Use of immersive sound devices to prevent or treat CNS related diseases

Abstract

The field of the invention relates to the glymphatic system, which is involved in the elimination of brain metabolic brain waste products. The field of the invention also relates to the use of specific sound waves to treat CNS patients or prevent CNS related diseases, whether or not simultaneously releasing or infusing cerebrospinal fluid. The field of the invention also relates to the use of specific sound waves as a tool for drug delivery to the central nervous system.

Description

[0001] USE OF IMMERSIVE SOUND DEVICES TO PREVENT OR TREAT CNS RELATED DISEASES

[0002] Field of the invention

[0003] The field of the invention relates to the glymphatic system, which is involved in the elimination of brain metabolic brain waste products. The field of the invention also relates to the use of specific sound waves to treat CNS patients or prevent CNS related diseases, whether or not simultaneously releasing or infusing cerebrospinal fluid. The field of the invention also relates to the use of specific sound waves as a tool for drug delivery to the central nervous system.

[0004] Background

[0005] As the brain lacks a conventional lymphatic drainage system, the elimination of brain metabolic waste products remained an enigma until the groundbreaking discovery of the glymphatic system. In 2012, the Nedergaard laboratory (Iliff JJ et al., Sci Transl Med. 2012) first described this brain-wide clearance pathway in mice. Since then, several magnetic resonance imaging studies have confirmed its existence in the human brain. Accumulating evidence indicates that malfunction of glymphatic system transport is involved in many neurodegenerative diseases, especially those associated with the accumulation of neurotoxic peptides, such as amyloid-p (Ap) peptides involved in the progression of Alzheimer’s disease (AD). The glymphatic system serves as a novel promising target in the treatment of a wide range of neurological conditions, including neurodegenerative diseases, such as AD, neurovascular disorders, conditions associated with altered cerebrospinal fluid (CSF) dynamics, neurodevelopmental disorders, chronic fatigue syndrome, long COVID-19 or post-COVID-19 conditions, and fibromyalgia.

[0006] Recent findings regarding spaceflight-associated alterations in cerebrospinal fluid spaces, demonstrating enlargement of the brain’s perivascular spaces from preflight to postflight, at least suggest reduced glymphatic clearance in microgravity, and have raised concerns about long-term cognitive health in astronauts. Therefore, it is critical for future long-duration human exploration missions to identify, develop and validate all potentially effective long-term countermeasures capable of reducing the risk of perivascular space enlargement and impaired glymphatic transport in space mission crews. Furthermore, it is crucial to implement effective strategies that would allow crew members to maintain optimal psychological well-being during future long-duration space exploration.

[0007] Summary of the invention

[0008] The invention is summarized in the following embodiments:

[0009] As a first embodiment, A sound-emitting device for treating a patient suffering from a disease related to the central nervous system (CNS) or for preventing CNS related diseases, characterized in that the device emits audible sound waves surrounding the patient or subject with frequencies ranging from 30 Hz to 50 Hz.

[0010] As a second embodiment, the sound-emitting device of embodiment 1 , wherein the sound waves are three-dimensional sound waves.

[0011] As a third embodiment, the sound-emitting device of embodiments 1 or 2, wherein the device is a headphone or an immersive sound device.

[0012] As a fourth embodiment, the sound-emitting device of any of the embodiments 1 to 3, wherein the device emits continuous sound waves ranging from 30 Hz to 50 Hz, combined with various sound waves ranging from 20 Hz to 20 KHz.

[0013] As a fifth embodiment, the sound-emitting device of any of the embodiments 1 to 4, wherein the device emits continuous sound waves of about 40 Hz.

[0014] As a sixth embodiment, the sound-emitting device of any of the embodiments 1 to 5 wherein the CNS related disease is selected from the list of fibromyalgia, chronic pain, depression, sleep disorders, Parkinson's disease, Alzheimer's disease, diabetes-induced dementia, amyotrophic lateral sclerosis, multiple sclerosis, post-infectious syndromes, long-COVID, chronic fatigue syndrome, Huntington’s disease, Frontotemporal dementia, normal-tension glaucoma, traumatic brain injury, ischemic stroke, cerebral microinfarcts, cerebral small vessel disease, intracranial hemorrhage, subarachnoid hemorrhage, normal pressure hydrocephalus and idiopathic intracranial hypertension.

[0015] As a seventh embodiment, A method of treating a patient suffering from a CNS related disease or preventing CNS related diseases by exposing the patient or subject to the sound-emitting device of any of the embodiments 1 to 6.

[0016] As an eight embodiment, a method of treating a patient suffering from a CNS related disease or preventing CNS related diseases according to the method of embodiment 7, while simultaneously administering or releasing cerebrospinal fluid (CSF) into or from the intrathecal space, cisterna magna, or cerebral ventricles of said patient or subject.

[0017] As a nineth embodiment, a method of treating a patient suffering from a CNS related disease or preventing CNS related diseases according to any of the methods of claim 7 or

[0018] 8, while simultaneously administering a therapeutic compound into the intrathecal space, cisterna magna, or cerebral ventricles of said patient or subject.

[0019] As a tenth embodiment, a method of treating a patient suffering from a CNS related disease or preventing CNS related diseases according to any of the methods of embodiment 7 to

[0020] 9, wherein the patient or subject is exposed to the sound-emitting device between 1 to 3 hours a day, during 1 to 7 times per week.

[0021] As an eleventh embodiment, a method of treating a patient suffering from a CNS related disease according to any of the methods of embodiments 7 to 10, wherein the CNS related disease is selected from the list of fibromyalgia, chronic pain, depression, sleep disorders, Parkinson's disease, Alzheimer's disease, diabetes-induced dementia, amyotrophic lateral sclerosis, multiple sclerosis, post-infectious syndromes, long-COVID, chronic fatigue syndrome, Huntington’s disease, Frontotemporal dementia, normal-tension glaucoma, traumatic brain injury, ischemic stroke, cerebral microinfarcts, cerebral small vessel disease, intracranial hemorrhage, subarachnoid hemorrhage, normal pressure hydrocephalus and idiopathic intracranial hypertension.

[0022] As a twelfth embodiment, a method of preventing a subject from developing a CNS related disease by exposing the subject to a sound-emitting device of any of the embodiments 1 to 5.

[0023] As a thirteenth embodiment, a method of preventing a subject from developing a CNS related disease according to any of the embodiments 8 to 10.

[0024] As a fourteenth embodiment, a method of a subject from developing a CNS related disease according to any of the methods of embodiments 12 or 13, wherein the CNS related disease is selected from the list of fibromyalgia, chronic pain, depression, sleep disorders, Parkinson's disease, Alzheimer's disease, diabetes-induced dementia, amyotrophic lateral sclerosis, multiple sclerosis, post-infectious syndromes, long-COVID, chronic fatigue syndrome, Huntington’s disease, Frontotemporal dementia, normal-tension glaucoma, traumatic brain injury, ischemic stroke, cerebral microinfarcts, cerebral small vessel disease, intracranial hemorrhage, subarachnoid hemorrhage, normal pressure hydrocephalus and idiopathic intracranial hypertension.

[0025] As a fifteenth embodiment, the use of the sound-emitting device of any of the embodiments 1 to 5 for the prevention of a CNS related diseases, wherein said use is taking place in an environment of microgravity, preferably when the subject is in an awakening state.

[0026] As a sixteenth embodiment, a system comprising a sound-emitting device; wherein the sound-emitting device is configured to emit an audible sound having a relative band energy of 0.01 to 0.15 of a gamma band; wherein the gamma band is the frequency band ranging from 30 Hz to 50 Hz; wherein the sound-emitting device is configured to deliver the audible sound to a person to simulate a three-dimensional audio experience to the person; wherein the system is configured to treat or prevent a central nervous system disorder.

[0027] As a seventeenth embodiment, a system of embodiment 16, wherein the sound-emitting device is a headphone.

[0028] As an eighteenth embodiment, a system of embodiments 16-17, wherein the sound system is an immersive sound device comprising at least four speakers arranged around the person.

[0029] As a nineteenth embodiment, system of embodiments 16-18, wherein the audible sound is music.

[0030] As a twentieth embodiment, a system of embodiments 16-19, wherein the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

[0031] As a twenty-first embodiment, a system of embodiments 16-20, wherein the relative band energy of the gamma band is 0.01 to 0.1 , preferably 0.02 to 0.075.

[0032] As a twenty-second embodiment, a system of embodiments 16-21 , comprising a cerebrospinal fluid access port configured to administer or release cerebrospinal fluid into or from the intrathecal space, cisterna magna, or cerebral ventricles of the person. As a twenty-third embodiment, a system of embodiments 16-22, comprising a drug delivery system configured to administer a therapeutic compound into the intrathecal space, cisterna magna, or cerebral ventricles of the person.

[0033] As a twenty-fourth embodiment, a method of treating or preventing a central nervous system disorder in a person, comprising the step of exposing the person to the system of any one of embodiments 16-23.

[0034] As a twenty-fifth embodiment, the method of treating or preventing the central nervous system disorder of embodiment 24, wherein the person is exposed to the system 1 to 3 hours per day for 1 to 7 times per week.

[0035] As a twenty-sixth embodiment, the method of treating or preventing the central nervous system disorder of embodiment 24 or 25, wherein the central nervous system disorder is fibromyalgia, chronic pain, depression, sleep disorders, Parkinson's disease, Alzheimer's disease, diabetes-induced dementia, amyotrophic lateral sclerosis, multiple sclerosis, post- infectious syndromes, long-COVID, chronic fatigue syndrome, Huntington’s disease, frontotemporal dementia, normal-tension glaucoma, traumatic brain injury, ischemic stroke, cerebral microinfarcts, cerebral small vessel disease, intracranial haemorrhage, subarachnoid haemorrhage, normal pressure hydrocephalus, or idiopathic intracranial hypertension.

[0036] As a twenty-seventh embodiment, a method of treating or preventing a central nervous system disorder related to spaceflight or spaceflight-associated neuro-ocular syndrome in a person, comprising the step of exposing the person to the system of any one of embodiments 16-23 in an environment of microgravity, preferably when the person is awake.

[0037] As a twenty-seventh embodiment, a method of operating a system as described in any one of embodiments 16-23, comprising the steps of: obtaining feedback from a person who has been predelivered with the system as described in any one of claims 1 to 8; and adapting the relative band energy of the gamma band based on the feedback of the person.

[0038] Definitions

[0039] Various terms relating to the systems, methods, compositions, formulations, uses and other aspects of the present invention are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art to which the invention pertains, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein.

[0040] Methods of carrying out the conventional techniques used in methods of the invention will be evident to the skilled worker. The practice of conventional techniques in molecular biology, biochemistry, computational chemistry, cell culture, recombinant DNA, bioinformatics, genomics, sequencing and related fields are well-known to those of skill in the art and are discussed, for example, in the following literature references: Sambrook et al., Molecular Cloning. A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 1989; Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1987 and periodic updates; and the series Methods in Enzymology, Academic Press, San Diego.

[0041] “A,” “an,” and “the”: these singular form terms include plural referents unless the content clearly dictates otherwise. The indefinite article "a" or "an" thus usually means "at least one". Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0042] “About” and “approximately”: these terms, when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1 %, and still more preferably ±0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods. Additionally, amounts, ratios, and other numerical values are sometimes presented herein in a range format. It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth.

[0043] “And / or”: The term “and / or” refers to a situation wherein one or more of the stated cases may occur, alone or in combination with at least one of the stated cases, up to with all of the stated cases.

[0044] “Comprising”: this term is construed as being inclusive and open ended, and not exclusive. Specifically, the term and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.

[0045] A “subject” or “subject in need” as used herein may be a human (preferred) or a non-human animal. In some embodiments, the subject (in need) can be a healthy subject, especially in the context of preventing a disease or condition related to the CNS.

[0046] “Exemplary": this terms means "serving as an example, instance, or illustration," and should not be construed as excluding other configurations disclosed herein.

[0047] As used in the following description of embodiments, an “audio object” includes 3-D positional data. Thus, an audio object should be understood to include a particular combined representation of an audio source with static or dynamic 3-D positional data. In contrast, a “sound source” is an audio signal for playback or reproduction in a final mix or render and it has an intended static or dynamic rendering method or purpose. A sound source may be associated with one or more specific channels (e.g., the signal “Front Left,” the low frequency effects (LFE) channel), associated with a panning between two or more sound source origination directions (e.g., panned from a center channel to 90 degrees to the right), or associated with other directional configurations. Detailed description

[0048] Described herein are sound systems for use in the treatment or prevention of diseases related to the Central Nervous System (CNS) that provide for enhanced audio in an immersive environment. A surround d sound system includes multiple speakers or headphones for reproducing an audio source for a listener (e.g., a patient suffering from a CNS related disease). A typical surround sound system may include front, rear, or side speakers arranged to create the perception of sound coming from any direction in a horizontal plane around the patient or subject. An immersive sound system may include speakers above or below a patient's or subject’s ears, which may be used to create the perception of sound coming from any location around the patient or subject.

[0049] Surround or immersive sound systems may be able to localize a sound to a particular point in a room, and typically localize sound at a “sweet spot” or primary listening position, which describes a patient's or subject’s physical position that localizes the reproduced sound at the location of the listener's ears.

[0050] The audio source may include multiple audio signals (i.e., signals representing physical sound), provided, however, that there is a continuous audio signal or sounds wave that produces a sound wave between 30 Hz and 50 Hz, preferably about 40 Hz. These audio signals are represented by digital electronic signals. These audio signals may be analog, however typical embodiments of the present subject matter would operate in the context of a time series of digital bytes or words, where these bytes or words form a discrete approximation of an analog signal or ultimately a physical sound or sound wave. The discrete, digital signal corresponds to a digital representation of a periodically sampled audio waveform. The techniques and apparatus of the present subject matter typically would be applied interdependently in a number of channels. For example, it could be used in the context of a “surround” audio system (e.g., having more than two channels).

[0051] As used herein, a “digital audio signal” or “audio signal” does not describe a mere mathematical abstraction, but instead denotes information embodied in or carried by a physical medium capable of detection by a machine or apparatus. These terms include recorded or transmitted signals, and should be understood to include conveyance by any form of encoding, including pulse code modulation (PCM) or other encoding. Outputs, inputs, or intermediate audio signals could be encoded or compressed by any of various known methods, including MPEG, ATRAC, AC3, or the proprietary methods of DTS, Inc. as described in U.S. Pat. Nos. 5,974,380; 5,978,762; and 6,487,535. Some modification of the calculations may be required to accommodate a particular compression or encoding method, as will be apparent to those with skill in the art.

[0052] In software, an audio “codec” includes a computer program that formats digital audio data according to a given audio file format or streaming audio format. Most codecs are implemented as libraries that interface to one or more multimedia players, such as QuickTime Player, XMMS, Winamp, Windows Media Player, Pro Logic, or other codecs. In hardware, audio codec refers to one or more devices that encode analog audio as digital signals and decode digital back into analog. In other words, it contains both an analog-to-digital converter (ADC) and a digital-to-analog converter (DAC) running off a common clock.

[0053] An audio codec may be implemented in a consumer electronics device, such as a DVD player, Blu-Ray player, TV tuner, CD player, handheld player, Internet audio / video device, gaming console, mobile phone, or another electronic device. A consumer electronic device includes a Central Processing Unit (CPU), which may represent one or more conventional types of such processors, such as an IBM PowerPC, Intel Pentium (x86) processors, or other processor. A Random Access Memory (RAM) temporarily stores results of the data processing operations performed by the CPU, and is interconnected thereto typically via a dedicated memory channel. The consumer electronic device may also include permanent storage devices such as a hard drive, which are also in communication with the CPU over an input / output (I / O) bus. Other types of storage devices such as tape drives, optical disk drives, or other storage devices may also be connected. A graphics card may also be connected to the CPU via a video bus, where the graphics card transmits signals representative of display data to the display monitor. External peripheral data input devices, such as a keyboard or a mouse, may be connected to the audio reproduction system over a USB port. A USB controller translates data and instructions to and from the CPU for external peripherals connected to the USB port. Additional devices such as printers, microphones, speakers, or other devices may be connected to the consumer electronic device.

[0054] The consumer electronic device may use an operating system having a graphical user interface (GUI), such as WINDOWS from Microsoft Corporation of Redmond, Wash., MAC OS from Apple, Inc. of Cupertino, Calif., various versions of mobile GUIs designed for mobile operating systems such as Android, or other operating systems. The consumer electronic device may execute one or more computer programs. Generally, the operating system and computer programs are tangibly embodied in a computer-readable medium, where the computer-readable medium includes one or more of the fixed or removable data storage devices including the hard drive. Both the operating system and the computer programs may be loaded from the aforementioned data storage devices into the RAM for execution by the CPU. The computer programs may comprise instructions, which when read and executed by the CPU, cause the CPU to perform the steps to execute the steps or features of the present subject matter.

[0055] The audio codec may include various configurations or architectures. Any such configuration or architecture may be readily substituted without departing from the scope of the present subject matter. A person having ordinary skill in the art will recognize the above-described sequences are the most commonly used in computer-readable mediums, but there are other existing sequences that may be substituted without departing from the scope of the present subject matter.

[0056] Elements of one embodiment of the audio codec may be implemented by hardware, firmware, software, or any combination thereof. When implemented as hardware, the audio codec may be employed on a single audio signal processor or distributed amongst various processing components. When implemented in software, elements of an embodiment of the present subject matter may include code segments to perform the necessary tasks. The software preferably includes the actual code to carry out the operations described in one embodiment of the present subject matter, or includes code that emulates or simulates the operations. The program or code segments can be stored in a processor or machine accessible medium or transmitted by a computer data signal embodied in a carrier wave (e.g., a signal modulated by a carrier) over a transmission medium. The “processor readable or accessible medium” or “machine readable or accessible medium” may include any medium that can store, transmit, or transfer information.

[0057] Examples of the processor readable medium include an electronic circuit, a semiconductor memory device, a read only memory (ROM), a flash memory, an erasable programmable ROM (EPROM), a floppy diskette, a compact disk (CD) ROM, an optical disk, a hard disk, a fiber optic medium, a radio frequency (RF) link, or other media. The computer data signal may include any signal that can propagate over a transmission medium such as electronic network channels, optical fibers, air, electromagnetic, RF links, or other transmission media. The code segments may be downloaded via computer networks such as the Internet, Intranet, or another network. The machine accessible medium may be embodied in an article of manufacture. The machine accessible medium may include data that, when accessed by a machine, cause the machine to perform the operation described in the following. The term “data” here refers to any type of information that is encoded for machine-readable purposes, which may include program, code, data, file, or other information.

[0058] Embodiments of the present subject matter may be implemented by software. The software may include several modules coupled to one another. A software module is coupled to another module to generate, transmit, receive, or process variables, parameters, arguments, pointers, results, updated variables, pointers, or other inputs or outputs. A software module may also be a software driver or interface to interact with the operating system being executed on the platform. A software module may also be a hardware driver to configure, set up, initialize, send, or receive data to or from a hardware device.

[0059] Embodiments of the present subject matter may be described as a process that is usually depicted as a flowchart, a flow diagram, a structure diagram, or a block diagram. Although a block diagram may describe the operations as a sequential process, many of the operations can be performed in parallel or concurrently. In addition, the order of the operations may be rearranged. A process may be terminated when its operations are completed. A process may correspond to a method, a program, a procedure, or other group of steps.

[0060] Although specific embodiments have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that any arrangement that is calculated to achieve the same purpose may be substituted for the specific embodiments shown. Various embodiments use permutations and / or combinations of embodiments described herein. It is to be understood that the above description is intended to be illustrative, and not restrictive, and that the phraseology or terminology employed herein is for the purpose of description. Combinations of the above embodiments and other embodiments will be apparent to those of skill in the art upon studying the above description. This disclosure has been described in detail and with reference to exemplary embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the embodiments. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents. Each patent and publication referenced or mentioned herein is hereby incorporated by reference to the same extent as if it had been incorporated by reference in its entirety individually or set forth herein in its entirety. Any conflicts of these patents or publications with the teachings herein are controlled by the teaching herein.

[0061] In an aspect, the invention provides a system comprising a sound-emitting device; wherein the sound-emitting device is configured to emit an audible sound having a relative band energy of 0.01 to 0.25 of a gamma band; wherein the gamma band is the frequency band ranging from 30 Hz to 50 Hz; wherein the sound-emitting device is configured to deliver the audible sound to a person to simulate a three-dimensional audio experience to the person; wherein the system is configured to treat or prevent a central nervous system disorder.

[0062] In embodiments, the gamma band is the frequency band ranging from 30 Hz to 50 Hz, from

[0063] 30.5 Hz to 49.5 Hz, from 31 Hz to 49 Hz, from 31 .5 Hz to 48.5 Hz, from 32 Hz to 48 Hz, from 32.5 Hz to 47.5 Hz, from 33 Hz to 47 Hz, from 33.5 Hz to 46.5 Hz, from 34 Hz to 46 Hz, from 34.5 Hz to

[0064] 45.5 Hz, from 35 Hz to 45 Hz, from 35.5 Hz to 44.5 Hz, from 36 Hz to 44 Hz, from 36.5 Hz to 43.5 Hz, from 37 Hz to 43 Hz, from 37.5 Hz to 42.5 Hz, from 38 Hz to 42 Hz, from 38.5 Hz to 41 .5 Hz, from 39 Hz to 41 Hz, or from 39.5 Hz to 40.5 Hz.

[0065] In embodiments, the relative band energy is 0.01 to 0.25, 0.02 to 0.25, 0.03 to 0.25, 0.04 to 0.25, 0.05 to 0.25, 0.06 to 0.25, 0.07 to 0.25, 0.08 to 0.25, 0.09 to 0.25, 0.10 to 0.25, 0.11 to 0.25, 0.12 to 0.25, 0.13 to 0.25, 0.14 to 0.25, 0.15 to 0.25, 0.16 to 0.25, 0.17 to 0.25, 0.18 to 0.25, 0.19 to 0.25, 0.20 to 0.25, 0.21 to 0.25, 0.22 to 0.25, 0.23 to 0.25, or 0.24 to 0.25. Preferably, the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

[0066] In embodiments, the relative band energy is 0.01 to 0.20, 0.02 to 0.20, 0.03 to 0.20, 0.04 to 0.20, 0.05 to 0.20, 0.06 to 0.20, 0.07 to 0.20, 0.08 to 0.20, 0.09 to 0.20, 0.10 to 0.20, 0.11 to 0.20, 0.12 to 0.20, 0.13 to 0.20, 0.14 to 0.20, 0.15 to 0.20, 0.16 to 0.20, 0.17 to 0.20, 0.18 to 0.20, or 0.19 to 0.20. Preferably, the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

[0067] In embodiments, the relative band energy is 0.01 to 0.15, 0.02 to 0.15, 0.03 to 0.15, 0.04 to 0.15, 0.05 to 0.15, 0.06 to 0.15, 0.07 to 0.15, 0.08 to 0.15, 0.09 to 0.15, 0.10 to 0.15, 0.11 to 0.15, 0.12 to 0.15, 0.13 to 0.15, or 0.14 to 0.15. Preferably, the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

[0068] In embodiments, the relative band energy is 0.01 to 0.10, 0.02 to 0.10, 0.03 to 0.10, 0.04 to 0.10, 0.05 to 0.10, 0.06 to 0.10, 0.07 to 0.10, 0.08 to 0.10, or 0.09 to 0.10. Preferably, the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

[0069] In embodiments, the relative band energy is 0.01 to 0.05, 0.02 to 0.05, 0.03 to 0.05, or 0.04 to 0.05. Preferably, the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

[0070] The relative band energy refers to a normalized measure of the energy present within a specified frequency band of an audio signal, expressed as a ratio with respect to the total energy of the signal over a broader reference frequency range. In this application, the relative band energy is thus defined as the integrated energy of the audio signal in the gamma band (30 Hz to 50 Hz, preferably 35 Hz to 45 Hz) to the total integrated energy of the audio signal (i.e. from 20 Hz to 20 KHz).

[0071] In one embodiment, an example speaker system includes a transparent material that covers an immersive display screen. The transparent material is wired to produce both sounddetecting and sound producing sections. The sections include microphone sections spread across the display screen and noise- cancelation speakers adjacent to the microphones, providing an active noise cancelation system. The sections may also include theater-speaker sections for presenting audio to a theater area.

[0072] In another embodiment, an in-seat speaker system includes several speakers in a theater chair, placed in various locations. In particular, the chair may contain a pair of speakers above the ears and a pair below the ears (or just one speaker for each ear), set within the headrest area of the chair.

[0073] In other embodiments, a speaker arrangement for an immersive theater area includes a speaker area in one section of the periphery of the theater area (upper center of the torus in a toroidal embodiment), and an additional speaker arrangement such as: i. In the case of a "font projection only" system, a screen made of a sound deadening material (such as foam) that includes thinner sections behind which speakers reside, ii. In the case of a "font projection only" system, a screen made of a material essentially transparent to sound (e.g., perforated aluminum), with both sound deadening material (e.g., fiberglass) and speakers residing behind it. Hi. In the case of a "one LED screen only" system: a screen made of "transparent" LED panels which are essentially transparent to sound, and behind which reside both speakers and sound deadening material, iv. In the case of any visual exhibition system, in order to supplement the in-seat system (so audio is audile when the audience member is not seated, or if certain audience members do not have an inseat system) speakers may be mounted upstage and facing up and away from the audience that propagate sound into and along the surface of the torus shape. The torus would ultimately direct the sound around itself and into the audience, effectively turning the entire torus itself into a speaker cabinet, v. In the case of a "compositing screen" (in which an image on a semi-transparent "front screen" is viewed simultaneously with an image on a back screen through the front screen), a "front screen" which is mostly transparent to sound (i.e., perforated aluminum), with a back screen made of transparent LED panels which are essentially transparent to sound, and behind which reside both speakers and sound deadening material.

[0074] In yet another embodiment, a method of immersive sound control may involve using sections of a material layer to detect sounds, and using adjacent sections of the material layer to produce out of phase acoustic vibrations that cancel out the detected sounds (so as to eliminate the reflected sound). The method may also involve using other sections of the material layer as theater speakers to present audio to the theater area.

[0075] Immersive sound, also termed a three-dimensional audio experience in this application, refers to a sound format where sounds, which are produced over loudspeakers or headphones, can be perceived as coming from all directions simultaneously. In other words, immersive sound or a three-dimensional audio experience refers to an audio signal or audio rendering technique configured to simulate the perception of sound originating from multiple spatial directions around a listener, including positions in the horizontal (azimuthal), vertical (elevation), and depth (distance) planes. In such setups, audio cues are generated or manipulated such that the listener perceives sound sources as being located in front of, behind, above, below, and / or around them, thereby creating a spatial auditory experience that emulates real-world acoustic environments. It mimics the way we hear sounds in our daily lives, giving the listener a natural, lifelike sound experience, and creating a sense of presence, i.e., a feeling of ‘being there’ through sound. Such non-invasive approach offers numerous advantages, making it an attractive candidate modulator of glymphatic function. One of the key advantages of immersive sound therapy is that the natural, lifelike sound experience makes people feel comfortable. Furthermore, it is a safe and relatively inexpensive method where a person may choose to participate in group sessions. Given that music can modify the bioelectrical activity of the brain, immersive sound can be specially designed to induce slow- wave activity, enhancing glymphatic clearance of harmful waste from the brain.

[0076] In embodiments, the sound-emitting device is an immersive sound device comprising at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 speakers. Preferably, the sound-emitting device does not comprise more than 10 speakers.

[0077] The sound emitting devices used in the invention hereunder, capable of emitting audible sound waves surrounding a patient or human subject with frequencies ranging from 30 Hz to 50 Hz, or frequencies ranging from 20Hz to 20KHz, that are designed to provide an enhanced, three- dimensional audio experience. These devices leverage advanced audio technologies to provide an immersive sound experience, making listeners feel as if they are part of the environment where the audio is being played, whether it's for home entertainment, gaming, virtual reality, or professional audio production. Examples of such devices that can be used in the invention hereunder are:

[0078] Home Theater Systems o Dolby Atmos Soundbars that have upward-firing speakers to create height channels, simulating a 3D sound environment (Sonos Arc, Samsung HW-Q950A, LG SN11 RG. o Surround Sound Speaker Systems, which are multi-speaker setups that include front, rear, and overhead speakers for a fully immersive audio experience (Bose Lifestyle 650, Klipsch Reference Premiere, JBL Bar 9.1 .)

[0079] Headphones and Earbuds o Binaural Headphones that are designed for binaural recording and playback to create a 3D sound experience through headphone (Sennheiser AMBEO Smart Headset, 3Dio Free Space Pro II) o 3D Audio Headphones that support spatial audio formats, providing an immersive listening experience (Sony WH-1000XM4 (with 360 Reality Audio), Bose QC35 II (with AR capabilities)).

[0080] Gaming Headsets o Gaming Headsets with Surround Sound that provide positional audio to enhance the gaming experience by allowing players to accurately locate sounds in a 3D space (SteelSeries Arctis Pro, Astro A50, Razer Kraken).

[0081] Smart Speakers o 360-Degree Smart Speakers that use multiple drivers and advanced audio processing to emit sound in all directions, creating an immersive audio experience (Amazon Echo Studio, Apple HomePod, Google Nest Audio).

[0082] VR and AR Headsets o VR Headsets with Spatial Audio that incorporate spatial audio technology to create a realistic and immersive VR experience by providing audio cues that match the virtual environment (Oculus Quest 2, HTC Vive Pro, Sony PlayStation VR).

[0083] Professional Audio Equipment o Immersive Audio Interfaces and Processors with high-end audio interfaces and processors used in professional studios to create and mix immersive audio content (Focusrite RedNet (for Dolby Atmos), Avid MTRX Studio (for immersive audio workflows).

[0084] Portable Speakers o 360-Degree Portable Speakers designed to emit sound in all directions, creating a more immersive listening experience outdoors or on the go (Ultimate Ears Megaboom 3, JBL Flip 5, Sony SRS-XB33).

[0085] Automotive Audio Systems o Car Audio Systems with Immersive Sound that use multiple speakers, including those placed in the ceiling and doors, to create a 3D sound environment within the vehicle (Bang & Olufsen 3D Advanced Sound System (in Audi), Burmester High- End 3D Surround Sound System (in Mercedes-Benz), Bose Panaray Sound System (in Cadillac)).

[0086] In a preferred embodiment, while the patient or subject is being exposed to or listens to the sound waves of the invention, being between 30 Hz and 50 Hz, preferably 40 Hz, the patient or subject is administered with CSF that flows from subarachnoid spaces into periarterial spaces to exchange with interstitial fluid (ISF) within the parenchyma, while interstitial solutes, including amyloid-p (Ap), are cleared from the brain along perivenous spaces for ultimate clearance via meningeal lymphatic vessels into cervical lymph nodes. The interchange between CSF and ISF is supported by aquaporin-4 (AQP4) water channels which are expressed in a highly polarized manner on the astrocytic endfeet ensheathing the cerebral vasculature.

[0087] Several key physiological modulators, including arterial pulsatility, respiration and slow vasomotion, can influence glymphatic flow, with cerebral arterial pulsatility as the main driving force of perivascular CSF flow. A remarkable finding further is that the glymphatic system is largely suppressed during wakefulness, while predominantly active during natural sleep, particularly nonrapid eye movement (non-REM) slow-wave sleep, or under certain anesthetics. Furthermore, the interstitial volume fraction increased by about 60% during natural sleep or ketamine / xylazine anesthesia compared with wakefulness, which presumably reduces the resistance to fluid flow. Further analysis showed that locus coeruleus-derived norepinephrine might be responsible for suppressing the glymphatic system in the wakened state as a result of contraction of the interstitial space. While norepinephrine is responsible for suppressing the glymphatic function, electroencephalographic (EEG) slow-wave activity (SWA) apparently has a facilitating effect. Slow waves or delta waves are high amplitude 0.5-4 Hz brain waves that are characteristic of deep sleep and certain types of anesthesia

[0088] Aging is associated with a dramatic impairment in glymphatic function. In the aging mouse brain, decreased cerebral arterial pulsatility and widespread loss of perivascular AQP4 polarization accompanied age-related impairment of glymphatic pathway function. In addition, glymphatic system dysfunction has been proposed to play a role in a variety of neurological diseases, such as AD, Parkinson’s disease, and idiopathic normal pressure hydrocephalus. Therefore, enhancing glymphatic function will have major preventive and therapeutic implications for brain health.

[0089] Based on the above findings, approaches for manipulating EEG spectra can be used to modulate glymphatic clearance. Various forms of external stimuli, including auditory stimuli like music, can alter the brain electrical activity. Immersive sound stimulation can be used as an intervention for inducing slow-wave delta oscillations, thereby promoting glymphatic clearance in a patient suffering from a CNS related disease. Immersive sound refers to a three-dimensional sound format where sounds, which are produced over loudspeakers or headphones, can be perceived as coming from all directions simultaneously. It mimics the way we hear sounds in our daily lives, giving the listener a natural, lifelike sound experience, and creating a sense of presence, i.e., a feeling of ‘being there’ through sound. Such non-invasive approach offers numerous advantages, making it an attractive candidate modulator of glymphatic function. One of the key advantages of immersive sound therapy is that the natural, lifelike sound experience makes people feel comfortable. Furthermore, it is a safe and relatively inexpensive method where a person may choose to participate in group sessions. Given that music can modify the bioelectrical activity of the brain, immersive sound could be specially designed to induce SWA, enhancing glymphatic clearance of harmful waste from the awake brain. However, it should be noted that delta oscillations during wakefulness are rare and that their occurrence is rather associated with states of impaired consciousness, including deep sleep, anesthesia, generalized epileptic seizures, coma and the vegetative state. In an embodiment of the invention we demonstrate that glymphatic activity can be modulated in the awake brain.

[0090] In an embodiment of the invention, inducing gamma oscillations using (multi)sensory stimulation at 40 Hz ameliorate patients suffering from a CNS related disease or prevent CNS related diseases. Such can also be obtained by visual stimulation by 40 Hz light flicker for one hour to induces 40 Hz oscillations. In a preferred embodiment, applying for consecutive days an exposure of one hour of 40 Hz light flicker to the patient, reduces toxic residues from the brain of such patient. Also one- hour daily exposure to 40 Hz auditory stimulation for at least 1 week results in significant reductions in toxic residue load in the brain. In another preferred embodiment, somatosensory stimulation is delivered by a chair which produced 40 Hz sound waves through multiple speakers. For example in patients suffering from Alzheimer’s Disease or memory loss, such treatment can result in improved cognition and has an impact on the cognitive function of patients with for example mild and moderate AD.

[0091] An important aspect of the invention hereunder is that 40 Hz auditory stimulation can serve as a neuroprotective strategy by maintaining and optimizing glymphatic clearance. This can be applied in both clinical and home-based settings, especially since this is a safe and feasible approach. Furthermore, to maximize the beneficial effects of 40 Hz auditory stimulation on brain function and disease pathology, integrating this approach into daily long-term usage would be essential. However, simple 40 Hz auditory stimuli are often perceived as rough and unpleasant sounds by listeners, posing a significant obstacle to the long-term use of 40 Hz auditory stimulation. Therefore, another embodiment of the invention is the integration of 40 Hz stimulation with music, representing various sound waves in the range 20 Hz to 20 KHz.

[0092] In another embodiment of the invention, gamma music-based interventions, particularly gamma music through immersive audio technology show beneficial effects on glymphatic function in the awake brain by promoting 40 Hz neural activity and enhancing glymphatic clearance, while offering a comfortable, natural three-dimensional sound experience to the listener. An important advantage of the invention is its non-invasive approach for promoting healthy brain aging and preventing neurodegenerative disorders such as AD. In another embodiment of the invention, modulation of glymphatic flow by immersive gamma music is used clinically to increase the delivery of intratheca lly administered drugs within the CNS in the awake state. The delivery of drugs to the CNS is particularly challenging due to the blood-brain barrier (BBB) but in an embodiment of the invention, direct administration of drugs to the CSF provides a method for bypassing the BBB, while enhanced glymphatic transport facilitated by immersive gamma music improves CNS delivery of therapeutics in the awake state. In an embodiment of the invention, immersive gamma music is used as an add-on countermeasure that in combination with existing countermeasures can optimize glymphatic clearance in astronauts while improving their mental well-being. The advantage of this embodiment of the invention is in the practice of space medicine to be used in future human missions, including a return to the moon and manned missions to Mars. The effect of the invention lies in providing optimal glymphatic function that is essential for overall astronaut brain health. The present invention reduces the risk of PVS expansion and glymphatic dysfunction in space crews, either alone or as an add-on to countermeasures such as artificial gravity via centrifugation, venoconstrictive thigh cuffs (VTC), lower body negative pressure (LBNP), and impedance threshold device (ITD) resistive inspiratory breathing.

[0093] The invention of providing immersive sound gamma music to astronauts hereunder is to enhance glymphatic clearance in the awake state while improving mental well-being. Various forms of external stimuli, including auditory stimuli like music, can alter the brain electrical activity. Immersive sound stimulation induces slow-wave delta oscillations, thereby promoting glymphatic clearance. In a preferred embodiment of the invention, the use of immersive sound gamma music provides glymphatic clearance in microgravity and during the awake state. Use of immersive sound gamma music is possible for daily long-term application which is required to exert beneficial effects on brain function during long-duration spaceflight.

[0094] Example 1 : Immersive gamma music for treatment of patients diagnosed with chronic fatigue syndrome

[0095] 10 patients diagnosed with chronic fatigue syndrome (CFS) are included in the study on the effect of immersive gamma music, combining 40 Hz auditory stimuli and immersive music, on CFS-related symptoms. All patients provide written and oral informed consent before inclusion. The hospital’s ethics committee approves the study protocol. The study is performed in accordance with the declaration of Helsinki.

[0096] Patients are included when they fulfill the Centers for Disease Control (CDC) diagnostic criteria for CFS. As recommended by the CDC criteria, patients can only be included when the body mass index is < 40 kg / m2. Main exclusion criteria are the presence of a somatic disease that could explain severe fatigue (eg..sleep apnea), psychiatric comorbidity (eg., depression) or the use of medication (with the exception of oral contraceptives and paracetamol).

[0097] After inclusion, patients listen to immersive gamma music one hour daily over a period of 3 months. Patients are asked to relax their bodies and listen to immersive gamma music without any body movements. Before, during and after the 3-month treatment period, all patients are monitored for changes in symptoms of CFS. Fatigue is measured using the fatigue severity subscale of the checklist individual strength (CIS), which has been used frequently in CFS patients. Scores on the CIS-f can vary between 8 and 56, and a score > 35 reflects severe fatigue. Furthermore, patients are asked to respond to several subjective rating items (table 1) regarding the previously presented immersive gamma music. At the end of the 3-month treatment period, all patients report an amelioration of CFS symptoms including fatigue, which persists about 1 month during the posttreatment follow-up period. Furthermore, patients report high levels of relaxation, comfort, preference, pleasantness, and naturalness while listening to this immersive gamma music.

[0098] Table 1 Subjective rating items

[0099] - How much this immersive gamma music made you feel relaxed or excited?

[0100] - How deeply did you feel absorbed in this immersive gamma music?

[0101] - Did you feel awake or sleepy?

[0102] - Did you feel comfortable or uncomfortable?

[0103] - Did this immersive gamma music align with your personal taste?

[0104] - Did you experience it as pleasant or unpleasant while listening to this immersive gamma music?

[0105] - Did you feel strange about this immersive gamma music?

[0106] Example 2: Lumbar cerebrospinal fluid drainage combined with immersive gamma music for treatment of patients diagnosed with chronic fatigue syndrome

[0107] 10 patients diagnosed with chronic fatigue syndrome (CFS) are included in the study on the effect of lumbar cerebrospinal fluid (CSF) drainage combined with immersive gamma music on CFS- related symptoms. All patients provide written and oral informed consent before inclusion. The hospital’s ethics committee approves the study protocol. The study is performed in accordance with the declaration of Helsinki.

[0108] Patients are included when they fulfill the Centers for Disease Control (CDC) diagnostic criteria for CFS. As recommended by the CDC criteria, patients can only be included when the body mass index is < 40 kg / m2. Main exclusion criteria are the presence of a somatic disease that could explain severe fatigue (eg..sleep apnea), psychiatric comorbidity (eg., depression) or the use of medication (with the exception of oral contraceptives and paracetamol).

[0109] After inclusion, patients receive external lumbar CSF drainage (performed by a neurosurgeon) 10- 15 ml / h over 72 h while listening to immersive gamma music, combining 40 Hz auditory stimuli and immersive music, in the awake state. CSF is drained through an external lumbar drain that is connected to a CSF bag. Before, during and after the 3-day treatment period, all patients are monitored for changes in symptoms of CFS. Fatigue is measured using the fatigue severity subscale of the checklist individual strength (CIS), which has been used frequently in CFS patients. Scores on the CIS-f can vary between 8 and 56, and a score > 35 reflects severe fatigue.

[0110] At the end of treatment, all patients report an amelioration of CFS symptoms including fatigue, sometimes immediately after external lumbar CSF drainage combined with immersive gamma music, which persists about 2 months during the posttreatment follow-up period.

[0111] Example 3: Immersive gamma music as a tool for drug delivery to the central nervous system 10 subjects are included in the study on the effect of immersive gamma music, combining 40 Hz auditory stimuli and immersive music, on drug delivery to the central nervous system (CNS). All subjects provide written and oral informed consent before inclusion. A hospital’s ethics committee approves the study protocol. The study is performed in accordance with the declaration of Helsinki. Nanoparticles are ultrafine particulate matter having considerable potential for treatment of CNS disorders. However, despite their tiny size, the blood-brain barrier restricts their access to the CNS. The present inventor proposes that listening to immersive gamma music would enhance the global CNS delivery of intrathecal small gold nanoparticles (AuNPs) within periarterial glymphatic spaces of penetrating arteries, leading to increased intracranial exposure and marked increase in the distribution of AuNPs to deep brain structures.

[0112] AuNPs labelled with the low energy gamma-emitter indium-111 (111 In) are administered to the cerebrospinal fluid-filled cisterna magna of 10 subjects after which the dynamic distributions are imaged using single-photon emission tomography. Five minutes prior to AuNP infusion, 5 subjects start listening to immersive gamma music, combining 40 Hz auditory stimuli and immersive music, while 5 subjects listen to conventional music without gamma stimulation. In both treatment groups the 111 ln-AuNP dispersion flows from the cisterna magna through the subarachnoid space along surface arteries to the circle of Willis and further along the posterior, middle, and anterior cerebral arteries. Intracranial exposure to 111 1n-AuNPs increases by 40% in the immersive gamma music group compared with the control group. To further examine the penetration of 111 1n-AuNPs to the brain parenchyma, radioactivity in deep brain regions is measured. Small spherical regions of interest are placed centrally in the bilateral caudate putamen and thalamus to measure dynamically the 111 In-AuNP concentrations. Listening to immersive gamma music increases the exposure to 111 1n-AuNPs by 3.7-fold in the striatum and 12-fold in the thalamus, respectively, demonstrating a dramatically enhanced deep brain penetration with immersive gamma music. These findings suggest that facilitating perivascular glymphatic influx by listening to immersive gamma music is an effective strategy for delivering small nanoparticles into deep brain regions using a non-invasive and safe approach.

Claims

Claims1 . A system comprising a sound-emitting device, wherein the sound-emitting device is configured to emit an audible sound having a relative band energy of 0.01 to 0.15 of a gamma band, wherein the gamma band is the frequency band ranging from 30 Hz to 50 Hz, wherein the sound-emitting device is configured to deliver the audible sound to a person to simulate a three-dimensional audio experience to the person, wherein the system is configured to treat or prevent a central nervous system disorder.

2. The system of claim 1 , wherein the sound-emitting device is a headphone.

3. The system of claim 1 , wherein the sound-emitting device is an immersive sound device comprising at least four speakers arranged around the person.

4. The system of any one of the preceding claims, wherein the audible sound is music.

5. The system of any one of the preceding claims, wherein the gamma band is the frequency band ranging from 35 Hz to 45 Hz.

6. The system of any one of the preceding claims, wherein the relative band energy of the gamma band is 0.01 to 0.1 , preferably 0.02 to 0.08.

7. The system of any one of the preceding claims, comprising a cerebrospinal fluid access port configured to administer or release cerebrospinal fluid into or from the intrathecal space, cisterna magna, or cerebral ventricles of the person.

8. The system of any one of the preceding claims, comprising a drug delivery system configured to administer a therapeutic compound into the intrathecal space, cisterna magna, or cerebral ventricles of the person.

9. A method of treating or preventing a central nervous system disorder in a person, comprising the step of exposing the person to the system of any one of the preceding claims.

10. The method of treating or preventing the central nervous system disorder according to claim 9, wherein the person is exposed to the system 1 to 3 hours per day for 1 to 7 times per week.11 . The method of treating or preventing the central nervous system disorder according to claim 9 or 10 wherein the central nervous system disorder is fibromyalgia, chronic pain, depression, sleep disorders, Parkinson's disease, Alzheimer's disease, diabetes-induced dementia, amyotrophic lateral sclerosis, multiple sclerosis, post-infectious syndromes, long- COVID, chronic fatigue syndrome, Huntington’s disease, frontotemporal dementia, normaltension glaucoma, traumatic brain injury, ischemic stroke, cerebral microinfarcts, cerebral small vessel disease, intracranial haemorrhage, subarachnoid haemorrhage, normal pressure hydrocephalus, or idiopathic intracranial hypertension.

12. A method of treating or preventing a central nervous system disorder related to spaceflight or spaceflight-associated neuro-ocular syndrome in a person, comprising the step of exposing the person to the system of any one of claims 1 to 8 in an environment of microgravity, preferably when the person is awake.

13. A method of operating a system as described in any one of claims 1 to 8, comprising the steps of:- obtaining feedback from a person who has been predelivered with the system as described in any one of claims 1 to 8,- adapting the relative band energy of the gamma band based on the feedback of the person.