, the regions) on the electrode(s). However, in this example, the cantilever electrode apparatus may flex or bend so that it is neurostimulator is configured to operate with a cantilevered contoured to match the curved and twisted surface. This electrode apparatus, and to attach both mechanically and Surface is a section of a saddle shape, in which there is an electrically to the electrode apparatus at a region that is axis of curvature around which the Surface is concavely off-center on the bottom (underside or skin-facing side) of curved, and an axis of twisting, which may distort the curved the neurostimulator, allowing one end region to be held surface (the two axes may be different or the same). securely to the skin while the other edge region is not pinned 0.124 Within the housing, any of the neurostimulators in this way. The “floating end may therefore adjust slightly described herein may include a processor (e.g., micropro to different curvatures of the head, even while the electrode cessor) or controller, a wireless communication module that assembly (which may be flexible) is securely held to the is connected to the processor, and a power source (e.g., skin. Thus, this cantilevered attachment mechanism may battery, etc.). The power source may be configured to enhance comfort and adjustability of the device. In addition, provide power to the internal circuitry and/or the circuitry the neurostimulator device may be configured specifically so driving current between anodic and cathodic regions of the that it can be comfortably worn at the user's temple, even in electrodes when worn by the user. The power supply may be users wearing glasses. For example, the apparatus may be a high-voltage power Supply, e.g., able to provide up to 60 configured so that the skin-facing side (which connects to V across these electrode terminals. In general, the apparatus the electrode assembly via one or more connectors) is may also include circuitry that is configured to regulate the curved with a slightly concave surface having a slight twist energy (e.g., current) delivered as required by the processor, angle. This curve shape may help the apparatus fit more which may in turn receive instructions via the wireless Snugly (more uniformly) to the Surface of the temple. In communications module from a controller. The controller addition, one end of the device (the end to be positioned may also communicate information, and in particular infor in-line with the edge of the user's eye and the user's ear) mation about the electrodes, including confirming that the may be thinner (e.g., less than 2 cm, less than 1.5 cm, less electrode assembly is connected and/or what type (e.g., than 1 cm, less than 0.8 cm, etc.) than the opposite end, calm, energy, make/model, batch, etc.) of electrode assem which may be worn higher up on the temple. bly is attached, and an indicator of the contact with the user's 0122) For example, FIGS. 3B-3G illustrate front, back, skin (e.g., conductance, a parameter proportional to conduc left side, right side, top and bottom perspective views, tance, or a value from which an estimate of the conductance respectively of a variation of a neurostimulation device of the electrode(s) may be derived). (neurostimulator or electrical stimulator) that may be used 0.125. The electrode assembly may mechanically and/or with cantilever electrode apparatuses. The overall shape of electrically connect to the neurostimulator, e.g., by Snapping the neurostimulator may be triangular, and particularly the to the underside of the neurostimulator at one or more (e.g., Surface of the neurostimulator (though curved/concave and two) connectors such as Snap receivers. Thus in some twisted) adapted to connect to the electrode apparatus and variations the neurostimulator may be held onto the sub face the patient may be three-sided (e.g., roughly triangular). jects (user's) head by the electrode assembly; the electrode This roughly triangular shape may include rounded edges, assembly may be adhesively connected to the user's head and the thickness of the stimulator (in the direction perpen and/or neck to form an electrical contact with the desired dicular to the Surface contacting the cantilever electrode regions on the user, and the neurostimulator may be con apparatus) may vary, e.g., be thinner along one side, and nected e.g., adhesively and/or electrically, to the electrode particularly the side (the portion between the orbital edge assembly. As described below, the connectors between the and the auricular edge) that will extend laterally from the neurostimulator and the electrode assembly may be posi edge of the eye in the direction of the ear. This shape may tioned in a particular and predetermined location that allows also be beneficial when helping to fit/be worn on most the neurostimulator to be robustly connected to the electrode US 2017/0182285 A1 Jun. 29, 2017 assembly and therefore the user's head/neck without dis body is also thin (having a much larger diameter and height rupting the connection, and while permitting the system to than thickness). The thickness is shown in FIG. 3.J. be worn on a variety of different body shapes. 0.130. In this example, two connectors 415, 417 (electri 0126 Electrode assemblies are generally described in cal and mechanical connectors, shown in this example as detail below, along with specific examples and variations. In snaps) extend from the front of the cantilever electrode particular, described herein are electrode assemblies that are apparatus. The front of the first electrical portion 403 may thin (e.g., generally less than 4 mm, less than 3 mm, less than also include an optional foam and/or adhesive material 421 2 mm, less than 1 mm, etc. thick, which may not include the through which the snaps extend proud of the first electrical thickness of the connectors that may extend proud from the portion. The first electrical portion is shaped and sized so thin electrode assembly), and flexible, and may be flat (e.g., that the Snaps will connect to plugs (ports, holders, opening, formed in a plane). For example, they may be printed on a female mating, etc.) on the electrical stimulator. As flex material. Such as the material used to print a flex circuit. described above, the connectors may be separated by In use, they can be wrapped around the head to contact it in between about 0.6 and about 0.9 inches (e.g., between about at least two locations (e.g. at the temple and on the back of 0.7 and about 0.8 inches, etc., shown in FIGS. 3H-3K as the neck). The electrode assembly may include a connector about 0.72 inches). The second electrode portion may also (electrical and/or mechanical) that extends proud of the include a foam or backing portion 423. This foam/backing otherwise flat/planar Surface to connect the active regions of region may be optional. In some variations the separation the electrode assembly to the neurostimulator. For example, between the connectors is not limited to 0.7 to 0.8, but may the neurostimulator may be mechanically and electrically be larger (e.g., between 0.7 and 1.2 inches, 0.7 and 1.1 connected by one or more Snaps extending from the front of inches, 0.7 and 1.0 inches, 0.7 and 0.9 inches, etc.) or the electrode assembly. In some examples, one Snap con smaller (e.g., between 0.2 and 0.7, 0.3 and 0.7, 0.4 and 0.7. nects to a first active electrode region (anodic or cathodic 0.5 and 0.7, 0.6 and 0.7 inches, etc.). region) that is surrounded by an adhesive to adhere the I0131 FIG.3K shows a back view of this first example of active region to the user's head. A second electrode region a cantilever electrode apparatus. In this example, the first (anodic or cathodic) on a separate part of the electrode 403 and second 405 electrode portions are also shown and assembly may be electrically connected to the other con include active regions 433, 435. The active regions are nector. For example, the second electrode region may be bordered by adhesive 440. The first 403 electrode portion adapted to fit either on a region across the user's neck at the includes, on the back (patient-contacting) side, a first active base of the hairline, e.g., near the midline of the neck (calm region 433, which is bounded, e.g., around its entire cir electrode configuration). cumference, or at least on, by an adhesive 440. The active 0127. The electrode apparatus may be printed (e.g., by region may include a conductive material (e.g., electrically flexographic printing, laser printing with conductive ink, conductive gel). Similarly, the back of the second electrode silk-screening, etc.) on a flexible (e.g. plastic) Substrate (flex portion 405 includes the second active region 435 Sur Substrate) and may also include a pair of connectors (Snaps) rounded on two sides by an adhesive material 440 that on the side opposite the skin-facing electrodes. The elec extends to the edge of the electrode region. The adhesive trode active regions on the back of the assembly may include may be any biocompatible adhesive that can releasably hold a layer of conductor (e.g., silver), over which a layer of the material to the skin. Ag/AgCl is placed that is sacrificial and acts as a pH buffer. 0.132. In general the elongate body region connecting the A next layer of hydrogel overlays the Ag/AgCl electrode so two electrode portions may be any appropriate length, but is that it can uniformly transfer charge across the active region generally longer than a few inches (e.g., longer than about into the skin. A portion of the electrode assembly around the 2 inches, longer than about 3 inches, longer than about 4 active electrode area may have an adhesive that permits inches, longer than about 5 inches, longer than about 6 inches, longer than about 7 inches, longer than about 8 good contact with a user's skin. inches, longer than about 9 inches, etc.). The elongate body 0128. There may be multiple configurations (e.g., shapes) region may also be bent or curved, as illustrated in FIGS. of the electrode assembly, and, as described in greater detail 3H-3K. The bend or curve, in which the elongate body may herein, the electrode assembly may generally be formed on even double back on itself, may allow the material to flex or a flexible material (flex circuit material) and mechanically bend to allow it to be adjustably positioned over and/or and electrically connected to the neurostimulator. around the subject’s head, as shown in FIGS.3L and 3M, for 0129 FIGS. 3H-3K illustrate one variation of a cantilever example. electrode apparatus (“electrode apparatus) that may be used 0.133 FIG.3L illustrates a cantilever electrode apparatus with a neurostimulator and may be worn on a Subjects head. (similar to those shown in FIGS. 1A and 4A) worn on a This variation is adapted to connect to a user's temple region Subject's head. As illustrated, the apparatus is positioned and the back of a user's neck. In this example, the cantilever with the first electrode portion adhesively attached at the electrode apparatus 400 includes a plurality of electrode temple region and a second electrode portion attached to a portions (two are shown) 403, 405. In FIG. 3H, a front region behind the head (e.g., neck region, not shown). A perspective view is shown. The front side is the side that will neurostimulator (not shown in FIG. 3L) may be attached to face away from the subject when worn. The cantilever the cantilever electrode apparatus either before or after it is electrode apparatus is thin, so that the electrode portions applied to the subject. As shown in FIG. 3M, the neuro include a front side (visible in FIGS. 3H and 3I) and a back stimulator may be attached to the front side of the cantilever side (visible in FIG.3K). As shown in the side view of FIG. electrode apparatus by Snapping onto the proud connectors, 3J, the device has a thin body that includes the electrode while the elongate body region 407 is bent to extend behind portions 403, 405 as well as an elongate body region 407 the subjects head and down to a portion on the midline of extending between the two electrode portions. The elongate the back of the patient’s neck. Both the first electrode US 2017/0182285 A1 Jun. 29, 2017 portion and the second electrode portion may be adhesively 0.135 The neurostimulator may apply an ensemble wave held with the electrically active regions against the skin, form for about 3-30 min (or longer) that is made up of allowing the neurostimulator to apply energy, and in par different “blocks” having repeated waveform characteris ticular the waveforms as described in application Ser. No. tics; the waveform ensemble may include transition regions 14/320,443, titled “TRANSDERMAL ELECTRICAL between the different blocks. In general, at least some of the STIMULATION METHODS FOR MODIFYING OR waveform blocks (and in some variations most or all of INDUCING COGNITIVE STATE, filed Jun. 30, 2014, and them) generally have a current amplitude of >3 mA (e.g., herein incorporated by reference in its entirety. 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 0134. In use, a user may interact with a controller (e.g., (e.g., between 250 Hz and 15 kHz, between 750 Hz and 25 a Smartphone controlled by application Software/firmware) kHz, between 750 Hz and 20 kHz, between 750 Hz, and 15 that pairs with the neurostimulator (e.g. by Bluetooth). The kHz, etc.), the current is typically biphasic and is charge user may operate the controller to select the operational imbalanced, and has a duty cycle of between 1-90% (e.g., mode, e.g., the type of cognitive effect to be induced, between 10-90%, between 30-80%, between 30-60%, etc.). including enhancing the quality of sleep or reducing sleep One or more of these characteristics may be changed during onset latency, and/or the device could automatically detect stimulation over timescales of every few seconds to minutes. based on the configuration of an electrode to which the FIG. 1 shows an exemplary cycle of a waveform for TES apparatus is attached. The user may select, for example, comprising a positive-going pulse of duration t, a negative from a set of ensemble waveforms which ensemble wave going pulse of duration t, and a total pulse duration oft. As form to execute. There may be separate waveforms to evoke shown in FIG. 1 the peak of the positive- and negative-going a desired experience/effect (e.g., “calm” ensemble wave pulses may be equal (absolute value). The duty cycle per forms for reducing anxiety so that a Subject may fall asleep centage may be defined as (t+t)/t, and the charge imbal vs. “drowsy ensemble waveforms that are likely to induce ance percentage may be defined as (t-t)/(t+t). sleep in a Subject). An ensemble waveform may generally be 0.136. In general, the TES control module may be spe between about 3-90 min (e.g., between about 3-60 min, cifically adapted to deliver a biphasic electrical stimulation between about 5-60 min, between about 5-40 min, etc., signal of 10 seconds or longer between the first and second between about 3-25 minutes, etc.) long, or longer (e.g., electrodes, where the signal has a frequency of 100 Hz or greater than 3 min, greater than 5 min, greater than 10 min, greater (e.g., 200 Hz or greater, 400 Hz or greater, 450 Hz greater than 12 min, etc.). In general, an ensemble waveform or greater, 500 Hz or greater, 600 Hz or greater, 700 Hz or may be broken up into segments with specific pulsing greater, etc.; optimally 750 Hz or greater, including 1 kHz or parameters, e.g., current amplitude, frequency, duty cycle, greater, 2 kHz or greater, 3 kHz or greater, 4 kHz or greater, charge imbalance, shorting/capacitive discharge, etc., and 5 kHz or greater, 7.5 kHz or greater, 10 kHz or greater, 20 these parameters may change at pre-specified times for kHz or greater, etc.) and an intensity of 2 mA or greater (e.g., Subsequent component waveforms. Once the user selects an 3 mA or greater, 4 mA or greater, 5 mA or greater, 6 mA or ensemble waveform, the user can start the neurostimulation greater, 7 mA or greater, 8 mA or greater, 9 mA or greater, and the user can control or change the perceived intensity 10 mA or greater, etc.). The control module may also be (e.g., by dialing the perceived intensity up or down), pause, configured to reduce pain when applying the stimulation by or stop the session using the phone (app). In general, the controlling the duty cycle (e.g., the percent of time that the perceived intensity can be scaled by the user between current applied is non-zero, and/or greater than Zero), e.g. So 0-100% of a target perceived intensity (e.g., a target current, that the duty cycle of the applied energy is greater than 10 frequency, duty cycle, charge imbalance, and/or shorting/ percent (e.g., greater than 15 percent, greater than 20 per capacitive discharge), using a control Such as one or more cent, greater than 30 percent) and less than 90 percent (e.g., buttons, sliders, dials, toggles, etc., that may be present on less than 75 percent, greater less than 70 percent, less than the controller (e.g., Smartphone) in communication with the 60 percent). In addition, the control module may be config neurostimulator. The controller may also allow a user to ured so that the applied current is biphasic and/or is not activate ('on demand') a waveform configuration that is charge balanced (e.g., has a DC offset, also referred to as DC designed to evoke a predetermined response. For example, bias, so that the mean amplitude of the applied waveform is the control device could be adapted to display one or more non-zero). Alternatively or in addition, the control module icons to trigger phosphenes or an intensification of the (TES control module) may be configured to deliver wave perceived cognitive effect or skin sensation intensity. In forms biphasically asymmetric (i.e. not having the same addition, the controller may be configured to allow the user pulse in the positive and negative direction) and/or to to press an icon to help in applying the electrode apparatus discharge capacitance built up on the electrodes (and in the and/or neurostimulator. For example, activating this control body), e.g., by occasionally or periodically “shorting the may cause the Smartphone to activate a front-facing camera electrodes, and/or by applying an opposite current(s). In on the phone to help the user to attach the apparatus to the general, a control module may be configured to generate head. During or after a session, a user can access help stimulation that includes these parameters, and may be screens, a profile page, social sharing interfaces (i.e. tweet configured to prevent stimulation outside of these param your experience), feedback about a session, and analysis & eters, in order to avoid inducing pain. history of previous use. In general, the system may also be 0.137 Described herein is a method of enhancing sleep, configured to pass data to and from the controller and/or the including facilitating falling asleep (e.g., reducing sleep neurostimulator and to/from a remote server via the Internet. onset time, increasing drowsiness, facilitating the passage These data may include user information, waveform data, into sleep in a subject, etc.). Such methods may generally information about the function or state of the hardware include: placing a first electrode of a wearable transdermal device or electrode assembly, etc. electrical stimulation (TES) applicator on the subjects skin US 2017/0182285 A1 Jun. 29, 2017 in a first region (e.g., on a temple region on a first side of the and a waveform generator, wherein the TES control module subjects body); placing a second electrode of the TES is adapted to deliver a biphasic electrical stimulation signal applicator on a second location (e.g., on the back of the of 10 seconds or longer between the first and second Subject’s neck above the vertebra prominens); activating the electrodes having a duty cycle of greater than 10 percent, a wearable TES applicator to deliver a transdermal electrical frequency of 250 Hz or greater, and an intensity of 3 mA or stimulation having a duty cycle of greater than 10 percent, greater, wherein the biphasic transdermal electrical stimu a frequency of 250 Hz or greater, and an intensity of 3 mA lation is asymmetric with respect to positive and negative or greater. The biphasic transdermal electrical stimulation going phases; and a wireless receiver connected to the TES may be asymmetric with respect to positive and negative control module; wherein the wearable TES applicator going phases; and facilitating the passage into sleep by weighs less than 50 grams. applying the biphasic transdermal electrical stimulation 0142. Any of these apparatuses may be specifically between the first and second electrodes for 10 seconds or adapted for use as a sleep-modifying apparatus. For longer. example, in Some variations, the apparatus includes one or 0138 Also described herein are methods of inducing more sensor that determine the sleep state (e.g., awake, sleep in a subject, which may include: placing a first asleep, drowsy, etc.) of the Subject wearing the apparatus. electrode of a wearable transdermal electrical stimulation Sensors may include one or more accelerometers, heart rate (TES) applicator on the Subject's skin (e.g., on a temple sensors, electroencephalogram (EEG) sensors, electromyo region on a first side of the Subject's body); placing the gram (EMG, including electrooculogram EOG), etc. As used second electrode on the Subject (e.g., on the back of the herein, a sensor may also include hardware and/or software Subject’s neck above the vertebra prominens); activating the for interpreting and/or modifying the resulting signals, wearable TES applicator to deliver a transdermal electrical including but not limited to filtering physiological signals, stimulation having a duty cycle of greater than 10 percent, amplifying physiological signals, etc. a frequency of 250 Hz or greater, and an intensity of 3 mA 0143. The methods and apparatuses (devices, systems) or greater. The stimulation may be biphasic transdermal described herein may use a TES waveform having one or electrical stimulation that is asymmetric with respect to more characteristics from the list including: a duty cycle positive and negative going phases. The method may gen between 30% and 60%; a frequency greater than 5 kHz or erally include inducing sleep by applying the biphasic greater than 10 kHz; an amplitude modulation, including transdermal electrical stimulation between the first and amplitude modulation with a frequency less than 250 Hz: second electrodes for 10 seconds or longer. and a burst mode wherein stimulation pauses intermittently 0.139. Also described herein is a method of maintaining (i.e. on for 100 ms, off for 900 ms: on for 500 ms, off for 500 sleep in a Subject, the method comprising: placing a first ms; and other more complex pulsing patterns, including electrode of a wearable transdermal electrical stimulation chirping and patterns repeating at 250 Hz or lower fre (TES) applicator on the Subject’s skin on a temple region on quency). a first side of the Subject's body; placing the second elec 0144. The methods and apparatuses (devices, systems) trode on the back of the subject’s neck above the vertebra described herein are useful for facilitating the passage into prominens; activating the wearable TES applicator to deliver sleep and/or inducing sleep and may include inducing one or a transdermal electrical stimulation having a duty cycle of more of the following states in the subject: increased drowsi greater than 10 percent, a frequency of 250 Hz or greater, ness; increased desire to sleep: and enhanced State of calm and an intensity of 5 mA or greater, wherein the biphasic ness and carefreeness (i.e. reduced anxiety) when preparing transdermal electrical stimulation is asymmetric with to fall asleep, attempting to fall asleep, or actually passing respect to positive and negative going phases; and main into a state of sleep. taining a state of sleep in the Subject by applying the 0145 The apparatuses (devices, systems) described biphasic transdermal electrical stimulation between the first herein may be activated while the subject is awake (before and second electrodes for 10 seconds or longer while the they fall asleep) or may be put on by the user before sleep Subject is asleep. but not activated until after the user has fallen asleep. For 0140. As mentioned above, any of the portable transder embodiments configured to deliver TES before a subject mal electrical stimulation (TES) applicators descried herein falls asleep, a visual indicator (i.e. LED or screen) of the for facilitating, inducing, and/or maintaining sleep in a transdermal electrical stimulator (or a connected user device Subject may include: a body; a first electrode; a second Such as a Smartphone running an app that controls the electrode; and a TES control module at least partially within transdermal electrical stimulator) may be turned down or the body and comprising a processor, a timer and a wave turned off when the wearable TES system is activated for form generator, wherein the TES control module is adapted facilitating the passage into sleep of the Subject. to deliver a biphasic electrical stimulation signal of 10 0146 Some versions of the methods and systems seconds or longer between the first and second electrodes described herein include sleep monitoring of the subject. having a duty cycle of greater than 10 percent, a frequency Sleep monitoring may comprise using a sensor (which may of 250 Hz or greater, and an intensity of 3 mA or greater, be included as part of the apparatus or used along with the wherein the biphasic transdermal electrical stimulation is apparatus) to measure a Subject's brain rhythms (i.e. EEG), asymmetric with respect to positive and negative going autonomic function (including sensors to measure one or phases. more of galvanic skin resistance, heart rate, heart rate 0141 For example, a wearable transdermal electrical variability, or breathing rate), and/or movements, including stimulation (TES) applicators for facilitating, inducing, and/ movement sensors worn by the Subject, coupled to the or maintaining sleep in a subject may include: a body; a first Subject’s bed, or configured to detect movements remotely electrode; a second electrode; a TES control module at least without direct or indirect physical contact with the subject partially within the body and comprising a processor, a timer (i.e. via ultrasound or a microphone). Variations of the US 2017/0182285 A1 Jun. 29, 2017 systems and methods described herein may further comprise deficit hyperactivity disorder; medication that affects the an automatic modification of a transdermal electrical stimu ability to fall asleep, including chemotherapeutic agents; and lation waveform based on the amount of time required for a age-related sleep changes. Subject to fall asleep. Thus, any of the apparatuses described 0150. The systems and methods described herein may herein may be configured to feed the sensor information further comprise a notification that reminds the subject to back to control (e.g., turn on/off) and/or modify the TES wear a neurostimulator before bed and configure it for stimulation applied. improving sleep. For example, the notification to the Subject 0147 For example, in some embodiments of the inven may be based on input from a location sensor in the tion, a subject will fall asleep within a short period of time neurostimulator or a device wirelessly connected to the (i.e. less than 15 minutes; less than 10 minutes; less than 5 neurostimulator to detect that a user is in their bedroom and minutes). A TES stimulation may stop automatically when a clock to determine whether the user is in their bedroom the Subject is asleep, as detected by a sleep monitoring during a time when they generally go to sleep. In other function and related components of the system. For embodiments, the system or method may further comprise a example, TES may automatically stop when the Subject is calming sensory stimulus (i.e. an auditory stimulus, includ asleep at a fixed delay (alarm mode), based on a sleep state ing binaural beat, and olfactory stimuli) and/or may further (or series of sleep states) experienced by the user, or by comprise an alarm that wakes a subject during an identified control of a third party (i.e. a sleep clinic technician who phase of light sleep to remind the user to remove the controls the system remotely via an Internet connection). In sleep-promoting TES system. another example, TES may be automatically or manually 0151. When a subject wakes (i.e. in the morning), feed (i.e. from a quick start button that can be pressed quickly and back may be provided to the subject showing how the easily to minimize likelihood of waking) triggered if a subjects use of transdermal electrical stimulation before Subject wakes up, even briefly, so that the Subject can get and/or during sleep affected a sleep quality metric selected back to sleep quickly. from the group including but not limited to: sleep onset time, 0148. In some variations of the systems and methods length of sleep, sleep latency, total length or percentage of described herein, a TES waveform may be started, stopped, REM sleep, total length or percentage of NREM sleep, total or modified based on sleep quality being below a threshold length or percentage of slow wave (deep) sleep, length of value, where sleep quality is defined by one or more of sleep sleep cycles, number and/or length of night awakenings, and latency, amount and/or sequence of sleep stages, sleep morning wake time. amount, and time during the day when sleep occurs. The sleep quality measurement may be a measurement of sleep Examples quality from the current bout of sleep and/or from one or 0152. As mentioned above, in general the use of certain more previous bouts of sleep. In other variations of the TES waveforms applied prior to sleeping may improve the systems and methods described herein, a TES waveform quantity and/or quality of sleep. In the morning, users may be started, stopped, or modified based on a measure typically wake up feeling more rested, with a more positive ment of the Subject's physiology or cognitive state including mood, less anxiety, and less stress (both as self-reported and but not limited to: activity, stress, immune system function, as assessed by biochemical assay of saliva). FIGS. 9-14B diet, and mood. The methods and apparatuses (devices, illustrate exemplary data comparing various TES waveform systems) described herein may be configured for use before that may be used to enhance sleep, including comparing to or during a nap and/or to enhance the function of the a control (“baseline') stimulation in which only sham TES immune system (i.e. by improving the quality and/or quan was applied. tity of slow-wave sleep in the subject). 0153. For example, FIG. 9 illustrates an example of an 0149. In addition to lifestyle applications (i.e. for gen overall assessment of the effect of two exemplary TES eral use by Subjects, not for treating or diagnosing any waveforms within a range of parameter values found to medical condition), the TES apparatuses (systems, devices) enhance sleep, compared to baseline. Comparison is made and methods described herein for facilitating, inducing, using the Pittsburgh Sleep Quality Index (PSQI). In this and/or maintaining sleep in a subject may be used to treat a example, the assessments compared, in a 1-week crossover sleep disorder in a patient, including but not limited to: design with no washout period, baseline (no TES before insomnia, including insomnias as a symptom of a psychiat sleep) and two different 15-minute TES waveforms deliv ric or mood disorder Such as post-traumatic stress disorder, ered through a configuration wherein an anode is at the anxiety, emotional distress, depression, bipolar disorder, or forehead/temple area and cathode on the neck of a Subject, Schizophrenia; restless leg syndrome and periodic limb similar to that shown in FIGS. 2A-2F. One waveform tested movement disorder; circadian rhythm disorders; sleeping was referred to as high F (or alternatively as Program B sickness; parasomnia; shift work and jet lag; and hyperSom or relaxCES) and is a pulsed waveform with variable nia. The TES apparatuses (systems, devices) and methods frequency, generally between 3 kHz and 11 kHz. FIGS. described herein for facilitating, inducing, and/or maintain 15A-15C describe three example of complete ensemble ing sleep in a patient may also be used to treat a disorder, waveforms that may be similar to the “high FTES wave disease, or symptom not generally described as a sleep forms used. disorder but for which sleep abnormalities occur in the 0154 The tables shown in FIGS. 15A-15C lists the patient, including but not limited to: post-traumatic stress waveform parameters for each of the component wave disorder, a neurodegenerative disease Such as Alzheimer's forms. In this example the ensemble waveform is configured disease, a neurodevelopmental disorder Such as Down Syn with short circuiting on (meaning that a capacitive discharge drome, autism spectrum disorder, and Rett's syndrome; pulse occurs in the opposite direction after each of the alcoholism, drug addiction; menopause; pregnancy; men biphasic pulses). In one example, the system transfers struation; attention-deficit disorders, including attention chunks (e.g., 400 ms segments) securely between the user US 2017/0182285 A1 Jun. 29, 2017 device and the worn neurostimulator every about 400 ms (or 0159 For example, seven nights of Program B (e.g., on multiples of about 400 ms), including the neurostimula using a high F ensemble TES waveform similar to that tion start frequency, end frequency, starting amplitude, end shown in FIG. 15A, running for 15 min. beginning prior to amplitude, start duty cycle, end duty cycle, start percent falling asleep) and seven nights of Program A (e.g., using a charge imbalance, end charge imbalance, etc. The timing of low F, approximately 750 Hz, pulsing TES waveform for 15 wireless communication chunks at about 400 ms should not min., similar to FIG. 16, prior to falling asleep). In the be construed as limiting the timing of communication studies shown in FIGS. 9-14B, morning and evening logs between a controller unit and the neurostimulator. FIG. 15B were kept for study duration, sleep monitoring (e.g., Acti illustrates a second example of a calm ensemble waveform graph and Polar chest strap, measuring HR and HRV) was having a slightly longer running time, running over 12 performed for the study duration during sleep. Baseline, 7 minutes. Similarly, 15C illustrates a third example of a calm Day and 14 Day general health Screening was done, assess ensemble waveform having a yet longer running time (over ing (by self-reporting): overall sleep score (FIG. 9), Stress, 16 minutes). Anxiety, Depression, Fatigue and the like (FIGS. 12A-12G). 0155. A second waveform tested in this study was (0160 For example, as partially reflected in FIGS. 10A referred to as low F (or alternatively as Program A). This 10C, comparison between low F and high F stimulation second waveform has a lower pulsing frequency, variable protocols suggests that the improved sleep quality (com but generally 750 Hz. FIG. 16 illustrates an example of a pared to baseline) in these two exemplary stimulation pro TES ensemble waveform such as the low F variations tocols may come in part due to fewer awakenings, fewer described herein. unknown awakenings, and in particular, fewer awakenings 0156. In FIG.9, a comparison of PSQI for n=10 subjects caused by needing to use a bathroom. See, e.g., FIG. 10A, examined between baseline (no TES), high F and low F showing a bar graph of WASO in minutes, and FIG. 10B, ensemble waveforms show a significant improvement of showing comparison between the percentage of time, and both low F and high F waveforms compared to baseline (and FIG. 10C, showing the self-reported WASO events. to other TES waveforms having parameters outside of the (0161 Similarly, FIGS. 11A-11C illustrate heart rate vari ranges described herein, data not shown). In general, a PSQI ability (FIG. 11A, showing HRV in very low frequency of greater than 5 is considered to reflect poor sleep quality. bands (e.g., oVLF of 57.5 to 75), HRV power in the 0157. In addition to the low F and high F parameters, low-frequency band, FIG. 11B shows plF (between 15 and acute studies performed in the afternoon used alternative 15 20), while FIG. 11C compares the pHF indicating slight minute TES ensemble waveforms with even lower fre differences between the low F and high F protocols. quency, e.g., 500 Hz, pulsing (full set of parameters below). 0162 FIGS. 14A and 14B compare two empirical mea Surprisingly, 5 of 10 people fell asleep during the 15 minute Sures of sleep quality, morning amylase and morning corti vibe. This effect appears to be stronger for lower frequencies sol, between the high F and low F groups. This biochemical (e.g., low F") compared to higher frequency (high F) analysis included collecting saliva on mornings during the ensembles, for which subjects tend to fall asleep after the treatment period for each of the high F and low F param vibe completes (though it is not that uncommon to fall asleep eters. The user collected saliva was processed by a third during a sleep-inducing waveform). Subjects self-reported party for alpha-amylase and cortisol, both of which are feeling increased sleepiness (e.g., very heavy drowsy physi known to correlate to acute and chronic stress. The lower cal feelings, “face is extremely relaxed, words are slowed down and shoulders drop.” feeling as though the Subject frequency regime (Low F) showed a slightly greater effect woke up from a nap physically relaxed and mentally alert, compared to the high F regime, consistent with the other etc.). In this example, the parameters (for very low F (self-reported) data, e.g., in FIGS. 11A-13B. stimulation) included stimulating at 500 Hz for a 15 min 0163. In general, the methods of improving sleep by TES ensemble, having a peak current of 3.5 mA. The (illustrated stimulation described herein show that, relative to baseline, in the table of FIG. 17) had a frequency of 500 Hz for 4 min both low F and high FTES ensemble waveforms improved and 30 sec, switching to a frequency of 550 Hz for 30 sleep quality as assessed by the Pittsburgh Sleep Quality seconds (and repeating for 3 cycles of this). The duty cycle, Index (for which higher scores correspond to lower quality as defined above, was 25 to 35% depending on patient sleep). Further, the Low F waveforms led to fewer awak comfort (they could self-adjust). The charge imbalance as enings and reduced the length of awake time after sleep defined above as the percent DC offset (see FIG. 1) was 3%. onset relative to the high F waveform (see, e.g., FIGS. Capacitive discharging was set to “on” So that a brief 10A-10C), and the low F waveforms caused a reduction in capacitive discharging pulse was emitted during a portion of power in the very low frequency band relative to high F. each positive- or negative-going pulse. Hear rate variability (HRV) in the low frequency and high 0158. In each of the sleep studies discussed herein the frequency bands is slightly higher after low F TES wave subject ages ranged between 18 and 50 years old. Subjects form than the high F waveform. These frequency bands are were monitoring using one or more sleep sensors (e.g., 7 typically described as high frequency (HF) brain activity, wore Actigraph sleep sensors, Phillips Activatch; 7 wore from 0.15 to 0.4 Hz, low frequency (LF) brain activity, from HRV monitor, Polar chest strap). Integrated sensors (e.g., 0.04 to 0.15 Hz, and the very low frequency (VLF) brain motion sensors, etc.) in the wearable apparatus could alter activity, from 0.0033 to 0.04 Hz. natively or additionally be used. In some examples, the 0164. In general, the high F and low F waveforms were procedure included seven nights of each protocol. In prac relatively similar, though both improved over baseline. For tice, Subjects may use these apparatuses for multiple nights example, improvements were seen in the time it takes to fall (e.g., 2 nights, 3 nights, 1 week, 2 weeks, one month, etc.) asleep (sleep onset latency), reductions in the occurrence of concurrently to enhance sleep. nightmares, increased total sleep time, and improved mood. US 2017/0182285 A1 Jun. 29, 2017 In a previous study, high F beat baseline on all above metrics specifically to configurations and methods for transdermal except for those related to middle of the night and early electrical stimulation systems adapted to improve sleep and morning awakenings. mood. This has been shown experimentally as will be 0.165 Thus, in general, the application of TES before bed described below. using either low For high F waveforms led to improvements 0169 Achieving optimal human performance that in Subject's mood and energy in the morning as assessed involves cognitive or physical work requires quality sleep with the positive and negative affect schedule (PANAS) and a positive mental attitude. The ascending reticular scale. These beneficial effects on mood may include reduced activating system (RAS) represents a powerful set of endog anxiety (FIG. 12A), reduced depressive feelings (FIG. 12B), enous neuromodulatory circuits that gate and tune global reduced stress (FIG. 12C), increased positive affect (FIG. brain responses to internal and external cues, thereby regu 12D), reduced negative affect (FIG. 12E), reduced irritabil lating consciousness, alertness, and attention. The activity of ity (FIG. 12F), and reduced fatigue (FIG. 12G). Application two major RAS nuclei, the locus coeruleus (LC) and pedun of TES as described herein before sleeping may also culopontine nucleus (PPN), can be altered by trigeminal improve depression, anxiety and stress, as indicated by the nerve modulation. Monosynaptic afferent inputs from the Depression, Anxiety and Stress Scale (DASS), a clinical sensory components of trigeminal nerve branches project to measure with a 0 to 3 scale used for FIGS. 12A-12G. the trigeminal sensory nuclear complex (TSNC), which has Affectivity was measured on a 5 point Scale, ranging from 1 direct and polysynaptic connections to the LC and PPN. We to 5, irritability was measured on a 0 to 3 scale, and fatigue previously found high-frequency (7-11 kHz) transdermal was measured on a 0 to 10 scale. electrical neuromodulation (TEN) of the trigeminal nerve (0166 The self-reported scores for PANAS and DASS are rapidly induces physiological relaxation, dampens sympa consistent with the biochemical markers examined (e.g., thetic nervous system responses to acute stress, and Sup decreased Awakening Amylase and Increased Awakening presses levels of noradrenergic biomarkers. Given the estab Cortisol) for the high F. low F and very low F TES lished roles of LC and PPN neuronal activity in sleep stimulation. Cortisol is on a diurnal pattern with its peak 30 regulation, psychophysiological arousal, and stress, we con min after waking; generally, the higher the morning rise in ducted three studies designed to test hypotheses that modu cortisol, the more normal the indicator is, whereas a lation of the TSNC can improve sleep quality and mood in blunted rise in morning cortisol may be indicative of a healthy individuals (n=99). Across a total of 1,386 days disease state Such as depression, post-traumatic stress dis monitored, we observed TEN modulation of trigeminal and order (PTSD), anxiety and/or sleep deprivation. In general, cervical nerves prior to sleep onset produced significant the majority (e.g., 2/3 or more) of Subjects reported feeling improvements in sleep quality and affective states, quanti more rejuvenated, less drowsy, less anxious, and less fied using clinically validated Surveys, overnight actigraph stressed the next day. Over 2/3 of subjects also reported and heart rate recordings, and biochemical analyses com having an easier time falling asleep and/or getting more pared to baseline or sham controls. Moreover, we observed sleep following the use of the TES methods described some frequency dependence in that TEN delivered at lower herein. frequencies (TEN: 0.50-0.75 kHz) was significantly more 0167. The TES waveforms that may be applied (e.g., to effective at improving sleep quality and reducing anxiety the Subject's neck or head and neck) to enhance sleep as than higher frequency TEN waveforms. Collectively our described herein include a range of parameters that may be results indicate that transdermal electrical neuromodulation adjusted for both efficacy and comfort. The data described of trigeminal and cervical nerve branches can influence herein suggest that in some variations it may be beneficial to TSNC activity in a manner that significantly improves sleep provide relatively low frequency (e.g., 250 Hz to 750 Hz, quality and significantly reduces stress. We conclude that 250 to 1 kHz, 250 to 3 kHz, 250 to 5 kHz, etc.) stimulation biasing RAS network activity to optimize sleep efficiency at relatively high current (e.g., >3 mA, greater than 4 m.A. and enhance mood by electrically modulating TSNC activity greater than 5 mA, etc.); however these two parameters through its afferent inputs holds tremendous potential for alone, low frequency and high current, typically result in optimizing mental health and human performance. painful and/or unpleasant sensations on the head and/or neck 0170 The ascending reticular activating system (RAS) is when applied there. In order to achieve a combination of low a collection of nuclei and circuits that sort, filter, integrate, (250-750 Hz) frequency and high current (>3 mA, 3-40 mA, and transmit incoming sensory information from the brain >5 mA, etc.) it may be beneficial to include one or more of stem to the cortex to regulate sleep/wake cycles, arousal/ the modulation schemes described herein, including DC alertness, attention, and sensorimotor behaviors. The endog offset (biphasic, asymmetric stimulation in which the posi enous neuromodulatory actions of the RAS on conscious tive and negative going pulses are different durations and/or ness and attention are orchestrated by at least three distinct amplitudes), percent duty-cycles (e.g., between 10-80%, sets of brain stem nuclei that include cholinergic neurons of etc.) and the use of an AC (carrier) frequency (<250 Hz). In the pedunculopontine nucleus (PPN), noradrenergic neurons Some variations, the use of just one or two of these modu of the locus coeruleus (LC), and serotonergic neurons of lation schemes may be sufficient (e.g., using just a DC offset raphe nuclei. Through a cytoarchitectural meshwork of and a percent duty cycle between 10-80%, or just a DC offset interconnected brain stem nuclei in the pons and midbrain, and an AC carrier frequency <250 Hz, or just a percent duty sensory inputs first act upon the brain to engage ascending cycle between 10-80% and an AC carrier frequency of <250 RAS networks, which generate global arousal (“waking”), HZ), while in Some variations, all three may or must be used. alerting, and orienting cues as parsed sensory information Example projects through thalamic pathways onto the cortex for additional processing and integration. More specifically the 0168 As discussed above, described herein are methods local and distal synaptic circuits formed by axons of neu and apparatuses for noninvasive neuromodulation, and more romodulatory RAS networks (including neurons of the LC, US 2017/0182285 A1 Jun. 29, 2017 PPN, RN) gate information flow from the sensory environ cervical afferents significantly Suppressed basal sympathetic ment to the cortex and, in an activity-dependent manner, are tone compared to sham as indicated by functional infrared capable of rapidly triggering neurobehavioral transitions thermography of facial temperatures, significantly lowered across different states of behavioral awareness and con levels of tension and anxiety on the Profile of Mood States sciousness. Depending on their firing rates for example, scale compared to sham, and in response to acute stress neurons of the PPN can differentially mediate REM sleep induction TEN significantly suppressed changes in heart rate states and neurons of the LC can trigger sleep/wake transi variability, galvanic skin conductance, and salivary C.-amy tions. Disrupted activity of ascending RAS networks under lase levels compared to sham. Based on these findings, we lies several neuropsychiatric conditions and disorders, such hypothesized that repeated daily dampening of psychophysi as insomnia, anxiety, depression, post-traumatic stress dis ological and biochemical arousal might improve mood if order (PTSD), and attention deficit hyperactivity disorder used nightly to increase the quality, duration or efficiency of (ADHD). Therefore, a neural interface capable of dynami sleep. Supportive of this hypothesis there are numerous lines cally and electrically modulating RAS networks should be of evidence that Suggest insomnia is a “waking disorder able to provide a chemical-free approach to restoring poor (hyper-arousal) of RAS networks rather than a sleep disor daily function attributable to sleep loss or attention and der per se. Viewed as such, we more specifically hypoth mood disorders. Such an interface would also Support new esized that decreasing neurobehavioral and psychophysi approaches capable of optimizing normal human perfor ological arousal by perturbing trigeminal LC/RAS networks aCC. prior to sleep onset for repetitive nights can enhance the 0171 The trigeminal nerve or the fifth cranial nerve restorative qualities of sleep on mood and mental health. (cranial nerve V) bilaterally innervates the anterior half of Below we describe the results from our findings that dem the head and face including around the top of the scalp, the onstrate TEN of trigeminal afferents significantly improves forehead, around eye orbits, nasal region, lips, jaw, and the sleep quality and mood on weeklong time scales. We specu oral cavity. Three main branches of the trigeminal nerve late noninvasive modulation of the TSNC will provide a (ophthalmic, maxillary, mandibular branches) and their valuable platform approach to restoring and optimizing thousands of Sub-branches transmit sensory information brain function and mental health. (chemical, thermal, mechanical, pain, and proprioceptive) via monosynaptic connections to the trigeminal sensory Results nuclear complex (TSNC). The TSNC itself is an elongated 0.174 Repeated nightly TEN significantly improves wak structure with several functional divisions (for example, the ing mood and reduces weekly stress compared to baseline. primary sensory nucleus and the spinal nucleus) spanning 0.175. In a first experiment (experiment 1), we examined from the cervical spinal cord to the midbrain. The TSNC has the impact of before bed TEN on mood and mental health. been functionally mapped using multimodal trigeminal Volunteers (n=38) completed a week of baseline assess stimulation combined with fMRI and DTI in humans. The ments followed by a week of nightly TEN treatments (20 TSNC also receives some non-trigeminal sensory informa min) self-administered within 30 min of going to bed (FIG. tion from the neck via cervical afferents. In turn the TSNC 18A). Each morning, participants reported their mood using projects incoming sensory information through ascending the Positive and Negative Affectivity Scale (PANAS) and by pathways to multiple brain regions that regulate arousal and rating their degree of waking drowsiness and refreshment coordinate neurobehavioral engagement with the environ (See Methods). Mental health was captured by weekly ment, such as the thalamus, the Superior colliculus, the responses to the Depression, Anxiety and Stress Scale cerebellum, and the inferior olive. Several other electro (DASS). The PANAS and DASS are validated and widely physiological and neuroanatomical studies have provided used scales that capture fluctuations in mood and indicators definitive evidence of functional synaptic connectivity of mental health, respectively. between trigeminal afferents and the PPN and LC. (0176 FIGS. 18A and 18B show experimental designs 0172 Besides its robust functional connectivity to implemented for testing the effects of nightly repeated, ascending RAS networks, a major advantage of the TSNC as self-administered transdermal electrical neuromodulation of a neuromodulation target is that its primary monosynaptic trigeminal and cervical nerve sensory afferents on sleep and inputs can be noninvasively accessed and coupled to using mood. A. The illustrations show that in Experiments 1 and safe and comfortable transdermal neurostimulation 2 volunteers had one week or baseline assessment then approaches. Transcutaneous trigeminal nerve stimulation self-administered transdermal electrical neuromodulation of (TNS) has been shown to be effective for treating neurop trigeminal and cervical nerve afferents or an indistinguish sychiatric conditions like depression, PTSD, generalized able active sham waveform nightly before bed during the anxiety disorder (GAD), ADHD, as well as neurological second week of testing. Several metrics were used to evalu disorders like epilepsy and headache. Interestingly, acute ate morning mood, weekly mental health indicators, and TNS at a frequency of 120 HZ has been demonstrated to sleep quality (see Methods). B. In Experiment 3 we imple induce sleepiness and sedative like effects in healthy adults mented a double-blinded crossover design where subjects while 2.5 Hz stimulation frequency did not. The observa self-administered an active sham treatment or real TEN tions made by Piquet and colleagues (2011) suggest that (3-11 kHz, 5-7 mA average current amplitude) treatment TNS may provide some benefit for some sleep disturbances nightly before bed for one week and then either real TEN or and insomnia. low-frequency TEN (TEN: 0.50-0.75 kHz, <5 mA average 0173 We recently described an approach to transdermal current amplitude). Again an array of metrics were used to electrical neuromodulation of trigeminal and cervical nerve determine the impact of sham treatment, TEN-treatment, afferents that Suppressed physiological and biochemical and TEN-treatment on sleep quality and mood. signatures of sympathetic tone and noradrenergic activity. (0177 Relative to baseline, TEN treatment improved We showed that pulsed (7-11 kHz) TEN of trigeminal and positive affect by 9% (t(35)–3.427, p=0.002) and reduced US 2017/0182285 A1 Jun. 29, 2017 20 negative affect by 10% (t(35)=-3.147, p=0.003) according 10.86% (t(17)=4.859, p<0.001), but failed to alter negative to the PANAS (FIG. 20). Compared to baseline, indicators affect (t(17)=-0.237, p=0.815; FIG. 21). Further, during the of mental health recorded by the DASS (FIG. 20) revealed TEN treatment period, participants felt 18.95% less drowsy that TEN significantly reduced stress (t(30)=-3.982, p<0. (t(17)=-4.859, p<0.001) and 13.33% more refreshed upon 001) and anxiety (t(29)=-2.177, p=0.038) by 41.3% and waking (t(17)=4.908, p<0.001; FIG. 21). During the sham 30% respectively, whereas depression scores remained treatment period, there were no changes from baseline in unchanged (p=0.469: FIG. 19A). Further, during the TEN affectivity (PANAS) or waking arousal (p>0.200; FIG. 21). treatment period, participants felt 27% less drowsy (t(36) To examine the impact of TEN on stress, anxiety, and =-4.859, p<0.001) and 17.92% more refreshed (t(36)–4. depression symptoms we conducted a series of one-way 908, p<0.001) upon waking compared to the baseline period analyses of variance (ANOVA) comparing DASS score (FIGS. 19B and 20). These data indicate that nightly TEN changes from baseline for the TEN- and sham-treatment treatments self-administered prior to bed improve morning groups. The TEN-treatment group reported a 59.53% greater mood, awakening affect and arousal, and reduces stress and reduction in stress (F(1, 25)=4.907 p=0.036) and 30.68% anxiety on weeklong time scales. The enhanced morning greater reduction in anxiety (F(1, 25)=4.392, p=0.047) com affectivity and arousal combined with the mechanisms of pared to the sham-treatment group (FIG. 22A). The change action posited by Tyler et al (2015) suggest TEN may in depression symptoms were similar across the two groups enhance sleep quality when used prior to bedtime. (F(1,25)=0.091, p=0.766). These results suggest that relative 0.178 FIGS. 19A and 19B illustrate acute transdermal to baseline, TEN-treatment prior to bed improves mood and neuromodulation of trigeminal and cervical afferents prior to symptoms of mental health whereas sham treatments do not. sleep onset significantly reduces stress and anxiety. Data 0183 Beyond improvements in mood, we observed that obtained from Experiment 1 are shown as a series of TEN produced favorable changes in sleep quality and sleep histograms. A. The histograms illustrate mean scores patterns. Compared to baseline, TEN treatment resulted in a obtained from the Depression. Anxiety, and Stress Scale 36.68% reduction in self-reported middle of the night awak (DASS) and show a significant reduction in stress and enings (t(17)=-3.531, p=0.003) and an improvement in anxiety following one week of nightly self-administered sleep quality (t(17)=2.155, p=0.046; FIG. 21). There were TEN compared to the baseline week. B. The histograms no differences in middle of night awakenings and sleep illustrate mean scores obtained on the daily-administered quality between the baseline period and sham-treatment Awakening Drowsiness and Refreshment Scale (see Meth period (p-0.145). Self-reported sleep improvements mir ods). These data show that nightly TEN significantly rored sleep cycle changes captured by actigraphy, such that increased the feelings associated with refreshment and sig compared to baseline, the TEN-treatment period resulted in nificantly decreased feelings associated with drowsiness in significantly increased sleep time (t(14)=2.255, p=0.041: the mornings compared to baseline. An asterisk indicates a FIG. 22B) and significantly decreased percent time awake p<0.05. (t(14)=-2.329, p=0.035). 0179 Repeated nightly TEN significantly modulates 0.184 FIGS. 22A and 22B show self-administered autonomic activity, increases sleep quality, and improves trigeminal and cervical afferent neuromodulation prior to indicators of mental health. sleep onset significantly improves mood and increases sleep 0180 Based on our observations in experiment 1 and our time. Data from Experiment 2 are shown as histograms of previously described observations, we hypothesized that the percent change in depression, stress, and anxiety as significantly elevated morning mood and rejuvenation is the indicated by the DASS, as well as actigraphy-recorded sleep result of improved sleep quality via TEN dampening sym time for TEN and active sham treatment groups compared to pathetic nervous system and LC activity prior to bedtime baseline. An asterisk indicates a p<0.05. (FIGS. 20, 19A and 19B). Therefore in a second experiment 0185. There were no significant differences in sleep time (experiment 2) we implemented a mixed design (FIG. 18A) or percent awake time recorded by actigraphy between the in a different group of participants to determine the repeat sham-treatment period and baseline (all p-values-0.466). ability of TEN effects on mood observed in Experiment 1, as Sleep changes due to TEN uses were also reflected by HRV well as to determine the impact of TEN treatment (20 min outcomes. Compared to the baseline period, during the nightly for 7 nights) on sleep quality and sleep patterns, TEN-treatment period participants demonstrated a 4.04% which are known to be regulated by the autonomic nervous decrease in the relative power of the very low frequency system, LC and alterations in norepinephrine. (pVLF) HRV band (t(14)=-2.469, p=0.027: FIG. 23) and 0181. In experiment 2, participants completed one week 9.04% increase in the relative power of the high frequency of baseline followed by one week of sham (n=17) or TEN (pHF) HRV band (t(14)=2.160, p=0.049), whereas no (n=18) treatments. Each morning, participants completed changes in other HRV metrics differed between sham treat the PANAS, rated waking drowsiness and refreshment, ments and baseline (all p-values 0.135). reported number of awakenings, and rated overall sleep 0186 TEN differentially impacts sleep patterns in a man quality, and at the end of each week, they completed the ner dependent on neuromodulation waveform pulse fre DASS. Throughout the experiment, to capture objective quency. sleep metrics, participants wore a Philips Activatch2, a 0187. In a third experiment (experiment 3) we imple clinically validated actigraph that reliably tracks sleep wake/ mented a randomized double-blinded crossover design (FIG. cycles (see Methods). Participants also wore a Polar H7 18B) in a different set of participants (n=25) to determine if heart rate monitor to sleep each night to record electrocar a frequency-shift in the neuromodulation waveform param diogram data (ECG), from which heart rate (HR) and heart eters used would produce the same impact on sleep quality rate variability (HRV) metrics were derived. and mood as we observed in Experiments 1 and 2. We 0182 Building on the findings from experiment 1, rela specifically compared the TEN waveform (3-11 kHz pulse tive to baseline, TEN treatment improved positive affect by frequency, 5-7 mA average current amplitude) used in US 2017/0182285 A1 Jun. 29, 2017 Experiments 1 and 2 to an active sham treatment (n=10) and increased the peak LF (t(14)=3.873, p=0.002: FIG.24B). All a lower frequency TEN treatment (TEN: 0.5-0.75 kHz, <5 other HRV metrics remained stable across the two condi mA average current amplitude, n=12). In pilot experiments tions (all p-values-0.289). we found TEN, compared to higher frequency TEN, 0191 FIGS. 24A and 24B shows actigraphy shows that produced more robust effects on subjective reports of relax TEN significantly improves sleep quality. Results from ation and physiological indicators of stress suggesting a Experiment 3 showing differences in actigraphy metrics and more pronounced dampening of sympathetic nervous sys HRV are shown for TEN and Control groups as histograms. tem activity (FIG. 27). We therefore hypothesized that A, The mean number of nightly wakeups, time awake after TEN might produce stronger effects on sleep. TEN treat sleep onset (WASO), and percent time awake recorded using ments were grouped as TEN and Control treatments, such actigraphy illustrate that TEN exerted a significant improve that TEN and active sham served as Control treatment ment in sleep quality compared to active sham Controls. B. groups while TEN, and TEN comprised the TEN treatment The mean R-R interval and root mean square of the standard group as specified. Each treatment period lasted one week deviation (RMSDD) for HRV, as well as the relative power beginning on consecutive Fridays, with assessments at simi of the low-frequency (pLF) band of HRV spectra are shown lar times for each week for each participant. At each of three for TEN and active sham Control treatments. An asterisk office visits participants completed the Pittsburgh Sleep indicates a p<0.05. Quality Index (PSQI) and the DASS. Each morning during 0.192 In the subset of participants that received the the treatment weeks participants completed the Karolinska TEN, and TEN treatments, we found that TEN, improved Sleep Diary (KSD), a validated measure used to capture sleep quality and mood outcomes beyond the effects evi information about prior nights sleep (see Methods). As in denced by TEN in Experiments 1 and 2. Compared to TEN, Experiment 2, participants wore the Philips Activatch2 TEN, reduced self-reported activatch-recorded number of throughout the testing period and a Polar H7 heart rate wake-ups (t(9)-2.796, p=0.021), wake time after sleep onset monitor throughout each night. (t(9)=2.808, p=0.020), and percent of time awake after sleep 0188 FIG. 23 shows nightly TEN influences autonomic onset (t(9)=3.006, p=0.015; FIG. 25A). In addition, we nervous system activity overnight indicated by changes observed that TEN produced a 32.17% greater reduction heart rate variability. in anxiety from baseline than TEN (t(8)=-2.382, p=0.044), 0189 Data from Experiment 2 are shown as histograms but there were no changes in symptoms of stress (t(8)=0. illustrating the relative powers of the very low-frequency 928, p=0.381) or depression (t(8)=-0.769, p=0.467: FIG. (pVLF) and high-frequency (pHF) bands of heart rate vari 25B). ability (HRV) spectra recorded overnight for one week per 0193 We also examined the effect of TENs as described treatment condition. The histograms illustrate TEN- and herein on stress and sleep biomarkers, cortisol and salivary active sham-treatment compared to baseline. An asterisk C.-amylase. The protein enzyme C.-amylase is widely recog indicates a p<0.05. nized as a biochemical marker of sympathetic nervous (0190. We first found that TEN produced the same effects system activity and sympathoadrenal medullary (SAM) axis on sleep quality and mood compared to control as we activation. More specifically, salivary levels of C-amylase observed in Experiments 1 and 2 (data not shown). We next directly correlate with plasma norepinephrine (NE) concen examined the changes that TEN produced on stress, anxiety trations following the induction of acute stress. It has been and depression (DASS) compared to control. We observed shown in animals ranging from flies to humans that C.-amy that TEN produced a 36.13% greater reduction in anxiety lase is a reporter of sleep drive as it increases with accu than sham Control (t(20)=-3.406, p=0.003). There were no mulating sleep debt. To assess the impact of TEN on SAM perceptible changes in symptoms of stress (t(20)=0.670, axis activity as it relates to sleep/wake cycles and daily p=0.510) or depression (t(20)=-1.418, p=0.172) between stress, we examined fluctuations in salivary C.-amylase the two conditions. Further, across the two conditions (TEN (SAA) and cortisol levels upon waking, in the evening and VS active sham Control), there were no changes in self before bed the final 3 days in each week of the TEN vs reported sleep patterns, including sleep quality, time till TEN, treatments during Experiment 3 (N=8, FIG. 18B). sleep onset, number of awakenings, and sleep duration. We found that the mean waking levels of SAA were signifi However, the objective actigraph measurements captured cantly lower in the TEN, group (TEN-133.78+85.83 changes in sleep/wake cycles such that TEN treatment U/mL) compared to the TEN group (TEN=217.33+134.23 resulted in 12.12% less wake time (t(19)=-2.381, p=0.028), U/mL); t(5)=-3.524, p=0.017: FIG. 25C). There were no 9.50% fewer middle of the night wake-ups (t(19)=-3.781, differences between TEN treatments in afternoon and bed p=0.001), and a 9.13% reduction in the percent of wake time time SAA (p-0.5). These data indicate that compared to (t(19)=-2.241, p=0.037) compared to sham Control (FIG. TEN, TEN, produced changes reflecting lower levels of the 24A). Despite stability of self-reported sleep pattern data sleep debt and stress upon awakening. between TEN and control treatments, the data obtained (0194 FIGS. 25A-25C shows low-frequency TEN using actigraphy reliably Suggest clear improvements in the improves the efficacy of trigeminal and cervical afferent sleep/wake cycle when using TEN compared to sham Con modulation for improving sleep quality. Results from trol. We also observed effects reflecting changes in auto Experiment 3 showing differences in actigraphy metrics and nomic balance as indicated by significant differences in HR HRV are shown for TEN low-frequency (TEN) and the and HRV between TEN and sham control treatment. Rela Control TEN groups as histograms. A. The mean number of tive to active sham Control, TEN decreased the R-R (t(14) nightly wakeups, time awake after sleep onset (WASO), and =-2.372, p=0.033), marginally increased HR (t(14)=1.927, percent time awake recorded using actigraphy illustrate that p=0.075), decreased RMSSD (t(14)=-4.144, p=0.050), mar TEN exerted a significant improvement in sleep quality ginally increased the relative power of the LF band of the compared to TEN Controls. B. Histograms illustrating data HRV spectrum (t(14)=1.878, p=0.081), and significantly obtained from the DASS across treatment groups are illus US 2017/0182285 A1 Jun. 29, 2017 22 trated. C. The histograms illustrate the results obtained from have explored the potential of utilizing peripheral nerve biochemical quantification of waking cortisol concentrations pathways to tap into brain function. Specifically, we have and C.-amylase activity in Saliva across treatment conditions. been focused on developing novel approaches to trigeminal An asterisk indicates a p<0.05. and cervical nerve modulation (FIG. 26). Each of these (0195 While SAA reflects NE levels and acute SAM axis nerves, as well as other peripheral and cranial nerves offer activity, cortisol is another biomarker, which is under com unique (and overlapping) structural inroads to deep-brain plex hormonal control of the hypothalamic-pituitary-adrenal nuclei responsible for regulating psychophysiological (HPA) axis. Elevated salivary cortisol levels prior to bedtime arousal, attention, neurobehavioral responses, and physi are a predictor of insomnia often related to hyper-arousal, ological performance through ascending and descending metabolic dysfunction and other mood disorders, but its circuitry. Based on the evidence we have accumulated from causal importance in poor sleep remains unclear. Reflective observations in thousands of participants we have strong of adrenal fatigue however, insomnia and poor sleep have beliefs that modulation of trigeminal and cervical nerve been shown to significantly dampen the cortisol awakening pathways can offer a chemical-free way of regulating auto response (CAR), which is a specific phase of the diurnal nomic arousal to improve and optimize mental health and cortisol rhythm. We observed no differences in afternoon or human performance. With continued research and develop bedtime cortisol levels across the treatment groups (all ment, there will be some near-term opportunities to offer p-values-0.5). We did find that when participants used treatments for some of the most broadly debilitating mental TEN, prior to bed they exhibited a stronger CAR, a health disorders facing the modern world using transdermal significant 26.3% higher salivary cortisol concentration trigeminal and cervical nerve modulation. Attention must be compared to when they used TEN (TEN, waking cortisol paid to what behavioral paradigms and treatment regimes concentration=1.44+0.41 ug/dL, TEN waking cortisol con best Support implementation for a specific indication, but the centration=1.14+0.322 ug/dL; t(5)=2.850, p=0.036; FIG. core neurobiological outcomes strongly suggest that treat 25C). These particular observations indicate that TEN ment of daily stress, anxiety, and comorbid sleep distur produced more robust effects than TEN on the restorative bances would be efficient and practical using TEN of the features of sleep by significantly improving the quality of trigeminal and cervical nerves. Likewise, we believe that the sleep/wake cycle. there will be an opportunity to modulate certain cognitive 0196. The ascending reticular activating system (RAS) processes using the same or similar bottom-up modulation represents a collection of brain stem nuclei and neuromodu approaches via cranial and cervical nerves to induce higher latory projections, such as noradrenergic radiations from the order plasticity in cortical and Subcortical brain regions. For locus coeruleus (LC) and cholinergic axons from the pedun example, pairing of bottom-up NE and ACh modulation culopontine nucleus (PPN) to higher brain circuits including using TEN of trigeminal and cervical nerves with top-down the thalamus, hippocampus, amygdala, and vast regions of cortical processing that occurs during skill training could cortex. These ascending networks are known to provide prove to be a powerful method of accelerating learning or strong neurophysiological control of consciousness, sleep/ acquiring expert proficiency. Future studies using peripheral wake cycles, attention, alertness, other aspects of cognition nerve modulation to enhance plasticity will directly address including behavioral flexibility. Starting from the periphery, this possibility. primary trigeminal and cervical afferent inputs to the 0199 FIG. 26 illustrates interfacing with the ascending trigeminal sensory nuclear complex (TSNC) from sensory reticular activating system through the trigeminal sensory and proprioceptive fibers located on the sides and front of nuclear complex. The illustration depicts the approach to the face, oral cavity, and anterior and posterior cervical modulating trigeminal and cervical nerve afferents, which regions of the neck provide robust disynaptic and polysyn provide primary sensory inputs to the trigeminal sensory aptic regulation of LC and PPN neuron activity. Demon nuclear complex (TSNC). Similar to previously described strating functional effects on ascending RAS circuitry, we methods Volunteers modulated their trigeminal and cervical have shown that high-frequency (7-11 kHz) transdermal nerves using a wearable transdermal neurostimulator for 20 electrical neuromodulation (TEN) of trigeminal and cervical min each night prior to sleep onset. The TSNC coordinates afferents can rapidly suppress psycho- and neuro-physi motor behaviors by sending projections through a series of ological arousal as indicated by a significant dampening of ascending and descending pathways communicating with sympathetic nervous system activity and Suppression of various targets (greyed out). An emphasis is placed however noradrenergic and sympathomedulary (SAM) axis biomark on the ascending reticular activating system (RAS), which ers in response to an acute stress challenge. Given this includes the pedunculopontine nucleus (PPN), the locus context, in the present report we tested the hypothesis that coeruleus (LC), and raphe nuclei (RN). These pathways self-administered, nightly TEN prior to bedtime would transmit neuromodulatory acetylcholine (ACh), norepineph improve sleep quality and mood. Our conclusions based on rine (NE), and serotonin (5-HT) signals to higher-order brain data and observations gathered from the three independent structures to gate attention and regulate awareness, arousal, experiments described in this study are that nightly TEN and sleep. As discussed in the text, the TSNC and its inputs does cause a significant improvement in the quality of sleep have been shown provide functional connections to the LC and mood across weeklong timescales. and PPN and thereby provides a path for the ability of (0197) Thus, it may be possible to interface with the trigeminal and cervical nerve modulation to influence sleep trigeminal sensory nuclear complex to functionally regulate as described in the present study. These pathways also open ascending neuromodulatory systems, using the apparatuses the possibility of regulating attention, cognition, and senso and methods described herein. rimotor behaviors using trigeminal and cervical nerve modu 0198 There is a growing need for neural interfaces lation paired with training or other approaches. capable of modulating brain function and behavior in the (0200. The use of TEN to modulate neural activity is least invasive manner possible. For the past several years we supported by a long history of safety obtained over four US 2017/0182285 A1 Jun. 29, 2017 decades. There are numerous methods and devices intended istered on mornings after real treatments compared to sham for modulating peripheral nerve structures using transcuta treatments or baseline nights (FIGS. 20 and 21). In Experi neous delivery of voltage/current waveforms from elec ments 2 and 3 we more closely inspected how TEN affected trodes applied to various locations on the body. These sleep quality using actigraphy. We found that compared to devices such as transcutaneous electrical nerve stimulation active sham treatment, TEN significantly increased the (TENS), powered muscle stimulation (PMS), electrical amount of sleep time and significantly reduced the time muscle stimulation (EMS) and others have amassed such a awake after sleep onset (WASO; FIGS. 22A, 22B, 24A and high degree of physical safety that they have been moved to 24B). As discussed in more detail below, a low-frequency an over-the-counter product rather than a medical device (0.5-0.75 kHz) shifted TEN waveform (TEN) caused a requiring a prescription depending on the intended use and significant improvement in sleep quality (FIGS. 25A-25C) design characteristics. For example, legally marketed elec compared to the standard high-frequency TEN waveform we trical nerve stimulation devices are already commercially used that has been previously described (see Transdermal available and have output levels far greater than the ones we neuromodulation waveform considerations below). We sus implemented here. These devices intended for over-the pect that the reduction in stress and anxiety, as well as the counter cosmetic applications of TENS target similar ana improved positive affect on weeklong timescales was a tomical regions and nerve targets such as the trigeminal secondary outcome of the primary effect that TEN of nerve. One example is an over-the-counter cosmetic TENS trigeminal and cervical nerves had on improving sleep device (Bio-medical Research Face), which is designed to quality in a natural or home environment. Future studies target the trigeminal nerve and provide neuromuscular elec examining how TEN of trigeminal and cervical nerves trical stimulation (NMES) to encourage facial rejuvenation affects sleep structure using polysomnography will inform for aesthetic purposes. A recent study examined the safety the design of enhanced approaches to improving general and efficacy of this device at a peak current intensity (35 sleep quality, as well as to optimizing the time spent asleep mA) that was nearly twice the one used in our study when or resting. Such approaches will have a significant impact on used five days per week for 20 minutes each day for 12 our ability to improve daily mental health and restore or weeks. There were no significant adverse events in this study enhance human performance. and the only reported side effects were minor skin redness 0203 There is known to be a tight coupling of central following stimulation, which disappeared with 10-20 min nervous system sleep regulation and the activity of the utes following use. Another device, which modulates Supra autonomic nervous system where heart-rate control under orbital branches of the trigeminal nerve to treat headache has different stages of sleep in healthy subjects is apparent. also demonstrated a high safety threshold when used daily During REM sleep heart rate is known to increase. The for multiple weeks. Other reports using trigeminal nerve relative power of the VLF and HF components of the HRV stimulation for the treatment of epilepsy, depression, and spectra have been shown to be dominant during REM sleep other disorders have likewise shown a high degree of safety. and deep sleep respectively. There is a marked decrease in Although there is a high degree of confidence in the safety the relative power of the VLF and LF HRV spectral bands of trigeminal nerve modulation, caution is always warranted during deep sleep and an increase during REM sleep com when delivering electrical currents to the human body and pared to HF. Since we captured data related to overall sleep we advise investigators to learn and implement safe prac quality rather than sleep structure, we cannot draw strong tices using qualified devices. conclusions related to the effects of TEN on HRV as it 0201 The effects of nightly self-administered TEN on relates to the stages of sleep. We do conclude however that mood and sleep quality in a natural environment given the specific changes observed in the HRV power 0202 We also examined the effects of trigeminal and spectra, compared to controls both TEN and TEN produce cervical TEN on sleep quality and mood in healthy volun significant alterations to sleep/wake cycling throughout the teers having mild to moderate sleep disturbances (PSQD5). night. This is somewhat expected given anatomical connec Various tools and sensors were deployed in real world tivity and the functional ability of trigeminal nerve and environments such that data could be acquired from within TSNC activity to modulate the activity of the PPN and LC, the homes of volunteers under baseline conditions or fol which are both known to be central regulators of sleep lowing self-administered TEN or sham treatments in a patterns including REM sleep and waking behaviors. More double-blinded fashion depending on the experimental pro detailed investigations examining sleep structure with addi tocol (see Methods). Through a cloud computing architec tional polysomnography measures will be required to pro ture, we were able to remotely monitor treatment sessions in vide further insight into how TEN affects the specific stages order to ensure compliance throughout the study (FIG. 26). of sleep. We found that one-week of nightly self-administered TEN of 0204 TEN methods utilizing pulse frequencies in the trigeminal and cervical afferents (20 min/night) significantly 2-20 kHZ range may be used. Stimulating neuronal activity improved mood and sleep quality in home environments. In in the LC and PPN at specific frequencies can trigger state Experiment 1, we found that one-week of nightly TEN (20 changes in sleep/wake cycles. Therefore, we questioned min/night) significantly reduced stress and anxiety com whether altering the pulse parameters of high-frequency pared to baseline DASS scores (FIGS. 19A and 19B). This TEN waveforms would produce different effects on sleep improvement in mental health indicators was accompanied quality or mood. We specifically chose to lower the fre by a significant reduction in morning drowsiness and sig quency of the TEN waveforms by about an order of mag nificant increase in morning refreshment following TEN of nitude Such that we maintained a neuromodulation fre trigeminal and cervical afferents compared to baseline morn quency above 0.12 kHz. We did this because it had ings (FIG. 20 and FIGS. 19A and 19B). TEN also caused a previously been shown that transcutaneous modulation of significant increase in positive affect and a significant supraorbital branches of trigeminal nerve afferents at 0.12 decrease in negative affect according to the PANAS admin kHz induces sedative-like states in humans whereas 0.025 US 2017/0182285 A1 Jun. 29, 2017 24 kHz did not. This observation indicated to us that frequen face (for example, as has been proposed to be a mechanism cies higher than 0.12 kHz could be even more effective at for transcranial direct current stimulation or tDCS). We inducing deep states of relaxation and perhaps, alter sleep cannot imagine a situation where the ascending endogenous quality. Based therefore on our previous observations and neuromodulatory pathways carrying sensory information via those made by Piquet and colleagues (2011) we investigated cranial nerves do not contribute a significant degree to the the effects of low-frequency TEN (TEN: 0.5-0.75 kHz) observations made using toCS and some other tS methods. waveforms that utilized a base neuromodulation frequency Our studies as well as the studies of many others on <7 kHz and >0.12 kHz on sleep quality and mood to electrical neuromodulation or stimulation of cranial nerves compare and contrast them to those obtained with high indicate that investigators applying electrical currents (DC, frequency TEN waveforms. We found that TEN, caused a AC, or other) to the skin of the head should consider the significant reduction in the number of nightly wake-ups, a impact of bottom-up pathways as illustrated in FIG. 26. The significant reduction in WASO, and a significant reduction in possible involvement of bottom-up pathways has been the percentage of time spent awake during the night com almost entirely overlooked by the scientific community that pared to high-frequency TEN, which itself was significantly implements tS. Modulation of afferent pathways via cra effective at improving sleep quality compared to sham and nial nerves, cervical spinal nerves, and other peripheral baseline observations (FIGS. 22A, 22B, 24A, 24B, and systems can explain many if not most of the outcomes 25A-25C). Interestingly, the effects of TEN, on sleep were observed in Studies implementing tS approaches. A simple observed at lower average current amplitudes than those inspection of neuroanatomy illustrates that cranial nerves used for standard TEN treatments (see Methods). We also carrying afferent signals to the brain stem and RAS struc found that TEN, produced a significant reduction in DASS tures cannot be avoided when placing electrodes on the anxiety scores compared to high-frequency TEN (FIGS. head. Further, electrical stimulation of the dura has been 25A-25C). There was additional biochemical evidence that shown to activate neurons in the TSNC, which then project TEN, was significantly better at improving restorative to numerous ascending neuromodulatory nuclei. sleep than high-frequency TEN. 0207 Highlighting mechanistic inconsistencies regard 0205 The protein enzyme C.-amylase is as a biochemical ing tS approaches, explanations underlying the top-down marker of noradrenergic activity and sympathoadrenal med modulation of PFC function using t|DCS have led to a ullary (SAM) axis activation. Further, it has been shown that high-degree of variability and uncertainty regarding the C.-amylase is a reporter of sleep drive as it increases with robustness of behavioral, neurophysiological, and cognitive accumulating sleep debt. Compared to high-frequency TEN outcomes. Modulation of the LC activity and noradrenergic treatments, the waking levels of salivary C.-amylase (SAA) signaling, which can be achieved via cranial nerve modu were significantly lower following treatment with TEN, lation as previously discussed, has been shown to effect: waveforms prior to bed (FIG. 25C). Cortisol is another stress vigilance and Sustained attention, alertness and arousal, biomarker, which is under the complex control of the working memory and decision making, the amplitude of hypothalamic-pituitary-adrenal (HPA) axis. Insomnia and motor evoked potentials, brain oscillations, sensory gating sleep debt can lead to adrenal fatigue and significantly and processing, and others. These same outcomes have also dampen the cortisol awakening response (CAR), which been claimed via direct modulation of cortical circuits by specific phase of the diurnal cortisol rhythm. We did find that numerous tS investigations. when participants used TEN, prior to bed they exhibited a 0208. Due to spatial and temporal resolution limits it significantly stronger CAR compared to when they used seems that fMRI, EEG, and other neurophysiological or TEN (FIG. 25C). These particular observations indicate that psychological measurements of slowly (hundreds of milli TEN, produced more robust effects than TEN on the seconds to seconds) evolving biological processes would restorative features of sleep by significantly improving the have difficulty resolving direct cortical effects versus those quality of the sleep/wake cycle, as well as altering morning delayed by transmission at only a couple synapses, which levels of stress biomarkers and sleep debt. In other words, happen to mediate some of the most powerful endogenous TEN produces a positive impact on mood and sleep quality neuromodulatory actions upon the human brain. For in a frequency-dependent manner. These observations illus example, transcranial alternating current stimulation (tACS) trate the need for systematic research exploring how discrete of the prefrontal cortex was recently shown to exert an effect waveform parameters. Such as pulse frequency affect physi on dreaming. It was reported that 25-40 Hz tACS delivered ological and biochemical responses in humans. Studies in to the prefrontal cortex triggered lucid dreaming and humans can be Supported by Studies in other animal models increased conscious self-awareness during dreaming. How where understanding circuit level input-output relationships ever trigeminal nerve entrainment of PPN neurons, which as by conducting electrophysiological recordings from differ previously mentioned are known to regulate REM sleep at ent brain regions is more feasible. those frequencies, could also explain the effects of tACS on 0206 Projections from the TSNC to brain structures like dream (sleep) and conscious self-awareness. Thus to chal the LC and PPN provide a foundation for the formulation of lenge the dogma, we urge the neuromodulation community alternative hypotheses that oppose conventional views on to explore cranial nerve modulation as an alternative hypoth top-down mechanisms of action underlying “transcranial esis capable of mechanistically explaining many of the electrical stimulation (tPS) approaches. We believe that outcomes observed in response to conventional tS. noninvasive RAS modulation via the TSNC and other 0209. The trigeminal nerves may provide a unique oppor ascending cranial/cervical neural (sensory) pathways offer a tunity to tap deep into human brain function and may be Solid framework for explaining many of the observations modulated as described herein. The embedded connectivity made using the passage of low-intensity direct currents (s.5 of the TSNC with RAS structures like the LC and PPN make mA peak) across the skin and presumably the scalp, dura, trigeminal nerves a high priority peripheral nerve target and cerebrospinal fluid before influencing the cortical sur when using neuromodulation to regulate stress, attention, US 2017/0182285 A1 Jun. 29, 2017 arousal, and sleep/wake cycles (FIG. 26). TEN of trigeminal from 19 to 59 (mean age=27.66+9.9) and 62.1% were white, and cervical nerves can significantly dampen sympathetic 17.2% were Asian, 17.2% were Black and 3.4% were nervous system activity in response to acute stress. Hispanic. Repeated, nightly TEN significantly improves sleep quality and significantly reduces stress and anxiety over the course 0214) Experiment 3 was designed to directly compare the of a week in healthy Volunteers. Transcutaneous trigeminal impact of bedtime TEN treatments to Sham treatments neurostimulation may be effective at treating drug-resistant (active or inactive) on sleep patterns and sleep quality. epilepsy and depression. Trigeminal neurostimulation may Experiment 3 employed the same metrics as Experiment 2, have therapeutic value in managing the symptoms of PTSD, with the addition of administration of the DASS during the generalized anxiety disorder, and ADHD. Peripheral nerves initial training visit and the PSQI at each visit. In addition, may induce brain plasticity, and may regulate brain function a subset of male participants (N=7) were randomly selected and behavior through peripheral nerve modulation. Trigemi to provide waking, afternoon and before bed saliva samples nal and cervical nerve modulation of ascending RAS circuits during the 3 final days of each treatment week. The enrolled may be useful for optimizing human performance by regu sample comprised 27 participants, 2 of which were removed lating states of consciousness, such as sleep/wake cycles, for failing to comply with study procedures or failing to neuro- and psychophysiological arousal, and attention or report for scheduled appointments. Ninety-three percent of Vigilance. participants were male, their average age was 32 years old 0210 Methods (SD+5.29) and 79% were Caucasian, 11% were Black, 7% were Asian and 4% were Hispanic. As mentioned above, all 0211 All experimental procedures were conducted on participants reported active sleep disturbance with PSQI human Volunteers using protocols approved by an indepen scores ranging from 5 to 15 (mean=9.56-2.55) and 50% of dent Institutional Review Board (Solutions IRB, Little the sample had a score of 9 or below. In addition, partici Rock, Ark.). All subjects provided written informed consent pants reported trouble falling asleep or trouble staying prior to experimentation. Exclusion criteria were as follows: asleep at least once or twice a week, with more than 50% of diagnosed sleep disorder, actively medicated for sleep dif participants on average taking more than 30 minutes to fall ficulties, neurological or psychiatric disorder, cranial or asleep each night (mean=34.63+24.02). facial metal plate or screw implants, severe face or head trauma, recent concussion or brain injury, recently hospital 0215. The transdermal electrical neuromodulation (TEN) ized for Surgery/illness, high blood pressure, heart disease, waveform used in these experiments was a pulse-modulated diabetes, pregnant, acute eczema on the scalp, and uncor (3-11 kHz), biphasic electrical current producing average rectable vision or hearing. In Experiment 3, we examined amplitudes of 5-7 mA for 20 min as similarly described in participants with moderate sleep impairment, screened as above. The sham waveform was an active stimulation con presenting with a score of 5 or greater on the Pittsburgh trol, in which the waveform parameters outlined above were Sleep Quality Index. A subset of these participants was active for only the first and last 30 secs of the 20 min selected to provide Saliva samples for biometric assays for treatment, providing a significantly lower dosage of the TEN which several additional exclusion criteria applied: nicotine treatment and offering skin sensations that mimicked real use, recreational drug use, and dental work during the treatment. Participants were not able to distinguish between experimental period. Further, to minimize experimental real TEN and sham waveforms. In a subset of participants in complexity due to health and due to female hormone fluc Experiment 3, the real TEN waveform described above was tuations, which impact the biometric markers being assayed, compared to a lower-frequency TEN waveform (TEN: age range was restricted to 20 to 40 years old and males were pulse frequency 0.50-0.75 kHz, <5 mA average amplitude), oversampled. which in lab tests produced more pronounced changes on autonomic nervous system balance (FIG. 27). During both 0212 Experiment 1 was designed to examine the impact the real TEN and sham stimulus protocols, subjects were of TEN prior to bedtime on acute and long-term mood, instructed to adjust the current output of a wearable TEN assessed each morning with the Positive and Negative device (Thync, Inc., Los Gatos, Calif.) using an iPod touch Affectivity Scale (PANAS) and ratings of drowsiness and connected to the device over a Bluetooth low energy net refreshment, and at the end of each week with the Depres work such that it was comfortable. TEN and sham wave sion, Anxiety and Stress Scale (DASS). Participants com forms were delivered to the right temple (10/20 site F8) and pleted a weeklong baseline assessment period followed by a base of the neck (5 cm below the inion) using custom weeklong TEN-treatment period. We enrolled 43 partici designed electrodes comprising a hydrogel material and a pants, 5 of which were withdrawn for failing to comply with conductive Ag/AgCl film secured to the wearable TEN study procedures. Twenty-one participants were men, 17 device. The anterior electrode positioned over F8 was a 4.9 were women, their ages ranged from 20 to 62 (mean cm oval having a major axis of 2.75 cm and a minor axis age=29.68+10.88 years), and 67.6% were white, 23.5% of 2.25 cm while the posterior electrode was a 12.5 cm were Asian, 2.9% were Black and 5.9% were Hispanic. rectangle with a length of 5 cm and a height of 2.5 cm. The 0213 Experiment 2 was designed to examine the impact average current density was <2 mA/cm at all times to keep of before bed TEN treatments on sleep patterns and sleep in accordance with general safety practices to prevent any quality, using actigraphy, heart rate monitoring, self-re damage to the skin. Across all experiments, participants ported number of wake-ups, ratings of sleep quality and the were trained to use the TEN device on their first visit and same mood assessment administration as Experiment 1. We were instructed to use within 30 min prior to bed. In enrolled 42 participants, 6 of whom withdrew due to sched Experiments 2 and 3, Subjects were assigned to experimental uling conflicts and time commitments and 1 that was conditions using a randomization method or a counterbal removed for failing to comply with study procedures. Of ancing approach, and Subjects and researchers were always these participants, 62.1% were female; their ages ranged kept blind to experimental conditions. US 2017/0182285 A1 Jun. 29, 2017 26 0216 We utilized several scales and schedules to evalu exported daily to secure servers. We had previously con ate the impact of TEN on mood and sleep quality. The firmed that HRV Logger recorded data accurately using self-reported scales used in the present study are described independent HRV analyses conducted with Kubios and below. The Awakening Drowsiness and Refreshment scale Matlab. We computed an average nightly HR, R-R interval, was a 5-item self-report measure that is administered in the standard deviation of the normal-to-normal heartbeat mornings, within a half hour of waking, to assess feelings of (SDNN), and root mean square of the standard deviation awakening drowsiness (tired and lethargic) and refreshment (RMSSD). Nightly R-R data were transformed into fre (refreshed, alert and clear-headed). Items were rated on a quency domain data to examine the relative power of the 1—low to 10 high scale. Across baseline and TEN treat very low-frequency (pVLF; 0.0033-0.04 Hz), low-fre ment periods for Experiments 1 and 2 internal consistencies quency (pLF; 0.04-0.15 Hz) and high-frequency (pHF: ranged from 0.72 to 0.83 for drowsiness and 0.72 to 0.89 for 0.15-0.4 Hz) bands of the HRV spectra, including peak low refreshed. The Positive Affect and Negative Affect Schedule frequency (pkLF), peak high frequency (pkHF) and the (PANAS) is a clinically validated scale that comprises two LF/HF ratio. 10-item scales: positive affectivity and negative affectivity. 0219. In Experiment 3, participants provided awakening, Participants rate “how they feel right now on a 5 point afternoon and bedtime saliva samples Tuesday, Wednesday scale: 1-very slightly/not at all to 5—extremely. Across all and Thursday of each week of the study. Participants were phases of experiments 1 and 2 internal consistencies ranged instructed not to eat or brush their teeth within an hour of from 0.94 to 0.96 for positive affectivity and 0.65 to 0.93 for providing a sample. Timing of saliva collection varied negative affectivity. The Karolinska Sleep Diary (KSD) is a across participants, but participants provided samples at the self-report questionnaire administered in the mornings that same times each day. All morning samples were taken captures information about the prior nights sleep (e.g., time immediately upon waking since this has been shown to in bed, time asleep, number of wake-ups, and ratings of reduce variability in assaying the cortisol awakening degree of dreaming, calm sleep, and sleep quality). This response. Afternoon saliva samples were taken between 3 questionnaire has been validated against polysomnography PM and 5 PM, and bedtime samples were taken within 30 and is correlated with objective EEG sleep metrics (for minutes before bed, which was just prior to TES usage. example, the amount of slow-wave sleep and sleep effi Salvia was collected via that passive drool method. As per ciency). The Depression, Anxiety, Stress Scale (DASS) is a manufacturers instructions (SalivaBio, Inc., State College, reliable clinically validated self-report measure that com Pa.), saliva is pooled at the front of the mouth and eased prises 42 negative emotional symptoms. Each item is rated through a tube, centered on the lips, directly into a cryovial. on a 4-point severity/frequency scale and indexed to the past Saliva samples were immediately stored at -20°C. and were week. Scores for the Depression, Anxiety and Stress scales transported back to the testing facility on ice, from there are determined by summing the scores for the relevant 14 saliva samples were sent to Salimetrics, LLC (State College, items. Reliabilities on the subscales ranged from 0.53 to 0.95 Pa.) where ELISA methods were employed to assess C.-amy across all baseline and treatment weeks for all experiments. lase (Salimetrics 1-1902) and cortisol levels (Salimetrics The Pittsburgh Sleep Quality Index (PSQI) is a 20-item 3002). Salivary C.-amylase is a biomarker for sleep in assessment that gauges overall sleep patterns over the past humans and is widely recognized as a biochemical marker of month, including duration of sleep, type of sleep distur sympathetic nervous system activity and sympathoadrenal bance, sleep latency, sleep efficiency, overall sleep quality, medullary (SAM) axis activation. The glucocorticoid hor and day dysfunction due to sleepiness. The PSQI was mone cortisol has a diurnal rhythm, which peaks within 45 administered in Experiment 3. The baseline administration of waking. The cortisol awakening response (CAR) is sen was indexed to the past month, and Subsequent assessments sitive to sleep disturbances where poor sleep correlates with were indexed to past week, capturing sleep changes due to a blunted CAR. TEN or sham treatment. Scores for the PSQI were calculated 0220 Given the quick but steep learning curve with according the algorithm outlined by Buysse and colleagues fitting the device and given that during training sessions (1989). participants received a TEN treatment, we excluded the first 0217. In Experiments 2 and 3, to monitor sleep/wake baseline and TEN-treatment day from all analyses in Experi cycles, participants wore the clinically validated Phillips ments 1 and 2. All Statistical analyses were completed with Respironics Activatch 2 (Phillips Healthcare) on their non IBM SPSS Statistics Software (IBM Corporation, Armonk, dominant wrist throughout the course of the study. The N.Y.). In Experiments 1 and 2, unless otherwise stated, all Activatch 2 was equipped with Solid-state piezoelectric statistical analyses were conducted using paired sample accelerometer to capture actigraph data at 32 HZ and event t-tests. In Experiment 3, order effects were examined using markers were used to capture bedtime and morning waking. two-way repeated measures analyses of variance The Activatch 2 has been shown to reliably tracks sleep/ (RMANOVA). All tests were not significant and were fol wake cycles and calculates duration, wake after sleep onset lowed by a series of one-way RMANOVA. Across all (WASO), sleep time, wake time, number of wake-ups, and studies, metrics that were assessed daily were averaged percent sleep/wake. separately across the each assessment period (baseline/TEN/ 0218. In Experiments 2 and 3, we acquired cardiac output Sham). Participants with fewer than 3 days of data on any using the Polar H7 heart rate monitor. Recordings started metric for any phase of an experiment were considered to immediately prior to bed, after sham/TEN use, and were have incomplete data on the given metric. Missing or terminated upon waking. During participants first office visit incomplete data were deleted listwise. Thresholds for sta they were trained according to manufacturers instructions on tistical significance were set at p<0.05. All data reported and preparation and usage of the device. Electrocardiogram shown are meantSD. (ECG) data were live streamed to the HRV Logger appli 0221. In general, any of the apparatuses described herein cation, which converted the ECG to R-R data that was (e.g., within the processor of the neurostimulator) may US 2017/0182285 A1 Jun. 29, 2017 27 include firmware and communication protocols for receiv relationship to another element(s) or feature(s) as illustrated ing and responding to the command messages. Any of the in the figures. It will be understood that the spatially relative processors (neurostimulators) described herein may also be terms are intended to encompass different orientations of the configured to transmit error codes back to the controller. For device in use or operation in addition to the orientation example, the processor may, during communication (e.g., depicted in the figures. For example, if a device in the figures via a communication circuit) check whether received wave is inverted, elements described as “under” or “beneath’ form parameters comply with limitations of hardware and other elements or features would then be oriented "over the safety standards. Examples of error codes that may be safety other elements or features. Thus, the exemplary term conditions (e.g., current requested too high, electrode con “under can encompass both an orientation of over and tact lost or poor connection, DC limit reached, communi under. The device may be otherwise oriented (rotated 90 cation lost), error codes related to the received command degrees or at other orientations) and the spatially relative messages/communication (e.g., too many wave segments, descriptors used herein interpreted accordingly. Similarly, fewer segments received than expected, received segments the terms “upwardly”, “downwardly”, “vertical”, “horizon too short, received segments too long, etc.) tal' and the like are used herein for the purpose of expla 0222 Any of the apparatuses for neurostimulation nation only unless specifically indicated otherwise. described herein may be configured to receive a plurality of 0226. Although the terms “first and “second may be neurostimulation command messages, including in particu used herein to describe various features/elements (including lar the new waveform message and Subsequent segment steps), these features/elements should not be limited by messages, which may include parameters from a controller these terms, unless the context indicates otherwise. These Such as a computing device (e.g., Smartphone, etc.) and terms may be used to distinguish one feature/element from apply them as stimulation. The neurostimulator may also another feature/element. Thus, a first feature/element dis adjust them and/or send one or more response error mes cussed below could be termed a second feature/element, and sages back to the controller if the parameters contained in similarly, a second feature/element discussed below could the messages do not comply with hardware limitations be termed a first feature/element without departing from the and/or safety limits which may be included in the neuro teachings of the present invention. stimulator. 0227. Throughout this specification and the claims which 0223. When a feature or element is herein referred to as follow, unless the context requires otherwise, the word being “on” another feature or element, it can be directly on “comprise', and variations such as "comprises' and "com the other feature or element or intervening features and/or prising means various components can be co-jointly elements may also be present. In contrast, when a feature or employed in the methods and articles (e.g., compositions element is referred to as being “directly on another feature and apparatuses including device and methods). For or element, there are no intervening features or elements example, the term “comprising will be understood to imply present. It will also be understood that, when a feature or the inclusion of any stated elements or steps but not the element is referred to as being “connected”, “attached' or exclusion of any other elements or steps. “coupled to another feature or element, it can be directly 0228. As used herein in the specification and claims, connected, attached or coupled to the other feature or including as used in the examples and unless otherwise element or intervening features or elements may be present. expressly specified, all numbers may be read as if prefaced In contrast, when a feature or element is referred to as being by the word “about' or “approximately, even if the term “directly connected”, “directly attached' or “directly does not expressly appear. The phrase “about' or “approxi coupled to another feature or element, there are no inter mately may be used when describing magnitude and/or vening features or elements present. Although described or position to indicate that the value and/or position described shown with respect to one embodiment, the features and is within a reasonable expected range of values and/or elements so described or shown can apply to other embodi positions. For example, a numeric value may have a value ments. It will also be appreciated by those of skill in the art that is +/-0.1% of the stated value (or range of values), that references to a structure or feature that is disposed +/-1% of the stated value (or range of values), +/-2% of the “adjacent another feature may have portions that overlap or stated value (or range of values), +/-5% of the stated value underlie the adjacent feature. (or range of values), +/-10% of the stated value (or range of 0224 Terminology used herein is for the purpose of values), etc. Any numerical values given herein should also describing particular embodiments only and is not intended be understood to include about or approximately that value, to be limiting of the invention. For example, as used herein, unless the context indicates otherwise. For example, if the the singular forms “a”, “an and “the are intended to value "10” is disclosed, then “about 10” is also disclosed. include the plural forms as well, unless the context clearly Any numerical range recited herein is intended to include all indicates otherwise. It will be further understood that the Sub-ranges Subsumed therein. It is also understood that when terms “comprises” and/or “comprising, when used in this a value is disclosed that “less than or equal to the value, specification, specify the presence of Stated features, steps, 'greater than or equal to the value' and possible ranges operations, elements, and/or components, but do not pre between values are also disclosed, as appropriately under clude the presence or addition of one or more other features, stood by the skilled artisan. For example, if the value “X” is steps, operations, elements, components, and/or groups disclosed the “less than or equal to X' as well as “greater thereof. As used herein, the term “and/or” includes any and than or equal to X' (e.g., where X is a numerical value) is all combinations of one or more of the associated listed also disclosed. It is also understood that the throughout the items and may be abbreviated as "/. application, data is provided in a number of different for 0225 Spatially relative terms, such as “under”,99 “below”, mats, and that this data, represents endpoints and starting “lower”, “over”, “upper” and the like, may be used herein points, and ranges for any combination of the data points. for ease of description to describe one element or feature's For example, if a particular data point “10' and a particular US 2017/0182285 A1 Jun. 29, 2017 28 data point “15” are disclosed, it is understood that greater 4. The method of claim 1, wherein attaching comprises than, greater than or equal to, less than, less than or equal to, attaching the second electrode to the Subject's neck above and equal to 10 and 15 are considered disclosed as well as the subjects vertebra prominens. between 10 and 15. It is also understood that each unit 5. The method of claim 1, further comprising allowing the between two particular units are also disclosed. For subject to select a set of parameter for the electrical stimu example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 lation to be applied, wherein the set of parameters includes are also disclosed. one or more of Stimulation duration, frequency, peak ampli 0229. Although various illustrative embodiments are tude, and duty cycle. described above, any of a number of changes may be made 6. The method of claim 1, further comprising wearing the to various embodiments without departing from the scope of electrodes while the subject sleeps. the invention as described by the claims. For example, the 7. The method of claim 1, further comprising removing order in which various described method steps are per the first and second electrodes and TES applicator prior to formed may often be changed in alternative embodiments, the Subject sleeping. and in other alternative embodiments one or more method 8. The method of claim 1, wherein applying comprises steps may be skipped altogether. Optional features of vari applying a biphasic electrical stimulation. ous device and system embodiments may be included in 9. The method of claim 1, wherein applying comprises some embodiments and not in others. Therefore, the fore applying a biphasic electrical stimulation and further going description is provided primarily for exemplary pur wherein the biphasic electrical stimulation is asymmetric poses and should not be interpreted to limit the scope of the with respect to positive and negative going phases. invention as it is set forth in the claims. 10. The method of claim 1, wherein applying comprises 0230. The examples and illustrations included herein applying the electrical stimulation having a duty cycle of show, by way of illustration and not of limitation, specific between 10% and 90%. embodiments in which the subject matter may be practiced. 11. The method of claim 1, wherein applying comprises As mentioned, other embodiments may be utilized and applying the electrical stimulation having a duty cycle of derived there from, such that structural and logical substi between 30% and 60%. tutions and changes may be made without departing from 12. The method of claim 1, wherein applying comprises the scope of this disclosure. Such embodiments of the applying the electrical stimulation having a peak amplitude inventive subject matter may be referred to herein individu of 5 mA or greater. ally or collectively by the term “invention” merely for 13. The method of claim 1, wherein applying comprises convenience and without intending to Voluntarily limit the applying the electrical stimulation having a frequency of Scope of this application to any single invention or inventive greater than 500 Hz. concept, if more than one is, in fact, disclosed. Thus, 14. The method of claim 1, wherein applying comprises although specific embodiments have been illustrated and applying the electrical stimulation having a frequency of described herein, any arrangement calculated to achieve the greater than 750 Hz. same purpose may be substituted for the specific embodi 15. The method of claim 1, wherein applying comprises ments shown. This disclosure is intended to cover any and applying the electrical stimulation having a frequency of all adaptations or variations of various embodiments. Com greater than 5 kHz. binations of the above embodiments, and other embodi 16. The method of claim 1, wherein continuing applica ments not specifically described herein, will be apparent to tion of the electrical stimulation for a stimulation duration those of skill in the art upon reviewing the above descrip comprises continuing for a stimulation duration of at least tion. five minutes. 17. The method of claim 1, wherein applying comprises What is claimed is: applying the electrical stimulation having amplitude modu 1. A method of non-invasively reducing sleep onset and lation. increasing sleep duration, the method comprising: 18. The method of claim 1, wherein applying comprises attaching a first electrode to a subjects head or neck at a applying the electrical stimulation having amplitude modu first location and a second electrode to the subjects lation, and further wherein the amplitude modulation has a head or neck at a second location, wherein the first and frequency of less than 250 Hz. the second electrode are coupled to a transdermal 19. The method of claim 1, wherein applying comprises electrical stimulation (TES) applicator worn by the Subject; applying the electrical stimulation having a burst mode. 20. A wearable transdermal electrical stimulation (TES) applying an electrical stimulation between the first and applicator for facilitating, inducing, and/or maintaining second electrodes, wherein the electrical stimulation sleep in a Subject, the device comprising: has a peak amplitude of greater than 3 mA, a frequency a body; of greater than 250 Hz, and a duty cycle of greater than a first electrode: 10%; and a second electrode; and continuing application of the electrical stimulation for a a TES control module at least partially within the body stimulation duration of at least one minutes to enhance and comprising a processor, a timer and a waveform sleepiness, Sustain sleep or to enhance sleepiness and generator, wherein the TES control module is adapted Sustain sleep. to deliver a biphasic electrical stimulation signal of 10 2. The method of claim 1, wherein attaching comprises seconds or longer between the first and second elec adhesively attaching. trodes having a duty cycle of greater than 10 percent, 3. The method of claim 1, wherein attaching comprises a frequency of 250 Hz or greater, and an intensity of 3 attaching the first electrode to the Subject's temple region. mA or greater, wherein the biphasic transdermal elec US 2017/0182285 A1 Jun. 29, 2017 29 trical stimulation is asymmetric with respect to positive 26. The device of claim 20, wherein the transdermal and negative going phases; electrical stimulation comprises a burst mode. wherein the wearable TES applicator weighs less than 50 27. The device of claim 20, wherein the transdermal grams; and electrical stimulation comprises a burst mode and wherein the frequency of bursting is less than 250 Hz. at least one sensor coupled to the body for sleep moni 28. The device of claim 20 wherein the at least one sensor toring of the Subject. measures the Subject's autonomic function. 21. The device of claim 20, wherein the duty cycle is 29. The device of claim 20 wherein the at least one sensor between 30% and 60%. measures the Subject's autonomic function, further wherein 22. The device of claim 20, wherein the transdermal the measurement of autonomic function measures one or electrical stimulation has a frequency greater than 750 Hz. more of galvanic skin resistance, heart rate, heart rate 23. The device of claim 20, wherein the transdermal variability, or breathing rate. electrical stimulation has a frequency greater than 5 kHz. 30. The device of claim 20 wherein the at least one sensor 24. The device of claim 20, wherein the transdermal comprises a sensor to detect the Subject's movements. electrical stimulation comprises amplitude modulation. 31. A method for improving sleep comprising transdermal 25. The device of claim 20, wherein the transdermal electrical stimulation of a Subject stimulating peripheral electrical stimulation comprises amplitude modulation and nerves of the head and neck and inducing a change in wherein the amplitude modulation has a frequency of less cognitive state that improves sleep and mood in the Subject. than 250 HZ. k k k k k