Combination therapies and methods for myelin growth and treatment of age- related hearing loss

Abstract

Embodiments of the present disclosure generally relate to combination therapies and methods for myelin growth and / or remyelination. Embodiments described herein also relate to such combination therapies and methods used for the treatment of various diseases or medical conditions, such as age-related hearing loss, in a patient. In an embodiment, a combination therapy for stimulating remyelination of a neuron in a patient having hearing loss is provided. The combination therapy includes a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof. The combination therapy further includes an audio file configured to facilitate remyelination of a neuron upon administration of the pharmaceutical or pharmaceutical composition.

Description

Combination Therapies and Methods for Myelin Growth and Treatment of Age- Related Hearing LossGOVERNMENT RIGHTS

[0001] The invention was made with government support under Grant No. R01 DC 017924 awarded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health. The government has certain rights in the invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims benefit of and priority to U.S. Provisional Patent Application No. 63 / 566,148, filed on March 15, 2024, which is incorporated herein by reference in its entirety.FIELD

[0003] Embodiments of the present disclosure generally relate to combination therapies and methods for myelin growth and / or remyelination. Embodiments described herein also relate to such combination therapies and methods used for the treatment of various diseases or medical conditions, such as age-related hearing loss, in a patient.BACKGROUND

[0004] Demyelination is implicated in various diseases and medical conditions such as age-related hearing loss. Age-related hearing loss, presbycusis, affects approximately one-third of adults starting in middle age, and greater than half of adults 70 years and older. Age-related hearing loss may be associated with secondary medical conditions, such as depression, dementia, or Alzheimer’s, and therefore early diagnosis and treatment of hearing loss is a central concern to healthy aging. Investigations into remyelination are ongoing. State-of-the-art techniques for remyelination include surgically implanting cells and inducing myelin repair with pharmaceuticals. However, surgical procedures are expensive and invasive. Although conventional pharmaceuticals for myelin repair may have beneficial effects on myelination, such pharmaceuticals are not enough to promote remyelination and sometimes have high risk profiles. In addition, there is no cure or treatment option for patients presenting with cocktail party deficits.

[0005] There is a need for new methods and combination therapies for myelin growth. There is also a need for methods and combination therapies for treatment of, e.g., age-related hearing loss. There is also a need for methods and combination therapies for treatment of cocktail party deficits.SUMMARY

[0006] Embodiments of the present disclosure generally relate to combination therapies and methods for myelin growth and / or remyelination. Embodiments described herein also relate to such combination therapies and methods used for the treatment of various diseases or medical conditions, such as age-related hearing loss, in a patient. In some examples, a combination therapy includes a pharmaceutical or pharmaceutical composition (e.g., clemastine fumarate) utilized in combinations with an audio file. A patient takes or is administered the pharmaceutical in any suitable dosage form, such as oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (for example, by injection or infusion). The patient listens to, or is caused to listen to, the audio file. The inventors found that combination therapies and methods of the present disclosure can be used for regrowth of myelin and remyelination. Besides age-related hearing loss, embodiments described herein may be used for treatment of various medical conditions such as, for example, autism, patients who were exposed to environmental noise, and early childhood ear infections, among others.

[0007] In an embodiment is provided a combination therapy. The combination therapy includes a pharmaceutical or pharmaceutical composition and an audio file. The combination therapy may be utilized for growing myelin in a patient, remyelination of a nerve in a patient, treating central hearing loss in a patient, treating cocktail party deficit in a patient, treating age related hearing loss in a patient, treating autism in a patient, treating cocktail party deficits resulting from, e.g., chronic childhood ear infections or exposure to environmental noise in a patient, or combinations thereof.

[0008] In another embodiment is provided a method for growing myelin in a patient. The method includes administering to the patient a pharmaceutical or pharmaceutical composition described herein and causing the patient to hear or listen to an audio file described herein.

[0009] In another embodiment is provided a method for remyelination of a nerve in a patient. The method includes administering to the patient a pharmaceutical or pharmaceutical composition described herein and causing the patient to hear or listen to an audio file described herein.

[0010] In another embodiment is provided a method for treating central hearing loss in a patient. The method includes administering to the patient a pharmaceutical or pharmaceutical composition described herein and causing the patient to hear or listen to an audio file described herein.

[0011] In another embodiment is provided a method for treating cocktail party deficit in a patient. The method includes administering to the patient a pharmaceutical or pharmaceutical composition described herein and causing the patient to hear or listen to an audio file described herein.

[0012] In another embodiment is provided a method for treating a disease or medical condition in a patient. The method includes administering to the patient a pharmaceutical or pharmaceutical composition described herein and causing the patient to hear or listen to an audio file described herein. The disease or medical condition may include age related hearing loss, autism, or cocktail party deficits resulting from chronic ear infections or exposure to environmental noise.

[0013] In another embodiment, a combination therapy for stimulating remyelination of a neuron in a patient having hearing loss is provided. The combination therapy includes a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof. The combination therapy further includes an audio file configured to facilitate remyelination of a neuron upon administration of the pharmaceutical or pharmaceutical composition.

[0014] In another embodiment, a method for stimulating remyelination of a neuron in a patient having hearing loss is provided. The method includes administering to the patient a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof. The method further includes causing the patient to hear or listen to an audio file, the audiofile configured to facilitate remyelination of the neuron upon administration of the pharmaceutical or pharmaceutical composition.

[0015] In another embodiment, a combination therapy for growing myelin on a neuron in a patient having hearing loss is provided. The combination therapy includes an antihistamine. The combination therapy further includes an audio file configured to facilitate myelin growth on a neuron upon administration of the antihistamine.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] So that the manner in which the above recited features of the present disclosure may be understood in detail, a more particular description of the disclosure, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only exemplary embodiments and are therefore not to be considered limiting of its scope, and may admit to other equally effective embodiments.

[0017] FIG. 1 A is a schematic showing the connectivity on the sound localization pathway, dashed arrows are excitatory projections; solid arrows are glycinergic projections. In FIG. 1 A, “LSO” refers to lateral superior olive, “MSO” refers to medial superior olive, and “MNTB” refers to medial nucleus of the trapezoid body.

[0018] FIG. IB provides an explanation of how PPI was measured in gerbils. PPI refers to pre-pulse inhibition and is a measurement of the animal’s ability to localize sound, with higher numbers indicating better localization abilities. The startle speaker is mounted on top of the animal and is not one of the speakers in the array. The various hatching in the speaker arc in the top portion of the figure indicate swaps within one experiment. Open speaker to other open speaker, in a different trial, hatched speaker to other hatched speaker, etc. Below the animal in the figure is shown a hypothetical timeline along the x axis: Speaker 1 is active, followed by speaker 2 active, followed by a startle sound. All in the same trial.

[0019] FIGS. 2A and 2B show sound localization data from humans and gerbils suggesting age-related decline in sound localization abilities or cocktail party performance is a common mammalian phenomenon. FIG. 2A: Human performance in a speech in a spatial noise separation task declines with age. FIG. 2B: Young gerbils (circles and rectangles hashed with forward slash “ / ”) perform much better in speaker swap tasks than old gerbils (open circles and open rectangles). The y-axis plots PPI (=pre- pulse inhibition), which is calculated as (1- startle during test / startle during control), such that values near zero indicate a lack of speaker swap detection while positive values indicate that the swap was detected.

[0020] FIGS. 3A-3C show that a decline in auditory brain stem response (ABR) wave III is a co-morbidity of spatial hearing deficits in humans and gerbils. FIG. 3A: Human wave III amplitudes of many of the same listeners as shown in FIG. 2 A, suggesting a decline in wave III with age. FIG. 3B: Wave III amplitude declines were especially prominent in subjects with spatial hearing deficits regardless of age, reemphasizing the relationship between these wave III changes and spatial hearing difficulties. FIG. 3C: Similar age-related decrease in wave III is observed in gerbils. These are also largely the same animals as discussed in FIG. 2B.

[0021] FIG. 3D shows a coherent anti-Stokes Raman spectroscopy (CARS) image with laser tuned to the resonant frequency of CH2 bonds (792.2 nm) with the vibrating CH2 bonds imaged.

[0022] FIG. 4 shows coherent anti-Stokes Raman spectroscopy (CARS) images and axon diameter data illustrating that old gerbils show demyelination in the MNTB afferent fiber bundle (bundle indicated by asterisk beside dashed arrow in FIG. 1A). Sample CARS old (top right panel) and young (top left panel) gerbils. Axon diameters were measured and quantified (bottom panel), showing small but highly significant differences (p<0.001) in axon diameter between old and young animals.

[0023] FIG. 5A shows pre-pulse inhibition (PPI) spatial acuity in control gerbils (hashed) and gerbils (unhashed) 1.5 and 3 weeks post lysolecithin (lyso) injection. The curves represent the average PPI across the population of animals tested (center line) average plus the standard error (upper border of the cloud) and average minus the standard error (lower border of cloud).

[0024] FIG. 5B shows monaural ABRs (left panel) and binaural interaction components (BICs, right panel) pre- and 1-3 weeks post injection. BIC DN1 (the first negative peak of BIC) is eliminated 1 and 2 weeks post injection but recovers by 3 weeks.

[0025] FIG. 5C shows the effects of lyso injections on axon diameter post injection.

[0026] FIG. 5D shows CARS images, indicating globular bushy cell axon diameters were significantly larger in a control (left panel) versus lyso treated (oneweek and two weeks after lyso injection). By three weeks post injection, axon diameters had recovered to control conditions.

[0027] FIG. 6 shows data indicating that treatment with clemastine and sound rescues sound localization in gerbils. Solid lines = PPI performance of old gerbils before treatment (pre-treatment). Dotted lines = PPI performance of the same animals after a one-month treatment (post-treatment) with: control solution and no sound (top left panel); control solution and sound (top right panel); clemastine solution and no sound (bottom left panel); clemastine solution and sound (bottom right panel). N=3 to 5 animals per group.

[0028] FIG. 7 shows data indicating that treatment with clemastine and sound rescues ABR wave III and components of the BIC. Top panel: Waveforms from an animal before and after treatment with control solution and no sound. Bottom panel: Waveforms of an animal treated with clemastine and sound. Note the increase in monaural wave III in the treatment group animal and the sharpening of the DN 1 wave in the BIC. By contrast, the control animal did not show such improvements but rather the curves deteriorated further during the timeline of the experiment.

[0029] FIG. 8 shows CARS imaging from a control / no sound animal (top left panel) and a clemastine / sound animal (top right panel). Quantitative analysis (bottom panel) of all CARS data from this experiment, suggesting a highly significant increase in axon thickness in the treatment group.

[0030] To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures. It is contemplated that elements and features of one embodiment may be beneficially incorporated in other embodiments without further recitation.DETAILED DESCRIPTION

[0031] Embodiments of the present disclosure generally relate to combination therapies and methods for myelin growth and / or remyelination. Embodiments described herein also relate to such combination therapies and methods used for the treatment of various diseases or medical conditions, such as age-related hearing loss, autism, exposure to sound, or ear infections, in a patient. The term “patient”, “subject”, or “individual” are used interchangeably herein and refer to a vertebrate, such as a mammal. Mammals may include, but are not limited to, humans, nonhuman primates,rodents such as rats, mice, or gerbils, and to domestic animals such as dogs and cats, among other animals. Compositions, combination therapies, methods, and treatments described herein are not limited to human diseases, but are also applicable to other mammals such as nonhuman primates, rodents such as rats, mice, or gerbils, and to domestic animals such as dogs and cats, among other animals.

[0032] With respect to hearing loss, there are different types of hearing loss: central hearing loss and peripheral hearing loss. Central hearing loss is a type of hearing impairment that occurs due to a dysfunction in the central auditory processing system, which includes the auditory nerve and the brain’s auditory pathways. This condition can result from various causes, such as neurological disorders, brain injury, or degenerative diseases, and affects the individual’s ability to interpret and understand sounds. Central hearing loss is associated with central auditory processing disorder (CAPD). Peripheral hearing loss is a type of hearing impairment that occurs due to dysfunction in the ear, for example due to hair cell loss in the inner ear. While both central and peripheral hearing loss are significant risk factors for physical and cognitive frailty, embodiments described herein are utilized for the treatment of central hearing loss. To date, there is no treatment for central hearing loss while peripheral hearing loss is treatable with hearing aids, cochlear implants, or other devices.

[0033] Combination therapies and methods described herein may function to grow myelin or facilitate remyelination of nerve cell axons. Myelin is a lipid-rich material that surrounds nerve cell axons. Myelin serves to insulate nerve cell axons and increase the rate at which electrical impulses pass along the axon’s length. Demyelination is a loss or degradation of the myelin sheath and is implicated in many neurodegenerative diseases including age-related hearing loss and multiple sclerosis.

[0034] Investigations into remyelination — the repair of damaged myelin sheaths — are ongoing. State-of-the-art techniques for remyelination include surgically implanting cells and inducing myelin repair with pharmaceuticals. However, surgical procedures are expensive and invasive. Although conventional pharmaceuticals for myelin repair may have beneficial effects on myelination, at least in the case of central hearing loss such pharmaceuticals are not enough to promote remyelination and sometimes have high risk profiles. In addition, there is no cure or treatment option for cocktail party deficits. Patients with cocktail party deficits lack the ability to segregate stimuli. Forexample, cocktail party deficits represent difficulties associated with understanding speech in multiple-talker situations.

[0035] Unlike conventional technologies, embodiments described herein are not invasive and promote remyelination. In addition, embodiments described herein provide the first known treatment for patients presenting with cocktail party deficits.

[0036] Embodiments of the present disclosure relate to combination therapies. The combination therapy includes a pharmaceutical or pharmaceutical composition. The combination therapy also includes an audio file.

[0037] The pharmaceutical or pharmaceutical composition may include antihistamines such as clemastine (for example, clemastine fumarate), GSK239512 (an orally-administered central nervous-penetrant antihistamine) or combinations thereof. The pharmaceutical or pharmaceutical composition may include disease modifying therapies prescribed for treatment of multiple sclerosis and / or remyelination therapies. These remyelination therapies enhance the regenerative response via myelin repair. Remyelination therapies include therapies targeting the recruitment, differentiation, and survival of oligodendrocyte precursors as well as overcoming inhibitors of remyelination.

[0038] Pharmaceutical or pharmaceutical compositions for treatment of multiple sclerosis and or remyelination may include, but are not limited to, the following: evobrutinib; SAR442168 (a Bruton’s tyrosine kinase inhibitor in Phase 2 clinical trials); masitinib; imatinib; ibudilast; BIIB033 (an anti-leucine rich repeat and immunoglobulin-like domain-containing protein 1 (anti -LINGO- 1) antibody); opicinumab (an antibody directed against LINGO-1); elezanumab; AHSCT (autologous hematopoietic stem cells transplantation); simvastatin; Vitamin D3; biotin (for example, MD1003 which is a high dose biotin); lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb (a monoclonal antibody directed against the envelope protein of a human endogenous retrovirus); IMU-838 (vidofludimus calcium); erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARC 1103 (a GAB AB receptor agonist); amantadine; modanafil; methylphenidate; BX-1 (dronabinol); ADS-5102 (amantadine extended release); arbaclofen (R enantiomer of baclofen); insulin; intranasal insulin; adderall; adderall extended release; GSK239512 (an orally-administered central nervous-penetrant antihistamine);ocrelizumab; quetiapine (such as quetiapine fumarate); domperidone; antisemaphorin 4D (for example, humanized anti-Sema4D monoclonal antibody VX15 / 2503); IRX4204 (an agonist of retinoic acid receptor gamma (RXR-y)); a kappa opioid agonist (for example, U-50488, CAS No: 67198-13-4); a spingosine-1 -phosphate (SIP) receptor modulator (for example, fmgolimod or siponimod); a y-secretase inhibitor (for example, quecertin); teriflunomide; bexarotene; bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; and riluzole.

[0039] Combinations of pharmaceutical (or pharmaceutical compositions) may be used.

[0040] Actual dosage levels of the pharmaceutical or pharmaceutical composition can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level can depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present disclosure employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0041] The dosage may be a “pharmacologically effective amount” or “therapeutically effective amount”. The terms “pharmacologically effective amount” or “therapeutically effective amount” refer to a non-toxic, but sufficient amount of the active agent (or composition containing the active agent) to provide the desired level in the bloodstream or at the site of action (for example, intracellularly) in the patient to be treated, and / or to provide a desired physiological, biophysical, biochemical, pharmacological or therapeutic response. The exact amount required will vary from patient to patient, and will depend on numerous factors, such as the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (for example, the number of doses administered per day), as well as patient considerations, such as species, age, and general condition of the patient, the severity of the condition being treated, additionaldrugs being taken by the patient, mode of administration, and the like. These factors and considerations can be determined by one skilled in the art. An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation, based upon the information provided herein.

[0042] For example, a therapeutically effective amount of a pharmaceutical or pharmaceutical composition can refer to an amount of the pharmaceutical or pharmaceutical composition that, in conjunction with hearing or listening to the audio file, facilitates myelin growth (or remyelination) of a neuron.

[0043] In some embodiments, which may be combined with other embodiments, the dosage of the pharmaceutical or pharmaceutical composition for a 72 kg patient may be from about 1 mg to about 40 mg in the case of clemastine.

[0044] The pharmaceutical or pharmaceutical composition may be formulated with pharmaceutically acceptable carriers or excipients as well as any other suitable adjuvants and diluents in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0045] For purposes of the present disclosure, a pharmaceutically acceptable carrier includes any suitable solvent, dispersion medium, coating, antibacterial agent, antifungal agent, isotonic delaying agent, and absorption delaying agent, and the like that are physiologically compatible. In some embodiments, the carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (for example, by injection or infusion). Depending on the route of administration, the active compound, e.g., pharmaceutical or pharmaceutical composition, can be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.

[0046] The carrier or excipient for use with the pharmaceutical or pharmaceutical composition may include, but is not limited to, maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, histidine, glycine, sodium chloride, potassium chloride, calcium chloride, zinc chloride, saline, dimethylsulfoxide (DMSO), water, dextrose, N-methylpyrrolidone, N,N- dimethylacetamide, ethanol, propylene glycol, polyethylene glycol, diethylene glycolmonoethyl ether, surfactant polyoxyethylene-sorbitan monooleate, or combinations thereof.

[0047] The audio file, or sound file, may be any suitable file or file type. The audio file may be an audio track. The audio file may be encoded in any suitable format, such as a digital format, for example, an MP3 or the like. The audio file may be decoded by any suitable communication device such as a personal communication device, such as a smartphone, a computer, a dedicated player, a player integrated with other technology, or combinations thereof. The audio file may be played as an audio broadcast through a speaker, headphones (such as over-ear headphones, on-ear headphones, earbuds headphones, or in-ear headphones), or other suitable audio projecting device.

[0048] The audio file may include various audio components. The audio components may be temporally fast. The audio components may include fast transients have a frequency in a range from about 100 Hz to about 800 Hz, such as from about 200 Hz to about 600 Hz. Additionally, or alternatively, the audio components of the audio file may include temporally fast components including, but not limited to, binaural beats with carrier frequencies in a range audible to older humans subjects (e.g., about 10 kHz or lower), amplitude modulated signals comprising carrier frequencies of about 10 kHz or lower and amplitude modulated by frequencies between about 50 Hz and about 500 Hz, frequency modulated signals with similar modulation parameters, fast percussions, or combinations thereof.

[0049] The audio file may have any suitable sound intensity. The sound intensity of the audio file may be about 85 decibels (dB) or lower, such as in a range from about 10 dB to about 85 dB, such as from about 20 dB to about 80 dB, such as from about 30 dB to about 75 dB, such as from about 40 dB to about 70 dB, such as from about 50 dB to about 65 or from about 60 dB to about 85 dB, such as from about 70 dB to 80 dB, or from about 75 dB to about 85 dB, or from about 80 to about 85 dB, though other values are contemplated. Any of the foregoing numbers may be used singly to describe an open-ended range or in combination to describe a closed-ended range.

[0050] Sound intensities of the audio file are typically 85 dB or lower because exposure to higher than 85 dB may cause hearing loss (hair cell loss at the level of the inner ear) with prolonged exposure.

[0051] The audio file may have any suitable audio duration such as in a range from about 1 minute to about 10 hours, such as from about 5 minutes to about 6 hours, such as from about 10 minutes to about 5 hours, such as from about 15 minutes to about 4 hours, such as from about 30 minutes to about 3 hours, such as from about 45 minutes to about 1.5 hours, such as about 1 hour, though other values are contemplated. Any of the foregoing numbers may be used singly to describe an open-ended range or in combination to describe a closed-ended range.

[0052] The audio file may be a one-hour audio file, in MP3 format, with fast transients and combines a number of temporally fast components such as binaural beats, amplitude and frequency modulated signals, and fast percussions.

[0053] The combination therapy may be used to treat various medical conditions such as age-related hearing loss, autism, hearing damage from noise exposure, or early childhood ear infections, among others, in a patient.

[0054] The combination therapy may be used for growing myelin in a patient, myelination, remyelination, treating central hearing loss in a patient, treating cocktail party deficit in a patient, or combinations thereof.

[0055] The combination therapy may induce myelin growth along one or more afferent fibers to the medial nucleus of the trapezoid body (MNTB, asterisk beside dashed arrow in FIG. 1 A).

[0056] Embodiments described herein also generally relate to various methods and methods of treatment that include use of a pharmaceutical (or pharmaceutical composition) described herein and an audio file described herein.

[0057] A method for growing myelin in a patient may include administering to the patient a pharmaceutical or pharmaceutical composition described herein, and causing the patient to hear or listen to an audio file described herein.

[0058] A method for remyelination of a nerve in a patient may include administering to a patient a pharmaceutical or pharmaceutical composition described herein, and causing the patient to hear or listen to an audio file described herein.

[0059] A method for treating central hearing loss in a patient may include administering to a patient a pharmaceutical or pharmaceutical composition described herein, and causing the patient to hear or listen to an audio file described herein.

[0060] A method for treating cocktail party deficit in a patient may include administering to a patient a pharmaceutical or pharmaceutical composition described herein, and causing the patient to hear or listen to an audio file described herein.

[0061] A method for treating a disease or medical condition in a patient may include administering to a patient a pharmaceutical or pharmaceutical composition described herein, and causing the patient to hear or listen to an audio file described herein administering to the patient a pharmaceutical or pharmaceutical composition. The disease or medical condition may include age related hearing loss, autism, or hearing damage from noise exposure or an ear infection (such as an early childhood ear infection).

[0062] In methods described herein, the administration of the pharmaceutical or pharmaceutical composition to the patient may be done prior to, concurrently with, or after the patient hears or listens to the audio file. Administration of the pharmaceutical or pharmaceutical composition to the patient and causing the patient to hear or listen to the audio file may induce myelin growth along one or more afferent fibers to the medial nucleus of the trapezoid body.

[0063] In addition to age-related hearing loss, embodiments described herein may be used for the treatment of autism and hearing damage from noise exposure or ear infections such as early childhood ear infections.

[0064] With respect to autism, it is well known that autistic people dislike situations such as crowded bars and restaurants, because they have trouble following a conversation when background noise is present. The exact same demyelination in autistic mice (Fragile X) is similar to demyelination in old gerbils presented herein. This alteration may be a reason for the cocktail party deficits of autistic listeners. Embodiments described herein can be utilized to remyelinate these pathways in autistic listeners in a similar way as it does in elderly or geriatric people, and may be utilized to address the cocktail party deficits of autistic listeners.

[0065] Many other listeners report difficulties listening to a single sound source when distracting background noises are present, yet these listeners have normal hearing thresholds - indicating that the problem is in the brain rather than the ear. Some of these listeners have been exposed to loud sounds or noises such as factory noises during their lifetime. Animal models of these listeners show the same demyelination as the aging orautistic animal models do. Embodiments described herein can be utilized to remyelinate these pathways in a similar way as it does in elderly or autistic listeners. Yet other listeners have experienced a large number of ear infections during childhood. This is the same time period where the sound localization circuits are calibrated. Ear infections result in mucus in the middle ear which muffles the incoming sound, as if there were an earplug in that ear. If an individual has “earplugs” or mucus in their ears on and off for a large portion of their life under age 2 (such as 50% which is the case for some children), the sound cues that calibrate the neural circuit constantly change and thus calibration is impossible. These listeners will have impaired cocktail party performance for life, which is unbeatable to date. Embodiments described herein may be used for the treatment of early childhood ear infections.

[0066] Chronic ear infections especially in childhood result in cocktail party deficits because the chronic ear infections change the loudness of the sound received at the infected ear due to the mucus acting like an ear plug. Thereby chronic ear infections disallow the correct development of the sound localization pathway. Embodiments described herein may be used for the treatment of early childhood chronic ear infections.

[0067] In other words, embodiments described herein may be used for treatment of any suitable situation where a listener reports cocktail party deficits but has normal hearing at the level of the ears (they do NOT need a hearing aid). These conditions baffle audiologists and ENTs and there is no treatment to date.

[0068] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use aspects of the present disclosure, and are not intended to limit the scope of aspects of the present disclosure. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, dimensions, etc.) but some experimental errors and deviations should be accounted for.EXAMPLESOverview

[0069] The same brain circuits which perform sound localization per se also play a major role in helping individuals perform at a cocktail party (or acoustically busy situation with many background noises, restaurants, bars, airports, cafeterias, etc.).Normal hearing humans can localize to 5 spatial degrees or better, meaning that in a cocktail party situation, a normal hearing human can separate any distracting sound from the sound of interest, as long as this sound is at least 5 degrees removed. As people age, the sound localization abilities and spatial accuracy declines such that older individuals can only localize to, e.g., 25 degrees, 45 degrees, or 90 degrees. A consequence is that now a distracting noise from, e.g., the next restaurant table falls into the same spatial channel, disallowing separation. About 50% of the aging population complains about this deficit and has trouble performing in such cocktail party situations. Additionally, autistic patients have the same problem and so do listeners with several other conditions such as chronic childhood ear infections, multiple sclerosis patients, or some implant users.

[0070] The inventors studied underlying brain circuits of this problem and determined that a sub cellular mechanism for the age related change is a demyelination in afferent fibers to the sound localization pathway, specifically afferents to the medial nucleus of the trapezoid body. This demyelination causes less temporally precise transmission of neural activity, leading to temporal “sloppiness”, imprecise localization, and the cocktail party deficits. The inventors tested whether the demyelination in animal subjects (Mongolian gerbils) can be reversed. A cohort of 2.5 year+ old gerbils (equivalent to humans at ages of 70s to 80s) were tested for sound localization defects and cocktail party performance. Then the animals were subjected to a one month treatment with clemastine fumarate vs. control. The carrier (control) is saline with dimethylsulfoxide (DMSO) as clemastine is dissolved in DMSO which is then diluted with saline for the experiments. Some animals were also exposed daily for one month to the one hour sound file. So, there were 4 study groups (carrier; carrier plus sound; clemastine (with carrier); and clemastine (with carrier) plus sound). Of these 4 groups, the clemastine plus sound group showed significant improvements in myelination (anatomy), auditory brain stem responses (physiology) and sound localization (behavior).

[0071] Only the combination of sound plus drug had that effect, not the drug alone and not any other group. This makes sense from a scientific point of view where brain pathways which are used in meaningful and relevant ways improve.A, IntroductionA.l. Central hearing loss leads to decreased hearing in typical acoustic environments

[0072] Several mechanisms contribute to presbycusis, the most well-known being progressive death of hair cells in the inner ear. However, there are also central components that are much less well understood, and for which no treatment options are available to date. This central component, termed “central hearing loss”, is independent of hair cell death, and patients affected by it may have completely or largely normal hearing thresholds - in other words, audibility and detection of sounds is not the issue. Central hearing loss is characterized by an inability to make sense of a conversation in everyday situations, such as busy restaurants, public places, most indoor spaces. Central hearing loss can affect up to 50% of the aging population. Virtually all listening scenarios are characterized by multiple simultaneously active sound sources, echoes, and reverberations when listeners typically attempt to focus on a single sound source. The inventors have shown that age related changes in the sound localization pathway of the auditory brain stem play a significant role in this form of central hearing loss. The inventors have also identified a subcellular alteration in this circuit which leads to less precise sound localization and less precise ability to spatially separate multiple simultaneous sounds from each other. The inventors found a novel approach to reverse these age-related alterations and partially restore spatial hearing abilities. In the next sections is described a scientific premise of the sound localization pathway being involved in cocktail party deficits.A.l. The sound localization pathway in the brain stem

[0073] The classical sound localization circuit in the brain stem is the lowest circuit in the ascending pathway where binaural cues to location are first encoded (FIG. 1 A).

[0074] For purposes of this discussion, the inventors considered the principal sound localization nuclei, the medial superior olive (MSO) and the lateral superior olive (LSO). Both nuclei receive fast and well-timed inhibition from the medial nucleus of the trapezoid body (MNTB; solid arrows, FIG. 1 A). During sound localization, sounds originating from different locations in space were discriminated based on differences in arrival time or intensity level between the ears — interaural time differences (ITDs) and interaural level differences (ILDs) — which varied systematically with horizontal sound source position. These cues were encoded by the sound localization circuit tolocalize the sound as well as to perform the initial segregation of different sound streams based on location. The sound localization process depended on temporally precise integration of the inputs from the two ears because the interaural differences to be analyzed can be very small. For MSO, fast and well-timed inhibition has been suggested as a factor in encoding of ITDs and hence localization of low frequencies. Typical ITDs are on the order of only tens to hundreds of microseconds in typical natural listening situations, thus one to two orders of magnitude shorter than the duration of atypical action potential. On the other hand, localization of high frequencies via ILDs has also been shown to be highly sensitive to temporal shifts of the inhibitory vs. excitatory inputs by as little as several tens of microseconds (ps). In effect, LSO neurons detect the coincidence of excitation and inhibition from the ears within windows < 1 ms leading to temporal constraints even on the processing of ILDs.

[0075] Because of these acoustical-physical constraints, neurons in the sound localization circuit have several subcellular specializations to be able to analyze these ITDs and IIDs with the necessary temporal precision. Probably the most extreme such adaptations are present in the pathway to and from the MNTB. This nucleus contributes well-timed neural inhibition to the sound localization process. The pathway includes a heavily myelinated excitatory input from the ventral cochlear nucleus (VCN) (a subdivision of the cochlear nucleus shown in FIG. 1 A) to the contralateral MNTB. The MNTB, in the trapezoid body, is composed of mainly neurons. Neurons in the MNTB receiving this input are glycinergic and send their inhibitory output to several nuclei in the auditory brain stem, including the principal sound localization nuclei LSO and MSO (FIG. 1A). Some of the extreme adaptations for temporal precision in this pathway include the calyx of Held, a type of giant synapse which innervates MNTB principal cell bodies directly, an electrically compact design of MNTB principal cells, small dendrites, said high level of myelination in the afferents, and numerous subcellular and ion channel adaptations to fast and precise firing.A.3. Age-related changes in the ascending auditory pathway

[0076] Because of the extreme demands for temporal precision in the sound localization circuit, even minor age-related changes in the amplitudes and / or kinetics of excitatory and / or inhibitory inputs to MSO and LSO may have major consequences on the encoding of ITD and ILD and thus binaural hearing in general. Consistent withthis concept is a large body of evidence suggesting that temporal processing ability and neural synchronization declines with age, and that this decline may lead to decreased ability to segregate multiple sounds. Age-related decline in temporal processing is not limited to humans but appears to be a general mammalian phenomenon. This is especially true for the glycinergic inhibition that is contributed by the MNTB, as these neurons appear to have the most extreme adaptations for temporal precision (see above). Additionally, MNTB projects glycinergic inhibition not only to LSO and MSO, but additionally to several other nuclei, and directly or indirectly controls firing in the majority of auditory brain stem nuclei (arrows not shown in FIG. 1 A). Overall, MNTB is at the center of one of the most precisely timed neural networks in the entire brain and can be considered a master switch of precisely timed inhibition in the auditory system. An overarching scientific premise is that subcellular age-related changes compromise the temporal precision of inputs to the sound localization pathway, especially the MNTB derived inhibitory inputs. This in turn leads to compromised sound localization and compromised cocktail party performance of affected listeners or animal models.A.4. Changes in myelination contribute to central hearing loss

[0077] A model computed the effects of axon demyelination in this circuit in isolation and concluded that demyelination in the order of what is experimentally observed also accounts for a large degradation of sound localization performance. Some research gives evidence that reduced peripheral activity may cause demyelination in cochlear nucleus axons and may reduce the overall number of large diameter axons; in adult rodents ear-plugged for 10 days, the number of large diameter axons was reduced and those that remained had significantly thinner myelin than controls. Beyond the auditory brain stem, activity-dependent myelin plasticity has been reported in different systems and studies generally agree that release of glutamate or ATP from electrically active axons causes depolarization of oligodendrocytes, their subsequent differentiation and finally increased myelination of active axons, a scenario that is consistent with what is observed here.

[0078] The inventors’ experimental design focused on auditory brain stem, but carefully controlled for other possible mechanisms of age related hearing loss. In short, histology of the cochlea to control for hair cell death and synaptopathy was performed;also performed was auditory brain stem response (ABR) recordings and assessed waves I - V which correspond to physiological responses of auditory areas from nerve through midbrain as well as the binaural interaction component (BIC) which is a measure of binaural responses in the sound localization pathway. Also assessed was the status of myelination in MNTB afferents with microscopy and the status of glycine receptors with RNAscope. In some experiments, the inventors performed distortion product otoacoustic emissions (DPOAE) recordings to further assess the physiological status of the cochlea (and the level of potential hair cell death).A.5. Experimental isolation — and reversal — of aging effects

[0079] In some embodiments, the investigation focused on the role of the sound localization circuit in age-related central hearing loss, specifically on the role of age- related changes in myelination of afferent axons to MNTB (asterisk beside dashed arrow, FIG. 1A). The myelin layer in these heavily myelinated axons decreases with age, resulting in less temporally precise action potential propagation, which in turn results in temporal deterioration of MNTB derived glycinergic inhibition and less precise sound localization abilities of both affected human subjects and animal models. The inventors experimentally compromised myelination in young animals in the MNTB pathway with a pharmacological approach to imitate the age-related changes observed in old animals. This allowed study of the effects of this alteration in isolation. More importantly, the inventors (partially) reversed these changes in old animals with a combination of pharmacology and sound stimulation. The pharmacological intervention used included clemastine fumarate (clemastine), a drug which has been FDA approved for almost 50 years and which has been proven to be completely safe for human subjects. Therefore, this approach may be translated into a treatment for human subjects with central hearing loss within a relatively short time - making this the first treatment option for central hearing loss.

[0080] FIG. IB provides an explanation of how PPI was measured in gerbils using a modification of the procedure described in N. T. Greene et al. “Spatial hearing ability of the pigmented Guinea pig (Cavia porcellus): Minimum audible angle and spatial release from masking in azimuth,” Hear. Res. 365, 62-76 (2018) and S. Poleg et al., “Age-related myelin deficits in the auditory brain stem contribute to cocktail-party deficits”, bioRxiv 2024.07.29.605710 (2024). Animals were in a holding cage beingforced to point forward, looking at the center of the speaker arc (left panel). There was a train of acoustic stimuli being emitted from one speaker of the array (Speaker 1). At some point and just before the loud startle sound, the same acoustic stimulus was presented from a different speaker along the array (Speaker 2). If the animal can localize this speaker swap, this served as an indicator that the startle sound is about to happen - animals startle less, resulting in higher PPI numbers. If the animal by contrast cannot localize the speaker swap, the animal was “surprised” by the startle sound (Startle speaker) and jump more, resulting in smaller PPIs (right panel of FIG. IB). Right panel of FIG. IB: typical sound localization abilities of old and young gerbils. Smaller numbers indicate a decreased ability to hear the speaker swap.B, Approach

[0081] One overarching hypothesis investigated was that age-related changes in the auditory brain stem contribute to a listener’s inability to isolate a sound source of interest from background noise, and that reversing these alterations can improve the listener’s ability to do so. To this end, the inventors manipulated the myelination of MNTB afferent fibers.B.l Methodical considerationsB.1.1. Species

[0082] All work on aging was done in Mongolian gerbils (Meriones unguiculatus). Gerbils are a commonly used model system for hearing research and there is a large body of literature obtained from gerbils. The species has excellent low-frequency hearing (similar to humans), such that brain areas processing low frequencies are well developed. Gerbils experience relatively low age-related hair cell loss such that central changes can be studied effectively. For this study, “aged” gerbils are at least 2 years old - the approximate equivalent of humans aged 60 or older. “Young” gerbils are between 3 and 6 months - the approximate equivalent of humans in their 20s. Old gerbils cannot be purchased and thus were aged in house. Work on autism was done in mice, and the work on early childhood hearing and noise exposure was done in guinea pigs and chinchillas.B.1.2. Behavioral assessment with Pre-Pulse inhibition (PPI)

[0083] Behavioral training in gerbils, while possible, is time consuming and takes weeks to months until any data can be obtained from the animals. Instead, the inventorsused the startle response approach for all behavioral assays. The methodology follows that described in M. D. Sergison et al., “Pre-pulse inhibition of the acoustic startle response as a behavioral assay for sound localization abilities of the Mongolian gerbil,” J. Acoust. Soc. Am. 151, A147-A147 (2022); N. T. Greene et al., Hear. Res. 365, 62- 76 (2018); K. L. Anbuhl et al., “Early temporary asymmetrical hearing impairs behavioral and neural sensitivity to sound location,” J. Acoust. Soc. Am. 143, 1720- 1720 (2018); and S. Poleg et al., bioRxiv 2024.07.29.605710 (2024). In short, the principle is that all animals (and human subjects) startle when a loud sound is presented unexpectedly, and the amount of startle can be measured quantitatively with an accelerometer placed under the animal’s holding / restraint cage. By contrast, whenever the animal receives a clue that the startle is about to happen, the startle will be (partially) inhibited.

[0084] The inventors exploited this naturally occurring reflex and its inhibition by presenting a train of sound stimuli from a given speaker along a horizontal array. Just before the startle, the presenting speaker was swapped such that the exact same sound was presented from a different location along the azimuth. If the animal localizes this “speaker swap” it startles less. The array has individual speakers placed in 7.5 spatial degree increments, such that sound localization accuracy can be measured in multiples of 7.5 degrees. The animal is restrained in a constant and reproducible position relative to the array with a restraint cage that does not allow the animal to turn its head or body. Pre-Pulse inhibition was calculated as (1- startle during test / startle during control), such that values near zero indicate a lack of speaker swap detection while positive values indicate that the swap was detected. At the beginning of data collection for each animal, the startle threshold was determined, and all experiments were performed at 20 dB above that threshold. All PPI testing was performed in a sound-proof chamber and with calibrated speakers.B.1.3. ABR recordings

[0085] This technique has been used for several decades and there is a wealth of literature interpreting the various waves. ABR has been used by both Tollin and Klug, and both labs have several publications with this technique, and the methodology follows these papers. In rodents, there is general agreement that wave I reflects activity in the auditory nerve, wave II activity in cochlear nucleus, and wave III activity inMNTB. Wave IV reflects the principal sound localization nuclei, LSO and MSO. Other than monaural ABRs, the inventors also stimulated binaurally and record binaural ABRs. The BIC was calculated by the point-by-point computation of (left ear ABR + right ear ABR - binaural ABR). If there were (hypothetically) no binaural circuits in the auditory brain stem, this equation should result in a zero-amplitude function for the BIC. Any non-zero values were caused by binaural interaction of the inputs. While auditory nerve, cochlear nucleus and MNTB are monaural, LSO and MSO are the lowest binaural nuclei, thus the first amplitudes of the BIC represent activity of these nuclei. ABR recordings were performed with a TDT RX6 and Medusa setup and controlled by custom written software. Gerbils received light ketamine-xylazine anesthesia although these recordings are virtually noninvasive, as the animals would move around the sound chamber during the procedure, thereby making it impossible to record any useful data. For the recordings, five electrodes were placed: behind each ear, at the top of the head, at the back of the head as a reference, and at the base of the tail as ground. At least 500 repetitions were recorded for each stimulus type. All ABR recordings were performed in a soundproof chamber and with calibrated speakers and equipment.B.1.4. CARS microscopy

[0086] Coherent Anti-Stokes Raman Spectroscopy (CARS) was used as a method to image lipids, such as myelin. The methodology follows that described in E. A. McCullagh et al., “Coherent Anti-Stokes Raman Spectroscopy (CARS) Application for Imaging Myelination in Brain Slices,” J Vis Exp, doi: 10.3791 / 64013 (2022); A. Lucas et al., “Myelination Deficits in the Auditory Brainstem of a Mouse Model of Fragile X Syndrome,” Front Neuroscience 15, 772943 (2021); and S. Poleg et al., bioRxiv 2024.07.29.605710 (2024).

[0087] The CARS laser was tuned to 792.2 nm, the resonant frequency of CEL bonds which are very common in lipids, to excite these molecular bonds. Because myelin represents the large majority of lipids in brain sections, this technique is largely specific for myelin. This method is a relatively simple and effective method to image and analyze myelin without the use of antibodies or electron microscopy. An additional strength is that CARS can be combined with immunohistochemistry and confocal lightmicroscopy. The laser is attached to an Olympus FV1000 confocal microscope and the CARS laser is recalibrated daily.B.1.5. Clemastine fumarate

[0088] Clemastine was initially approved by the U.S. Government in the late 1960s as a first-generation antihistamine. While it is still approved for this application, including for over-the-counter use in some counties, it is rarely used today. However, there is a second independent effect of the drug, where it supports oligodendrocytes through a cholinergic signaling pathway. Remyelination restores conduction velocity and promotes neurophysiological recovery, underscoring the therapeutic potential of myelin repair. Clemastine treatment of patients with multiple sclerosis shortens the latency delay of sensory-evoked potentials indicating promising early results. Furthermore, clemastine-induced generation of new oligodendrocytes is expected to have long-lasting effects as mature oligodendrocytes are remarkably long-lived and once these cells form myelin it is extremely stable.

[0089] From an experimental point of view, clemastine may be dissolved in dimethyl sulfoxide (DMSO) before this mix is diluted with saline. Thus, the control solution includes DMSO mixed with saline.B.1.6. Lysolecithin

[0090] There are several experimental models to study the regenerative response following myelin damage or loss. One of the main focal toxin models of demyelination is lysolecithin (lyso), which is stereotactically injected to cause demyelination only within the injected area. The temporal nature of the demyelination and subsequent remyelination response has characterized over that last fifty years. The maximum damage can be observed about one week after injection. Subsequently, myelination recovers over about three weeks. Lyso was mixed with a fluorescent dye to control for the location and extent of the injection per established protocols.B.2 Preliminary DataB.2.1. Older listeners have difficulties in cocktail party situations, and gerbils recapitulate this deficit

[0091] Many older listeners have difficulties in cocktail party situations, which can be assessed both in subjective self-assessments and in objective sound localization and hearing in noise studies. These deficits are recapitulated in the Mongolian gerbils.

[0092] FIG. 2 A shows results from 40 human subjects who were tested for the ability to spatially separate speech from noise. A result from this graph was that with increasing age, human subjects require a larger and larger spatial angle to successfully separate a signal from background noise. Furthermore, this difficulty does not suddenly start at a certain age but seems to slowly develop over the lifetime.

[0093] FIG. 2B shows equivalent results from Mongolian gerbils. In this case, an animal’s ability to localize sound was tested with the startle response and pre-pulse inhibition, showing results from old animals (open circles and open rectangles) and results from young animals are shown (circles and rectangles hashed with forward slash “ / ”). The data suggest that old gerbils performed much poorer at sound localization tasks than young animals do. Overall, the data in FIGS. 2A and 2B suggest that this decrease in sound localization abilities is not just a human phenomenon but appears to be a standard mammalian feature.B.2.2. ABR wave III alterations are a co-morbidity of localization deficits in both human subjects and gerbils

[0094] The same individual human listeners and the same individual gerbils from above were also subjected to ABR recordings. Data is shown in FIGS. 3A-3C. ABR is a physiological assessment of the lower auditory brain. Waves in the ABR trace represent activity in certain auditory centers, and wave III is MNTB in both humans and rodents. A smaller wave III amplitude indicates that the neurons producing this wave (mostly MNTB neurons) fire during a larger temporal window, thus less precisely. In humans, wave III is generally smaller in old listeners. Because this condition affects about 50% of the population (and thus 50% are unaffected), it makes sense to ask if wave III is lower specifically in humans who report cocktail party deficits (it is, FIG. 3B) - and this is the case.

[0095] As shown by the data in FIGS. 3A-3C, many older human subjects (FIGS. 3A and 3B) and many older gerbils (FIG. 3C) had reduced wave 3 amplitudes. Gerbils also had reduced BIC (FIG. 7, right panel). This reduced BIC also occurred specifically in subjects who performed less well at sound localization tasks. Additionally, human subjects were given a questionnaire to self-assess their sound localization abilities. Those subjects who self-assessed their abilities as poor specifically had lower wave 3 amplitudes (FIG. 3B). The data indicates that both humans and gerbils perform lesswell in sound localization tasks as they age. Here, humans require a larger and larger spatial separation between speech and noise as they get older (FIG. 3 A). So do gerbils except that in the case of gerbils, the startle response was used, resulting in pre-pulse inhibition (PPI) measurements. In short, lager numbers mean better sound localization (FIG. 3B). Overall, the data suggest that ABR recordings and BIC can serve as a biomarker to assess sound localization deficits both in human subjects and animal models.B.2.3. A subcellular mechanism for these deficits in gerbils

[0096] Gerbils offer the ability for invasive testing to determine the neural mechanisms underlying the observed sound localization deficits and ABR alterations. One mechanism is demyelination of afferent axons to MNTB principal neurons. These fibers are exceptionally heavily myelinated to propagate action potentials with high levels of speed and temporal precision. As discussed above, even minor age-related changes in this pathway have major effects on the precision of sound localization.

[0097] The method of measuring myelination in animal brains included imaging of brain tissue with CARS. The principle of this technique is that a laser is tuned to the resonant frequency of CH2 bonds which are very common in lipids (myelin is a lipid). These vibrating CH2 bonds are then imaged as shown in FIG. 3D. For this method, the CARS laser was tuned to 792.2 nm for CH2 bonds.

[0098] FIG. 4 shows data from CARS imaging of young and old gerbils, assessing myelination. Here, the myelinated fiber bundle that goes from the cochlear nucleus to the MNTB, ending in the calyx of Held was imaged. FIG. 4 also shows axon diameter data. The data provided in FIG. 4 show that old gerbils have a highly significant reduction in total axon diameter caused by a reduction in myelination of these fibers, indicating that old gerbils have significantly thinner fibers.B.2.4. Targeted demyelination of MNTB off erents can recapitulate the age-related changes

[0099] To further confirm the role of MNTB afferent demyelination in cocktail party deficits, the inventors recapitulated the demyelination discussed above in young gerbils with normal sound localization abilities. To this end, the inventors stereotactically injected lysolecithin into the afferent fiber pathway to MNTB.Lysolecithin compromises myelin in the injected area within about one week, after which myelination recovers within about three to four weeks.

[0100] FIGS. 5A-5D show results from artificially compromising the same fiber bundle in young animals. The inventors injected lysolecithin (lyso), a detergent, directly into this fiber bundle (drilling a hole into the animal skull and pressure ejecting through a glass pipette). This result recapitulated in young animals what is observed in old animals: Compromising myelin (1 week post injection) resulted in ABRs that show similarities with old gerbils. Also, sound localization was affected. After 3 weeks the system had recovered and so have the physiological and behavioral measurements. In short, this approach makes “young animals old”.

[0101] Specifically, FIG. 5A shows results from a cohort of animals which were injected with this chemical and tested with PPI after 1.5 and three weeks post injection. Consistent with lyso’s method of action and recovery, PPI values dropped during the demyelination period (1.5 weeks), suggesting compromised sound localization (FIG. 5A) and were recovered by 3 weeks. Similarly, waves III and IV of the ABR and the BIC were compromised for the same time period that sound localization was compromised - and also recovered after about 3 weeks (FIG. 5B). Additionally, lyso injected animals were sacrificed after one, two, and three weeks post injection, and myelination in the MNTB afferent pathway was imaged with CARS (FIGS. 5C and 5D). Consistent with the behavioral and physiological results, myelin was compromised 1 week post injection and recovered by week 3 (FIGS. 5C and 5D). These data suggest that a targeted insult of myelin in the MNTB afferent pathway can at least partially recapitulate the age-related changes that is observed in older animals, suggesting the demyelination is not just a general aging phenomenon, but causally related to central hearing loss. All measurements and analyses were performed by blinded observers.B.2.5. Clemastine in combination with sound exposure can rescue compromised myelin in older animals

[0102] The inventors also performed the reverse experiment of what is described above. Clemastine fumarate stimulates oligodendrocyte generation through antagonizing cholinergic signaling. The inventors designed a series of experiments to test a cohort of old gerbils with PPI and ABR, followed by daily administration of clemastine or control solution for one month. Some of these animals were alsosubjected to sound exposure once daily. Thus, there were four study groups: control solution, control and sound exposure, clemastine solution, and clemastine and sound exposure.

[0103] The sound exposure included one hour of sound presentation in a specifically designed round holding cage without sound shadows and animals were allowed to freely move within this cage. The presented sound included sound clips with temporally fast components, such as binaural beats, fast amplitude modulations, fast frequency modulations and other fast transient components. After the one-month treatment period, the same animals were tested again for PPI and ABR, followed by anatomical analysis with CARS.

[0104] FIG. 6 shows PPI results from this rescue experiment, suggesting that the treatment with clemastine and sound together (but not clemastine alone and not sound alone) can rescue sound localization abilities in old gerbils to a surprising degree (FIG. 6, bottom right graph). The approach makes “old animals young”. Old gerbils were tested for sound localization abilities (solid lines), then were divided into four groups. The group which received clemastine AND sound together improved significantly in sound localization abilities, the other groups did not.

[0105] FIG. 7 shows ABR recordings from control (top panel) vs. clemastine plus sound (bottom panel, treatment group). While in control wave III and the BIC deteriorated significantly during the 4 month testing period, the same parameters improved in the treatment group. The data in FIG. 7 suggests that the same animals that improved in PPI values also showed improvements in their monaural AB Rs (left panel) as well as the BIC (right panel). Note that monaural wave III in the control animal (black) showed a minimal wave III before treatment (solid line, top left). This wave completely disappeared during the treatment period, most likely due to progressing natural aging (dotted line, top left). In the same animal, the BIC also deteriorated significantly during the same period. By contrast, the clemastine / sound treated animal (bottom panel) showed an improvement in wave III (dotted line has more substantial wave III than solid line) as well as a substantial improvement in the temporal properties of the BIC (dotted line in the left bottom panel rises much sharper). The clemastine only and sound only animals did not show such any significant improvements (data not shown).

[0106] FIG. 8 shows CARS imaging from a control / no sound animal (top left panel) and a clemastine / sound animal (top right panel). Quantitative analysis (bottom panel) of all CARS data from this experiment is also shown. FIG. 8 suggests that the underlying mechanism of this behavioral and physiological rescue may be a partial remyelination of afferent MNTB fibers. The left image (top left panel) shows CARS of the MNTB afferent fiber bundle from an animal from the control / no sound group while the right image (top right panel) shows fibers from a clemastine / sound animal. The graph on the bottom shows quantitative analysis of all pilot data from this experiment, suggesting a highly significant increase in axon width in the treatment group (the other two groups did not show such improvements, data not shown). Overall the results shown in FIG. 8 indicate that the combination therapy of clemastine plus sound partially restored myelination.

[0107] Overall, the data presented herein indicates that a pharmaceutical or pharmaceutical composition (e.g., clemastine) and an audio file (sound) can at least partially rescue the age-related demyelination observed in the MNTB afferent pathway, and that this remyelination rescues ABR wave III and the BIC, and that these rescues also substantially improve the sound localization abilities of the treated animals.EMBODIMENTS LISTING

[0108] The present disclosure provides, among others, the following embodiments, each of which can be considered as optionally including any alternate embodiments:

[0109] Embodiment 1. A combination therapy, comprising: a pharmaceutical or pharmaceutical composition; and an audio file.

[0110] Embodiment 2. The combination therapy of Embodiment 1, wherein the combination therapy is used for growing myelin in a patient, remyelination of a nerve in a patient, treating central hearing loss in a patient, treating cocktail party deficit in a patient, treating age related hearing loss in a patient, treating autism in a patient, treating an ear infection in a patient, or combinations thereof.[OHl] Embodiment 3. The combination therapy of any one of Embodiments 1-2, wherein the pharmaceutical or pharmaceutical composition comprises an antihistamine, a therapy prescribed for treatment of multiple sclerosis, a remyelination therapy, or combinations thereof.

[0112] Embodiment 4. The combination therapy of any one of Embodiments 1-3, wherein: the pharmaceutical or pharmaceutical composition comprises an antihistamine; and the antihistamine comprises clemastine, GSK239512, or combinations thereof.

[0113] Embodiment 5. The combination therapy of any one of Embodiments 1-4, wherein: the pharmaceutical or pharmaceutical composition comprises a therapy prescribed for treatment of multiple sclerosis, a remyelination therapy, or combinations thereof; and the therapy prescribed for treatment of multiple sclerosis, the remyelination therapy, or combinations thereof comprises evobrutinib; SAR442168 (a Bruton’s tyrosine kinase inhibitor in Phase 2 clinical trials); masitinib; imatinib; ibudilast; BIIB033 (an anti -leucine rich repeat and immunoglobulin-like domain-containing protein 1 (anti-LINGO-1) antibody); opicinumab (an antibody directed against LINGO- 1); elezanumab; AHSCT (autologous hematopoietic stem cells transplantation); simvastatin; Vitamin D3; biotin (for example, MD1003 which is a high dose biotin); lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb (a monoclonal antibody directed against the envelope protein of a human endogenous retrovirus); IMU-838 (vidofludimus calcium); erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARC 1103 (a GAB AB receptor agonist); amantadine; modanafil; methylphenidate; BX-1 (dronabinol); ADS-5102 (amantadine extended release); arbaclofen (R enantiomer of baclofen); insulin; intranasal insulin; adderall; adderall extended release; GSK239512 (an orally-administered central nervous- penetrant antihistamine); ocrelizumab; quetiapine (such as quetiapine fumarate); domperidone; antisemaphorin 4D (for example, humanized anti-Sema4D monoclonal antibody VX15 / 2503); IRX4204 (an agonist of retinoic acid receptor gamma (RXR- y)); a kappa opioid agonist (for example, U-50488, CAS No: 67198-13-4); a spingosine-1 -phosphate (SIP) receptor modulator (for example, fmgolimod or siponimod); a y-secretase inhibitor (for example, quecertin); teriflunomide; bexarotene;bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; riluzole; or combinations thereof.

[0114] Embodiment 6. The combination therapy of any one of Embodiments 1-5, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

[0115] Embodiment 7. The combination therapy of Embodiment 6, wherein the temporally fast components comprise binaural beats, amplitude modulated signals, frequency modulated signals, fast percussions, or combinations thereof.

[0116] Embodiment 8. The combination therapy of any one of Embodiments 1-7, wherein the combination therapy induces myelin growth along an afferent fiber to the medial nucleus of the trapezoid body.

[0117] Embodiment 9. A method for growing myelin in a patient, the method comprising: administering to the patient a pharmaceutical or pharmaceutical composition; and causing the patient to hear or listen to an audio file.

[0118] Embodiment 10. A method for remyelination of a nerve in a patient, the method comprising: administering to the patient a pharmaceutical or pharmaceutical composition; and causing the patient to hear or listen to an audio file.

[0119] Embodiment 11. A method for treating central hearing loss in a patient, the method comprising: administering to the patient a pharmaceutical or pharmaceutical composition; and causing the patient to hear or listen to an audio file.

[0120] Embodiment 12. A method for treating cocktail party deficit in a patient, the method comprising: administering to the patient a pharmaceutical or pharmaceutical composition; and causing the patient to hear or listen to an audio file.

[0121] Embodiment 13. A method for treating a disease or medical condition in a patient, the method comprising: administering to the patient a pharmaceutical or pharmaceutical composition; and causing the patient to hear or listen to an audio file.

[0122] Embodiment 14. The method of Embodiment 13, wherein the disease or medical condition comprises age related hearing loss, autism, or an ear infection.

[0123] Embodiment 15. The method of any one of Embodiments 9-14, wherein the pharmaceutical or pharmaceutical composition comprises an antihistamine, a therapy prescribed for treatment of multiple sclerosis, a remyelination therapy, or combinations thereof.

[0124] Embodiment 16. The method of any one of Embodiments 9-15, wherein: the pharmaceutical or pharmaceutical composition comprises an antihistamine; and the antihistamine comprises clemastine, GSK239512, or combinations thereof.

[0125] Embodiment 17. The method of any one of Embodiments 9-16, wherein: the pharmaceutical or pharmaceutical composition comprises a therapy prescribed for treatment of multiple sclerosis, a remyelination therapy, or combinations thereof; and the therapy prescribed for treatment of multiple sclerosis, the remyelination therapy, or combinations thereof comprises evobrutinib; SAR442168 (a Bruton’s tyrosine kinase inhibitor in Phase 2 clinical trials); masitinib; imatinib; ibudilast; BIIB033 (an anti -leucine rich repeat and immunoglobulin-like domain-containing protein 1 (anti-LINGO-1) antibody); opicinumab (an antibody directed against LINGO- 1); elezanumab; AHSCT (autologous hematopoietic stem cells transplantation); simvastatin; Vitamin D3; biotin (for example, MD1003 which is a high dose biotin); lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb (a monoclonal antibody directed against the envelope protein of a human endogenous retrovirus); IMU-838 (vidofludimus calcium); erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARC 1103 (a GAB AB receptor agonist); amantadine; modanafil; methylphenidate; BX-1 (dronabinol); ADS-5102 (amantadine extendedrelease); arbaclofen (R enantiomer of baclofen); insulin; intranasal insulin; adderall; adderall extended release; GSK239512 (an orally-administered central nervous- penetrant antihistamine); ocrelizumab; quetiapine (such as quetiapine fumarate); domperidone; antisemaphorin 4D (for example, humanized anti-Sema4D monoclonal antibody VX15 / 2503); IRX4204 (an agonist of retinoic acid receptor gamma (RXR- y)); a kappa opioid agonist (for example, U-50488, CAS No: 67198-13-4); a spingosine-1 -phosphate (SIP) receptor modulator (for example, fmgolimod or siponimod); a y-secretase inhibitor (for example, quecertin); teriflunomide; bexarotene; bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; riluzole; or combinations thereof.

[0126] Embodiment 18. The method of any one of Embodiments 9-17, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

[0127] Embodiment 19. The method of Embodiment 18, wherein the temporally fast components comprise binaural beats, amplitude modulated signals, frequency modulated signals, fast percussions, or combinations thereof.

[0128] Embodiment 20. The method of any one of Embodiments 9-19, wherein the method induces myelin growth along an afferent fiber to the medial nucleus of the trapezoid body.

[0129] Embodiment 21. A combination therapy for stimulating remyelination of a neuron (for example, a neuron axon) in a patient having hearing loss, comprising: a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and an audio file configured to facilitate remyelination of a neuron upon administration of the pharmaceutical or pharmaceutical composition.

[0130] Embodiment 22. The combination therapy of Embodiment 21, wherein the hearing loss comprises central hearing loss, cocktail party deficit, age related hearing loss, hearing loss due to ear infection, or combinations thereof.

[0131] Embodiment 23. The combination therapy of any one of Embodiments 21- 22, wherein: the pharmaceutical or pharmaceutical composition comprises theantihistamine; and the antihistamine comprises clemastine, GSK239512, or combinations thereof.

[0132] Embodiment 24. The combination therapy of any one of Embodiments 21-23, wherein: the pharmaceutical or pharmaceutical composition comprises the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof comprises evobrutinib; SAR442168; masitinib; imatinib; ibudilast; BIIB033; opicinumab; elezanumab; AHSCT; simvastatin; Vitamin D3; biotin; lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb; IMU-838; erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARCI 103; amantadine; modanafil; methylphenidate; BX-1; ADS-5102; arbaclofen; insulin; intranasal insulin; adderall; adderall extended release; GSK239512; ocrelizumab; quetiapine; domperidone; antisemaphorin 4D; IRX4204; a kappa opioid agonist; a spingosine-1 -phosphate (SIP) receptor modulator; a y-secretase inhibitor; teriflunomide; bexarotene; bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; riluzole; or combinations thereof.

[0133] Embodiment 25. The combination therapy of any one of Embodiments 21-24, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

[0134] Embodiment 26. The combination therapy of Embodiment 25, wherein the temporally fast components comprise binaural beats, amplitude modulated signals, frequency modulated signals, fast percussions, or combinations thereof.

[0135] Embodiment 27. The combination therapy of any one of Embodiments 25-26, wherein the fast transients have a frequency in a range from about 100 Hz to about 800 Hz, such as from about 200 Hz to about 600 Hz.

[0136] Embodiment 28. The combination therapy of any one of Embodiments 21-27, wherein the combination therapy induces myelin growth along an afferent fiber to the medial nucleus of the trapezoid body.

[0137] Embodiment 29. A method for stimulating remyelination of a neuron (for example, a neuron axon) in a patient having hearing loss, the method comprising:administering to the patient a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and causing the patient to hear or listen to an audio file, the audio file configured to facilitate remyelination of the neuron upon administration of the pharmaceutical or pharmaceutical composition.

[0138] Embodiment 30. The method of Embodiment 29, wherein the hearing loss comprises central hearing loss, cocktail party deficit, age related hearing loss, hearing loss due to noise exposure, hearing loss due to ear infections, or combinations thereof.

[0139] Embodiment 31. The method of any one of Embodiments 29-30, wherein: the pharmaceutical or pharmaceutical composition comprises the antihistamine; and the antihistamine comprises clemastine, GSK239512, or combinations thereof.

[0140] Embodiment 32. The method of any one of Embodiments 29-31, wherein: the pharmaceutical or pharmaceutical composition comprises the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof comprises evobrutinib; SAR442168; masitinib; imatinib; ibudilast; BIIB033; opicinumab; elezanumab; AHSCT; simvastatin; Vitamin D3; biotin; lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb; IMU-838; erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARCI 103; amantadine; modanafil; methylphenidate; BX-1; ADS-5102; arbaclofen; insulin; intranasal insulin; adderall; adderall extended release; GSK239512; ocrelizumab; quetiapine; domperidone; antisemaphorin 4D; IRX4204; a kappa opioid agonist; a spingosine-1 -phosphate (SIP) receptor modulator; a y-secretase inhibitor; teriflunomide; bexarotene; bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; riluzole; or combinations thereof.

[0141] Embodiment 33. The method of any one of Embodiments 29-32, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

[0142] Embodiment 34. The method of Embodiment 33, wherein the temporally fast components comprise binaural beats, amplitude modulated signals, frequency modulated signals, fast percussions, or combinations thereof.

[0143] Embodiment 35. The method of any one of Embodiments 33 or 34, wherein the fast transients have a frequency in a range from about 100 Hz to about 800 Hz, such as from about 200 Hz to about 600 Hz.

[0144] Embodiment 36. The method of any one of Embodiments 29-35, wherein the method induces myelin growth along an afferent fiber to the medial nucleus of the trapezoid body.

[0145] Embodiment 37. A combination therapy for growing myelin on a neuron (for example, a neuron axon) in a patient having hearing loss, comprising: a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine; and an audio file configured to facilitate myelin growth on a neuron upon administration of the pharmaceutical or pharmaceutical composition.

[0146] Embodiment 38. The combination therapy of Embodiment 37, wherein the antihistamine comprises clemastine, GSK239512, or combinations thereof.

[0147] Embodiment 39. The combination therapy of any one of Embodiments 37-38, wherein the hearing loss comprises central hearing loss, cocktail party deficit, age related hearing loss, hearing loss due to noise exposure, hearing loss due to ear infections, or combinations thereof.

[0148] Embodiment 30. The combination therapy of any one of Embodiments 37-39, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

[0149] All documents described herein are incorporated by reference herein, including any priority documents and / or testing procedures to the extent they are not inconsistent with this text. As is apparent from the foregoing general description and the specific embodiments, while forms of the embodiments have been illustrated and described, various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, it is not intended that the present disclosure be limited thereby. Likewise, the term “comprising” is considered synonymous with the term “including.” Likewise whenever a composition, an element,a group of elements, or a method is preceded with the transitional phrase “comprising,” it is understood that we also contemplate the same composition, method, or group of elements with transitional phrases “consisting essentially of,” “consisting of,” “selected from the group of consisting of,” or “Is” preceding the recitation of the composition, element, elements, or method, and vice versa, such as the terms “comprising,” “consisting essentially of,” “consisting of’ also include the product of the combinations of elements listed after the term.

[0150] In the foregoing, reference is made to embodiments of the disclosure. However, it should be understood that the disclosure is not limited to specific described embodiments. Instead, any combination of the following features and elements, whether related to different embodiments or not, is contemplated to implement and practice the disclosure. Furthermore, although embodiments of the disclosure may achieve advantages over other possible solutions and / or over the prior art, whether or not a particular advantage is achieved by a given embodiment is not limiting of the disclosure. Thus, the foregoing aspects, features, embodiments and advantages are merely illustrative and are not considered elements or limitations of the appended claims except where explicitly recited in a claim(s). Likewise, reference to “the disclosure” shall not be construed as a generalization of any inventive subject matter disclosed herein and shall not be considered to be an element or limitation of the appended claims except where explicitly recited in a claim(s).

[0151] For purposes of this present disclosure, and unless otherwise specified, all numerical values within the detailed description and the claims herein are modified by “about” or “approximately” the indicated value, and consider experimental error and variations that would be expected by a person having ordinary skill in the art. For the sake of brevity, only certain ranges are explicitly disclosed herein. However, ranges from any lower limit may be combined with any upper limit to recite a range not explicitly recited, as well as, ranges from any lower limit may be combined with any other lower limit to recite a range not explicitly recited, in the same way, ranges from any upper limit may be combined with any other upper limit to recite a range not explicitly recited. For example, the recitation of the numerical range 1 to 5 includes the subranges 1 to 4, 1.5 to 4.5, 1 to 2, among other subranges. As another example, the recitation of the numerical ranges 1 to 5, such as 2 to 4, includes the subranges 1 to 4and 2 to 5, among other subranges. Additionally, within a range includes every point or individual value between its end points even though not explicitly recited. For example, the recitation of the numerical range 1 to 5 includes the numbers 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, among other numbers. Thus, every point or individual value may serve as its own lower or upper limit combined with any other point or individual value or any other lower or upper limit, to recite a range not explicitly recited.

[0152] As used herein, the indefinite article “a” or “an” shall mean “at least one” unless specified to the contrary or the context clearly indicates otherwise. For example, embodiments comprising “a pharmaceutical” include embodiments comprising one, two, or more pharmaceuticals, unless specified to the contrary or the context clearly indicates only one pharmaceutical is included.

[0153] While the foregoing is directed to embodiments of the present disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.

Claims

CLAIMSWhat is claimed is:

1. A combination therapy for stimulating remyelination of a neuron in a patient having hearing loss, comprising: a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and an audio file configured to facilitate remyelination of a neuron upon administration of the pharmaceutical or pharmaceutical composition.

2. The combination therapy of claim 1, wherein the hearing loss comprises central hearing loss, cocktail party deficit, age related hearing loss, hearing loss due to noise exposure, hearing loss due to ear infections, or combinations thereof.

3. The combination therapy of claim 1, wherein: the pharmaceutical or pharmaceutical composition comprises the antihistamine; and the antihistamine comprises clemastine, GSK239512, or combinations thereof.

4. The combination therapy of claim 1, wherein: the pharmaceutical or pharmaceutical composition comprises the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof comprises evobrutinib; SAR442168; masitinib; imatinib; ibudilast; BIIB033; opicinumab; elezanumab; AHSCT; simvastatin; Vitamin D3; biotin; lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb; IMU-838; erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARCI 103; amantadine; modanafil; methylphenidate; BX-1; ADS-5102; arbaclofen; insulin; intranasal insulin; adderall; adderall extended release; GSK239512; ocrelizumab; quetiapine; domperidone; antisemaphorin 4D; IRX4204; a kappa opioid agonist; a spingosine-1 -phosphate (SIP) receptor modulator; a y-secretase inhibitor;teriflunomide; bexarotene; bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; riluzole; or combinations thereof.

5. The combination therapy of claim 1, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

6. The combination therapy of claim 5, wherein the temporally fast components comprise binaural beats, amplitude modulated signals, frequency modulated signals, fast percussions, or combinations thereof.

7. The combination therapy of claim 5, wherein the fast transients have a frequency in a range from about 100 Hz to about 800 Hz.

8. The combination therapy of claim 1, wherein the combination therapy induces myelin growth along an afferent fiber to the medial nucleus of the trapezoid body.

9. A method for stimulating remyelination of a neuron in a patient having hearing loss, the method comprising: administering to the patient a pharmaceutical or pharmaceutical composition, the pharmaceutical or pharmaceutical composition comprising an antihistamine, a remyelination therapy, a therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and causing the patient to hear or listen to an audio file, the audio file configured to facilitate remyelination of the neuron upon administration of the pharmaceutical or pharmaceutical composition.

10. The method of claim 9, wherein the hearing loss comprises central hearing loss, cocktail party deficit, age related hearing loss, hearing loss due to noise exposure, hearing loss due to ear infections, or combinations thereof11. The method of claim 9, wherein:the pharmaceutical or pharmaceutical composition comprises the antihistamine; and the antihistamine comprises clemastine, GSK239512, or combinations thereof.

12. The method of claim 9, wherein: the pharmaceutical or pharmaceutical composition comprises the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof; and the remyelination therapy, the therapy prescribed for treatment of multiple sclerosis, or combinations thereof comprises evobrutinib; SAR442168; masitinib; imatinib; ibudilast; BIIB033; opicinumab; elezanumab; AHSCT; simvastatin; Vitamin D3; biotin; lipoic acid; nanocrystalline gold; laquinimod; GNbACl mAb; IMU-838; erythropoietin alfa; pioglitazone; montelukast; hydroxychloroquine; losartan; SPARCI 103; amantadine; modanafil; methylphenidate; BX-1; ADS-5102; arbaclofen; insulin; intranasal insulin; adderall; adderall extended release; GSK239512; ocrelizumab; quetiapine; domperidone; antisemaphorin 4D; IRX4204; a kappa opioid agonist; a spingosine-1 -phosphate (SIP) receptor modulator; a y-secretase inhibitor; teriflunomide; bexarotene; bazedoxifene; phenytoin; amiloride; adrenocorticotropic hormone; fluoxetine; riluzole; or combinations thereof.

13. The method of claim 9, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

14. The method of claim 13, wherein the temporally fast components comprise binaural beats, amplitude modulated signals, frequency modulated signals, fast percussions, or combinations thereof.

15. The method of claim 13, wherein the fast transients have a frequency in a range from about 100 Hz to about 800 Hz.

16. The method of claim 9, wherein the method induces myelin growth along an afferent fiber to the medial nucleus of the trapezoid body.

17. A combination therapy for growing myelin on a neuron in a patient having hearing loss, comprising: an antihistamine; and an audio file configured to facilitate myelin growth on a neuron upon administration of the antihistamine.

18. The combination therapy of claim 17, wherein the antihistamine comprises clemastine, GSK239512, or combinations thereof.

19. The combination therapy of claim 17, wherein the hearing loss comprises central hearing loss, cocktail party deficit, age related hearing loss, hearing loss due to noise exposure, hearing loss due to ear infections, or combinations thereof.

20. The combination therapy of claim 17, wherein the audio file comprises fast transients, temporally fast components, or combinations thereof.

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