WO2021016624A1

WO2021016624A1 - Apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia

Info

Publication number: WO2021016624A1
Application number: PCT/US2020/043782
Authority: WO
Inventors: Anthony MARTORELL
Original assignee: Click Therapeutics Inc
Current assignee: Click Therapeutics Inc
Priority date: 2019-07-25
Filing date: 2020-07-27
Publication date: 2021-01-28
Anticipated expiration: 2022-01-25

Abstract

A computer implemented method for slow- wave sleep modulation therapy is provided. The method includes determining a need for sleep wave modulation; and providing the modulation via slow- wave stimulus to a user, wherein the slow- wave stimulus comprises oscillations of a frequency between 0.25 and 8 Hz, and wherein, in response to the slow- wave stimulus, a brain frequency of the user receiving the slow- wave stimulus is modulated closer to the frequency of the slow- wave stimulus than the brain frequency prior to receiving the slow- wave stimulus.

Description

APPARATUS, SYSTEM AND METHOD FOR SLOW- WAVE SLEEP MODULATION THERAPY FOR TREATMENT, PREVENTION, AND/OR MITIGATION OF

INSOMNIA

PRIORITY

[0001] The present application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No. 62/878,726, which was filed in the United States Patent and Trademark Office on July 25, 2019, the entire disclosure of which is incorporated herein by reference.

INTRODUCTION

[0002] Embodiments of the invention relate generally to treatment of insomnia disorders, and more particularly, to methods of treatment of insomnia using slow-wave modulation therapies.

[0003] Global epidemiological estimates of insomnia symptoms are approximately 30-35% of the population, while the average prevalence rate of insomnia disorder is 10% for studies that used the Diagnostic and Statistical Manual of Mental Disorders IV (“DSM IV”) criteria.

Insomnia is characterized by nocturnal and diurnal symptoms, including daytime tiredness, and irritability, and predominantly involves a dissatisfaction with sleep quality or duration. Clinical studies indicate that insomnia symptoms may be attributed to the inability of the brain to switch from aroused to sleep-states. Accumulating physiological evidence suggests that insomnia characteristics may be attributed to atypical high frequency electroencephalography (“EEG”) activity at sleep onset, and during both non-rapid eye movement (“NREM”) and rapid eye movement (“REM”) sleep. Specifically, insomnia patients have shown increased beta wave (14- 35 Hertz (Hz)) activity during sleep states in place of desired slow- wave alpha (8-12 Hz) and delta (1-4 Hz) oscillations, which should be predominant.

[0004] Polysomnography recordings show that patients with insomnia exhibit an abnormal amount of beta wave (14-35 Hz) activity during sleep onset and/or NREM sleep when compared to those without insomnia symptoms. Abnormal beta activity during sleep is considered potentially pathological, as beta oscillations are functionally associated with arousal states, such as attention, perception, and cognitive function in mammals. Lower frequency oscillation states in the alpha and delta ranges are functionally associated with sleep-states (REM/NREM) and/or memory consolidation, a key role of sleep. Thus, the occurrence of beta activity during sleep- states in insomnia patients may provide a physiological indication explaining the disposition to frequent sleep-awakenings and difficulty of sleep onset, potentially due to the brain being inappropriately primed for cognitive function.

[0005] Current pharmacological therapies such as sleep-medications provide acute periods of sleep relief, however they are not capable of providing reliable long-term sleep solutions to insomnia. Specifically, acute sleep-medications do not provide for induction of natural sleep cycles. Moreover, such pharmacological therapies often result in dependence, and may produce a host of side effects.

[0006] Auditory and visual stimulations may be useful for modulating neuronal oscillations. Neuronal oscillations may be brainwaves that include rhythmic or repetitive patterns of neural activity, typically in the central nervous system. In such instances, modulation of neural activity has been indicated to directly affect cognitive function and behavior, and has been recently investigated for its potential to affect slow-wave sleep states.

[0007] It would be desirable, therefore, to provide systems and methods for identifying specific stimuli and frequencies for modulating neural activity.

[0008] It would be additionally desirable to provide systems and methods for affecting slow- wave sleep states.

[0009] It would be further desirable to provide a closed-loop EEG stimulation feedback system, whereby brain stimulation parameters are altered due to certain measured brain states or frequencies, that can reduce or eliminate error rates in monitoring and identifying the efficiency of slow-wave sleep oscillation.

[0010] It would be yet further desirable to provide systems and methods that can monitor and match tones in synchrony with specific sleep oscillations, based on EEG detections.

[0011] It would be yet further desirable to provide a system and method for modulating, altering and re-aligning neural activity using sensory stimuli and EEG, without the need for implanted or invasive sensors.

[0012] It would be further desirable to provide systems and methods for correcting and increasing accuracy of EEG sensors based on the above. [0013] It would be desirable, therefore, to provide systems and methods for utilizing improved closed-loop EEG stimulation feedback systems for modulating slow-wave sleep states.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 illustrates a block diagram of a distributed computer system that can implement one or more aspects of an embodiment of the present invention;

[0015] FIG. 2 illustrates a block diagram of an electronic device that can implement one or more aspects of an embodiment of the invention;

[0016] FIG. 3 illustrates a phase-locked loop according to one or more aspects of an embodiment of the present invention.

[0017] While the invention is described with reference to the above drawings, the drawings are intended to be illustrative, and the invention contemplates other embodiments within the spirit of the invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION

[0018] The present invention will now be described more fully hereinafter with reference to the accompanying drawings which show, by way of illustration, specific embodiments by which the invention may be practiced. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Among other things, the present invention may be embodied as devices or methods. Accordingly, the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment, or an embodiment combining software and hardware aspects. The following detailed description is, therefore, not to be taken in a limiting sense.

[0019] Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrases“in one

embodiment,”“in an embodiment,” and the like, as used herein, does not necessarily refer to the same embodiment, though it may. Furthermore, the phrase“in another embodiment” as used herein does not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.

[0020] In addition, as used herein, the term“or” is an inclusive“or” operator, and is equivalent to the term“and/or,” unless the context clearly dictates otherwise. The term“based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of“a,”“an,” and“the” includes plural references. The meaning of“in” includes“in” and“on.”

[0021] It is noted that description herein is not intended as an extensive overview, and as such, concepts may be simplified in the interests of clarity and brevity.

[0022] All documents mentioned in this application are hereby incorporated by reference in their entirety. Any process described in this application may be performed in any order and may omit any of the steps in the process. Processes may also be combined with other processes or steps of other processes.

[0023] FIG. 1 illustrates components of one embodiment of an environment in which the invention may be practiced. Not all of the components may be required to practice the invention, and variations in the arrangement and type of the components may be made without departing from the spirit or scope of the invention. As shown, the system 100 includes one or more Local Area Networks (“LANs”)/Wide Area Networks (“WANs”) 112, one or more wireless networks 110, one or more wired or wireless client devices 106, mobile or other wireless client devices 102-106, servers 107-109, and may include or communicate with one or more data stores or databases. Various of the client devices 102-106 may include, for example, desktop computers, laptop computers, set top boxes, tablets, cell phones, smart phones, and the like. The servers 107- 109 can include, for example, one or more application servers, content servers, search servers, and the like.

[0024] FIG. 2 illustrates a block diagram of an electronic device 200 that can implement one or more aspects of systems and methods for slow-wave sleep modulation therapy according to one embodiment of the invention. Instances of the electronic device 200 may include servers, e.g., servers 107-109, and client devices, e.g., client devices 102-106. In general, the electronic device 200 can include a processor/CPU 202, memory 230, a power supply 206, and input/output (I/O) components/devices 240, e.g., microphones, speakers, displays, touchscreens, keyboards, mice, keypads, microscopes, GPS components, etc., which may be operable, for example, to provide graphical user interfaces or text user interfaces.

[0025] A user may provide input via a touchscreen of an electronic device 200. A touchscreen may determine whether a user is providing input by, for example, determining whether the user is touching the touchscreen with a part of the user's body such as his or her fingers. The electronic device 200 can also include a communications bus 204 that connects the

aforementioned elements of the electronic device 200. Network interfaces 214 can include a receiver and a transmitter (or transceiver), and one or more antennas for wireless

communications.

[0026] The processor 202 can include one or more of any type of processing device, e.g., a Central Processing Unit (CPU), and a Graphics Processing Unit (GPU). Also, for example, the processor can be central processing logic, or other logic, may include hardware, firmware, software, or combinations thereof, to perform one or more functions or actions, or to cause one or more functions or actions from one or more other components. Also, based on a desired application or need, central processing logic, or other logic, may include, for example, a software controlled microprocessor, discrete logic, e.g., an Application Specific Integrated Circuit (ASIC), a programmable/programmed logic device, memory device containing instructions, etc., or combinatorial logic embodied in hardware. Furthermore, logic may also be fully embodied as software.

[0027] The memory 230, which can include Random Access Memory (RAM) 212 and Read Only Memory (ROM) 232, can be enabled by one or more of any type of memory device, e.g., a primary (directly accessible by the CPU) or secondary (indirectly accessible by the CPU) storage device (e.g., flash memory, magnetic disk, optical disk, and the like). The RAM can include an operating system 221, data storage 224, which may include one or more databases, and programs and/or applications 222, which can include, for example, software aspects of the slow-wave sleep modulation therapy program 223. The ROM 232 can also include Basic Input/Output System (BIOS) 220 of the electronic device.

[0028] Software aspects of the slow-wave sleep modulation therapy program 223 are intended to broadly include or represent all programming, applications, algorithms, models, software and other tools necessary to implement or facilitate methods and systems according to embodiments of the invention. The elements may exist on a single server computer or be distributed among multiple computers, servers, devices or entities, such as systems and engines as described in embodiments herein.

[0029] The power supply 206 contains one or more power components, and facilitates supply and management of power to the electronic device 200.

[0030] The input/output components, including Input/Output (I/O) interfaces 240, can include, for example, any interfaces for facilitating communication between any components of the electronic device 200, components of external devices (e.g., components of other devices of the network or system 100), and end users. For example, such components can include a network card that may be an integration of a receiver, a transmitter, a transceiver, and one or more input/output interfaces. A network card, for example, can facilitate wired or wireless

communication with other devices of a network. In cases of wireless communication, an antenna can facilitate such communication. Also, some of the input/output interfaces 240 and the bus 204 can facilitate communication between components of the electronic device 200, and in an example can ease processing performed by the processor 202.

[0031] Where the electronic device 200 is a server, it can include a computing device that can be capable of sending or receiving signals, e.g., via a wired or wireless network, or may be capable of processing or storing signals, e.g., in memory as physical memory states. The server may be an application server that includes a configuration to provide one or more applications, e.g., aspects of the slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, via a network to another device. Also, an application server may, for example, host a Web site that can provide a user interface for administration of example aspects of the apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia.

[0032] Any computing device capable of sending, receiving, and processing data over a wired and/or a wireless network may act as a server, such as in facilitating aspects of implementations of the apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia. Thus, devices acting as a server may include devices such as dedicated rack-mounted servers, desktop computers, laptop computers, set top boxes, integrated devices combining one or more of the preceding devices, and the like. [0033] Servers may vary widely in configuration and capabilities, but they generally include one or more central processing units, memory, mass data storage, a power supply, wired or wireless network interfaces, input/output interfaces, and an operating system such as Windows Server, Mac OS X, Unix, Linux, FreeBSD, and the like.

[0034] A server may include, for example, a device that is configured, or includes a

configuration, to provide data or content via one or more networks to another device, such as in facilitating aspects of an example apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia. One or more servers may, for example, be used in hosting a Web site, such as the web site www.microsoft.com. One or more servers may host a variety of sites, such as, for example, business sites, informational sites, social networking sites, educational sites, wikis, financial sites, government sites, personal sites, and the like.

[0035] Servers may also, for example, provide a variety of services, such as Web services, third- party services, audio services, video services, email services, HTTP or HTTPS services, Instant Messaging (IM) services, Short Message Service (SMS) services, Multimedia Messaging Service (MMS) services, File Transfer Protocol (FTP) services, Voice Over IP (VOIP) services, calendaring services, phone services, and the like, all of which may work in conjunction with example aspects of an example systems and methods for the apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia. Content may include, for example, text, images, audio, video, and the like.

[0036] In example aspects of the apparatus, system and method for slow- wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, client devices may include, for example, any computing device capable of sending and receiving data over a wired and/or a wireless network. Such client devices may include desktop computers as well as portable devices such as cellular telephones, smart phones, display pagers, Radio Frequency (RF) devices,

Infrared (IR) devices, Personal Digital Assistants (PDAs), handheld computers, GPS-enabled devices tablet computers, sensor-equipped devices, laptop computers, set top boxes, wearable computers, integrated devices combining one or more of the preceding devices, and the like.

[0037] Client devices, as may be used in an example apparatus, system and method for slow- wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, may range widely in terms of capabilities and features. For example, a cell phone, smart phone or tablet may have a numeric keypad and a few lines of monochrome Liquid-Crystal Display (LCD) display on which only text may be displayed. In another example, a Web-enabled client device may have a physical or virtual keyboard, data storage (such as flash memory or SD cards), accelerometers, gyroscopes, GPS or other location-aware capability, and a 2D or 3D touch- sensitive color screen on which both text and graphics may be displayed.

[0038] Client devices, such as client devices 102-106, for example, as may be used in an example apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, may run a variety of operating systems, including personal computer operating systems such as Windows, iOS or Linux, and mobile operating systems such as iOS, Android, Windows Mobile, and the like. Client devices may be used to run one or more applications that are configured to send or receive data from another computing device. Client applications may provide and receive textual content, multimedia information, and the like. Client applications may perform actions such as browsing webpages, using a web search engine, interacting with various apps stored on a smart phone, sending and receiving messages via email, SMS, or MMS, playing games (such as fantasy sports leagues), receiving advertising, watching locally stored or streamed video, or participating in social networks.

[0039] In example aspects of the apparatus, system and method for slow- wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, one or more networks, such as networks 110 or 112, for example, may couple servers and client devices with other computing devices, including through wireless network to client devices. A network may be enabled to employ any form of computer readable media for communicating information from one electronic device to another. The computer readable media may be non-transitory. A network may include the Internet in addition to Local Area Networks (LANs), Wide Area Networks (WANs), direct connections, such as through a Universal Serial Bus (USB) port, other forms of computer-readable media (computer-readable memories), or any combination thereof. On an interconnected set of LANs, including those based on differing architectures and protocols, a router acts as a link between LANs, enabling data to be sent from one to another.

[0040] Communication links within LANs may include twisted wire pair or coaxial cable, while communication links between networks may utilize analog telephone lines, cable lines, optical lines, full or fractional dedicated digital lines including Tl, T2, T3, and T4, Integrated Services Digital Networks (ISDNs), Digital Subscriber Lines (DSLs), wireless links including satellite links, optic fiber links, or other communications links known to those skilled in the art.

Furthermore, remote computers and other related electronic devices could be remotely connected to either LANs or WANs via a modem and a telephone link.

[0041] A wireless network, such as wireless network 110, as in an example apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, may couple devices with a network. A wireless network may employ stand-alone ad-hoc networks, mesh networks, Wireless LAN (WLAN) networks, cellular networks, and the like.

[0042] A wireless network may further include an autonomous system of terminals, gateways, routers, or the like connected by wireless radio links, or the like. These connectors may be configured to move freely and randomly and organize themselves arbitrarily, such that the topology of wireless network may change rapidly. A wireless network may further employ a plurality of access technologies including 2nd (2G), 3rd (3G), 4th (4G) generation, Long Term Evolution (LTE) radio access for cellular systems, WLAN, Wireless Router (WR) mesh, and the like. Access technologies such as 2G, 2.5G, 3G, 4G, and future access networks may enable wide area coverage for client devices, such as client devices with various degrees of mobility.

For example, a wireless network may enable a radio connection through a radio network access technology such as Global System for Mobile communication (GSM), Universal Mobile Telecommunications System (UMTS), General Packet Radio Services (GPRS), Enhanced Data GSM Environment (EDGE), 3 GPP Long Term Evolution (LTE), LTE Advanced, Wideband Code Division Multiple Access (WCDMA), Bluetooth, 802.1 lb/g/n, and the like. A wireless network may include virtually any wireless communication mechanism by which information may travel between client devices and another computing device, network, and the like.

[0043] Internet Protocol (IP) may be used for transmitting data communication packets over a network of participating digital communication networks, and may include protocols such as TCP/IP, UDP, DECnet, NetBEUI, IPX, Appletalk, and the like. Versions of the Internet Protocol include IPv4 and IPv6. The Internet includes local area networks (LANs), Wide Area Networks (WANs), wireless networks, and long haul public networks that may allow packets to be communicated between the local area networks. The packets may be transmitted between nodes in the network to sites each of which has a unique local network address. A data communication packet may be sent through the Internet from a user site via an access node connected to the Internet. The packet may be forwarded through the network nodes to any target site connected to the network provided that the site address of the target site is included in a header of the packet. Each packet communicated over the Internet may be routed via a path determined by gateways and servers that switch the packet according to the target address and the availability of a network path to connect to the target site.

[0044] The header of the packet may include, for example, the source port (16 bits), destination port (16 bits), sequence number (32 bits), acknowledgement number (32 bits), data offset (4 bits), reserved (6 bits), checksum (16 bits), urgent pointer (16 bits), options (variable number of bits in multiple of 8 bits in length), padding (may be composed of all zeros and includes a number of bits such that the header ends on a 32 bit boundary). The number of bits for each of the above may also be higher or lower.

[0045] A“content delivery network” or“content distribution network” (CDN), as may be used in an example apparatus, system and method for slow-wave sleep modulation therapy for treatment, prevention, and/or mitigation of insomnia, generally refers to a distributed computer system that comprises a collection of autonomous computers linked by a network or networks, together with the software, systems, protocols and techniques designed to facilitate various services, such as the storage, caching, or transmission of content, streaming media and applications on behalf of content providers. Such services may make use of ancillary

technologies including, but not limited to,“cloud computing,” distributed storage, DNS request handling, provisioning, data monitoring and reporting, content targeting, personalization, and business intelligence. A CDN may also enable an entity to operate and/or manage a third party's Web site infrastructure, in whole or in part, on the third party's behalf.

[0046] A Peer-to-Peer (or P2P) computer network relies primarily on the computing power and bandwidth of the participants in the network rather than concentrating it in a given set of dedicated servers. P2P networks are typically used for connecting nodes via largely ad hoc connections. A pure peer-to-peer network does not have a notion of clients or servers, but only equal peer nodes that simultaneously function as both“clients” and“servers” to the other nodes on the network.

[0047] Client devices 102-106 may include or be directly or indirectly communicatively coupled to an EEG machine, as shown in FIG. 3.

[0048] Embodiments of the present invention include apparatuses, systems and methods for modulating neuronal oscillations for preventing, mitigating, and/or treating insomnia.

Embodiments of the present invention may be implemented on one or more of client devices 102-106, which are communicatively coupled to servers including servers 107-109.

[0049] Insomnia is characterized by disrupted sleep patterns, which can manifest as difficulty falling asleep or difficulty remaining asleep. Insomnia may be classified broadly as either cognitive or physiological-based insomnia.

[0050] In instances of physiological-based insomnia, dysregulation of circadian rhythms may be a cause of sleep difficulty. The dysregulation may result from a variety of reasons, including mutations in clock genes responsible for the regulation of the awake-sleep cycle, as well as a shifted circadian pacemaker, where the insomnia subject naturally falls asleep much earlier or later than normal and thus wakes up at inappropriate times for a typical day-time schedule. Over time, this dysregulation will result in tiredness and“sleep debt” during the daytime.

[0051] In an embodiment, apparatuses, systems and methods for preventing, mitigating and/or treating insomnia (hereinafter, collectively referred to as“the therapy”) in an individual are provided. The therapy may utilize a neuronal wave-modulation using sensory stimuli therapy. Specifically, in accordance with an embodiment, the therapy utilizes specific stimuli for specified durations, as well as specific frequencies and at specially determined points in time.

The therapy is specifically formulated to cause the individual to be: (1) induced with slow-wave oscillations; (2) modulate real-time slow-wave oscillations; and/or (3) indirectly modulate other frequency-band oscillations (e.g. beta oscillations).“Oscillation” refers to a rhythmic pattern of neural activity in the central nervous system.“Slow-wave” refers to periods of sleep where slow- frequency oscillations ranging from delta to alpha (0.25-8 Hz) predominantly occur, with a similar frequency to the inducing stimuli. Thus, as disclosed herein, the invention may include determining a need for sleep wave modulation, and providing the modulation via slow-wave stimulus. [0052] In one embodiment, sleep modulation occurs via the induction of slow frequency sensory stimulation. The therapy may include administration of a stimulus, or plurality of stimuli. The stimulus may be any suitable stimulus, including, but not limited to auditory, visual, mechanical, electrical, and haptic. The stimulus is generated by electronic device 200 or a device

communicatively coupled thereto (such as earphones/headphones plugged into electronic device 200). For example, electronic device 200, which may be a smartphone, may include a speaker or an earphone/headphone port and earphones/headphones connected to such port to deliver the auditory stimulus to a user near the electronic device 200. The electronic device 200, which may be a smartphone, may include one or more LEDs (including the screen or other lights) or other lights to deliver the visual stimulus to the user. The electronic device 200 may include one or more actuators producing vibratory effects used to deliver haptic feedback to a user in physical contact with the electronic device 200. The electronic device 200 may also include or be coupled to (directly or indirectly including by wireless means) electrodes (in physical contact with the user) capable of delivering mild electric shocks to deliver the electrical stimulus (the user will not sense these mild shocks as pain). The electronic device 200 may also include or be coupled to an actuator capable of delivering a mechanical stimulus to a user. In an embodiment, the stimulus/stimuli may be administered at different frequencies. For example, a first frequency may be chosen for a specific stimulus, in order to trigger and/or modulate a desired brain frequency (or a brain frequency that is closer to the frequency of the administered stimulus than the brain frequency prior to the administered stimulus). In the case an auditory stimulus is used, an electroacoustic transducer may be used to convert an electrical audio signal into a

corresponding sound stimulus. For example, the sound stimulus may be a click train with the desired frequency (Hz). The click train may be a sound stimulus that is triggered mechanically or electrically (such as via a clicker), and results in a sound or series of sounds. In a further embodiment, the stimulus/stimuli may be administered for a specified period of time, such as for a period of seconds, minutes or even hours. In an example, the stimulus may be administered for a period of approximately twenty seconds (between 18 and 22 seconds), or any other suitable amount of time.

[0053] In one embodiment, individuals with insomnia are known to have reduced slow-wave oscillation brain activity. In one aspect, a method of reducing insomnia symptoms may include: (1) determining, via EEG, increased amplitude of slow-wave oscillations during sleep states; (2) determining the proper stimulation needed to trigger and/or modulate slow-waves in an individual; (3) determining the right point in time to trigger the slow-wave oscillation therapy;

(4) determining the duration of stimulation and wave needed; (5) determining the proper frequency of wave; (5) providing non-invasive neural stimulation for insomnia via the stimulus; and (6) monitoring, via the EEG in real-time, the result of the stimulation in triggering slow- wave oscillation.

[0054] For example, determining the right point in time to trigger the slow- wave oscillation therapy may include: (1) analyzing, via an EEG, oscillations during a period of time for desired sleep; (2) monitoring oscillations, via the EEG, for onset of a truncated, defective or low amplitude slow-wave oscillation; (3) in response to the onset, producing a predetermined stimulus; and (4) based on the predetermined stimulus, causing the brain to trigger an increased amplitude or duration slow-wave oscillation sufficient to reduce insomnia.

[0055] In an embodiment, determining the proper stimulation needed to trigger and/or modulate slow-waves in an individual may be determined via a closed-loop system. Thus, detection of a slow-wave oscillation during sleep may occur via EEG, and an auditory tone would then be emitted in real-time to modulate the slow wave frequency.

[0056] In a further embodiment, the determining of the right point in time to trigger slow-wave oscillation therapy may occur at the start of a slow-wave sleep cycle, whereby an individual begins to“fall asleep" and slow-wave oscillations are shown to predominate via an EEG.

[0057] Thus, in certain embodiments, an embodiment of the invention includes inducing slow- wave oscillations by stimulating slow-wave sensory stimuli, as well as determining the proper stimulus, and proper timing for the sleep wave modulation.

[0058] In an embodiment, personalized regimens of varying duration and longevity are provided, whereby each individual’s frequency, duration, and/or form of stimulation may be personalized, based on the results of a baseline EEG measurement and/or calculation. This is due to variable neural states, in this case during sleep, in humans, where each human subject may differ in baseline slow-wave states, thus requiring sensory stimuli to occur at different intensities, periods, and durations. In another embodiment, oscillations are modulated in real-time. [0059] In an embodiment, the system may determine the presence of an abnormal amount of beta activity, such as a frequency of 14-35 Hz, present during sleep onset or NREM sleep. This would in turn indicate that the individual’s brain does not predominantly demonstrate slow-wave patterns necessary for sleep, and suggest modulation. Thus, the system may then transmit to the individual via sensory stimuli to produce slow-wave oscillations and indirectly reduce beta activity, inducing sleep.

[0060] It should be noted that, in accordance with embodiments of the invention, the slow-wave oscillations are non-invasive, and are specifically formed to stimulate electrophysiological activity, and synchronize neural activity, using sensory stimuli at various frequencies.

[0061] In certain embodiments, sensory stimuli are utilized at various frequencies, with oscillations modulated at times during sleep cycles. Thus, neural activity, and specifically an individual’s slow wave modulations, are modulated or altered during sleep to induce or improve sleep patterns. The stimuli may be specifically modulated to a frequency similar or identical to the desired slow- wave oscillation to be produced. For example, the frequency of the stimuli may be 10 Hz, if desired to produce a 10 Hz oscillation in the individual.

[0062] In one embodiment, the stimulation may be auditory stimulation, whereby neural activity of an individual is non-invasively modulated with auditory signals at specific frequencies to modulate cortical neural activity. For example, a delta range of 1-4 Hz may be used (for example, for sleep), or a higher range, such as a gamma range (greater than 40 Hz) may be used.

[0063] In accordance with some embodiments, modulation of slow- wave oscillations via slow- frequency sensory stimuli may be specifically timed to begin when a slow-wave oscillation in the individual is detected. For example, the EEG may detect that a series of slow-wave oscillations have occurred, and may then begin to synchronize sensory stimuli to each slow-wave oscillation. Non-invasive sensory stimuli may include using an auditory or other suitable stimulation, and would be synchronized to the upstart-phase (such as, for example, when the wave begins its “ascent”) of a slow-wave oscillation. In other embodiments, the system may instead artificially produce slow-wave oscillations, at any suitable time.

[0064] In an embodiment, the EEG is specifically a closed-loop, non-invasive and portable EEG. The synchronization and modulation of brain oscillations may be performed via a real-time phase-locked stimulation, where a sensory stimulus such as an auditory tone is emitted at the upstart-phase of an ongoing EEG-detected slow-wave oscillation. That is, as disclosed above, slow-wave sleep modulation may be specifically timed to occur at a phase of a predicted or ongoing, but improper or insufficient, slow-wave sleep rhythm. This increases the likelihood of proper sleep induction, and elimination or reduction of insomnia.

[0065] Accordingly, novel methods for modulation of slow-wave oscillations may utilize a closed-loop EEG system. The methods may include auditory stimulation feedback. For example, the auditory stimulation may include audio tones, to be delivered via speakers or headphone-like devices and is based on EEG-detected feedback. In a further example, the system may monitor for the upstate phase of slow-wave oscillations, using the EEG. Once an upstate phase is detected via the EEG, the system initiates a sensory stimulation, such as auditory stimulation, to produce and effect slow- wave oscillations in an individual.

[0066] For example, in an auditory tone stimulation, an EEG signal may be processed and transmitted to a computer processor, where an electroacoustic transducer will convert an electrical audio signal into a corresponding sound stimulus, and the sound stimulus would include a click train with a desired frequency. Slow-frequency tones for auditory stimuli for the purpose of modulating slow-wave oscillations may be formed of bursts of pink 1 If noise of 50 ms in duration, emitted as square-waves, and calibrated between 40-50 decibels (dB) of sound- pressure level (SPL). Tones may be presented binaurally via ear headphones.

[0067] In a further embodiment, the stimulation causes the reduction of high frequency oscillations in an individual, thereby affecting sleep and reducing insomnia. Further, the stimulation may cause the amplitude of the high frequency oscillations to decrease, in response to amplitude modulation via slow-wave oscillations.

[0068] In accordance with an embodiment, the EEG as disclosed herein may be specifically modified to address these needs. In particular, the EEG may be modified to a closed-loop EEG that monitors and provides feedback in substantially real-time, while being wireless and non- invasive.

[0069] In an embodiment, the EEG is configured to convert an electrical brain wave signal to a digital signal. This process may occur by the amplification of an electrical signal via an amplifier which would amplify the voltage of the active electrode. The electrical signal is then filtered and digitized through an analog-to-digital converter. The digital signal is then stored electronically and analyzed.

[0070] The EEG may non-invasively capture cortical neuronal information in a manner that is quick and relatively affordable. EEG therefore allows for the visualization of cortical neuronal activity in a relatively short-period of time. Moreover, the EEG is specifically programmed to reduce and address inaccuracies in non-invasive EEG monitoring systems, such as inaccurate wave frequency and amplitude.

[0071] An illustrative process may include, at a time determined to be appropriate for sleep (for example, such as between 10 PM-4 AM): (1) providing a portable, non-invasive EEG device; (2) providing a stimulus receiver (such as headphones for placement over the ear, any suitable form of haptic feedback receiver, a visual feedback receiver, or any other suitable device); (3) monitoring and recording oscillations using the non-invasive EEG device; (4) converting the monitored signal from an electrical signal to a digital signal; (5) upon determining the presence of the beginning of a slow-wave oscillation in the wearer’s brain, or a truncated slow- wave oscillation, executing a stimulation synchronized with the produced oscillation; (6) monitoring for feedback via the EEG; and (7) determining if an appropriate amount of slow-wave oscillation has been conducted.

[0072] Thus, as described above, the EEG records and analyzes brain wave oscillations from an individual. The EEG may be a modified EEG headband device. Further, the headphones provide auditory stimuli during EEG acquisition, which is when electrical activity of the brain is recorded from the scalp. In an embodiment, when the individual’s brain is detected to produce a slow-wave oscillation, the system runs the closed-loop program to synchronize a sensory stimulation with the slow-wave oscillation. This causes the wave to increase in amplitude, resulting in better sleep. All EEG and stimulation data is then synchronized and transferred to memory.

[0073] In an embodiment, oscillations may be synchronized with stimuli using a phase-locked loop. In order to detect slow-wave oscillations in real-time and present auditory stimuli in a phase-locked fashion, an algorithm may process signals from specific EEG channels (bipolar, Fpz-Ml), through a dedicated amplifier. The EEG signal will be filtered in real-time between 0.25 and 4 Hz (e.g., slow-wave oscillation frequency) and sampled at a rate of 500 Hz; each time a filtered EEG signal crosses a specified voltage threshold, an auditory tone will be triggered and sent through a speaker at approximately 45-50 dB.

[0074] In FIG. 3, a schematic of phase-locked loop is shown. In particular, Input sinusoidal signals from EEG electrodes 301 are amplified and digitized into EEG-software by a processor, which may be processor 202 or the processor of another computer. The raw data is then low and high-pass filtered to visualize delta-range frequency (305) and then further filtered for a voltage threshold common in slow-wave oscillations (307). Changes in the depolarization state of slow- wave oscillation signal (307) will trigger auditory tone signal 309 to occur in a phase-locked fashion, while a reference signal of the auditory tone trigger is marked in the FI data.

[0075] With reference to FIG. 3, the algorithm may trigger the auditory tone during the upstate (or beginning) of the slow-wave by setting a depolarization threshold in the filtered EEG signal (threshold will be set to -80pV). Setting the auditory tone during the upstart of the slow-wave allows for the accurate delivery of auditory stimuli due to the millisecond-range delay in signal processing .

[0076] It should be noted that an embodiment of the invention modulates the user’s oscillations in real time, developing a personalized sleep schedule based on the outcome. Slow frequency auditory stimuli, or other suitable stimuli, are synchronized to each slow-wave oscillation detected by the EEG, which results in enhancement of the amplitude of the slow-wave oscillation in the user.

[0077] In an embodiment, the slow-wave therapy is configured for use at specified times. For example, the slow-wave therapy may be used just at the beginning of the sleep cycle, to induce sleep. In a further example, slow-wave therapy may be used throughout the night (or sleep period), at multiple stages, to enhance slow-wave oscillations that occur numerous times during a sleep session.

[0078] As discussed above, preferred frequencies of sleep activity, e.g., preferred slow-wave oscillation frequencies, may be alpha (8-12 Hz) and delta (1-4 Hz) wave ranges. When excessive beta (12-30 Hz) wave ranges are present, insomnia is found to be more prevalent.

[0079] Thus, embodiments disclosed herein are configured to non-invasively modulate brain activity by amplifying slow wave oscillations. The modulation is accomplished by utilizing stimuli, such as sound-based stimuli, haptic-based stimuli, or other suitable forms. The brain activity is monitored and measured using a closed-loop EEG, which, at a predetermined proper time, wirelessly signals a synchronized slow-frequency auditory stimulus.

[0080] In an embodiment, exemplary auditory stimulation is formed of clicks or tones. In one embodiment, pink noise, formed of equal energy per octave, is used for auditory stimulation, with tones or clicks at approximately 30-60 dB. The frequency of the pink noise may be set to 1- 12 Hz, and/or delivered through wireless earphones.

[0081] In embodiments, auditory stimulation may be adjusted to different frequencies, which will depend and be modified, based on the individual’s natural slow-wave oscillations during sleep. The auditory tones, as disclosed, are synchronized with the upstate of specified EEG- detected oscillations, resulting in a closed-loop feedback method. In embodiments, the EEG is in communication with an amplifier. The amplifier is configured to detect specific predetermined oscillations, and only based on those predetermined oscillations, synchronize stimuli, such as auditory tones, in response. This then produces or amplifies slow-wave oscillations in the user.

[0082] In certain embodiments, the therapy may be used as part of a treatment regimen, in conjunction with the use of one or more pharmaceutical compositions. Exemplary

pharmaceutical compositions known for treating insomnia that may be used in conjunction with the therapy include: (a) GABA-A receptor Agonists, including benzodiazepines and

benzodiazepine receptor agonists that act on GABA receptor sites and exert sedative, anxiolytic, muscle relaxant, and/or hypnotic effects, such as Zolpidem, Zaleplon and Eszopiclone; (b) Melatonin Receptor Agonists, such as Melatonin, Ramelteon and Tasimelteon; (c) Orexin Receptor Agonists, such as Suvorexant (in doses of, for example, 5 mg, 10 mg, 15 mg, or 20 mg); (d) Histamine- 1 Receptor Antagonists, such as Doxepin (in doses of, for example, 3 mg and 6 mg; (e) Selective Serotonin Reuptake Inhibitors, such as mirtazapine, fluoxetine, citalopram and sertraline; (f) Tricylic antidepressants, such as doxepin, amitriptyline, and trimipramine; and (g) other suitable anti-depressants, anti convulsants or atypical antipsychotics.

[0083] While this invention has been described in conjunction with the embodiments outlined above, many alternatives, modifications and variations will be apparent to those skilled in the art upon reading the foregoing disclosure. Accordingly, the embodiments of the invention, as set forth above, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention.

Claims

WHAT IS CLAIMED IS:

1. A computer system for slow-wave sleep modulation therapy comprising one or more processors, one or more computer-readable memories, and one or more computer-readable storage devices, and program instructions stored on at least one of the one or more storage devices for execution by at least one of the one or more processors via at least one of the one or more memories, the stored program instructions comprising:

determining a need for sleep wave modulation; and

providing the modulation via slow-wave stimulus to a user, wherein the slow-wave stimulus comprises oscillations of a frequency between 0.25 and 8 Hz, and wherein, in response to the slow-wave stimulus, a brain frequency of the user receiving the slow-wave stimulus is modulated closer to the frequency of the slow-wave stimulus than the brain frequency prior to receiving the slow-wave stimulus.

2. The slow-wave sleep modulation therapy system according to claim 1, wherein the slow- wave stimulus is at least one of an auditory stimulus, a visual stimulus, a mechanical stimulus, an electrical stimulus, and a haptic stimulus.

3. The slow-wave sleep modulation therapy system according to claim 2, wherein the slow- wave stimulus is the auditory stimulus, and wherein the auditory stimulus is delivered to a user via a speaker, and wherein an electroacoustic transducer is used to convert an electrical audio signal into the auditory stimulus.

4. The slow-wave sleep modulation therapy system according to claim 2, wherein the slow- wave stimulus is the auditory stimulus, and wherein the auditory stimulus is delivered to a user via a speaker and wherein the auditory stimulus is a click train, wherein the click train comprises a plurality of clicks.

5. The slow-wave sleep modulation therapy system according to claim 2, wherein the slow- wave stimulus is the electrical stimulus.

6. The slow-wave sleep modulation therapy system according to claim 5, wherein the electrical stimulus delivers the slow-wave stimulus by generating a plurality of clicks.

7. The slow-wave sleep modulation therapy system according to claim 5, wherein a duration of the slow-wave stimulus is approximately 20 seconds.

8. The slow-wave sleep modulation therapy system according to claim 1, wherein determining the need for sleep wave modulation comprises determining, via

electroencephalography (“EEG”) on a brain of the user, whether the user has reduced slow-wave oscillation brain activity.

9. The slow-wave sleep modulation therapy system according to claim 8, wherein a time for beginning administration of the slow-wave stimulus is determined based on presence of a truncated, defective or low amplitude slow-wave oscillation on the EEG.

10. The slow-wave sleep modulation therapy system according to claim 8, wherein a time for administration of the slow-wave stimulus is determined based on at the start of a slow-wave sleep cycle.

11. The slow-wave sleep modulation therapy system according to claim 1, wherein determining the need for sleep wave modulation comprises determining, via

electroencephalography (“EEG”) on a brain of the user, whether the user has an abnormal amount of beta activity.

12. The slow-wave sleep modulation therapy system according to claim 11, wherein an abnormal amount of beta activity comprises consistent brain activity at a frequency of 14-35 Hz.

13. The slow-wave sleep modulation therapy system according to claim 1, wherein the frequency of the slow-wave stimulus is 1-4 Hz.

14. The slow-wave sleep modulation therapy system according to claim 2, wherein the slow- wave stimulus is an auditory stimulus, and wherein the auditory stimulus is delivered to the user binaurally via ear headphones.

15. A computer implemented method for slow- wave sleep modulation therapy, the method comprising:

determining a need for sleep wave modulation; and

16. The slow-wave sleep modulation therapy method according to claim 1, wherein the slow- wave stimulus is at least one of an auditory stimulus, a visual stimulus, a mechanical stimulus, an electrical stimulus, and a haptic stimulus.

17. The slow-wave sleep modulation therapy method according to claim 16, wherein the slow-wave stimulus is the auditory stimulus, and wherein the auditory stimulus is delivered to a user via a speaker, and wherein an electroacoustic transducer is used to convert an electrical audio signal into the auditory stimulus.

18. The slow-wave sleep modulation therapy method according to claim 16, wherein the slow-wave stimulus is the auditory stimulus, and wherein the auditory stimulus is delivered to a user via a speaker and wherein the auditory stimulus is a click train, wherein the click train comprises a plurality of clicks.

19. The slow-wave sleep modulation therapy method according to claim 1, wherein determining the need for sleep wave modulation comprises determining, via

20. The slow-wave sleep modulation therapy method according to claim 19, wherein a time for administration of the slow-wave stimulus is determined based on a truncated, defective or low amplitude slow-wave oscillation.